2021年03月, 北海道大学大学院医学研究院, 北海道大学大学院医学研究院・大学院医学院・医学部医学科 優秀研究賞　　　　　　　　　　　　　　　
心血管リモデリングにおける炎症制御機構の解明

2014年11月, 日本医師会, 日本医師会医学研究奨励賞　　　　　　　　　　　　　　　

2005年, 慶應義塾大学医学振興基金、特別研究奨励　　　　　　　　　　　　　　　
日本国

2004年, 第３３回かなえ医薬振興財団 研究助成　　　　　　　　　　　　　　　
日本国

2003年, Finalist of Poster Competition, The 76th annual session meeting of American Heart Association Annual Scientific Meeting　　　　　　　　　　　　　　　

2001年, 三四会研究奨励賞　　　　　　　　　　　　　　　
日本国

2000年, 慶應義塾大学医学部 坂口記念研究助成B　　　　　　　　　　　　　　　
日本国

1999年, 日本心臓財団 分子循環器研究助成　　　　　　　　　　　　　　　
日本国

1999年, 武田科学振興財団 研究助成　　　　　　　　　　　　　　　
日本国

1997年, American Heart Association, California Affiliate, Post-doctoral Fellowship Award　　　　　　　　　　　　　　　
日本国

1996年, Young Investigator Travel Award, American Heart Association Council for Basic Science Research　　　　　　　　　　　　　　　

1995年, 病態代謝研究会留学助成　　　　　　　　　　　　　　　
日本国

1994年, 慶応医師会研究奨励賞　　　　　　　　　　　　　　　
日本国

Validation of Left Ventricular Filling Pressure Evaluation by Order of Tricuspid and Mitral Valve Opening in Patients With Atrial Fibrillation.
Hisao Nishino, Michito Murayama, Hiroyuki Iwano, Nobuyuki Kagiyama, Yutaka Nakamura, Yuka Akama, Misako Toki, Sachiko Takamatsu, Taiji Okada, Yasuyuki Chiba, Masahiro Nakabachi, Shinobu Yokoyama, Mana Goto, Yukino Suzuki, Suguru Ishizaka, Ko Motoi, Yoji Tamaki, Hiroyuki Aoyagi, Kosuke Nakamura, Sanae Kaga, Chiaki Watanabe, Kiwamu Kamiya, Toshiyuki Nagai, Takanori Teshima, Toshihisa Anzai
Circulation. Cardiovascular imaging, 17, 11, e017134, 2024年11月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Accurate assessment of left ventricular filling pressure in patients with atrial fibrillation or flutter (AF) remains difficult. A novel 2-dimensional scoring system, visually assessing time difference between mitral valve and tricuspid valve opening (VMT) score, based on temporal analysis of early diastolic valve opening, could be applied to these patients. We aimed to determine the usefulness of the VMT score in patients with AF. METHODS: We analyzed 119 consecutive patients with AF who underwent cardiac catheterization as a derivation cohort. The diagnostic performance of the VMT score was further evaluated in an external data set containing 189 patients with AF. Elevated left ventricular filling pressure was defined as a mean pulmonary arterial wedge pressure ≥15 mm Hg. The time sequence of atrioventricular valve opening was visually assessed and scored (0, tricuspid valve first; 1, simultaneous; 2, mitral valve first). When the inferior vena cava was dilated, 1 point was added, and the VMT score was finally graded as 0 to 3. Conventional Doppler parameters to estimate left ventricular filling pressure were also measured. RESULTS: Pulmonary arterial wedge pressure was elevated with an increase in the VMT score (0: 10±3, 1: 13±5, 2: 22±7, 3: 27±6 mm Hg; P<0.001), resulting in a significant rise in pulmonary arterial wedge pressure from VMT score 1 to 2. VMT≥2 predicted elevated pulmonary arterial wedge pressure with an accuracy of 87%, and the diagnostic accuracy of the VMT score was significantly higher than that of conventional Doppler parameters (C index, 0.88 versus 0.54-0.68; P<0.001). In addition, VMT ≥2 showed an incremental predictive value over plasma brain natriuretic peptide levels (C index, 0.79-0.93; P<0.001). In the external validation cohort, VMT≥2 demonstrated acceptable accuracy of 72%. CONCLUSIONS: VMT scoring was a useful echocardiographic marker of elevated left ventricular filling pressure and had an incremental benefit over practical biomarkers in patients with AF.

From Optional to Default - Enhancing Article Viewership Through X (Formerly Twitter) Posting.
Atsushi Mizuno, Daisuke Yoneoka, Takuya Kishi, Kenya Kusunose, Chisa Matsumoto, Yuki Sahashi, Mari Ishida, Shoji Sanada, Memori Fukuda, Tadafumi Sugimoto, Miki Hirano, Masataka Sata, Toshihisa Anzai, Koichi Node
Circulation reports, 6, 9, 389, 394, 2024年09月10日, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The influence of a change to a default X summary posting strategy on article viewership has not been investigated. METHODS AND RESULTS: We conducted a retrospective analysis of X-posting rates and journal viewership data for both the Circulation Journal and Circulation Reports from April 2022 to September 2023. Following protocol modifications in March 2023, there was a notable increase in the X-posting rate from 12.4% to 61.7%, along with an uptick in median access counts to article pages within 30 days, from 175 to 231.5. CONCLUSIONS: Trend analysis of journal viewership after a default X-posting strategy revealed an increase in viewer access.

Orthotopic heart transplantation in patient with situs inversus and pectus excavatum: a case report.
Satoru Wakasa, Tomonori Ooka, Takuma Sato, Yasushige Shingu, Nobuyasu Kato, Toshiyuki Nagai, Toshihisa Anzai, Minoru Ono, Yoshiro Matsui
Surgical case reports, 10, 1, 202, 202, 2024年08月30日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Heart transplantation in patients with situs inversus is challenging, especially in terms of reconstruction of the systemic venous return. Several rerouting techniques have been presented but are associated with vulnerability to external compression, which might cause hemodynamic instability, especially in the presence of chest deformity. In this study, we report a rare case of successful heart transplantation in the presence of situs inversus and pectus excavatum. CASE PRESENTATION: A 55-year-old man, with a history of surgeries for corrected transposition of the great arteries with ventricular septal defect, was registered for heart transplantation owing to progression of heart failure. Subsequently, he had undergone a left ventricular assist device implantation; 14 years after registration, he underwent transplantation of the heart with normal anatomy. The inferior vena cava was reconstructed by anastomosing the left atria with a counterclockwise rotation of the donor heart and by lengthening the recipient inferior vena cava with a conduit made of the residual right atrial tissue. The superior vena cava was reconstructed using a donor innominate vein harvested with sufficient length. After successful weaning from cardiopulmonary bypass, the chest could not be closed because the heart was compressed owing to chest deformity, resulting in hemodynamic instability. Therefore, to exclude the left lung, a left pericardial screen was created using a bovine pericardium, allowing the chest to be closed with acceptable hemodynamics. The patient suffered postoperatively from a higher venous pressure, suggesting an obstruction of venous return early after surgery. The obstruction gradually resolved, and the patient was transferred for rehabilitation. CONCLUSIONS: Heart transplantation in the presence of situs inversus is challenging; moreover, the presence of pectus excavatum further complicates the procedure. The paradoxically larger left lung and chest deformity compressed and impaired reconstructed systemic venous return. Although intrathoracic exclusion of the left lung was effective, an intraoperative or early postoperative thoracoplasty for pectus excavatum was also a viable option. Patient-specific management is mandatory, depending on the anatomy.

Normalization of increasing shocking coil impedance with full output synchronized shock.
Takahide Kadosaka, Masaya Watanabe, Motoki Nakao, Taro Koya, Taro Temma, Toshihisa Anzai
Journal of cardiovascular electrophysiology, 2024年08月21日, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Impedance is a crucial parameter in cardiovascular implantable electronic devices (CIEDs). Clinically, most CIEDs measure impedance using low voltage sub-threshold measurement (LVSM). Although the LVSM of shock impedance (LVSM-SI) is generally comparable with high voltage shock impedance (HVSI), LVSM-SI might be inaccurate if peri-lead tissue degeneration occurs. METHODS AND RESULTS: We present a case of elevated LVSM-SI occurring 8 years post-lead implantation, possibly attributed to encapsulation of the right ventricular lead coil. After 0.1 J shock was delivered, a full output synchronized shock was administered to measure HVSI, revealing a normal value. Furthermore, LVSM-SI was normalized and maintained within the normal range during long-term follow-up. CONCLUSION: Our findings suggest conducting a full-output synchronized shock test to assess HVSI when abnormal LVSM-SI is detected in the remote phase post-ICD implantation, which may be considered to help normalize LVSM shock impedance.

Differential impacts of self-care behavior on clinical outcomes in patients with and without recent heart failure hospitalization.
Taro Koya, Toshiyuki Nagai, Atsushi Tada, Motoki Nakao, Suguru Ishizaka, Yoshifumi Mizuguchi, Hiroyuki Aoyagi, Fusako George, Shogo Imagawa, Yusuke Tokuda, Yoshiya Kato, Masashige Takahashi, Hiroto Sakai, Masaharu Machida, Kenichi Matsutani, Takahiko Saito, Hiroshi Okamoto, Toshihisa Anzai
International journal of cardiology, 132452, 132452, 2024年08月14日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Although clinical guidelines recommend self-care assessment for patients with chronic heart failure (CHF), its prognostic significance remains controversial. This study aimed to compare the prognostic significance of self-care behavior on mortality between patients with and without a history of recent hospitalization for heart failure (HF). METHODS: We analyzed consecutive 1907 CHF patients from a Japanese multicenter registry (January 2020-June 2023) using the 9-item European Heart Failure Self-care Behavior Scale (EHFScBS-9) at enrolment. Suboptimal self-care behavior was defined as a score < 70 on the EHFScBS-9. Patients were divided into recent (within 30 days post-discharge, n = 664) and no recent hospitalization for HF groups (n = 1263), respectively. The primary outcome was a composite of all-cause death and rehospitalization for HF. RESULTS: During a median follow-up period of 427 (interquartile range 273-630) days, the primary outcome occurred in 100 patients. Patients with suboptimal self-care behavior exhibited a higher incidence of the primary outcome in the recent hospitalization for HF group (p = 0.020) but not in the no recent hospitalization for HF group (P = 0.16). Multivariable regressions showed suboptimal self-care behavior was independently associated with the primary outcome in the recent hospitalization for HF group with a significant interaction (P = 0.029). CONCLUSION: In patients recently hospitalized for HF, but not in those without a recent hospitalization history for HF, suboptimal self-care behavior was associated with adverse events. This indicates the importance of self-care education for these patients.

Bereaved family members' perspectives on quality of death in deceased acute cardiovascular disease patients compared with cancer patients - a comparison of the J-HOPE3 study and the quality of palliative care in heart disease (Q-PACH) study.
Takahiro Suzuki, Mitsunori Miyashita, Takashi Kohno, Jeffrey Rewley, Naoko Igarashi, Maho Aoyama, Michiaki Higashitani, Naoto Kawamatsu, Takeshi Kitai, Tatsuhiro Shibata, Makoto Takei, Kotaro Nochioka, Gaku Nakazawa, Hiroki Shiomi, Shigeru Tateno, Toshihisa Anzai, Atsushi Mizuno
BMC palliative care, 23, 1, 188, 188, 2024年07月26日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Outcome measures during acute cardiovascular disease (CVD) phases, such as quality of death, have not been thoroughly evaluated. This is the first study that compared the family members' perceptions of quality of death in deceased CVD patients and in deceased cancer patients using a bereaved family survey. METHODS: Retrospectively sent questionnaire to consecutive family members of deceased patients with CVD from ten tertiary hospitals from October 2017 to August 2018. We used the short version of the Good Death Inventory (GDI) and assessed overall care satisfaction. Referencing the GDI, the quality of death was compared between CVD patients admitted to a non-palliative care unit (non-PCU) and cancer patients in palliative care units (PCU) and non-PCUs in the Japan Hospice and Palliative Care Evaluation Study (J-HOPE Study). Additionally, in the adjusted analysis, multivariable linear regression was performed for total GDI score adjusted by the patient and participant characteristics to estimate the difference between CVD and other patients. RESULTS: Of the 243 bereaved family responses in agreement (response rate: 58.7%) for CVD patients, deceased patients comprised 133 (54.7%) men who were 80.2 ± 12.2 years old on admission. The GDI score among CVD patients (75.0 ± 15.7) was lower (worse) than that of cancer patients in the PCUs (80.2 ± 14.3), but higher than in non-PCUs (74.4 ± 15.2). After adjustment, the total GDI score for CVD patients was 7.10 points lower [95% CI: 5.22-8.97] than for cancer patients in PCUs and showed no significant differences compared with those in non-PCUs (estimates, 1.62; 95% CI [-0.46 to 5.22]). CONCLUSIONS: The quality of death perceived by bereaved family members among deceased acute CVD patients did not differ significantly from that of deceased cancer patients in general wards, however, was significantly lower than that of deceased cancer patients admitted in PCUs.

Phenotypic Characteristics of Acute Decompensated Heart Failure With Preserved Ejection Fraction in Japanese Population.
Yohei Sotomi, Toshiyuki Nagai, Shungo Hikoso, Tsutomu Yoshikawa, Yoshihiko Saito, Kazuhiro Yamamoto, Yoshio Yasumura, Takahisa Yamada, Toshihisa Anzai, Yasushi Sakata
JACC. Asia, 4, 7, 566, 568, 2024年07月, ［国際誌］
英語, 研究論文（学術雑誌）

Public awareness of palliative care for heart failure in Japan: A cross-sectional study.
Tatsuhiro Shibata, Atsushi Mizuno, Takashi Ohmori, Shogo Oishi, Kimitaka Nishizaki, Takeru Nabeta, Takuya Kishi, Toshiyuki Nagai, Toshihisa Anzai
Journal of cardiology, 2024年06月03日, ［国際誌］
英語, BACKGROUND: Palliative care (PC) benefits cancer patients and those with heart failure (HF), improving quality of life and symptom burden. Despite guidelines recommending the integration of PC into HF care, its use remains inadequate, partly due to insufficient public awareness. This study aimed to assess the public awareness of PC for HF in Japan and identify factors associated with awareness. METHODS: A cross-sectional online survey was conducted from March 6-13, 2023, using a panel operated by Intage Inc. (Tokyo, Japan), which has a pool of 3.78 million potential Japanese respondents. The survey included 51,790 participants, matched for sex, age, and region of residence. Participants were asked about their awareness of PC eligibility for HF, along with demographic information, history of hospitalization for sudden illness, outpatient visits, and health status in the previous 2 years. The χ2 test and Cramer's V were used to analyze associations between awareness and variables, and multivariate logistic regression was used to estimate awareness predictors. RESULTS: In total, 91 % of participants were unaware of PC eligibility for HF. Age group, healthcare professional occupation, and history of hospitalization for acute myocardial infarction, acute HF, acute pulmonary embolism, and ruptured aortic aneurysm had weak to moderate associations with awareness. Multivariate analysis revealed that a history of hospitalization for sudden cardiovascular illness and being a healthcare professional were positively related to awareness, while age, female sex, and being married were associated with lower odds of awareness. CONCLUSION: The low public awareness of PC for HF in Japan underscores the importance of increasing awareness of the eligibility of PC for HF, as well as cancer, to integrate PC into HF practice as basic care.

Head-to-Head Comparison of Hepatic Vein and Superior Vena Cava Flow Velocity Waveform Analyses for Predicting Elevated Right Atrial Pressure.
Michito Murayama, Sanae Kaga, Airi Onoda, Hisao Nishino, Shinobu Yokoyama, Mana Goto, Yukino Suzuki, Yusuke Yanagi, Yui Shimono, Kosuke Nakamura, Hiroyuki Aoyagi, Yoji Tamaki, Suguru Ishizaka, Hiroyuki Iwano, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
Ultrasound in medicine & biology, 2024年06月03日, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Blood flow in the hepatic veins and superior vena cava (SVC) reflects right heart filling; however, their Doppler profiles are often not identical, and no studies have compared their diagnostic efficacies. We aimed to determine which venous Doppler profile is reliable for detecting elevated right atrial pressure (RAP). METHODS: In 193 patients with cardiovascular diseases who underwent cardiac catheterization within 2 d of echocardiography, the hepatic vein systolic filling fraction (HV-SFF) and the ratio of the peak systolic to diastolic forward velocities of the SVC (SVC-S/D) were measured. HV-SFF < 55% and SVC-S/D < 1.9 were regarded as elevated RAP. We also calculated the fibrosis 4 index (FIB-4) as a serum liver fibrosis marker. RESULTS: HV-SFF and SVC-S/D were feasible in 177 (92%) and 173 (90%) patients, respectively. In the 161 patients in whom both venous Doppler waveforms could be measured, HV-SFF and SVC-S/D were inversely correlated with RAP (r = -0.350, p < 0.001; r = -0.430, p < 0.001, respectively). SVC-S/D > 1.9 showed a significantly higher diagnostic accuracy of RAP elevation compared with HV-SFF < 55% (area under the curve, 0.842 vs. 0.614, p < 0.001). Multivariate analyses showed that both FIB-4 (β = -0.211, p = 0.013) and mean RAP (β = -0.319, p < 0.001) were independent determinants of HV-SFF. In contrast, not FIB-4 but mean RAP (β = -0.471, p < 0.001) was an independent determinant of SVC-S/D. The diagnostic accuracy remained unchanged when HV-SFF < 55% was considered in conjunction with the estimated RAP based on the inferior vena cava morphology. Conversely, SVC-S/D showed an incremental diagnostic value over the estimated RAP. CONCLUSIONS: SVC-S/D enabled a more accurate diagnosis of RAP elevation than HV-SFF.

Multimodal Assessment of Immunosuppressive Therapy in a Patient With Chronic Active Myocarditis 3 Months Following COVID-19 Infection.
Yuta Kobayashi, Takeshi Hamaya, Toshiyuki Nagai, Yuki Mori, Takuma Sato, Satonori Tsuneta, Kento Wakabayashi, Kohsuke Kudo, Yoshihiro Matsuno, Toshihisa Anzai
CJC open, 6, 6, 826, 829, 2024年06月, ［国際誌］
英語, 研究論文（学術雑誌）

肺動脈弁逆流速度計測に基づく右室一回仕事係数の非侵襲的推定法　　　　　　　　　　　　　　　
立石 優太, 村山 迪史, 加賀 早苗, 塚本 真帆, 後藤 真奈, 鈴木 ゆき乃, 柳 裕介, 横山 しのぶ, 西野 久雄, 石坂 傑, 岩野 弘幸, 安斉 俊久
超音波検査技術, 49, 3, 271, 271, (一社)日本超音波検査学会, 2024年06月
日本語

Simultaneous epicardial ablation based on intraoperative electroanatomic mapping during left ventricular assist device implantation.
Kotaro Nishino, Masaya Watanabe, Tomonori Ooka, Takuma Sato, Toshihisa Anzai
Journal of arrhythmia, 40, 3, 632, 635, 2024年06月, ［国内誌］
英語, 研究論文（学術雑誌）, Intraoperative ventricular tachycardia (VT) ablation targeting the epicardial substrate using three-dimensional electroanatomic mapping (EAM) was performed during left ventricular assist device (LVAD) implantation. We proved that EAM can be safely performed during LVAD implantation and that an ablation strategy based on electrophysiological information may reduce VT recurrence after LVAD implantation.

Validity and reliability of the palliative care needs assessment tool in Japanese patients with heart failure
Daishiro Tatsuta, Takuma Sato, Toshiyuki Nagai, Jiro Koya, Kotaro Nishino, Seiichiro Naito, Yoshifumi Mizuguchi, Taro Temma, Kiwamu Kamiya, Hisashi Narita, Kenkichi Tsuruga, Toshihisa Anzai
ESC Heart Failure, Wiley, 2024年05月29日, ［国際誌］
英語, 研究論文（学術雑誌）, Abstract

Aims

Although patients with heart failure (HF) frequently experience considerable symptom burden and require significant care, most HF patients do not receive timely intervention due to the absence of a standardized method for identifying those in need of palliative care. The Needs Assessment Tool: Progressive Disease‐Heart Failure (NAT: PD‐HF) assesses the palliative care needs of patients with HF. However, its validity and reliability have yet to be fully examined. We aimed to assess the validity and reliability of the NAT: PD‐HF in Japanese patients with HF.

Methods

We prospectively enrolled 106 consecutive patients with chronic HF admitted to our university hospital between February 2023 and July 2023. Their caregivers (n = 95) and healthcare providers (n = 17) were also included. The NAT: PD‐HF was translated from English to Japanese using a forward–backward translation procedure and adapted based on Japanese cultural and medical backgrounds by our professional multidisciplinary team. We assessed the internal consistency of the Japanese NAT: PD‐HF version with Cronbach's alpha coefficient and the inter‐rater and test–retest reliabilities with Cohen's kappa coefficient. After using the tool, all participants were asked to complete a questionnaire about the tool to determine its validity.

Results

The proportion of female patients in this study was 47 (44%). The median age was 72 years [interquartile range (IQR) 59–81]. The median time spent assessing the patients' and their caregivers' needs using the Japanese NAT: PD‐HF was 14 min (IQR 12–17). The Cronbach's alpha coefficient was 0.82, and the minimum kappa coefficient was 0.77 for inter‐rater reliability and 0.88 for test–retest reliability. In total, 103 patients (97%) and all caregivers responded that the tool was easy to understand. One hundred (94%) patients and 89 (94%) caregivers felt that the tool would improve the quality of care, and 102 (96%) patients and 91 (96%) caregivers indicated that the discussions using this tool allowed them to confide in all their burdens and care needs. All healthcare providers expressed that this tool is helpful in understanding the burden and care needs of both patients and caregivers comprehensively.

Conclusions

The NAT: PD‐HF is a reliable and valid tool for Japanese patients with HF and their caregivers. This tool was very well accepted by patients, caregivers and healthcare providers to identify burdens and care needs.

Chronic Active Myocarditis After Transapical Transcatheter Aortic Valve Implantation.
Yuta Kobayashi, Toshiyuki Nagai, Kiwamu Kamiya, Satonori Tsuneta, Yasushige Shingu, Kento Wakabayashi, Kohsuke Kudo, Yoshihiro Matsuno, Satoru Wakasa, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 88, 6, 1008, 1008, 2024年05月24日, ［国内誌］
英語, 研究論文（学術雑誌）

Is growth differentiation factor-15 a useful biomarker for chronic heart failure across body size?
Atsushi Tada, Toshiyuki Nagai, Toshihisa Anzai
International journal of cardiology, 410, 132204, 132204, 2024年05月23日, ［国際誌］
英語

Announcement of the 2024 JCS Meeting Activities (2).
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 88, 5, 621, 625, 2024年04月25日, ［国内誌］
英語, 研究論文（学術雑誌）

Acute onset of constrictive pericarditis due to acute myelomonocytic leukemia: A case and literature review.
Naoki Kosaka, Takanori Uchiyama, Masahiro Onozawa, Jun Nagai, Jiro Koya, Suguru Ishizaka, Toshiyuki Nagai, Yohei Ikebe, Kenjiro Kato, Zen-Ichi Tanei, Jun Sakakibara-Konishi, Yuta Hasegawa, Hiroyuki Ohigashi, Hideki Goto, Daigo Hashimoto, Hideki Ujiie, Satoshi Hirano, Satoshi Konno, Toshihisa Anzai, Koji Taniguchi, Shinya Tanaka, Takanori Teshima
Internal medicine (Tokyo, Japan), 2024年04月16日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, We herein present a fatal case of constrictive pericarditis (CP) due to acute myelomonocytic leukemia (AMML) in a patient who initially complained of an acute onset of chest pain two days after COVID-19 vaccination. An autopsy revealed pericardial infiltration of leukemic cells. CP is rarely associated with leukemia and only 14 cases have been reported in the literature. The etiology of CP in previous reports included leukemic infiltration, graft-versus-host disease, drug-induced, post-radiation, autoimmune, and otherwise unidentified. This case indicates that leukemic infiltration can cause CP and that clinicians should include leukemia in the differential diagnosis of CP.

Non-invasive assessment of left ventricular filling pressure in aortic stenosis.
Hiroyuki Aoyagi, Hiroyuki Iwano, Yoji Tamaki, Michito Murayama, Suguru Ishizaka, Ko Motoi, Kosuke Nakamura, Mana Goto, Yukino Suzuki, Shinobu Yokoyama, Hisao Nishino, Sanae Kaga, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
Echocardiography (Mount Kisco, N.Y.), 41, 4, e15808, 2024年04月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The assessment of left ventricular (LV) filling pressure (FP) is important for the management of aortic stenosis (AS) patients. Although, it is often restricted for predict LV FP in AS because of mitral annular calcification and a certain left ventricular hypertrophy. Thus, we tested the predictive ability of the algorithm for elevated LV FP in AS patients and also applied a recently-proposed echocardiographic scoring system of LV FP, visually assessed time difference between the mitral valve and tricuspid valve opening (VMT) score. METHODS: We enrolled consecutive 116 patients with at least moderate AS in sinus rhythm who underwent right heart catheterization and echocardiography within 7 days. Mean pulmonary artery wedge pressure (PAWP) was measured as invasive parameter of LV FP. LV diastolic dysfunction (DD) was graded according to the ASE/EACVI guidelines. The VMT score was defined as follows: time sequence of opening of mitral and tricuspid valves was scored to 0-2 (0: tricuspid valve first, 1: simultaneous, 2: mitral valve first). When the inferior vena cava was dilated, one point was added and VMT score was finally calculated as 0-3. RESULTS: Of the 116 patients, 29 patients showed elevated PAWP. Ninety patients (93%) and 67 patients (63%) showed increased values for left atrium volume index (LAVI) and E/e', respectively when the cut-off values recommended by the guidelines were applied and thus the algorism predicted elevated PAWP with a low specificity and positive predictive value (PPV). VMT ≥ 2 predicted elevated PAWP with a sensitivity of 59%, specificity of 90%, PPV of 59%, and negative predictive value of 89%. An alternative algorithm that applied tricuspid regurgitation velocity and VMT scores was tested, and its predictive ability was markedly improved. CONCLUSION: VMT score was applicable for AS patients. Alternative use of VMT score improved diagnostic accuracy of guideline-recommended algorism.

Iron supplementation is a residual piece of management in Asian patients with heart failure?
Motoki Nakao, Toshiyuki Nagai, Toshihisa Anzai
International Journal of Cardiology, 406, 132014, 132014, Elsevier BV, 2024年04月, ［国際誌］
英語, 研究論文（学術雑誌）

Influence of epicardial adipose tissue inflammation and adipocyte size on postoperative atrial fibrillation in patients after cardiovascular surgery
Hiroyuki Natsui, Masaya Watanabe, Takashi Yokota, Satonori Tsuneta, Yoshizuki Fumoto, Haruka Handa, Matsushima Shouji, Jiro Koya, Kotaro Nishino, Daishiro Tatsuta, Takuya Koizumi, Takahide Kadosaka, Motoki Nakao, Taro Koya, Taro Temma, Yoichi M. Ito, Hatanaka C. Kanako, Yutaka Hatanaka, Shingu Yasushige, Satoru Wakasa, Shuhei Miura, Takahiko Masuda, Naritomo Nishioka, Shuichi Naraoka, Kayoko Ochi, Tomoko Kudo, Tsugumine Ishikawa, Toshihisa Anzai
Physiological Reports, 12, 6, e15957, Wiley, 2024年03月28日, ［国際誌］
英語, 研究論文（学術雑誌）, Abstract

Epicardial adipose tissue (EAT) is an active endocrine organ that is closely associated with occurrence of atrial fibrillation (AF). However, the role of EAT in the development of postoperative AF (POAF) remains unclear. We aimed to investigate the association between EAT profile and POAF occurrence in patients who underwent cardiovascular surgery. We obtained EAT samples from 53 patients to evaluate gene expression, histological changes, mitochondrial oxidative phosphorylation (OXPHOS) capacity in the EAT, and protein secretion in EAT‐conditioned medium. EAT volume was measured using computed tomography scan. Eighteen patients (34%) experienced POAF within 7 days after surgery. Although no significant difference was observed in EAT profile between patients with and without POAF, logistic regression analysis identified that the mRNA expression levels of tumor necrosis factor‐alpha (TNF‐α) were positively correlated and adipocyte size in the EAT was inversely correlated with onset of POAF, respectively. Mitochondrial OXPHOS capacity in the EAT was not associated with POAF occurrence; however, it showed an inverse correlation with adipocyte size and a positive correlation with adiponectin secretion. In conclusion, changes in the secretory profile and adipocyte morphology of the EAT, which represent qualitative aspects of the adipose tissue, were present before the onset of AF.

Rapid Publication and Announcement of the 2024 JCS Meeting Activities.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 88, 4, 437, 438, 2024年03月25日, ［国内誌］
英語, 研究論文（学術雑誌）

Prolonged delirium during hospitalization is associated with worse long-term and short-term outcomes in patients with acute heart failure.
Yukio Aikawa, Soshiro Ogata, Satoshi Honda, Toshiyuki Nagai, Shunsuke Murata, Isao Morii, Toshihisa Anzai, Kunihiro Nishimura, Teruo Noguchi
International journal of cardiology, 399, 131776, 131776, 2024年03月15日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The association between prolonged delirium during hospitalization and long-term prognosis in patients with acute heart failure (AHF) admitted to the cardiac intensive care unit (CICU) has not been fully elucidated. METHODS: We conducted a prospective registry study of patients with AHF admitted to the CICU at 2 hospitals from 2013 to 2021. We divided study patients into 3 groups according to the presence or absence of delirium and prolonged delirium as follows: no delirium, resolved delirium, or prolonged delirium. Main outcomes were in-hospital mortality and 3-year mortality after discharge. RESULTS: A total of 1555 patients with AHF (median age, 80 years) were included in the analysis. Of these, 406 patients (26.1%) developed delirium. We divided patients with delirium into 2 groups: the resolved delirium group (n = 201) or the prolonged delirium group (n = 205). Multivariate Cox proportional hazards models for long-term prognosis demonstrated that the prolonged delirium group had a higher incidence of all-cause death (hazard ratio [HR], 1.52; 95% CI, 1.08 to 2.14) and non-cardiovascular death (HR, 1.84; 95% CI, 1.21 to 2.78) than the resolved delirium group. Regarding in-hospital outcomes, multivariate logistic regression modeling showed that prolonged delirium is associated with all-cause death (odds ratio [OR], 9.55; 95% confidential interval [CI], 2.99 to 30.53) and cardiovascular death (OR, 13.02; 95% CI, 2.86 to 59.27) compared with resolved delirium. CONCLUSIONS: Prolonged delirium is associated with worse long-term and short-term outcomes than resolved delirium in patients with AHF.

Prognostic Value of Combined Assessments of Late Gadolinium Enhancement and Fluorodeoxyglucose Uptake in Cardiac Sarcoidosis.
Sho Kazui, Sakae Takenaka, Toshiyuki Nagai, Satonori Tsuneta, Kenji Hirata, Yoshiya Kato, Hirokazu Komoriyama, Yuta Kobayashi, Akinori Takahashi, Kiwamu Kamiya, Taro Temma, Takuma Sato, Atsushi Tada, Yutaro Yasui, Michikazu Nakai, Takahiro Sato, Ichizo Tsujino, Kohsuke Kudo, Satoshi Konno, Toshihisa Anzai
JACC. Cardiovascular imaging, 17, 6, 710, 712, 2024年03月11日, ［国際誌］
英語

Two-Year Clinical Outcome of MitraClip Transcatheter Edge-to-Edge Repair From the J-MITRA Registry Data.
Teruhiko Imamura, Michikazu Nakai, Yoshitaka Iwanaga, Yoko Sumita, Misato Tao, Yohei Ohno, Kentaro Hayashida, Yoshihiro Morino, Yoshihiro Seo, Yoshikatsu Saiki, Toshihisa Anzai, Koichi Toda, Goro Matsumiya, Kazuhiro Yamamoto, Kenichi Hirata, Koichiro Kinugawa
Circulation journal : official journal of the Japanese Circulation Society, 88, 4, 539, 548, 2024年03月06日, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The introduction of transcatheter edge-to-edge repair for moderate-to-severe or severe mitral regurgitation (MR) utilizing the MitraClip system became reimbursed and clinically accessible in Japan in April 2018. This study presents the 2-year clinical outcomes of all consecutively treated patients who underwent MitraClip implantation in Japan and were prospectively enrolled in the Japanese Circulation Society-oriented J-MITRA registry.Methods and Results: Analysis encompassed 2,739 consecutive patients enrolled in the J-MITRA registry with informed consent (mean age: 78.3±9.6 years, 1,550 males, STS risk score 11.7±8.9), comprising 1,999 cases of functional MR, 644 of degenerative MR and 96 in a mixed group (DMR and FMR). The acute procedure success rate was 88.9%. After MitraClip implantation, >80% exhibited an MR grade ≤2+ and the trend was sustained over the 2 years. Within this observation period, the mortality rate was 19.3% and the rate of heart failure readmissions was 20.6%. The primary composite endpoint, inclusive of cardiovascular death and heart failure readmission, was significantly higher in patients with functional MR than in with degenerative MR (32.0% vs. 17.5%, P<0.001). CONCLUSIONS: The 2-year clinical outcomes after MitraClip implantation were deduced from comprehensive data within an all-Japan registry.

Machine Learning-based Gait Analysis to Predict Clinical Frailty Scale in Elderly Patients with Heart Failure
Yoshifumi Mizuguchi, Motoki Nakao, Toshiyuki Nagai, Yuki Takahashi, Takahiro Abe, Shigeo Kakinoki, Shogo Imagawa, Kenichi Matsutani, Takahiko Saito, Masashige Takahashi, Yoshiya Kato, Hirokazu Komoriyama, Hikaru Hagiwara, Kenji Hirata, Takahiro Ogawa, Takuto Shimizu, Manabu Otsu, Kunihiro Chiyo, Toshihisa Anzai
European Heart Journal - Digital Health, 5, 2, 152, 162, Oxford University Press (OUP), 2023年12月20日, ［国際誌］
英語, 研究論文（学術雑誌）, Abstract

Aims

Although frailty assessment is recommended for guiding treatment strategies and outcome prediction in elderly patients with heart failure (HF), most frailty scales are subjective and the scores vary among raters. We sought to develop a machine learning-based automatic rating method/system/model of the clinical frailty scale (CFS) for patients with HF.

Methods and Results

We prospectively examined 417 elderly (≥75 years) with symptomatic chronic HF patients from seven centers between January 2019 and October 2023. The patients were divided into derivation (n = 194) and validation (n = 223) cohorts. We obtained body-tracking motion data using a deep learning-based pose estimation library, on a smartphone camera. Predicted CFS was calculated from 128 key features, including gait parameters, using the Light Gradient Boosting Machine (LightGBM) model. To evaluate the performance of this model, we calculated Cohen’s weighted kappa (CWK) and intraclass correlation coefficient (ICC) between the predicted and actual CFSs. In the derivation and validation datasets, the LightGBM models showed excellent agreements between the actual and predicted CFSs (CWK 0.866, 95% CI 0.807-0.911; ICC 0.866, 95% CI 0.827-0.898; CWK 0.812, 95% CI 0.752-0.868; ICC 0.813, 95% CI 0.761-0.854, respectively). During a median follow-up period of 391 (IQR 273-617) days, the higher predicted CFS was independently associated with a higher risk of all-cause death (HR 1.60, 95% CI 1.02-2.50) after adjusting for significant prognostic covariates.

Conclusion

Machine learning-based algorithms of automatically CFS rating are feasible, and the predicted CFS is associated with the risk of all-cause death in elderly patients with HF.

Exercise Capacity and Clinical Outcomes in Chronic Heart Failure Patients with Mild Tricuspid Regurgitation.
Kosuke Nakamura, Suguru Ishizaka, Kazunori Omote, Yutaro Yasui, Yoshifumi Mizuguchi, Sakae Takenaka, Yui Shimono, Ko Motoi, Hiroyuki Aoyagi, Yoji Tamaki, Sho Kazui, Yuki Takahashi, Kohei Saiin, Seiichiro Naito, Atsushi Tada, Yuta Kobayashi, Takuma Sato, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
Journal of clinical medicine, 12, 23, 2023年12月01日, ［国際誌］
英語, 研究論文（学術雑誌）, AIM: The present study aimed to investigate the impact of mild tricuspid regurgitation (TR) on the exercise capacity or clinical outcomes in patients with chronic heart failure (CHF). METHODS AND RESULTS: The study enrolled 511 patients with CHF who underwent cardiopulmonary exercise testing (CPET) between 2013 and 2018. The primary outcome was a composite of heart failure hospitalization and death. Patients with mild TR (n = 324) or significant TR (moderate or greater; n = 60) displayed worse NHYA class and reduced exercise capacity on CPET than those with non-TR (n = 127), but these were more severely impaired in patients with significant TR. A total of 90 patients experienced events over a median follow-up period of 3.3 (interquartile range 0.8-5.5) years. Patients with significant TR displayed a higher risk of events, while patients with mild TR had a 3.0-fold higher risk of events than patients with non-TR (hazard ratio (HR) 3.01; 95% confidence interval (CI), 1.50-6.07). Multivariate Cox regression analysis showed that, compared with non-TR, mild TR was associated with increased adverse events, even after adjustment for co-variates (HR 2.97; 95% CI, 1.35-6.55). CONCLUSIONS: TR severity was associated with worse symptoms, reduced exercise capacity, and poor clinical outcomes. Even patients with mild TR had worse clinical characteristics than those with non-TR.

Differences in blood flow dynamics between balloon- and self-expandable valves in patients with aortic stenosis undergoing transcatheter aortic valve replacement.
Yuki Takahashi, Kiwamu Kamiya, Toshiyuki Nagai, Satonori Tsuneta, Noriko Oyama-Manabe, Takeshi Hamaya, Sho Kazui, Yutaro Yasui, Kohei Saiin, Seiichiro Naito, Yoshifumi Mizuguchi, Sakae Takenaka, Atsushi Tada, Suguru Ishizaka, Yuta Kobayashi, Kazunori Omote, Takuma Sato, Yasushige Shingu, Kohsuke Kudo, Satoru Wakasa, Toshihisa Anzai
Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance, 25, 1, 60, 60, 2023年10月26日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The differences in pre- and early post-procedural blood flow dynamics between the two major types of bioprosthetic valves, the balloon-expandable valve (BEV) and self-expandable valve (SEV), in patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR), have not been investigated. We aimed to investigate the differences in blood flow dynamics between the BEV and SEV using four-dimensional flow cardiovascular magnetic resonance (4D flow CMR). METHODS: We prospectively examined 98 consecutive patients with severe AS who underwent TAVR between May 2018 and November 2021 (58 BEV and 40 SEV) after excluding those without CMR because of a contraindication, inadequate imaging from the analyses, or patients' refusal. CMR was performed in all participants before (median interval, 22 [interquartile range (IQR) 4-39] days) and after (median interval, 6 [IQR 3-6] days) TAVR. We compared the changes in blood flow patterns, wall shear stress (WSS), and energy loss (EL) in the ascending aorta (AAo) between the BEV and SEV using 4D flow CMR. RESULTS: The absolute reductions in helical flow and flow eccentricity were significantly higher in the SEV group compared in the BEV group after TAVR (BEV: - 0.22 ± 0.86 vs. SEV: - 0.85 ± 0.80, P < 0.001 and BEV: - 0.11 ± 0.79 vs. SEV: - 0.50 ± 0.88, P = 0.037, respectively); there were no significant differences in vortical flow between the groups. The absolute reduction of average WSS was significantly higher in the SEV group compared to the BEV group after TAVR (BEV: - 0.6 [- 2.1 to 0.5] Pa vs. SEV: - 1.8 [- 3.5 to - 0.8] Pa, P = 0.006). The systolic EL in the AAo significantly decreased after TAVR in both the groups, while the absolute reduction was comparable between the groups. CONCLUSIONS: Helical flow, flow eccentricity, and average WSS in the AAo were significantly decreased after SEV implantation compared to BEV implantation, providing functional insights for valve selection in patients with AS undergoing TAVR. Our findings offer valuable insights into blood flow dynamics, aiding in the selection of valves for patients with AS undergoing TAVR. Further larger-scale studies are warranted to confirm the prognostic significance of hemodynamic changes in these patients.

心臓サルコイドーシス患者の免疫抑制療法開始後における心筋トロポニン値経時的評価の予後的意義　　　　　　　　　　　　　　　
數井 翔, 竹中 秀, 永井 利幸, 加藤 喜哉, 小森山 弘和, 小林 雄太, 高橋 昌寛, 神谷 究, 佐藤 琢真, 多田 篤司, 安井 悠太郎, 中井 陸運, 佐藤 隆博, 辻野 一三, 今野 哲, 安斉 俊久
日本サルコイドーシス/肉芽腫性疾患学会雑誌, 43, サプリメント号, 64, 64, 日本サルコイドーシス, 2023年10月
日本語

心臓サルコイドーシス患者におけるガドリニウム遅延造影心臓MRIとFDG-PETを用いた複合的画像評価の予後的意義　　　　　　　　　　　　　　　
數井 翔, 竹中 秀, 永井 利幸, 常田 慧徳, 加藤 喜哉, 小森山 弘和, 小林 雄太, 高橋 昌寛, 神谷 究, 天満 太郎, 佐藤 琢真, 多田 篤司, 安井 悠太郎, 中井 陸運, 佐藤 隆博, 辻野 一三, 工藤 與亮, 今野 哲, 安斉 俊久
日本サルコイドーシス/肉芽腫性疾患学会雑誌, 43, サプリメント号, 65, 65, 日本サルコイドーシス, 2023年10月
日本語

心臓サルコイドーシス患者の免疫抑制療法開始後における心筋トロポニン値経時的評価の予後的意義　　　　　　　　　　　　　　　
數井 翔, 竹中 秀, 永井 利幸, 加藤 喜哉, 小森山 弘和, 小林 雄太, 高橋 昌寛, 神谷 究, 佐藤 琢真, 多田 篤司, 安井 悠太郎, 中井 陸運, 佐藤 隆博, 辻野 一三, 今野 哲, 安斉 俊久
日本サルコイドーシス/肉芽腫性疾患学会雑誌, 43, サプリメント号, 64, 64, 日本サルコイドーシス, 2023年10月
日本語

心臓サルコイドーシス患者におけるガドリニウム遅延造影心臓MRIとFDG-PETを用いた複合的画像評価の予後的意義　　　　　　　　　　　　　　　
數井 翔, 竹中 秀, 永井 利幸, 常田 慧徳, 加藤 喜哉, 小森山 弘和, 小林 雄太, 高橋 昌寛, 神谷 究, 天満 太郎, 佐藤 琢真, 多田 篤司, 安井 悠太郎, 中井 陸運, 佐藤 隆博, 辻野 一三, 工藤 與亮, 今野 哲, 安斉 俊久
日本サルコイドーシス/肉芽腫性疾患学会雑誌, 43, サプリメント号, 65, 65, 日本サルコイドーシス, 2023年10月
日本語

Impact of Cardiac Power Output on Exercise Capacity and Clinical Outcome in Patients With Chronic Heart Failure.
Yui Shimono, Suguru Ishizaka, Kazunori Omote, Kosuke Nakamura, Yutaro Yasui, Yoshifumi Mizuguchi, Sakae Takenaka, Hiroyuki Aoyagi, Yoji Tamaki, Takuma Sato, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
The American journal of cardiology, 206, 4, 11, 2023年09月05日, ［国際誌］
英語, 研究論文（学術雑誌）, Less data are available regarding the impact of cardiac power output on exercise capacity or clinical outcome in patients with chronic heart failure (CHF). The study enrolled 280 consecutive patients with CHF referred for cardiopulmonary exercise testing and right-sided heart catheterization between 2013 and 2018. The primary outcome was composite of heart failure hospitalization or death. Cardiac power output was calculated as (mean arterial pressure × CO) ÷ 451. Patients with low cardiac power output (<0.53 W, n = 99) were older and had a higher brain natriuretic peptide level than patients with high cardiac power output (≥0.53W, n = 181). Cardiac power output was correlated with peak oxygen consumption (peak V̇O2), peak workload achievement, and ventilatory efficiency (V̇E/V̇CO2 slope) in cardiopulmonary exercise testing, whereas each of cardiac output or mean arterial pressure was not. There were 48 patients with events over a median follow-up period of 3.5 (interquartile range 1.0 to 6.0) years. Patients with low cardiac power output had about a 2-fold higher risk of events than those with a high cardiac power output (hazard ratio 1.97, 95% confidence interval 1.12 to 3.48). In the multivariable Cox regression, a 0.1-W decrease in cardiac power output was associated with 19% increased adverse events (hazard ratio 0.81, 95% confidence interval 0.67 to 0.99). In conclusion, cardiac power output was associated with reduced exercise capacity and poor clinical outcome, suggesting that cardiac power output is useful for risk stratification in patients with CHF. Further study is required to identify therapies targeting cardiac power output to improve the exercise capacity or clinical outcome in patients with CHF.

Association of longitudinal cardiac troponin trajectory with adverse events in patients with cardiac sarcoidosis.
Sho Kazui, Sakae Takenaka, Toshiyuki Nagai, Yoshiya Kato, Hirokazu Komoriyama, Yuta Kobayashi, Akinori Takahashi, Kiwamu Kamiya, Takuma Sato, Atsushi Tada, Yutaro Yasui, Michikazu Nakai, Takahiro Sato, Ichizo Tsujino, Satoshi Konno, Toshihisa Anzai
International journal of cardiology, 389, 131268, 131268, 2023年08月15日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Although high-sensitivity cardiac troponins may be sensitive and easily repeatable markers of disease activity in patients with cardiac sarcoidosis (CS), the association between longitudinal cardiac troponin trajectory and adverse events remains unclear. This study aimed to clarify whether longitudinal cardiac troponin levels were associated with adverse events in patients with CS. METHODS: We examined 63 consecutive CS-initiated prednisolone (PSL) patients with available longitudinal high-sensitivity cardiac troponin T (cTnT) data between December 2013 and March 2023. The area under the cTnT trajectory, which reflected cumulative cTnT release, was calculated to assess the association between longitudinal cTnT levels and adverse events. Patients were divided into two groups according to the median area under the cTnT trajectory per month. The primary outcome was a composite of sustained ventricular tachycardia or fibrillation, worsening heart failure, and sudden cardiac death (SCD). RESULTS: In total, 463 cTnT measurements were collected over a median follow-up period of 30.4 (interquartile range [IQR] 15.6-34.2) months. The primary outcome was observed in 12 (19%) patients. A higher area under the cTnT trajectory was significantly associated with an increased incidence of the primary outcome (P = 0.027), while cTnT levels before and one month after initiation of PSL, and these changes were not related to adverse events (P = 0.179, 0.096, and 0.95, respectively). CONCLUSIONS: Longitudinal cTnT trajectory following PSL initiation was associated with adverse cardiac events in patients with CS, suggesting that longitudinal measurement of cTnT would be useful for the early identification of high-risk patients.

Association between Non-Lipid Residual Risk Factors and Cardiovascular Events in Patients with Stable Coronary Artery Disease Treated with Pitavastatin: An Observation from the REAL-CAD Study.
Kiwamu Kamiya, Makoto Takei, Toshiyuki Nagai, Toru Miyoshi, Hiroshi Ito, Yoshihiro Fukumoto, Hitoshi Obara, Tatsuyuki Kakuma, Ichiro Sakuma, Hiroyuki Daida, Satoshi Iimuro, Hiroaki Shimokawa, Takeshi Kimura, Ryozo Nagai, Toshihisa Anzai
Journal of atherosclerosis and thrombosis, 2023年08月11日, ［国内誌］
英語, 研究論文（学術雑誌）, AIMS: We aimed to investigate the association between non-lipid residual risk factors and cardiovascular events in patients with stable coronary artery disease (CAD) who achieved low-density lipoprotein cholesterol (LDL-C) ＜100 mg/dL from the Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study. METHODS: The REAL-CAD study was a prospective, multicenter, open-label trial. As a sub-study, we examined the prognostic impact of non-lipid residual risk factors, including blood pressure, glucose level, and renal function, in patients who achieved LDL-C ＜100 mg/dL at 6 months after pitavastatin therapy. Each risk factor was classified according to severity. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, and unstable angina requiring emergency hospitalization. RESULTS: Among 8,743 patients, the mean age was 68±8.2 years, and the mean LDL-C level was 84.4±18 mg/dL. After adjusting for the effects of confounders, an estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m2 showed the highest risk of the primary outcome (hazard ratio [HR] 1.92; 95% confidence interval [CI] 1.45-2.53). The combination of eGFR ≤ 60 and hemoglobin A1c (HbA1c) ≥ 6.0% also showed the highest risk of all-cause death (HR, 2.42; 95% CI, 1.72-3.41). CONCLUSIONS: In patients with stable CAD treated with pitavastatin and who achieved guidelines-directed levels of LDL-C, eGFR and HbA1c were independently associated with adverse events, suggesting that renal function and glycemic control could be residual non-lipid therapeutic targets after statin therapy.

Cost-effective analysis of transcatheter aortic valve replacement in patients with severe symptomatic aortic stenosis: A prospective multicenter study.
Makoto Amaki, Kensuke Moriwaki, Michikazu Nakai, Tetsuhiro Yamano, Atsushi Okada, Hideaki Kanzaki, Masaki Izumo, Hiroki Usuku, Tetsuari Onishi, Toshiyuki Nagai, Yoshihiro Miyamoto, Tomoyuki Fujita, Hiroya Kawai, Yoshihiro Akashi, Kenichi Tsujita, Satoaki Matoba, Junjiro Kobayashi, Chisato Izumi, Toshihisa Anzai
Journal of cardiology, 2023年08月03日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Transcatheter aortic valve replacement (TAVR) for severe symptomatic aortic stenosis (AS) does not benefit all patients. We performed a prospective multicenter study to investigate the cost-effectiveness of TAVR in a Japanese cohort. METHODS AND RESULTS: We prospectively enrolled 110 symptomatic patients with severe AS who underwent TAVR from five institutions. The quality of life measurement (QOL) was performed for each patient before and at 6 months after TAVR. Patients without an improvement in QOL at 6 months after TAVR were defined as non-responders. Pre-TAVR higher QOL, higher clinical frailty scale predicted the non-responders. Three models, 1) conservative treatment for all patients strategy, 2) TAVR for all patients strategy, and 3) TAVR for a selected patient strategy who is expected to be a responder, were simulated. Lifetime cost-effectiveness was estimated using incremental cost-effectiveness ratio (ICER) and cost per quality-adjusted life-year (QALY) gained. In comparison to conservative therapy for all patients, ICER was estimated to be 5,765,800 yen/QALY for TAVR for all patients and 2,342,175 yen/QALY for TAVR for selected patient strategy patients, which is less than the commonly accepted ICER threshold of 5,000,000 yen/QALY. CONCLUSIONS: TAVR for selected patient strategy model is more cost-effective than TAVR for all patient strategy without reducing QOL in the Japanese healthcare system. TAVR for selected patient strategy has potential benefit for optimizing the TAVR treatment in patients with high frailty and may direct our resources toward beneficial interventions.

Efficacy of azilsartan on left ventricular diastolic dysfunction compared with candesartan: J-TASTE randomized controlled trial.
Shin Ito, Hiroyuki Takahama, Masanori Asakura, Yukio Abe, Masayoshi Ajioka, Toshihisa Anzai, Takuo Arikawa, Takaharu Hayashi, Yorihiko Higashino, Shinya Hiramitsu, Noriaki Iwahashi, Chisato Izumi, Kazuo Kimura, Koichiro Kinugawa, Hidetaka Kioka, Young-Jae Lim, Ken Matsuoka, Satoshi Matsuoka, Hirohiko Motoki, Sunao Nakamura, Takafumi Nakayama, Akihiro Nomura, Taishi Sasaoka, Shin Takiuchi, Shigeru Toyoda, Tomoya Ueda, Tetsuya Watanabe, Akira Yamada, Masayoshi Yamamoto, Takashi Sozu, Masafumi Kitakaze
Scientific reports, 13, 1, 12517, 12517, 2023年08月02日, ［国際誌］
英語, 研究論文（学術雑誌）, Characterized by ventricular and vascular stiffness, heart failure with preserved ejection fraction (HFpEF) has led to high morbidity and mortality. As azilsartan is an angiotensin receptor blocker with the highest myocardial and vascular affinities, azilsartan may improve the left ventricular (LV) diastolic function in patients with hypertension and either HFpEF or HF with mildly reduced ejection fraction (HFmrEF) more than candesartan. In this randomized, open-label trial, we randomly assigned 193 hypertensive patients with HF and LV ejection fraction ≥ 45% to 20 mg of azilsartan (n = 95) or 8 mg of candesartan (n = 98), once daily for 48 weeks. After the initiation of treatment, changes in the doses of the study drugs were permitted based on the patient's conditions, including blood pressure (median dose at 48 weeks: azilsartan 20.0 mg/day, candesartan 8.0 mg/day). The primary endpoint was the baseline-adjusted change in the ratio of peak early diastolic transmitral flow velocity (E) to early diastolic mitral annular velocity (e') (E/e'). Adjusted least-squares mean (LSM) change in E/e' was - 0.8 (95% confidence interval [CI] - 1.49 to - 0.04) in the azilsartan group and 0.2 (95% CI - 0.49 to 0.94) in the candesartan group, providing the LSM differences of - 1.0 (95% CI - 2.01 to 0.03, P = 0.057). The median change in left atrial volume index was - 2.7 mL/m2 with azilsartan vs 1.4 mL/m2 with candesartan (P = 0.091). The frequency of adverse events related to hypotension and hyperkalemia did not differ between the groups. The current study did not provide strong evidence that azilsartan improves LV diastolic dysfunction, and further confirmatory study is required.

Increased Piezo1 expression in myofibroblasts in patients with symptomatic carotid atherosclerotic plaques undergoing carotid endarterectomy: A pilot study.
Takao Konishi, Kenji Kamiyama, Toshiaki Osato, Tetsuyuki Yoshimoto, Takeshi Aoki, Toshihisa Anzai, Shinya Tanaka
Vascular, 17085381231192380, 17085381231192380, 2023年07月27日, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: We aimed to investigate Piezo1 expression in myofibroblasts in symptomatic and asymptomatic patients undergoing carotid endarterectomy and its relationship with atherosclerotic plaque formation. METHODS: This cross-sectional study analyzed carotid plaques of 17 randomly selected patients who underwent carotid endarterectomy from May 2015 to August 2017. In total, 51 sections (the most stenotic lesion, and the sections 5-mm proximal and distal) stained with hematoxylin-eosin and elastica-Masson were examined. Immunohistochemistry was performed using antibodies to Piezo1. The Piezo1 score of a section was calculated semiquantitatively, averaged across 30 randomly selected myofibroblasts in the fibrous cap of the plaque. RESULTS: Of 17 patients (mean age: 74.2 ± 7.1 years), 15 were men, 9 had diabetes mellitus, and 13 had hypertension. Symptomatic patients had higher mean Piezo1 score than asymptomatic patients (1.78 ± 0.23 vs 1.34 ± 0.17, p < .001). Univariate linear regression analyses suggested an association between plaque rupture, thin-cap fibroatheroma and microcalcifications and the Piezo1 score (p = .001, .008, and 0.003, respectively). CONCLUSIONS: Increased Piezo1 expression of myofibroblasts may be associated with atherosclerotic carotid plaque instability. Further study is warranted to support this finding.

Relationship between Canagliflozin, Sodium Glucose Cotransporter 2 Inhibitor, and Hematopoietic Effects in Patients with Diabetes and Mild Heart Failure: Results from the CANDLE Trial
Daisaku Nakatani, Tomoharu Dohi, Shungo Hikoso, Atsushi Tanaka, Mamoru Nanasato, Wataru Shimizu, Koichi Node, Yasushi Sakata, Masayoshi Ajioka, Junya Ako, Rie Amano, Toshihisa Anzai, Mitsutoshi Asai, Kaoru Dohi, Kazuo Eguchi, Kenichi Eshima, Shinya Fujiki, Masashi Fujita, Shinya Hiramitsu, Satoshi Hoshide, Akihiko Hoshino, Yuki Ikeda, Yumi Ikehara, Takayuki Inomata, Teruo Inoue, Katsuhisa Ishii, Nobukazu Ishizaka, Masaaki Ito, Noriaki Iwahashi, Katsuomi Iwakura, Toshiaki Kadokami, Haruo Kamiya, Takahiro Kanbara, Yumiko Kanzaki, Ken Kashimura, Keisuke Kida, Kazuo Kimura, Satoru Kishi, Shuichi Kitada, Akihiro Kiyosue, Kazuhisa Kodama, Takayuki Kojima, Takumi Kondo, Yoshiaki Kubota, Kenya Kusunose, Noritaka Machii, Kazuo Matsunaga, Yasuto Matsuo, Yashushi Matsuzawa, Takeshi Mikami, Toru Minamino, Takahiro Nagai, Yasuko Nagano, Masashi Nagumo, Ikuko Nakamura, Katsunori Nakamura, Hiriyuki Naruse, Masami Nishino, Shinichi Niwano, Mitsutoshi Oguri, Nobuyuki Ohte, Masayoshi Oikawa, Takahiro Okumura, Masanori Okumura, Katsuya Onishi, Yukio Ozaki, Kan Saito, Tomohiro Sakamoto, Masashi Sakuma, Hisakuni Sekino, Kazuki Shiina, Michio Shimabukuro, Makoto Suzuki, Kunihiro Suzuki, Hiroyuki Takahama, Naohiko Takahashi, Yasuchika Takeishi, Shunsuke Tamaki, Akihiro Tanaka, Syuzo Tanimoto, Hiroki Teragawa, Tomoyuki Tobushi, Takafumi Toita, Kotaro Tokuda, Hirofumi Tomiyama, Hiroyuki Tsutsui, Hiroki Uehara, Masaaki Uematsu, Hirotaka Watada, Kazuyuki Yahagi, Takahisa Yamada, Hirotsugu Yamada, Tatsuya Yoshida, Akiomi Yoshihisa
Journal of Cardiovascular Pharmacology, 82, 1, 61, 68, 2023年07月19日
研究論文（学術雑誌）, Abstract:There were few clinical studies on the relationship between sodium glucose cotransporter 2 inhibitors (SGLT2i) and hematopoiesis in patients with diabetes (DM) and heart failure (HF) with consideration of systemic volume status. A total of 226 DM patients with HF enrolled in the CANDLE trial, a multicenter, prospective, randomized open-label blinded-endpoint trial, were studied. Estimated plasma volume status (ePVS) was calculated based on a weight-and hematocrit-based formula. At baseline, there was no significant difference in hematocrit and hemoglobin between the canagliflozin (n = 109) and glimepiride (n = 116) groups. Hematocrit and hemoglobin at 24 weeks, changes in hematocrit and hemoglobin difference (24 weeks-baseline), and hematocrit and hemoglobin ratio (24 weeks/baseline) were significantly higher in the canagliflozin than in the glimepiride group, respectively. There was no significant difference in ePVS at baseline and 24 weeks between the 2 groups. After adjustment for baseline parameters, canagliflozin correlated positively with changes in hematocrit and hemoglobin difference, and hematocrit and hemoglobin ratio by multivariate linear regression analyses. The difference in hematocrit and hemoglobin between the 2 groups became statistically significant at 3 and 6 months after randomization. There was no heterogeneity between canagliflozin and the characteristics of the patients for hematocrit and hemoglobin difference and ratio. A correlation of the changes in hematocrit and hemoglobin with cardiac and renal improvement was not observed. In conclusion, canagliflozin was associated with an increased hematocrit and hemoglobin in patients with diabetes and HF regardless of their volume status and characteristics.

Paradoxical increase in global longitudinal strain by handgrip exercise despite left ventricular diastolic dysfunction.
Ko Motoi, Hiroyuki Iwano, Suguru Ishizaka, Kosuke Nakamura, Yoji Tamaki, Hiroyuki Aoyagi, Masahiro Nakabachi, Shinobu Yokoyama, Hisao Nishino, Michito Murayama, Sanae Kaga, Toshihisa Anzai
Echocardiography (Mount Kisco, N.Y.), 40, 8, 810, 821, 2023年07月14日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Although global longitudinal strain (GLS) is recognized as a sensitive marker of intrinsic left ventricular (LV) dysfunction, its afterload dependency has also been pointed. We hypothesized that decrease in GLS during handgrip exercise could be more sensitive marker of intrinsic myocardial dysfunction. METHODS: Handgrip exercise-stress echocardiography was performed in 90 cardiovascular disease patients with preserved LV ejection fraction. LV diastolic function was graded according to the guidelines. Diastolic wall stress (DWS) and ratio of left atrial (LA) volume index to late-diastolic mitral annular velocity (LAVI/a') were measured at rest as LV stiffness. As well, LA strains were measured to assess LA function. GLS was expressed as absolute value and significant changes in GLS by handgrip exercise was defined as changes over prespecified mean absolute test-retest variability (2.65%). RESULTS: While mean value of GLS did not change by the exercise, substantial patients showed significant changes in GLS: decreased (group I, n = 28), unchanged (group II, n = 34), and increased (group III, n = 28). Unexpectedly, patients in group I did not show any clinical and echocardiographic characteristics, while those in group III were characterized by elevated natriuretic peptide levels, blunted heart rate response to handgrip exercise, and advanced LV diastolic dysfunction. Multivariable analyses revealed that DWS, left atrial booster strain, and grade II or more diastolic dysfunction determined the increase in GLS even after adjustment for elevated natriuretic peptides and the changes in heart rate by the exercise. CONCLUSION: In contrast to our hypothesis, paradoxical increase in GLS by handgrip exercise could be associated with advanced LV diastolic dysfunction in cardiovascular patients with preserved LV ejection fraction. Our findings suggest that HG exercise for heart failure patients does not enhance the afterload straightforward, resulting in variable changes of GLS according to the individual conditions.

Prognostic Value of Liver Fibrotic Markers in Patients With Heart Failure.
Atsushi Tada, Toshiyuki Nagai, Yoshiya Kato, Noriko Oyama-Manabe, Satonori Tsuneta, Michikazu Nakai, Yutaro Yasui, Sho Kazui, Yuki Takahashi, Kohei Saiin, Seiichiro Naito, Sakae Takenaka, Yoshifumi Mizuguchi, Yuta Kobayashi, Suguru Ishizaka, Kazunori Omote, Takuma Sato, Takao Konishi, Kiwamu Kamiya, Kohsuke Kudo, Toshihisa Anzai
The American journal of cardiology, 200, 115, 123, 2023年06月10日, ［国際誌］
英語, 研究論文（学術雑誌）, Several liver fibrotic markers are associated with prognosis in patients with heart failure (HF). However, the optimal markers for outcome prediction remain unclear. This study aimed to simultaneously investigate the prognostic value of liver fibrotic markers and the associations between these markers and clinical parameters in patients with HF without organic liver disease. We prospectively examined 211 consecutive patients with chronic HF between April 2018 and August 2021, excluding those with organic liver disease, using liver magnetic resonance imaging and ultrasound. A total of 7 representative liver fibrotic markers were measured in all patients. The primary outcome of interest was the composite of all-cause death and hospitalization for worsening HF. During a median follow-up period of 747 (interquartile range 465 to 1,042) days, the primary outcome occurred in 45 patients. Patients with higher hyaluronic acid and type III procollagen N-terminal peptide (P-III-P) levels showed a significantly higher incidence of the primary outcome than those without (p <0.001 and p = 0.005, respectively). The multivariable Cox regression analysis revealed that hyaluronic acid and P-III-P levels were independently associated with the risk of adverse events (hazard ratio 1.84, 95% confidence interval 1.18 to 2.87 and hazard ratio 2.89, 95% confidence interval 1.32 to 6.34, respectively) even after adjustment for a mortality prediction model, whereas the other 5 markers were not associated with the primary outcome. In conclusion, among the representative liver fibrotic markers, hyaluronic acid and P-III-P might be the optimal markers for outcome prediction in patients with HF.

Leadless Pacemaker With Acute but Transient Elevation of Lead Impedance and Pacing Threshold.
Hikaru Hagiwara, Junpei Morimoto, Toshifumi Tamura, Akinori Takahashi, Hirokazu Komoriyama, Yoshiya Kato, Toshihisa Anzai
CJC open, 5, 6, 412, 414, 2023年06月, ［国際誌］
英語

Application of an echocardiographic scoring system of left ventricular filling pressure to diagnose acute heart failure in patients complaining dyspnea.
Yoji Tamaki, Hiroyuki Iwano, Michito Murayama, Suguru Ishizaka, Ko Motoi, Hiroyuki Aoyagi, Kosuke Nakamura, Mana Goto, Yukino Suzuki, Shinobu Yokoyama, Hisao Nishino, Masahiro Nakabachi, Sanae Kaga, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
Journal of cardiology, 82, 1, 62, 68, 2023年04月27日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Dyspnea is a common symptom in acute heart failure (AHF) patients. Although an accurate and rapid diagnosis of AHF is essential to improve prognosis, estimation of left ventricular (LV) filling pressure (FP) remains challenging, especially for noncardiologists. We evaluated the usefulness of a recently-proposed parameter of LV FP, visually assessed time difference between the mitral valve and tricuspid valve opening (VMT) score, to detect AHF in patients complaining of dyspnea. METHODS: Echocardiography and lung ultrasonography (LUS) were performed in 121 consecutive patients (68 ± 14 years old, 75 males) presenting with dyspnea. The VMT score was determined from the atrioventricular valve opening phase (tricuspid valve first: 0, simultaneous: 1, mitral valve first: 2) and inferior vena cava dilatation (absent: 0, present: 1), and VMT ≥2 was judged as positive. LUS was performed with the 8 zones method and judged as positive if 3 or more B-lines were observed in bilateral regions. The AHF diagnosis was performed by certified cardiologists according to recent guidelines. RESULTS: Of the 121 patients, 33 were diagnosed with AHF. The sensitivity and specificity for diagnosing AHF were 64 % and 84 % for LUS and 94 % and 88 % for VMT score. In logistic regression analysis, VMT score showed a significantly higher c-index than LUS (0.91 vs 0.74, p = 0.002). In multivariable analyses, VMT score was associated with AHF independently of clinically relevant covariates and LUS. In addition, serial assessment of VMT score followed by LUS provided a diagnostic flow chart to diagnose AHF (VMT 3: AHF definitive, VMT 2 and LUS positive: AHF highly suspicious; VMT 2 and LUS negative: further investigation is needed; VMT ≤ 1: AHF rejected). CONCLUSIONS: VMT score showed high diagnostic accuracy in diagnosing AHF. Combined assessment of the VMT score and LUS could become a reliable strategy for diagnosis of AHF by non-cardiologists.

Heart failure with preserved ejection fraction phenogroup classification using machine learning
Atsushi Kyodo, Koshiro Kanaoka, Ayaka Keshi, Maki Nogi, Kazutaka Nogi, Satomi Ishihara, Daisuke Kamon, Yukihiro Hashimoto, Yasuki Nakada, Tomoya Ueda, Ayako Seno, Taku Nishida, Kenji Onoue, Tsuneari Soeda, Rika Kawakami, Makoto Watanabe, Toshiyuki Nagai, Toshihisa Anzai, Yoshihiko Saito
ESC Heart Failure, 10, 3, 2019, 2030, Wiley, 2023年04月12日
研究論文（学術雑誌）

Vieussens' arterial ring forming a fistula that drains into the pulmonary artery through an aneurysm.
Hikaru Hagiwara, Akinori Takahashi, Hirokazu Komoriyama, Yoshiya Kato, Toshihisa Anzai
European heart journal. Cardiovascular Imaging, 2023年04月04日, ［国際誌］
英語, 研究論文（学術雑誌）

静脈血流速度波形分析に基づく右房圧推定に肝静脈と上大静脈のどちらが優れるか　　　　　　　　　　　　　　　
村山 迪史, 加賀 早苗, 境田 ひな, 小野田 愛梨, 中鉢 雅大, 西野 久雄, 横山 しのぶ, 石坂 傑, 岩野 弘幸, 安斉 俊久
超音波医学, 50, Suppl., S740, S740, (公社)日本超音波医学会, 2023年04月
日本語

静脈血流速度波形分析に基づく右房圧推定に肝静脈と上大静脈のどちらが優れるか　　　　　　　　　　　　　　　
村山 迪史, 加賀 早苗, 境田 ひな, 小野田 愛梨, 中鉢 雅大, 西野 久雄, 横山 しのぶ, 石坂 傑, 岩野 弘幸, 安斉 俊久
超音波医学, 50, Suppl., S740, S740, (公社)日本超音波医学会, 2023年04月
日本語

Multimodal Imaging of Constrictive Pericarditis Induced by Long-term Pergolide Treatment for Parkinson's Disease.
Hiroyuki Aoyagi, Shingo Tsujinaga, Yuki Takahashi, Seiichiro Naito, Takuma Sato, Takuya Otsuka, Yoji Tamaki, Ko Motoi, Suguru Ishizaka, Yasuyuki Chiba, Kiwamu Kamiya, Hiroyuki Iwano, Toshiyuki Nagai, Satoru Wakasa, Toshihisa Anzai
Internal medicine (Tokyo, Japan), 2023年03月31日, ［国内誌］
英語, 研究論文（学術雑誌）, We herein report the first case of constrictive pericarditis (CP) induced by long-term pergolide treatment for Parkinson's disease that was assessed using multimodal imaging in a 72-year-old patient with leg edema and dyspnea. The patient was correctly diagnosed with CP using multimodal imaging and successfully treated with pericardiectomy. The treatment history of Parkinson's disease and pathological findings of the removed pericardium suggested that long-term pergolide was the cause of CP. Properly recognizing pergolide as the cause of CP and accurately diagnosing CP using multimodal imaging may contribute to the early detection and treatment of pergolide-induced CP.

Impact of COVID-19 pandemic on emergency medical system and management strategies in patients with acute coronary syndrome.
Kohei Saiin, Sakae Takenaka, Toshiyuki Nagai, Akinori Takahashi, Yoshifumi Mizuguchi, Takao Konishi, Toshihisa Anzai, Daisuke Hotta, Mitsunori Kamigaki, Seiji Yamazaki, Tsutomu Fujita, Takehiro Yamashita, Kandoh Kawahatsu, Takashi Suzuki, Yoichi Nozaki, Taku Sakurada, Takashi Takenaka, Yasumi Igarashi, Takao Makino
Scientific reports, 13, 1, 5120, 5120, 2023年03月29日, ［国際誌］
英語, 研究論文（学術雑誌）, The global coronavirus disease-2019 (COVID-19) pandemic is associated with reduced rate of percutaneous coronary intervention (PCI). However, there were a few data showing how emergency medical system (EMS) and management strategies for acute coronary syndrome (ACS) changed during the pandemic. We sought to clarify changes on characteristics, treatments, and in-hospital mortality of patients with ACS transported via EMS between pre- and post-pandemic. We examined consecutive 656 patients with ACS admitted to Sapporo City ACS Network Hospitals between June 2018 and November 2021. The patients were divided into pre- and post-pandemic groups. The number of ACS hospitalizations declined significantly during the pandemic (proportional reduction 66%, coefficient -0.34, 95% CI -0.50 to -0.18, p < 0.001). The median time from an EMS call to hospital was significantly longer in post-pandemic group than in pre-pandemic group (32 [26-39] vs. 29 [25-36] min, p = 0.008). There were no significant differences in the proportion of patients with ACS receiving PCI, and in-hospital mortality between the groups. The COVID-19 pandemic had a significant impact on EMS and management in patients with ACS. Although a significant decline was observed in ACS hospitalizations, the proportion of patients with ACS receiving emergency PCI remained during the pandemic.

Impact of right ventricular stiffness on discordance between hemodynamic parameter and regurgitant volume in patients with pulmonary regurgitation.
Ko Motoi, Hiroyuki Iwano, Satonori Tsuneta, Suguru Ishizaka, Yoji Tamaki, Hiroyuki Aoyagi, Kosuke Nakamura, Michito Murayama, Masahiro Nakabachi, Shinobu Yokoyama, Hisao Nishino, Sanae Kaga, Atsuhito Takeda, Toshihisa Anzai
The international journal of cardiovascular imaging, 39, 6, 1133, 1142, 2023年03月17日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Accurate detection of significant pulmonary regurgitation (PR) is critical in management of patients after right ventricular (RV) outflow reconstruction in Tetralogy of Fallot (TOF) patients, because of its influence on adverse outcomes. Although pressure half time (PHT) of PR velocity is one of the widely used echocardiographic markers of the severity, shortened PHT is suggested to be seen in conditions with increased RV stiffness with mild PR. However, little has been reported about the exact characteristics of patients showing discrepancy between PHT and PR volume in this population. METHODS: Echocardiography and cardiac magnetic resonance imaging (MRI) were performed in 74 TOF patients after right ventricular outflow tract (RVOT) reconstruction [32 ± 10 years old]. PHT was measured from the continuous Doppler PR flow velocity profile and PHT < 100 ms was used as a sign of significant PR. Presence of end-diastolic RVOT forward flow was defined as RV restrictive physiology. By using phase-contrast MRI, forward and regurgitant volumes through the RVOT were measured and regurgitation fraction was calculated. Significant PR was defined as regurgitant fraction ≥ 25%. RESULTS: Significant PR was observed in 54 of 74 patients. While PHT < 100 ms well predicted significant PR with sensitivity of 96%, specificity of 52%, and c-index of 0.72, 10 patients showed shortened PHT despite regurgitant fraction < 25% (discordant group). Tricuspid annular plane systolic excursion and left ventricular (LV) ejection fraction were comparable between discordant group and patients showing PHT < 100 ms and regurgitant fraction ≥ 25% (concordant group). However, discordant group showed significantly smaller mid RV diameter (30.7 ± 4.5 vs. 39.2 ± 7.3 mm, P < 0.001) and higher prevalence of restrictive physiology (100% vs. 42%, P < 0.01) than concordant group. When mid RV diameter ≥ 32 mm and presence of restrictive physiology were added to PHT, the predictive value was significantly improved (sensitivity: 81%, specificity: 90%, and c-index: 0.89, P < 0.001 vs. PHT alone by multivariable logistic regression model). CONCLUSION: Patients with increased RV stiffness and non-enlarged right ventricle showed short PHT despite mild PR. Although it has been expected, this was the first study to demonstrate the exact characteristics of patients showing discrepancy between PHT and PR volume in TOF patients after RVOT reconstruction.

JCS 2023 Guideline on the Diagnosis and Treatment of Myocarditis.
Toshiyuki Nagai, Takayuki Inomata, Takashi Kohno, Takuma Sato, Atsushi Tada, Toru Kubo, Kazufumi Nakamura, Noriko Oyama-Manabe, Yoshihiko Ikeda, Takeo Fujino, Yasuhide Asaumi, Takahiro Okumura, Toshiyuki Yano, Kazuko Tajiri, Hiroyuki Matsuura, Yuichi Baba, Haruki Sunami, Shingo Tsujinaga, Yasutoshi Ota, Keiko Ohta-Ogo, Yusuke Ishikawa, Hideo Matama, Nobutaka Nagano, Kimi Sato, Kazushi Yasuda, Yasushi Sakata, Koichiro Kuwahara, Tohru Minamino, Minoru Ono, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 87, 5, 674, 754, 2023年03月10日, ［国内誌］
英語, 研究論文（学術雑誌）

日本人高齢患者における植え込み型除細動器の有用性(Benefit of Implantable Cardioverter-defibrillator in Elderly Japanese Patients)　　　　　　　　　　　　　　　
甲谷 次郎, 天満 太郎, 立田 大志郎, 西野 広太郎, 夏井 宏征, 門坂 崇秀, 小泉 拓也, 甲谷 太郎, 中尾 元基, 渡邉 昌也, 安斉 俊久
日本循環器学会学術集会抄録集, 87回, PJ113, 4, (一社)日本循環器学会, 2023年03月
英語

大動脈弁狭窄症患者に対する左室充満圧の心エコースコアリングシステムの適用(Application of an Echocardiographic Scoring System of Left Ventricular Filling Pressure for Patients with Aortic Stenosis)　　　　　　　　　　　　　　　
青柳 裕之, 岩野 弘幸, 後藤 真奈, 鈴木 ゆき乃, 村山 迪史, 横山 しのぶ, 西野 久雄, 中鉢 雅大, 中村 公亮, 玉置 陽生, 本居 昂, 石坂 傑, 加賀 早苗, 神谷 究, 永井 利幸, 安斉 俊久
日本循環器学会学術集会抄録集, 87回, PJ065, 2, (一社)日本循環器学会, 2023年03月
英語

心不全患者における複数の超音波指標を組み合わせたうっ血肝診断モデルの確立　　　　　　　　　　　　　　　
小野田 愛梨, 村山 迪史, 加賀 早苗, 中鉢 雅大, 横山 しのぶ, 西野 久雄, 石坂 傑, 本居 昴, 青柳 裕之, 玉置 陽生, 中村 公亮, 岩野 弘幸, 安斉 俊久
日本循環器学会学術集会抄録集, 87回, CO1, 3, (一社)日本循環器学会, 2023年03月
日本語

Optogenetic termination of atrial tachyarrhythmias by brief pulsed light stimulation
Motoki Nakao, Masaya Watanabe, Lucile Miquerol, Hiroyuki Natsui, Takuya Koizumi, Takahide Kadosaka, Taro Koya, Hikaru Hagiwara, Rui Kamada, Taro Temma, Antoine A.F. de Vries, Toshihisa Anzai
Journal of Molecular and Cellular Cardiology, Elsevier BV, 2023年03月
研究論文（学術雑誌）

Impact of right ventricular reserve on exercise capacity and quality of life in patients with left ventricular assist device.
Sakae Takenaka, Takuma Sato, Toshiyuki Nagai, Kazunori Omote, Yuta Kobayashi, Kiwamu Kamiya, Takao Konishi, Atsushi Tada, Yoshifumi Mizuguchi, Yuki Takahashi, Seiichiro Naito, Kohei Saiin, Suguru Ishizaka, Satoru Wakasa, Toshihisa Anzai
American journal of physiology. Heart and circulatory physiology, 324, 3, H355-H363, 2023年03月01日, ［国際誌］
英語, 研究論文（学術雑誌）, Although measuring right ventricular (RV) function during exercise is more informative than assessing it at rest, the relationship between RV reserve function, exercise capacity, and health-related quality of life (HRQoL) in patients with left ventricular assist devices (LVAD) remains unresolved. We aimed to investigate whether RV reserve assessed by the change in RV stroke work index (RVSWI) during exercise is correlated with exercise capacity and HRQoL in patients with LVAD. We prospectively assessed 24 consecutive patients with LVAD who underwent invasive right heart catheterization in the supine position. Exercise capacity and HRQoL were assessed using the 6-min walk distance (6 MWD) and peak oxygen consumption (V̇o2) in cardiopulmonary exercise testing, and the EuroQol visual analog scale (EQ-VAS), respectively. The patients were divided into two groups according to the median ΔRVSWI (change from rest to peak exercise). Patients with lower ΔRVSWI had significantly lower changes in cardiac index and absolute value of RV dP/dt than those with higher ΔRVSWI. The ΔRVSWI was positively correlated with 6 MWD (r = 0.59, P = 0.003) and peak V̇o2 (r = 0.56, P = 0.006). In addition, ΔRVSWI was positively correlated with the EQ-VAS (r = 0.44, P = 0.030). In contrast, there was no significant correlation between RVSWI at rest and 6 MWD (r = -0.34, P = 0.88), peak V̇o2 (r = 0.074, P = 0.74), or EQ-VAS (r = 0.127, P = 0.56). Our findings suggest that the assessment of RV reserve function is useful for risk stratification in patients with LVAD.NEW & NOTEWORTHY The change in right ventricular stroke work index (RVSWI) during exercise, not RVSWI at rest, was associated with exercise capacity and HRQoL. Our findings suggest that the assessment of change in RVSWI during exercise as a surrogate of RV reserve function may aid in risk stratification of patients with LVAD.

Prognostic Significance of Peak Workload-to-Weight Ratio by Cardiopulmonary Exercise Testing in Chronic Heart Failure.
Yutaro Yasui, Kosuke Nakamura, Kazunori Omote, Suguru Ishizaka, Sakae Takenaka, Yoshifumi Mizuguchi, Yui Shimono, Sho Kazui, Yuki Takahashi, Kohei Saiin, Seiichiro Naito, Atsushi Tada, Yuta Kobayashi, Takuma Sato, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
The American journal of cardiology, 193, 37, 43, 2023年03月01日, ［国際誌］
英語, 研究論文（学術雑誌）, The prognostic impact of peak workload-to-weight ratio (PWR) during cardiopulmonary exercise testing (CPET) and its determinants in patients with chronic heart failure (CHF) are not well understood. Consecutive 514 patients with CHF referred for CPET at the Hokkaido University Hospital between 2013 and 2018 were identified. The primary outcome was a composite of hospitalization because of worsening heart failure and death. PWR was calculated as peak workload normalized to body weight (W/kg) by CPET. Patients with low PWR (cut-off median 1.38 [W/kg], n = 257) were older and more anemic than those with high PWR (n = 257). In CPET, patients with low PWR displayed reduced peak oxygen consumption and impaired ventilatory efficiency compared with those with high PWR, whereas the peak respiratory exchange ratio was not significantly different between the 2 groups. There were 89 patients with events over a median follow-up period of 3.3 (interquartile range 0.8 to 5.5) years. The incidence of composite events was significantly higher in patients with low PWR than in those with high PWR (log-rank p <0.0001). In the multivariable Cox regression, lower PWR was associated with adverse events (hazard ratio 0.31, 95% confidence interval 0.13 to 0.73, p = 0.008). Low hemoglobin concentration was strongly related to impaired PWR (β coefficient = 0.43, per 1 g/100 ml increased, p <0.0001). In conclusion, PWR was associated with worse clinical outcomes, where blood hemoglobin was strongly related to PWR. Further study is required to identify therapies targeting peak workload achievements in exercise stress tests to improve the outcome in patients with CHF.

Empagliflozin suppresses mitochondrial reactive oxygen species generation and mitigates the inducibility of atrial fibrillation in diabetic rats
Takuya Koizumi, Masaya Watanabe, Takashi Yokota, Masumi Tsuda, Haruka Handa, Jiro Koya, Kotaro Nishino, Daishiro Tatsuta, Hiroyuki Natsui, Takahide Kadosaka, Taro Koya, Motoki Nakao, Hikaru Hagiwara, Rui Kamada, Taro Temma, Shinya Tanaka, Toshihisa Anzai
Frontiers in Cardiovascular Medicine, 10, Frontiers Media SA, 2023年02月06日
研究論文（学術雑誌）, Introduction

Recent studies have demonstrated that sodium-glucose co-transporter-2 inhibitors (SGLT2-i) reduce the risk of atrial fibrillation (AF) in patients with diabetes mellitus (DM), in which oxidative stress due to increased reactive oxygen species (ROS) contributes to the pathogenesis of AF. We aimed to further investigate this, and examine whether the SGLT2-i empagliflozin suppresses mitochondrial-ROS generation and mitigates fibrosis.

Methods

A high-fat diet and low-dose streptozotocin treatment were used to induce type-2 DM (T2DM) in Sprague-Dawley rats. The rats were randomly divided into three groups: control, DM, and DM treated with empagliflozin (30 mg/kg/day) for 8 weeks. The mitochondrial respiratory capacity and ROS generation in the atrial myocardium were measured using a high-resolution respirometer. Oxidative stress markers and protein expression related to mitochondrial biogenesis and dynamics as well as the mitochondrial morphology were examined in the atrial tissue. Additionally, mitochondrial function was examined in H9c2 cardiomyoblasts. Atrial tachyarrhythmia (ATA) inducibility, interatrial conduction time (IACT), and fibrosis were also measured.

Results

Inducibility of ATA, fibrosis, and IACT were increased in rats with DM when compared to controls, all of which were restored by empagliflozin treatment. In addition, the rats with DM had increased mitochondrial-ROS with an impaired complex I-linked oxidative phosphorylation capacity. Importantly, empagliflozin seemed to ameliorate these impairments in mitochondrial function. Furthermore, empagliflozin reversed the decrease in phosphorylated AMPK expression and altered protein levels related to mitochondrial biogenesis and dynamics, and increased mitochondrial content. Empagliflozin also improved mitochondrial function in H9c2 cells cultured with high glucose medium.

Discussion

These data suggest that empagliflozin has a cardioprotective effect, at least in part, by reducing mitochondrial ROS generation through AMPK signaling pathways in the atrium of diabetic rats. This suggests that empagliflozin might suppress the development of AF in T2DM.

Fragmented QRS on 12-lead electrocardiogram predicts long-term prognosis in patients with cardiac sarcoidosis.
Hikaru Hagiwara, Masaya Watanabe, Takahide Kadosaka, Takuya Koizumi, Yuta Kobayashi, Taro Koya, Motoki Nakao, Satonori Tsuneta, Yoshiya Kato, Hirokazu Komoriyama, Rui Kamada, Toshiyuki Nagai, Kohsuke Kudo, Toshihisa Anzai
Heart and vessels, 2023年01月13日, ［国内誌］
英語, 研究論文（学術雑誌）, Fragmented QRS (fQRS) on a 12-lead electrocardiogram is a known marker of fatal arrhythmias or cardiac adverse events in ischemic and non-ischemic cardiomyopathy patients. Nonetheless, the association between fQRS and clinical outcomes in patients with cardiac sarcoidosis (CS) remains unclear. Herein, we investigated whether fQRS is associated with long-term clinical outcomes in CS patients. A total of 78 patients who received immunosuppressive therapy (IST) for clinically diagnosed CS were retrospectively examined. Patients were classified into two groups according to the presence (n = 19) or absence (n = 59) of fQRS on electrocardiogram before IST. The primary outcome was the composite event of all-cause death, ventricular tachyarrhythmias (VTs), and hospitalization for heart failure. Results of late gadolinium enhancement on cardiac magnetic resonance imaging were also analyzed. During a median follow-up period of 3.7 years (interquartile range: 1.6-6.2 years), the primary outcome occurred more frequently in patients with fQRS than in those without (47% vs. 13%, log-rank p = 0.002). Multivariable Cox regression analyses showed that fQRS was an independent determinant of the primary outcome. The incidence of VTs, within 12 months of IST initiation, was comparable between the two groups; however, late-onset VTs, defined as those occurring ≥ 12 months after IST initiation, occurred more frequently in the fQRS group (21% vs. 2%, log-rank p = 0.002). The scar zone and scar border zone were greater in patients with fQRS than in those without it. In conclusion, our analysis suggests that fQRS is an independent predictor of adverse events, particularly late-onset VTs, in patients with CS.

Empagliflozin attenuates arrhythmogenesis in diabetic cardiomyopathy by normalizing intracellular Ca2+ handling in ventricular cardiomyocytes.
Takahide Kadosaka, Masaya Watanabe, Hiroyuki Natsui, Takuya Koizumi, Motoki Nakao, Taro Koya, Hikaru Hagiwara, Rui Kamada, Taro Temma, Fuyuki Karube, Fumino Fujiyama, Toshihisa Anzai
American journal of physiology. Heart and circulatory physiology, 324, 3, H341-H354, 2023年01月06日, ［国際誌］
英語, 研究論文（学術雑誌）, Diabetic cardiomyopathy has been reported to increase the risk of fatal ventricular arrhythmia. The beneficial effects of the selective sodium-glucose co-transporter 2 inhibitor have not been fully examined in the context of anti-arrhythmic therapy, especially its direct cardioprotective effects despite the negligible SGLT2 expression in cardiomyocytes. We aimed to examine the anti-arrhythmic effects of empagliflozin (EMPA) treatment on diabetic cardiomyocytes, with a special focus on Ca2+ handling. We conducted echocardiography and hemodynamic studies and studied electrophysiology, Ca2+ handling, and protein expression in C57BLKS/J-leprdb/db mice (db/db mice) and their non-diabetic lean heterozygous Leprdb/+ littermates (db/+ mice). Preserved systolic function with diastolic dysfunction was observed in 16-week-old db/db mice. During arrhythmia induction, db/db mice had significantly increased premature ventricular complexes (PVCs) than controls, which was attenuated by EMPA. In protein expression analyses, calmodulin-dependent protein kinase II (CaMKII) Thr287 autophosphorylation and CaMKII-dependent RyR2 phosphorylation (S2814) were significantly increased in diabetic hearts, which were inhibited by EMPA. Additionally, global O-GlcNAcylation significantly decreased with EMPA treatment. Furthermore, EMPA significantly inhibited ventricular cardiomyocyte glucose uptake. Diabetic cardiomyocytes exhibited increased spontaneous Ca2+ events and decreased sarcoplasmic reticulum (SR) Ca2+ content, along with impaired Ca2+ transient, all of which normalized with EMPA treatment. Notably, most EMPA-induced improvements in Ca2+ handling were abolished by the addition of an O-GlcNAcase (OGA) inhibitor. In conclusion, EMPA attenuated ventricular arrhythmia inducibility by normalizing the intracellular Ca2+ handling, and we speculated that this effect was, at least partly, due to the inhibition of O-GlcNAcylation via the suppression of glucose uptake into cardiomyocytes.

Plans for the Circulation Journal.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 88, 1, 1, 1, 2023年, ［国内誌］
英語, 研究論文（学術雑誌）

Association of coronary plaque morphology with inflammatory biomarkers and target lesion revascularization in patients with chronic coronary syndrome: an optical coherence tomography study.
Kohei Saiin, Takao Konishi, Sho Kazui, Yutaro Yasui, Yuki Takahashi, Seiichiro Naito, Sakae Takenaka, Yoshifumi Mizuguchi, Atsushi Tada, Yuta Kobayashi, Yoshiya Kato, Kazunori Omote, Takuma Sato, Kiwamu Kamiya, Toshiyuki Nagai, Shinya Tanaka, Toshihisa Anzai
American journal of cardiovascular disease, 13, 5, 309, 319, 2023年, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The characteristics of high-risk coronary atherosclerosis evaluated using optical coherence tomography (OCT) can have a prognostic role. Inflammatory biomarkers may be related to the severity of coronary artery disease. This study investigated the association of high-risk morphological features of coronary plaques on OCT with circulating levels of inflammatory biomarkers and target lesion revascularization (TLR). MATERIALS AND METHODS: We prospectively analyzed the data of 30 consecutive patients with chronic coronary syndrome who underwent percutaneous coronary intervention (PCI) using OCT. The levels of interleukin-6, tumor necrosis factor-alpha, high-sensitivity C-reactive protein, pentraxin 3, vascular endothelial growth factor, and monocyte chemoattractant protein-1 (MCP-1) were measured in plasma samples. Coronary plaque characteristics were scored quantitatively in the form of coronary plaque risk score (CPRS). The estimated high-risk plaque characteristics for TLR were plaque rupture, plaque erosion, calcified nodule, lipid-rich plaque, thin-cap fibroatheroma, cholesterol crystals, macrophage infiltration, microchannels, calcification angle >90°, and microcalcifications. Each high-risk feature carries 1 point. Patients were defined as having a low CPRS (CPRS ≤3) or a high CPRS (CPRS ≥4). RESULTS: The primary outcome was TLR. TLR occurred in 6 (20%) patients within 15 months of PCI. High CPRS on OCT was directly correlated with TLR (P=0.029). In logistic regression analysis, CPRS was associated with TLR (odds ratio, 10.0; 95% confidence interval, 1.34-74.5). Serum MCP-1 level was significantly correlated with the CPRS (P=0.020). CONCLUSIONS: In patients with chronic coronary syndrome, CPRS may be a surrogate predictor of TLR. Serum MCP-1 may aid in the detection of high-risk coronary atherosclerosis.

Closed VSDを合併した右室二腔症の手術症例　　　　　　　　　　　　　　　
齋藤 翔太, 石坂 傑, 下野 裕依, 甲谷 太郎, 神谷 究, 阿部 慎司, 加藤 伸康, 永井 利幸, 若狭 哲, 安斉 俊久
日本成人先天性心疾患学会雑誌, 12, 1, 200, 200, (一社)日本成人先天性心疾患学会, 2023年01月
日本語

心エコー法による右房圧推定精度の検証：ガイドラインに基づく副次的指標の再考
村山 迪史, 加賀 早苗, 小野田 愛梨, 岡田 一範, 中鉢 雅大, 横山 しのぶ, 西野 久雄, 青柳 裕之, 玉置 陽生, 本居 昂, 石坂 傑, 岩野 弘幸, 永井 利幸, 辻野 一三, 安斉 俊久
超音波検査技術, advpub, 一般社団法人 日本超音波検査学会, 2023年
日本語, 目的：アメリカ心エコー図学会のガイドラインには，下大静脈計測に基づく右房圧推定の精度を補完するものとして，拘束型の右室流入血流速波形，拡張早期の右室流入血流速度と三尖弁輪運動速度との比，肝静脈血流速波形のsystolic filling fractionが示されている．本研究では，これらの副次的指標が右房圧上昇の予測能を改善させるかを明らかにするとともに，右房面積計測の付加的価値を検討する．

対象と方法：心疾患患者128例において右心カテーテル検査で平均右房圧を計測し，≧8 mmHgを上昇とした．下大静脈の径とsniffによる虚脱率から，推定右房圧を3, 8，15 mmHgに分類した（モデル1）．右室流入血流速波形の拘束型パターン，拡張早期の右室流入血流速度と三尖弁輪運動速度との比，systolic filling fractionを評価に加えて，推定右房圧の再分類を行った（モデル2）．右房の最小と最大面積および容積を計測し，それぞれのexpansion indexを算出した．

結果：右房圧の上昇を29例に認めた．ロジスティック回帰分析で，モデル1における推定右房圧とsystolic filling fractionは，平均右房圧上昇と有意に関連した（ともにp＜0.05）．拘束型パターンを呈した例はなく，拡張早期の右室流入血流速度と三尖弁輪運動速度との比は右房圧上昇と関連しなかった．右房の形態・機能指標は，いずれも右房圧上昇と関連し（すべてp＜0.05），最小右房面積が最も強く関連した（右室面積変化率で補正後のオッズ比：10.64, p＜0.01）．尤度比検定では，モデル2の右房圧上昇の予測能はモデル1と同等であったが，systolic filling fractionと最小右房面積を用いた新しいモデルは，モデル1より良好に右房圧上昇を予測できた．

結論：従来の副次的指標を用いた再分類により右房圧上昇の予測能は改善しなかった．肝静脈血流速波形のsystolic filling fractionと最小右房面積を右房圧の評価に加えると，右房圧上昇の予測能は改善した．

Applicability of new proposed criteria for iron deficiency in Japanese patients with heart failure.
Atsushi Tada, Toshiyuki Nagai, Taro Koya, Motoki Nakao, Suguru Ishizaka, Yoshifumi Mizuguchi, Hiroyuki Aoyagi, Shogo Imagawa, Yusuke Tokuda, Masashige Takahashi, Yoshiya Kato, Masaharu Machida, Kenichi Matsutani, Takahiko Saito, Toshihisa Anzai
ESC heart failure, 2022年12月10日, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF). A recent study showed that ID defined by the current guideline criteria was not associated with worse clinical outcomes, and new ID criteria was proposed in patients with HF. However, the external applicability of the new proposed criteria is unclear. We sought to investigate the applicability of the proposed ID criteria in Japanese patients with HF. METHODS AND RESULTS: We prospectively examined 763 patients with chronic HF from a Japanese multicentre registry. The proposed ID criteria were transferrin saturation (TSAT) < 20% and serum iron ≤13 mmol/L and the guideline ID criteria were serum ferritin <100 ng/mL or, when ferritin was 100-299 ng/mL, TSAT <20%. Among all patients (456 male, mean age 71 ± 13 years), 213 (28%) and 444 (58%) met the proposed and guideline ID criteria, respectively. During a median follow-up period of 436 days (interquartile range 297-565), the primary outcome of all-cause mortality occurred in 56 (7%) patients. There was no significant difference in the primary outcome between the patients with and without guideline ID criteria (P = 0.32), whereas patients with serum iron ≤10 μmol/L showed higher mortality (P = 0.002). In multivariable Cox regressions, the proposed ID criteria, but not guideline ID criteria, were independently associated with the risk of all-cause mortality (HR 2.01, 95% CI 1.16-3.51 and HR 1.32, 95% CI 0.76-2.28, respectively), even after adjustment for covariates. CONCLUSIONS: When defined by the proposed criteria and not the guideline criteria, ID was associated with higher mortality in patients with chronic HF, suggesting that the proposed ID criteria is applicable to the Japanese population.

Associations of right ventricular pulsatile load and cardiac power output to clinical outcomes in heart failure: Difference from systemic circulation.
Yasuyuki Chiba, Hiroyuki Iwano, Hiroyuki Aoyagi, Yoji Tamaki, Ko Motoi, Suguru Ishizaka, Michito Murayama, Shinobu Yokoyama, Masahiro Nakabachi, Hisao Nishino, Sanae Kaga, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
Journal of cardiology, 81, 4, 404, 412, 2022年12月08日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Although left ventricular (LV) cardiac power output (CPO) is a powerful prognostic indicator in heart failure (HF), the significance of right ventricular (RV) CPO is unknown. In contrast, RV pulsatile load is a key prognostic marker in HF. We investigated the impact of RV-CPO and pulsatile load on cardiac outcome and the prognostic performance of the combined systemic and pulmonary circulation parameters in HF. METHODS: Right heart catheterization and echocardiography were performed in 231 HF patients (62 ± 16 years, LV ejection fraction 42 ± 18 %). Invasive and noninvasive CPOs were calculated from mean systemic or pulmonary arterial pressure and cardiac output. LV-CPO was then normalized to LV mass (LV-P/M). Pulmonary arterial capacitance and the ratio of acceleration time to ejection time (AcT/ET) of RV outflow were used as parameters of RV pulsatile load. The primary endpoints, defined as a composite of cardiac death, HF hospitalization, ventricular arrythmia, and LVAD implantation after the examination, were recorded. RESULTS: Noninvasive CPOs were moderately correlated with invasive ones (LV: ρ = 0.787, RV: ρ = 0.568, and p < 0.001 for both). During a median follow-up period of 441 days, 57 cardiovascular events occurred. Lower LV-P/M and higher RV pulsatile load were associated with cardiovascular events; however, RV-CPO was not associated with the outcome. Echocardiographic LV-P/M and AcT/ET showed significant incremental prognostic value over the clinical parameters. CONCLUSIONS: RV pulsatile load assessed by AcT/ET may be a predictor of clinical events in HF patients. The combination of echocardiographic LV-P/M and AcT/ET could be a novel noninvasive prognostic indicator in HF patients.

Canagliflozin independently reduced plasma volume from conventional diuretics in patients with type 2 diabetes and chronic heart failure: a subanalysis of the CANDLE trial
Kazuki Shiina, Hirofumi Tomiyama, Atsushi Tanaka, Takumi Imai, Itaru Hisauchi, Isao Taguchi, Akira Sezai, Shigeru Toyoda, Kaoru Dohi, Haruo Kamiya, Keisuke Kida, Toshihisa Anzai, Taishiro Chikamori, Koichi Node, Masayoshi Ajioka, Junya Ako, Rie Amano, Mitsutoshi Asai, Kazuo Eguchi, Kenichi Eshima, Shinya Fujiki, Masashi Fujita, Shungo Hikoso, Shinya Hiramitsu, Satoshi Hoshide, Akihiko Hoshino, Yuki Ikeda, Yumi Ikehara, Takayuki Inomata, Teruo Inoue, Katsuhisa Ishii, Nobukazu Ishizaka, Masaaki Ito, Noriaki Iwahashi, Katsuomi Iwakura, Toshiaki Kadokami, Takahiro Kanbara, Yumiko Kanzaki, Ken Kashimura, Kazuo Kimura, Satoru Kishi, Shuichi Kitada, Masafumi Kitakaze, Akihiro Kiyosue, Kazuhisa Kodama, Takayuki Kojima, Takumi Kondo, Yoshiaki Kubota, Kenya Kusunose, Noritaka Machii, Kazuo Matsunaga, Yasuto Matsuo, Yashushi Matsuzawa, Takeshi Mikami, Toru Minamino, Toyoaki Murohara, Takahiro Nagai, Yasuko Nagano, Masashi Nagumo, Ikuko Nakamura, Katsunori Nakamura, Daisaku Nakatani, Mamoru Nanasato, Hiriyuki Naruse, Masami Nishino, Shinichi Niwano, Mitsutoshi Oguri, Nobuyuki Ohte, Masayoshi Oikawa, Takahiro Okumura, Masanori Okumura, Katsuya Onishi, Jun-ichi Oyama, Yukio Ozaki, Kan Saito, Tomohiro Sakamoto, Yasushi Sakata, Masashi Sakuma, Masataka Sata, Hisakuni Sekino, Michio Shimabukuro, Wataru Shimizu, Makoto Suzuki, Kunihiro Suzuki, Hiroyuki Takahama, Naohiko Takahashi, Yasuchika Takeishi, Shunsuke Tamaki, Akihiro Tanaka, Syuzo Tanimoto, Hiroki Teragawa, Tomoyuki Tobushi, Takafumi Toita, Kotaro Tokuda, Hiroyuki Tsutsui, Shinichiro Ueda, Hiroki Uehara, Masaaki Uematsu, Hirotaka Watada, Kazuyuki Yahagi, Takahisa Yamada, Hirotsugu Yamada, Tatsuya Yoshida, Akiomi Yoshihisa
Hypertension Research, Springer Science and Business Media LLC, 2022年11月15日
研究論文（学術雑誌）

Features and Outcomes of Histologically Proven Myocarditis With Fulminant Presentation
Koshiro Kanaoka, Kenji Onoue, Satoshi Terasaki, Tomoya Nakano, Michikazu Nakai, Yoko Sumita, Kinta Hatakeyama, Fumio Terasaki, Rika Kawakami, Yoshitaka Iwanaga, Yoshihiro Miyamoto, Yoshihiko Saito, Satoshi Yuda, Masaya Tanno, Toru Takahashi, Hisashi Yokoshiki, Masahiro Toba, Toshihisa Anzai, Toshiyuki Nagai, Takuma Sato, Takashi Takenaka, Seiji Yamazaki, Yuki Katagiri, Toshiharu Takeuchi, Kazuya Sugitatsu, Shigeo Kakinoki, Tomoaki Matsumoto, Kazushi Urasawa, Michinao Tan, Ichizo Tsujino, Mitsunori Kamigaki, Hirofumi Tomita, Kenji Hanada, Motoi Kushibiki, Akihiro Nakamura, Yoshihiro Morino, Takahito Nasu, Satoshi Yasuda, Hideaki Suzuki, Kaoru Iwabuchi, Kanako Tsuji, Shigeto Namiuchi, Tatsuya Komaru, Masahiro Yagi, Shoko Uematsu, Toshiaki Takahashi, Satoru Takeda, Toru Nakanishi, Masafumi Watanabe, Masahiro Wanezaki, Motoyuki Matsui, Shigeo Sugawara, Yasuchika Takeishi, Masayoshi Oikawa, Nobuo Komatsu, Satoshi Suzuki, Hiroshi Okamoto, Noriyuki Takeyasu, Daiki Akiyama, Yutaka Eki, Tsunekazu Kakuta, Tomoyo Sugiyama, Tomomi Koizumi, Koji Ueno, Kazuomi Kario, Mizuri Taki, Yuri Matsumoto, Takanori Yasu, Osamu Nishioka, Shigeto Naito, Makoto Murata, Shoichi Tange, Katsumi Kaneko, Makoto Muto, Hiroshi Inagaki, Shuichi Hasegawa, Eizo Tachibana, Wataru Atsumi, Masahiro Suzuki, Toshihiro Muramatsu, Yoshihiro Yamada, Isao Taguchi, Yoshiaki Fukuda, Akihiro Matsui, Junji Kanda, Koji Hozawa, Akihiko Matsumura, Wataru Shimizu, Takeshi Yamamoto, Issei Komuro, Masaru Hatano, Takanori Ikeda, Shunsuke Kiuchi, Taishiro Chikamori, Yasuyoshi Takei, Kyoko Soejima, Toshinori Minamishima, Hiroyuki Tanaka, Shigeo Shimizu, Masashi Kasao, Tadayuki Kadohira, Tohru Minamino, Kazunori Shimada, Hiroshi Iwata, Yukihiko Momiyama, Takashi Ashikaga, Toshihiro Nozato, Yasumasa Fujiwara, Kenji Inoue, Tetsuo Sasano, Junji Matsuda, Yasuhiro Ishii, Yuichi Ono, Kengo Tanabe, Yu Horiuchi, Toshiro Shinke, Yusuke Kodama, Masao Moroi, Yoshiyuki Yazaki, Taisuke Mizumura, Hiroshi Ohta, Yoshihiro Akashi, Nozomi Kotoku, Yuji Ikari, Mitsunori Maruyama, Yasuhiro Sato, Koichi Tamura, Masaaki Konishi, Hiroshi Suzuki, Mio Ebato, Kazuki Fukui, Kazuhiko Yumoto, Takamasa Iwasawa, Takeshi Kashimura, Kazuyoshi Takahashi, Yoshinobu Okada, Bunji Kaku, Kazuo Usuda, Michiro Maruyama, Tomoki Kameyama, Toshinori Higashikata, Akihiko Hodatsu, Kazuo Osato, Yoji Nagata, Koji Maeno, Kazuo Satake, Takao Sawanobori, Noboru Watanabe, Koichiro Kuwahara, Hirohiko Motoki, Hiroshi Kitabayashi, Kyuhachi Otagiri, Tsunesuke Kono, Daisuke Yamagishi, Yoshikazu Yazaki, Toshiyuki Noda, Itsuro Morishima, Naoki Watanabe, Shinichiro Tanaka, Tomoya Onodera, Ryuzo Nawada, Akinori Watanabe, Masaki Matsunaga, Satoru Suwa, Hiroshi Sakamoto, Hiroki Sakamoto, Takeshi Aoyama, Norio Kanamori, Masahiro Muto, Yuichiro Maekawa, Hayato Ohtani, Yukio Ozaki, Kenshin Naruse, Kenji Takemoto, Haruo Kamiya, Takeshi Suzuki, Yasushi Tomita, Susumu Suzuki, Ryosuke Kametani, Hidekazu Aoyama, Hiroyuki Osanai, Ken Harada, Kenji Kada, Tomoaki Saeki, Koichi Kobayashi, Yasuhiro Ogawa, Akihiro Terasawa, Masanori Shinoda, Mitsutoshi Oguri, Kiyokazu Shimizu, Akinori Sawamura, Atsushi Sugiura, Kosuke Hattori, Shinji Mokuno, Kazuhisa Kondo, Kaoru Dohi, Keishi Moriwaki, Atsunobu Kasai, Tetsuya Nakakuki, Kazuaki Kaitani, Toshikazu Jinnai, Takashi Yamamoto, Hiroyuki Kurata, Atsuyuki Wada, Masaharu Akao, Yasuhiro Hamatani, Kazuya Ishibashi, Yoshiki Akakabe, Yasuhide Asaumi, Hideo Matama, Yasushi Sakata, Hidetaka Kioka, Hiroshi Takaishi, Yoshitaka Iwanaga, Toru Takase, Mitsuo Matsuda, Fumi Sato, Shinji Hasegawa, Kenichi Ishigami, Minoru Ichikawa, Takashi Takagi, Moriaki Inoko, Masaaki Hoshiga, Shuichi Fujita, Yoshihiro Takeda, Takahiko Kawarabayashi, Hideyuki Takaoka, Kenji Nakajima, Tadashi Yuguchi, Tatsuya Kawasaki, Yukinori Shinoda, Yukihito Sato, Masaharu Ishihara, Yuki Matsumoto, Hiroya Kawai, Tomofumi Takaya, Kouki Matsuo, Toshiaki Mano, Kenichi Hirata, Eriko Hisamatsu, Nobutaka Inoue, Koichi Tamita, Naoki Mukohara, Hisashi Shimoyama, Toru Miyajima, Toshihiro Tamura, Yodo Tamaki, Megumi Suzuki, Ryoji Yokota, Manabu Horii, Kazuo Yamanaka, Hiroyuki Kawata, Yukihiro Hashimoto, Yasuki Nakada, Hitoshi Nakagawa, Tomoya Ueda, Taku Nishida, Ayako Seno, Makoto Watanabe, Takashi Akasaka, Takashi Tanimoto, Mamoru Toyofuku, Kazuhiro Yamamoto, Yoshiharu Kinugasa, Masayuki Hirai, Hiroshi Nasu, Kinya Shirota, Tsuyoshi Oda, Takefumi Oka, Kazushige Kadota, Masanobu Ohya, Hiroshi Ito, Kazufumi Nakamura, Soichiro Ogura, Soichiro Fuke, Shiro Uemura, Hiromi Matsubara, Atsuyuki Watanabe, Nobuyuki Morishima, Yasuki Kihara, Takayuki Hidaka, Hironori Ueda, Yujiro Ono, Yuji Muraoka, Miyo Hatanari, Yoshinori Miyamoto, Keigo Dote, Masaya Kato, Masafumi Yano, Mamoru Mochizuki, Yasuhiro Ikeda, Hiroyuki Fujinaga, Shinobu Hosokawa, Masataka Sata, Koji Yamaguchi, Naoko Aki, Tetsuo Minamino, Yuichi Miyake, Yuichiro Takagi, Masayuki Doi, Yoshio Taketani, Hideki Okayama, Tatsuya Shigematsu, Akinori Higaki, Osamu Yamaguchi, Shinji Inaba, Shuntaro Ikeda, Kazuya Kawai, Hiroaki Kitaoka, Toru Kubo, Kenji Ando, Kaoru Inui, Yoshihiro Fukumoto, Kensuke Hori, Takehiro Homma, Tomohiro Kawasaki, Masahiro Mohri, Masaki Fujiwara, Hiroyuki Tsutsui, Tomomi Ide, Shin-Ichiro Miura, Takashi Kuwano, Hideki Shimomura, Toshiaki Kadokami, Masanao Taba, Katsuhiro Kondou, Toru Kubota, Daisuke Nagatomo, Yasushi Mukai, Ryuichi Matsukawa, Hideki Tashiro, Mitsuhiro Shimomura, Koji Maemura, Hiroaki Kawano, Koji Oku, Toshihiko Yamasa, Yoshihisa Kizaki, Tomohiro Sakamoto, Yudai Tamura, Teruhiko Ito, Kazuteru Fujimoto, Kenichi Tsujita, Seiji Takashio, Hirofumi Kurokawa, Naohiko Takahashi, Shotaro Saito, Masaya Arikawa, Yoshisato Shibata, Kensaku Nishihira, Toshihiro Tsuruda, Masahiro Sonoda, Nobuhiko Atsuchi, Mitsuru Ohishi, Koji Higuchi, Masaaki Miyata, Naoya Oketani, Yoshinori Akimoto, Tomohiro Asahi, Minoru Wake
Circulation, 146, 19, 1425, 1433, Ovid Technologies (Wolters Kluwer Health), 2022年11月08日, ［査読有り］
研究論文（学術雑誌）, Background:

Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence.

Methods:

This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis.

Results:

This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion (<40%) on admission, and ventricular tachycardia or fibrillation on admission day were associated with worse 90-day survival. Severe histologic damage (damaged cardiomyocytes comprising ≥50% of the total cardiomyocytes) was associated with a worse 90-day prognosis in patients with lymphocytic myocarditis.

Conclusions:

The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP.

Registration:

URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000039763.

Liver stiffness assessed by magnetic resonance elastography predicts clinical outcomes in patients with heart failure and without chronic liver disease.
Atsushi Tada, Toshiyuki Nagai, Yoshiya Kato, Kazunori Omote, Noriko Oyama-Manabe, Satonori Tsuneta, Yusuke Kudo, Mutsumi Nishida, Michikazu Nakai, Yuki Takahashi, Kohei Saiin, Seiichiro Naito, Yuta Kobayashi, Sakae Takenaka, Yoshifumi Mizuguchi, Kiwamu Kamiya, Takao Konishi, Takuma Sato, Kohsuke Kudo, Toshihisa Anzai
European radiology, 33, 3, 2062, 2074, 2022年11月03日, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: Evaluation of liver stiffness (LS) by magnetic resonance elastography (MRE) is useful for estimating right atrial pressure (RAP) in patients with heart failure (HF). However, its prognostic implications are unclear. We sought to investigate whether LS measured by MRE (LS-MRE) could predict clinical outcomes in patients with HF. METHODS: We prospectively examined 207 consecutive HF patients between April 2018 and May 2021 after excluding those with organic liver disease. All patients underwent 3.0-T MRE. The primary outcome of interest was the composite of all-cause death and hospitalisation for HF. RESULTS: During a median follow-up period of 720 (interquartile range [IQR] 434-1013) days, the primary outcome occurred in 44 patients (21%), including 15 (7%) all-cause deaths and 29 (14%) hospitalisations for HF. The patients were divided into two groups according to median LS-MRE of 2.54 (IQR 2.34-2.82) kPa. Patients with higher LS-MRE showed a higher incidence of the primary outcome compared to those with lower LS-MRE (p < 0.001). Multivariable Cox regression analyses revealed that LS-MRE value was independently associated with the risk of adverse events (hazard ratio 2.49, 95% confidence interval 1.46-4.24). In multivariable linear regression, RAP showed a stronger correlation with LS-MRE (β coefficient = 0.31, p < 0.001) compared to markers related to liver fibrosis. CONCLUSIONS: In patients without chronic liver disease and presenting with HF, elevated LS-MRE was independently associated with worse clinical outcomes. Elevated LS-MRE may be useful for risk stratification in patients with HF and without chronic liver disease. KEY POINTS: • Magnetic resonance elastography (MRE) is an emerging non-invasive imaging technique for evaluating liver stiffness (LS) which can estimate right atrial pressure. • Elevated LS-MRE, which mainly reflects liver congestion, was independently associated with worse clinical outcomes in patients with heart failure. • The assessment of LS-MRE would be useful for stratifying the risk of adverse events in heart failure patients without chronic liver disease.

抗ミトコンドリアM2抗体陽性筋炎17例の臨床的特徴
長井 梓, 永井 利幸, 矢口 裕章, 藤井 信太朗, 上床 尚, 白井 慎一, 岩田 育子, 松島 理明, 堀内 一宏, 浦 茂久, 安斉 俊久, 矢部 一郎
神経治療学, 39, 6, S263, S263, (一社)日本神経治療学会, 2022年10月
日本語

日本人心臓サルコイドーシス患者におけるAHA/ACC/HRSガイドライン植込型除細動器適応の外的妥当性　　　　　　　　　　　　　　　
竹中 秀, 小林 雄太, 永井 利幸, 加藤 喜哉, 小森山 弘和, 永野 伸卓, 神谷 究, 小西 崇夫, 佐藤 琢真, 表 和徳, 多田 篤司, 水口 賢史, 草野 研吾, 植田 初江, 安斉 俊久
日本サルコイドーシス/肉芽腫性疾患学会雑誌, 42, サプリメント号, 64, 64, 日本サルコイドーシス, 2022年10月
日本語

Pharmacological nNOS inhibition modified small conductance Ca2+-activated K+ channel without altering Ca2+ dynamics.
Taro Koya, Masaya Watanabe, Hiroyuki Natsui, Takahide Kadosaka, Takuya Koizumi, Motoki Nakao, Hikaru Hagiwara, Rui Kamada, Taro Temma, Toshihisa Anzai
American journal of physiology. Heart and circulatory physiology, 323, 5, H869-H878, 2022年09月23日, ［国際誌］
英語, 研究論文（学術雑誌）, Atrial fibrillation (AF) is associated with electrical remodeling processes that promote a substrate for the maintenance of AF. Although the small-conductance Ca2+-activated K+ (SK) channel is a key factor in atrial electrical remodeling, the mechanism of its activation remains unclear. Regional nitric oxide (NO) production by neuronal nitric oxide synthase (nNOS) is involved in atrial electrical remodeling. In this study, atrial tachyarrhythmia (ATA) induction and optical mapping were performed on perfused rat hearts. nNOS is pharmacologically inhibited by S-methylthiocitrulline (SMTC). The influence of the SK channel was examined using a specific channel inhibitor, apamin. Parameters such as action potential duration (APD), conduction velocity, and calcium transient (CaT) were evaluated using voltage and calcium optical mapping. The dominant frequency was examined in the analysis of AF dynamics. SMTC (100 nM) increased the inducibility of ATA and apamin (100 nM) mitigated nNOS inhibition-induced arrhythmogenicity. SMTC caused abbreviations and enhanced the spatial dispersion of APD, which was reversed by apamin. By contrast, conduction velocity and other parameters associated with CaT were not affected by SMTC or apamin administration. Apamin reduced the frequency of SMTC-induced ATA. In summary, nNOS inhibition abbreviates APD by modifying the SK channels. A specific SK channel blocker, apamin, mitigated APD abbreviation without alteration of CaT, implying an underlying mechanism of post-translational modification of SK channels.

Determinants of exercise capacity in patients with heart failure without left ventricular hypertrophy.
Suguru Ishizaka, Hiroyuki Iwano, Shingo Tsujinaga, Michito Murayama, Satonori Tsuneta, Hiroyuki Aoyagi, Yoji Tamaki, Ko Motoi, Yasuyuki Chiba, Asuka Tanemura, Masahiro Nakabachi, Shinobu Yokoyama, Hisao Nishino, Kazunori Okada, Brett A Meyers, Pavlos P Vlachos, Takuma Sato, Kiwamu Kamiya, Masaya Watanabe, Sanae Kaga, Toshiyuki Nagai, Noriko Oyama-Manabe, Toshihisa Anzai
Journal of cardiology, 81, 1, 33, 41, 2022年09月16日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Determinants of exercise intolerance in a phenotype of heart failure with preserved ejection fraction (HFpEF) with normal left ventricular (LV) structure have not been fully elucidated. METHODS: Cardiopulmonary exercise testing and exercise-stress echocardiography were performed in 44 HFpEF patients without LV hypertrophy. Exercise capacity was determined by peak oxygen consumption (peak VO2). Doppler-derived cardiac output (CO), transmitral E velocity, systolic (LV-s') and early diastolic mitral annular velocities (e'), systolic pulmonary artery (PA) pressure (SPAP), tricuspid annular plane systolic excursion (TAPSE), and peak systolic right ventricular (RV) free wall velocity (RV-s') were measured at rest and exercise. E/e' and TAPSE/SPAP were used as an LV filling pressure parameter and RV-PA coupling, respectively. RESULTS: During exercise, CO, LV-s', RV-s', e', and SPAP were significantly increased (p < 0.05 for all), whereas E/e' remained unchanged and TAPSE/SPAP was significantly reduced (p < 0.001). SPAP was higher and TAPSE/SPAP was lower at peak exercise in patients showing lower-half peak VO2. In univariable analyses, LV-s' (R = 0.35, p = 0.022), SPAP (R = -0.40, p = 0.008), RV-s' (R = 0.47, p = 0.002), and TAPSE/SPAP (R = 0.42, p = 0.005) were significantly correlated with peak VO2. In multivariable analyses, not only SPAP, but also TAPSE/SPAP independently determined peak VO2 even after the adjustment for clinically relevant parameters. CONCLUSIONS: In HFpEF patients without LV hypertrophy, altered RV-PA coupling by exercise could be associated with exercise intolerance, which might not be caused by elevated LV filling pressure.

末期心不全患者の難治性不整脈に対するICD治療機能停止(deactivation)の検討を多職種で行った一例　　　　　　　　　　　　　　　
甲谷 次郎, 佐藤 琢真, 立田 大志郎, 西野 広太郎, 小林 雄太, 成田 尚, 敦賀 健吉, 青陽 千果, 池田 陽子, 小島 尚子, 古山 勇気, 小野田 紘子, 加藤 美香, 永井 利幸, 安斉 俊久
日本心臓病学会学術集会抄録, 70回, C, 3, (一社)日本心臓病学会, 2022年09月
日本語

COVID-19で入院加療中に冠攣縮性狭心症を併発した褐色細胞腫の一例　　　　　　　　　　　　　　　
高橋 昌寛, 佐藤 琢真, 立田 大志郎, 甲谷 次郎, 西野 広太郎, 小林 雄太, 小西 崇夫, 永井 利幸, 安斉 俊久
日本心臓病学会学術集会抄録, 70回, C, 5, (一社)日本心臓病学会, 2022年09月
日本語

Clinical features of anti-mitochondrial M2 antibody-positive myositis: case series of 17 patients.
Azusa Nagai, Toshiyuki Nagai, Hiroaki Yaguchi, Shintaro Fujii, Hisashi Uwatoko, Shinichi Shirai, Kazuhiro Horiuchi, Ikuko Iwata, Masaaki Matsushima, Shigehisa Ura, Toshihisa Anzai, Ichiro Yabe
Journal of the neurological sciences, 442, 120391, 120391, 2022年08月28日, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: In 2012, a large number of myositis cases with anti-mitochondrial M2 (AMA-M2) antibody, which had well been known as the serological hallmark for primary biliary cholangitis (PBC), were reported in Japan. Recently, some case series from Japan, France, America, China and India have shown that approximately 2.5% to 19.5% of patients with myositis have AMA-M2 antibody. The objective of this study was to clarify the prevalence, clinical features, treatment outcome, and severity determinants of AMA-M2 positive myositis. METHODS: This study was a multicenter observational study. We enrolled patients who were diagnosed with myositis during a ten-year period between 2012 and 2021. RESULTS: Of the total of 185 patients with inflammatory myopathy, 17 patients were positive for AMA-M2 antibody. The typical symptoms were weakness mainly involving paravertebral muscles, weight loss, respiratory failure, and cardiac complications. Thirteen of the 17 patients had cardiac complications. A strong correlation was found between respiratory failure and modified Rankin Scale (mRS) score. A strong correlation was also found between respiratory failure and body weight, indicating that weight loss can be an indicator of potential progression of respiratory failure. Six of the 17 patients were complicated by malignancy. CONCLUSIONS: This study showed significant correlations between % vital capacity (VC), body mass index (BMI), and mRS score in patients with AMA-M2-positive myositis. Immunotherapy often improved CK level and respiratory dysfunction. We therefore propose that %VC and BMI should be monitored as disease indicators in treatment of AMA-M2-positive myositis.

Dual Gate Doppler法による左房収縮時の肺静脈血流と経僧帽弁血流の時相解析
岡田 一範, 岡田 由佳, 村山 迪史, 加賀 早苗, 政氏 伸夫, 西野 久雄, 横山 しのぶ, 中鉢 雅大, 西田 睦, 本居 昂, 石坂 傑, 千葉 泰之, 辻永 真吾, 岩野 弘幸, 安斉 俊久
超音波検査技術, 47, 4, 353, 362, 一般社団法人 日本超音波検査学会, 2022年08月01日
日本語, 目的：肺静脈血流（PVF）と経僧帽弁血流（TMF）の心房収縮期（A）波の持続時間の差（ΔA_dur）は拡張後期の左室硬さを反映する指標として知られるが，再現性に問題がある．最近，我々は，PVF全体に占める逆行性A波の割合とTMF全体に占めるA波の割合との比（F_PVA/F_A）が，侵襲的左室硬さ指標ときわめてよく対応することを報告したが，この計測はやや煩雑である．今回，Dual Gate Doppler（DD）法によるPVFとTMFの同時記録から得られる指標の有用性を検討した．

対象と方法: DD法が施行された80例において，通常のパルスドプラ法でΔA_dur（S-ΔA_dur）を計測するとともにF_PVA/F_Aを算出した．また，DD法によるPVFとTMFの同時記録から，ΔA_dur（D-ΔA_dur）と各々のA波の終了時相差（D-ΔA_end）を計測した．

結果: S-ΔA_dur，D-ΔA_durおよびD-ΔA_endはいずれもF_PVA/F_Aと有意に相関した（順にr＝0.50, 0.51, 0.71）．このうち，D-ΔA_endとF_PVA/F_Aとの相関は，他2者より有意に良好であった．対象中の20例における検者間および検者内再現性は，S-ΔA_durよりもD-ΔA_durとD-ΔA_endで良好であった．

結論: DD法によるD-ΔA_endは，通常のΔA_durよりも再現性よく拡張後期左室硬さを評価できると考えられた．

Predictors of cardiovascular mortality after an electrical storm in patients with structural heart disease.
Takuya Koizumi, Rui Kamada, Masaya Watanabe, Hisashi Yokoshiki, Taro Temma, Hikaru Hagiwara, Taro Koya, Motoki Nakao, Takahide Kadosaka, Hiroyuki Natsui, Masayuki Takahashi, Kazuya Mizukami, Hirofumi Mitsuyama, Toshihisa Anzai
Journal of cardiology, 80, 2, 167, 171, 2022年08月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Electrical storms (ESs) in patients with structural heart disease (SHD) have been reported to be associated with a poor prognosis. However, the detailed cause of death and influence of implantable cardioverter defibrillator (ICD) therapy in ES patients have not been fully investigated. Therefore, we sought to explore the detailed clinical course after an ES and the impact of the ICD therapy in patients with SHDs. METHODS: We retrospectively analyzed 31 consecutive patients with ESs who had undergone an ICD implantation. ESs were defined as three or more ventricular arrhythmias within 24 h. RESULTS: During a mean follow up of 4.5 years, 13 patients died. Among them, cardiovascular death (CVD) was observed in 11/13 (85%), and the leading cause of the CVD was end-stage heart failure. A New York Heart Association class ≥III at the time of the ES occurrence (HR 6.51 95% CI 1.94-25.1, p = 0.003) and any shock therapy (HR 5.94 95% CI 1.06-112.2, p = 0.04) were associated with CVD. CONCLUSION: In the current single center study, the major cause of death in ES patients with SHDs was end-stage heart failure. Any shock therapy was associated with CVD. Arrhythmia management to avoid ICD shocks might reduce the mortality in ES patients.

Usefulness of the pulmonary venous flow waveform for assessing left atrial stiffness
Takehiro Abe, Kazunori Okada, Michito Murayama, Sanae Kaga, Masahiro Nakabachi, Shinobu Yokoyama, Hisao Nishino, Hiroyuki Aoyagi, Yoji Tamaki, Ko Motoi, Yasuyuki Chiba, Suguru Ishizaka, Shingo Tsujinaga, Hiroyuki Iwano, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
The International Journal of Cardiovascular Imaging, Springer Science and Business Media LLC, 2022年07月16日
研究論文（学術雑誌）

MitraClip実施後にたこつぼ症候群を呈した1例　　　　　　　　　　　　　　　
甲谷 次郎, 神谷 究, 立田 大志郎, 西野 広太郎, 高橋 勇樹, 斎院 康平, 内藤 正一郎, 竹中 秀, 多田 篤司, 水口 賢史, 石坂 傑, 小林 雄太, 佐藤 琢真, 永井 利幸, 安斉 俊久
日本心血管インターベンション治療学会抄録集, 30回, [YIA4, 2], (一社)日本心血管インターベンション治療学会, 2022年07月
英語

Myocardial T-Lymphocytes as a Prognostic Risk-Stratifying Marker of Dilated Cardiomyopathy - Results of the Multicenter Registry to Investigate Inflammatory Cell Infiltration in Dilated Cardiomyopathy in Tissues of Endomyocardial Biopsy (INDICATE Study).
Keiko Ohta-Ogo, Yasuo Sugano, Soshiro Ogata, Takafumi Nakayama, Takahiro Komori, Kazuo Eguchi, Kaoru Dohi, Tetsuro Yokokawa, Hiromitsu Kanamori, Shigeyuki Nishimura, Kazufumi Nakamura, Yoshihiko Ikeda, Kunihiro Nishimura, Genzou Takemura, Toshihisa Anzai, Michiaki Hiroe, Kinta Hatakeyama, Hatsue Ishibashi-Ueda, Kyoko Imanaka-Yoshida
Circulation journal : official journal of the Japanese Circulation Society, 86, 7, 1092, 1101, 2022年06月24日, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Dilated cardiomyopathy (DCM) associated with inflammation is diagnosed by endomyocardial biopsy; patients with this have a poorer prognosis than patients without inflammation. To date, standard diagnostic criteria have not been established.Methods and Results: This study analyzed clinical records and endomyocardial biopsy samples of 261 patients with DCM (201 males, median left ventricular ejection fraction; 28%) from 8 institutions in a multicenter retrospective study. Based on the European Society of Cardiology criteria and CD3 (T-lymphocytes) and CD68 (macrophages) immunohistochemistry, 48% of patients were categorized as having inflammatory DCM. For risk-stratification, we divided patients into 3 groups using Akaike Information Criterion/log-rank tests, which can determine multiple cut-off points: CD3+-Low, <13/mm2(n=178, 68%); CD3+-Moderate, 13-24/mm2(n=58, 22%); and CD3+-High, ≥24/mm2(n=25, 10%). The survival curves for cardiac death or left ventricular assist device implantation differed significantly among the 3 groups (10-year survival rates: CD3+-Low: 83.4%; CD3+-Moderate: 68.4%; CD3+-High: 21.1%; Log-rank P<0.001). Multivariate Cox analysis revealed CD3+count as a potent independent predictive factor for survival (fully adjusted hazard ratio: CD3+-High: 5.70, P<0.001; CD3+-Moderate: 2.64, P<0.01). CD3+-High was also associated with poor left ventricular functional and morphological recovery at short-term follow up. CONCLUSIONS: Myocardial CD3+T-lymphocyte infiltration has a significant prognostic impact in DCM and a 3-tiered risk-stratification model could be helpful to refine patient categorization.

Cogan Syndrome with Aortic Regurgitation and Multiple Vasculopathy.
Kohei Saiin, Takao Konishi, Keita Ninagawa, Toshihisa Anzai
Internal medicine (Tokyo, Japan), 61, 12, 1921, 1922, 2022年06月15日, ［国内誌］
英語, 研究論文（学術雑誌）

Luseogliflozin preserves the pancreatic beta-cell mass and function in db/db mice by improving mitochondrial function.
Yuki Yamauchi, Akinobu Nakamura, Takashi Yokota, Kiyohiko Takahashi, Shinichiro Kawata, Kazuhisa Tsuchida, Kazuno Omori, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Toshihisa Anzai, Shinya Tanaka, Yasuo Terauchi, Hideaki Miyoshi, Tatsuya Atsumi
Scientific reports, 12, 1, 9740, 9740, 2022年06月13日, ［国際誌］
英語, 研究論文（学術雑誌）, We aimed to determine the mechanism by which the sodium glucose co-transporter 2 inhibitor, luseogliflozin, preserves pancreatic beta-cell mass and function in db/db mice. Six-week-old db/db mice were fed to standard chow or standard chow containing 0.01% luseogliflozin. After 4 weeks, DNA microarray analysis, real-time PCR analysis, and measurement of mitochondrial respiratory capacity and reactive oxygen species (ROS) generation were performed using isolated islets. Immunohistochemistry and electron microscopic analysis were performed using pancreatic tissues. Metabolites extracted from the islets were measured by capillary electrophoresis mass spectrometry. The expression of genes involved in the tricarboxylic acid (TCA) cycle and electron transport chain was upregulated by luseogliflozin. Luseogliflozin improved the mitochondrial complex II-linked oxidative phosphorylation capacity and reduced ROS generation. Mitochondrial morphology was normally maintained by luseogliflozin. Luseogliflozin increased NK6 homeobox 1 (NKX6.1) expression and TCA cycle metabolites. Relief of glucotoxicity by luseogliflozin may involve lower mitochondrial ROS generation and an improvement in complex II-linked mitochondrial respiration. Reducing ROS generation through preventing complex II damage likely increases NKX6.1 expression and ameliorate glucose metabolism in the TCA cycle, contributing to the protection of pancreatic beta-cells. Protection of complex II in pancreatic beta-cells represents a novel therapeutic target for type 2 diabetes.

Long-term preservation of functional capacity and quality of life in advanced heart failure patients with bridge to transplant therapy: A report from Japanese nationwide multicenter registry.
Takuma Sato, Yuta Kobayashi, Toshiyuki Nagai, Takeshi Nakatani, Jon Kobashigawa, Yoshikatsu Saiki, Minoru Ono, Satoru Wakasa, Toshihisa Anzai
International journal of cardiology, 356, 66, 72, 2022年06月01日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Under the revised heart allocation system in the United States, bridge to transplant (BTT) patients with left ventricular assist device (LVAD) have a longer waitlist period, as they are now lowly prioritized. However, little is known regarding the long-term trajectory of functional capacity (FC) and health-related quality of life (HR-QOL) among BTT-LVAD patients. METHODS: We retrospectively analyzed 442 consecutive patients with BTT-LVAD between April 2013 and May 2019 from a Japanese nationwide registry. FC (New York Heart Association [NYHA] functional class, peak oxygen uptake [VO2], and 6-min walk test [6MWT]) and HR-QOL (European Quality of Life [EQ-5D index] and Visual Analogue Scale [EQ-VAS]) were assessed at baseline and for up to 60 months after LVAD implantation. RESULTS: During the follow-up period of 30 months (IQR 18-42 months), 100 (22.6%) patients underwent transplantation, 37 (8.3%) died, and 14 (3.1%) underwent explantation for recovery. Mean peak VO2, 6MWT distance, EQ-5D index, and EQ-VAS significantly improved 3 months after LVAD implantation (p = 0.0012, p = 0.0037, p < 0.001, p < 0.001, respectively). Furthermore, these improvements were sustained for up to 60 months following LVAD implantation. Major adverse events including device failure, infection, stroke, and bleeding, which occurred within the first 3 months after LVAD implantation may have not affected FC or HR-QOL for up to 60 months (p = 0.15, p = 0.22, respectively). CONCLUSIONS: BTT patients showed long-term preservation of FC and HR-QOL, suggesting that BTT remains an option despite the long waiting time to HTx.

Stimulation of the mitochondrial calcium uniporter mitigates chronic heart failure-associated ventricular arrhythmia in mice.
Hikaru Hagiwara, Masaya Watanabe, Yoichiro Fujioka, Takahide Kadosaka, Takuya Koizumi, Taro Koya, Motoki Nakao, Rui Kamada, Taro Temma, Kazufumi Okada, Jose Antonio Moreno, Ohyun Kwon, Hisakata Sabe, Yusuke Ohba, Toshihisa Anzai
Heart rhythm, 19, 10, 1725, 1735, 2022年05月31日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: An aberrant increase in the diastolic calcium concentration ([Ca2+]i) level is a hallmark of heart failure (HF) and the cause of delayed afterdepolarization and ventricular arrhythmia (VA). Although mitochondria play a role in regulating [Ca2+]i, whether they can compensate for the [Ca2+]i abnormality in ventricular myocytes is unknown. OBJECTIVE: We investigated whether enhanced Ca2+ uptake of mitochondria may compensate for an abnormal increase in the [Ca2+]i of ventricular myocytes in HF to effectively mitigate VA. METHODS: We used a HF mouse model, in which myocardial infarction was induced by permanent left anterior descending coronary artery ligation. The mitochondrial Ca2+ uniporter was stimulated by kaempferol. Ca2+ dynamics and membrane potential were measured using an epifluorescence microscope, a confocal microscope, and the perforated patch-clamp technique. VA was induced in the Langendorff-perfused hearts, and the hemodynamic parameters were measured using a microtip transducer catheter. RESULTS: Protein expression of the mitochondrial Ca2+ uniporter, as assessed by its subunit expression, did not change between HF and sham mice. Treatment of cardiomyocytes with kaempferol, isolated from HF mice at 28 days after coronary ligation, reduced the appearance of aberrant diastolic [Ca2+]i waves and sparks and spontaneous action potentials. Kaempferol effectively reduced the VA occurring in Langendorff-perfused hearts. Intravenous administration of kaempferol did not markedly affect the left ventricular hemodynamic parameters. CONCLUSION: The effects of kaempferol in HF of mice implied that mitochondria may have the potential to compensate for abnormal [Ca2+]i. Mechanisms involved in mitochondrial Ca2+ uptake may provide novel targets to treat HF-associated VA.

Two cases showing alterations of the order of tricuspid and mitral valve opening during loading manipulations: a new approach for quick assessment of stress-induced left ventricular filling pressure elevation.
Michito Murayama, Hiroyuki Iwano, Ko Motoi, Suguru Ishizaka, Shingo Tsujinaga, Toshiyuki Nagai, Toshihisa Anzai
Journal of medical ultrasonics (2001), 49, 3, 489, 491, 2022年05月30日, ［国内誌］
英語, 研究論文（学術雑誌）

Visual echocardiographic scoring system of the left ventricular filling pressure and outcomes of heart failure with preserved ejection fraction.
Michito Murayama, Hiroyuki Iwano, Masaru Obokata, Tomonari Harada, Kazunori Omote, Kazuki Kagami, Shingo Tsujinaga, Yasuyuki Chiba, Suguru Ishizaka, Ko Motoi, Yoji Tamaki, Hiroyuki Aoyagi, Masahiro Nakabachi, Hisao Nishino, Shinobu Yokoyama, Asuka Tanemura, Kazunori Okada, Sanae Kaga, Mutsumi Nishida, Toshiyuki Nagai, Masahiko Kurabayashi, Toshihisa Anzai
European heart journal. Cardiovascular Imaging, 23, 5, 616, 626, 2022年04月18日, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Elevated left ventricular filling pressure (LVFP) is a powerful indicator of worsening clinical outcomes in heart failure with preserved ejection fraction (HFpEF); however, detection of elevated LVFP is often challenging. This study aimed to determine the association between the newly proposed echocardiographic LVFP parameter, visually assessed time difference between the mitral valve and tricuspid valve opening (VMT) score, and clinical outcomes of HFpEF. METHODS AND RESULTS: We retrospectively investigated 310 well-differentiated HFpEF patients in stable conditions. VMT was scored from 0 to 3 using two-dimensional echocardiographic images, and VMT ≥2 was regarded as a sign of elevated LVFP. The primary endpoint was a composite of cardiac death or heart failure hospitalization during the 2 years after the echocardiographic examination. In all patients, Kaplan-Meier curves showed that VMT ≥2 (n = 54) was associated with worse outcomes than the VMT ≤1 group (n = 256) (P < 0.001). Furthermore, VMT ≥2 was associated with worse outcomes when tested in 100 HFpEF patients with atrial fibrillation (AF) (P = 0.026). In the adjusted model, VMT ≥2 was independently associated with the primary outcome (hazard ratio 2.60, 95% confidence interval 1.46-4.61; P = 0.001). Additionally, VMT scoring provided an incremental prognostic value over clinically relevant variables and diastolic function grading (χ2 10.8-16.3, P = 0.035). CONCLUSIONS: In patients with HFpEF, the VMT score was independently and incrementally associated with adverse clinical outcomes. Moreover, it could also predict clinical outcomes in HFpEF patients with AF.

SGLT2阻害薬はミトコンドリア機能の改善を介し膵β細胞量・機能を保護する
山内 裕貴, 中村 昭伸, 横田 卓, 高橋 清彦, 川田 晋一朗, 土田 和久, 大森 一乃, 野本 博司, 亀田 啓, 曹 圭龍, 安斉 俊久, 田中 伸哉, 寺内 康夫, 三好 秀明, 渥美 達也
日本内分泌学会雑誌, 98, 1, 361, 361, (一社)日本内分泌学会, 2022年04月
日本語

Difference in left atrial myocardial dynamics during reservoir phase between hypertrophic cardiomyopathy and hypertensive heart determined using three-dimensional speckle tracking echocardiography
Yusuke Yanagi, Kazunori Okada, Sanae Kaga, Taisei Mikami, Miho Aiba, Nobuo Masauzi, Michito Murayama, Asuka Tanemura, Shinobu Yokoyama, Hisao Nishino, Masahiro Nakabachi, Yoji Tamaki, Hiroyuki Aoyagi, Ko Motoi, Suguru Ishizaka, Yasuyuki Chiba, Shingo Tsujinaga, Hiroyuki Iwano, Toshihisa Anzai
INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING, SPRINGER, 2022年04月
英語, 研究論文（学術雑誌）, We aimed to investigate left atrial (LA) myocardial dynamics during reservoir phase using three-dimensional speckle-tracking echocardiography (3DSTE) focusing on its longitudinal-circumferential relationship in patients with left ventricular (LV) hypertrophy and clarifying the difference in LA myocardial reservoir dynamics between hypertrophic cardiomyopathy (HCM) and hypertension with LV hypertrophy (HT-LVH). We studied 4 age-matched groups consisting of 27 patients with HCM, 16 with HT-LVH, 22 hypertensive patients without LV hypertrophy (HT), and 18 normal controls. Using 3DSTE, we measured LA global longitudinal strain (LA-LSR), global circumferential strain (LA-CSR), and global area strain (LA-AS(R)) during the reservoir phase, as well as LV global longitudinal strain (LV-LS), global circumferential strain (LV-CS), and global area strain (LV-AS). LA-LSR was significantly lower in the HCM and HT-LVH groups than in the controls, but there was no significant difference between the HCM and HT-LVH groups. LA-CSR and LA-AS(R) were significantly lower in the HCM group than in the other three groups, among which no significant difference was detected. In all subjects, LA-LSR was significantly correlated with LV-LS but not with LV-CS. LA-CSR was correlated with neither LV-LS nor LV-CS. In conclusion, both longitudinal and circumferential LA myocardial expansion during reservoir phase were reduced in HCM, while only the longitudinal one was reduced in HT-LVH. Reduction of LA circumferential expansion may reflect a more serious and intrinsic impairment of LA myocardial distensibility in HCM. Measuring LA-CSR and LA-AS(R) using 3DSTE would contribute to a more accurate understanding of LA reservoir function abnormality in HCM.

Prognostic value of an echocardiographic index reflecting right ventricular operating stiffness in patients with heart failure.
Ryosuke Fujisawa, Kazunori Okada, Sanae Kaga, Michito Murayama, Masahiro Nakabachi, Shinobu Yokoyama, Hisao Nishino, Asuka Tanemura, Nobuo Masauzi, Ko Motoi, Suguru Ishizaka, Yasuyuki Chiba, Shingo Tsujinaga, Hiroyuki Iwano, Toshihisa Anzai
Heart and vessels, 37, 4, 583, 592, 2022年04月, ［国内誌］
英語, 研究論文（学術雑誌）, PURPOSE: We recently reported a noninvasive method for the assessment of right ventricular (RV) operating stiffness that is obtained by dividing the atrial-systolic descent of the pulmonary artery-RV pressure gradient (PRPGDAC) derived from the pulmonary regurgitant velocity by the tricuspid annular plane movement during atrial contraction (TAPMAC). Here, we investigated whether this parameter of RV operating stiffness, PRPGDAC/TAPMAC, is useful for predicting the prognosis of patients with heart failure (HF). METHODS: We retrospectively included 127 hospitalized patients with HF who underwent an echocardiographic examination immediately pre-discharge. The PRPGDAC/TAPMAC was measured in addition to standard echocardiographic parameters. Patients were followed until 2 years post-discharge. The endpoint was the composite of cardiac death, readmission for acute decompensation, and increased diuretic dose due to worsening HF. RESULTS: 58 patients (46%) experienced the endpoint during follow-up. Univariable and multivariable Cox regression analyses demonstrated that the PRPGDAC/TAPMAC was associated with the endpoint. In a Kaplan-Meier analysis, the event rate of the greater PRPGDAC/TAPMAC group was significantly higher than that of the lesser PRPGDAC/TAPMAC group. In a sequential Cox analysis for predicting the endpoint's occurrence, the addition of PRPGDAC/TAPMAC to the model including age, sex, NYHA functional classification, brain natriuretic peptide level, and several echocardiographic parameters including tricuspid annular plane systolic excursion significantly improved the predictive power for prognosis. CONCLUSION: A completely noninvasive index of RV operating stiffness, PRPGDAC/TAPMAC, was useful for predicting prognoses in patients with HF, and it showed an incremental prognostic value over RV systolic function.

Right atrial pressure represents cumulative cardiac burden in heart failure with preserved ejection fraction.
Reika Nagata, Tomonari Harada, Kazunori Omote, Hiroyuki Iwano, Kotaro Yoshida, Toshimitsu Kato, Koji Kurosawa, Toshiyuki Nagai, Toshihisa Anzai, Masaru Obokata
ESC heart failure, 9, 2, 1454, 1462, 2022年04月, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Right-sided filling pressure is elevated in some patients with heart failure (HF) and preserved ejection fraction (HFpEF). We hypothesized that right atrial pressure (RAP) would represent the cumulative burden of abnormalities in the left heart, pulmonary vasculature, and the right heart. METHODS AND RESULTS: Echocardiography was performed in 399 patients with HFpEF. RAP was estimated from inferior vena cava morphology and its respiratory change [estimated right atrial pressure (eRAP)], and patients were divided according to eRAP (3 or ≥8 mmHg). Patients with higher eRAP displayed more severe abnormalities in LV diastolic function as well as right heart structure and function than those with normal eRAP. Cardiac deaths or HF hospitalization occurred in 84 patients over a median follow-up of 19.0 months (interquartile range 6.7-36.9). The presence of higher eRAP was independently associated with an increased risk of the composite outcome (adjusted hazard ratio 2.20 vs. normal eRAP group, 95% confidence interval 1.34-3.62, P = 0.002). Kaplan-Meier curves separating the patients into four groups based on eRAP and E/e' ratio showed that event-free survival varied among the groups, providing an incremental prognostic value of eRAP over E/e' ratio. The classification and regression tree analysis demonstrated that eRAP was the strongest predictor of the outcome followed by right ventricular dimension, E/e' ratio, and estimated right ventricular systolic pressure, stratifying the patients into four risk groups (incident rate 8.8-72.2%). CONCLUSIONS: These data may provide new insights into the prognostic role of RAP in the complex pathophysiology of HFpEF and suggest the utility of eRAP for the risk stratification in patients with HFpEF.

Rapid Publication and Announcement of the 2022 JCS Meeting Activities.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 86, 4, 589, 590, 2022年03月25日, ［国内誌］
英語, 研究論文（学術雑誌）

Impact of Tweeting Summaries by the Japanese Circulation Society Official Account on Article Viewership - Pilot Trial.
Atsushi Mizuno, Kenya Kusunose, Takuya Kishi, Jeffrey Rewley, Chisa Matsumoto, Yuki Sahashi, Mari Ishida, Shoji Sanada, Memori Fukuda, Tadafumi Sugimoto, Miki Hirano, Daisuke Yoneoka, Masataka Sata, Toshihisa Anzai, Koichi Node
Circulation journal : official journal of the Japanese Circulation Society, 86, 4, 715, 720, 2022年03月25日, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The impact of promotional tweets from the official journal account (forCirculation JournalandCirculation Reports) on article viewership has not been thoroughly evaluated.Methods and Results:We retrospectively collected journal viewership data forCirculation JournalandCirculation Reportsfrom March 2021 to August 2021. We compared viewership between articles with (n=15) and without (n=250) tweets. After 1 : 4 propensity score matching (15 tweeted articles and 60 non-tweeted matched controls), journal viewership metrics within 7 days of the tweeting date (and the hypothetical tweeting date), was larger in tweeted articles than non-tweeted articles (median [interquartile range] Abstract page views 89 [60-104] vs. 18 [8-41]). CONCLUSIONS: This pilot study suggests a positive relationship between journal-posted promotional tweets and article viewership.

Results of PRospect trial to Elucidate the utility of EchocarDiography-based Cardiac ouTput in acute heart failure (PREDICT).
Hiroyuki Iwano, Hiroto Utsunomiya, Kentaro Shibayama, Hidekazu Tanaka, Akihiro Isotani, Toshinari Onishi, Masaru Obokata, Masaki Izumo, Kenya Kusunose, Atsuko Furukawa, Masahiro Yamada, Takeshi Kitai, Tetsuari Onishi, Masayoshi Yamamoto, Shunsuke Sasaki, Kotaro Nochioka, Yoichi M Ito, Toshihisa Anzai
Journal of cardiology, 80, 3, 218, 225, 2022年03月17日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The predictive value of echocardiographic parameters for early worsening heart failure (WHF), worsening of symptoms of heart failure requiring intensification of therapy during an admission for acute decompensated heart failure (ADHF), has not been elucidated. METHODS: Sixteen centers in Japan prospectively enrolled 303 ADHF hospitalized patients who did not receive positive inotropic agents as an initial therapy. Physical and Doppler echocardiographic examinations were performed before the initial therapy and the association of low output findings and occurrence of early WHF were tested. RESULTS: Early WHF occurred in 63 patients with a median duration of 6 (IQR: 2-23) hours from the administration of the initial therapy. In patients with left ventricular (LV) ejection fraction <40% (N = 153), echocardiographic stroke volume index, and cardiac index showed greater c-index [95% confidence interval, 0.71 (0.61-0.79) and 0.72 (0.63-0.80), respectively] compared to single low perfusion finding (symptomatic hypotension, reduced pulse pressure, and impaired mentation) other than cool extremities. When physical findings were combined (low perfusion score), the predictive ability improved to the similar levels of echocardiographic LV output parameters [c-index: 0.69 (0.60-0.76)]. However, addition of cardiac index significantly improved the prognostic ability when added to low perfusion score [0.82 (0.74-0.87), p < 0.001]. In contrast, in patients with LV ejection fraction ≥40% (N = 150), low perfusion score, rather than LV output parameters, was predictive of early WHF [c-index: 0.73 (0.56-0.85)]. CONCLUSIONS: We demonstrated the predictive value of echocardiographic LV output indices for early WHF in ADHF patients with LV systolic dysfunction. These data support the motivation for routine use of echocardiography for initial assessment of ADHF.

Circulation Journal Awards for the Year 2021.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 86, 3, 365, 375, 2022年02月25日, ［国内誌］
英語, 研究論文（学術雑誌）

Clinical Utility of Superior Vena Cava Flow Velocity Waveform Measured from the Subcostal Window for Estimating Right Atrial Pressure.
Michito Murayama, Sanae Kaga, Kazunori Okada, Hiroyuki Iwano, Masahiro Nakabachi, Shinobu Yokoyama, Hisao Nishino, Shingo Tsujinaga, Yasuyuki Chiba, Suguru Ishizaka, Ko Motoi, Kiwamu Kamiya, Mutsumi Nishida, Toshiyuki Nagai, Toshihisa Anzai
Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography, 35, 7, 727, 737, 2022年02月09日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The superior vena cava (SVC) flow velocity waveform from the supraclavicular window reflects right atrial pressure (RAP) status. Recent guidelines have stated that the subcostal window is an alternative view for recording SVC flow, but the validity of this approach remains unclear. The aim of this study was to determine the usefulness of SVC flow evaluation from the subcostal window for estimating RAP. METHODS: Differences in SVC flow characteristics between opposite approaches were examined in 38 healthy adults. In 115 patients with cardiovascular diseases who underwent cardiac catheterization and echocardiography within 48 hours, the ratio of peak systolic to diastolic forward SVC flow (SVC-S/D) was measured, and the diagnostic ability of SVC-S/D for elevated RAP was tested. A validation cohort was used to confirm the diagnostic ability of SVC-S/D in 48 patients who underwent both cardiac catheterization and echocardiography within 24 hours. In 59 patients in the derivation and validation cohorts, the relationship between SVC flow and RAP was compared between the opposite windows. RESULTS: Both systolic and diastolic SVC flow velocities were higher in the subcostal than in the supraclavicular approach, and effect of position change on subcostal SVC-S/D was smaller than that on supraclavicular SVC-S/D in healthy adults. Measurement of SVC-S/D from the subcostal window was feasible in 98 patients (85%). RAP was inversely correlated with SVC-S/D (r = -0.50, P < .001) and was an independent determinant of SVC-S/D after adjustment for right ventricular systolic function (β = -0.48, P < .001). A cutoff value of 1.9 for SVC-S/D showed 85% sensitivity and 74% specificity in identifying elevated RAP. Additionally, SVC-S/D showed an incremental diagnostic value combined with inferior vena cava size and collapsibility (P = .006). When a cutoff value of SVC-S/D < 1.9 was applied to the validation cohort, it showed acceptable accuracy of 72% and incremental diagnostic value combined with inferior vena cava parameters (P = .033). SVC-S/D from the subcostal window correlated better with RAP than that from the supraclavicular window (P < .001, Meng's test). CONCLUSIONS: Measurement of SVC flow velocity from the subcostal window was feasible, and SVC-S/D from the subcostal window could be an additive parameter for estimating RAP.

Cardiac Power Output Is Independently and Incrementally Associated With Adverse Outcomes in Heart Failure With Preserved Ejection Fraction.
Tomonari Harada, Miho Yamaguchi, Kazunori Omote, Hiroyuki Iwano, Yoshifumi Mizuguchi, Shiro Amanai, Kuniko Yoshida, Toshimitsu Kato, Koji Kurosawa, Toshiyuki Nagai, Kazuaki Negishi, Toshihisa Anzai, Masaru Obokata
Circulation. Cardiovascular imaging, 15, 2, e013495, 2022年02月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Cardiac power output is a measure of cardiac performance, and its prognostic significance has been shown in heart failure (HF) with reduced ejection fraction. Patients with HF with preserved ejection fraction may have altered cardiac performance, but the prognostic relevance of cardiac power output is unknown. This study sought to determine the association between cardiac power output and clinical outcomes in HF with preserved ejection fraction and to compare its prognostic effect to other measures of cardiac performance including ventricular-arterial coupling and mechanical efficiency. METHODS: Cardiac power output normalized to left ventricular mass was assessed by echocardiography in 408 patients with HF with preserved ejection fraction. Load-independent contractility (end-systolic elastance), arterial elastance, its coupling (arterial elastance/end-systolic elastance), left ventricular global longitudinal strain, and mechanical efficiency (stroke work/pressure-volume area) were also estimated noninvasively. The primary end point was a composite of cardiovascular mortality or HF hospitalization. RESULTS: The primary composite outcome occurred in 84 patients during a median follow-up of 19.4 months. There was a dose-dependent association between cardiac power output and the composite outcomes, in which patients with the lowest tertile of cardiac power output had >3-fold risk than those with the highest tertile (hazard ratio, 3.04 [95% CI, 1.66-5.57]; P=0.0003). In a multivariable model, lower cardiac power output was independently associated with adverse outcomes (hazard ratio, 0.70 per 1 SD [95% CI, 0.49-0.97]; P=0.03). In contrast, left ventricular size, end-systolic elastance, arterial elastance, arterial elastance/end-systolic elastance ratio, and left ventricular mechanical efficiency were not associated with outcomes. Cardiac power output provided an incremental prognostic effect over the model based on clinical (age, gender, diastolic blood pressure, and atrial fibrillation) and echocardiographic markers (left atrial size, pulmonary pressures, global longitudinal strain, and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular tissue velocity; P=0.03). CONCLUSIONS: In patients with HF with preserved ejection fraction, cardiac power output was independently and incrementally associated with adverse outcomes whereas other markers of cardiac performance were not.

Editorial Statistics and Best Reviewers Award for 2021.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 86, 2, 173, 175, 2022年01月25日, ［国内誌］
英語, 研究論文（学術雑誌）

Left ventricular mass index-to-QRS-voltage ratio predicts outcomes in heart failure with preserved ejection fraction.
Yoshiharu Kinugasa, Kensuke Nakamura, Hiroko Kamitani, Masayuki Hirai, Kiyotaka Yanagihara, Masahiko Kato, Toshiyuki Nagai, Tsutomu Yoshikawa, Yoshihiko Saito, Yasuchika Takeishi, Kazuhiro Yamamoto, Toshihisa Anzai
ESC heart failure, 9, 2, 1098, 1106, 2022年01月25日, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Increased left ventricular mass index (LVMI) disproportionate to electrocardiographic QRS voltage has been reported to be associated with cardiac fibrosis and amyloid infiltration to myocardium. This study aimed to assess whether the LVMI-to-QRS-voltage ratio predicts clinical outcomes in heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: The Japanese Heart Failure Syndrome with Preserved Ejection Fraction (JASPER) registry is a nationwide, observational, and prospective registration of Japanese patients hospitalized with HFpEF (EF ≥ 50%). LVMI was assessed by echocardiography using the cube formula. QRS voltage was assessed by Sokolow-Lyon voltage criteria. We divided 290 patients in the registry who met inclusion criteria into five groups according to the quintile values of their LVMI-to-QRS-voltage ratio. In the highest quintile group (≥71.8 g/m2 /mV), approximately 50% of the patients had concentric hypertrophy and 30% had eccentric hypertrophy. These patients had the highest proportion of atrial fibrillation (61.4%) and history of pacemaker implantation (12.1%) among the five groups (P < 0.05). During the mean follow-up of 587 ± 300 days, 31.4% of all patients met the composite endpoint of all-cause death or rehospitalization for HF. Even after adjustment for demographic and baseline variables, the highest quintile group had a significantly higher incidence of the composite endpoints than the lowest quintile group (<30.7 g/m2 /mV) (hazard ratio: 2.205, 95% confidence interval: 1.106-4.395, P < 0.05). CONCLUSIONS: A high LVMI-to-QRS-voltage ratio is independently associated with poor outcomes in patients with HFpEF.

Determinants of altered left ventricular suction in pre-capillary pulmonary hypertension.
Yasuyuki Chiba, Hiroyuki Iwano, Satonori Tsuneta, Shingo Tsujinaga, Brett Meyers, Pavlos Vlachos, Suguru Ishizaka, Ko Motoi, Hiroyuki Aoyagi, Yoji Tamaki, Asuka Tanemura, Michito Murayama, Shinobu Yokoyama, Masahiro Nakabachi, Hisao Nishino, Sanae Kaga, Kiwamu Kamiya, Hiroshi Ohira, Ichizo Tsujino, Toshihisa Anzai
European heart journal. Cardiovascular Imaging, 23, 10, 1399, 1406, 2022年01月10日, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Although the left ventricular (LV) dysfunction in pre-capillary pulmonary hypertension (PH) has been recently recognized, the mechanism of LV dysfunction in this entity is not completely understood. We thus aimed to elucidate the determinants of intraventricular pressure difference (IVPD), a measure of LV suction, in pre-capillary PH. METHODS AND RESULTS: Right heart catheterization and echocardiography were performed in 86 consecutive patients with pre-capillary PH (57 ± 18 years, 85% female). IVPD was determined using colour M-mode Doppler to integrate the Euler equation. In overall, IVPD was reduced compared to previously reported value in normal subjects. In univariable analyses, QRS duration (P = 0.028), LV ejection fraction (P = 0.006), right ventricular (RV) end-diastolic area (P < 0.001), tricuspid annular plane systolic excursion (P = 0.004), and LV early-diastolic eccentricity index (P = 0.009) were associated with IVPD. In the multivariable analyses, RV end-diastolic area and LV eccentricity index independently determined the IVPD. CONCLUSION: Aberrant ventricular interdependence caused by RV enlargement could impair the LV suction. This study first applied echocardiographic IVPD, a reliable marker of LV diastolic suction, to investigate the mechanism of LV diastolic dysfunction in pre-capillary PH.

ドプラ心エコー法による肺動脈弁逆流重症度の過大評価の要因に関する検討　　　　　　　　　　　　　　　
本居 昂, 岩野 弘幸, 常田 慧徳, 村山 迪史, 加賀 早苗, 青柳 裕之, 玉置 陽生, 石坂 傑, 千葉 泰之, 辻永 真吾, 種村 明日香, 横山 しのぶ, 中鉢 雅大, 西野 久雄, 岡田 一範, 武田 充人, 安斉 俊久
日本成人先天性心疾患学会雑誌, 11, 1, 216, 216, 日本成人先天性心疾患学会, 2022年01月
日本語

Neoatherosclerosis with silent plaque rupture in a saphenous vein graft causing no re-flow phenomenon assessed by optical coherence tomography and histopathology.
Takao Konishi, Yuki Takahashi, Sho Kazui, Yutaro Yasui, Kohei Saiin, Seiichiro Naito, Sakae Takenaka, Yoshifumi Mizuguchi, Atsushi Tada, Yuta Kobayashi, Kazunori Omote, Takuma Sato, Kiwamu Kamiya, Toshiyuki Nagai, Shinya Tanaka, Toshihisa Anzai
Cardiology journal, 29, 4, 718, 719, 2022年, ［国際誌］
英語, 研究論文（学術雑誌）

Vulnerable plaque derived from aspirated thrombi in recurrent acute coronary syndrome with familial hypercholesterolemia despite intensive lipid-lowering statin therapy.
Hiroyuki Natsui, Takao Konishi, Kohei Saiin, Youji Tamaki, Tomoya Sato, Sakae Takenaka, Atsushi Tada, Yoshifumi Mizuguchi, Yuta Kobayashi, Takuma Sato, Rui Kamada, Kiwamu Kamiya, Toshiyuki Nagai, Shinya Tanaka, Toshihisa Anzai
Cardiology journal, 29, 2, 362, 363, 2022年, ［国際誌］
英語, 研究論文（学術雑誌）

Functional Tricuspid Regurgitation and Right Atrial Remodeling in Heart Failure With Preserved Ejection Fraction.
Tomonari Harada, Masaru Obokata, Kazunori Omote, Hiroyuki Iwano, Takahiro Ikoma, Kenya Okada, Kuniko Yoshida, Toshimitsu Kato, Koji Kurosawa, Toshiyuki Nagai, Toshihisa Anzai, Barry A Borlaug, Masahiko Kurabayashi
The American journal of cardiology, 162, 129, 135, 2022年01月01日, ［国際誌］
英語, 研究論文（学術雑誌）, Tricuspid regurgitation (TR) is common in patients with heart failure with preserved ejection fraction (HFpEF), but it has not been well characterized. We hypothesized that right atrial (RA) remodeling would be associated with TR in HFpEF, forming a type of atrial functional TR (AFTR). Echocardiography was performed in 328 patients with HFpEF. TR severity was defined using a guidelines-based approach. Ventricular functional TR was defined as the presence of right ventricular (RV) systolic pressure >50 mm Hg or RV dilation, and the remaining patients were classified as having AFTR if they had RA dilation or tricuspid annular enlargement. RA dilation was common (78%) in the significant TR group (more than mild), exceeding the prevalence of RV dilation (32%), and RA dilation was correlated with tricuspid annular diameter and TR vena contracta width (r = 0.67 and r = 0.70, both p <0.0001). Despite the absence of RV dilation and pulmonary hypertension, 38% of patients with significant TR had AFTR. Patients with AFTR and those with ventricular functional TR displayed higher heart failure hospitalization rates than those with nonsignificant TR (adjusted hazard ratios, 2.45 and 4.31; 95% confidence interval 1.12 to 5.35 and 2.44 to 7.62, p = 0.02 and p <0.0001, respectively). In conclusion, TR in HFpEF is related to RA remodeling, and the presence of AFTR was associated with poor clinical outcomes. The current data highlight the importance of RA remodeling in the pathophysiology of TR in HFpEF.

Messages From the Editor-in-Chief.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 86, 1, 1, 1, 2021年12月24日, ［国内誌］
英語, 研究論文（学術雑誌）

The Circulation Journal Official Impact Factor and the Most Frequently Cited Papers in 2020.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 86, 1, 2, 5, 2021年12月24日, ［国内誌］
英語, 研究論文（学術雑誌）

Molecular ratio of mature B-type natriuretic peptide in acute heart failure: an indicator for ventricular contractile recovery.
Akihisa Kimura, Hiroyuki Takahama, Toshio Nishikimi, Seiji Takashio, Tomohiro Hayashi, Chiaki Nagai-Okatani, Yasuaki Nakagawa, Satoshi Yasuda, Toshihisa Anzai, Naoto Minamino, Chisato Izumi
ESC heart failure, 8, 6, 5617, 5621, 2021年12月, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: The methodology to distinguish between the heart failure (HF) with recovered ejection fraction (HFrecEF) and those with continuously reduced ejection fraction (EF) (HFcrEF) on admission has not been established. We recently demonstrated that the ratio of plasma levels of pro-B-type natriuretic peptide (proBNP) to total BNP (proBNP plus mature BNP) is decreased on admission in patients with mild acute HF, but not in severe acute HF as a compensatory mechanism for activating cyclic GMP via increases of bioactive mature BNP. We aimed to test the hypothesis that the ratio of bioactive mature BNP to total BNP is associated with reverse remodelling capacity in patients with HF with reduced EF. METHODS AND RESULTS: Plasma proBNP and total BNP were measured in patients with acute decompensated HF by using specific and sensitive enzyme immunochemiluminescent assay. Estimated percent mature BNP (%emBNP) was calculated as ([total BNP - proBNP]/total BNP) × 100. We retrospectively identified the patients with reduced EF (≤40%, on admission) who had echocardiographic data after discharge (n = 93). We defined patients with increased EF by >10% during the follow-up term (median, 545 days) after the admission as HFrecEF group. We compared patient characteristics, %emBNP, and other biomarkers between HFrecEF and HFcrEF. Of the enrolled patients with HFrecEF (n = 32) and HFcrEF (n = 61), on admission, %emBNP was significantly higher in HFrecEF than in HFcrEF (44.1% vs. 36.9%; P < 0.05). There were no significant differences in left ventricular EF on admission between the two groups. The univariate analysis revealed that %emBNP on admission was associated with HFrecEF occurrence rate (P < 0.05), in contrast both total BNP and high-sensitive cardiac troponin-T levels were not associated with HFrecEF occurrence rate. CONCLUSIONS: The ratio of mature BNP to total BNP in plasma at the time of hospital admission may be predictive of left ventricular contractile recovery. Preservation of the capacity to convert proBNP to mature BNP, but not myocardial injury itself, is associated with future ventricular contractile recovery.

Reduction of tethering distance by papillary muscle tugging approximation with mitral valve replacement for non-ischemic functional mitral regurgitation induces left ventricular reverse remodeling
Takahiro Ishigaki, Satoru Wakasa, Yasushige Shingu, Yohei Ohkawa, Akira Yamada, Toshihisa Anzai, Yoshiro Matsui
Journal of Cardiology, 79, 4, 530, 536, Elsevier BV, 2021年11月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Functional mitral regurgitation (FMR) is caused by left ventricular (LV) remodeling and subsequent tethering of the mitral valve (MV). If LV remodeling is irreversibly advanced, it could not be attenuated by the MV procedure alone, although the additional subvalvular procedure could induce LV reverse remodeling by forcibly reducing MV tethering. This study aimed to assess the anti-tethering effect of papillary muscle tugging approximation (PMTA) on LV reverse remodeling after mitral valve replacement (MVR) for non-ischemic FMR. METHODS: The study subjects were 19 patients who underwent MVR with and without PMTA [MVR + PMTA (n = 11) and MVR alone (n = 8), respectively] for non-ischemic FMR. The tethering distance (TD) and LV end-systolic volume (ESV) at the preoperative, postoperative, and follow-up periods were assessed in terms of their correlation and time-dependent changes. The intra-LV energy efficiency was also evaluated through vector flow mapping analysis. RESULTS: TD and ESV were comparable between both procedures preoperatively and did not change after MVR alone. In MVR + PMTA, however, a significant decrease was identified in TD and ESV at the early postoperative and follow-up periods, respectively [TD = 48, 30, and 31 mm (p < 0.001) and ESV = 159, 133, and 82 mL (p < 0.001) at the preoperative, postoperative, and follow-up periods, respectively]. Finally, at follow-up, the extent of change from the preoperative value in ESV significantly correlated with that in TD (ρ = 0.81, p < 0.001 for overall; ρ = 0.93, p < 0.001 for MVR + PMTA; ρ = 0.86, p = 0.011 for MVR alone). The ratio of TD to ESV was also significantly correlated with systolic energy loss to LV stroke work after MVR + PMTA (ρ = 0.81, p = 0.015). CONCLUSIONS: PMTA for non-ischemic FMR could induce LV reverse remodeling depending on the extent of postoperative TD reduction. A smaller TD to ESV was associated with a higher intra-LV energy efficiency after PMTA + MVR.

Performance of the H2FPEF and the HFA-PEFF scores for the diagnosis of heart failure with preserved ejection fraction in Japanese patients: A report from the Japanese multicenter registry.
Atsushi Tada, Toshiyuki Nagai, Kazunori Omote, Hiroyuki Iwano, Shingo Tsujinaga, Kiwamu Kamiya, Takao Konishi, Takuma Sato, Hirokazu Komoriyama, Yuta Kobayashi, Sakae Takenaka, Yoshifumi Mizuguchi, Tomoya Sato, Kazuhiro Yamamoto, Tsutomu Yoshikawa, Yoshihiko Saito, Toshihisa Anzai
International journal of cardiology, 342, 43, 48, 2021年11月01日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Diagnosing heart failure with preserved ejection fraction (HFpEF) is challenging. Although the H2FPEF score and HFA-PEFF algorithm have been proposed for diagnosing HFpEF, previous validation studies were conducted in stable chronic heart failure (HF). Moreover, information on their applicability in the Asian population is limited. We sought to investigate these scores' diagnostic performance for HFpEF in Japanese patients recently hospitalized due to acute decompensated HF. METHODS: We examined patients with HFpEF recently hospitalized with acute decompensated HF from a nationwide HFpEF-specific multicenter registry (HFpEF group) and control patients who underwent echocardiography to investigate the cause of dyspnea in our hospital (Non-HFpEF group). RESULTS: The studied population included 372 patients (194 HFpEF group and 178 Non-HFpEF group; HFpEF prevalence, 52%). A high H2FPEF score (6-9 points) could diagnose HFpEF with a high specificity of 97% and a positive predictive value (PPV) of 94%, and a low H2FPEF score (0-1 point) could rule out HFpEF with a high sensitivity of 97% and a negative predictive value (NPV) of 93%. HFpEF could be diagnosed with a high HFA-PEFF score (5-6 points) (specificity, 84%; PPV, 82%) or ruled out with a low HFA-PEFF score (0-1 point) (sensitivity, 99%; NPV, 89%). The H2FPEF score was significantly superior to the HFA-PEFF score in diagnostic accuracy (area under the curve: 0.89 vs. 0.82, respectively, p = 0.004). CONCLUSIONS: The H2FPEF and the HFA-PEFF scores had acceptable diagnostic accuracy in diagnosing HFpEF in Japanese patients.

Hospitalization for heart failure in the USA, UK, Taiwan and Japan: an international comparison of administrative health records on 417,385 individual patients.
Varun Sundaram, Toshiyuki Nagai, Chern-En Chiang, Yogesh Nv Reddy, Tze-Fan Chao, Rosita Zakeri, Chloe Bloom, Michikazu Nakai, Kunihiro Nishimura, Chung-Lieh Hung, Yoshihiro Miyamoto, Satoshi Yasuda, Amitava Banerjee, Toshihisa Anzai, Daniel I Simon, Sanjay Rajagopalan, John Gf Cleland, Jayakumar Sahadevan, Jennifer K Quint
Journal of cardiac failure, 28, 3, 353, 366, 2021年10月08日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Registries show international variations in the characteristics and outcome of patients with heart failure (HF) but national samples are rarely large, and case-selection may be biased due to enrolment in academic centres. National administrative datasets provide large samples with a low risk of bias. In this study, we compared the characteristics, healthcare resource utilization (HRU) and outcomes of patients with primary HF hospitalizations (HFH) using electronic health records (EHR) from four high-income countries (USA, UK, Taiwan, Japan) on three continents. METHODS AND RESULTS: We used EHR to identify unplanned HFH between 2012-2014. We identified 231,512, 10,991, 36,900 and 133,982 patients with a primary HFH from USA, UK, Taiwan and Japan, respectively. HFH per 100,000 population was highest in USA and lowest in Taiwan. Patients in Taiwan and Japan were older but fewer were obese or had chronic kidney disease. LOHS was shortest in USA (median 4 days) and longer in UK, Taiwan and Japan (medians 7, 9 and 17 days, respectively). HRU during hospitalization was highest in Japan and lowest in UK. Crude and direct standardized in-hospital mortality was lowest in USA (direct standardized rates: 1.8 [95%CI:1.7-1.9]%)and progressively higher in Taiwan (direct standardized rates: 3.9 [95%CI:3.8-4.1]%), UK (direct standardized rates: 6.4 [95%CI:6.1-6.7]%) and Japan (direct standardized rates: 6.7 [95%CI:6.6-6.8]%). 30-day all-cause (25.8%) and HF (7.2%) readmissions were highest in USA and lowest in Japan (11.9% and 5.1% respectively). CONCLUSION: Marked international variations in patient characteristics, HRU and clinical outcome exist; understanding them might inform health care policy and international trial design.

Sudden death after inappropriate shocks of implantable cardioverter defibrillator in a catecholaminergic polymorphic ventricular tachycardia case with a novel RyR2 mutation.
Hideki Itoh, Takashi Murayama, Nagomi Kurebayashi, Seiko Ohno, Takuya Kobayashi, Yusuke Fujii, Masaya Watanabe, Haruo Ogawa, Toshihisa Anzai, Minoru Horie
Journal of electrocardiology, 69, 111, 118, 2021年10月07日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic syndrome and a cause of exercise-related sudden death. CPVT has been reported to be caused by gain of function underlying a mutation of cardiac ryanodine receptor (RyR2). METHODS: In a family with a CPVT patient, genomic DNA was extracted from peripheral blood lymphocytes, and the RyR2 gene underwent target gene sequence using MiSeq. The activity of wild-type (WT) and mutant RyR2 channel were evaluated by monitoring Ca2+ signals in HEK293 cells expressing WT and mutant RyR2. We investigated a role of a RyR2 mutation in the recent tertiary structure of RyR2. RESULTS: Though a 17-year-old man diagnosed as CPVT had implantable cardioverter defibrillator (ICD) and was going to undergo catheter ablation for the control of paroxysmal atrial fibrillation, he suddenly died at the age of twenty-one because of ventricular fibrillation which was spontaneously developed after maximum inappropriate ICD shocks against rapid atrial fibrillation. The genetic test revealed a de novo RyR2 mutation, Gln4936Lys in mosaicism which was located at the α-helix interface between U-motif and C-terminal domain. In the functional analysis, Ca2+ release from endoplasmic reticulum via the mutant RyR2 significantly increased than that from WT. CONCLUSION: A RyR2 mutation, Gln4936Lys, to be documented in a CPVT patient with exercise-induced ventricular tachycardias causes an excessive Ca2+ release from the sarcoplasmic reticulum which corresponded to clinical phenotypes of CPVT. The reduction of inappropriate shocks of ICD is essential to prevent unexpected sudden death in patients with CPVT.

Paravalvular leak vanishing at end-diastole during transcatheter aortic valve replacement.
Yoji Tamaki, Shingo Tsujinaga, Hiroyuki Iwano, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
Journal of echocardiography, 21, 2, 81, 82, 2021年10月06日, ［国内誌］
英語, 研究論文（学術雑誌）

Influence of left ventricular systolic dysfunction on occurrence of pulsus tardus in patients with aortic stenosis.
Suguru Ishizaka, Hiroyuki Iwano, Ko Motoi, Yasuyuki Chiba, Shingo Tsujinaga, Asuka Tanemura, Michito Murayama, Masahiro Nakabachi, Shinobu Yokoyama, Hisao Nishino, Kazunori Okada, Sanae Kaga, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
Journal of cardiology, 78, 4, 322, 327, 2021年10月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Although the time difference between peak of left ventricular (LV) and aortic systolic pressures (TLV-Ao), which is considered to in part reflect pulsus tardus, is reported to be associated with clinical outcome in aortic stenosis (AS), its physiological determinants remain to be elucidated. We hypothesized that not only AS severity but also LV systolic dysfunction could be associated with occurrence of pulsus tardus. METHODS: TLV-Ao was measured by simultaneous LV and aortic pressure tracing in 74 AS patients and prolonged TLV-Ao was defined as ≥66 ms according to the previous report. Mean transaortic valvular pressure gradient (mPG) and effective orifice area index (EOAI) were estimated by Doppler echocardiography and severe AS was defined as EOAI ≤0.60 cm2/m2. Global longitudinal strain (GLS) was measured by using speckle-tracking method. RESULTS: Although a weak correlation was observed between EOAI and TLV-Ao, there was substantial population showing discordance between the parameters: severe AS despite normal TLV-Ao (10 of 47 patients) and moderate AS despite prolonged TLV-Ao (9 of 17 patients). In severe AS, mPG was significantly higher in patients showing prolonged TLV-Ao (57±20 vs 36±10 mmHg, p<0.0001) whereas GLS was comparable between the groups (-15.2±3.5% vs -14.8±3.2%). In contrast, in moderate AS, GLS was significantly smaller in patients showing prolonged TLV-Ao (-12.6±4.7% vs -17.4±3.4%, p=0.0271) while mPG was comparable (34±7 mmHg vs 35±8 mmHg). Multivariable analysis revealed that not only mPG but also GLS was an independent determinant of TLV-Ao. CONCLUSIONS: The occurrence of pulsus tardus could be associated with not only AS severity but also LV systolic dysfunction in AS patients.

Influence of Left Ventricular Function on the "Aortic Regurgitation Index" Proposed for the Hemodynamic Assessment of Postprocedural Aortic Regurgitation.
Hideaki Kanzaki, Makoto Amaki, Atsushi Okada, Hiroyuki Takahama, Chisato Izumi, Toshihisa Anzai
International heart journal, 62, 5, 1019, 1025, 2021年09月30日, ［国内誌］
英語, 研究論文（学術雑誌）, The aortic regurgitation (AR) index, proposed as an objective indicator of postprocedural AR, decreases in proportion to AR severity, besides reportedly providing additional prognostic information. Meanwhile, left ventricular (LV) function has also been considered an essential prognostic factor. This study aimed to clarify whether LV function affected the AR index using cardiac catheterization data.A retrospective study was performed in patients whose LV function was evaluated using a micromanometer-tipped catheter. Patients with grade 2 or higher AR were excluded to explore non-AR factors affecting the AR index value. The AR index was calculated as a ratio of the gradient between the aortic diastolic blood pressure (DBP) and the LV end-diastolic pressure (EDP) to the aortic systolic blood pressure (SBP): AR Index = [ (DBP - LVEDP) / SBP] × 100.A total of 64 patients [age, 62 (interquartile range: 48-70) years; LV ejection fraction, 19% (16%-26%) ] were examined. AR index values ranged from 18.3 to 68.6. Despite having no AR, two patients displayed an AR index < 25, indicating significant AR. Multiple-regression analysis revealed that LV diastolic stiffness (β = -0.750, P < 0.001), LV max dP/dt (β = -0.296, P = 0.006), and heart rate (β = 0.284, P = 0.011) were independent determinants of the AR index value.Patients with impaired LV diastolic function and preserved systolic function had low AR index values. The additional prognostic information of the AR index may be related to LV diastolic function.

Application of the proximal isovelocity surface area method for estimation of the effective orifice area in aortic stenosis.
Masahiro Nakabachi, Hiroyuki Iwano, Michito Murayama, Hisao Nishino, Shinobu Yokoyama, Shingo Tsujinaga, Yasuyuki Chiba, Suguru Ishizaka, Ko Motoi, Kazunori Okada, Sanae Kaga, Mutsumi Nishida, Takanori Teshima, Toshihisa Anzai
Heart and vessels, 37, 4, 638, 646, 2021年09月25日, ［国内誌］
英語, 研究論文（学術雑誌）, Although the echocardiographic effective orifice area (EOA) calculated using the continuity equation is widely used for the assessment of severity in aortic stenosis (AS), the existence of high flow velocity at the left ventricular outflow tract (LVOT) potentially causes its overestimation. The proximal isovelocity surface area (PISA) method could be an alternative tool for the estimation of EOA that limits the influence of upstream flow velocity. EOA was calculated using the continuity equation (EOACont) and PISA method (EOAPISA), respectively, in 114 patients with at least moderate AS. The geometric orifice area (GOA) was also measured using the planimetry method in 51 patients who also underwent three-dimensional transesophageal echocardiography. Patients were divided into two groups according to the median LVOT flow velocity. EOAPISA could be obtained in 108 of the 114 patients (95%). Although there was a strong correlation between EOACont and EOAPISA (r = 0.78, P < 0.001), EOACont was statistically significantly larger than EOAPISA (0.86 ± 0.33 vs 0.75 ± 0.29 cm2, P < 0.001). Both EOACont and EOAPISA similarly correlated with GOA (r = 0.70, P < 0.001 and r = 0.77, P < 0.001, respectively). However, a fixed bias, which is hydrodynamically supposed to exist between EOA and GOA, was not observed between EOACont and GOA. In contrast, there was a negative fixed bias between EOAPISA and GOA with smaller EOAPISA than GOA. The difference between EOACont and GOA was significantly greater with a larger EOACont relative to GOA in patients with high LVOT flow velocity than in those without (0.16 ± 0.25 vs - 0.07 ± 0.10 cm2, P < 0.001). In contrast, the difference between EOAPISA and GOA was consistent regardless of the LVOT flow velocity (- 0.07 ± 0.12 vs - 0.07 ± 0.15 cm2, P = 0.936). The PISA method was applied to estimate EOA in patients with AS. EOAPISA could be an alternative parameter for AS severity grading in patients with high LVOT flow velocity in whom EOACont would potentially overestimate the orifice area.

Association of high serum soluble interleukin 2 receptor levels with risk of adverse events in cardiac sarcoidosis.
Yuta Kobayashi, Takuma Sato, Toshiyuki Nagai, Kenji Hirata, Satonori Tsuneta, Yoshiya Kato, Hirokazu Komoriyama, Kiwamu Kamiya, Takao Konishi, Kazunori Omote, Hiroshi Ohira, Kohsuke Kudo, Satoshi Konno, Toshihisa Anzai
ESC heart failure, 8, 6, 5282, 5292, 2021年09月12日, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Although soluble interleukin 2 receptor (sIL-2R) is a potentially useful biomarker in the diagnosis and evaluation of disease severity in patients with sarcoidosis, its prognostic implication in patients with cardiac sarcoidosis (CS) is unclear. We sought to investigate whether sIL-2R was associated with clinical outcomes and to clarify the relationship between sIL-2R levels and disease activity in patients with CS. METHODS AND RESULTS: We examined 83 consecutive patients with CS in our hospital who had available serum sIL-2R data between May 2003 and February 2020. The primary outcome was a composite of advanced atrioventricular block, ventricular tachycardia or ventricular fibrillation, heart failure hospitalization, and all-cause death. Inflammatory activity in the myocardium and lymph nodes was assessed by 18 F-fluorideoxyglucose positron emission tomography/computed tomography. During a median follow-up period of 2.96 (IQR 2.24-4.27) years, the primary outcome occurred in 24 patients (29%). Higher serum sIL-2R levels (>538 U/mL, the median) were significantly related to increased incidence of primary outcome (P = 0.037). Multivariable Cox regression analysis showed that a higher sIL-2R was independently associated with an increased subsequent risk of adverse events (HR 3.71, 95% CI 1.63-8.44, P = 0.002), even after adjustment for significant covariates. sIL-2R levels were significantly correlated to inflammatory activity in lymph nodes (r = 0.346, P = 0.003) but not the myocardium (r = 0.131, P = 0.27). CONCLUSIONS: Increased sIL-2R is associated with worse long-term clinical outcomes accompanied by increased systemic inflammatory activity in CS patients.

心臓サルコイドーシス患者における血清可溶性インターロイキン2レセプター高値は長期予後と関連する　　　　　　　　　　　　　　　
小林 雄太, 永井 利幸, 加藤 喜哉, 小森山 弘和, 神谷 究, 小西 崇夫, 佐藤 琢真, 安斉 俊久
日本心臓病学会学術集会抄録, 69回, O, 282, (一社)日本心臓病学会, 2021年09月
日本語

慢性心不全における右室cardiac power outputの意義　　　　　　　　　　　　　　　
千葉 泰之, 岩野 弘幸, 本居 昂, 石坂 傑, 辻永 真吾, 村山 迪史, 横山 しのぶ, 中鉢 雅大, 西野 久雄, 岡田 一範, 加賀 早苗, 神谷 究, 永井 利幸, 安斉 俊久
日本心臓病学会学術集会抄録, 69回, O, 029, (一社)日本心臓病学会, 2021年09月
日本語

器質的心疾患患者における繰り返す心室頻拍後の心臓死規定因子の検討　　　　　　　　　　　　　　　
小泉 拓也, 鎌田 塁, 夏井 宏征, 門坂 崇秀, 中尾 元基, 甲谷 太郎, 萩原 光, 渡邉 昌也, 横式 尚司, 安斉 俊久
日本心臓病学会学術集会抄録, 69回, O, 232, (一社)日本心臓病学会, 2021年09月
日本語

Relevance of early-diastolic mitral regurgitation in dilated heart.
Asuka Tanemura, Michito Murayama, Hiroyuki Iwano, Yasuyuki Chiba, Mutsumi Nishida, Takanori Teshima, Toshihisa Anzai
Journal of echocardiography, 21, 1, 50, 52, 2021年08月30日, ［国内誌］
英語, 研究論文（学術雑誌）

心筋梗塞後偽性仮性左室瘤に収縮性心膜炎の合併が考えられた1例
甲谷 太郎, 安斉 俊久
循環器専門医, 30, 118, 123, (一社)日本循環器学会, 2021年08月
日本語, 50歳男性。歩行時のふらつきに対する精査目的で当科へ入院となった。軽胸壁心エコー検査および造影CT、心臓MRI、冠動脈造影検査より発症時期不明の陳旧性心筋梗塞後左室仮性瘤に収縮性心膜炎を合併したと考えられた。本症例は組織癒着・心嚢液貯留によって心タンポナーデ様の血行動態を呈しており、左室瘤破裂も懸念されたため、治療は準緊急で冠動脈バイパス術・左室形成術、心膜切除術が行われた。その結果、術中所見と病理組織所見より確定診断が得られた。

Long-Term Prognostic Significance of Ventricular Repolarization Dispersion in Patients with Cardiac Sarcoidosis.
Yuta Kobayashi, Toshiyuki Nagai, Sakae Takenaka, Yoshiya Kato, Hirokazu Komoriyama, Nobutaka Nagano, Kiwamu Kamiya, Takao Konishi, Takuma Sato, Kazunori Omote, Shingo Tsujinaga, Hiroyuki Iwano, Kengo Kusano, Satoshi Yasuda, Hisao Ogawa, Hatsue Ishibashi-Ueda, Toshihisa Anzai
The American journal of cardiology, 152, 125, 131, 2021年08月01日, ［国際誌］
英語, 研究論文（学術雑誌）, Cardiac sarcoidosis (CS) is frequently complicated by fatal ventricular arrhythmias. T-peak to T-end interval to QT interval ratio (TpTe/QT) on electrocardiograms (ECG) was proposed as a marker of ventricular repolarization dispersion. Although this ratio could be associated with the incidence of ventricular arrhythmias in cardiovascular diseases, its prognostic implication in patients with CS is unclear. We sought to investigate whether TpTe/QT was associated with long-term clinical outcomes in patients with CS. Ninety consecutive patients with CS in 2 tertiary hospitals who had ECG data before initiation of immunosuppressive therapy between November 1995 and March 2019 were examined. The primary outcome was a composite of advanced atrioventricular block, ventricular tachycardia or ventricular fibrillation (VT/VF), heart failure hospitalization, and all-cause death. During a median follow-up period of 4.70 (interquartile range 2.06-7.23) years, the primary outcome occurred in 21 patients (23.3%). Survival analyses revealed that the primary outcome (p < 0.001), especially VT/VF or sudden cardiac death (p = 0.002), occurred more frequently in patients with higher TpTe/QT (≥ 0.242, the median) than in those with lower TpTe/QT. Multivariable Cox regression analysis showed that a higher TpTe/QT was independently associated with increased subsequent risk of adverse events (hazard ratio1.11, 95% confidence interval 1.03-1.20, p = 0.008) even after adjustment for the significant covariates. In conclusion, a higher TpTe/QT was associated with worse long-term clinical outcomes, especially fatal ventricular arrhythmic events, in patients with cardiac sarcoidosis, suggesting the importance of assessing TpTe/QT as a surrogate for risk stratification in these patients.

Fulminant cardiac and renal sarcoidosis revealed by electron microscope: challenging aspect of diagnosis
Seiichiro Naito, Shingo Tsujinaga, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
European Heart Journal - Case Reports, 5, 11, ytab298, Oxford University Press (OUP), 2021年07月28日, ［国際誌］
英語, 研究論文（学術雑誌）

Hybrid epicardial ventricular tachycardia ablation with lateral thoracotomy in a patient with a history of left ventricular reconstruction surgery
Taro Koya, Masaya Watanabe, Rui Kamada, Hikaru Hagiwara, Motoki Nakao, Takahide Kadosaka, Takuya Koizumi, Toshihisa Anzai
Journal of Cardiology Cases, 25, 1, 37, 41, Elsevier BV, 2021年07月, ［国内誌］
英語, 研究論文（学術雑誌）, Although a hybrid procedure involving surgical access may be feasible for epicardial catheter ablation in individuals with prior cardiac surgery, surgical approaches in thoracotomy are important in patients with advanced adhesions. We performed an epicardial ventricular tachycardia (VT) ablation in a patient with dilated phase hypertrophic cardiomyopathy after left ventricular reconstruction. We gained surgical epicardial access via lateral thoracotomy based on the anticipated VT circuit in the apical anteroseptal area, which was estimated using prior endocardial mapping. The remaining epicardial myocardium around the surgical incision was involved in the central isthmus, and the VT was eliminated by radiofrequency catheter ablation. .

Simple Two-Dimensional Echocardiographic Scoring System for the Estimation of Left Ventricular Filling Pressure.
Michito Murayama, Hiroyuki Iwano, Hisao Nishino, Shingo Tsujinaga, Masahiro Nakabachi, Shinobu Yokoyama, Miho Aiba, Kazunori Okada, Sanae Kaga, Miwa Sarashina, Yasuyuki Chiba, Suguru Ishizaka, Ko Motoi, Mutsumi Nishida, Hitoshi Shibuya, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography, 34, 7, 723, 734, 2021年07月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: When left ventricular filling pressure (LVFP) increases, the mitral valve opens early and precedes tricuspid valve opening in early diastole. The authors hypothesized that a visually assessed time sequence of atrioventricular valve opening could become a new marker of elevated LVFP. The aim of this study was to test the diagnostic ability of a novel echocardiographic scoring system, the visually assessed time difference between mitral valve and tricuspid valve opening (VMT) score, in patients with heart failure. METHODS: One hundred nineteen consecutive patients who underwent cardiac catheterization within 24 hours of echocardiographic examination were retrospectively analyzed as a derivation cohort. In addition, a prospective study was conducted to validate the diagnostic ability of the VMT score in 50 patients. Elevated LVFP was defined as mean pulmonary artery wedge pressure (PAWP) ≥ 15 mm Hg. The time sequence of atrioventricular valve opening was visually assessed and scored (0 = tricuspid valve first, 1 = simultaneous, 2 = mitral valve first). When the inferior vena cava was dilated, 1 point was added, and VMT score was ultimately graded as 0 to 3. Cardiac events were recorded for 1 year after echocardiography. RESULTS: In the derivation cohort, PAWP was elevated with higher VMT scores (score 0, 10 ± 5; score 1, 12 ± 4; score 2, 22 ± 8; score 3, 28 ± 4 mm Hg; P < .001, analysis of variance). VMT score ≥ 2 predicted elevated PAWP with accuracy of 86% and showed incremental predictive value over clinical variables and guideline-recommended diastolic function grading. These observations were confirmed in the prospective validation cohort. Importantly, VMT score ≥ 2 discriminated elevated PAWP with accuracy of 82% in 33 patients with monophasic left ventricular inflow in the derivation cohort. Kaplan-Meier analysis demonstrated that patients with VMT scores ≥ 2 were at higher risk for cardiac events than those with VMT scores ≤ 1 (P < .001). CONCLUSIONS: VMT scoring could be a novel additive marker of elevated LVFP and might also be associated with adverse outcomes in patients with heart failure.

Blood flow dynamics with four-dimensional flow cardiovascular magnetic resonance in patients with aortic stenosis before and after transcatheter aortic valve replacement.
Hirokazu Komoriyama, Kiwamu Kamiya, Toshiyuki Nagai, Noriko Oyama-Manabe, Satonori Tsuneta, Yuta Kobayashi, Yoshiya Kato, Miwa Sarashina, Kazunori Omote, Takao Konishi, Takuma Sato, Shingo Tsujinaga, Hiroyuki Iwano, Yasushige Shingu, Satoru Wakasa, Toshihisa Anzai
Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance, 23, 1, 81, 81, 2021年06月28日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Pre- and post-procedural hemodynamic changes which could affect adverse outcomes in aortic stenosis (AS) patients who undergo transcatheter aortic valve replacement (TAVR) have not been well investigated. Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) enables accurate analysis of blood flow dynamics such as flow velocity, flow pattern, wall shear stress (WSS), and energy loss (EL). We sought to examine the changes in blood flow dynamics of patients with severe AS who underwent TAVR. METHODS: We examined 32 consecutive severe AS patients who underwent TAVR between May 2018 and June 2019 (17 men, 82 ± 5 years, median left ventricular ejection fraction 61%, 6 self-expanding valve), after excluding those without CMR because of a contraindication or inadequate imaging from the analyses. We analyzed blood flow patterns, WSS and EL in the ascending aorta (AAo), and those changes before and after TAVR using 4D flow CMR. RESULTS: After TAVR, semi-quantified helical flow in the AAo was significantly decreased (1.4 ± 0.6 vs. 1.9 ± 0.8, P = 0.002), whereas vortical flow and eccentricity showed no significant changes. WSS along the ascending aortic circumference was significantly decreased in the left (P = 0.038) and left anterior (P = 0.033) wall at the basal level, right posterior (P = 0.011) and left (P = 0.010) wall at the middle level, and right (P = 0.012), left posterior (P = 0.019) and left anterior (P = 0.028) wall at the upper level. EL in the AAo was significantly decreased (15.6 [10.8-25.1 vs. 25.8 [18.6-36.2]] mW, P = 0.012). Furthermore, a significant negative correlation was observed between EL and effective orifice area index after TAVR (r = - 0.38, P = 0.034). CONCLUSIONS: In severe AS patients undergoing TAVR, 4D flow CMR demonstrates that TAVR improves blood flow dynamics, especially when a larger effective orifice area index is obtained.

Takotsubo Syndrome After Transcatheter Mitral Valve Repair.
Takahide Kadosaka, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 85, 7, 1100, 1100, 2021年06月25日, ［国内誌］
英語, 研究論文（学術雑誌）

Applicability of the AHA/ACC/HRS Guideline for Implantable Cardioverter Defibrillator Implantation in Japanese Patients With Cardiac Sarcoidosis.
Sakae Takenaka, Yuta Kobayashi, Toshiyuki Nagai, Yoshiya Kato, Hirokazu Komoriyama, Nobutaka Nagano, Kiwamu Kamiya, Takao Konishi, Takuma Sato, Kazunori Omote, Yoshifumi Mizuguchi, Atsushi Tada, Tomoya Sato, Hiroyuki Iwano, Kengo Kusano, Hatsue Ishibashi-Ueda, Toshihisa Anzai
JACC. Clinical electrophysiology, 7, 11, 1410, 1418, (一社)日本心臓病学会, 2021年06月22日, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: This study aimed to assess, among Japanese patients with cardiac sarcoidosis (CS), the implantable cardioverter-defibrillator (ICD) recommendations from the 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death (SCD). BACKGROUND: Although ICDs are used to prevent SCD from ventricular tachycardia or ventricular fibrillation (VT/VF) in patients with CS, the generalizability of the AHA/ACC/HRS guidelines for Japanese patients with CS remains unclear. METHODS: This study examined 188 consecutive patients with CS in 2 tertiary hospitals between 1979 and 2020. Patients were followed for a primary outcome of VT/VF or SCD. RESULTS: During a median follow-up of 5.68 years, the primary outcome occurred in 44 patients (23%). Patients with a class I recommendation for ICD implantation showed the highest incidence of the primary outcome among patients in whom the guideline recommendations for ICD implantation were used (log-rank test; p = 0.03). However, compared with patients with left ventricular ejection fractions (LVEFs) ≤35%, there was no significant difference in the incidence of the primary outcome among patients with LVEFs >35% and those who required a permanent pacemaker (p = 0.31); similar results were observed in those with LVEFs >35% and late gadolinium enhancement during cardiovascular magnetic resonance imaging (p = 0.22). CONCLUSIONS: The American guideline recommendations for ICD implantation might be applicable to Japanese patients with CS. Implantation of an ICD may need to be considered in these patients if they require a permanent pacemaker or have late gadolinium enhancement, regardless of LVEF.

Improved Mitochondria! Function by Luseogliflozin Prevents Pancreatic Beta-Cell Damage
Yuki Yamauchi, Akinobu Nakamura, Takashi Yokota, Kiyohiko Takahashi, Shinichiro Kawata, Kazuhisa Tsuchida, Kazuno Omori, Hiroshi Nomoto, Hiraku Kameda, Kyuyong Cho, Toshihisa Anzai, Shinya Tanaka, Yasuo Terauchi, Hideaki Miyoshi, Tatsuya Atsumi
DIABETES, 70, AMER DIABETES ASSOC, 2021年06月
英語

Prognostic value of admission serum magnesium in acute myocardial infarction complicated by malignant ventricular arrhythmias.
Yoshifumi Mizuguchi, Takao Konishi, Toshiyuki Nagai, Tomoya Sato, Sakae Takenaka, Atsushi Tada, Yuta Kobayashi, Hirokazu Komoriyama, Yoshiya Kato, Kazunori Omote, Takuma Sato, Kiwamu Kamiya, Shingo Tsujinaga, Hiroyuki Iwano, Kenjiro Kikuchi, Shinya Tanaka, Toshihisa Anzai
The American journal of emergency medicine, 44, 100, 105, 2021年06月, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: Although electrolyte abnormalities are related to worse clinical outcomes in patients with acute myocardial infarction (AMI), little is known about the association between admission serum magnesium level and adverse events in AMI patients complicated by out-of-hospital cardiac arrest presenting with malignant ventricular arrhythmias (OHCA-MVA). We investigated the prognostic value of serum magnesium level on admission in these patients. METHODS: We retrospectively analyzed the data of 165 consecutive reperfused AMI patients complicated with OHCA-MVA between April 2007 and February 2020 in our university hospital. Serum magnesium concentration was measured on admission. The primary outcome was in-hospital death. RESULTS: Fifty-four patients (33%) died during hospitalization. Higher serum magnesium level was significantly related to in-hospital death (Fine & Gray's test; p < 0.001). In multivariable logistic regression analyses, serum magnesium level on admission was independently associated with in-hospital death (hazard ratio 2.68, 95% confidence interval 1.24-5.80) even after adjustment for covariates. Furthermore, the incidences of cardiogenic shock necessitating an intra-aortic balloon pump (p = 0.005) or extracorporeal membrane oxygenation (p < 0.001), tracheal intubation (p < 0.001) and persistent vegetative state (p = 0.002) were significantly higher in patients with higher serum magnesium level than in those with lower serum magnesium level. CONCLUSIONS: In reperfused AMI patients complicated by OHCA-MVA, admission serum magnesium level might be a potential surrogate marker for predicting in-hospital death.

Anemia has an impact on prognosis in heart failure with preserved ejection fraction with mild chronic kidney disease.
Keisuke Okuno, Yoshiro Naito, Masanori Asakura, Masataka Sugahara, Tetsuo Horimatsu, Seiki Yasumura, Saki Tahara, Toshiyuki Nagai, Yoshihiko Saito, Tsutomu Yoshikawa, Tohru Masuyama, Masaharu Ishihara, Toshihisa Anzai
International journal of cardiology. Heart & vasculature, 34, 100796, 100796, 2021年06月, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Anemia and chronic kidney disease (CKD) are common in patients with heart failure with preserved left ventricular fraction (HFpEF). However, it is entirely unknown about the impact of anemia on prognosis in HFpEF patients with CKD. In this study, we investigated the impact of anemia on prognosis and the optimal hemoglobin (Hb) levels to predict prognosis in HFpEF patients with CKD. Methods and Results: We prospectively examined 523 consecutive HFpEF patients enrolled in Japanese heart failure syndrome with preserved ejection fraction registry. CKD was defined as an estimated glomerular filtration rate (eGFR) of <60 mL /min/1.73 m2. The prevalence rate of anemia was 78% in HFpEF patients with CKD by using the World Health Organization criteria. Kaplan-Meier analysis for all-cause mortality and heart failure rehospitalization demonstrated that anemic patients had poor prognosis compared with non-anemic patients in HFpEF patients with CKD, but not those without CKD. According to the degree of CKD, anemia affected prognosis in HFpEF patients with mild CKD (45 ≤ eGFR < 60), but not those with moderate to severe CKD (15 ≤ eGFR < 45). Additionally, multivariate analysis revealed that anemia and Hb levels were independent predictors of composite outcomes in HFpEF patients with mild CKD, but not those with moderate to severe CKD. Finally, survival classification and regression tree analysis showed that the optimal Hb levels to predict composite outcomes were 10.7 g/dL in those with mild CKD. Conclusions: Anemia has an impact on prognosis in HFpEF patients, especially among those with mild CKD.

4-Dimensional Flow Cardiovascular Magnetic Resonance Imaging of Changes in Blood Flow Dynamics After Surgery for Discrete Subaortic Stenosis.
Hirokazu Komoriyama, Kiwamu Kamiya, Yuta Kobayashi, Satonori Tsuneta, Takao Konishi, Takuma Sato, Hiroyuki Iwano, Toshiyuki Nagai, Satoru Wakasa, Kohsuke Kudo, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 85, 6, 954, 954, 2021年05月25日, ［国内誌］
英語, 研究論文（学術雑誌）

Intramural Tissueの二つの遅延伝導領域を交互に伝播することで維持されるリエントリーを機序とする交代性QRS波形を呈するVTを認めた非虚血性心筋症の1例　　　　　　　　　　　　　　　
鎌田 塁, 渡邉 昌也, 天満 太郎, 萩原 光, 甲谷 太郎, 中尾 元基, 安斉 俊久, 横式 尚司, 四倉 昭彦, 南部 忠詞, 吉田 泉, 櫻井 正之
臨床心臓電気生理, 44, 183, 191, 臨床心臓電気生理研究会, 2021年05月
日本語, 症例は50代男性。非虚血性心筋症による心室頻拍(VT)に対し心内膜より心筋焼灼術を施行。二つの波形を交互に繰り返すVTが頻発した。心臓MRIでは左室基部側壁と中隔の深部のみに遅延造影を認め、心内膜電位マッピングでも電位波高は保たれていた。基部側壁では右心室からのペーシング中にlate potential(LP)を認め、VT中は各々の波形で連結期が異なる拡張期電位(dp)を認め、連続するdp間隔が各々の波形のRR間隔を規定していた。収縮電位に対する早期性マッピングでは波形aは比較的広範囲に早期性を認めた。波形bでは限局的であった。dpを認める領域への焼灼中にVTは停止し、その後一定の連結期を有する波形aの心室期外収縮(PVC)が出現し、さらなる焼灼によりPVCは消失した。しかしながら半年後に波形aに類似したVT、PVCの再発を認め、心外膜アプローチを含めた再治療を行った。dp、収縮期電位は心外膜で先行し、両側からの焼灼で治療し得た。Intramural tissueに二つの遅延伝導領域が存在する回路が想定された。(著者抄録)

Epsilon wave disappearance by catheter ablation for ventricular arrhythmia from the left ventricular outflow tract.
Hikaru Hagiwara, Masaya Watanabe, Rui Kamada, Taro Koya, Motoki Nakao, Toshihisa Anzai
HeartRhythm case reports, 7, 5, 343, 346, 2021年05月, ［国際誌］
英語

Risk Stratification Towards Precision Medicine in Heart Failure - Current Progress and Future Perspectives.
Toshiyuki Nagai, Motoki Nakao, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 85, 5, 576, 583, 2021年04月23日, ［国内誌］
英語, 研究論文（学術雑誌）, Clinical risk stratification is a key strategy used to identify low- and high-risk subjects to optimize the management, ranging from pharmacological treatment to palliative care, of patients with heart failure (HF). Using statistical modeling techniques, many HF risk prediction models that combine predictors to assess the risk of specific endpoints, including death or worsening HF, have been developed. However, most risk prediction models have not been well-integrated into the clinical setting because of their inadequacy and diverse predictive performance. To improve the performance of such models, several factors, including optimal sampling and biomarkers, need to be considered when deriving the models; however, given the large heterogeneity of HF, the currently advocated one-size-fits-all approach is not appropriate for every patient. Recent advances in techniques to analyze biological "omics" information could allow for the development of a personalized medicine platform, and there is growing awareness that an integrated approach based on the concept of system biology may be an excessively naïve view of the multiple contributors and complexity of an individual's HF phenotype. This review article describes the progress in risk stratification strategies and perspectives of emerging precision medicine in the field of HF management.

JCS/JHFS 2021 Statement on Palliative Care in Cardiovascular Diseases.
Toshihisa Anzai, Takuma Sato, Yoshihiro Fukumoto, Chisato Izumi, Yoshiyuki Kizawa, Masatoshi Koga, Katsuji Nishimura, Mitsuru Ohishi, Akihiro Sakashita, Yasushi Sakata, Tsuyoshi Shiga, Yasuchika Takeishi, Satoshi Yasuda, Kazuhiro Yamamoto, Takahiro Abe, Rie Akaho, Yasuhiro Hamatani, Hayato Hosoda, Naoki Ishimori, Mika Kato, Yoshiharu Kinugasa, Takuro Kubozono, Toshiyuki Nagai, Shogo Oishi, Katsuki Okada, Tatsuhiro Shibata, Atsushi Suzuki, Tsuyoshi Suzuki, Masahito Takagi, Yasuko Takada, Kenkichi Tsuruga, Akiomi Yoshihisa, Dai Yumino, Keiichi Fukuda, Yasuki Kihara, Yoshihiko Saito, Yoshiki Sawa, Hiroyuki Tsutsui, Takeshi Kimura
Circulation journal : official journal of the Japanese Circulation Society, 85, 5, 695, 757, 2021年04月23日, ［国内誌］
英語, 研究論文（学術雑誌）

Announcement of the 2021 JCS Meeting Activities (2).
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 85, 5, 573, 575, 2021年04月23日, ［国内誌］
英語, 研究論文（学術雑誌）

Association of Low Body Weight with Clinical Outcomes in Elderly Atrial Fibrillation Patients Receiving Apixaban-J-ELD AF Registry Subanalysis.
Takahide Kadosaka, Toshiyuki Nagai, Shinya Suzuki, Ichiro Sakuma, Masaharu Akao, Takeshi Yamashita, Toshihisa Anzai, Ken Okumura
Cardiovascular drugs and therapy, 36, 4, 691, 703, 2021年04月08日, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Although direct oral anticoagulants are effective and safe in preventing stroke in atrial fibrillation (AF) patients with low body weight, data remain limited in AF patients with extremely low body weight (<50 kg). We aimed to investigate the association of this body weight category with clinical outcomes in elderly AF patients receiving apixaban. METHODS: The J-ELD AF Registry is a large-scale, multicenter prospective observational study of Japanese non-valvular AF patients aged ≥ 75 years taking on-label doses of apixaban. The entire cohort (3025 patients from 110 institutions) was divided into three body weight subgroups: >60 kg (n = 1019, 33.7%), 50-60 kg (n = 1126, 37.2%), and <50 kg (n = 880, 29.1%). RESULTS: The event incidence rates (/100 person years) were 1.69, 1.82, and 1.23 for stroke or systemic embolism (P = 0.60); 1.37, 1.73, and 2.73 for bleeding requiring hospitalization (P = 0.154); 2.02, 2.67, and 4.92 for total death (P = 0.003); and 0.73, 0.95, and 1.23 for cardiovascular death (P = 0.57), respectively. After adjusting for confounders by Cox regression analysis, body weight <50 kg was not an independent risk for stroke or systemic embolism, bleeding requiring hospitalization, total death, or cardiovascular death. CONCLUSIONS: The incidence of events in each body weight group was comparable for stroke or systemic embolism and bleeding requiring hospitalization, and body weight <50 kg might not be an independent risk for death in Japanese non-valvular AF patients aged ≥ 75 years taking on-label doses of apixaban.

拡張機能学再考:beyond E/E' 時相解析に基づく新たな左室充満圧推定指標 僧帽弁輪石灰化例、心房細動例への適用　　　　　　　　　　　　　　　
岩野 弘幸, 村山 迪史, 辻永 真吾, 千葉 泰之, 石坂 傑, 本居 昂, 中鉢 雅大, 加賀 早苗, 安斉 俊久
超音波医学, 48, Suppl., S205, S205, (公社)日本超音波医学会, 2021年04月
日本語

SK channel blockade prevents hypoxia-induced ventricular arrhythmias through inhibition of Ca2+/voltage uncoupling in hypertrophied hearts.
Masayuki Takahashi, Hisashi Yokoshiki, Hirofumi Mitsuyama, Masaya Watanabe, Taro Temma, Rui Kamada, Hikaru Hagiwara, Yumi Takahashi, Toshihisa Anzai
American journal of physiology. Heart and circulatory physiology, 320, 4, H1456-H1469, 2021年04月01日, ［国際誌］
英語, 研究論文（学術雑誌）, Ventricular arrhythmia (VA) is the major cause of death in patients with left ventricular (LV) hypertrophy and/or acute ischemia. We hypothesized that apamin, a blocker of small-conductance Ca2+-activated K+ (SK) channels, alters Ca2+ handling and exhibits anti-arrhythmic effects in ventricular myocardium. Spontaneous hypertensive rats were used as a model of LV hypertrophy. A dual optical mapping of membrane potential (Vm) and intracellular calcium (Cai) was performed during global hypoxia (GH) on the Langendorff perfusion system. The majority of pacing-induced VAs during GH were initiated by triggered activities. Pretreatment of apamin (100 nmol/L) significantly inhibited the VA inducibility. Compared with SK channel blockers (apamin and NS8593), non-SK channel blockers (glibenclamide and 4-AP) did not exhibit anti-arrhythmic effects. Apamin prevented not only action potential duration (APD80) shortening (-18.7 [95% confidence interval, -35.2 to -6.05] ms vs. -2.75 [95% CI, -10.45 to 12.65] ms, P = 0.04) but also calcium transient duration (CaTD80) prolongation (14.52 [95% CI, 8.8-20.35] ms vs. 3.85 [95% CI, -3.3 to 12.1] ms, P < 0.01), thereby reducing CaTD80 - APD80, which denotes "Cai/Vm uncoupling" (33.22 [95% CI, 22-48.4] ms vs. 6.6 [95% CI, 0-14.85] ms, P < 0.01). The reduction of Cai/Vm uncoupling was attributable to less prolonged Ca2+ decay constant and suppression of diastolic Cai increase by apamin. The inhibition of VA inducibility and changes in APs/CaTs parameters caused by apamin was negated by the addition of ouabain, an inhibitor of Na+/K+ pump. Apamin attenuates APD shortening, Ca2+ handling abnormalities, and Cai/Vm uncoupling, leading to inhibition of VA occurrence in hypoxic hypertrophied hearts.NEW & NOTEWORTHY We demonstrated that hypoxia-induced ventricular arrhythmias were mainly initiated by Ca2+-loaded triggered activities in hypertrophied hearts. The blockades of small-conductance Ca2+-activated K+ channels, especially "apamin," showed anti-arrhythmic effects by alleviation of not only action potential duration shortening but also Ca2+ handling abnormalities, most notably the "Ca2+/voltage uncoupling."

Rapid Publication and Announcement of the 2021 JCS Meeting Activities.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 85, 4, 331, 332, 2021年03月25日, ［国内誌］
英語, 研究論文（学術雑誌）

Characterizing the role of, and physical and emotional burden on caregivers of patients with heart failure: Results from a cross-sectional survey in Japan
Erika Hayashi, Hironobu Mitani, Hiroki Murayama, Toshihisa Anzai, Rachel Studer, Sarah Cotton, James Jackson, Hollie Bailey, Hiroshi Kitagawa, Naotsugu Oyama
Geriatric Nursing, 42, 2, 379, 385, Mosby Inc., 2021年03月01日
英語, 研究論文（学術雑誌）, The aim of this cross-sectional survey was to characterize the role of and burden on caregivers of heart failure (HF) patients in Japan, since such data are limited at present. Data from 126 caregivers whose average age was 63.5 years were analyzed. Helping to prepare meals/cooking was the most frequently reported activity (47% of caregivers)
24% found this the most burdensome. The most frequently reported physical consequence of caregiving was feeling physically tired (44%)
emotionally worrying about the patient (62%) was the most frequent psychological consequence. Approximately half of the caregivers reported that caring for patients impacted their lifestyle. Although 40% of caregivers asked questions to physicians regarding diet or lifestyle modifications, 19% did not ask any. Caregivers play a crucial role in the management of HF patients in Japan but experience physical and emotional burden. Solutions are required to reduce the caregiver burden associated with HF.

循環器疾患患者のこころの問題にどう向き合うか?(緩和ケアも含めて) 当院における心不全緩和ケアチームの立ち上げと現状　　　　　　　　　　　　　　　
阿部 隆宏, 佐藤 琢真, 加藤 美香, 笠谷 美鈴, 成田 尚, 福澤 宏之, 片山 真育, 池田 陽子, 小島 尚子, 杉本 由佳, 永井 利幸, 安斉 俊久
日本循環器学会学術集会抄録集, 85回, CS5, 3, (一社)日本循環器学会, 2021年03月
日本語

Circulation Journal Awards for the Year 2020.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 85, 3, 225, 234, 2021年02月25日, ［国内誌］
英語, 研究論文（学術雑誌）

Takotsubo syndrome in association with acute myocardial infarction: diagnostic caveats and clinical implications. Authors' reply.
Takao Konishi, Naohiro Funayama, Tadashi Yamamoto, Daisuke Hotta, Shinya Tanaka, Toshihisa Anzai
Kardiologia polska, 79, 1, 96, 96, 2021年01月25日, ［国際誌］
英語

Editorial Statistics and Best Reviewers Award for 2020.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 85, 2, 127, 129, 2021年01月25日, ［国内誌］
英語, 研究論文（学術雑誌）

Current practice and effects of intravenous anticoagulant therapy in hospitalized acute heart failure patients with sinus rhythm.
Hiroki Nakano, Yasuhiro Hamatani, Toshiyuki Nagai, Michikazu Nakai, Kunihiro Nishimura, Yoko Sumita, Hisao Ogawa, Toshihisa Anzai
Scientific reports, 11, 1, 1202, 1202, 2021年01月13日, ［国際誌］
英語, 研究論文（学術雑誌）, Although the risk of thromboembolism is increased in heart failure (HF) patients irrespective of atrial fibrillation (AF), especially during the acute decompensated phase, the effects of intravenous anticoagulants for these patients remain unclear. We sought to investigate the current practice and effects of intravenous anticoagulant therapy in acute HF (AHF) patients with sinus rhythm. We analyzed a nationwide prospective cohort from April 2012 to March 2016. We extracted 309,015 AHF adult patients. After application of the exclusion criteria, we divided the 92,573 study population into non-heparin [n = 70,621 (76.3%)] and heparin [n = 21,952 (23.7%)] groups according to the use of intravenous heparin for the first 2 consecutive days after admission. Multivariable logistic regression analyses demonstrated that heparin administration was not associated with in-hospital mortality (OR 0.97, 95% CI 0.91-1.03) and intracranial hemorrhage (OR 1.18, 95% CI 0.78-1.77), while heparin administration was significantly associated with increased incidence of ischemic stroke (OR 1.49, 95% CI 1.29-1.72) and venous thromboembolism (OR 1.62, 95% CI 1.14-2.30). In conclusion, intravenous heparin administration was not associated with favorable in-hospital outcomes in AHF patients with sinus rhythm. Routine additive use of intravenous heparin to initial treatment might not be recommended in AHF patients.

High-Density Lipoprotein Cholesterol and Cardiovascular Events in Patients with Stable Coronary Artery Disease Treated with Statins: An Observation from the REAL-CAD Study.
Kazunori Omote, Isao Yokota, Toshiyuki Nagai, Ichiro Sakuma, Yoshihisa Nakagawa, Kiwamu Kamiya, Hiroshi Iwata, Katsumi Miyauchi, Yukio Ozaki, Kiyoshi Hibi, Takafumi Hiro, Yoshihiro Fukumoto, Hiroyoshi Mori, Seiji Hokimoto, Yasuo Ohashi, Hiroshi Ohtsu, Hisao Ogawa, Hiroyuki Daida, Satoshi Iimuro, Hiroaki Shimokawa, Yasushi Saito, Takeshi Kimura, Masunori Matsuzaki, Ryozo Nagai, Toshihisa Anzai
Journal of atherosclerosis and thrombosis, 29, 1, 50, 68, 2021年01月09日, ［国内誌］
英語, 研究論文（学術雑誌）, AIM: The association between high-density lipoprotein cholesterol (HDL-C) level after statin therapy and cardiovascular events in patients with stable coronary artery disease (CAD) remains unclear. Thus, in this study, we sought to determine how HDL-C level after statin therapy is associated with cardiovascular events in stable CAD patients. METHODS: From the REAL-CAD study which had shown the favorable prognostic effect of high-dose pitavastatin in stable CAD patients with low-density lipoprotein cholesterol (LDL-C) ＜120 mg/dL, 9,221 patients with HDL-C data at baseline and 6 months, no occurrence of primary outcome at 6 months, and reported non-adherence for pitavastatin, were examined. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission after 6 months of randomization. Absolute difference and ratio of HDL-C levels were defined as (those at 6 months-at baseline) and (absolute difference/baseline)×100, respectively. RESULTS: During a median follow-up period of 4.0 (IQR 3.2-4.7) years, the primary outcome occurred in 417 (4.5%) patients. The adjusted risk of all HDL-C-related variables (baseline value, 6-month value, absolute, and relative changes) for the primary outcome was not significant (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.91-1.08, HR 1.03, 95% CI 0.94-1.12, HR 1.05, 95% CI 0.98-1.12, and HR 1.08, 95% CI 0.94-1.24, respectively). Furthermore, adjusted HRs of all HDL-C-related variables remained non-significant for the primary outcome regardless of on-treatment LDL-C level at 6 months. CONCLUSIONS: After statin therapy with modestly controlled LDL-C, HDL-C level has little prognostic value in patients with stable CAD.

CORRIGENDUM: Announcement of the 2021 JCS Meeting Activities (2).
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 86, 1, 171, 171, 2021年, ［国内誌］
英語, 研究論文（学術雑誌）

右房圧の推定に用いられる超音波指標の精度比較
小野田 愛梨, 村山 迪史, 加賀 早苗, 岡田 一範, 相庭 美穂, 藤澤 亮介, 中鉢 雅大, 横山 しのぶ, 西野 久雄, 西田 睦, 岩野 弘幸, 安斉 俊久
超音波検査技術抄録集, 46, S197, S197, 一般社団法人 日本超音波検査学会, 2021年
日本語

Influence of advanced pulmonary vascular remodeling on accuracy of echocardiographic parameters of left ventricular filling pressure
Yasuyuki Chiba, Hiroyuki Iwano, Sanae Kaga, Mio Shinkawa, Michito Murayama, Hiroshi Ohira, Suguru Ishizaka, Miwa Sarashina, Shingo Tsujinaga, Shinobu Yokoyama, Masahiro Nakabachi, Hisao Nishino, Kazunori Okada, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
Pulmonary Circulation, 11, 1, 204589402098372, 204589402098372, SAGE Publications, 2021年01月
研究論文（学術雑誌）, Evaluation of left ventricular filling pressure plays an important role in the clinical management of pulmonary hypertension. However, the accuracy of echocardiographic parameters for the determination of left ventricular filling pressure in the presence of pulmonary vascular lesions has not been fully addressed. We retrospectively investigated 124 patients with pulmonary hypertension due to pulmonary vascular lesions (noncardiac pulmonary hypertension group) and 113 patients with ischemic heart disease (control group) who underwent right heart catheterization and echocardiography. The noncardiac pulmonary hypertension group was subdivided into less-advanced and advanced groups according to median pulmonary vascular resistance. Pulmonary artery wedge pressure was determined as left ventricular filling pressure. As echocardiographic parameters of left ventricular filling pressure, the ratio of early- (E) to late-diastolic transmitral flow velocity (E/A), ratio of E to early-diastolic mitral annular velocity (E/e′), and left atrial volume index were measured. In the less-advanced noncardiac pulmonary hypertension and control groups, positive correlations were observed between pulmonary artery wedge pressure and late-diastolic transmitral flow velocity ( R = 0.41, P = 0.002 and R = 0.71, P < 0.001, respectively) and left atrial volume index ( R = 0.53, P < 0.001 and R = 0.41, P < 0.001), whereas in the advanced noncardiac pulmonary hypertension group, pulmonary artery wedge pressure was only correlated with left atrial volume index ( R = 0.27, P = 0.032). In the controls, only pulmonary artery wedge pressure determined E (β = 0.48, P < 0.001), whereas both pulmonary artery wedge pressure and pulmonary vascular resistance were independent determinants of E (β = 0.29, P < 0.001 and β = –0.28, P = 0.001, respectively) in the noncardiac pulmonary hypertension group. In conclusion, in the presence of advanced pulmonary vascular lesions, conventional echocardiographic parameters may not accurately reflect left ventricular filling pressure. Elevated pulmonary vascular resistance would lower the E, even when pulmonary artery wedge pressure is elevated, resulting in blunting of echocardiographic parameters for the detection of elevated left ventricular filling pressure.

Acute Myocardial Infarction of the Left Main Coronary Artery Presenting with Cardiogenic Shock and Pulmonary Edema during Noncardiac Surgery.
Sakae Takenaka, Takao Konishi, Tomoya Sato, Atsushi Tada, Takuya Koizumi, Yoshifumi Mizuguchi, Takahide Kadosaka, Ko Motoi, Yuta Kobayashi, Hirokazu Komoriyama, Yoshiya Kato, Miwa Sarashina, Kazunori Omote, Shingo Tsujinaga, Takuma Sato, Rui Kamada, Kiwamu Kamiya, Hiroyuki Iwano, Toshiyuki Nagai, Tatsuya Orimo, Hirofumi Kamachi, Akinobu Taketomi, Toshihisa Anzai
Case reports in cardiology, 2021, 5460816, 5460816, 2021年, ［国際誌］
英語, Acute myocardial infarction (AMI) caused by severe stenosis of left main coronary artery (LMCA) presenting with cardiogenic shock and pulmonary edema during noncardiac surgery is uncommon, but a catastrophic event. A 77-year-old male with cholangiocarcinoma underwent hepatectomy. During the surgery, he presented with cardiogenic shock, which did not respond to infusion administration or vasopressor. A transesophageal echocardiogram revealed anterior, septal, and lateral severe hypokinesia and impaired left ventricular function. Emergent coronary angiogram showed severe stenosis of LMCA. The patient underwent primary percutaneous coronary intervention (PCI) under the support of intra-aortic balloon pump, followed by extracorporeal membrane oxygenation. The chest roentgenogram showed pulmonary edema. Two days after PCI, he successfully underwent hepatectomy and bile duct resection. Early identification of the cause of hemodynamic instability during noncardiac surgery and invasive strategy are important for minimizing the myocardial injury and improving clinical outcomes in AMI of LMCA.

The effectiveness of drug-coated balloons for two dissimilar calcific lesions assessed by near-infrared spectroscopy intravascular ultrasound and optical coherence tomography.
Takao Konishi, Kohei Saiin, Youji Tamaki, Hiroyuki Natsui, Tomoya Sato, Sakae Takenaka, Atsushi Tada, Yoshifumi Mizuguchi, Yuta Kobayashi, Hirokazu Komoriyama, Yoshiya Kato, Takuma Sato, Rui Kamada, Kiwamu Kamiya, Toshiyuki Nagai, Shinya Tanaka, Toshihisa Anzai
Cardiology journal, 28, 5, 794, 795, 2021年, ［国際誌］
英語, 研究論文（学術雑誌）

Presence and relevance of mid-systolic notching on right ventricular outflow tract flow velocity envelopes in pulmonary hypertension due to heart failure.
Yasuyuki Chiba, Hiroyuki Iwano, Michito Murayama, Sanae Kaga, Ko Motoi, Suguru Ishizaka, Shingo Tsujinaga, Asuka Tanemura, Shinobu Yokoyama, Masahiro Nakabachi, Hisao Nishino, Kazunori Okada, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography, 34, 6, 690, 692, 2020年12月28日, ［国際誌］
英語, 研究論文（学術雑誌）

Message From the Editor-in-Chief.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 85, 1, 1, 1, 2020年12月25日, ［国内誌］
英語, 研究論文（学術雑誌）

Lower left ventricular ejection fraction and higher serum angiotensin-converting enzyme activity are associated with histopathological diagnosis by endomyocardial biopsy in patients with cardiac sarcoidosis.
Hirokazu Komoriyama, Kazunori Omote, Toshiyuki Nagai, Yoshiya Kato, Nobutaka Nagano, Kazuhiro Koyanagawa, Kiwamu Kamiya, Takao Konishi, Takuma Sato, Yuta Kobayashi, Shingo Tsujinaga, Hiroyuki Iwano, Kengo Kusano, Satoshi Yasuda, Hisao Ogawa, Hatsue Ishibashi-Ueda, Toshihisa Anzai
International journal of cardiology, 321, 113, 117, 2020年12月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The histopathological diagnosis of cardiac sarcoidosis (CS) is challenging because of sampling error in endomyocardial biopsy (EMB) and the determinants of positive EMB are unclear. Reduced left ventricular ejection fraction (LVEF) is a simple parameter of the extent of myocardial damage, and higher serum angiotensin-converting enzyme (ACE) activity would indicate the spread of disease activity in CS patients. Thus, we sought to examine whether these parameters are related to the histopathological diagnosis of CS by EMB. METHODS: A total of 94 consecutive clinically diagnosed CS patients between August 1986 and March 2019 who were admitted to two academic hospitals were examined. We determined EMB as positive if non-caseating epithelioid granulomas were confirmed in the myocardial tissue. Patients were divided into two groups according to positive (n = 37) and negative (n = 57) EMB. We assessed the relationship between LVEF, serum ACE activity and positive EMB. RESULTS: Multivariable analysis revealed that both LVEF and serum ACE were independently associated with positive EMB (OR 0.83, 95% CI 0.70-0.99; OR 1.39, 95% CI 1.02-1.90, respectively). Moreover, patients with both lower LVEF (<37%, median) and higher ACE activity (≥13.5 IU/L, median) had the highest frequency of positive EMB (p = .003). The combination of lower LVEF and higher serum ACE showed better specificity (91.2%) and positive predictive value (73.7%) than either LVEF or serum ACE alone for positive EMB. CONCLUSIONS: Lower LVEF and higher serum ACE activity were associated with positive EMB, suggesting that these parameters might be useful for predicting positive EMB in CS patients.

A propensity score matching analysis for cardio metabolic risk of antipsychotics in patients with schizophrenia using Japanese claims data.
Ichiro Kusumi, Sachie Inoue, Kenji Baba, Tadashi Nosaka, Toshihisa Anzai
BMC psychiatry, 20, 1, 584, 584, 2020年12月09日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The aim of this study was to evaluate the cardio-metabolic risk in schizophrenia patients treated by atypical antipsychotic drugs compared with that in those treated without atypical antipsychotic drugs using a nationwide insurance claims database and medical examination database in Japan. METHODS: Eligible patients were defined as those meeting the following two criteria: (i) A diagnosis of schizophrenia (ICD-10 code: F20) was made between 1 January 2005 and 31 December 2017, with data available for at least 6 months before the diagnosis was made (index month), and (ii) health check-up data were available within ±3 months of the index month. The primary endpoint was changes in cardio-metabolic risk based on the Suita score at 1 year, and the secondary endpoints were changes in medical examination data related to cardio-metabolic risk (total cholesterol [TC], triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, body mass index [BMI], and hemoglobin A1c) at 1 year. The primary endpoint was evaluated by multivariate analysis, with the cumulative chlorpromazine equivalent amount and the baseline Suita score added as covariates. RESULTS: One-hundred eighty five pairs of propensity score (PS)-matched patients were evaluated. Patients receiving atypical antipsychotic drugs exhibited a greater change in the Suita score and a risk of coronary heart disease based on the Suita score of 0.530 and 0.098%, respectively, than patients not receiving atypical antipsychotic drugs, but there was no significant difference (p = 0.412 and 0.610). The significant changes in TC and BMI were determined as 6.525 mg/dL and 0.380 kg/m2 greater, respectively, in patients treated with atypical antipsychotic drugs (p = 0.037 and 0.011). CONCLUSIONS: There were no significant increases in changes in the Suita score at 1 year by treatment with atypical antipsychotic drugs compared with treatment without atypical antipsychotic drugs. However, the TC and BMI were significantly higher in patients treated with atypical antipsychotic drugs.

Refractory Ventricular Tachycardia in a Patient With a Left Ventricular Assist Device Successfully Treated With Stellate Ganglion Phototherapy.
Tomoya Sato, Rui Kamada, Takuya Koizumi, Sakae Takenaka, Atsushi Tada, Shingo Tsujinaga, Takao Konishi, Takuma Sato, Masaya Watanabe, Toshiyuki Nagai, Toshihisa Anzai
The Canadian journal of cardiology, 36, 12, 1977.e1-1977.e3, 2020年12月, ［査読有り］, ［国際誌］
英語, Neuraxial modulation therapies, such as stellate ganglion block, thoracic epidural anaesthesia, and cardiac sympathetic denervation, are effective for ventricular arrhythmias. However, these treatments can increase the risk of bleeding and infection. In this case report, stellate ganglion phototherapy was safely and effectively performed for refractory ventricular tachycardias in a patient with a history of left ventricular assist device implantation. Stellate ganglion phototherapy may have the potential to treat refractory ventricular arrhythmias as an additive therapy or bridge therapy.

Study protocol for prospect trial to elucidate the utility of echocardiography-based cardiac output in acute heart failure (PREDICT).
Hiroyuki Iwano, Kentaro Shibayama, Takeshi Kitai, Kenya Kusunose, Tetsuari Onishi, Hidekazu Tanaka, Toshihisa Anzai
Journal of echocardiography, 18, 4, 235, 239, 2020年12月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Early worsening heart failure (WHF), defined as worsening of symptoms and signs of heart failure requiring intensification of medical or mechanical therapy during an admission for acute decompensated heart failure (ADHF), has recently been recognized as a risk of morbidity or mortality after the discharge. Although echocardiographic parameters of left ventricular (LV) output has been shown to be associated with long-term outcome in heart failure patients, its predictive value for early WHF has not been elucidated. METHODS: Prospect trial to Elucidate the utility of EchocarDiography-based Cardiac output in acute heart failure (PREDICT) is a multicenter, nonrandomized, prospective observational study to test the predictive value of echocardiographic LV output parameters for early WHF in ADHF patients. We will enroll patients admitted to 16 participating hospitals due to ADHF who did not receive positive inotropic agents as an initial therapy. Primary outcome will be set at early WHF defined as need for initiation of positive inotropic agents within 7 days after the admission. Predictive accuracy will be compared between Doppler echocardiographic LV output (stroke distance, stroke volume index, and cardiac index) and low perfusion findings assessed by physical examination. RESULTS: N/A. CONCLUSIONS: The PREDICT is expected to provide large data set to test the predictive value of echocardiographic LV output for early WHF in ADHF patients.

Activation of invariant natural killer T cells by alpha-galactosylceramide ameliorates doxorubicin-induced cardiotoxicity in mice.
Yoshikuni Obata, Naoki Ishimori, Akimichi Saito, Shintaro Kinugawa, Takashi Yokota, Shingo Takada, Ippei Nakano, Naoya Kakutani, Katsuma Yamanashi, Toshihisa Anzai
European journal of preventive cardiology, 27, 19, 2358, 2361, 2020年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

18F-FDG uptake of the right ventricle is an important predictor of histopathologic diagnosis by endomyocardial biopsy in patients with cardiac sarcoidosis.
Kazunori Omote, Masanao Naya, Kazuhiro Koyanagawa, Tadao Aikawa, Osamu Manabe, Toshiyuki Nagai, Kiwamu Kamiya, Yoshiya Kato, Hirokazu Komoriyama, Masato Kuzume, Nagara Tamaki, Toshihisa Anzai
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology, 27, 6, 2135, 2143, 2020年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The aim of this study was to determine whether right ventricle (RV) 18F-fluorodeoxyglucose (FDG) uptake can predict positive findings of endomyocardial biopsy (EMB) in patients with cardiac sarcoidosis (CS). METHODS: 70 consecutive patients with clinically diagnosed CS who had undergone FDG PET were registered in the present study. Patients without EMB (n = 42) were excluded. Ultimately, 28 patients were studied. EMB samples were obtained from the RV septum. We evaluated the FDG uptake on six segments (RV, left ventricle anterior, septal, lateral, inferior, and apex). RESULTS: Positive EMB was found in six patients (21%). Patients were divided into two groups according to positive (n = 12 [43%]) or negative (n = 16 [57%]) RV FDG uptake. Patients with positive RV FDG uptake had a significantly higher frequency of positive EMB than those without (42% vs. 6%, P = 0.024). On the other hand, there was no EMB-predictive value for the FDG uptakes in the other five segments, the cardiac metabolic volume, total lesion glycolysis, left ventricular ejection fraction, or any electrocardiogram findings. CONCLUSIONS: FDG uptake of the RV but no other heart segment was associated with positive EMB in CS patients. The presence of RV FDG uptake could improve the rate of positive EMB up to 42% in patients with CS.

Higher Pulmonary Arterial Pressure Was Related to Non-Pulmonary Vein Atrial Tachyarrhythmia.
Wei-Chieh Lee, Masaya Watanabe, Hisashi Yokoshiki, Taro Temma, Rui Kamada, Hikaru Hagiwara, Yumi Takahashi, Taro Koya, Motoki Nakao, Toshihisa Anzai
International heart journal, 61, 6, 1150, 1156, 2020年11月28日, ［国内誌］
英語, 研究論文（学術雑誌）, Recurrence of atrial tachyarrhythmias (ATA) following catheter ablation for atrial fibrillation (AF) is often associated with the recovery of conduction into previously isolated pulmonary veins (PVs). Little evidence concerning repeat PV isolation (PVI) and non-PV ATA ablation has been reported. This study aimed to explore the clinical outcome of recurrent ATA ablation after PVI and the difference between patients with and without non-PV ATA.A total of 49 patients without structural heart diseases who received catheter ablation for recurrent AF between January 2014 and December 2018 were recruited (prior ablation with PVI only 71.4% and PVI with cavotricuspid isthmus line ablation 28.6%). Patients were divided into two groups according to the presence or absence of non-PV ATA.Most patients (53.1%) experienced very late recurrence with a median duration of 15 months. A total of 15 patients had non-PV ATA and received non-PV ATA ablation whereas 34 patients received only repeat PVI for reconnected PVs. A higher pulmonary arterial systolic pressure (PASP) was associated with non-PV ATA (odds ratio: 1.161; 95% confidence interval: 1.021-1.321; P = 0.023). During 4.7 ± 1 months, 4/15 (26.7%) and 1/34 (2.9%) patients with and without non-PV ATA, respectively, had ATA recurrence (P = 0.011). The cumulative incidence of ATA recurrence after repeat ablation was significantly lower in patients without non-PV ATA (P = 0.013).In our study, a high PASP was associated with non-PV ATA in patients with recurrent AF. Repeat PVI had a high rate of maintenance of sinus rhythm in patients without non-PV ATA.

Message From the Editor-in-Chief.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 84, 12, 2127, 2128, 2020年11月25日, ［国内誌］
英語, 研究論文（学術雑誌）

Burden of Heart Failure on Patient Daily Life and Patient-Physician Discordance in Disease Management - Results From a Cross-Sectional Survey in Japan.
Tomoko Hayashi, Yohei Morita, Hironobu Mitani, Hiroki Murayama, Toshihisa Anzai, Rachel Studer, Sarah Cotton, James Jackson, Hollie Bailey, Hiroshi Kitagawa, Naotsugu Oyama
Circulation reports, 2, 12, 722, 729, 2020年11月17日, ［国内誌］
英語, 研究論文（学術雑誌）, Background: We investigated the impact of heart failure (HF) on daily life and satisfaction with current HF medication from the patient perspective in a real-world study in Japan. Methods and Results: A cross-sectional survey of 154 HF patients treated by 58 cardiologists was conducted in Japan using patient self-completed questionnaires about their daily life and satisfaction with HF medication, as well as patient record forms completed by their physicians capturing corresponding data. The mean age of patients was 72.7 years. The proportion of patients within New York Heart Association Class I, II, III, and IV was 39%, 44%, 16%, and 1%, respectively. Symptoms reported by patients included dyspnea when active (46%), nocturia (43%), anxiety (18%), and depression (6%). There was a discordance between physician- and patient-reported symptoms, especially for nocturia and inability to sleep. The most frequent lifestyle recommendation from physicians was 'reduce salt/sodium intake', but only 51% of patients receiving this recommendation followed the advice. In all, 44% of patients reported dissatisfaction with their current medication; according to the patients, 27% reported no discussion with their physicians about their prescribed medication, while physicians reported the opposite. Conclusions: HF negatively impacts patient daily life. There is discordance between patients and physicians in symptom reporting, lifestyle modification advice and adherence, and reported medication decision making. Gaps in patient-physician communication exist.

Independent and incremental prognostic value of semiquantitative measures of tricuspid regurgitation severity in heart failure with preserved ejection fraction.
Tomonari Harada, Masaru Obokata, Kazunori Omote, Hiroyuki Iwano, Takahiro Ikoma, Kenya Okada, Kuniko Yoshida, Toshimitsu Kato, Koji Kurosawa, Toshiyuki Nagai, Kazuaki Negishi, Toshihisa Anzai, Masahiko Kurabayashi
European heart journal cardiovascular Imaging, 2020年11月07日, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: This study sought to determine the independent and incremental prognostic value of semiquantitative measures of tricuspid regurgitation (TR) severity over right heart remodelling and pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Echocardiography was performed on 311 HFpEF patients. TR severity was defined by the semiquantitative measures [i.e. vena contracta width (VCW) and jet area] and by the guideline-based integrated qualitative approach (absent, mild, moderate, or severe). All-cause mortality or heart failure hospitalization occurred in 101 patients over a 2.1-year median follow-up. There was a continuous association between TR severity and the composite outcome with a hazard ratio (HR) of 1.17 per 1 mm increase of VCW [95% confidence interval (CI) 1.08-1.26, P < 0.0001]. Compared with patients with the lowest VCW category (≤1 mm), RV-adjusted HRs for the outcome were 1.99 (95% CI 1.05-3.77), 2.63 (95% CI 1.16-5.95), and 5.00 (95% CI 1.60-15.7) for 1-3, 3-7, and ≥7 mm VCW categories, respectively. TR severity as defined by the guideline-based approach showed a similarly graded association, but it was no longer significant in models including PH. In contrast, VCW remained independently and incrementally associated with the outcome after adjusting for established prognostic factors, as well as RV diameter and PH (fully adjusted HR 1.14 per 1 mm, 95% CI 1.02-1.27, P = 0.02; χ2 58.8 vs. 51.5, P = 0.03). CONCLUSION: The current data highlight the potential value of the semiquantitative measures of TR severity for the risk stratification in patients with HFpEF.

肺静脈血流速度波形を用いたリザーバ期の左房硬さの非侵襲的評価法の検討　　　　　　　　　　　　　　　
阿部 剛大, 岡田 一範, 加賀 早苗, 政氏 伸夫, 三神 大世, 村山 迪史, 中鉢 雅大, 辻永 真吾, 岩野 弘幸, 安斉 俊久
超音波医学, 47, Suppl., S246, S246, (公社)日本超音波医学会, 2020年11月
日本語

房室弁開放時相差の視覚的評価に基づいたスコアリングによる左室充満圧推定と予後予測　　　　　　　　　　　　　　　
村山 迪史, 岩野 弘幸, 辻永 真吾, 西野 久雄, 中鉢 雅大, 横山 しのぶ, 西田 睦, 渋谷 斉, 加賀 早苗, 安斉 俊久
超音波医学, 47, Suppl., S165, S165, (公社)日本超音波医学会, 2020年11月
日本語

収縮期の右房容量負荷が三尖弁輪収縮期移動距離と右室駆出率との関係に及ぼす影響　　　　　　　　　　　　　　　
村山 迪史, 加賀 早苗, 岡田 一範, 三神 大世, 中鉢 雅大, 横山 しのぶ, 西野 久雄, 西田 睦, 岩野 弘幸, 安斉 俊久
超音波医学, 47, Suppl., S222, S222, (公社)日本超音波医学会, 2020年11月
日本語

経カテーテル的大動脈弁置換術による左室機能の変化と左室外的仕事量との関連　　　　　　　　　　　　　　　
辻永 真吾, 岩野 弘幸, 石坂 傑, 千葉 泰之, 更科 美羽, 中鉢 雅大, 神谷 究, 永井 利幸, 安斉 俊久
超音波医学, 47, Suppl., S208, S208, (公社)日本超音波医学会, 2020年11月
日本語

Placebo-Controlled, Double-Blind Study of Empagliflozin (EMPA) and Implantable Cardioverter-Defibrillator (EMPA-ICD) in Patients with Type 2 Diabetes (T2DM): Rationale and Design.
Shinya Fujiki, Kenichi Iijima, Masaaki Okabe, Shinichi Niwano, Kenichi Tsujita, Shigeto Naito, Kenji Ando, Kengo Kusano, Ritsushi Kato, Junichi Nitta, Tetsuji Miura, Takeshi Mitsuhashi, Kazuomi Kario, Yusuke Kondo, Masaki Ieda, Nobuhisa Hagiwara, Toyoaki Murohara, Kazuyoshi Takahashi, Hirofumi Tomita, Yasuchika Takeishi, Toshihisa Anzai, Wataru Shimizu, Masafumi Watanabe, Yoshihiro Morino, Takeshi Kato, Hiroshi Tada, Yoshihisa Nakagawa, Masafumi Yano, Koji Maemura, Takeshi Kimura, Hisako Yoshida, Keiko Ota, Takahiro Tanaka, Nobutaka Kitamura, Koichi Node, Yoshifusa Aizawa, Ippei Shimizu, Daisuke Izumi, Kazuyuki Ozaki, Tohru Minamino
Diabetes therapy : research, treatment and education of diabetes and related disorders, 11, 11, 2739, 2755, 2020年11月, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Type 2 diabetes (T2DM) is associated with cardiovascular death, including sudden cardiac death due to arrhythmias. Patients with an implantable cardioverter-defibrillator (ICD) are also at high risk of developing a clinically significant ventricular arrhythmia. It has been reported that sodium-glucose cotransporter 2 (SGLT2) inhibitors can reduce cardiovascular deaths; however, the physiological mechanisms of this remain unclear. It is, however, well known that SGLT2 inhibitors increase blood ketone bodies, which have been suggested to have sympatho-suppressive effects. Empagliflozin (EMPA) is an SGLT2 inhibitor. The current clinical trial titled "Placebo-controlled, double-blind study of empagliflozin (EMPA) and implantable cardioverter-defibrillator (EMPA-ICD) in patients with type 2 diabetes (T2DM)" was designed to investigate the antiarrhythmic effects of EMPA. METHODS: The EMPA-ICD study is a prospective, multicenter, placebo-controlled, double-blind, randomized, investigator-initiated clinical trial currently in progress. A total of 210 patients with T2DM (hemoglobin A1c 6.5-10.0%) will be randomized (1:1) to receive once-daily placebo or EMPA, 10 mg, for 24 weeks. The primary endpoint is the number of clinically significant ventricular arrhythmias for 24 weeks before and 24 weeks after study drug administration, as documented by the ICD. The secondary endpoints of the study are the change from baseline concentrations in blood ketone and catecholamine 24 weeks after drug treatment. CONCLUSION: The EMPA-ICD study is the first clinical trial to assess the effect of an SGLT2 inhibitor on clinically significant ventricular arrhythmias in patients with T2DM and an ICD. TRIAL REGISTRATION: Unique trial number, jRCTs031180120 ( https://jrct.niph.go.jp/latest-detail/jRCTs031180120 ).

Functional significance of intra-left ventricular vortices on energy efficiency in normal, dilated, and hypertrophied hearts.
Miwa Sarashina-Motoi, Hiroyuki Iwano, Ko Motoi, Suguru Ishizaka, Yasuyuki Chiba, Shingo Tsujinaga, Michito Murayama, Masahiro Nakabachi, Shinobu Yokoyama, Hisao Nishino, Kazunori Okada, Sanae Kaga, Toshihisa Anzai
Journal of clinical ultrasound : JCU, 49, 4, 358, 367, 2020年10月24日, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: To investigate the influence of changes in vortices within the left ventricle (LV) on energy efficiency (EE) in normal and diseased hearts. METHODS: We performed vector flow mapping echocardiography in 36 normal participants (N), 36 patients with dilated cardiomyopathy (D), and 36 patients with LV hypertrophy (H). The circulation of the main anterior vortex was measured as a parameter of vortex strength. Energy loss (EL) was measured for one cardiac cycle, and EE was calculated as EL divided by stroke work (SW), which represents the loss of kinetic energy per unit of LV external work. RESULTS: Circulation increased in the order of N, H, and D (N: 15 ± 4, D: 19 ± 8, H: 17 ± 6 × 10-3 m2 /s; analysis of variance [ANOVA] P < .01). Conversely, EE increased in the order of N, D, and H (N: 0.22 ± 0.07, D: 0.26 ± 0.16, H: 0.30 ± 0.16 10-5 J/mm Hg mL m s; ANOVA P = .04), suggesting worst EE in group H. We found a positive correlation between circulation and SW only in group N, and positive correlation between circulation and EE only in diseased groups (D: R = 0.55, P < .01; H: R = 0.44, P < .01). Multivariable analyses revealed that circulation was the independent determinant of EE in groups D and H. CONCLUSIONS: Enhanced vortices could be associated with effective increase in LV external work in normal hearts. Conversely, they were associated with loss of EE without an optimal increase in external work in failing hearts, regardless of the LV morphology.

Greetings From the New Editor-in-Chief.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 84, 11, 1889, 1889, 2020年10月23日, ［国内誌］
英語, 研究論文（学術雑誌）

Mechanism of Early-Diastolic Mitral Regurgitation.
Michito Murayama, Hiroyuki Iwano, Miwa Sarashina, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 84, 11, 2036, 2036, 2020年10月23日, ［国内誌］
英語, 研究論文（学術雑誌）

Message From the Editor-in-Chief.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 84, 11, 1890, 1894, 2020年10月23日, ［国内誌］
英語, 研究論文（学術雑誌）

Derivation and Validation of Clinical Prediction Models for Rapid Risk Stratification for Time-Sensitive Management for Acute Heart Failure.
Yasuyuki Shiraishi, Shun Kohsaka, Takayuki Abe, Toshiyuki Nagai, Ayumi Goda, Yosuke Nishihata, Yuji Nagatomo, Mike Saji, Yuichi Toyosaki, Makoto Takei, Takeshi Kitai, Takashi Kohno, Keiichi Fukuda, Yuya Matsue, Toshihisa Anzai, Tsutomu Yoshikawa
Journal of clinical medicine, 9, 11, 2020年10月23日, ［国際誌］
英語, 研究論文（学術雑誌）, Early and rapid risk stratification of patients with acute heart failure (AHF) is crucial for appropriate patient triage and outcome improvements. We aimed to develop an easy-to-use, in-hospital mortality risk prediction tool based on data collected from AHF patients at their initial presentation. Consecutive patients' data pertaining to 2006-2017 were extracted from the West Tokyo Heart Failure (WET-HF) and National Cerebral and Cardiovascular Center Acute Decompensated Heart Failure (NaDEF) registries (n = 4351). Risk model development involved stepwise logistic regression analysis and prospective validation using data pertaining to 2014-2015 in the Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure Syndrome (REALITY-AHF) (n = 1682). The final model included data describing six in-hospital mortality risk predictors, namely, age, systolic blood pressure, blood urea nitrogen, serum sodium, albumin, and natriuretic peptide (SOB-ASAP score), available at the time of initial triage. The model showed excellent discrimination (c-statistic = 0.82) and good agreement between predicted and observed mortality rates. The model enabled the stratification of the mortality rates across sixths (from 14.5% to <1%). When assigned a point for each associated factor, the integer score's discrimination was similar (c-statistic = 0.82) with good calibration across the patients with various risk profiles. The models' performance was retained in the independent validation dataset. Promptly determining in-hospital mortality risks is achievable in the first few hours of presentation; they correlate strongly with mortality among AHF patients, potentially facilitating clinical decision-making.

Acute anterior myocardial infarction complicated by takotsubo syndrome: the value of multimodality imaging.
Takao Konishi, Naohiro Funayama, Tadashi Yamamoto, Daisuke Hotta, Shinya Tanaka, Toshihisa Anzai
Kardiologia polska, 78, 10, 1055, 1056, 2020年10月23日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

A Rare Combination: Cardiac Myxoma and Aortic Stenosis.
Takao Konishi, Daisuke Hotta, Shinya Tanaka, Toshihisa Anzai
Internal medicine (Tokyo, Japan), 60, 6, 961, 962, 2020年10月14日, ［国内誌］
英語, 研究論文（学術雑誌）

Abnormal FDG uptake predicting the instability of thoracic aortic aneurysms.
Yasuyuki Chiba, Kiwamu Kamiya, Tadao Aikawa, Hiroyuki Iwano, Toshiyuki Nagai, Takahiro Ishigaki, Yasushige Shingu, Ai Shimizu, Yoshiro Matsui, Toshihisa Anzai
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology, 27, 5, 1841, 1843, 2020年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

心臓サルコイドーシス患者でfragmented QRSは、心事故、慢性期致死性不整脈と関連する
萩原 光, 渡邉 昌也, 中尾 元基, 甲谷 太郎, 小林 雄太, 加藤 喜哉, 小森山 弘和, 鎌田 塁, 永井 利幸, 安斉 俊久
日本サルコイドーシス/肉芽腫性疾患学会雑誌, 40, サプリメント号, 56, 56, 日本サルコイドーシス, 2020年10月
日本語

【循環器疾患のPrecision Medicine】臨床 心不全個別化医療
永井 利幸, 安斉 俊久
Cardiac Practice, 31, 1, 32, 36, (株)メディカルレビュー社, 2020年10月
日本語

Rapid-rate nonsustained ventricular tachycardias in high-risk dilated cardiomyopathy patients.
Wei-Chieh Lee, Masaya Watanabe, Hisashi Yokoshiki, Taro Temma, Rui Kamada, Masayuki Takahashi, Hikaru Hagiwara, Yumi Takahashi, Toshihisa Anzai
Pacing and clinical electrophysiology : PACE, 43, 10, 1086, 1095, 2020年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Nonsustained ventricular tachycardia (NSVT) occurs frequently in patients with dilated cardiomyopathy (DCM), especially in high-risk patients. The role of rapid-rate NSVT (RR-NSVT) documented by an implantable cardioverter-defibrillator (ICD) in DCM patients has not been fully explored. This study aimed to determine the relationship between RR-NSVT and the occurrence of ventricular tachyarrhythmias (VTAs) in DCM patients with ICD. METHODS: From December 2000 to December 2017, 136 DCM patients received ICD or cardiac resynchronization therapy defibrillator (CRT-D) implantation for primary or secondary prevention of VTAs. Based on the occurrence of documented RR-NSVT, patients were classified into RR-NSVT (-) or RR-NSVT (+) groups. RESULT: During the median follow-up of 4.5 years, 50.0% (68/136) patients experienced ≥1 episode, and 25.0% (34/136) patients experienced ≥3 episodes of RR-NSVT. Event-free survival for VTAs was significantly higher in the RR-NSVT (-) group, whereas those for heart failure admission and cardiovascular mortality were comparable between groups. In the multivariate Cox regression analysis, any RR-NSVT showed a positive association with the occurrence of VTAs (hazard ratio: 5.087; 95% confidence interval: 2.374-10.900; P < .001). In RR-NSVT (+) patients, a cluster (≥3 times/6 months) and frequent pattern (≥3 runs/day) of RR-NSVT were observed in 42.6% (29/68) and 30.9% (21/68) patients, respectively, who showed further increased incidence of VTAs. CONCLUSION: In DCM patients with ICD/CRT-D, 50.0% patients experienced at least one episode of RR-NSVT. RR-NSVT documentation showed a positive association with subsequent occurrence of VTAs, suggesting the importance of constructive arrhythmia management for patients with RR-NSVT.

Type 2 diabetes is an independent predictor of lowered peak aerobic capacity in heart failure patients with non-reduced or reduced left ventricular ejection fraction.
Takahiro Abe, Takashi Yokota, Arata Fukushima, Naoya Kakutani, Takashi Katayama, Ryosuke Shirakawa, Satoshi Maekawa, Hideo Nambu, Yoshikuni Obata, Katsuma Yamanashi, Ippei Nakano, Shingo Takada, Isao Yokota, Koichi Okita, Shintaro Kinugawa, Toshihisa Anzai
Cardiovascular diabetology, 19, 1, 142, 142, 2020年09月19日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Although type 2 diabetes mellitus (T2DM) is one of the most frequent comorbidities in patients with chronic heart failure (CHF), the effects of T2DM on the exercise capacity of CHF patients are fully unknown. Here, we tested the hypothesis that the coexistence of T2DM lowers CHF patients' peak aerobic capacity. METHODS: We retrospectively analyzed the cases of 275 Japanese CHF patients with non-reduced ejection fraction (left ventricular ejection fraction [LVEF] ≥ 40%) or reduced EF (LVEF < 40%) who underwent cardiopulmonary exercise testing. We divided them into diabetic and nondiabetic groups in each CHF cohort. RESULTS: The mean peak oxygen uptake (VO2) value was 16.87 mL/kg/min in the non-reduced LVEF cohort and 15.52 mL/kg/min in the reduced LVEF cohort. The peak VO2 was lower in the diabetics versus the nondiabetics in the non-reduced LVEF cohort with the mean difference (95% confidence interval [95% CI]) of - 0.93 (- 1.82 to - 0.04) mL/kg/min and in the reduced LVEF cohort with the mean difference of - 1.05 (- 1.96 to - 0.15) mL/kg/min, after adjustment for age-squared, gender, anemia, renal function, LVEF, and log B-type natriuretic peptide (BNP). The adjusted VO2 at anaerobic threshold (AT), a submaximal aerobic capacity, was also decreased in the diabetic patients with both non-reduced and reduced LVEFs. Intriguingly, the diabetic patients had a lower adjusted peak O2 pulse than the nondiabetic patients in the reduced LVEF cohort, but not in the non-reduced LVEF cohort. A multivariate analysis showed that the presence of T2DM was an independent predictor of lowered peak VO2 in CHF patients with non-reduced LVEF and those with reduced LVEF. CONCLUSIONS: T2DM was associated with lowered peak VO2 in CHF patients with non-reduced or reduced LVEF. The presence of T2DM has a negative impact on CHF patients' exercise capacity, and the degree of impact is partly dependent on their LV systolic function.

Acute Gastric Dilation after Catheter Ablation.
Tomoya Sato, Takao Konishi, Rui Kamada, Toshihisa Anzai
Internal medicine (Tokyo, Japan), 59, 18, 2341, 2341, 2020年09月15日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

Cardiac involvement with anti-mitochondrial antibody-positive myositis mimicking cardiac sarcoidosis.
Takahide Kadosaka, Shingo Tsujinaga, Hiroyuki Iwano, Kiwamu Kamiya, Azusa Nagai, Yoshifumi Mizuguchi, Ko Motoi, Kazunori Omote, Toshiyuki Nagai, Ichiro Yabe, Toshihisa Anzai
ESC heart failure, 2020年09月11日, ［国際誌］
英語, Anti-mitochondrial antibody (AMA)-positive myositis is an atypical inflammatory myopathy characterized by chronic progressive respiratory muscle weakness, muscular atrophy, and cardiac involvement. Arrhythmias, cardiomyopathy, and myocarditis have been reported as cardiac manifestations. Herein, we present the first report of a patient diagnosed with having AMA-positive myositis with cardiac involvement mimicking cardiac sarcoidosis.

Myocardial T1-mapping and Extracellular Volume Quantification in Patients and Putative Carriers of Muscular Dystrophy: Early Experience.
Kazuhiro Koyanagawa, Yuta Kobayashi, Tadao Aikawa, Atsuhito Takeda, Hideaki Shiraishi, Satonori Tsuneta, Noriko Oyama-Manabe, Hiroyuki Iwano, Toshiyuki Nagai, Toshihisa Anzai
Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine, 20, 3, 320, 324, 2020年09月07日, ［国内誌］
英語, 研究論文（学術雑誌）, To assess myocardial fibrosis associated with muscular dystrophy, T1-mapping and extracellular volume fraction (ECV) quantification was prospectively performed using cardiovascular MR (CMR) imaging in 6 male patients with muscular dystrophy and 5 female putative carriers of Duchenne or Becker muscular dystrophy. Five patients and all putative carriers had an elevated ECV (>29.5% for men and >35.2% for women), suggesting that ECV has a potential to detect diffuse fibrotic changes in patients and putative carriers of muscular dystrophy.

Usefulness of Liver Magnetic Resonance Elastography for Estimating Right-Atrial Pressure in Heart Failure Patients.
Yoshiya Kato, Toshiyuki Nagai, Noriko Oyama-Manabe, Satonori Tsuneta, Michikazu Nakai, Yuta Kobayashi, Hirokazu Komoriyama, Kazunori Omote, Shingo Tsujinaga, Takuma Sato, Takao Konishi, Kiwamu Kamiya, Hiroyuki Iwano, Toshihisa Anzai
JACC. Cardiovascular imaging, 13, 9, 2050, 2052, 2020年09月, ［査読有り］, ［国際誌］
英語

Reversible Cancer Therapeutics-related Cardiac Dysfunction Complicating Intra-cardiac Thrombi.
Shingo Tsujinaga, Hiroyuki Iwano, Tomohiro Oshino, Takahide Kadosaka, Yoshifumi Mizuguchi, Ko Motoi, Yasuyuki Chiba, Taro Koya, Taro Temma, Kiwamu Kamiya, Arata Fukushima, Takuya Koizumi, Tomoya Sato, Sakae Takenaka, Atsushi Tada, Suguru Ishizaka, Miwa Sarashina, Kazunori Omote, Rui Kamada, Takao Konishi, Takuma Sato, Toshiyuki Nagai, Hiroko Yamashita, Toshihisa Anzai
Internal medicine (Tokyo, Japan), 59, 17, 2155, 2160, 2020年09月01日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Epirubicin-based chemotherapy carries a risk of inducing heart failure, although the frequency is rare. Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, has recently been widely used in patients with recurrent breast cancer as a first-line chemotherapeutic agent. Heart failure or arterial thromboembolism has been reported as a rare cardiovascular complication of bevacizumab. We herein report a breast cancer patient with reversible cancer therapeutics-related cardiac dysfunction associated with bevacizumab and epirubicin complicating intracardiac thrombi in the left atrium and left ventricle. This case underscores the importance of tailored medical planning according to the individual status in patients receiving anti-cancer therapies.

Outer Retinal Abnormalities in a Patient with Danon Disease.
Ayaka Hasegawa, Kousuke Noda, Akio Fujiya, Kiriko Hirooka, Toshihisa Anzai, Susumu Ishida
Retinal cases & brief reports, 2020年08月31日, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: To report outer retinal abnormalities evaluated using high-resolution imaging modalities in a patient with Danon disease. METHODS: Case report. RESULTS: A 26-year-old woman, diagnosed with Danon disease based on genetic testing, was referred to our department for further evaluation of ocular findings. Her best-corrected visual acuity was 20/20, and color vision was normal. Fundus examination revealed pigmentary changes consisting of mottled depigmentation and pigmentation in the peripheral retina of both eyes. Spectral-domain optical coherence tomography (SD-OCT) revealed disruptions of the ellipsoid and interdigitation zones, irregularity of the retinal pigment epithelium (RPE), and hyperreflectivity of the outer nuclear layer. In addition, an adaptive optics retinal camera demonstrated the ambiguous macular cone mosaic pattern. CONCLUSION: Danon disease is caused by a primary deficiency in lysosomal associated membrane protein 2 (LAMP-2), an important constituent of the lysosomal membrane that plays a crucial role in the process of autophagy. It is possible that the findings of SD-OCT and adaptive optics retinal camera are early changes associated with the accumulation of autophagosomes and/or phagosomes due to LAMP-2 dysfunction in the photoreceptors, eventually followed by outer retinal degeneration, such as thinning of both the photoreceptor and RPE layers at the fovea.

JCS 2020 Guideline on Diagnosis and Treatment of Cardiac Amyloidosis.
Hiroaki Kitaoka, Chisato Izumi, Yasuhiro Izumiya, Takayuki Inomata, Mitsuharu Ueda, Toru Kubo, Jun Koyama, Motoaki Sano, Yoshiki Sekijima, Nobuhiro Tahara, Nobuhiro Tsukada, Kenichi Tsujita, Hiroyuki Tsutsui, Takeshi Tomita, Masashi Amano, Jin Endo, Atsushi Okada, Seitaro Oda, Seiji Takashio, Yuichi Baba, Yohei Misumi, Masahide Yazaki, Toshihisa Anzai, Yukio Ando, Mitsuaki Isobe, Takeshi Kimura, Keiichi Fukuda
Circulation journal : official journal of the Japanese Circulation Society, 84, 9, 1610, 1671, 2020年08月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

Enhanced Echo Intensity of Skeletal Muscle Is Associated With Exercise Intolerance in Patients With Heart Failure.
Ippei Nakano, Hiroaki Hori, Arata Fukushima, Takashi Yokota, Shintaro Kinugawa, Shingo Takada, Katsuma Yamanashi, Yoshikuni Obata, Yasuyuki Kitaura, Naoya Kakutani, Takahiro Abe, Toshihisa Anzai
Journal of cardiac failure, 26, 8, 685, 693, 2020年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Skeletal muscle is quantitatively and qualitatively impaired in patients with heart failure (HF), which is closely linked to lowered exercise capacity. Ultrasonography (US) for skeletal muscle has emerged as a useful, noninvasive tool to evaluate muscle quality and quantity. Here we investigated whether muscle quality based on US-derived echo intensity (EI) is associated with exercise capacity in patients with HF. METHODS AND RESULTS: Fifty-eight patients with HF (61 ± 12 years) and 28 control subjects (58 ± 14 years) were studied. The quadriceps femoris echo intensity (QEI) was significantly higher and the quadriceps femoris muscle thickness (QMT) was significantly lower in the patients with HF than the controls (88.3 ± 13.4 vs 81.1 ± 7.5, P= .010; 5.21 ± 1.10 vs 6.54 ±1.34 cm, P< .001, respectively). By univariate analysis, QEI was significantly correlated with age, peak oxygen uptake (VO2), and New York Heart Association class in the HF group. A multivariable analysis revealed that the QEI was independently associated with peak VO2 after adjustment for age, gender, body mass index, and QMT: β-coefficient = -11.80, 95%CI (-20.73, -2.86), P= .011. CONCLUSION: Enhanced EI in skeletal muscle was independently associated with lowered exercise capacity in HF. The measurement of EI is low-cost, easily accessible, and suitable for assessment of HF-related alterations in skeletal muscle quality.

Prognostic impact of moderate mitral regurgitation on hospitalized heart failure patients with preserved ejection fraction: A report from the JASPER registry.
Masayoshi Oikawa, Akiomi Yoshihisa, Yu Sato, Toshiyuki Nagai, Tsutomu Yoshikawa, Yoshihiko Saito, Kazuhiro Yamamoto, Yasuchika Takeishi, Toshihisa Anzai
Heart and vessels, 35, 8, 1087, 1094, 2020年08月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A growing body of evidence suggests that mitral regurgitation (MR) is associated with higher mortality in heart failure patients with reduced ejection fraction. However, prognostic impact of MR on heart failure patients with preserved ejection fraction (HFpEF) has not been fully examined. The Japanese Heart Failure Syndrome with Preserved Ejection Fraction (JASPER) registry is a nationwide, observational, prospective registration of consecutive Japanese hospitalized HFpEF patients with LVEF ≥ 50%. Severe valvular heart disease was excluded from this cohort. We divided the consecutive 341 patients into two groups based on the severity of MR at discharge: no or mild MR group (n = 317) and moderate MR group (n = 24). Compared with no or mild MR group, moderate MR group showed larger left ventricular end-diastolic diameter (52 [48-59] vs. 46 [42-50] mm, P < 0.001), left ventricular systolic diameter (35 [30-37] vs. 29 [26-34] mm, P = 0.006), left atrial diameter (49 [46-56] vs. 45 [40-50] mm, P < 0.001), and higher tricuspid regurgitation peak gradient (33 [25-40] vs. 27 [21-33] mmHg, P = 0.012). In contrast, levels of plasma B-type natriuretic peptide and left ventricular ejection fraction were comparable between the two groups. In the follow-up period (median 738 days), there were 57 all-cause deaths. In the Kaplan-Meier analysis, all-cause mortality was higher in moderate MR group than in no or mild MR group (log-rank P = 0.023). In the Cox proportional hazard analysis, moderate MR at discharge was a predictor of all-cause mortality (hazard ratio 2.256, 95% confidence interval 1.035-4.917, P = 0.041). Moderate MR at discharge is associated with adverse prognosis in hospitalized patients with HFpEF.

Significance and prognostic impact of v wave on pulmonary artery pressure in patients with heart failure: beyond the wedge pressure.
Hiroyuki Iwano, Shinobu Yokoyama, Kiwamu Kamiya, Toshiyuki Nagai, Shingo Tsujinaga, Miwa Sarashina, Suguru Ishizaka, Yasuyuki Chiba, Masahiro Nakabachi, Hisao Nishino, Michito Murayama, Kazunori Okada, Sanae Kaga, Toshihisa Anzai
Heart and vessels, 35, 8, 1079, 1086, 2020年08月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: A v wave on pulmonary artery wedge (PAW) pressure sometimes augments and appears on pulmonary artery (PA) pressure wave in patients with heart failure (HF). However, the significance of PA v wave in HF remains to be elucidated. METHODS: We retrospectively analyzed pressure waveforms in 61 HF patients (left ventricular ejection fraction 35 ± 15%). On the PAW and PA pressure waveforms, mean pressure as well as peak and amplitude of v waves (ampPAWv and ampPAv, respectively) were measured. Occurrence of worsening HF and cardiac death was recorded for 2 years after the catheterization. RESULTS: The ampPAWv did not correlate with ampPAv. When the patients were divided into 4 groups: I (high-ampPAWv/high-ampPAv), II (high-ampPAWv/low-ampPAv), III (low-ampPAWv/high-ampPAv), and IV (low-ampPAWv/low-ampPAv), the prevalence of group III was low (I: 13, II: 17, III: 4, IV: 27). Mean pressures of PAW and PA were similarly elevated in groups I and II. Cardiac index was lowest (I: 2.0 ± 0.4, II: 2.8 ± 0.6, III: 2.2 ± 0.2, IV: 2.4 ± 0.6 L/min/m2, ANOVA P < 0.01, P < 0.01 for I vs II) and tricuspid annular plane systolic excursion / systolic PA pressure was impaired (I: 0.27 ± 0.07, II: 0.48 ± 0.22, III: 0.59 ± 0.35, IV: 0.68 ± 0.35 mm/mmHg, ANOVA P < 0.01) in group I. During the follow-up, 13 events were observed. Kaplan-Meier analysis showed that patients in group I were at highest risk of cardiac events. CONCLUSIONS: PA v was observed mainly in patients with augmented PAW v wave and decreased cardiac index, suggesting an advanced stage of HF. Moreover, augmented PAv was associated with worse outcome in HF patients.

Prognostic value of base excess as indicator of acid-base balance in acute heart failure.
Hiroki Nakano, Toshiyuki Nagai, Yasuyuki Honda, Satoshi Honda, Naotsugu Iwakami, Chisa Matsumoto, Yasuhide Asaumi, Takeshi Aiba, Teruo Noguchi, Kengo Kusano, Hiroyuki Yokoyama, Hisao Ogawa, Satoshi Yasuda, Taishiro Chikamori, Toshihisa Anzai
European heart journal. Acute cardiovascular care, 9, 5, 399, 405, 2020年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Acid-base balance can change as a result of pulmonary oedema and low tissue perfusion in acute heart failure patients. However, its long-term prognostic significance remains to be clarified. METHODS: We prospectively examined a cohort of 472 consecutive acute heart failure patients who underwent arterial blood gas analysis on admission between January 2013 and May 2016. Acidaemia, alkalaemia and normal range of base excess were defined as pH <7.38, >7.42 and -2 to 2 mEq/L, respectively. The primary outcome was all-cause death. RESULTS: During a median follow-up period of 714 days, 101 patients died. Although there was no difference in mortality among patients with acidaemia, normal pH and alkalaemia (p = 0.92), patients with high base excess had the highest mortality compared with others. Multivariable Cox proportional hazard models revealed that high base excess was an independent determinant of mortality (hazard ratio 1.83, 95% confidence interval 1.08-3.13 (high versus normal base excess), hazard ratio 0.81, 95% confidence interval 0.47-1.41 (low versus normal base excess)), even after adjustment for significant prognostic covariates. Furthermore, regarding mortality stratified by base excess and carbon dioxide partial pressure (pCO2), patients with high base excess (>2.1 mEq/L) and high pCO2 (>40 mmHg) had the highest mortality compared with others. CONCLUSIONS: High base excess, but not low base excess, on admission was associated with long-term mortality in acute heart failure patients, indicating the importance of evaluating acid-base balance on admission by base excess for stratifying the risk of mortality in patients with acute heart failure.

Elevated admission urinary N-acetyl-β-D-glucosamidase level is associated with worse long-term clinical outcomes in patients with acute heart failure.
Sayaka Funabashi, Kazunori Omote, Toshiyuki Nagai, Yasuyuki Honda, Hiroki Nakano, Satoshi Honda, Naotsugu Iwakami, Yasuhiro Hamatani, Michikazu Nakai, Kunihiro Nishimura, Yasuhide Asaumi, Takeshi Aiba, Teruo Noguchi, Kengo Kusano, Hiroyuki Yokoyama, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
European heart journal. Acute cardiovascular care, 9, 5, 429, 436, 2020年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The prognostic significance of urinary N-acetyl-β-D-glucosamidase in acute heart failure has not been fully elucidated. Accordingly, this study investigated whether urinary N-acetyl-β-D-glucosamidase could be associated with subsequent adverse events in acute heart failure patients. METHODS: We studied 708 consecutive acute heart failure patients who had accessible N-acetyl-β-D-glucosamidase data on admission from the National Cerebral and Cardiovascular Center Acute Decompensated Heart Failure registry. We assessed the relationship between the admission N-acetyl-β-D-glucosamidase level and the combined endpoint of all-cause death and worsening heart failure. Worsening heart failure was defined as worsening symptoms and signs of heart failure requiring intensification of intravenous therapy such as diuretics, vasodilators and inotropes or initiation of mechanical support after stabilisation with initial treatment during hospitalisation, or readmission due to heart failure after discharge. RESULTS: During a median follow-up period of 763 (interquartile range 431-1028) days, higher urinary N-acetyl-β-D-glucosamidase was significantly related to increased events of all-cause death and worsening heart failure. In addition, patients with higher urinary N-acetyl-β-D-glucosamidase and lower estimated glomerular filtration rate on admission had the worst clinical outcomes. In multivariable Cox regression, urinary N-acetyl-β-D-glucosamidase on admission was independently associated with adverse events (hazard ratio 1.19, 95% confidence interval 1.04-1.35) even after adjustment by covariates including the baseline estimated glomerular filtration rate. CONCLUSIONS: Higher urinary N-acetyl-β-D-glucosamidase level on admission was independently associated with worse clinical outcomes. Our findings indicate the potential value of assessing urinary N-acetyl-β-D-glucosamidase on admission for further risk stratification in patients with acute heart failure.

Quality indicators of palliative care for acute cardiovascular diseases.
Atsushi Mizuno, Mitsunori Miyashita, Takashi Kohno, Yasuharu Tokuda, Shuhei Fujimoto, Masato Nakamura, Morimasa Takayama, Koichiro Niwa, Terunobu Fukuda, Shinichi Ishimatsu, Satomi Kinoshita, Shogo Oishi, Hiroki Mochizuki, Akemi Utsunomiya, Yasuko Takada, Ryota Ochiai, Toshiaki Mochizuki, Ken Nagao, Saran Yoshida, Akitoshi Hayashi, Ryuichi Sekine, Toshihisa Anzai
Journal of cardiology, 76, 2, 177, 183, 2020年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Although recent attention to palliative care for patients with cardiovascular diseases has been increasing, there are no specific recommendations on detailed palliative care practices. We proceed on a discussion of the appropriateness and applicability of potential quality indicators for acute cardiovascular diseases according to our previous systematic review. METHODS: We created a multidisciplinary panel of 20 team members and 7 external validation clinicians composed of clinical cardiologists, a nutritionist, a physiotherapist, a clinical psychologist, a critical and emergent care specialist, a catheterization specialist, a primary care specialist, a palliative care specialist, and nurses. After crafting potential indicators, we performed a Delphi rating, ranging from "1 = minimum" to "9 = maximum". The criterion for the adoption of candidate indicators was set at a total mean score of seven or more. Finally, we subcategorized these indicators into several domains by using exploratory factor analysis. RESULTS: Sixteen of the panel members (80%) were men (age, 49.5 ± 13.7 years old). Among the initial 32 indicators, consensus was initially reached on total 23 indicators (71.8%), which were then summarized into 21 measures by selecting relatively feasible time variations. The major domains were "symptom palliation" and "supporting the decision-making process". Factor analysis could not find optimal model. Narratively-developed seven sub-categories included "presence of palliative care team", "patient-family relationship", "multidisciplinary team approach", "policy of approaching patients", "symptom screening and management", "presence of ethical review board", "collecting and providing information for decision-maker", and "determination of treatment strategy and the sharing of the care team's decision". CONCLUSION: In this study we developed 21 quality indicators, which were categorized into 2 major domains and 7 sub-categories. These indicators might be useful for many healthcare providers in the initiation and enhancement of palliative care practices for acute cardiovascular diseases in Japan.

Phosphoglyceride crystal deposition disease as a rare tumour after cardiac surgery.
Tomoya Sato, Takao Konishi, Satoru Wakasa, Noriko Oyama-Manabe, Toshihisa Anzai
European heart journal, 41, 27, 2596, 2596, 2020年07月14日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Prevalence, Determinants, and Prognostic Significance of Hospital Acquired Pneumonia in Patients with Acute Heart Failure.
Atsushi Tada, Kazunori Omote, Toshiyuki Nagai, Yasuyuki Honda, Hiroki Nakano, Satoshi Honda, Naotsugu Iwakami, Yasuhiro Hamatani, Michikazu Nakai, Kunihiro Nishimura, Yasuhide Asaumi, Takeshi Aiba, Teruo Noguchi, Kengo Kusano, Hiroyuki Yokoyama, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
Journal of clinical medicine, 9, 7, 2020年07月13日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The prognostic impact of hospital-acquired pneumonia (HAP) in acute heart failure (AHF) patients have not been fully elucidated. We evaluated 776 consecutive hospitalized AHF patients. The primary in-hospital outcomes were all-cause death and worsening heart failure (WHF), while the outcome following discharge was all-cause death. The clinical diagnosis of HAP was based on clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Patients with HAP had a significantly higher incidence of in-hospital death (12% vs. 1%, p < 0.001), WHF during the hospitalization (28% vs. 7%, p < 0.001), and longer length of hospital stay (p = 0.003) than those without. Among patients who survived at discharge, during a median follow-up period of 741 (interquartile range 422-1000) days, the incidence of all-cause death was significantly higher in patients with HAP than in those without (p < 0.001). In the multivariable Cox regression, HAP development was independently associated with all-cause death after discharge (HR [hazard ratio] 1.86, 95%CI [confidence interval] 1.08-3.19). Furthermore, older age (OR [odds ratio] 1.04, 95%CI 1.01-1.08), male sex (OR 2.21, 95%CI 1.14-4.28), and higher serum white blood cell count (OR 1.18, 95%CI 1.09-1.29) and serum C-reactive protein (OR 1.08, 95%CI 1.01-1.06) were independently associated with HAP development. In hospitalized patients with AHF, HAP development was associated with worse clinical outcomes, suggesting the importance of prevention and early screening for HAP.

Successful epicardial ablation for ventricular tachycardia originating from the true apex of apical aneurysm associated with hypertrophic cardiomyopathy
Motoki Nakao, Masaya Watanabe, Rui Kamada, Hikaru Hagiwara, Yumi Takahashi, Taro Koya, Takahide Kadosaka, Takuya Koizumi, Masanori Hirose, Toshihisa Anzai
Journal of Electrocardiology, 61, 170, 174, Elsevier BV, 2020年07月
研究論文（学術雑誌）

Radiofrequency catheter ablation of a sporadically occurring ventricular arrhythmia originating from the right ventricular outflow tract: A novel arrhythmia induction strategy involving atrial fibrillation provocation.
Taro Koya, Taro Temma, Masaya Watanabe, Rui Kamada, Toshiyuki Nagai, Toshihisa Anzai
HeartRhythm case reports, 6, 7, 411, 414, 2020年07月, ［査読有り］, ［国際誌］
英語

Invasive Cardiac Lipoma Complicating Visceral Inversion
Takahide Kadosaka, Shingo Tsujinaga, Hiroyuki Iwano, Noriko Oyama-Manabe, Toshihisa Anzai
JACC: Case Reports, 2, 10, 1570, 1571, Elsevier BV, 2020年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We report a case of cardiac lipoma with intramyocardial invasion complicated by visceral inversion, which, to the best of our knowledge, has not been reported before. Multimodality imaging played an important role in differential diagnosis and determination of the management strategy. (Level of Difficulty: Advanced.).

Detailed visualization of the right and left ventricular, left atrial, and epicardial involvement of cardiac sarcoidosis with novel semiconductor PET/CT.
Osamu Manabe, Noriko Oyama-Manabe, Toshiyuki Nagai, Sho Furuya, Toshihisa Anzai
European journal of nuclear medicine and molecular imaging, 47, 7, 1773, 1774, 2020年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Experience of morphine therapy for refractory dyspnea as palliative care in advanced heart failure patients.
Juri Kawaguchi, Yasuhiro Hamatani, Atsushi Hirayama, Kunihiro Nishimura, Eri Nakai, Emi Nakamura, Michi Miyata, Yukie Kawano, Yasuko Takada, Yuta Anchi, Sayaka Funabashi, Kensuke Kuroda, Michiyo Azechi, Hiroyuki Takahama, Toshihisa Anzai, Satoshi Yasuda, Hiroaki Kitaoka, Chisato Izumi
Journal of cardiology, 75, 6, 682, 688, 2020年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: In the field of palliative care, morphine is known to be effective for alleviating dyspnea in cancer patients. However, little is known regarding the safety and efficacy of morphine therapy for refractory dyspnea as palliative care in advanced heart failure (HF) patients. METHODS: We retrospectively reviewed consecutive advanced HF patients who were referred to the Palliative Care Team at our institution and administered morphine for refractory dyspnea during hospitalization between September 2013 and December 2018. We investigated the details of morphine usage, vital signs, an 11-point quantitative symptom scale, and adverse events at baseline, 24 h, and 72 h after the start of treatment. RESULTS: Morphine was administered for refractory dyspnea in 43 advanced HF patients [mean age: 73.5 years, male: 28 (65%), New York Heart Association functional class IV: 43 (100%), median left ventricular ejection fraction: 25%, median B-type natriuretic peptide level: 927 pg/ml, concurrent intravenous inotrope: 33 (77%)]. Median initial dose of morphine was 5 mg/day in both oral and intravenous administration and median duration of administration was 5 days. Significant decreases in an 11-point quantitative symptom scale [7 (5, 9) vs. 2 (1, 6); p <  0.01, (data available in 8 patients)] and respiratory rate (22.2 ± 6.1 vs. 19.7 ± 5.2 breaths per minute; p < 0.01) were observed 24 h after the start of morphine administration. Meanwhile, oxygen saturation, blood pressure, and heart rate were not significantly altered after treatment (NS). Common adverse events were delirium (18%) and constipation (8%); however, no lethal adverse event definitely related to morphine therapy occurred during treatment. CONCLUSIONS: This single-center retrospective study revealed the clinical practice of morphine therapy and suggested that morphine therapy might be feasible for refractory dyspnea as palliative care in advanced HF patients.

What is this image? 2020: Image 6 result : A case of ventricular apical aneurysm with suspected IgG4-related arteritis on steroid therapy.
Kazuhiro Koyanagawa, Masanao Naya, Osamu Manabe, Toshihisa Anzai
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology, 27, 3, 719, 722, 2020年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Branched-chain amino acid supplementation ameliorates angiotensin II-induced skeletal muscle atrophy.
Katsuma Yamanashi, Shintaro Kinugawa, Arata Fukushima, Naoya Kakutani, Shingo Takada, Yoshikuni Obata, Ippei Nakano, Takashi Yokota, Yasuyuki Kitaura, Yoshiharu Shimomura, Toshihisa Anzai
Life sciences, 250, 117593, 117593, 2020年06月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Sarcopenia is characterized by muscle mass and strength loss and reduced physical activity. Branched-chain amino acids (BCAAs) were recently described as an activator of protein synthesis via mammalian target of rapamycin (mTOR) signaling for muscle atrophy. In cardiovascular diseases, excessive activation of the renin-angiotensin system may induce an imbalance of protein synthesis and degradation, and this plays a crucial role in muscle atrophy. We investigated the effects of BCAAs on angiotensin II (Ang II)-induced muscle atrophy in mice. MATERIALS AND METHODS: We administered Ang II (1000 ng/kg/min) or vehicle to 10-12-week-old male C57BL/6J mice via subcutaneous osmotic minipumps for 4 weeks with or without BCAA supplementation (3% BCAA in tap water). KEY FINDINGS: The skeletal muscle weight/tibial length and cross-sectional area were smaller in the Ang II mice than the vehicle mice; these changes were induced by an imbalance of protein synthesis and degradation signaling such as Akt/mTOR and MuRF-1/Atrogin-1. Compared to the Ang II mice, the mTOR signaling was significantly activated and Ang II-induced muscle atrophy was ameliorated in the Ang II + BCAA mice, and this attenuated the reduction of exercise capacity. Notably, the decrease of muscle weight/tibial length in the fast-twitch dominant muscles (e.g., the extensor digitorum longus) was significantly ameliorated compared to that in the slow-twitch dominant muscles (e.g., soleus). Histologically, the effect of BCAA was larger in fast-twitch than slow-twitch fibers, which may be related to the difference in BCAA catabolism. SIGNIFICANCE: BCAA supplementation could contribute to the prevention of skeletal muscle atrophy induced by Ang II.

Sex differences in Japanese patients with ruptured aortic aneurysms.
Tetsuo Yamaguchi, Michikazu Nakai, Yoko Sumita, Kunihiro Nishimura, Toshihiro Nozato, Takashi Ashikaga, Toshiyuki Nagai, Toshihisa Anzai, Yasushi Sakata, Hitoshi Ogino
Journal of vascular surgery, 71, 6, 1907, 1912, 2020年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: This study aimed to assess the sex differences in clinical presentation and outcomes of Japanese patients with ruptured aortic aneurysm (rAA) using a large nationwide claims-based database in Japan. METHODS: We identified patients hospitalized in certified teaching hospitals in Japan with rAA between April 1, 2012, and March 31, 2015. Patients' characteristics and in-hospital outcomes were compared between men and women. The Barthel index was used for evaluating functional status at discharge by examining the ability to perform basic daily activities. RESULTS: Of 7086 eligible patients, 32.3% (2291/7086) were women. Women were older than men (81.9 years vs 76.1 years; P < .001), had higher prevalence of coma at admission (33.2% vs 25.2%; P < .001), and were less likely to undergo emergency operation including endovascular aneurysm repair (35.7% vs 51.1%; P < .001). The unadjusted mortality rate (62.5% vs 52.0%; P < .001) and Barthel index at discharge (78.7 vs 86.1; P < .001) were significantly worse in women than in men. However, multilevel mixed-effect logistic regression analyses showed that female sex itself was not an independent predictor for in-hospital death (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.78-1.04; P = .17). Older age, coma at admission, and vasopressor use were detected as independent predictors for in-hospital death. The same results were confirmed for each rupture site. Stratified analyses showed that older women (threshold, 80 years; OR, 0.81; 95% CI, 0.66-0.98; P = .028) and those who underwent emergency operation (OR, 0.75; 95% CI, 0.61-0.93; P = .009) showed significantly better outcomes than men. CONCLUSIONS: In a univariate analysis, female patients with rAA showed worse mortality than men because of their older age, more severe clinical presentation, and low emergency operation rate. However, after adjustment for covariates, female sex itself was not associated with increased mortality.

Cardiac sarcoidosis mimicking myocardial infarction: a comprehensive evaluation using computed tomography and positron emission tomography.
Tadao Aikawa, Kazuhiro Koyanagawa, Noriko Oyama-Manabe, Toshihisa Anzai
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology, 27, 3, 1066, 1067, 2020年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Refractory Right Ventricular Failure in a Patient with Emery-Dreifuss Muscular Dystrophy.
Yasuyuki Chiba, Arata Fukushima, Motoki Nakao, Yuta Kobayashi, Takahiro Ishigaki, Taro Tenma, Kiwamu Kamiya, Yasushige Shingu, Tomonori Ooka, Yoshiro Matsui, Toshihisa Anzai
Internal medicine (Tokyo, Japan), 59, 10, 1277, 1281, 2020年05月15日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 23-year-old man had progressive muscle weakness and Emery-Dreifuss muscular dystrophy (EDMD) due to a LMNA (lamin A/C) mutation. Congestive heart failure diagnosed at 19 years of age. Maximal drug treatment/cardiac resynchronization failed to improve the cardiac function. He was therefore hospitalized due to heart failure. Despite extracorporeal membrane oxygenation, he developed severe right heart dysfunction and died (multiple organ failure). A cardiac lesion's presence determines the prognosis of EDMD. While there are many arrhythmia reports, few reports on heart failure (particularly severe heart failure requiring cardiac transplantation) have been published. Right heart function monitoring and early ventricular-assist device use plus right heart support considering heart transplantation are important.

Inhibition of xanthine oxidase in the acute phase of myocardial infarction prevents skeletal muscle abnormalities and exercise intolerance.
Hideo Nambu, Shingo Takada, Satoshi Maekawa, Junichi Matsumoto, Naoya Kakutani, Takaaki Furihata, Ryosuke Shirakawa, Takashi Katayama, Takayuki Nakajima, Katsuma Yamanashi, Yoshikuni Obata, Ippei Nakano, Masaya Tsuda, Akimichi Saito, Arata Fukushima, Takashi Yokota, Junko Nio-Kobayashi, Hironobu Yasui, Kei Higashikawa, Yuji Kuge, Toshihisa Anzai, Hisataka Sabe, Shintaro Kinugawa
Cardiovascular research, 117, 3, 805, 819, 2020年05月13日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Exercise intolerance in patients with heart failure (HF) is partly attributed to skeletal muscle abnormalities. We have shown that reactive oxygen species (ROS) play a crucial role in skeletal muscle abnormalities, but the pathogenic mechanism remains unclear. Xanthine oxidase (XO) is reported to be an important mediator of ROS overproduction in ischemic tissue. Here we tested the hypothesis that skeletal muscle abnormalities in HF are initially caused by XO-derived ROS and are prevented by the inhibition of their production. METHODS AND RESULTS: Myocardial infarction (MI) was induced in male C57BL/6J mice, which eventually led to HF, and a sham operation was performed in control mice. The time course of XO-derived ROS production in mouse skeletal muscle post-MI was first analyzed. XO-derived ROS production was significantly increased in MI mice from days 1 to 3 postsurgery (acute phase), whereas it did not differ between the MI and sham groups from 7 to 28 days (chronic phase). Second, mice were divided into three groups: sham+vehicle (Sham+Veh), MI+vehicle (MI+Veh), and MI+febuxostat (an XO inhibitor, 5 mg/kg body weight/day; MI+Feb). Febuxostat or vehicle was administered at 1 hr and 24 hr before surgery, and once-daily on days 1-7 postsurgery. On day 28 postsurgery, exercise capacity and mitochondrial respiration in skeletal muscle fibers were significantly decreased in MI+Veh compared with Sham+Veh mice. An increase in damaged mitochondria in MI+Veh compared with Sham+Veh mice was also observed. The wet weight and cross-sectional area of slow muscle fibers (higher XO-derived ROS) was reduced via the downregulation of protein synthesis-associated mTOR-p70S6K signaling in MI+Veh compared with Sham+Veh mice. These impairments were ameliorated in MI+Feb mice, in association with a reduction of XO-derived ROS production, without affecting cardiac function. CONCLUSIONS: XO inhibition during the acute phase post-MI can prevent skeletal muscle abnormalities and exercise intolerance in mice with HF. A TRANSLATIONAL PERSPECTIVE: We clearly demonstrated that febuxostat, an inhibitor of xanthine oxidase (XO), prevents exercise intolerance and skeletal muscle abnormalities (mitochondrial dysfunction and atrophy) via the suppression of XO-derived reactive oxygen species increase during hypoxia (e.g., myocardial infarction [MI]) in skeletal muscle during the early phase of heart failure (HF) model mouse. Our results shed light on the pathogenic mechanism of skeletal muscle abnormalities in HF after MI. The use of XO inhibitors requires consideration of the time course of XO activity. Our results indicate that the timing of administration is very important to achieve maximum beneficial effects when using XO inhibitors.

Heart Failure With Preserved Ejection Fraction vs. Reduced Ejection Fraction ― Mechanisms of Ventilatory Inefficiency During Exercise in Heart Failure ―
Shingo Tsujinaga, Hiroyuki Iwano, Yasuyuki Chiba, Suguru Ishizaka, Miwa Sarashina, Michito Murayama, Masahiro Nakabachi, Hisao Nishino, Shinobu Yokoyama, Kazunori Okada, Sanae Kaga, Toshihisa Anzai
Circulation Reports, 2, 5, 271, 279, Japanese Circulation Society, 2020年05月08日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Background: Ventilatory inefficiency during exercise assessed using the lowest minute ventilation/carbon dioxide production (V̇E/V̇CO2) ratio was recently proven to be a strong prognostic marker of heart failure (HF) regardless of left ventricular ejection fraction (LVEF). Its physiological background, however, has not been elucidated. Methods and Results: Fifty-seven HF patients underwent cardiopulmonary exercise testing and exercise-stress echocardiography. The lowest V̇E/V̇CO2 ratio was assessed on respiratory gas analysis. Echocardiography was obtained at rest and at peak exercise. LVEF was measured using the method of disks. Cardiac output (CO) and the ratio of transmitral early filling velocity (E) to early diastolic tissue velocity (e') were calculated using the Doppler method. HF patients were divided into preserved EF (HFpEF) and reduced EF (HFrEF) using the LVEF cut-off 40% at rest. Twenty-four patients were classified as HFpEF and 33 as HFrEF. In HFpEF, age (r=0.58), CO (r=-0.44), e' (r=-0.48) and E/e' (r=0.45) during exercise correlated with the lowest V̇E/V̇CO2 ratio (P<0.05 for all). In contrast, in HFrEF, age (r=0.47) and CO (r=-0.54) during exercise, but not e' and E/e', correlated with the lowest V̇E/V̇CO2 ratio. Conclusions: Loss of CO augmentation was associated with ventilatory inefficiency in HF regardless of LVEF, although lung congestion determined ventilatory efficiency only in HFpEF.

Procedural Volume and Outcomes After Percutaneous Coronary Intervention for Unprotected Left Main Coronary Artery Disease-Report From the National Clinical Data (J-PCI Registry).
Tadao Aikawa, Kyohei Yamaji, Toshiyuki Nagai, Shun Kohsaka, Kiwamu Kamiya, Kazunori Omote, Taku Inohara, Yohei Numasawa, Kenichi Tsujita, Tetsuya Amano, Yuji Ikari, Toshihisa Anzai
Journal of the American Heart Association, 9, 9, e015404, 2020年05月05日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background There is a limited evidence base to support the volume-outcome relationship in patients undergoing percutaneous coronary intervention (PCI) for unprotected left main coronary artery disease (UPLMD). This study aimed to evaluate the relationship between institutional and operator volume and in-hospital outcomes in patients undergoing PCI for unprotected left main coronary artery disease. Methods and Results We analyzed characteristics and clinical outcomes of 24 320 patients undergoing PCI for unprotected left main coronary artery disease at 1102 hospitals by 7244 operators using data from the Japanese nationwide J-PCI Registry (National PCI Data Registry) between January 2014 and December 2017. We classified institutions and operators into quartiles based on the mean annual volume of PCI. A generalized linear mixed-effects model was used to evaluate the association between institutional and operator PCI volume and in-hospital outcomes. Among the 24 320 patients, 4027 (16.6%), 6147 (25.3%), and 14 146 (58.2%) presented with ST-segment-elevation myocardial infarction, non-ST-segment-elevation acute coronary syndrome, and stable ischemic heart disease; their crude in-hospital mortality was 15%, 3.1%, and 0.3%, respectively. Compared with patients in the lowest quartile of institutional volume (1-216 PCIs/y), the adjusted odds ratio of in-hospital death in patients in the second (217-323 PCIs/y), third (324-487 PCIs/y), and fourth (488-3015 PCIs/y) quartile of institutional volume was 0.75 (95% CI, 0.51-1.10; P=0.14), 0.87 (95% CI, 0.57-1.34; P=0.54), and 0.51 (95% CI, 0.30-0.86; P=0.01), respectively. These findings were consistent in rates of in-hospital death or any complication. Conversely, operator PCI volume was not significantly associated with in-hospital outcomes. Conclusions Institutional rather than operator-based PCI volume was associated with better in-hospital outcomes in patients undergoing PCI for unprotected left main coronary artery disease.

Optimal sampling in derivation studies was associated with improved discrimination in external validation for heart failure prognostic models.
Naotsugu Iwakami, Toshiyuki Nagai, Toshiaki A Furukawa, Aran Tajika, Akira Onishi, Kunihiro Nishimura, Soshiro Ogata, Michikazu Nakai, Misa Takegami, Hiroki Nakano, Yohei Kawasaki, Ana Carolina Alba, Gordon Henry Guyatt, Yasuyuki Shiraishi, Shun Kohsaka, Takashi Kohno, Ayumi Goda, Atsushi Mizuno, Tsutomu Yoshikawa, Toshihisa Anzai
Journal of clinical epidemiology, 121, 71, 80, 2020年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: The objective of the study was to identify determinants of external validity of prognostic models. STUDY DESIGN AND SETTING: We systematically searched for studies reporting prognostic models of heart failure (HF) and examined their performance for predicting 30-day death in a cohort of consecutive 3,452 acute HF patients. We applied published critical appraisal tools and examined whether bias or other characteristics of original derivation studies determined model performance. RESULTS: We identified 224 models from 6,354 eligible studies. The mean c-statistic in the cohort was 0.64 (standard deviation, 0.07). In univariable analyses, only optimal sampling assessed by an adequate and valid description of the sampling frame and recruitment details to collect the population of interest (total score range: 0-2, higher scores indicating lower risk of bias) was associated with high performance (standardized β = 0.25, 95% CI: 0.12 to 0.38, P < 0.001). It was still significant after adjustment for relevant study characteristics, such as data source, scale of study, stage of illness, and study year (standardized β = 0.24, 95% CI: 0.07 to 0.40, P = 0.01). CONCLUSION: Optimal sampling representing the gap between the population of interest and the studied population in derivation studies was a key determinant of external validity of HF prognostic models.

Impact of Hospital Practice Factors on Mortality in Patients Hospitalized for Heart Failure in Japan - An Analysis of a Large Number of Health Records From a Nationwide Claims-Based Database, the JROAD-DPC.
Hidetaka Kaku, Kouta Funakoshi, Tomomi Ide, Takeo Fujino, Shouji Matsushima, Kisho Ohtani, Taiki Higo, Michikazu Nakai, Yoko Sumita, Kunihiro Nishimura, Yoshihiro Miyamoto, Toshihisa Anzai, Hiroyuki Tsutsui
Circulation journal : official journal of the Japanese Circulation Society, 84, 5, 742, 753, 2020年04月24日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: An inverse relationship exists between hospital case volume and mortality in patients with heart failure (HF). However, hospital performance factors associated with mortality in HF patients have not been examined. We aimed to identify these using exploratory factor analysis and assess the relationship between these factors and 7-day, 30-day, and in-hospital mortality among HF patients in Japan.Methods and Results:We analyzed the records of 198,861 patients admitted to 683 certified hospitals of the Japanese Circulation Society between 2012 and 2014. Records were obtained from the nationwide database of the Japanese Registry Of All cardiac and vascular Diseases-Diagnostic Procedure Combination (JROAD-DPC). Using exploratory factor analysis, 90 hospital survey items were grouped into 5 factors, according to their collinearity: "Interventional cardiology", "Cardiovascular surgery", "Pediatric cardiology", "Electrophysiology" and "Cardiac rehabilitation". Multivariable logistic regression analysis was performed to determine the association between these factors and mortality. The 30-day mortality was 8.0%. Multivariable logistic regression analysis showed the "Pediatric cardiology" (odds ratio (OR) 0.677, 95% confidence interval [CI]: 0.628-0.729, P<0.0001), "Electrophysiology" (OR 0.876, 95% CI: 0.832-0.923, P<0.0001), and "Cardiac rehabilitation" (OR 0.832, 95% CI: 0.792-0.873, P<0.0001) factors were associated with lower mortality. In contrast, "Interventional cardiology" (OR 1.167, 95% CI: 1.070-1.272, P<0.0001) was associated with higher mortality. CONCLUSIONS: Hospital factors, including various cardiovascular therapeutic practices, may be associated with the early death of HF patients.

Difference in the prevalence of subclinical left ventricular impairment among left ventricular geometric pattern in a community-based population.
Takuya Hasegawa, Masanori Asakura, Hiroshi Asanuma, Makoto Amaki, Hiroyuki Takahama, Yasuo Sugano, Hideaki Kanzaki, Satoshi Yasuda, Toshihisa Anzai, Chisato Izumi, Masafumi Kitakaze
Journal of cardiology, 75, 4, 439, 446, 2020年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Left ventricular (LV) hypertrophy is reported to cause LV diastolic dysfunction. This study aimed to examine the prevalence of LV diastolic dysfunction in each group categorized by the geometric pattern of LV hypertrophy in a community-based population. METHODS: We studied 1260 community-dwelling subjects who experienced no symptoms of obvious heart disease (461 men, 799 women) and who participated in annual health check-ups in a rural Japanese community. The subjects were divided into 4 groups according to LV mass index and relative wall thickness: normal geometry, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. We investigated the prevalence of LV diastolic dysfunction in the overall and stratified population by LV geometric pattern. LV diastolic function was determined by 3 echocardiographic parameters of LV diastolic function: early diastolic myocardial velocity, the ratio of early diastolic mitral inflow velocity and myocardial velocity, and indexed left atrial dimension. LV diastolic dysfunction was defined as the presence of abnormal values in more than 2 of 3 echocardiographic parameters. RESULTS: The prevalence of LV diastolic dysfunction was higher in the categories with more severe LV hypertrophy. However, LV mass index, rather than relative wall thickness, was a significant determinant of LV diastolic dysfunction, after adjustment for comorbidities. In addition, 71 (10%) out of 740 subjects with normal LV geometric pattern had LV diastolic dysfunction even without obvious LV geometric change. CONCLUSIONS: The prevalence of LV diastolic dysfunction was higher in the subjects with more severe LV hypertrophy in a community-based population. Subclinical LV diastolic dysfunction without obvious LV geometric change should be noted and its clinical impact should be elucidated.

Prognostic Value of 18F-FDG PET Using Texture Analysis in Cardiac Sarcoidosis.
Osamu Manabe, Kazuhiro Koyanagawa, Kenji Hirata, Noriko Oyama-Manabe, Hiroshi Ohira, Tadao Aikawa, Sho Furuya, Masanao Naya, Ichizo Tsujino, Yuuki Tomiyama, Yuka Otaki, Toshihisa Anzai, Nagara Tamaki
JACC. Cardiovascular imaging, 13, 4, 1096, 1097, 2020年04月, ［査読有り］, ［国際誌］
英語

Development and Practical Test of Quality Indicators for Palliative Care in Patients With Chronic Heart Failure.
Yasuhiro Hamatani, Yasuko Takada, Yoshihiro Miyamoto, Yukie Kawano, Yuta Anchi, Tatsuhiro Shibata, Atsushi Suzuki, Mitsunori Nishikawa, Hiroto Ito, Masashi Kato, Tsuyoshi Shiga, Yoshihiro Fukumoto, Chisato Izumi, Satoshi Yasuda, Hisao Ogawa, Yasuo Sugano, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 84, 4, 584, 591, 2020年03月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Palliative care is highly relevant for patients with heart failure (HF), and there is a need for quantitative information on quality of care. Accordingly, this study aimed to develop a set of quality indicators (QIs) for palliative care of HF patients, and to conduct a practical pilot measurement of the proposed QIs in clinical practice.Methods and Results:We used a modified Delphi technique, a consensus method that involves a comprehensive literature review, face-to-face multidisciplinary panel meeting, and anonymous rating in 2 rounds. A 15-member multidisciplinary expert panel individually rated each potential indicator on a scale of 1 (lowest) to 9 (highest) for appropriateness. All indicators receiving a median score ≥7 without significant disagreement were included in the final set of QIs. Through the consensus-building process, 35 QIs were proposed for palliative care in HF patients. Practical measurement in HF patients (n=131) from 3 teaching hospitals revealed that all of the proposed QIs could be obtained retrospectively from medical records, and the following QIs had low performance (<10%): "Intervention by multidisciplinary team", "Opioid therapy for patients with refractory dyspnea", and "Screening for psychological symptoms". CONCLUSIONS: The first set of QIs for palliative care of HF patients was developed and could clarify quantitative information and might improve the quality of care.

Measurements of liver stiffness in patients with left ventricular assist device support.
Kazunori Omote, Takuma Sato, Toshiyuki Nagai, Toshihisa Anzai
Heart and vessels, 35, 3, 442, 442, 2020年03月, ［査読有り］, ［国内誌］
英語

Prognostic Value of Serum Uric Acid in Hospitalized Heart Failure Patients With Preserved Ejection Fraction (from the Japanese Nationwide Multicenter Registry).
Yuta Kobayashi, Kazunori Omote, Toshiyuki Nagai, Kiwamu Kamiya, Takao Konishi, Takuma Sato, Yoshiya Kato, Hirokazu Komoriyama, Shingo Tsujinaga, Hiroyuki Iwano, Kazuhiro Yamamoto, Tsutomu Yoshikawa, Yoshihiko Saito, Toshihisa Anzai
The American journal of cardiology, 125, 5, 772, 776, 2020年03月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Elevated serum uric acid (UA) is associated with an increased risk of cardiovascular disease and worse clinical outcome in patients with cardiovascular disease. Nevertheless, the prognostic value of serum UA level in hospitalized heart failure patients with preserved ejection fraction (HFpEF) has not been fully elucidated. The aim of this study was to investigate whether serum UA level on admission could be associated with subsequent mortality in hospitalized patients with HFpEF. We examined 516 consecutive hospitalized HFpEF (left ventricular ejection fraction ≥50%) patients with decompensated heart failure from our HFpEF-specific multicenter registry who had serum UA data on admission. The primary outcome of interest was all-cause death. During a median follow-up period of 749 (interquartile range 540 to 831) days, 90 (17%) patients died. Higher serum UA level was significantly related to increased incidence of all-cause death (p = 0.016). In addition, patients with higher serum UA (≥6.6 mg/dl, median) and plasma B-type natriuretic peptide (≥401.2 pg/ml, median) levels had the highest incidence of all-cause death in the groups (p = 0.002). In multivariable Cox regression analysis, serum UA was an independent determinant of mortality (hazards ratio 1.23, 95% confidence interval 1.10 to 1.39) even after adjustment for prespecified confounders, renal function and the use of diuretics before admission. In conclusions, higher admission serum UA was an independent determinant of mortality in hospitalized HFpEF patients. Our findings indicate the importance of assessing admission serum UA level for further risk stratification in hospitalized patients with HFpEF.

Differential Prognostic Impact of Atrial Fibrillation in Hospitalized Heart Failure Patients With Preserved Ejection Fraction According to Coronary Artery Disease Status - Report From the Japanese Nationwide Multicenter Registry.
Taro Temma, Toshiyuki Nagai, Masaya Watanabe, Rui Kamada, Yumi Takahashi, Hikaru Hagiwara, Taro Koya, Motoki Nakao, Kazunori Omote, Kiwamu Kamiya, Hiroyuki Iwano, Kazuhiro Yamamoto, Tsutomu Yoshikawa, Yoshihiko Saito, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 84, 3, 397, 403, 2020年02月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Atrial fibrillation (AF) is an important prognostic determinant in heart failure (HF) with preserved ejection fraction (HFpEF). However, it is unclear which HFpEF phenotypes are affected by AF in terms of long-term clinical outcomes because HFpEF is a heterogeneous syndrome with comorbidities such as coronary artery disease (CAD). In this study we determined the differential prognostic significance of AF in HFpEF patients according to CAD status.Methods and Results:Data for 408 hospitalized HFpEF patients enrolled in the Japanese Heart Failure Syndrome with Preserved Ejection Fraction Nationwide Multicenter Registry were analyzed. Patients were divided into 4 groups according to the presence of AF and CAD. The primary outcome was the composite of all-cause death and HF rehospitalization. The incidence of adverse events was higher in the AF-non-CAD than non-AF-non-CAD group (P=0.004). On multivariable Cox regression analysis with prespecified confounders, AF-non-CAD was significantly associated with an increased risk of adverse events than non-AF-non-CAD (adjusted HR, 1.91; 95% CI: 1.02-3.92) regardless of the type of AF. In contrast, risk was comparable between the AF-CAD and non-AF-CAD groups (adjusted HR, 1.24; 95% CI: 0.64-2.47). CONCLUSIONS: In HFpEF patients without CAD, AF was independently related to adverse events, indicating that intensive management of AF would have more beneficial effects particularly in HFpEF patients without CAD.

Impact of Endovascular Repair on the Outcomes of Octogenarians with Ruptured Abdominal Aortic Aneurysms: A Nationwide Japanese Study.
Tetsuo Yamaguchi, Michikazu Nakai, Yoko Sumita, Kunihiro Nishimura, Toshiyuki Nagai, Toshihisa Anzai, Yasushi Sakata, Hitoshi Ogino
European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery, 59, 2, 219, 225, 2020年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: This study aimed to clarify the impact of endovascular aneurysm repair (EVAR) on clinical outcomes in Japanese patients of advanced age with ruptured abdominal aortic aneurysm (rAAA). METHODS: This was a national registry based retrospective comparative study, using data from the Japanese Registry Of All cardiac and vascular Diseases-Diagnostic Procedure Combination (JROAD-DPC), a nationwide claim based database from more than 600 hospitals. Patients admitted with rAAA between April 1, 2012, and March 31, 2015 were included in the study. Patient characteristics, management, and outcomes were compared between the elderly (aged ≥ 80 y) and the less old. The primary endpoint was in hospital mortality; the secondary endpoint was the functional status at discharge. RESULTS: Of 3 969 eligible patients, 49.9% were categorised as elderly. Elderly patients had a higher prevalence of female gender (41.8% vs. 17.0%, p < .001) and disturbance of consciousness on admission (28.6% vs. 20.7%, p < .001). They were less likely to undergo open surgical repair (31.6% vs. 56.7%, p < .001), although EVAR was performed similarly in both groups (13.7% vs. 14.8%, p = .33). The unadjusted mortality rate (61.8% vs. 37.6%, p < .001) and mean Barthel index at discharge (73.0 vs. 91.8, p < .001) were statistically significantly worse in the elderly. Multilevel mixed effect logistic regression analyses showed that old age was detected as an independent predictor of in hospital death (odds ratio 2.75; 95% confidence interval, 2.39-3.17; p < .001). However, for patients who received EVAR, old age was not statistically significant (odds ratio 1.13; 95% confidence interval, 0.77-1.66; p = .53). CONCLUSION: Elderly patients with rAAA were less likely to be offered open surgical repair, and the mortality among those who received surgery was high. However, for the small subgroup of elderly patients currently selected for EVAR there was a favourable outcome. The further implementation of EVAR for rAAA in Japan, especially for elderly patients with suitable anatomy, may be justified.

Left ventricular outflow tract velocity time integral in hospitalized heart failure with preserved ejection fraction.
Kazunori Omote, Toshiyuki Nagai, Hiroyuki Iwano, Shingo Tsujinaga, Kiwamu Kamiya, Tadao Aikawa, Takao Konishi, Takuma Sato, Yoshiya Kato, Hirokazu Komoriyama, Yuta Kobayashi, Kazuhiro Yamamoto, Tsutomu Yoshikawa, Yoshihiko Saito, Toshihisa Anzai
ESC heart failure, 7, 1, 167, 175, 2020年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: The prognostic implication of left ventricular outflow tract velocity time integral (LVOT-VTI) on admission in hospitalized heart failure with preserved ejection fraction (HFpEF) patients has not been determined. We sought to investigate whether LVOT-VTI on admission is associated with worse clinical outcomes in hospitalized patients with HFpEF. METHODS AND RESULTS: We studied consecutive 214 hospitalized HFpEF patients who had accessible LVOT-VTI data on admission, from a prospective HFpEF-specific multicentre registry. The primary outcome of interest was the composite of all-cause death and readmission due to heart failure. During a median follow-up period of 688 (interquartile range 162-810) days, the primary outcome occurred in 83 patients (39%). The optimal cut-off value of LVOT-VTI for the primary outcome estimated by receiver operating characteristic analysis was 15.8 cm. Lower LVOT-VTI was significantly associated with the primary outcome compared with higher LVOT-VTI (P = 0.005). Multivariable Cox regression analyses revealed that lower LVOT-VTI was an independent determinant of the primary outcome (hazard ratio 0.94, 95% confidence interval 0.91-0.98). In multivariable linear regression, haemoglobin level was the strongest independent determinant of LVOT-VTI among clinical parameters (β coefficient = -0.61, P = 0.007). Furthermore, patients with lower LVOT-VTI and anaemia had the worst clinical outcomes among the groups (P < 0.001). CONCLUSIONS: Lower admission LVOT-VTI was an independent determinant of worse clinical outcomes in hospitalized HFpEF patients, indicating that LVOT-VTI on admission might be useful for categorizing a low-flow HFpEF phenotype and risk stratification in hospitalized HFpEF patients.

Viability assessment by 18F-FDG PET in a patient with a large left ventricular aneurysm and obstructive coronary artery disease.
Eigo Kurebayashi, Osamu Manabe, Masanao Naya, Shiro Miura, Takehiro Yamashita, Yoshihiro Imai, Akira Ando, Chihoko Miyazaki, Toshihisa Anzai
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology, 27, 1, 326, 329, 2020年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Serum Brain-Derived Neurotrophic Factor Levels Are Associated with Skeletal Muscle Function but Not with Muscle Mass in Patients with Heart Failure.
Ippei Nakano, Shintaro Kinugawa, Hiroaki Hori, Arata Fukushima, Takashi Yokota, Shingo Takada, Naoya Kakutani, Yoshikuni Obata, Katsuma Yamanashi, Toshihisa Anzai
International heart journal, 61, 1, 96, 102, 2020年01月31日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Heart failure (HF) is associated with aberrant skeletal muscle impairments, which are closely linked to the severity of HF. A low level of brain-derived neurotrophic factor (BDNF), a myokine produced in the skeletal muscle, is known to be involved in reduced exercise capacity and poor prognosis in HF. However, little is known about the factors or conditions of skeletal muscle associated with BDNF levels. We investigated the association between serum BDNF levels and the skeletal muscle mass and function in HF patients (n = 60, 63 ± 13 years) and age-matched controls (n = 29, 61 ± 16 years). The serum BDNF level was significantly lower in the HF patients compared to the controls (24.9 ± 0.9 versus 28.6 ± 1.3, P = 0.021). In a univariate analysis, BDNF was significantly correlated with the peak oxygen uptake, estimated glomerular filtration rate, 10-m gait speed, and muscle strength, but not with the body mass index or lean mass in the HF group. A multiple linear regression analysis revealed that BDNF was independently associated with muscle strength (β-coefficient = 2.80, 95%CI: 1.89-11.8, P = 0.008). Serum BDNF levels were associated with exercise capacity and skeletal muscle function, but not with muscle mass. These novel findings may suggest that BDNF production is controlled by muscle function and activity and consequently regulates exercise capacity, highlighting the importance of adequate training regarding skeletal muscle in HF patients.

Improved regional myocardial blood flow and flow reserve after coronary revascularization as assessed by serial 15O-water positron emission tomography/computed tomography.
Tadao Aikawa, Masanao Naya, Kazuhiro Koyanagawa, Osamu Manabe, Masahiko Obara, Keiichi Magota, Noriko Oyama-Manabe, Nagara Tamaki, Toshihisa Anzai
European heart journal cardiovascular Imaging, 21, 1, 36, 46, 2020年01月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Myocardial perfusion imaging without and with quantitative myocardial blood flow (MBF) and myocardial flow reserve (MFR) plays an important role in the diagnosis and risk stratification of patients with stable coronary artery disease (CAD). We aimed to quantify the effects of coronary revascularization on regional stress MBF and MFR and to determine whether the presence of subendocardial infarction was associated with these changes. METHODS AND RESULTS: Forty-seven patients with stable CAD were prospectively enrolled. They underwent 15O-water positron emission tomography at baseline and 6 months after optimal medical therapy alone (n = 16), percutaneous coronary intervention (PCI) (n = 18), or coronary artery bypass grafting (CABG) (n = 13). Stenosis of ≥50% diameter was detected in 98/141 vessels (70%). The regional MFR was significantly increased from baseline to follow-up [1.84 (interquartile range, IQR 1.28-2.17) vs. 2.12 (IQR 1.69-2.63), P < 0.001] in vessel territories following PCI or CABG due to an increase in the stress MBF [1.33 (IQR 0.97-1.67) mL/g/min vs. 1.64 (IQR 1.38-2.17) mL/g/min, P < 0.001], whereas there was no significant change in the regional stress MBF or MFR in vessel territories without revascularization. A multilevel mixed-effects models adjusted for baseline characteristics, subendocardial infarction assessed by cardiovascular magnetic resonance imaging, and intra-patient correlation showed that the degree of angiographic improvement after coronary revascularization was significantly associated with increased regional stress MBF and MFR (P < 0.05 for all). CONCLUSION: Coronary revascularization improved the regional stress MBF and MFR in patients with stable CAD. The magnitude of these changes was associated with the extent of revascularization independent of subendocardial infarction.

Dual Gate Doppler法による左房収縮時の血流時相解析
岡田 一範, 岡田 由佳, 加賀 早苗, 村山 迪史, 中鉢 雅大, 横山 しのぶ, 西野 久雄, 三神 大世, 更科 美羽, 辻永 真吾, 岩野 弘幸, 安斉 俊久
超音波検査技術抄録集, 45, S110, S110, 一般社団法人 日本超音波検査学会, 2020年
日本語

Diagnosis, prevention, and treatment of cardiovascular diseases in people with type 2 diabetes and prediabetes: a consensus statement jointly from the Japanese Circulation Society and the Japan Diabetes Society
Eiichi Araki, Atsushi Tanaka, Nobuya Inagaki, Hiroshi Ito, Kohjiro Ueki, Toyoaki Murohara, Kenjiro Imai, Masataka Sata, Takehiro Sugiyama, Hideki Ishii, Shunsuke Yamane, Takashi Kadowaki, Issei Komuro, Koichi Node, Tetsuya Amano, Toshihisa Anzai, Tetsuya Babazono, Masanori Emoto, Keiichi Fukuda, Nobuhisa Hagiwara, Ken ichi Hirata, Yuji Ikari, Takanori Ikeda, Chisato Izumi, Masahiro Jinzaki, Hideaki Kaneto, Hideki Katagiri, Takeshi Kimura, Yoshio Kobayashi, Koji Maemura, Satoaki Matoba, Tetsuo Minamino, Yoshihide Mitani, Shin ichiro Miura, Yoshihio Morino, Jiro Nakamura, Yoshihiko Nishio, Wataru Ogawa, Mitsuru Ohishi, Hiroyuki Okura, Minoru Ono, Yasushi Sakata, Asako Sato, Akira Shimada, Wataru Shimizu, Iichiro Shimomura, Ichiro Shiojima, Masayuki Takamura, Yasutomo Takeishi, Kazuo Tanemoto, Yukio Tanizawa, Yasuo Terauchi, Kazuyuki Tobe, Yayoi Tetsuou, Hirotaka Watada, Toshimasa Yamauchi, Masafumi Yano, Narihito Yoshioka
Diabetology International, 2020年
研究論文（学術雑誌）

Emery-Dreifuss muscular dystrophy as a possible cause of coronary embolism.
Atsushi Tada, Takao Konishi, Takuma Sato, Tomoya Sato, Takuya Koizumi, Sakae Takenaka, Yoshifumi Mizuguchi, Takahide Kadosaka, Ko Motoi, Yuta Kobayashi, Hirokazu Komoriyama, Yoshiya Kato, Kazunori Omote, Shingo Tsujinaga, Rui Kamada, Kiwamu Kamiya, Hiroyuki Iwano, Toshiyuki Nagai, Nanase Okazaki, Yoshihiro Matsuno, Toshihisa Anzai
Cardiology journal, 27, 4, 443, 444, 2020年, ［国際誌］
英語, 研究論文（学術雑誌）

心エコー法とMRIによる肺動脈弁逆流重症度に乖離を認めた総動脈幹症の術後症例　　　　　　　　　　　　　　　
岩野 弘幸, 村山 迪史, 山澤 弘州, 武田 充人, 真鍋 徳子, 石森 直樹, 千葉 泰之, 石坂 傑, 更科 美羽, 辻永 真吾, 中鉢 雅大, 加賀 早苗, 安斉 俊久
日本成人先天性心疾患学会雑誌, 9, 1, 288, 288, 日本成人先天性心疾患学会, 2020年01月, ［査読有り］
日本語

心エコー法とMRIによる肺動脈弁逆流重症度に乖離を認めた総動脈幹症の術後症例　　　　　　　　　　　　　　　
岩野 弘幸, 村山 迪史, 山澤 弘州, 武田 充人, 真鍋 徳子, 石森 直樹, 千葉 泰之, 石坂 傑, 更科 美羽, 辻永 真吾, 中鉢 雅大, 加賀 早苗, 安斉 俊久
日本成人先天性心疾患学会雑誌, 9, 1, 288, 288, 日本成人先天性心疾患学会, 2020年01月, ［査読有り］
日本語

Histopathologically confirmed very late stent thrombosis associated with stent fracture after implantation of first-generation drug eluting stent.
Takao Konishi, Naohiro Funayama, Tadashi Yamamoto, Daisuke Hotta, Yuta Kobayashi, Hirokazu Komoriyama, Yoshiya Kato, Kazunori Omote, Takuma Sato, Kiwamu Kamiya, Toshiyuki Nagai, Shinya Tanaka, Toshihisa Anzai
Cardiology journal, 27, 2, 204, 205, 2020年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

18F-FMISO PET/CT detects hypoxic lesions of cardiac and extra-cardiac involvement in patients with sarcoidosis.
Sho Furuya, Masanao Naya, Osamu Manabe, Kenji Hirata, Hiroshi Ohira, Tadao Aikawa, Kazuhiro Koyanagawa, Keiichi Magota, Ichizo Tsujino, Toshihisa Anzai, Yuji Kuge, Noriko Oyama-Manabe, Kohsuke Kudo, Tohru Shiga, Nagara Tamaki
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology, 28, 5, 2141, 2148, 2019年12月09日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: 18F-fluoromisonidazole (FMISO) is a hypoxia positron emission tomography (PET) tracer. Here, we evaluated cardiac and extra-cardiac sarcoidosis using both FMISO and 18F-fluorodeoxyglucose (FDG) PET/CT in a prospective cohort of patients with sarcoidosis. METHODS: Ten consecutive sarcoidosis patients with suspected cardiac involvement were prospectively enrolled. Each patient fasted overnight (for ≥ 18 hours) preceded by a low-carbohydrate diet before FDG PET/CT but not given special dietary instructions before the FMISO PET/CT scan. We visually and semiquantitatively assessed the uptakes of FMISO and FDG using the maximal standardized uptake value (SUVmax). The metabolic volume (MV) of FDG was calculated as the volume within the boundary determined by the threshold (mean SUV of blood pool × 1.5). RESULTS: Nine patients showed focal FDG uptake in the myocardium and were diagnosed with cardiac sarcoidosis. Among the patients with extra-cardiac lesions, FDG uptake was seen in 8 lymph nodes and 3 lung lesions. FMISO uptake was seen in the 7 cardiac (77.8%) and 6 extra-cardiac (54.5%) lesions. None of the patients showed physiological FMISO uptake in the myocardium. The SUVmax values of the lesions with FMISO uptake were higher than those of the lesions without FMISO uptake in both the cardiac (SUVmax: 9.9, IQR: 8.4-10.0 vs 7.3, IQR: 6.3-8.2) and non-cardiac lesions (SUVmax: 17.6, IQR: 14.5-19.3 vs 6.1, IQR: 5.9-6.2; P = 0.006). The MV values of the lesions with FMISO uptake were significantly higher than those of the lesions without FMISO uptake (111.3, IQR: 78.3-135.7 vs 6.4, IQR: 1.9-23.3; P = 0.0009). CONCLUSIONS: FMISO showed no physiological myocardial uptake and did not require special preparation. FMISO PET has the potential to detect hypoxic lesions in patients with sarcoidosis.

Evidence-Based Utilization of Prognostic Prediction Models in Cardiovascular Medicine.
Naotsugu Iwakami, Toshiyuki Nagai, Toshiaki A Furukawa, Kunihiro Nishimura, Toshihisa Anzai
Circulation reports, 2, 1, 10, 16, 2019年12月05日, ［国内誌］
英語, 研究論文（学術雑誌）, Prediction models are combinations of predictors to assess the risks of specific endpoints such as the presence or prognosis of a disease. Many novel predictors have been developed, modelling techniques have been evolving, and prediction models are currently abundant in the medical literature, especially in cardiovascular medicine, but evidence is still lacking regarding how to use them. Recent methodological advances in systematic reviews and meta-analysis have enabled systematic evaluation of prediction model studies and quantitative analysis to identify determinants of model performance. Knowing what is critical to model performance, under what circumstances model performance remains adequate, and when a model might require further adjustment and improvement will facilitate effective utilization of prediction models and will enhance diagnostic and prognostic accuracy in clinical practice. In this review article, we provide a current methodological overview of the attempts to implement evidence-based utilization of prognostic prediction models for all potential model users, including patients and their families, health-care providers, administrators, researchers, guideline developers and policy makers.

Long-term Prognostic Significance of Admission Tricuspid Regurgitation Pressure Gradient in Hospitalized Patients With Heart Failure With Preserved Ejection Fraction: A Report From the Japanese Real-World Multicenter Registry.
Kazunori Omote, Toshiyuki Nagai, Kiwamu Kamiya, Tadao Aikawa, Shingo Tsujinaga, Yoshiya Kato, Hirokazu Komoriyama, Hiroyuki Iwano, Kazuhiro Yamamoto, Tsutomu Yoshikawa, Yoshihiko Saito, Toshihisa Anzai
Journal of cardiac failure, 25, 12, 978, 985, 2019年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Doppler-estimated peak systolic tricuspid regurgitation pressure gradient (TRPG) is a representative noninvasive parameter for evaluating pulmonary artery systolic pressure, which can be a determinant of adverse outcomes in chronic heart failure with preserved ejection fraction (HFpEF). However, the prognostic implications of TRPG at admission for hospitalized patients with HFpEF are undetermined. METHODS AND RESULTS: We examined 469 consecutive hospitalized patients with decompensated HFpEF (left ventricular ejection fraction ≥ 50%) who underwent TRPG measurement at admission in our HFpEF multicenter registry. The primary outcome of interest was all-cause death. Admission TRPG was significantly correlated with estimated pulmonary capillary wedge pressure and left atrial dimension (r = 0.24, P < 0.001 and r = 0.21, P < 0.001, respectively). During a median follow-up period of 748 (IQR 540-820) days, 83 patients died. Higher TRPG was significantly associated with higher mortality compared to lower TRPG (log-rank; P = 0.007). Multivariable analysis revealed that elevated TRPG was an independent determinant of mortality (HR 1.02, 95% CI 1.01-1.04, P = 0.008) after adjustment for prespecified confounders and renal function. CONCLUSIONS: Elevated TRPG at admission was an independent determinant of mortality in hospitalized patients with HFpEF, indicating that TRPG at admission could be a useful marker for risk stratification in these patients.

収縮機能維持の心不全入院患者における入院時の三尖弁逆流圧較差の長期予後的意義 多施設レジストリーからの報告 TRPGとHFpEFにおける長期転帰(Long-term prognostic significance of admission tricuspid regurgitation pressure gradient in hospitalized heart failure patients with preserved ejection fraction: a report from the Japanese real-world multicenter registry: TRPG and long-term outcomes in HFpEF)
Omote Kazunori, Nagai Toshiyuki, Kamiya Kiwamu, Aikawa Tadao, Tsujinaga Shingo, Kato Yoshiya, Komoriyama Hirokazu, Iwano Hiroyuki, Yamamoto Kazuhiro, Yoshikawa Tsutomu, Saito Yoshihiko, Anzai Toshihisa
福田記念医療技術振興財団情報, 32, 41, 54, (公財)福田記念医療技術振興財団, 2019年12月
英語, 収縮機能維持心不全(HFpEF)多施設レジストリーにて、入院時に三尖弁逆流圧較差(TRPG)を測定した非代償性HFpEF患者(左室駆出分画≧50%)469名(女232名、平均78.3歳)を対象として、入院TRPGの予後的意義を検討した。主要評価項目は総死亡率とした。その結果、入院時TRPGは推定肺毛細血管楔入圧(PCWP)および左房径(LAD)と有意に相関した。追跡期間中央値の748日までに患者83名が死亡した。TRPG高値患者はTRPG低値患者に比べて有意に死亡率が高かった。多変量解析では、TRPG上昇が事前指定の交絡因子と腎機能による調整後の死亡率の独立決定因子であった。以上より、入院TRPG上昇はHFpEF入院患者の死亡率の独立決定因子であり、入院時のTRPGは有用なリスク分類の指標になると考えられた。

A mitochondrial delivery system using liposome-based nanocarriers that target myoblast cells.
Takashi Katayama, Shintaro Kinugawa, Shingo Takada, Takaaki Furihata, Arata Fukushima, Takashi Yokota, Toshihisa Anzai, Mitsue Hibino, Hideyoshi Harashima, Yuma Yamada
Mitochondrion, 49, 66, 72, 2019年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Mitochondrial function is reduced in skeletal muscles of many patients with systemic diseases and it is difficult to deliver medicinal substances to mitochondria in such tissue. In this study, we report on attempts to develop liposome-based carriers for mitochondrial delivery using mouse myoblasts (C2C12) by varying the lipid composition of the carriers. We found that a liposome that contains an optimal lipid modified with the KALA peptide (a cellular uptake and mitochondrial targeting device) was the most effective nanocarrier for achieving mitochondrial delivery in C2C12 cells. We also report on successful mitochondrial transgene expression using the carriers encapsulating a mitochondrial DNA vector as we previously reported.

Impact of Left Ventricular Suction During Exercise on Clinical Outcomes in Patients With Heart Failure
Shingo Tsujinaga, Hiroyuki Iwano, Suguru Ishizaka, Yasuyuki Chiba, Miwa Sarashina, Michito Murayama, Masahiro Nakabachi, Shinobu Yokoyama, Hisao Nishino, Kazunori Okada, Sanae Kaga, Takuma Sato, Toshihisa Anzai
CIRCULATION, 140, LIPPINCOTT WILLIAMS & WILKINS, 2019年11月, ［査読有り］
英語, 0

JCS 2016 Guideline on Diagnosis and Treatment of Cardiac Sarcoidosis - Digest Version.
Fumio Terasaki, Arata Azuma, Toshihisa Anzai, Nobukazu Ishizaka, Yoshio Ishida, Mitsuaki Isobe, Takayuki Inomata, Hatsue Ishibashi-Ueda, Yoshinobu Eishi, Masafumi Kitakaze, Kengo Kusano, Yasushi Sakata, Noriharu Shijubo, Akihito Tsuchida, Hiroyuki Tsutsui, Takatomo Nakajima, Satoshi Nakatani, Taiko Horii, Yoshikazu Yazaki, Etsuro Yamaguchi, Tetsuo Yamaguchi, Tomomi Ide, Hideo Okamura, Yasuchika Kato, Masahiko Goya, Mamoru Sakakibara, Kyoko Soejima, Toshiyuki Nagai, Hiroshi Nakamura, Takashi Noda, Takuya Hasegawa, Hideaki Morita, Tohru Ohe, Yasuki Kihara, Yoshihiko Saito, Yukihiko Sugiyama, Shin-Ichiro Morimoto, Akira Yamashina
Circulation journal : official journal of the Japanese Circulation Society, 83, 11, 2329, 2388, 2019年10月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

Mitochondrial reactive oxygen species generation in blood cells is associated with disease severity and exercise intolerance in heart failure patients.
Ryosuke Shirakawa, Takashi Yokota, Takayuki Nakajima, Shingo Takada, Miwako Yamane, Takaaki Furihata, Satoshi Maekawa, Hideo Nambu, Takashi Katayama, Arata Fukushima, Akimichi Saito, Naoki Ishimori, Flemming Dela, Shintaro Kinugawa, Toshihisa Anzai
Scientific reports, 9, 1, 14709, 14709, 2019年10月11日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Systemic oxidative stress plays a key role in the development of chronic heart failure (CHF). We tested the hypothesis that mitochondrial reactive oxygen species (ROS) generation in circulating peripheral blood mononuclear cells (PBMCs) contributes to CHF progression. A total of 31 patients who had a history of hospital admission due to worsening HF were enrolled and grouped as having either mild CHF defined as New York Heart Association (NYHA) functional class I-II or moderate-to-severe CHF defined as NYHA functional class III. ROS levels in PBMC mitochondria were significantly increased in CHF patients with NYHA functional class III compared to those with NYHA functional class I-II, accompanied by impaired mitochondrial respiratory capacity in PBMCs. ROS generation in PBMC mitochondria was positively correlated with urinary 8-hydroxydeoxyguanosine, a systemic oxidative stress marker, in CHF patients. Importantly, mitochondrial ROS generation in PBMCs was directly correlated with plasma levels of B-type natriuretic peptide, a biomarker for severity of HF, and inversely correlated with peak oxygen uptake, a parameter of exercise capacity, in CHF patients. The study showed that ROS generation in PBMC mitochondria was higher in patients with advanced CHF, and it was associated with disease severity and exercise intolerance in CHF patients.

The rate of myocardial perfusion recovery after steroid therapy and its implication for cardiac events in cardiac sarcoidosis and primarily preserved left ventricular ejection fraction.
Kazuhiro Koyanagawa, Masanao Naya, Tadao Aikawa, Osamu Manabe, Sho Furuya, Masato Kuzume, Noriko Oyama-Manabe, Hiroshi Ohira, Ichizo Tsujino, Toshihisa Anzai
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology, 28, 4, 1745, 1756, 2019年10月11日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Sarcoidosis is a multisystemic disorder of unknown cause characterized by immune granuloma formation in the involved organs. Few studies have reported on the myocardial perfusion changes by immunosuppression therapy in cardiac sarcoidosis (CS). Additionally, the relationship between myocardial perfusion changes and prognosis is unknown. Therefore, this study aimed to clarify myocardial perfusion recovery after steroid therapy and its prognostic value for major adverse cardiac events (MACE) in patients with CS. METHODS AND RESULTS: Thirty-eight consecutive patients with CS {median age, 63 [interquartile range (IQR) 51-68] years; 10 men} underwent both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (CT) and electrocardiography-gated single-photon emission CT (SPECT) pre- and post-steroid therapy. Patients with improved or preserved myocardial perfusion after post-therapy were defined as the recovery group and those with worsened myocardial perfusion as the non-recovery group. Twenty-six patients (68%) were categorized as the recovery group. MACE occurred in eight patients. The Kaplan-Meier curves revealed a significantly higher rate of MACE in the non-recovery group (17.4%/y vs 2.9%/y, P = 0.007). CONCLUSIONS: Myocardial perfusion was recovered by steroid therapy in 61% and preserved in 8% of patients. Myocardial perfusion recovery after steroid therapy was significantly associated with a low incidence of MACE.

Development and validation of support tools for advance care planning in patients with chronic heart failure.
Yasuko Takada, Yasuhiro Hamatani, Yukie Kawano, Yuta Anchi, Michikazu Nakai, Chisato Izumi, Satoshi Yasuda, Hisao Ogawa, Yasuo Sugano, Toshihisa Anzai, Tatsuhiro Shibata, Atsushi Suzuki, Mitsunori Nishikawa, Hiroto Ito, Masashi Kato, Tsuyoshi Shiga, Yoshihiro Fukumoto
International journal of palliative nursing, 25, 10, 494, 502, 2019年10月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Advance care planning (ACP) is recommended as part of the management of patients with heart failure (HF). AIMS: To develop and validate ACP support tools for patients with HF. METHODS: An ACP support tool was developed based on a systematic literature review. A multi-center, prospective before and after study was conducted to evaluate the usefulness of the support tool. This study included 21 patients with HF, 11 patients formed the control group and 10 patients were part of the intervention group who received ACP from medical staff using the ACP support tools developed for this study. Participants of the study were surveyed about their experience of ACP using a 6-point Likert scale. FINDINGS: All of the healthcare professionals (n=9) involved in the study found the ACP tool useful and about 90% of patients considered the support tool useful. The score for 'the patient did not feel anxious about the future after receiving ACP discussion' was significantly higher (3.5 [3.0, 4.0] vs 2.0 [1.0, 3.0]; P=0.04) in the intervention group that used the ACP tool. CONCLUSION: ACP support tools are useful to manage patients with HF and could enable effective ACP without increasing patient anxiety.

心臓サルコイドーシス診療におけるFDG-PETによる活動性評価をガイドとした免疫抑制療法戦略の限界
永井 利幸, 相川 忠夫, 安斉 俊久
日本サルコイドーシス/肉芽腫性疾患学会雑誌, 39, 1-2, 73, 76, 日本サルコイドーシス, 2019年10月, ［査読有り］
日本語, 18F-fluorodeoxyglucose-positron emission tomography(FDG-PET)は,心臓サルコイドーシス(心サ症)の診断および病態評価に有用と考えられるが,FDG-PETにより評価された活動性炎症所見と臨床経過の乖離がしばしば経験される.今回我々はFDG-PET所見に増悪所見を認めた一方で臨床経過は改善を認めた症例,およびFDG-PET所見に改善所見を認めた一方で臨床経過は増悪を認めた症例を経験した.また,心サ症確診症例111例のうち,長期経過観察中にFDG-PET所見の増悪を認めた13例を検討した結果,同時に有害事象を伴う症例は6例であり,そのうち増悪時免疫抑制療法が中止されていた症例は3例であった.全例免疫抑制療法を強化したものの,その後2例に再度有害事象が発生した.一方,FDG-PET所見の増悪に有害事象を伴わない症例は7例であり,そのうち5例で免疫抑制療法を強化したものの,2例に再度有害事象が発生した.免疫抑制療法中のFDG-PET所見の変化が持つ臨床的意義には未だ不明な点が多く,今後の症例蓄積と前向き多施設研究が必要である.(著者抄録)

心筋サルコイドーシスにおける心筋血流の改善から予想される心イベントの減少化(Improvement in myocardial perfusion predicts fewer cardiac events in cardiac sarcoidosis)　　　　　　　　　　　　　　　
小梁川 和宏, 納谷 昌直, 相川 忠夫, 真鍋 治, 古家 翔, 葛目 将人, 真鍋 徳子, 大平 洋, 辻野 一三, 安斉 俊久
核医学, 56, Suppl., S137, S137, (一社)日本核医学会, 2019年10月, ［査読有り］
英語

Hyponatremia at discharge is associated with adverse prognosis in acute heart failure syndromes with preserved ejection fraction: a report from the JASPER registry.
Yu Sato, Akiomi Yoshihisa, Masayoshi Oikawa, Toshiyuki Nagai, Tsutomu Yoshikawa, Yoshihiko Saito, Kazuhiro Yamamoto, Yasuchika Takeishi, Toshihisa Anzai
European heart journal. Acute cardiovascular care, 8, 7, 623, 633, 2019年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Hyponatremia predicts adverse prognosis in patients with heart failure in particular with reduced ejection fraction. In contrast, it has recently been reported that hyponatremia on admission is not a predictor of post-discharge mortality in patients with heart failure with preserved ejection fraction. We investigated the prognostic impact of hyponatremia at discharge in patients with heart failure with preserved ejection fraction and its clinical characteristics. METHODS AND RESULTS: The Japanese Heart Failure Syndrome with Preserved Ejection Fraction (JASPER) registry is a nationwide, observational, prospective registration of consecutive Japanese patients hospitalised with heart failure with preserved ejection fraction and left ventricular ejection fraction of 50% or greater. Five hundred consecutive patients were enrolled in this analysis. We divided the patients into two groups based on their sodium serum levels at discharge: hyponatremia group (sodium <135 mEq/L, n=50, 10.0%) and control group (sodium ⩾135 mEq/L, n=450, 90.0%). This present analysis had two primary endpoints: all-cause death and all-cause death or rehospitalisation for heart failure. At discharge, the hyponatremia group had lower systolic blood pressure (110.0 mmHg vs. 114.5 mmHg, P=0.014) and higher levels of urea nitrogen (31.9 mg/dL vs. 24.2 mg/dL, P=0.032). In the Kaplan-Meier analysis, more patients in the hyponatremia group reached the primary endpoints than those in the control group (log rank <0.01, respectively). In the Cox proportional hazard analysis, hyponatremia at discharge was a predictor of the two endpoints (all-cause death, hazard ratio 2.708, 95% confidence interval 1.557-4.708, P<0.001; all-cause death or rehospitalisation for heart failure, hazard ratio 1.829, 95% confidence interval 1.203-2.780, P=0.005). CONCLUSIONS: Hyponatremia at discharge is associated with adverse prognosis in hospitalised patients with heart failure with preserved ejection fraction.

Simple and noninvasive method to estimate right ventricular operating stiffness based on echocardiographic pulmonary regurgitant velocity and tricuspid annular plane movement measurements during atrial contraction.
Michito Murayama, Kazunori Okada, Sanae Kaga, Hiroyuki Iwano, Shingo Tsujinaga, Miwa Sarashina, Masahiro Nakabachi, Shinobu Yokoyama, Hisao Nishino, Mutsumi Nishida, Hitoshi Shibuya, Nobuo Masauzi, Toshihisa Anzai, Taisei Mikami
The international journal of cardiovascular imaging, 35, 10, 1871, 1880, 2019年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, It was recently shown that invasively determined right ventricular (RV) stiffness was more closely related to the prognosis of patients with pulmonary hypertension than RV systolic function. So far, a completely noninvasive method to access RV stiffness has not been reported. We aimed to clarify the clinical usefulness of our new echocardiographic index of RV operating stiffness using atrial-systolic descent of the pulmonary artery-RV pressure gradient derived from pulmonary regurgitant velocity (PRPGDAC) and tricuspid annular plane movement during atrial contraction (TAPMAC). We studied 81 consecutive patients with various cardiac diseases who underwent echocardiography and cardiac catheterization. We measured PRPGDAC and TAPMAC using continuous-wave Doppler and M-mode echocardiography, respectively, and calculated PRPGDAC/TAPMAC. RV end-diastolic pressure (RVEDP) and RV pressure increase during atrial contraction (ΔRVPAC) were invasively measured, and RV volume change during atrial contraction (ΔVAC) was calculated from echocardiographic late-diastolic transtricuspid flow time-velocity integral and tricuspid annular area; thus ΔRVPAC/ΔVAC was used as the standard index for RV operating stiffness. PRPGDAC/TAPMAC well correlated with ΔRVPAC/ΔVAC (r = 0.84, p < 0.001) and RVEDP (r = 0.80, p < 0.001), and the area under the receiver operating characteristic curve to discriminate RVEDP > 12 mmHg was 0.94. Multivariate regression analysis revealed that PRPGDAC/TAPMAC was the single independent determinant of ΔRVPAC/ΔVAC (β = 0.86, p < 0.001). PRPGDAC/TAPMAC is useful to estimate RV operating stiffness and a good practical indicator of RVEDP.

Long-Term Tolvaptan Treatment in Refractory Heart Failure.
Teruhiko Imamura, Shintaro Kinugawa, Toshihiro Muramatsu, Tsuyoshi Shiga, Akiyoshi Ogimoto, Toshihisa Anzai, Nobuhisa Hagiwara, Hiroyuki Tsutsui, Issei Komuro, Koichiro Kinugawa
Circulation reports, 1, 10, 431, 437, 2019年09月26日, ［国内誌］
英語, 研究論文（学術雑誌）, Background: The vasopressin type-2 receptor antagonist tolvaptan is an essential tool in the management of decompensated heart failure (HF) in the inpatient setting for short-term use with careful monitoring. There is conflicting evidence, however, for its long-term use. Methods and Results: In this prospective, multi-center, open-labeled, randomized control trial, Assessment of QUAlity of life during long-term treatment of ToLVaptan in refractory HF (AQUA-TLV study), patients with congestive HF refractory to furosemide ≥60 mg/day were randomly assigned to a control group or tolvaptan add-on group and followed for 6 months, after confirmation of baseline urine osmolality ≥350 mOsm/L. Twenty-nine patients (median age, 60 years; 22 male) were enrolled and assigned to a control group (n=16) or a tolvaptan group (n=13). Minnesota Living with Heart Failure Questionnaire score improved significantly in the tolvaptan group (from 58 to 10, P=0.030). In the tolvaptan group, diuretics dose reduced (P=0.001), serum creatinine decreased (P=0.040), and hyponatremia tended to improve (P=0.12). The tolvaptan group had a lower HF readmission rate compared with the control group (0.213 vs. 1.242 events/year, P=0.13). Conclusions: Six-month tolvaptan therapy improved quality of life and renal function and reduced HF readmissions, when given to the estimated responders (UMIN Clinical Trial Registry Number: UMIN 000009604).

JCS 2017/JHFS 2017 Guideline on Diagnosis and Treatment of Acute and Chronic Heart Failure - Digest Version.
Hiroyuki Tsutsui, Mitsuaki Isobe, Hiroshi Ito, Hiroshi Ito, Ken Okumura, Minoru Ono, Masafumi Kitakaze, Koichiro Kinugawa, Yasuki Kihara, Yoichi Goto, Issei Komuro, Yoshikatsu Saiki, Yoshihiko Saito, Yasushi Sakata, Naoki Sato, Yoshiki Sawa, Akira Shiose, Wataru Shimizu, Hiroaki Shimokawa, Yoshihiko Seino, Koichi Node, Taiki Higo, Atsushi Hirayama, Miyuki Makaya, Tohru Masuyama, Toyoaki Murohara, Shin-Ichi Momomura, Masafumi Yano, Kenji Yamazaki, Kazuhiro Yamamoto, Tsutomu Yoshikawa, Michihiro Yoshimura, Masatoshi Akiyama, Toshihisa Anzai, Shiro Ishihara, Takayuki Inomata, Teruhiko Imamura, Yu-Ki Iwasaki, Tomohito Ohtani, Katsuya Onishi, Takatoshi Kasai, Mahoto Kato, Makoto Kawai, Yoshiharu Kinugasa, Shintaro Kinugawa, Toru Kuratani, Shigeki Kobayashi, Yasuhiko Sakata, Atsushi Tanaka, Koichi Toda, Takashi Noda, Kotaro Nochioka, Masaru Hatano, Takayuki Hidaka, Takeo Fujino, Shigeru Makita, Osamu Yamaguchi, Uichi Ikeda, Takeshi Kimura, Shun Kohsaka, Masami Kosuge, Masakazu Yamagishi, Akira Yamashina
Circulation journal : official journal of the Japanese Circulation Society, 83, 10, 2084, 2184, 2019年09月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

Change in the NT-proBNP/Mature BNP Molar Ratio Precedes Worsening Renal Function in Patients With Acute Heart Failure: A Novel Predictor Candidate for Cardiorenal Syndrome.
Hiroyuki Takahama, Toshio Nishikimi, Seiji Takashio, Tomohiro Hayashi, Chiaki Nagai-Okatani, Takashi Asada, Akihiro Fujiwara, Yasuaki Nakagawa, Masashi Amano, Yasuhiro Hamatani, Atsushi Okada, Makoto Amaki, Takuya Hasegawa, Hideaki Kanzaki, Kunihiro Nishimura, Satoshi Yasuda, Kenji Kangawa, Toshihisa Anzai, Naoto Minamino, Chisato Izumi
Journal of the American Heart Association, 8, 17, e011468, 2019年09月03日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background Early detection for worsening renal function (WRF) is indispensable in patients with acute decompensated heart failure (HF). We tested the hypothesis that the difference in the circulating levels of each B-type or brain natriuretic peptide (BNP) molecular form is associated with the occurrence of WRF. Methods and Results Circulating levels of proBNP, the NT-proBNP (N-terminal proBNP), and total BNP (proBNP+mature BNP) were prospectively measured in patients with acute decompensated HF using specific and sensitive enzyme immunochemiluminescent assays. An estimated mature BNP (emBNP) concentration was calculated by subtracting proBNP levels from total BNP levels. WRF was defined as a >20% decrease in the estimated glomerular filtration rate during the hospitalization. One-way repeated-measures ANOVA was used to compare the changes of variables between the patients with and without WRF. In patients with acute decompensated HF (New York Heart Association class III-IV; 96%) hospitalized for HF, NT-proBNP levels did not differ during the hospitalization between patients with and without WRF (n=42 and 140, respectively). By contrast, emBNP levels were lower in patients with WRF than in those without WRF on day 3 after admission. NT-proBNP/emBNP molar ratios were elevated on day 3 after admission in the patients with WRF, before estimated glomerular filtration rate declined, but were unchanged in patients without WRF. On day 3 after hospital admission, NT-proBNP/emBNP ratios were strongly associated with percentage decreases in estimated glomerular filtration rate. Conclusions These findings suggest that elevation of NT-proBNP/emBNP ratio precedes WRF in patients with acute HF and can be a potentially useful biomarker for risk stratification of cardiorenal syndrome.

Combined heart and kidney transplantation-Is there a protective effect against cardiac allograft vasculopathy using intravascular ultrasound?
Takuma Sato, Richard Cheng, Babak Azarbal, Michelle Kittleson, Jignesh Patel, Lawrence Czer, Ryan Levine, Sadia Dimbil, Michael Olymbios, Toshihisa Anzai, Evan Kransdorf, David H Chang, Michele A Hamilton, Fardad Esmailian, Jon Kobashigawa
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 38, 9, 956, 962, 2019年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Because cardiac and renal disease are physiologically related and often coexist, the prevalence of combined heart and kidney transplantation (HKTx) has significantly increased over the last few years. It has been suggested that combined organ allografts modulate the immune system favorably for one or both allografts resulting in successful clinical outcomes. However, whether the addition of kidney transplantation has a protective immune effect against developing cardiac allograft vasculopathy (CAV) has not been fully investigated. METHODS: From March 2010 to September 2018, 30 HKTx recipients who had baseline (4-6 weeks) and 1-year intravascular ultrasound (IVUS) were matched with 60 isolated heart transplant (HTx-alone) recipients using propensity scores. First-year changes in maximal intimal thickness (MIT), maximal intimal area (MIA), maximal percent stenosis (MPS), percent atheroma volume (PAV), and incidence of rapid plaque progression were compared between the groups. RESULTS: First-year coronary plaque progression was significantly decreased in HKTx recipients compared with HTx-alone recipients by change in the MIT (0.11 ± 0.14 mm vs 0.40 ± 0.32 mm, p < 0.001), MIA (0.52 ± 1.52 mm2 vs 1.86 ± 2.68 mm2, p = 0.002), MPS (2.10% ± 5.64 percentage points vs 7.22% ± 8.59 percentage points, p = 0.001), and PAV (1.62% ± 3.07 percentage points vs 5.90% ± 5.92 percentage points, p < 0.001). Rapid plaque progression occurred in 2 of 30 in HKTx (6.7%) and in 22 of 60 HTx alone (36.7%), p = 0.002. CONCLUSIONS: Combined heart and kidney transplantation is associated with a decrease in CAV by coronary plaque progression on IVUS. These results suggest that HKTx may have an immune modulating benefit over HTx alone.

Tricuspid regurgitation occurring in the early-diastolic phase in a case of heart failure: Insights from echocardiographic and invasive hemodynamic findings.
Michito Murayama, Hiroyuki Iwano, Shingo Tsujinaga, Miwa Sarashina, Suguru Ishizaka, Yasuyuki Chiba, Masahiro Nakabachi, Shinobu Yokoyama, Hisao Nishino, Kazunori Okada, Sanae Kaga, Hitoshi Shibuya, Mutsumi Nishida, Toshihisa Anzai
Echocardiography (Mount Kisco, N.Y.), 36, 9, 1771, 1775, 2019年09月, ［査読有り］, ［国際誌］
英語, Although the presence and physiological significance of late-diastolic tricuspid regurgitation (TR) have been reported, those in TR occurring in early diastole have not been well known. We herein first presented a case of heart failure due to dilated cardiomyopathy showing functional TR occurring in the early-diastolic phase in whom the mechanism for its genesis could be precisely assessed from echocardiographic findings and intra-cardiac pressure recordings.

Rapidly Progressive Heart Failure in a Female Carrier of Becker Muscular Dystrophy with No Skeletal Muscle Symptoms.
Hirokazu Komoriyama, Arata Fukushima, Yumi Takahashi, Shintaro Kinugawa, Fusako Sera, Tomohito Ohtani, Akinori Nakamura, Yasushi Sakata, Toshihisa Anzai
Internal medicine (Tokyo, Japan), 58, 17, 2545, 2549, 2019年09月01日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Becker muscular dystrophy (BMD) carriers are at risk to developing cardiac dysfunction. The prevalence of female BMD carriers remains underestimated, and the disease progression varies. We herein report the case of a young female BMD carrier who developed dilated cardiomyopathy (DCM) and heart failure without any skeletal muscle signs. Her cardiac dysfunction progressed over a mere two months, resulting in the need for left ventricular assist device implantation. Her case demonstrates that progressive cardiomyopathy can be the only clinical manifestation in some BMD carriers, suggesting the need for a more aggressive implementation of genetic testing in female DCM patients.

POEMS Syndrome Showing Left Ventricular Dysfunction and Extracellular Edema Assessed by Cardiac Magnetic Resonance Imaging.
Yumi Takahashi, Hiroyuki Iwano, Ippei Nakano, Arata Fukushima, Masanao Naya, Ai Shimizu, Yoshihiro Matsuno, Noriko Oyama-Manabe, Toshihisa Anzai
Internal medicine (Tokyo, Japan), 58, 17, 2539, 2543, 2019年09月01日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Although cardiac involvement is rare in polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome, the clinical course becomes considerably worse on complication with cardiac lesions. The increased release of various cytokines has been observed in the pathogenesis of POEMS syndrome, and serum vascular endothelial growth factor (VEGF) levels are known to be associated with the disease activity. We herein report a patient with POEMS syndrome who showed left ventricular systolic dysfunction and was treated with lenalidmide therapy. Of note, the reduction in extracellular edema in the left ventricular wall was clearly visualized by changes in the native T1 values and extracellular volumes on cardiac magnetic resonance imaging.

Clinical significance of end-diastolic opening of pulmonary valve in a case complicating left ventricular systolic dysfunction.
Hisao Nishino, Hiroyuki Iwano, Sanae Kaga, Mutsumi Nishida, Koji Akizawa, Takanori Teshima, Toshihisa Anzai
Journal of echocardiography, 19, 1, 53, 55, 2019年08月03日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

Rationale and Design of the CANONICAL Study - Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Canagliflozin for Heart Failure With Preserved Ejection Fraction With Type 2 Diabetes Mellitus.
Shu Kasama, Tohru Masuyama, Shiro Uemura, Yukihito Sato, Shinya Hiramitsu, Izuru Masuda, Kazuhiro Yamamoto, Sei Komatsu, Toshihisa Anzai, Kunihiro Nishimura, Tomoya Ueda, Masato Kasahara, Hiroyuki Tanaka, Yutaka Susuta, Yoshihiko Saito
Circulation reports, 1, 8, 347, 351, 2019年08月03日, ［国内誌］
英語, 研究論文（学術雑誌）, Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2-I) have beneficial cardiovascular effects, including reduction in hospitalization for heart failure (HF). The aim of this study is to explore the efficacy and safety of canagliflozin compared with standard diabetes treatment in elderly patients with type 2 diabetes (T2DM) and HF with preserved ejection fraction (HFpEF). Methods and Results: This is a multicenter, randomized, open-label, parallel-group comparison study designed to evaluate the effects of canagliflozin on fluid retention and cardiac function in T2DM patients with HFpEF. Eligible participants are patients aged ≥65 years with insufficient glycemic control. Qualified patients will be randomly assigned to treatment with 100 mg of canagliflozin or standard diabetic treatment other than SGLT2-I; both groups will be treated for 24 weeks. The primary endpoints are changes in body weight as an indicator of fluid retention and plasma brain natriuretic peptide as an indicator of cardiac function. The secondary endpoints include cardiovascular event rates, changes in the dose of loop diuretics, echocardiographic left ventricular function, and nutritional status. Conclusions: This study is expected to provide valuable findings regarding the mechanisms of canagliflozin on cardiac function and a potential new therapeutic approach for HFpEF. (UMIN000028668 and jRCTs051180030).

Does ex vivo perfusion lead to more or less intimal thickening in the first-year post-heart transplantation?
Takuma Sato, Babak Azarbal, Richard Cheng, Fardad Esmailian, Jignesh Patel, Michelle Kittleson, Lawrence Czer, Maria Thottam, Ryan Levine, Sadia Dimbil, Michael Olymbios, Toshihisa Anzai, Michele A Hamilton, Tamer Khayal, Jon A Kobashigawa
Clinical transplantation, 33, 8, e13648, 2019年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The Organ Care System (OCS), an ex vivo heart perfusion platform, represents an alternative to the current standard of cold organ storage that sustains the donor heart in a near-physiologic state. Previous reports showed that this system had significantly shortened the cold ischemic time from standard cold storage (CS). However, the effect of reduced ischemic injury against the coronary vascular bed has not been examined by intravascular ultrasound (IVUS). METHODS: Between August 2011 and February 2013, heart transplant (HTx) candidates enrolled in the PROCEED 2 trial were randomized to either CS or OCS. IVUS was performed at 4-6 weeks (baseline) and repeated 1 year after transplantation. The change in maximal intimal thickness (MIT) and other clinical outcomes were examined. RESULTS: Thirty-nine patients were randomized and underwent HTx by OCS (n=16) or CS (n=18). Of these, 18 patients (OCS: n=5, CS: n=13) with paired IVUS were examined. There were no significant differences in the change of MIT and other clinical outcomes between the groups. CONCLUSION: The incidence of cardiac allograft vasculopathy in donor hearts preserved with the OCS versus CS was similar. These results suggest that this ex vivo allograft perfusion system is a promising and valid platform for donor heart transportation.

Relation of Systolic Blood Pressure on the Following Day with Post-Discharge Mortality in Hospitalized Heart Failure Patients with Preserved Ejection Fraction.
Yu Sato, Akiomi Yoshihisa, Masayoshi Oikawa, Toshiyuki Nagai, Tsutomu Yoshikawa, Yoshihiko Saito, Kazuhiro Yamamoto, Yasuchika Takeishi, Toshihisa Anzai
International heart journal, 60, 4, 876, 885, 2019年07月27日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, The clinical scenario, which is based on systolic blood pressure (SBP) upon admission, is useful for classifying and determining initial treatment for acute heart failure (HF). However, the prognostic significance of SBP following the initial treatment is unclear.The Japanese Heart Failure Syndrome with Preserved Ejection Fraction (JASPER) registry is a nationwide, observational, and prospective registration of consecutive Japanese patients hospitalized with HF with preserved ejection fraction (HFpEF) and left ventricular ejection fraction ≥ 50%. We divided 525 patients into three groups based on their SBP on the day following hospitalization: high (SBP > 140 mmHg, n = 72, 13.7%); normal (100 ≤ SBP ≤ 140 mmHg, n = 379, 72.2%); and low (SBP < 100 mmHg, n = 74, 14.1%) groups. This analysis had two primary endpoints: (1) all-cause death and (2) all-cause death or rehospitalization for HF. In the Kaplan-Meier analysis, both of the endpoints were the highest in the low group (Log-Rank < 0.05, respectively). Compared to the normal and high groups, the low group demonstrated a higher prevalence of atrial fibrillation (67.1%, 63.9%, and 47.8%, P = 0.026) and the lowest left ventricular outflow tract velocity time integral determined by echocardiography (16.4 cm, 19.4 cm, and 23.3 cm, P = 0.001). In the multivariable Cox proportional hazard analysis, low SBP on the day following hospitalization was an independent predictor of all-cause death (hazard ratio 1.868, 95% confidence interval 1.024-3.407, P = 0.042) and the composite endpoint (hazard ratio 1.660, 95% confidence interval 1.103-2.500, P = 0.015).Classification based on SBP on the day following initial treatment predicts post-discharge prognosis in hospitalized patients with HFpEF.

Serum potassium and glucose levels, and mortality in acute myocardial infarction; fact or myth?
Tadao Aikawa, Toshiyuki Nagai, Toshihisa Anzai
International journal of cardiology, 287, 50, 52, 2019年07月15日, ［査読有り］, ［国際誌］
英語

Validation and Recalibration of Seattle Heart Failure Model in Japanese Acute Heart Failure Patients.
Yasuyuki Shiraishi, Shun Kohsaka, Toshiyuki Nagai, Ayumi Goda, Atsushi Mizuno, Yuji Nagatomo, Yasumori Sujino, Ryoma Fukuoka, Mitsuaki Sawano, Takashi Kohno, Keiichi Fukuda, Toshihisa Anzai, Ramin Shadman, Todd Dardas, Wayne C Levy, Tsutomu Yoshikawa
Journal of cardiac failure, 25, 7, 561, 567, 2019年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Precise risk stratification in heart failure (HF) patients enables clinicians to tailor the intensity of their management. The Seattle Heart Failure Model (SHFM), which uses conventional clinical variables for its prediction, is widely used. We aimed to externally validate SHFM in Japanese HF patients with a recent episode of acute decompensation requiring hospital admission. METHODS AND RESULTS: SHFM was applied to 2470 HF patients registered in the West Tokyo Heart Failure and National Cerebral And Cardiovascular Center Acute Decompensated Heart Failure databases from 2006 to 2016. Discrimination and calibration were assessed with the use of the c-statistic and calibration plots, respectively, in HF patients with reduced ejection fraction (HFrEF; <40%) and preserved ejection fraction (HFpEF; ≥40%). In a perfectly calibrated model, the slope and intercept would be 1.0 and 0.0, respectively. The method of intercept recalibration was used to update the model. The registered patients (mean age 74 ± 13 y) were predominantly men (62%). Overall, 572 patients (23.2%) died during a mean follow-up of 2.1 years. Among HFrEF patients, SHFM showed good discrimination (c-statistic = 0.75) but miscalibration, tending to overestimate 1-year survival (slope = 0.78; intercept = -0.22). Among HFpEF patients, SHFM showed modest discrimination (c-statistic = 0.69) and calibration, tending to underestimate 1-year survival (slope = 1.18; intercept = 0.16). Intercept recalibration (replacing the baseline survival function) successfully updated the model for HFrEF (slope = 1.03; intercept = -0.04) but not for HFpEF patients. CONCLUSIONS: In Japanese acute HF patients, SHFM showed adequate performance after recalibration among HFrEF patients. Using prediction models to tailor the care for HF patients may improve the allocation of medical resources.

Effective blood hemoglobin level to predict prognosis in heart failure with preserved left ventricular ejection fraction: results of the Japanese heart failure syndrome with preserved ejection fraction registry.
Keisuke Okuno, Yoshiro Naito, Masanori Asakura, Masataka Sugahara, Tomotaka Ando, Seiki Yasumura, Toshiyuki Nagai, Yoshihiko Saito, Tsutomu Yoshikawa, Tohru Masuyama, Toshihisa Anzai
Heart and vessels, 34, 7, 1168, 1177, 2019年07月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, High prevalence of anemia in heart failure with preserved left ventricular ejection fraction (HFpEF) has been reported. However, little is known about the association of anemia and gender with prognosis in HFpEF patients. In addition, effective blood hemoglobin (Hb) level for prognosis in HFpEF patients remains largely unknown. In this study, we investigated the association between anemia, gender, and prognosis in 535 HFpEF patients enrolled in Japanese heart failure syndrome with preserved ejection fraction registry. Furthermore, we assessed effective blood Hb level to predict prognosis in HFpEF patients. According to the World Health Organization criteria, the prevalence rate of anemia on admission was about 70% in both male and female HFpEF patients. Kaplan-Meier analysis for all-cause mortality demonstrated that anemic patients had poor prognosis compared with non-anemic patients in both male and female HFpEF patients. Interestingly, multivariate analysis revealed that blood Hb level at discharge was an independent predictor of all-cause mortality in both male and female HFpEF patients. According to survival classification and regression tree analysis, blood Hb level at discharge of 9.4 g/dL for male and 12.3 g/dL for female was more accurate cutoff value to predict all-cause mortality in HFpEF patients. Anemia was implicated in poor prognosis in both male and female HFpEF patients. In particular, blood Hb level at discharge was an independent predictor of all-cause mortality in both male and female HFpEF patients. Effective cutoff value of blood Hb level at discharge to predict all-cause mortality was lower in male than in female HFpEF patients.

Long-Term Results of Intracardiac Mesenchymal Stem Cell Transplantation in Patients With Cardiomyopathy.
Takeshi Yagyu, Satoshi Yasuda, Noritoshi Nagaya, Kaori Doi, Takeshi Nakatani, Kazuhiro Satomi, Wataru Shimizu, Kengo Kusano, Toshihisa Anzai, Teruo Noguchi, Hajime Ohgushi, Soichiro Kitamura, Kenji Kangawa, Hisao Ogawa
Circulation journal : official journal of the Japanese Circulation Society, 83, 7, 1590, 1599, 2019年06月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Mesenchymal stem cells (MSCs), which have the potential to differentiate into cardiomyocytes or vascular endothelial cells, have been used clinically as therapy for cardiomyopathy. In this study, we aimed to evaluate the long-term follow-up results.Methods and Results:We studied 8 patients with symptomatic heart failure (HF) on guideline-directed therapy (ischemic cardiomyopathy, n=3; nonischemic cardiomyopathy, n=5) who underwent intracardiac MSC transplantation using a catheter-based injection method between May 2004 and April 2006. Major adverse events and hospitalizations were investigated up to 10 years afterward. Compared with baseline, there were no significant differences in B-type natriuretic peptide (BNP) (from 211 to 173 pg/mL), left ventricular ejection fraction (LVEF) (from 24% to 26%), and peak oxygen uptake (from 16.5 to 19.2 mL/min/kg) at 2 months. During the follow-up period, no patients experienced serious adverse events such as arrhythmias. Three patients died of pneumonia in the 1st year, liver cancer in the 6th year, and HF in the 7th year. Of the remaining 5 patients, 3 patients were hospitalized for exacerbated HF, 1 of whom required heart transplantation in the 2nd year; 2 patients survived for 10 years without worsening HF. CONCLUSIONS: The results of this exploratory study of intracardiac MSCs administration suggest further research regarding the feasibility and efficacy is warranted.

Survey of Palliative Sedation at End of Life in Terminally Ill Heart Failure Patients - A Single-Center Experience of 5-Year Follow-up.
Yasuhiro Hamatani, Eri Nakai, Emi Nakamura, Michi Miyata, Yukie Kawano, Yasuko Takada, Yuta Anchi, Sayaka Funabashi, Atsushi Hirayama, Kensuke Kuroda, Masashi Amano, Yasuo Sugano, Toshihisa Anzai, Chisato Izumi
Circulation journal : official journal of the Japanese Circulation Society, 83, 7, 1607, 1611, 2019年06月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Little is known about palliative sedation in terminally ill heart failure (HF) patients.Methods and Results:We retrospectively reviewed terminally ill HF patients who received palliative sedation from September 2013 to August 2018. Among 95 terminally ill HF patients, 25 were prescribed dexmedetomidine and 12 were prescribed midazolam at the end of life. Richmond Agitation-Sedation Scale was significantly reduced (P<0.01), but blood pressure and heart rate were unaltered after treatment in both the dexmedetomidine and midazolam groups. CONCLUSIONS: Prescription of dexmedetomidine and/or midazolam might be feasible in selected terminally ill HF patients.

冠血行再建治療後の局所心筋血流量と心筋血流予備能の改善メカニズム 15O標識水PETと心臓MRIを用いた検討　　　　　　　　　　　　　　　
相川 忠夫, 納谷 昌直, 小梁川 和宏, 真鍋 治, 真鍋 徳子, 玉木 長良, 安斉 俊久
日本心臓核医学会ニュースレター, 21, 2, 96, 96, 日本心臓核医学会, 2019年06月, ［査読有り］
日本語

Impact of admission liver stiffness on long-term clinical outcomes in patients with acute decompensated heart failure.
Kazunori Omote, Toshiyuki Nagai, Naoya Asakawa, Kiwamu Kamiya, Yusuke Tokuda, Tadao Aikawa, Arata Fukushima, Keiji Noguchi, Yoshiya Kato, Hirokazu Komoriyama, Mutsumi Nishida, Yusuke Kudo, Hiroyuki Iwano, Takashi Yokota, Toshihisa Anzai
Heart and vessels, 34, 6, 984, 991, 2019年06月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Liver stiffness (LS) has been reported to be a marker of liver congestion caused by elevated central venous pressure in heart failure (HF) patients. Recent studies demonstrated that LS could be non-invasively measured by virtual touch quantification (VTQ). However, its prognostic implication in patients with acute decompensated heart failure (ADHF) is unclear. This study sought to determine whether LS measured by VTQ could be a determinant of subsequent adverse events in ADHF patients. We prospectively recruited 70 ADHF patients who underwent LS measurement by VTQ on admission in our university hospital between June 2016 and April 2018. The primary outcome of interest was the composite of all-cause mortality and worsening HF. During a median follow-up period of 272 (interquartile range 122-578) days, there were 26 (37%) events, including 5 (7%) deaths and 21 (30%) cases of worsening HF. The c-index of LS for predicting the composite of adverse events was 0.77 (95% CI 0.66-0.88), and the optimal cut-off value of LS was 1.50 m/s. Adverse events were more frequently observed in patients with high LS (≥ 1.50 m/s) compared to those with low LS (< 1.50 m/s). Multivariable Cox regression analyzes revealed that higher LS was independently associated with increased subsequent risk of adverse events after adjustment for confounders. In conclusion, high admission LS was an independent determinant of worse clinical outcomes in patients with ADHF. This finding suggests that LS on admission is useful for risk stratification of patients with ADHF.

Prognostic impact of chronic obstructive pulmonary disease on adverse prognosis in hospitalized heart failure patients with preserved ejection fraction - A report from the JASPER registry.
Yu Sato, Akiomi Yoshihisa, Masayoshi Oikawa, Toshiyuki Nagai, Tsutomu Yoshikawa, Yoshihiko Saito, Kazuhiro Yamamoto, Yasuchika Takeishi, Toshihisa Anzai
Journal of cardiology, 73, 6, 459, 465, 2019年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The prognostic impact of chronic obstructive pulmonary disease (COPD) on heart failure (HF) with preserved ejection fraction (HFpEF) patients and its clinical characteristics have not yet been fully examined. METHODS: The Japanese Heart Failure Syndrome with Preserved Ejection Fraction (JASPER) registry is a nationwide, observational, prospective registration of consecutive Japanese hospitalized HFpEF patients with left ventricular ejection fraction (LVEF) of ≥50%. Among 535 patients enrolled in the registry, 10 lacking COPD data, and seven who died during the first hospitalization, were excluded. Finally, 518 patients were enrolled in this analysis. We divided these patients into two groups: the COPD group (n=40, 7.7%) and the non-COPD group (n=478, 92.3%). This analysis had two primary endpoints: (1) all-cause death and (2) all-cause death or rehospitalization for HF. RESULTS: The COPD group showed a higher prevalence of male sex (70.0% vs. 48.1%, p=0.008), history of prior hospitalization for HF (63.2% vs. 35.1%, p=0.001), smoking history (71.8% vs. 43.3%, p=0.001), and a higher usage of loop diuretics (70.0% vs. 50.0%, p=0.015). In the follow-up period after discharge (median 733 days), there were 82 all-cause deaths and 127 rehospitalizations for HF. In the Kaplan-Meier analysis, the COPD group showed higher all-cause death and reached the composite endpoint more often than in the non-COPD group (all-cause death, log-rank 0.035; all-cause death or rehospitalization for HF, log-rank 0.025). In the Cox proportional hazard analysis, COPD was a predictor of all-cause death (hazard ratio 1.957, 95% confidence interval 1.037-3.694, p=0.038) and the composite endpoint (hazard ratio 1.694, 95% confidence interval 1.064-2.697, p=0.026). CONCLUSIONS: COPD is associated with adverse prognosis in hospitalized patients with HFpEF.

Atrial Fibrillation Does Not Matter in Japanese Ventricular Assist Device Patients? - Half-Way Up the Hill.
Toshiyuki Nagai, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 83, 6, 1202, 1203, 2019年05月24日, ［査読有り］, ［国内誌］
英語

Clinical Usefulness of an Echo-Doppler Model in Predicting Elevated Pulmonary Capillary Wedge Pressure in Patients With Heart Failure.
Daigo Chinen, Toshiyuki Nagai, Kazunori Uemura, Yukio Aikawa, Tetsufumi Motokawa, Yasuhide Asaumi, Takeshi Ogo, Hideaki Kanzaki, Teruo Noguchi, Toshihisa Anzai, Wataru Shimizu, Hisao Ogawa, Masaru Sugimachi, Satoshi Yasuda
The American journal of cardiology, 123, 9, 1464, 1469, 2019年05月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Although several tissue-Doppler imaging (TDI) models for pulmonary capillary wedge pressure (PCWP) estimation have been reported, their reliability remains uncertain. Our previous theoretical and experimental analyses suggest that right atrial pressure (RAP) corrected by tissue-Doppler imaging tricuspid/mitral annular peak systolic velocities (ST/SM) (RAP × ST/SM) reliably predicts elevated PCWP. We sought to investigate its clinical usefulness for predicting elevated PCWP in heart failure (HF) patients. Ninety-eight patients admitted with HF who underwent right heart catheterization were prospectively studied. RAP and PCWP were measured by right heart catheterization. Simultaneously, ST/SM, early diastolic transmitral flow velocity to mitral annular velocity ratio (E/Ea), and diameter of inferior vena cava at inspiration (IVCDi), a noninvasive surrogate for RAP, were measured by echocardiography. RAP correlated with IVCDi (R2 = 0.57). A significantly stronger correlation was observed between IVCDi corrected by ST/SM (IVCDi × ST/SM) and PCWP than between E/Ea and PCWP (R2 = 0.47 vs 0.18). Receiver-operating characteristic analyses indicated that IVCDi × ST/SM >16 mm predicted PCWP >18 mm Hg with 90% sensitivity and 77% specificity, and the area under the curve was 0.86, which was significantly larger than that of E/Ea (area under the curve=0.72). In conclusions, IVCDi × ST/SM is a new useful noninvasive model to predict elevated PCWP in HF patients.

Prescription Rates of Guideline-Directed Medications Are Associated With In-Hospital Mortality Among Japanese Patients With Acute Myocardial Infarction: A Report From JROAD - DPC Study.
Kazuhiro Nakao, Satoshi Yasuda, Kunihiro Nishimura, Teruo Noguchi, Michikazu Nakai, Yoshihiro Miyamoto, Yoko Sumita, Toshiaki Shishido, Toshihisa Anzai, Hiroshi Ito, Hiroyuki Tsutsui, Yoshihiko Saito, Issei Komuro, Hisao Ogawa
Journal of the American Heart Association, 8, 7, e009692, 2019年04月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background The JROAD-DPC (Japanese Registry of All Cardiac and Vascular Diseases Diagnosis Procedure Combination) is a nationwide claims database comprised of the Japanese DPC /Per Diem Payment System. This study aimed to investigate the relationship between prescription rates of guideline-directed medications in each hospital and in-hospital mortality among patients with acute myocardial infarction. Methods and Results A total of 61 838 Japanese patients from 741 hospitals with acute myocardial infarction between 2012 and 2013 were enrolled. The relationship between prescription rates of 4 guideline-directed medications for acute myocardial infarction and in-hospital mortality was analyzed. There were variations in the prescription ratio of β-blockers on admission (median prescription rate 23% [interquartile range 11% to 38%]) and at discharge (51% [36% to 63%]), and of angiotensin converting enzyme/receptor blocker (60% [47% to 70%]). The highest prescription rate quartile of each medication was associated with a significantly lower mortality compared with the lowest prescription rate quartile (aspirin on admission, incidence rate ratio 0.67 [95% CI 0.61-0.74], P<0.001; aspirin at discharge, incidence rate ratio 0.50 [95% CI 0.46-0.55], P<0.001; β-blocker on admission, 0.83 [0.76-0.92], P<0.001; β-blocker at discharge, 0.78 [0.71-0.85], P<0.001; angiotensin converting enzyme/receptor blocker, 0.68 [0.62-0.75], P<0.001; statin, 0.63 [0.57-0.70], P<0.001). The composite prescription score was inversely associated with in-hospital mortality (β coefficient=-0.48, P<0.001) and was closer to the plateau in the high-score range (median mortality for composite prescription scores of 6, 15, and 24 were 10.6%, 6.8%, and 4.6%, respectively). Conclusions The prescription rates of guideline-directed medications for treatment of Japanese acute myocardial infarction patients were inversely associated with in-hospital mortality.

Prolonged QRS duration as a predictor of right ventricular dysfunction after balloon pulmonary angioplasty.
Ryotaro Asano, Takeshi Ogo, Keiko Ohta-Ogo, Shigefumi Fukui, Akihiro Tsuji, Jin Ueda, Nao Konagai, Tetsuya Fukuda, Yoshiaki Morita, Teruo Noguchi, Kengo Kusano, Toshihisa Anzai, Hatsue Ishibashi-Ueda, Satoshi Yasuda
International journal of cardiology, 280, 176, 181, 2019年04月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Balloon pulmonary angioplasty (BPA) has shown beneficial effects for chronic thromboembolic pulmonary hypertension (CTEPH). However, previous studies have shown less cardiac output improvement and symptoms remaining after BPA, implying poor right ventricular (RV) function recovery. Therefore, we investigated the residual RV dysfunction after BPA to reveal risk factors, clinical effects, and possible underlying histopathological mechanisms. METHODS AND RESULTS: We investigated 61 consecutive CTEPH patients who underwent cardiovascular magnetic resonance before and 3 and 12 months after BPA series. Residual dysfunction (RD) of RV was defined as RV end-diastolic volume index >100 ml/m2 or RV ejection fraction (EF) <45% at 12-month follow-up. Patients were divided into RD (44%) and normalized dysfunction (ND) (56%) groups. Compared with the ND group, the RD group had significantly worse World Health Organization (WHO) functional class at follow-up. No significant hemodynamic differences were observed between the groups. On multivariable logistic regression analysis, male sex (odds ratio [OR] 12.5, p = 0.004) and prolonged QRS duration (OR 1.08, p = 0.029) were independently associated with residual RV dysfunction. Additionally, RV histopathology in 11 CTEPH autopsy cases showed that QRS duration was correlated with RV fibrosis area. CONCLUSIONS: Relatively high percentage (44%) of residual RV dysfunction with worse WHO functional class was observed in CTEPH patients even after BPA. Prolonged QRS duration may predict poor recovery in RV function after BPA.

Effect of intravenous carperitide versus nitrates as first-line vasodilators on in-hospital outcomes in hospitalized patients with acute heart failure: Insight from a nationwide claim-based database.
Toshiyuki Nagai, Naotsugu Iwakami, Michikazu Nakai, Kunihiro Nishimura, Yoko Sumita, Atsushi Mizuno, Hiroyuki Tsutsui, Hisao Ogawa, Toshihisa Anzai
International journal of cardiology, 280, 104, 109, 2019年04月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUNDS: Carperitide is a recombinantly produced intravenous formulation of human atrial natriuretic peptide. Despite of negative impacts of nesiritide on clinical outcomes for acute heart failure (AHF), carperitide has been used for around a half of Japanese AHF patients as a vasodilator based on limited evidences. We sought to determine the effect of carperitide compared to nitrates in the early care for AHF patients treated with vasodilators. METHODS AND RESULTS: We conducted a cohort study of patients admitted with AHF to 808 hospitals from April 2012 to March 2014. Patients were extracted from 1,422,703 hospitalizations according to ICD-10 heart failure codes. Patients who had sepsis or mechanical supports during hospitalization were excluded. Outcomes were in-hospital death, length of hospitalization and cost of hospitalization. Among 76,924 patients, 45,595 were in patients treated with either carperitide or nitrates during the first 2 days (carperitide; 33,386, nitrates; 12,209). After application of inverse probability of treatment weighting with variables including demographics, comorbidities and treatments, there was perfect balance in both groups. Patients who were treated with carperitide had substantially higher covariate adjusted in-hospital mortality (HR 1.49 95%CI 1.35-1.64), longer length of hospitalization (Coefficients 0.062 95%CI 0.048 to 0.076) and greater cost of hospitalization (Coefficients 0.024 95%CI 0.010 to 0.037) compared to those treated with nitrates. CONCLUSIONS: In Japanese AHF patients during their early inpatient care, carperitide use was significantly associated with worse outcomes when compared to nitrates use, suggesting the routine use of carperitide might not be recommended as a first-line vasodilator for AHF.

Diastolic Intra-Left Ventricular Pressure Difference During Exercise: Strong Determinant and Predictor of Exercise Capacity in Patients With Heart Failure.
Shingo Tsujinaga, Hiroyuki Iwano, Miwa Sarashina, Taichi Hayashi, Michito Murayama, Ayako Ichikawa, Masahiro Nakabachi, Hisao Nishino, Shinobu Yokoyama, Arata Fukushima, Takashi Yokota, Kazunori Okada, Sanae Kaga, Pavlos P Vlachos, Toshihisa Anzai
Journal of cardiac failure, 25, 4, 268, 277, 2019年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Although the enhancement of early-diastolic intra-left ventricular pressure difference (IVPD) during exercise is considered to maintain exercise capacity, little is known about their relationship in heart failure (HF). METHODS AND RESULTS: Cardiopulmonary exercise testing and exercise-stress echocardiography were performed in 50 HF patients (left ventricular [LV] ejection fraction 39 ± 15%). Echocardiographic images were obtained at rest and submaximal and peak exercise. Color M-mode Doppler images of LV inflow were used to determine IVPD. Thirty-five patients had preserved exercise capacity (peak oxygen consumption [VO2] ≥14 mL·kg-1·min-1; group 1) and 15 patients had reduced exercise capacity (group 2). During exercise, IVPD increased only in group 1 (group 1: 1.9 ± 0.9 mm Hg at rest, 4.1 ± 2.0 mm Hg at submaximum, 4.7 ± 2.1 mm Hg at peak; group 2: 1.9 ± 0.8 mm Hg at rest, 2.1 ± 0.9 mm Hg at submaximum, 2.1 ± 0.9 mm Hg at peak). Submaximal IVPD (r = 0.54) and peak IVPD (r = 0.69) were significantly correlated with peak VO2. Peak IVPD determined peak VO2 independently of LV ejection fraction. Moreover, submaximal IVPD could well predict the reduced exercise capacity. CONCLUSION: Early-diastolic IVPD during exercise was closely associated with exercise capacity in HF. In addition, submaximal IVPD could be a useful predictor of exercise capacity without peak exercise in HF patients.

Endomyocardial fibrosis presenting as apical calcification and infective endocarditis.
Tadao Aikawa, Kiwamu Kamiya, Tomoko Mitsuhashi, Toshihisa Anzai
European heart journal, 40, 12, 1016, 1016, 2019年03月21日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Independent Prognostic Value of Pulmonary Diffusing Capacity in Nonsmoking Patients with Chronic Heart Failure.
Kenji Nakamura, Hideaki Kanzaki, Atsushi Okada, Makoto Amaki, Hiroyuki Takahama, Takuya Hasegawa, Yasuo Sugano, Satoshi Yasuda, Toshihisa Anzai
International heart journal, 60, 2, 366, 373, 2019年03月20日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, The diffusing capacity of the lung for carbon monoxide (DLCO) is indicative of the alveolar-capillary membrane function. A reduced DLCO is associated with poor prognosis in chronic heart failure (HF). However, the significance of DLCO as an independent prognostic predictor has not been established. Here, we aimed to determine the prognostic value of DLCO in patients with chronic HF.We enrolled 214 patients (139 females, mean age: 63 ± 16 years, left ventricular ejection fraction [LVEF]: 45 ± 21%) with stable chronic HF who underwent pulmonary function tests. Only never smokers were included in the analysis because smoking can decrease DLCO.During a median follow-up period of 2.1 years, 52 patients (24.3%) experienced cardiac events, including unplanned HF admissions, left ventricular assist device (LVAD) implantations, all-cause deaths, and cardiopulmonary arrests (CPAs). The median percent predicted DLCO (%DLCO) was 87.3%. In a Cox regression analysis, a %DLCO of ≤87.3% was independently associated with the cardiac events, even after adjusting for age, sex, systolic blood pressure (SBP), LVEF, anemia, brain natriuretic peptide, estimated glomerular filtration rate (eGFR), and prior HF admission (hazard ratio [HR]: 1.87, 95% confidence interval: 1.03-3.53, P = 0.030).A reduced DLCO is an independent predictor of poor prognosis in nonsmoking patients with chronic HF.

心血管疾患の非侵襲評価および定量的評価における現在の試み 心血管画像診断のためのハートチームのアプローチ(Our Current Efforts on Noninvasive and Quantitative Assessment of Cardiovascular Disease: A Heart Team Approach for Cardiovascular Imaging)　　　　　　　　　　　　　　　
相川 忠夫, Naya Masanao, Oyama-Manabe Noriko, Koyanagawa Kazuhiro, Manabe Osamu, Anzai Toshihisa
日本循環器学会学術集会抄録集, 83回, RT4, 2, (一社)日本循環器学会, 2019年03月, ［査読有り］
英語

冠血行再建術がPET CTで評価する局所心筋血流予備能に与える影響(The Impact of Coronary Revascularization on Regional Myocardial Flow Reserve Assessed by Positron Emission Tomography)　　　　　　　　　　　　　　　
相川 忠夫, 納谷 昌直, 小梁川 和宏, 真鍋 治, 真鍋 徳子, 安斉 俊久
日本循環器学会学術集会抄録集, 83回, PJ103, 2, (一社)日本循環器学会, 2019年03月, ［査読有り］
英語

心不全患者におけるMRエラストグラフィで評価した肝硬度の増加は右心房圧の上昇を予測する(Increased Liver Stiffness Assessed by Magnetic Resonance Elastography Predicts Elevated Right Atrial Pressure in Patients with Heart Failure)　　　　　　　　　　　　　　　
加藤 喜哉, 永井 利幸, 小森山 弘和, 表 和徳, 相川 忠夫, 神谷 究, 常田 慧徳, 真鍋 徳子[大山], 安斉 俊久
日本循環器学会学術集会抄録集, 83回, PJ096, 6, (一社)日本循環器学会, 2019年03月, ［査読有り］
英語

心筋生検のリンパ管増殖所見は心サルコイドーシスの診断の助けとなる可能性がある(Lymph Vessel Proliferation on Cardiac Biopsy may Help for the Diagnosis of Cardiac Sarcoidosis)
大江 由紀子, 植田 初江, 松山 高明, 永井 利幸, 池田 善彦, 大郷 恵子, 野口 暉夫, 安斉 俊久
日本循環器学会学術集会抄録集, 83回, 2, PJ073, 6, (一社)日本循環器学会, 2019年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background The diagnosis of cardiac sarcoidosis ( CS ) is challenging because endomyocardial biopsy has only a 20% to 30% sensitivity rate for diagnosis and it presents with similar clinical features of idiopathic dilated cardiomyopathy ( DCM ). Lymphatic vessel proliferation in pulmonary sarcoidosis has been previously demonstrated. In this study, we compared endomyocardial biopsy samples obtained from patients with CS and DCM to determine whether lymph vessel counts using D2-40 immunostaining can be utilized as a complementary tool to distinguish CS from DCM . Methods and Results Endomyocardial biopsy tissues were obtained from 62 patients with CS (30 patients with a diagnosis made histologically, 32 patients with a diagnosis made clinically), and hematoxylin/eosin, Masson trichrome, and D2-40 immunostaining were performed. Their results were compared with those from 53 patients with DCM. The histological CS group showed significantly increased lymphatic vessels (12.0 [4.0-40.0] versus 2.6 [1.9-3.4], P<0.0001) and more severe mosaic fibrosis ( P<0.0001) compared with the DCM group. The optimal threshold was 7.5 lymphatic vessels, and this resulted in a sensitivity of 0.67 and specificity of 0.96. The clinical CS group diagnosed according to Japanese Circulation Society 2016 criteria showed increased lymphatic vessels (4.0 [3.3-9.0] versus 2.6 [1.9-3.4], P<0.0001), more severe mosaic fibrosis ( P<0.0001), more inflammatory cell infiltration (53% versus 0%, P<0.0001), and fatty infiltration within fibroblasts (50% versus 17%, P=0.0012) compared with the DCM group. The optimal threshold of lymphatic vessels was 3.5, which resulted in a sensitivity of 0.75 and specificity of 0.68. Conclusions Lymphatic vessel counts using D2-40 immunostaining may help to distinguish clinical CS without granuloma from DCM .

駆出率が保持されている心不全患者における腎機能悪化の予後的影響 JASPERレジストリからの報告(Prognostic Impact of Worsening Renal Function in Heart Failure Patients with Preserved Ejection Fraction: A Report from the JASPER Registry)
佐藤 悠, 義久 精臣, 及川 雅啓, 永井 利幸, 吉川 勉, 斎藤 能彦, 山本 一博, 竹石 恭知, 安斉 俊久
日本循環器学会学術集会抄録集, 83回, 8, PJ073, 3, (一社)日本循環器学会, 2019年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The characteristics and prognostic impact of persistent worsening renal function (WRF; defined as an increase in serum creatinine of >0.3 mg/dL during hospitalization) on heart failure with preserved ejection fraction have not yet been fully examined. METHODS AND RESULTS: This was a post hoc analysis of the Japanese Heart Failure Syndrome with Preserved Ejection Fraction (JASPER) registry. We divided 523 patients with heart failure with preserved ejection fraction: the WRF group (n = 92 [17.6%]) and the non-WRF group (n = 431 [82.4%]). The WRF group showed a higher systolic blood pressure on admission and a higher prevalence of atherosclerotic diseases, respectively. Logistic regression analysis revealed that systolic blood pressure and loop diuretics were associated with WRF development (P < .05). The Kaplan-Meier analysis (median, 732 days) showed a higher all-cause death in the WRF group, as well as a higher composite end point of all-cause death or rehospitalization for HF (log-rank P < .001). The Cox proportional hazard analysis revealed WRF to be a predictor of both all-cause death (hazard ratio, 2.725; 95% confidence interval, 1.709-4.344; P < .001) and the composite end point (hazard ratio, 2.083; 95% confidence interval, 1.488-2.914; P < .001). CONCLUSIONS: Persistent WRF was associated with systolic blood pressure, atherosclerotic diseases, diuretics, and poor postdischarge prognosis in patients with heart failure with preserved ejection fraction.

Prognostic value of phase analysis on gated single photon emission computed tomography in patients with cardiac sarcoidosis.
Kazuhiro Koyanagawa, Masanao Naya, Tadao Aikawa, Osamu Manabe, Masato Kuzume, Hiroshi Ohira, Ichizo Tsujino, Nagara Tamaki, Toshihisa Anzai
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology, 28, 1, 128, 136, 2019年02月27日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: We aimed to determine the correlation between phase analysis, reflecting the heterogeneity of perfusion defects, and the dyssynchrony of the left ventricle wall motion, and adverse cardiac events in cardiac sarcoidosis (CS) patients. METHODS: Fifty-seven consecutive patients with diagnosed CS (64 [IQR 55-71] years old, 14 males), who underwent 18F-FDG PET/CT and ECG-gated SPECT, were studied. FDG PET was analysed to measure cardiac metabolic volume (CMV), and total lesion glycolysis (TLG). The SPECT findings, such as LVEF, Summed Rest Score (SRS), bandwidth (BW) were evaluated. RESULTS: The median of BW was 56° (IQR 40-95). BW showed a strong inverse correlation with LVEF (r = - 0.60, P < 0.0001), and positive correlation with SRS (r = 0.82, P < 0.0001). However, there were no significant correlations between BW and CMV or TLG. The Kaplan-Meier curves revealed a significantly higher rate of MACE in the high BW group (BW > 56°) than the low BW group (BW ≤ 56°) (15.1%/years vs. 4.4%/years, P = 0.025). In multivariable analysis, BW was a significant independent predictor of MACE (P = 0.015). CONCLUSION: Phase analysis on gated SPECT was a significant and independent predictor of MACE in patients with CS.

Comparison of Mortality Prediction Models on Long-Term Mortality in Hospitalized Patients With Acute Heart Failure - The Importance of Accounting for Nutritional Status.
Hiroki Nakano, Kazunori Omote, Toshiyuki Nagai, Michikazu Nakai, Kunihiro Nishimura, Yasuyuki Honda, Satoshi Honda, Naotsugu Iwakami, Yasuo Sugano, Yasuhide Asaumi, Takeshi Aiba, Teruo Noguchi, Kengo Kusano, Hiroyuki Yokoyama, Satoshi Yasuda, Hisao Ogawa, Taishiro Chikamori, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 83, 3, 614, 621, 2019年02月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The ideal mortality prediction model (MPM) for acute heart failure (AHF) patients would have sufficient and stable predictive ability for long-term as well as short-term mortality. However, published MPMs for AHF predominantly predict short-term mortality up to 90 days, and their prognostic performance for long-term mortality remains unclear. Methods and Results: We analyzed 609 AHF patients in a prospective registry from January 2013 to May 2016. We compared the prognostic performance for long-term mortality among 8 systematically identified MPMs for AHF that predict short-term mortality up to 90 days from admission. The PROTECT 7-day model showed the highest c-index for long-term as well as short-term mortality among the studied MPMs. Sensitivity analyses revealed serum albumin and total cholesterol to be the most important variables, as dropping these variables resulted in a significant decline in c-index, when compared with other variables specific to the PROTECT 7-day model. Furthermore, significant improvements in c-index and net reclassification were observed when serum albumin or serum albumin plus total cholesterol was added to the studied MPMs, other than the PROTECT 7-day model. CONCLUSIONS: The PROTECT 7-day model demonstrated the highest predictive performance for long-term as well as short-term mortality in AHF patients among the published MPMs. Our findings indicate the importance of accounting for nutritional status such as serum albumin and total cholesterol in AHF patients when developing a MPM.

Progressive Mobilization Program for Patients With Acute Heart Failure Reduces Hospital Stay and Improves Clinical Outcome.
Naoya Kakutani, Arata Fukushima, Shintaro Kinugawa, Takashi Yokota, Tatsuya Oikawa, Mikito Nishikawa, Risako Nakamura, Takanori Tsukada, Shigeki Mori, Ichiro Yoshida, Toshihisa Anzai
Circulation reports, 1, 3, 123, 130, 2019年02月19日, ［国内誌］
英語, 研究論文（学術雑誌）, Background: Early ambulation has been shown to be associated with shorter hospital stay and better clinical outcomes in patients with acute heart failure (HF). Early mobilization program in combination with structured exercise training is recommended, but has yet to be developed and implemented in HF. Methods and Results: We developed a progressive mobilization program for HF patients that classifies the mobilization process into 7 stages based on disease condition and physical function. We retrospectively analyzed 136 patients with acute HF (80±11 years), who were assigned either to the mobilization program (intervention group, n=75) or to usual care (control group, n=61). The program was safely implemented without any adverse events. Hospital stay was significantly reduced in the intervention group compared with the control group (33±25 vs. 51±36 days, P<0.01). The intervention group had higher activities of daily living (ADL) score at discharge evaluated using the Barthel index (64±38 vs. 49±36, P<0.05). The intervention group also had a higher percentage of discharge to home (71% vs. 52%, P<0.05) and a lower rate of HF-related readmission (16% vs. 36%, P<0.05) compared with the control group. Conclusions: The progressive mobilization program for acute HF was feasible and was associated with better ADL and reduced hospital stay, leading to improvement of clinical outcome.

Arrhythmogenic β-adrenergic signaling in cardiac hypertrophy: The role of small-conductance calcium-activated potassium channels via activation of CaMKII.
Kamada R, Yokoshiki H, Mitsuyama H, Watanabe M, Mizukami K, Tenma T, Takahashi M, Takada S, Anzai T
European journal of pharmacology, 844, 110, 117, (一社)日本循環器学会, 2019年02月05日, ［査読有り］, ［国際誌］
英語, Sustained ventricular arrhythmias (SVAs) lead to sudden cardiac death, for which β- adrenoreceptor blockers are effective. We hypothesized that electrophysiological changes and arrhythmias by β- adrenoreceptor stimulation are crucially related to activation of small-conductance calcium-activated potassium (SK) channels via the increase in Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs). The latter served as a model of left ventricular hypertrophy. We performed dual optical mapping of action potentials and Ca2+ transients, and the effects of isoproterenol and apamin, an SK channel blocker, were evaluated in the Langendorff-perfused hearts. Action potential duration was abbreviated by isoproterenol (100 nM) in both WKY rats and SHRs. In contrast, the CaMKII activity was increased by isoproterenol only in SHRs. In the presence of isoproterenol, apamin prolonged the action potential duration only in SHRs (n = 10, from 116.6 ± 5.05 ms to 125.4 ± 3.80 ms, P = 0.011), which was prevented by KN-93, a CaMKII inhibitor. Increase in Ca2+ transients and shortening of Ca2+ transient duration by isoproterenol were similarly observed in both animals, which was not affected by apamin. Apamin reduced the isoproterenol-induced SVAs and maximal slope of action potential duration restitution curve specifically in SHRs. In conclusion, β- adrenoreceptor stimulation creates arrhythmogenic substrates via the CaMKII-dependent activation of SK channels in cardiac hypertrophy.

Progressive left ventricular dysfunction and myocardial fibrosis in Duchenne and Becker muscular dystrophy: a longitudinal cardiovascular magnetic resonance study.
Tadao Aikawa, Atsuhito Takeda, Noriko Oyama-Manabe, Masanao Naya, Hirokuni Yamazawa, Kazuhiro Koyanagawa, Yoichi M Ito, Toshihisa Anzai
Pediatric cardiology, 40, 2, 384, 392, 2019年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, This study examined the progression of left ventricular dysfunction and myocardial fibrosis in patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) to evaluate the effects of angiotensin-converting enzyme inhibitor (ACEI). Ninety-eight cardiovascular magnetic resonance (CMR) studies in 34 consecutive patients with DMD (n = 21) or BMD (n = 13) were retrospectively reviewed. Left ventricular ejection fraction (LVEF) and the extent of myocardial late gadolinium enhancement (LGE) were semiautomatically quantified. During the study period, five patients had already been treated with ACEI at the first CMR; five were started on ACEI at LVEF ≥ 55% and 10 at LVEF < 55%. All patients had hyperenhanced myocardium on LGE images at the first CMR (median extent, 3.3%; interquartile range 0.1-14.3%). A mixed-effects model for longitudinal data of each patient, adjusted for age, type of muscular dystrophy, steroid use, and ACEI use showed that higher age (β = - 1.1%/year; 95% confidence interval [CI], - 1.8% to - 0.4%; p = 0.005) and no use of ACEI (β = - 3.1%; 95% CI, - 5.4% to - 0.8%; p = 0.009) were significantly associated with a lower LVEF. When ACEI use was stratified by time of initiation (LVEF ≥ 55% vs. < 55%), only ACEI initiation at LVEF < 55% had a beneficial effect on LVEF at each imaging examination (β = 3.7%; 95% CI, 0.9-6.4%; p = 0.010). ACEI use or the time of initiation of ACEI did not significantly affect age-related increase in LGE. ACEI attenuated the age-related decline in LVEF only in patients with DMD or BMD and reduced LVEF, suggesting that further investigation on prophylactic use of cardioprotective therapy in these patients is warranted.

Effect of Statins on Mortality in Heart Failure With Preserved Ejection Fraction Without Coronary Artery Disease - Report From the JASPER Study.
Kyohei Marume, Seiji Takashio, Toshiyuki Nagai, Kenichi Tsujita, Yoshihiko Saito, Tsutomu Yoshikawa, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 83, 2, 357, 367, 2019年01月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Statins might be associated with improved survival in patients with heart failure with preserved ejection fraction (HFpEF). The effect of statins in HFpEF without coronary artery disease (CAD), however, remains unclear. Methods and Results: From the JASPER registry, a multicenter, observational, prospective cohort with Japanese patients aged ≥20 years requiring hospitalization with acute HF and LVEF ≥50%, 414 patients without CAD were selected for outcome analysis. Based on prescription of statins at admission, we divided patients into the statin group (n=81) or no statin group (n=333). We followed them for 25 months. The association between statin use and primary (all-cause mortality) and secondary (non-cardiac death, cardiac death, or rehospitalization for HF) endpoints was assessed in the entire cohort and in a propensity score-matched cohort. In the propensity score-matched cohort, 3-year mortality was lower in the statin group (HR, 0.21; 95% CI: 0.06-0.72; P=0.014). The statin group had a significantly lower incidence of non-cardiac death (P=0.028) and rehospitalization for HF (P<0.001), but not cardiac death (P=0.593). The beneficial effect of statins on mortality did not have any significant interaction with cholesterol level or HF severity. CONCLUSIONS: Statin use has a beneficial effect on mortality in HFpEF without CAD. The present findings should be tested in an adequately powered randomized clinical trial.

Superiority of proatrial natriuretic peptide in the prognostic power in patients with acute decompensated heart failure on hospital admission: comparison with B-type natriuretic peptide and other natriuretic peptide forms.
Seiji Takashio, Hiroyuki Takahama, Toshio Nishikimi, Tomohiro Hayashi, Chiaki Nagai-Okatani, Ayaka Matsuo, Yasuaki Nakagawa, Masashi Amano, Yasuhiro Hamatani, Atsushi Okada, Makoto Amaki, Takuya Hasegawa, Hideaki Kanzaki, Satoshi Yasuda, Kenji Kangawa, Toshihisa Anzai, Naoto Minamino, Chisato Izumi
Open heart, 6, 2, e001072, 2019年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Aims: There are significant differences in how atrial (A-type) and B-type natriuretic peptide (ANP and BNP) are secreted and metabolised, but there is little information available about the relative clinical significance of the two peptides. The aim of the present study was to investigate: (1) the association between the circulating level of each ANP molecular form and patient clinical background and (2) their prognostic power for patients with acute decompensated heart failure (ADHF). Methods: We used specific chemiluminescence enzyme immunoassays to prospectively evaluate the levels of six bioactive molecular forms of ANP (pro-ANP, β-ANP and total ANP) and BNP (pro-BNP, N-terminal pro-BNP (NT-pro-BNP) and total BNP) in plasma samples collected from 173 patients with ADHF on their hospital admission. Results: We found that pro-ANP levels were strongly associated with left ventricular (LV) size and ejection fraction (p<0.001), but were not associated with left atrial size. Percent pro-ANP ([pro-ANP/total ANP]x100) was also associated with LV size and function. During the follow-up term (median: 469 days), composite adverse events (all causes of death or rehospitalisation for HF) occurred in 67 patients (38.7 %). Pro-ANP was significantly associated with composite adverse events even after adjusting by estimated glomerular filtration rate (eGFR) (p<0.05). In contrast, NT-pro-BNP was not independent of eGFR in the multivariate analysis. Conclusion: Circulating levels of pro-ANP are strongly associated with LV function and clinical outcomes of patients with ADHF. These findings suggest that during the acute phases of HF, pro-ANP has a prognostic power comparable with NT-pro-BNP independently of renal function.

CORRIGENDUM: Survey of Palliative Sedation at End of Life in Terminally Ill Heart Failure Patients - A Single-Center Experience of 5-Year Follow-up.
Yasuhiro Hamatani, Eri Nakai, Emi Nakamura, Michi Miyata, Yukie Kawano, Yasuko Takada, Yuta Anchi, Sayaka Funabashi, Atsushi Hirayama, Kensuke Kuroda, Masashi Amano, Yasuo Sugano, Toshihisa Anzai, Chisato Izumi
Circulation journal : official journal of the Japanese Circulation Society, 83, 11, 2389, 2389, 2019年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

Reduced Myocardial Flow Reserve Is Associated with Subendocardial Infarction and Coronary Stenosis in Patients with Coronary Artery Disease: A Perfusion MRI Study
Osamu Manabe, Noriko Oyama-Manabe, Masanao Naya, Masahiko Obara, Yasuka Kikuchi, Tadao Aikawa, Yuuki Tomiyama, Hiroyuki Sugimori, Chietsugu Katoh, Nagara Tamaki, Toshihisa Anzai
Cardiovascular Imaging Asia, 3, 1, 8, 8, Asian Society of Cardiovascular Imaging, 2019年
研究論文（学術雑誌）

Clinical impacts and associated factors of delayed ambulation in patients with acute heart failure
Ishikawa K, Fukushima A, Yokota T, Takada S, Furihata T, Kakutani N, Yamanashi K, Obata Y, Nakano I, Abe T, Kinugawa S, Anzai T
Circ Rep, 1, 4, 179, 186, Japanese Circulation Society, 2019年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Background: In heart failure (HF) management, early ambulation is recommended to prevent physical deconditioning. The effects of delayed ambulation on later clinical outcomes and the factors linked to delayed ambulation in hospitalized HF patients, however, remain unestablished. Methods and Results: We retrospectively investigated 101 patients (mean age, 66±17 years) who were hospitalized for acute decompensated HF. During the mean follow-up of 244±15 days after hospital discharge, 34 patients had cardiovascular events leading to death or unplanned readmission. Patients with cardiovascular events had longer median days to acquire ambulation than those without cardiovascular events (11 days, IQR, 8-20 days vs. 7 days, IQR, 5-15 days, P<0.001). The optimal cut-off period until initiation of ambulation to discriminate cardiovascular events was 8 days, indicating that longer days (≥8 days) to acquire ambulation was associated with higher rates of cardiovascular events, even after adjustment of multiple confounders. On multivariate analysis, age >65 years (odds ratio [OR], 2.49; 95% confidence interval [CI]: 1.04-6.09) and increase in blood urea nitrogen (BUN; OR, 1.04; 95% CI: 1.01-1.08) were independent predictors of delayed ambulation. Conclusions: Delayed ambulation is associated with older age and increased BUN in patients with acute HF. Time to ambulation in the recovery phase of acute HF is important, and delayed ambulation may increase the rate of cardiovascular events after hospital discharge.

Evaluation of the pulmonary artery potential using a 20-polar circumferential catheter and three-dimensional integrated intracardiac echocardiography.
Masayuki Takahashi, Hisashi Yokoshiki, Hirofumi Mitsuyama, Taro Tenma, Masaya Watanabe, Rui Kamada, Ryo Sasaki, Yuki Chiba, Motoki Maeno, Toshihisa Anzai
Heart and vessels, 34, 1, 74, 83, 2019年01月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Prolongation of the pulmonary artery potentials (PAPs) in response to short coupling intervals was related to polymorphic QRS configurations during the ventricular tachycardia originating above the pulmonary valve (PA-VT). This prospective study was aimed to investigate the mechanisms of polymorphic changes during the PA-VT. We performed the mapping above the pulmonary valve using a 20-polar circumferential catheter and three-dimensional integrated intracardiac echocardiography in 9 consecutive patients with outflow tract arrhythmias undergoing catheter ablation (UMIN ID: UMIN000021682). The location of successful ablation was right ventricular outflow tract (RVOT) in 6 patients, above the pulmonary valve in 1 patient, left coronary cusp in 1 patient, and unknown in 1 patient. The PAP was detected in six (67%) patients with bipolar voltage of 0.56 ± 0.27 mV. Pacing from bipolar electrodes of the circumferential catheter located above the pulmonary valve captured the PA myocardium only in 1 patient who had the PA-VT (100% in PA-VT vs 0% in non-PA-VT, P = 0.0046), and slight changes of the QRS morphology was observed in accordance with the conduction delay from the stimulus to activation of the RVOT myocardium. The selective PAP capture with conduction delays evoked by bipolar stimulations through a 20-polar circumferential catheter may be a characteristic property of patients with the PA-VT. Conduction delays within the PA and PA-RVOT junction appears to contribute polymorphic QRS changes during the PA-VT.

Effects of coronary revascularization on global coronary flow reserve in stable coronary artery disease.
Tadao Aikawa, Masanao Naya, Masahiko Obara, Osamu Manabe, Keiichi Magota, Kazuhiro Koyanagawa, Naoya Asakawa, Yoichi M Ito, Tohru Shiga, Chietsugu Katoh, Toshihisa Anzai, Hiroyuki Tsutsui, Venkatesh L Murthy, Nagara Tamaki
Cardiovascular research, 115, 1, 119, 129, 2019年01月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Aims: Coronary flow reserve (CFR) is an integrated measure of the entire coronary vasculature, and is a powerful prognostic marker in coronary artery disease (CAD). The extent to which coronary revascularization can improve CFR is unclear. This study aimed to evaluate the impact of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) on CFR in patients with stable CAD. Methods and results: In a prospective, multicentre observational study, CFR was measured by 15O-water positron emission tomography as the ratio of stress to rest myocardial blood flow at baseline and 6 months after optimal medical therapy (OMT) alone, PCI, or CABG. Changes in the SYNTAX and Leaman scores were angiographically evaluated as indicators of completeness of revascularization. Follow-up was completed by 75 (25 OMT alone, 28 PCI, and 22 CABG) out of 82 patients. The median SYNTAX and Leaman scores, and baseline CFR were 14.5 [interquartile range (IQR): 8-24.5], 5.5 (IQR: 2.5-12.5), and 1.94 (IQR: 1.67-2.66), respectively. Baseline CFR was negatively correlated with the SYNTAX (ρ = -0.40, P < 0.001) and Leaman scores (ρ = -0.33, P = 0.004). Overall, only CABG was associated with a significant increase in CFR [1.67 (IQR: 1.14-1.96) vs. 1.98 (IQR: 1.60-2.39), P < 0.001]. Among patients with CFR <2.0 (n = 41), CFR significantly increased in the PCI [1.70 (IQR: 1.42-1.79) vs. 2.21 (IQR: 1.78-2.49), P = 0.002, P < 0.001 for interaction between time and CFR] and CABG groups [1.28 (IQR: 1.13-1.80) vs. 1.86 (IQR: 1.57-2.22), P < 0.001]. The reduction in SYNTAX or Leaman scores after PCI or CABG was independently associated with the percent increase in CFR after adjusting for baseline characteristics (P = 0.012 and P = 0.011, respectively). Conclusion: Coronary revascularization ameliorated reduced CFR in patients with obstructive CAD. The degree of improvement in angiographic CAD burden by revascularization was correlated with magnitude of improvement in CFR.

Severely Impaired Leaflet Mobility of the Tricuspid Valve in an Elderly Woman.
Tatsuro Hitsumoto, Takuya Hasegawa, Yasuhiro Hamatani, Atsushi Okada, Makoto Amaki, Hiroyuki Takahama, Yasuo Sugano, Hideaki Kanzaki, Satoshi Yasuda, Toshihisa Anzai, Chisato Izumi
Circulation reports, 1, 1, 42, 42, 2018年12月15日, ［国内誌］
英語, 研究論文（学術雑誌）

A Case of Severe Aortic Regurgitation Caused by Takayasu's Arteritis Showing End-Diastolic Opening of Aortic Valve.
Michito Murayama, Hiroyuki Iwano, Yusuke Kudo, Mutsumi Nishida, Koji Akizawa, Hitoshi Shibuya, Toshihisa Anzai
CASE (Philadelphia, Pa.), 2, 6, 248, 253, 2018年12月, ［査読有り］, ［国際誌］
英語

Left ventricular noncompaction with intractable heart failure responsive to empagliflozin.
Yasuyuki Chiba, Kazuya Yonezawa, Masahumi Himeno, Midori Yukino, Kyo Shimazu, Shogo Imagawa, Kaoru Komuro, Noriko Kimura, Teisuke Anzai, Toshihisa Anzai
Journal of cardiology cases, 18, 6, 192, 196, 2018年12月, ［査読有り］, ［国内誌］
英語, Despite several reports on the mechanism of the effect of empagliflozin, which has the potential for improved prognosis in heart failure, it is still not fully understood. We experienced a case of left ventricular noncompaction that caused fluid retention in a patient who showed resistance to existing diuretics. By using empagliflozin, we successfully treated this case of acute heart failure and observed stabilized symptoms with no renal dysfunction and deterioration of patient condition. Although the potential for improved prognosis with this drug in a high-risk group for cardiovascular events has been reported, based on EMPA-REG OUTCOME trial results, there are few reports on its effect of treatment and mechanism in treating acute heart failure. The effect of this drug in treating heart failure from the acute phase to the chronic phase can be expected. .

Refractory cardiac myocarditis associated with drug rash with eosinophilia and systemic symptoms syndrome due to anti-bipolar disorder drugs: a case report.
Hikaru Hagiwara, Arata Fukushima, Hiroyuki Iwano, Toshihisa Anzai
European heart journal. Case reports, 2, 4, yty100, 2018年12月, ［査読有り］, ［国際誌］
英語, Background: Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a severe adverse drug reaction accompanied by multiple organ dysfunction. Myocarditis is a manifestation, and once acute necrotizing eosinophilic myocarditis (ANEM) develops, the mortality rate is high. Case summary: We report the case of a 37-year-old man who developed myocarditis associated with DRESS syndrome after starting treatment with lithium and quetiapine for bipolar disorder. At that time, he presented with fever, morbilliform eruption, lymphadenopathy, eosinophilia with atypical lymphocytes, and liver dysfunction; bipolar drugs were discontinued and oral prednisolone begun. Four months later, he was admitted to our institution with worsening skin rash and dyspnoea. Transthoracic echocardiography revealed reduced systolic function in both ventricles, and endocardial biopsy indicated hypersensitivity myocarditis. Cardiac function was temporarily normalized by high-dose prednisolone. However, the inflammation was persistent as shown by a re-elevation of troponin T and fall of left ventricular ejection fraction several months later; in addition, 18F-fluoro-deoxyglucose positron emission tomography with chest computed tomography (FDG-PET/CT) showed focal FDG uptake in the left ventricle. Despite additional treatment with mycophenolate mofetil, the cardiac function deteriorated further, and the patient eventually manifested refractory heart failure classified as New York Heart Association (NYHA) Class III. Myocardial biopsy showed myocyte necrosis associated with ANEM. Discussion: This is the first case report of DRESS-associated myocarditis due to treatment for bipolar disorder. Although the pathophysiology remains incompletely understood, lithium and/or quetiapine can induce refractory myocarditis in DRESS syndrome. Regular measurements of troponin T and FDG-PET/CT are useful for assessing disease progression in DRESS-associated myocarditis.

Transcatheter Aortic Valve Replacement for Severe Aortic Stenosis Complicated by Sigmoid Septum.
Kizuku Yamashita, Tomoyuki Fujita, Satsuki Fukushima, Yusuke Shimahara, Yuta Kume, Yorihiko Matsumoto, Naonori Kawamoto, Kimito Minami, Daijiro Kabata, Hideaki Kanzaki, Chisato Izumi, Toshihisa Anzai, Junjiro Kobayashi
Circulation journal : official journal of the Japanese Circulation Society, 82, 12, 3090, 3099, 2018年11月24日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: In patients undergoing transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS), a sigmoid septum, characterized by subaortic interventricular hypertrophy, often results in the need for new pacemaker implantation (PMI). In this study, we reviewed the feasibility and treatment efficacy of TAVR for AS in patients with a sigmoid septum. Methods and Results: Between 2011 and 2016, 48 patients (25.4%; mean age 84.9±5.4 years; 9 males) with a sigmoid septum and 141 (74.6%; mean age 82.9±5.5 years; 61 males) without underwent TAVR. Their operative outcomes, echocardiographic and electrocardiographic findings, and long-term outcomes were retrospectively compared. Second TAVR because of valve malposition was performed in 3 patients with a sigmoid septum (6.3%) and in 2 patients without a sigmoid septum (1.4%), with no significant difference between the 2 groups. Although there was no significant difference in valve hemodynamics between the 2 groups, sigmoid septum and deep implantation (implantation depth ≥10 mm) were independent predictors of new PMI following TAVR. CONCLUSIONS: Although a sigmoid septum did not preclude the feasibility, safety, or efficacy of TAVR for severe AS, its presence was associated with new PMI. Our approach to TAVR in patients with a sigmoid septum may contribute to clinical outcomes comparable to those of patients without this pathology.

Peripartum Serial Echocardiographic Findings in a Patient with Life-threatening Peripartum Cardiomyopathy.
Daisetsu Aoyama, Yasuhiro Hamatani, Chizuko Kamiya, Keiko Ohta-Ogo, Makoto Amaki, Shoji Kawakami, Atsushi Okada, Hiroyuki Takahama, Takuya Hasegawa, Yasuo Sugano, Hideaki Kanzaki, Hatsue Ishibashi-Ueda, Satoshi Yasuda, Toshihisa Anzai
Internal medicine (Tokyo, Japan), 57, 21, 3105, 3109, 2018年11月01日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 35-year-old woman was referred to our hospital for the management of acutely decompensated heart failure due to peripartum cardiomyopathy (PPCM). Generally, cardiac examinations are performed after the manifestation of heart failure in patients with PPCM. Thus, reports of serial cardiac examinations before the onset of PPCM are scarce. In this case, we were able to document the serial echocardiographic findings before the onset of life-threatening PPCM. We found that the left ventricular systolic function was preserved at 35 weeks of gestation but declined acutely after delivery at 38 weeks. Although speculative, these findings suggest that left ventricular dilation might precede the onset of PPCM.

A case of medical management of tricuspid regurgitation related to atrial fibrillation with constrictive pericarditis-like hemodynamics.
Yoshiya Kato, Arata Fukushima, Hiroyuki Iwano, Kiwamu Kamiya, Toshiyuki Nagai, Toshihisa Anzai
Journal of cardiology cases, 18, 5, 175, 179, 2018年11月, ［査読有り］, ［国内誌］
英語, Severe tricuspid regurgitation (TR) is reported to represent a hemodynamic pattern similar to that of constrictive pericarditis (CP), which should be clearly differentiated for appropriate management. We report the case of a patient with severe TR due to atrial fibrillation (AF) in whom hemodynamic monitoring played a role in the selection of the management strategy. An 81-year-old Japanese man with chronic AF was admitted due to worsening heart failure. Echocardiography showed the dilation of bilateral atria and a right ventricle with severe TR. The right heart catheterization demonstrated the elevation and equalization of diastolic pressures of four cardiac chambers with impaired diastolic filling pattern, which are hallmarks of pericardial constriction due to CP. Of note, the CP-like hemodynamics were completely normalized by 10 days of medical therapies including diuretics and carperitide. After his discharge and over a 1-year follow-up, he has never experienced worsening heart failure and remained NYHA class II with moderate TR. Medical management targeted at volume reduction and vasodilation can be a therapeutic option for CP-like hemodynamics in isolated severe TR related to AF. Repeated hemodynamic assessment is an appropriate tool to help our understanding of the CP-like physiology caused by severe TR based on chronic AF. .

Brain-Derived Neurotrophic Factor Improves Limited Exercise Capacity in Mice With Heart Failure.
Junichi Matsumoto, Shingo Takada, Shintaro Kinugawa, Takaaki Furihata, Hideo Nambu, Naoya Kakutani, Masaya Tsuda, Arata Fukushima, Takashi Yokota, Shinya Tanaka, Hidehisa Takahashi, Masashi Watanabe, Shigetsugu Hatakeyama, Masaki Matsumoto, Keiichi I Nakayama, Yutaro Otsuka, Hisataka Sabe, Hiroyuki Tsutsui, Toshihisa Anzai
Circulation, 138, 18, 2064, 2066, 2018年10月30日, ［査読有り］, ［国際誌］
英語

Impact of High Respiratory Exchange Ratio During Submaximal Exercise on Adverse Clinical Outcome in Heart Failure.
Naoya Kakutani, Arata Fukushima, Takashi Yokota, Takashi Katayama, Hideo Nambu, Ryosuke Shirakawa, Satoshi Maekawa, Takahiro Abe, Shingo Takada, Takaaki Furihata, Kota Ono, Koichi Okita, Shintaro Kinugawa, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 82, 11, 2753, 2760, 2018年10月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Oxygen uptake (V̇O2) at peak workload and anaerobic threshold (AT) workload are often used for grading heart failure (HF) severity and predicting all-cause mortality. The clinical relevance of respiratory exchange ratio (RER) during exercise, however, is unknown. Methods and Results: We retrospectively studied 295 HF patients (57±15 years, NYHA class I-III) who underwent cardiopulmonary exercise testing. RER was measured at rest; at AT workload; and at peak workload. Peak V̇O2 had an inverse correlation with RER at AT workload (r=-0.256), but not at rest (r=-0.084) or at peak workload (r=0.090). Using median RER at AT workload, we divided the patients into high RER (≥0.97) and low RER (<0.97) groups. Patients with high RER at AT workload were characterized by older age, lower body mass index, anemia, and advanced NYHA class. After propensity score matching, peak V̇O2 tended to be lower in the high-RER than in the low-RER group (14.9±4.5 vs. 16.1±5.0 mL/kg/min, P=0.06). On Kaplan-Meier analysis, HF patients with a high RER at AT workload had significantly worse clinical outcomes, including all-cause mortality and rate of readmission due to HF worsening over 3 years (29% vs. 15%, P=0.01). CONCLUSIONS: High RER during submaximal exercise, particularly at AT workload, is associated with poor clinical outcome in HF patients.

Which is the proper reference tissue for measuring the change in FDG PET metabolic volume of cardiac sarcoidosis before and after steroid therapy?
Sho Furuya, Osamu Manabe, Hiroshi Ohira, Kenji Hirata, Tadao Aikawa, Masanao Naya, Ichizo Tsujino, Kazuhiro Koyanagawa, Toshihisa Anzai, Noriko Oyama-Manabe, Tohru Shiga
EJNMMI research, 8, 1, 94, 94, 2018年10月05日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Cardiac sarcoidosis (CS) is a rare but potentially life-threatening disease that causes conduction disturbance, systolic dysfunction, and, most notably, sudden cardiac death. 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) plays important roles not only in diagnosing CS but also in evaluating the effects of anti-inflammatory therapy. A volume-based analysis of parameters measured by FDG PET, so-called cardiac metabolic volume (CMV), has emerged as a new assessment tool. CMV is measured as the volume within the boundary determined by a reference tissue such as the liver and the blood pool uptake. However, there is a possibility that oral steroid therapy could lead to variations of the liver and the blood pool uptake. Here, we attempted to evaluate the steroid effects on the liver and the blood pool uptake. A total of 38 CS patients who underwent FDG PET/CT before and during steroid therapy were retrospectively enrolled. Volumes of interest (VOIs) were placed in the right lobe of the liver and descending aorta (DA). The maximum standardized uptake value (SUVmax), SUVmean, and SUVpeak of the liver and DA were compared between time points before and during steroid therapy. RESULTS: The SUVmax, SUVmean, and SUVpeak of the liver during steroid therapy significantly increased from the time point before the therapy (SUVmax 3.5 ± 0.4 vs. 3.8 ± 0.6, p = 0.014; SUVmean 2.7 ± 0.3 vs. 3.0 ± 0.5, p = 0.0065; SUVpeak 3.0 ± 0.4 vs. 3.4 ± 0.6, p = 0.006). However, the SUVmax, SUVmean, and SUVpeak in the DA did not significantly change (SUVmax 2.2 ± 0.3 vs. 2.2 ± 0.4, p = 0.46; SUVmean 1.9 ± 0.3 vs. 2.0 ± 0.4, p = 0.56; SUVpeak 2.0 ± 0.3 vs. 2.0 ± 0.3, p = 0.70). CONCLUSIONS: We measured FDG uptake in the liver and blood pool before and during steroid therapy. Steroid therapy increased the liver uptake but not the blood pool uptake. Our findings suggested that the DA uptake is a more suitable threshold than liver uptake to evaluate therapeutic effects using volume-based analysis of cardiac FDG PET.

Protein acetylation in skeletal muscle mitochondria is involved in impaired fatty acid oxidation and exercise intolerance in heart failure.
Masaya Tsuda, Arata Fukushima, Junichi Matsumoto, Shingo Takada, Naoya Kakutani, Hideo Nambu, Katsuma Yamanashi, Takaaki Furihata, Takashi Yokota, Koichi Okita, Shintaro Kinugawa, Toshihisa Anzai
Journal of cachexia, sarcopenia and muscle, 9, 5, 844, 859, 2018年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Exercise intolerance is a common clinical feature and is linked to poor prognosis in patients with heart failure (HF). Skeletal muscle dysfunction, including impaired energy metabolism in the skeletal muscle, is suspected to play a central role in this intolerance, but the underlying mechanisms remain elusive. Lysine acetylation, a recently identified post-translational modification, has emerged as a major contributor to the derangement of mitochondrial metabolism. We thus investigated whether mitochondrial protein acetylation is associated with impaired skeletal muscle metabolism and lowered exercise capacity in both basic and clinical settings of HF. METHODS: We first conducted a global metabolomic analysis to determine whether plasma acetyl-lysine is a determinant factor for peak oxygen uptake (peak VO2 ) in HF patients. We then created a murine model of HF (n = 11) or sham-operated (n = 11) mice with or without limited exercise capacity by ligating a coronary artery, and we tested the gastrocnemius tissues by using mass spectrometry-based acetylomics. A causative relationship between acetylation and the activity of a metabolic enzyme was confirmed in in vitro studies. RESULTS: The metabolomic analysis verified that acetyl-lysine was the most relevant metabolite that was negatively correlated with peak VO2 (r = -0.81, P < 0.01). At 4 weeks post-myocardial infarction HF, a treadmill test showed lowered work (distance × body weight) and peak VO2 in the HF mice compared with the sham-operated mice (11 ± 1 vs. 23 ± 1 J, P < 0.01; 143 ± 5 vs. 159 ± 3 mL/kg/min, P = 0.01; respectively). As noted, the protein acetylation of gastrocnemius mitochondria was 48% greater in the HF mice than the sham-operated mice (P = 0.047). Acetylproteomics identified the mitochondrial enzymes involved in fatty acid β-oxidation (FAO), the tricarboxylic acid cycle, and the electron transport chain as targets of acetylation. In parallel, the FAO enzyme (β-hydroxyacyl CoA dehydrogenase) activity and fatty acid-driven mitochondrial respiration were reduced in the HF mice. This alteration was associated with a decreased expression of mitochondrial deacetylase, Sirtuin 3, because silencing of Sirtuin 3 in cultured skeletal muscle cells resulted in increased mitochondrial acetylation and reduced β-hydroxyacyl CoA dehydrogenase activity. CONCLUSIONS: Enhanced mitochondrial protein acetylation is associated with impaired FAO in skeletal muscle and reduced exercise capacity in HF. Our results indicate that lysine acetylation is a crucial mechanism underlying deranged skeletal muscle metabolism, suggesting that its modulation is a potential approach for exercise intolerance in HF.

Japanese Antibacterial Drug Management for Cardiac Sarcoidosis (J-ACNES): A multicenter, open-label, randomized, controlled study.
Kohei Ishibashi, Yoshinobu Eishi, Nobuhiro Tahara, Masanori Asakura, Naka Sakamoto, Kazufumi Nakamura, Yoichi Takaya, Tomohisa Nakamura, Yoshikazu Yazaki, Tetsuo Yamaguchi, Koko Asakura, Toshihisa Anzai, Teruo Noguchi, Satoshi Yasuda, Fumio Terasaki, Toshimitsu Hamasaki, Kengo Kusano
Journal of arrhythmia, 34, 5, 520, 526, 2018年10月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Background: Cardiac sarcoidosis (CS) is a noncaseating granulomatous disease of unknown etiology. Lifelong immunosuppressive therapy, most frequently using corticosteroids, is a standard therapy to control hypersensitivity of immune reactions and prevent inflammation. However, it sometimes causes various systemic adverse effects and requires dose escalation. Thus, additional therapy may be required for the treatment of this disease. Recently, Propionibacterium acnes (P. acnes) was reported as one of the etiologic agents of CS, indicating that antibacterial drugs (ABD) may be effective for the treatment of CS. The objective of this study was to investigate the effect of ABD treatment, in addition to standard corticosteroid therapy, in patients with CS. Methods: The Japanese Antibacterial Drug Management for Cardiac Sarcoidosis (J-ACNES) trial was designed as a prospective, multicenter, randomized, open-label, controlled clinical trial. The patients will be randomized to receive either standard corticosteroid therapy plus ABD therapy (ABD group) or standard corticosteroid therapy (standard group). The primary endpoint is change in the total standardized uptake value at 6 months vs baseline using fluorine-18 fluorodeoxyglucose positron emission tomography and computed tomography. Secondary endpoints include efficacy, prognosis, and safety. Results: The results of this study are currently under investigation. Conclusion: The J-ACNES trial will be the first prospective study assessing the clinical benefit and safety of ABD therapy, in addition to corticosteroid treatment, in patients with CS. Our findings may improve treatment of patients with CS, as additional ABD therapy reduces recurrence of inflammation and elucidates the mechanism of sarcoidosis.

Long-term reliability of the defibrillator lead inserted by the extrathoracic subclavian puncture.
Masaya Watanabe, Hisashi Yokoshiki, Hirofumi Mitsuyama, Kazuya Mizukami, Taro Tenma, Rui Kamada, Masayuki Takahashi, Yoshiro Matsui, Toshihisa Anzai
Journal of arrhythmia, 34, 5, 541, 547, 2018年10月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Background: As the transvenous defibrillator lead is fragile and its failure may cause a life-threatening event, reliable insertion techniques are required. While the extrathoracic puncture has been introduced to avoid subclavian crush syndrome, the reports on the long-term defibrillator lead survival using this approach, especially the comparison with the cephalic cutdown (CD), remain scarce. We aimed to evaluate the long-term survival of the transvenous defibrillator lead inserted by the extrathoracic subclavian puncture (ESCP) compared with CD. Methods: Between 1998 and 2011, 324 consecutive patients who underwent an implantable cardioverter-defibrillator (ICD) implantation in Hokkaido University Hospital were included. ICD leads were inserted by CD from 1998 to 2003 and by contrast venography-guided ESCP thereafter. Lead failure was defined as a nonphysiologic high-rate oversensing with abnormal lead impedance or highly elevated sensing and pacing threshold. Results: Of 324 patients, CD was used in 37 (11%) and ESCP in 287 patients (89%). During the median follow-up of 6.2 years (IQR:3.2-8.3), 7 leads (2 in CD and 5 leads in ESCP group) failed. All patients with lead failure in ESCP group were implanted with either SJM Riata (n = 1) or Medtronic Fidelis lead (n = 4). Five-year lead survival was 93.8% (CI95%:77.3-98.4%) in CD compared with 99.1% (CI95%:96.6-99.8%) in ESCP group (P = 0.903). Univariate Cox regression analysis showed that the use of Fidelis or Riata lead was the strong predictor of the ICD lead failure (HR 13.8, CI95%:2.9-96.5; P = 0.001). Conclusions: Contrast venography-guided extrathoracic puncture ensures the reliable long-term survival in the transvenous defibrillator leads.

The first multicenter, randomized, controlled trial of home telemonitoring for Japanese patients with heart failure: home telemonitoring study for patients with heart failure (HOMES-HF)
Norihiko Kotooka, Masafumi Kitakaze, Kengo Nagashima, Machiko Asaka, Yoshiharu Kinugasa, Kotaro Nochioka, Atsushi Mizuno, Daisuke Nagatomo, Daigo Mine, Yoko Yamada, Akiko Kuratomi, Norihiro Okada, Daisuke Fujimatsu, So Kuwahata, Shigeru Toyoda, Shin ichi Hirotani, Takahiro Komori, Kazuo Eguchi, Kazuomi Kario, Takayuki Inomata, Kaoru Sugi, Kazuhiro Yamamoto, Hiroyuki Tsutsui, Tohru Masuyama, Hiroaki Shimokawa, Shin ichi Momomura, Yoshihiko Seino, Yasunori Sato, Teruo Inoue, Koichi Node, Mika Nakamizo, Chika Nishiyama, Kikumi Morita, Yuko Horiuchi, Michiko Hanawa, Takako Kanai, Hideki Hanaoka, Tohru Izumi, Yoshihiko Saito, Yukihito Sato, A. Haruyama, S. Inami, Y. Nishi, A. Amano, T. Arikawa, M. Kikuchi, Y. Eto, K. Ishii, K. Fukuda, S. Soejima, R. Hisano, D. Goto, S. Kinugawa, Y. Naito, A. Goda, T. Iwasaku, A. Eguchi, Y. Okuhara, R. Taniguchi, Y. Takatsu, K. Washida, T. Miyamoto, M. Toma, K. Yoshitani, R. Fukuhara, H. Fujiwara, K. Matsunaga, T. Iwata, Y. Nishimura, S. Hoshide, M. Shinpo, K. Kario, T. Katsuya, S. Katsuya, T. Naruke, M. Kiryu, S. Kurokawa, T. Sato, T. Koitabashi, M. Kajiwara, Y. Hiramatsu, Y. Sedutsu, T. Hashimoto, U. Yamamoto, K. Miyata, M. Mohri, H. Yamamoto, H. Origuchi, T. Hasegawa, A. Funada, H. Takahama, T. Ohara, H. Kanzaki, M. Asakura, T. Noguchi, Y. Goto, T. Anzai, C. Ibuki, T. Oba, M. Takano
Heart and Vessels, 33, 8, 866, 876, 2018年08月01日, ［査読有り］
英語, 研究論文（学術雑誌）, © 2018, Springer Japan KK, part of Springer Nature. Home telemonitoring is becoming more important to home medical care for patients with heart failure. Since there are no data on home telemonitoring for Japanese patients with heart failure, we investigated its effect on cardiovascular outcomes. The HOMES-HF study was the first multicenter, open-label, randomized, controlled trial (RCT) to elucidate the effectiveness of home telemonitoring of physiological data, such as body weight, blood pressure, and pulse rate, for Japanese patients with heart failure (UMIN Clinical Trials Registry 000006839). The primary end-point was a composite of all-cause death or rehospitalization due to worsening heart failure. We analyzed 181 recently hospitalized patients with heart failure who were randomly assigned to a telemonitoring group (n = 90) or a usual care group (n = 91). The mean follow-up period was 15 (range 0–31) months. There was no statistically significant difference in the primary end-point between groups [hazard ratio (HR), 0.95; 95% confidence interval (CI), 0.548–1.648; p = 0.572]. Home telemonitoring for Japanese patients with heart failure was feasible; however, beneficial effects in addition to those of usual care were not demonstrated. Further investigation of more patients with severe heart failure, participation of home medical care providers, and use of a more integrated home telemonitoring system emphasizing communication as well as monitoring of symptoms and physiological data are required.

Clinical determinants of successful weaning from extracorporeal membrane oxygenation in patients with fulminant myocarditis.
Manabu Matsumoto, Yasuhide Asaumi, Yuichi Nakamura, Takeshi Nakatani, Toshiyuki Nagai, Tomoaki Kanaya, Shoji Kawakami, Satoshi Honda, Yu Kataoka, Seiko Nakajima, Osamu Seguchi, Masanobu Yanase, Kunihiro Nishimura, Yoshihiro Miyamoto, Kengo Kusano, Toshihisa Anzai, Teruo Noguchi, Tomoyuki Fujita, Junjiro Kobayashi, Hatsue Ishibashi-Ueda, Hiroaki Shimokawa, Satoshi Yasuda
ESC heart failure, 5, 4, 675, 684, 2018年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Patients with fulminant myocarditis (FM) often present with cardiogenic shock and require mechanical circulatory support, including extracorporeal membrane oxygenation (ECMO) and ventricular assist device (VAD) implantation. This study sought to clarify the determinants of successful weaning from ECMO in FM patients. METHODS AND RESULTS: We studied 37 consecutive FM patients supported by ECMO as the initial form of mechanical circulatory support between January 1995 and December 2014 in our hospital. Twenty-two (59%) patients were successfully weaned from ECMO, while 15 (41%) were not. There were significant differences in levels of peak creatine kinase and those of its MB isoform (CK-MB), left ventricular posterior wall thickness (LVPWT), and prevalence of cardiac rhythm disturbances. Receiver operating characteristic curve analysis revealed that a peak CK-MB level of 185 IU/L and LVPWT of 11 mm were the optimal cut-off values for predicting successful weaning from ECMO (areas under the curve, 0.89 and 0.85, respectively). During the follow-up [median 48 (interquartile range 8-147) months], 83% of FM patients who were weaned from ECMO survived, with preserved fractional shortening based on echocardiography. Of the 15 FM patients who were not weaned from ECMO, nine bridged to VAD, and only two were successfully weaned from VAD and survived. CONCLUSIONS: These results indicate that myocardial injury, as evidenced by CK-MB and LVPWT, and prolonged presence of cardiac rhythm disturbances are important clinical determinants of successful weaning from ECMO.

Validation of U.S. mortality prediction models for hospitalized heart failure in the United Kingdom and Japan.
Toshiyuki Nagai, Varun Sundaram, Ahmad Shoaib, Yasuyuki Shiraishi, Shun Kohsaka, Kieran J Rothnie, Susan Piper, Theresa A McDonagh, Suzanna M C Hardman, Ayumi Goda, Atsushi Mizuno, Mitsuaki Sawano, Alan S Rigby, Jennifer K Quint, Tsutomu Yoshikawa, Andrew L Clark, Toshihisa Anzai, John G F Cleland
European journal of heart failure, 20, 8, 1179, 1190, 2018年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Prognostic models for hospitalized heart failure (HHF) were developed predominantly for patients of European origin in the United States of America; it is unclear whether they perform similarly in other health care systems or for different ethnicities. We sought to validate published prediction models for HHF in the United Kingdom (UK) and Japan. METHODS AND RESULTS: Patients in the UK (n =894) and Japan (n =3158) were prospectively enrolled and were similar in terms of sex (∼60% men) and median age (∼77 years). Models predicted that British patients would have a higher mortality than Japanese, which was indeed true both for in-hospital (4.8% vs. 2.5%) and 180-day (20.7% vs. 9.5%) mortality. The model c-statistics for the published/derivation (range 0.70-0.76) and Japanese (range 0.75-0.77) cohorts were similar and higher than for the UK (0.62-0.75) but models consistently overestimated mortality in Japan. For in-hospital mortality, the OPTIMIZE-HF model performed best, providing similar discrimination in published/derivation, UK and Japanese cohorts [c-indices: 0.75 (0.74-0.77); 0.75 (0.68-0.81); and 0.77 (0.70-0.83), respectively], and least overestimated mortality in Japan. For 180-day mortality, the c-statistics for the ASCEND-HF model were similar in published/derivation (0.70) and UK [0.69 (0.64-0.74)] cohorts but higher in Japan [0.75 (0.71-0.79)]; calibration was good in the UK but again overestimated mortality in Japan. CONCLUSION: Calibration of published prediction models appears moderately accurate and unbiased when applied to British patients but consistently overestimates mortality in Japan. Identifying the reason why patients in Japan have a better than predicted prognosis is of great interest.

Rationale and Design of the Multicenter Trial on Japan Working Group on the Effects of Angiotensin Receptor Blockers Selection (Azilsartan vs. Candesartan) on Diastolic Function in the Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE Trial.
Hiroyuki Takahama, Masanori Asakura, Yukio Abe, Masayoshi Ajioka, Kazutaka Aonuma, Toshihisa Anzai, Takaharu Hayashi, Shinya Hiramitsu, Hiroya Kawai, Hidetaka Kioka, Kazuo Kimura, Young-Jae Lim, Ken Matsuoka, Hirohiko Motoki, Yoji Nagata, Sunao Nakamura, Nobuyuki Ohte, Yukio Ozaki, Taishi Sasaoka, Shunsuke Tamaki, Toshimitsu Hamasaki, Masafumi Kitakaze
Cardiovascular drugs and therapy, 32, 4, 381, 388, 2018年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Previous studies suggest that the pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterized not only by high ventricular stiffness, but also by vascular stiffness. Azilsartan has higher vascular affinity compared with other angiotensin II receptor blockers (ARBs), which were proven to have no beneficial effects on clinical outcomes in patients with HFpEF in earlier clinical trials. We aimed to test the hypothesis that azilsartan may improve left ventricular diastolic function in HFpEF patients with hypertension in this trial. METHODS: The Effects of Angiotensin Receptor Blockers on Diastolic Function in Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE trial is a multicenter, randomized, open-labeled, and assessor(s)-blinded, active controlled using candesartan, parallel-group clinical trial, to compare changes in left ventricular (LV) diastolic dysfunction between HFpEF patients with hypertension who have received candesartan or azilsartan for 48 weeks. The primary endpoint is the change in early diastolic wave height/early diastolic mitral annulus velocity (E/e') assessed by echocardiography from the baseline to the end of the study (48 weeks). A total of 190 patients will be recruited into the study. CONCLUSIONS: The design of the J-TASTE trial will provide data on whether differences between the effects of the two tested drugs on LV diastolic function exist in HFpEF patients with hypertension and will improve understanding of the pathophysiological role of vascular stiffness on diastolic function.

Mitral Regurgitation and Heart Failure as the First Presentation in a Patient with Features of Two Connective Tissue Disorders: A Rare Combination of Mucopolysaccharidosis and Osteogenesis Imperfecta?
Yasuhiro Hamatani, Junko Nakashima, Keiko Ohta-Ogo, Makoto Amaki, Masashi Koga, Daisetsu Aoyama, Kyohei Marume, Kenichiro Sawada, Yasuteru Nakashima, Atsushi Shibata, Atsushi Okada, Hiroyuki Takahama, Takuya Hasegawa, Yasuo Sugano, Hideaki Kanzaki, Yoshihiko Ikeda, Satoshi Yasuda, Hatsue Ishibashi-Ueda, Toshihisa Anzai
Internal medicine (Tokyo, Japan), 57, 15, 2209, 2215, 2018年08月01日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Connective tissue disorders sometimes involve cardiovascular systems. This report describes the case of a middle-aged man with mitral regurgitation and heart failure. He had distinctive features of mucopolysaccharidosis type (MPS) III, but no gene mutations that were known to be associated with MPS. Meanwhile, he had a COL1A2 gene mutation that is associated with osteogenesis imperfecta (OI), and had some features that were compatible with OI. The patient might have had a rare connective tissue disorder with the characteristics of MPS III and OI, which was initially detected as a result of the cardiovascular manifestations.

Performance of the MAGGIC heart failure risk score and its modification with the addition of discharge natriuretic peptides.
Mitsuaki Sawano, Yasuyuki Shiraishi, Shun Kohsaka, Toshiyuki Nagai, Ayumi Goda, Atsushi Mizuno, Yasumori Sujino, Yuji Nagatomo, Takashi Kohno, Toshihisa Anzai, Keiichi Fukuda, Tsutomu Yoshikawa
ESC heart failure, 5, 4, 610, 619, 2018年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Predictive models for heart failure patients are widely used in the clinical practice to stratify patients' mortality and enable clinicians to tailor and intensify their approach. However, such models have not been validated internationally. In addition, biomarkers are now frequently measured to obtain prognostic information, and the implications of this practice are not known. In this study, we aimed to validate the model performance of the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) score in a Japanese acute heart failure registry and further explore the incremental prognostic value of discharge B-type natriuretic peptide (BNP) level. METHODS AND RESULTS: In this study, we evaluated the registered data of 2215 consecutive acute HF patients (with 694 119 person-years follow-up) from a prospective multicentre registry (the West Tokyo Heart Failure) conducted in Japan from April 2006 to August 2016. The mean age was 73.0 ± 13.0, and 61.2% were male. The MAGGIC score demonstrated modest discrimination (c-index = 0.71, 95% confidence interval 0.67-0.74) and good calibration (R2 value = 0.97); there was constant overestimation for 1 year mortality. However, when the BNP level was added to the original MAGGIC variables, the model demonstrated good discrimination (c-index = 0.74, 95% confidence interval 0.70-0.78) with adequate calibration (R2 value = 0.91). The modified MAGGIC BNP score was externally validated in a separate Japanese registry (NaDEF) and demonstrated moderate discrimination (c-index = 0.69, 95% confidence interval 0.65-0.73) and calibration (R2 value = 0.85). CONCLUSION: The original MAGGIC score performed modestly in Japanese patients, but the addition of discharge BNP level enhanced model performance. The addition of objective biomarkers may result in effective modification of preexisting internationally recognized risk models and aid in multinational comparisons of heart failure patients' outcomes.

Left ventricular myxoma with Carney complex.
Naoto Kuyama, Yasuhiro Hamatani, Satsuki Fukushima, Yoshihiko Ikeda, Eri Nakai, Atsushi Okada, Hiroyuki Takahama, Makoto Amaki, Takuya Hasegawa, Yasuo Sugano, Hideaki Kanzaki, Tomoyuki Fujita, Hatsue Ishibashi-Ueda, Satoshi Yasuda, Toshihisa Anzai, Junjiro Kobayashi
ESC heart failure, 5, 4, 713, 715, 2018年08月, ［査読有り］, ［国際誌］
英語, The left ventricle is a less frequent location of cardiac myxomas overall. Meanwhile, cardiac myxomas related to Carney complex (CNC), which is a multiple neoplasia syndrome involving cardiac, endocrine, neural, and cutaneous tumours, more frequently occur in the left ventricle compared with sporadic cardiac myxomas. Herein, we report a case of a 20-year-old woman with CNC who underwent complete surgical excision of a large and mobile left ventricular myxoma. In our case, echocardiography performed 4 years earlier was normal. This case highlights the importance of annual follow-up by echocardiography in patients with CNC, because early diagnosis of cardiac myxomas might improve their prognosis. Besides, we should bear in mind the possibility of CNC if the patients have cardiac myxoma in a cardiac chamber other than the left atrium at a younger age.

Elevated Plasma D-Dimer Level Is Associated With Short-Term Risk of Ischemic Stroke in Patients With Acute Heart Failure.
Yasuhiro Hamatani, Toshiyuki Nagai, Michikazu Nakai, Kunihiro Nishimura, Yasuyuki Honda, Hiroki Nakano, Satoshi Honda, Naotsugu Iwakami, Yasuo Sugano, Yasuhide Asaumi, Takeshi Aiba, Teruo Noguchi, Kengo Kusano, Kazunori Toyoda, Satoshi Yasuda, Hiroyuki Yokoyama, Hisao Ogawa, Toshihisa Anzai
Stroke, 49, 7, 1737, 1740, 2018年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND PURPOSE: The incidence of heart failure increases the subsequent risk of ischemic stroke, and its risk could be higher in the short-term period after an acute heart failure (AHF) event. However, its determinants remain to be clarified. Plasma D-dimer level reflects fibrin turnover and exhibits unique properties as a biomarker of thrombosis. The aim of this study is to investigate whether D-dimer level is a determinant of short-term incidence of ischemic stroke in patients with AHF. METHODS: We examined 721 consecutive hospitalized AHF patients with plasma D-dimer level on admission from our prospective registry between January 2013 and May 2016. The study end points were incidence of ischemic stroke during hospitalization and at 30 days after admission. RESULTS: Of the total participants (mean age, 76 years; male, 60%; atrial fibrillation, 54%; mean left ventricular ejection fraction, 38%), in-hospital ischemic stroke occurred in 18 patients (2.5%) during a median hospitalization period of 21 days, and 30-day ischemic stroke occurred in 16 patients (2.2%). Higher D-dimer level on admission was an independent determinant of subsequent risk of in-hospital ischemic stroke even after adjustment by CHA2DS2-VASc score (odds ratio, 2.29; 95% confidence interval, 1.46-3.60; P<0.001) or major confounders, including age, atrial fibrillation, and antithrombotic therapy (odds ratio, 2.31; 95% confidence interval, 1.43-3.74; P<0.001). Subgroup analyses showed consistent findings in patients without atrial fibrillation (odds ratio, 2.46; 95% confidence interval, 1.39-4.54; P=0.002) and those without antithrombotic therapy (odds ratio, 2.79; 95% confidence interval, 1.53-5.57; P<0.001). Similar results were obtained for 30-day ischemic stroke as an alternative outcome. CONCLUSIONS: Elevated plasma D-dimer level on admission was significantly associated with increased incidence of ischemic stroke shortly after admission for AHF, suggesting a predictive role of D-dimer for short-term ischemic stroke events in patients with AHF. CLINICAL TRIAL REGISTRATION: URL: https://www.umin.ac.jp/ctr/index.htm. Unique identifier: UMIN000017024.

Impact of iron deficiency on long-term clinical outcomes of hospitalized patients with heart failure.
Hiroki Nakano, Toshiyuki Nagai, Varun Sundaram, Michikazu Nakai, Kunihiro Nishimura, Yasuyuki Honda, Satoshi Honda, Naotsugu Iwakami, Yasuo Sugano, Yasuhide Asaumi, Takeshi Aiba, Teruo Noguchi, Kengo Kusano, Hiroyuki Yokoyama, Hisao Ogawa, Satoshi Yasuda, Taishiro Chikamori, Toshihisa Anzai
International journal of cardiology, 261, 114, 118, 2018年06月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Iron deficiency (ID) is commonly observed in chronic heart failure (HF) patients and is associated with worse clinical outcomes. While ID is frequent finding in hospitalized heart failure (HHF), its impact on long-term outcome in HHF patients remains unclear. METHODS: We evaluated iron status at discharge in 578 HHF patients. Absolute ID was defined as serum ferritin <100 μg/L, and functional ID (FID) was defined as serum ferritin of 100-299 μg/L with transferrin saturation <20%. The primary outcome of interest was the composite of all-cause mortality and HF admission at one year. RESULTS: Among the study population, 185 had absolute ID, 88 had FID and 305 had no evidence of ID. At one-year post-discharge, 64 patients had died and 112 had been readmitted with HF. Patients with absolute ID had more adverse events than those with FID or no ID (p = 0.021). In multivariate Cox regression analyses, absolute ID was significantly associated with increased risk of adverse events at one year (HR 1.50, 95% CI 1.02-2.21, p = 0.040) compared with the remaining patients. Sensitivity analysis revealed that its prognostic effect did not differ across anemic status, or between HF with reduced and preserved ejection fraction (p for interaction = 0.17, 0.68, respectively). CONCLUSION: Absolute ID, but not FID, at discharge was associated with increased risk of one-year mortality or HF admission in patients with HHF. Further studies are required to evaluate the role of repleting iron stores and its impact on clinical outcomes in patients with HHF.

Clinical Utility of Echocardiographic Hemodynamic Monitoring during Manual Compression of Arteriovenous Shunt in a Patient with High-Output Heart Failure.
Hiroyuki Iwano, Shingo Tsujinaga, Daiki Iwami, Naoya Asakawa, Satoshi Yamada, Toshihisa Anzai
CASE (Philadelphia, Pa.), 2, 3, 103, 108, 2018年06月, ［査読有り］, ［国際誌］
英語

Clinical Characteristics, Management, and Outcomes of Japanese Patients Hospitalized for Heart Failure With Preserved Ejection Fraction - A Report From the Japanese Heart Failure Syndrome With Preserved Ejection Fraction (JASPER) Registry.
Toshiyuki Nagai, Tsutomu Yoshikawa, Yoshihiko Saito, Yasuchika Takeishi, Kazuhiro Yamamoto, Hisao Ogawa, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 82, 6, 1534, 1545, 2018年05月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Despite the specific characteristics of heart failure with preserved ejection fraction (HFpEF) having been demonstrated predominantly from registries in Western countries, important international differences exist in terms of patient characteristics, management and medical infrastructure between Western and Asian countries.Methods and Results:We performed nationwide registration of consecutive Japanese hospitalized HFpEF patients with left ventricular EF ≥50% from 15 sites between November 2012 and March 2015. Follow-up data were obtained up to 2 years post-discharge. A total of 535 patients were registered. The median age was 80 years and 50% were female. The most common comorbid conditions were hypertension (77%) and atrial fibrillation (AF: 62%), but body mass index was relatively low. In-hospital mortality rate was 1.3% and the median length of hospitalization was 16 days. By 2 years post-discharge, 40.8% of patients had all-cause death or HF hospitalization. Approximately one-half of deaths had a cardiac cause. Lower serum albumin on admission was one of the strongest independent determinants of worse clinical outcome. CONCLUSIONS: Japanese HFpEF patients were less obese, but had a substantially higher prevalence of AF and lower incidence of subsequent events compared with previous reports. Our findings indicated that specific preventative and therapeutic strategies focusing on AF and nutritional status might need to be considered for Japanese hospitalized patients with HFpEF.

Subacute Left Atrial Thrombus Formation After Percutaneous Edge-to-Edge Mitral Valve Repair for Functional Mitral Regurgitation.
Makoto Amaki, Yu Kataoka, Hideaki Kanzaki, Koji Miyamoto, Atsushi Okada, Yasuhiro Hamatani, Masashi Fujino, Hiroyuki Takahama, Takuya Hasegawa, Yasuo Sugano, Kengo Kusano, Yoshihiko Ohnishi, Tomoyuki Fujita, Junjiro Kobayashi, Toshihisa Anzai, Satoshi Yasuda
Circulation journal : official journal of the Japanese Circulation Society, 82, 6, 1712, 1713, 2018年05月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

Relation between total shock energy and mortality in patients with implantable cardioverter-defibrillator.
Taro Tenma, Hisashi Yokoshiki, Hirofumi Mitsuyama, Masaya Watanabe, Kazuya Mizukami, Rui Kamada, Masayuki Takahashi, Ryo Sasaki, Motoki Maeno, Kaori Okamoto, Yuki Chiba, Toshihisa Anzai
International journal of cardiology, 259, 94, 99, 2018年05月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Implantable Cardioverter-Defibrillator (ICD) shocks have been associated with mortality. However, no study has examined the relation between total shock energy and mortality. The aim of this study is to assess the association of total shock energy with mortality, and to determine the patients who are at risk of this association. METHODS: Data from 316 consecutive patients who underwent initial ICD implantation in our hospital between 2000 and 2011 were retrospectively studied. We collected shock energy for 3 years from the ICD implantation, and determined the relation of shock energy on mortality after adjusting confounding factors. RESULTS: Eighty-seven ICD recipients experienced shock(s) within 3 years from ICD implantation and 43 patients had died during the follow-up. The amount of shock energy was significantly associated with all-cause death [adjusted hazard ratio (HR) 1.26 (per 100 joule increase), p < 0.01] and tended to be associated with cardiac death (adjusted HR 1.30, p = 0.08). The survival rate of patients with high shock energy accumulation (≥182 joule) was lower (p < 0.05), as compared to low shock energy accumulation (<182 joule), likewise to no shock. Besides, the relation between high shock energy accumulation and all-cause death was remarkable in the patients with low left ventricular ejection fraction (LVEF ≤40%) or atrial fibrillation (AF). CONCLUSIONS: Increase of shock energy was related to mortality in ICD recipients. This relation was evident in patients with low LVEF or AF.

Ratio of pro-B-type natriuretic peptide (BNP) to total BNP is decreased in mild, but not severe, acute decompensated heart failure patients: A novel compensatory mechanism for acute heart failure.
Hiroyuki Takahama, Seiji Takashio, Toshio Nishikimi, Tomohiro Hayashi, Chiaki Nagai-Okatani, Yasuaki Nakagawa, Makoto Amaki, Takahiro Ohara, Takuya Hasegawa, Yasuo Sugano, Hideaki Kanzaki, Satoshi Yasuda, Kenji Kangawa, Naoto Minamino, Toshihisa Anzai
International journal of cardiology, 258, 165, 171, 2018年05月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: A recent study showed that both glycosylation of pro-B-type natriuretic peptide (BNP) and the proBNP/total BNP ratio are decreased in acute decompensated heart failure (ADHF). However, the following points regarding the proBNP/total BNP ratio have not been determined in patients with ADHF: 1) the relationship with the severity of ADHF, 2) the changes in the ratio during treatment, and 3) the relationship with cyclic guanosine monophosphate (cGMP)-generating activity. METHODS: Plasma proBNP and total BNP (proBNP+mature BNP) were measured in patients with ADHF (n=154). Measurement was performed on admission, 3 and 7days after admission, and before discharge using recently developed sandwich chemiluminescence enzyme immunoassays. The percent proBNP was calculated as: (proBNP/total BNP)×100. RESULTS: On admission, %proBNP was higher in patients with severe ADHF than in patients with mild ADHF (median: 61.7% vs. 56.2%, respectively; p<0.01), while the plasma cGMP/total BNP ratio, an index of the biological activity of BNP, was lower (p<0.001). In patients with severe ADHF, the higher %proBNP and lower cGMP/total BNP ratio were unchanged during hospitalization, whereas %proBNP increased gradually in patients with mild ADHF and the cGMP/total BNP ratio also increased at 3days after admission. CONCLUSION: These findings suggest that in patients with mild ADHF, compensation for heart failure occurs via increased proBNP processing, leading to increase of mature BNP and activation of the BNP/cGMP cascade. In contrast, this compensatory mechanism may be impaired in patients with severe ADHF and a vicious cycle can potentially occur.

Successful Treatment of Mitral Regurgitation after Transapical Transcatheter Aortic Valve Implantation by Percutaneous Edge-to-edge Mitral Valve Repair (MitraClip^®) -The First Combination Therapy Performed in Japan.
Okada A, Kanzaki H, Amaki M, Kataoka Y, Miyamoto K, Hamatani Y, Fujino M, Takahama H, Hasegawa T, Shimahara Y, Morita Y, Sugano Y, Kusano K, Ohnishi Y, Fujita T, Kobayashi J, Anzai T, Yasuda S
Internal medicine (Tokyo, Japan), 57, 8, 1105, 1109, 2018年04月15日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 75-year old man with a history of inferior myocardial infarction was admitted with symptoms of progressive heart failure 3 months after undergoing transapical transcatheter aortic valve implantation (TAVI). Echocardiography revealed severe mitral regurgitation (MR) caused by posterior leaflet tethering, without traumatic injury of the mitral valve or chordae. The patient was successfully treated by percutaneous edge-to-edge mitral valve repair (MitraClip®). This case highlights the role of MitraClip® in high-risk patients suffering from MR, and suggests that apical contractile loss or adhesion caused by apical puncture and suturing in transapical TAVI may be one of the mechanisms of worsening MR.

Assessment of renal perfusion impairment in a rat model of acute renal congestion using contrast-enhanced ultrasonography
Kaoru Komuro, Yoshihiro Seo, Masayoshi Yamamoto, Seika Sai, Tomoko Ishizu, Kyo Shimazu, Yumi Takahashi, Shogo Imagawa, Teisuke Anzai, Kazuya Yonezawa, Kazutaka Aonuma
Heart and Vessels, 33, 4, 434, 440, Springer Tokyo, 2018年04月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Renal congestion is caused by elevated central venous pressure (CVP), and decreases glomerular filtration in patients with congestive heart failure. Since real-time contrast-enhanced ultrasonography (CEUS) using microbubble-based contrast agents can visualize the perfused microvascular bed, we sought to evaluate the impairment of renal perfusion during acute renal congestion with CEUS. In Wister rats, CEUS of kidney was performed with the direct monitoring of CVP and intra-renal pressure (IRP). When CVP was elevated to 10 and 15 mmHg after the bolus injection of normal saline via the femoral vein, peak intensity (PI, dB) and time to PI (TTP) in the renal cortex and medulla were compared with control rats. There was a strong correlation between IRP and CVP (r = 0.95, p <
 0.0001). In the congestion model, more time was required for enhancement of the parenchyma, especially in the medulla compared to control
TTP of the medulla and cortex at 15 mmHg CVP (CVP15) was significantly prolonged compared with controls (medulla, 4351 ± 98 vs. 1415 ± 267 ms, p = 0.003
cortex, 3219 ± 106 vs. 1335 ± 264 ms, p = 0.005). In addition, medullary PI at CVP15 decreased, but not significantly, compared to those of controls and at 10 mmHg CVP (20.1 ± 0.9, 22.8 ± 1.6, 21.6 ± 0.2 dB). In contrast, cortical PIs at CVP15 were significantly lower than that of control (24.6 ± 1.0 vs. 31.4 ± 1.0 dB, p = 0.007). CEUS revealed that impaired renal parenchymal flow in an acute congestion model is accompanied with increased renal interstitial pressure.

Increased serum Wisteria floribunda agglutinin positive Mac-2 binding protein (Mac-2 binding protein glycosylation isomer) in chronic heart failure: a pilot study.
Atsushi Okada, Hideaki Kanzaki, Yasuhiro Hamatani, Seiji Takashio, Hiroyuki Takahama, Makoto Amaki, Takuya Hasegawa, Yasuo Sugano, Satoshi Yasuda, Toshihisa Anzai
Heart and vessels, 33, 4, 385, 392, 2018年04月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Serum Wisteria floribunda agglutinin positive Mac-2 binding protein (WFA+-M2BP) or Mac-2 Binding Protein Glycosylation Isomer (M2BPGi) is a novel biomarker currently applied for evaluating hepatic fibrosis. The aim of this study was to evaluate the utility of serum WFA+-M2BP level as a biomarker in chronic heart failure (HF) patients with abnormal liver function. METHODS AND RESULTS: Fifty chronic HF patients who underwent measurement of serum WFA+-M2BP were evaluated. The median value of serum WFA+-M2BP was 0.88 (interquartile range 0.48-1.29) cut-off index, and positive WFA+-M2BP (≥ 1.00 cut-off index) was observed in 22 (44%). Elevated WFA + -M2BP was associated with longer HF history, older age, female sex, valvular heart disease, decreased estimated glomerular filtration rate (eGFR), albumin, and cholinesterase. Stepwise multiple regression analysis showed that HF history, eGFR, and albumin were independent determinants of serum WFA+-M2BP values. Repeated measurements of serum WFA+-M2BP suggested association between the decrease of WFA+-M2BP and improvement of New York Heart Association (NYHA) functional class. CONCLUSIONS: Elevation of serum WFA+-M2BP showed a high prevalence in chronic HF patients with abnormal liver function with relation to HF history, decreased hepatic protein synthesis, and renal dysfunction. Our results suggest that serum WFA+-M2BP may be a novel biomarker of chronic HF.

Response to letter regarding article by Formiga et al., "Utility of the Controlling Nutritional Status (CONUT) score in patients admitted due to acute heart failure".
Naotsugu Iwakami, Toshiyuki Nagai, Toshiaki A Furukawa, Toshihisa Anzai
International journal of cardiology, 256, 25, 25, 2018年04月01日, ［査読有り］, ［国際誌］
英語

An Exploratory Study of Dapagliflozin for the Attenuation of Albuminuria in Patients with Heart Failure and Type 2 Diabetes Mellitus (DAPPER).
Fumiki Yoshihara, Miki Imazu, Toshimitsu Hamasaki, Toshihisa Anzai, Satoshi Yasuda, Shin Ito, Haruko Yamamoto, Kazuhiko Hashimura, Yoshio Yasumura, Kiyoshi Mori, Masataka Watanabe, Masanori Asakura, Masafumi Kitakaze
Cardiovascular drugs and therapy, 32, 2, 183, 190, 2018年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND AIMS: Sodium-dependent glucose transporter-2 (SGLT-2) inhibitors, which are anti-diabetic drugs, reportedly decrease the incidence of cardiovascular events in high-risk patients with cardiovascular diseases, and thus chronic heart failure (CHF). SGLT-2 inhibitors also decrease albuminuria in patients with type 2 diabetes mellitus (T2D). Since albuminuria is a biomarker of not only chronic kidney disease but also cardiovascular events, we hypothesized that, among T2D patients with CHF, SGLT-2 inhibitors will decrease the extent of albuminuria and also improve CHF concomitantly. METHODS: DAPPER (UMIN000025102) is a multicenter, randomized, open-labeled, parallel-group, standard treatment-controlled study, which is designed to evaluate whether dapagliflozin, one of the SGLT-2 inhibitors, decreases albuminuria in T2D patients with CHF and exerts cardioprotective effects on the failing heart. The patients are randomized to either of the dapagliflozin (5 or 10 mg, once daily orally) or control group (administration of anti-diabetic drugs administered other than SGLT 2 inhibitors). The estimated number of patients that need to be enrolled is 446 in total (223 in each group). The primary objective is the changes in the urinary albumin-to-creatinine ratio from the baseline after 2-year treatment. The key secondary objectives are (1) the safety of dapagliflozin and (2) the cardiovascular and renal efficacies of dapagliflozin. CONCLUSION AND PERSPECTIVES: DAPPER study investigates whether dapagliflozin decreases albuminuria and exerts beneficial effects on the failing heart in T2D patients. (UMIN000025102).

Mortality and Sudden Cardiac Death Risk Stratification Using the Noninvasive Combination of Wide QRS Duration and Late Gadolinium Enhancement in Idiopathic Dilated Cardiomyopathy.
Kyohei Marume, Teruo Noguchi, Emi Tateishi, Yoshiaki Morita, Tsukasa Kamakura, Kohei Ishibashi, Takashi Noda, Hiroyuki Miura, Kunihiro Nishimura, Michikazu Nakai, Naoaki Yamada, Kenichi Tsujita, Toshihisa Anzai, Kengo Kusano, Hisao Ogawa, Satoshi Yasuda
Circulation. Arrhythmia and electrophysiology, 11, 4, e006233, 2018年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The aim of this study was to investigate whether the combination of QRS duration ≥120 ms (wide QRS duration [wQRS]) and late gadolinium enhancement (LGE) is a precise prognostic indicator for dilated cardiomyopathy. METHODS AND RESULTS: We investigated the association between the combination of LGE plus wQRS and the primary end point (all-cause death) and a composite of sudden cardiac death (SCD) or aborted SCD in 531 patients with dilated cardiomyopathy. We also analyzed the association between the combination of LGE and wQRS and these end points among patients with a class I indication for implantable cardioverter defibrillator implantation. We divided study patients into 3 groups according to LGE status and QRS duration: 2 negative indices (LGE negative and narrow QRS), 1 positive index (LGE positive or wQRS), or 2 positive indices (LGE positive and wQRS), and followed them for 3.8 years. Multivariable Cox regression analysis identified 2 positive indices as a significant predictor of all-cause death (hazard ratio, 4.29 [1.19-15.47]; P=0.026). Among 317 patients with a class I indication for implantable cardioverter defibrillator, the 5-year event rate of SCD or aborted SCD was the lowest in the 2 negative indices group (1.4%). With propensity score-matching cohorts, the 2 negative indices group had a significantly lower event rate of SCD or aborted SCD than the other 2 groups (hazard ratio, 0.12 [0.01-0.97]; P=0.046). CONCLUSIONS: The combination of LGE and wQRS provides additional prognostic stratification compared with LGE status alone and might improve the appropriate use of implantable cardioverter defibrillator therapy in patients with dilated cardiomyopathy.

Long-Term Prognostic Significance of Plasma B-Type Natriuretic Peptide Level in Patients With Acute Heart Failure With Reduced, Mid-Range, and Preserved Ejection Fractions.
Yasuhiro Hamatani, Toshiyuki Nagai, Yasuyuki Shiraishi, Shun Kohsaka, Michikazu Nakai, Kunihiro Nishimura, Takashi Kohno, Yuji Nagatomo, Yasuhide Asaumi, Ayumi Goda, Atsushi Mizuno, Satoshi Yasuda, Hisao Ogawa, Tsutomu Yoshikawa, Toshihisa Anzai
The American journal of cardiology, 121, 6, 731, 738, 2018年03月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Plasma B-type natriuretic peptide (BNP) is an important prognostic marker in patients with acute heart failure (AHF). However, it is unclear which BNP parameter, on admission, at discharge, or change during hospitalization, has the highest predictive performance for long-term adverse outcomes, and whether its prognostic impact differs according to the new European heart failure (HF) phenotype classification by left ventricular ejection fraction: heart failure with reduced ejection fraction (HFrEF), heart failure with mid-range ejection fraction (HFmrEF), and heart failure with preserved ejection fraction (HFpEF). We examined 1,792 patients with AHF consisting of 860 (48%) HFrEFs, 318 (18%) HFmrEFs, and 614 (34%) HFpEFs. Prognostic performance of each BNP parameter was assessed by the Harrell c-index. During a median follow-up of 664 days, 344 (19%) patients died. Discharge BNP had the highest c-index (0.69) for mortality among all BNP parameters (p <0.001). In multivariate Cox proportional hazard modeling, discharge BNP was associated with mortality in HFrEF, HFmrEF, and HFpEF patients with significant interaction (hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.57 to 2.41; HR 1.76, 95% CI 1.10 to 2.82; HR 1.46, 95% CI 1.12 to 1.91, respectively; p = 0.011 for interaction). Moreover, the c-index of discharge BNP for mortality in HFrEF patients (0.72) was higher than that in HFmrEF patients (0.68) and HFpEF patients (0.65). Similar results were obtained for mortality or HF rehospitalization as alternative outcomes, except there was no statistically significant interaction among HF phenotypes. In conclusion, discharge BNP is a more reliable marker than other BNP parameters on long-term outcome prediction in patients with AHF, but its prognostic impact may be weakened in HFmrEF and HFpEF compared with HFrEF.

LONG-TERM EFFECTS OF ANGIOTENSIN CONVERTING ENZYME INHIBITOR ON LEFT VENTRICULAR EJECTION FRACTION IN DUCHENNE AND BECKER MUSCULAR DYSTROPHY: A LONGITUDINAL CARDIAC MAGNETIC RESONANCE IMAGING STUDY
Tadao Aikawa, Atsuhito Takeda, Noriko Oyama-Manabe, Masanao Naya, Hirokuni Yamazawa, Kazuhiro Koyanagawa, Yoichi M. Ito, Yuka Ishikawa, Yukitoshi Ishikawa, Toshihisa Anzai
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 71, 11, 1565, 1565, ELSEVIER SCIENCE INC, 2018年03月, ［査読有り］
英語

Long-term prognostic significance of urinary sodium concentration in patients with acute heart failure.
Satoshi Honda, Toshiyuki Nagai, Kunihiro Nishimura, Michikazu Nakai, Yasuyuki Honda, Hiroki Nakano, Naotsugu Iwakami, Yasuo Sugano, Yasuhide Asaumi, Takeshi Aiba, Teruo Noguchi, Kengo Kusano, Hiroyuki Yokoyama, Hisao Ogawa, Satoshi Yasuda, Toshihisa Anzai
International journal of cardiology, 254, 189, 194, 2018年03月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Lower urinary sodium concentration (UNa) may reflect impaired renal perfusion, higher neurohormonal activity and diuretic resistance. However, the prognostic impact of UNa in patients with acute heart failure (AHF) has not been fully elucidated. METHODS: We investigate the association between UNa and clinical outcomes in 669 patients admitted with AHF in our prospective registry. Patients were stratified into tertiles based on UNa in a spot urine sample on admission. RESULTS: Patients with lower UNa were more likely to have a history of prior heart failure admission, β-blockers and diuretics use, and had lower blood pressure and serum sodium level, and higher blood urea nitrogen, estimated glomerular filtration rate, blood glucose and troponin T levels on admission than those with higher UNa. Plasma renin activity, aldosterone, cortisol and dopamine levels were also significantly higher in patients with lower UNa (all p<0.001). Furthermore, patients with lower UNa had significantly less weight loss, lower net fluid loss/furosemide equivalent dose and higher incidence of worsening renal function during hospitalization than those with higher UNa (all p<0.01). During a median follow-up period of 560days, lower UNa was significantly associated with the composite of all-cause death and worsening heart failure (p<0.001). In multivariable Cox-proportional hazards model, UNa remained an independent determinant of long-term adverse events (HR, 1.24, 95% CI, 1.06-1.45, p=0.006). CONCLUSIONS: Lower UNa was associated with worse long-term clinical outcomes along with increased neurohormonal activities, impaired response to diuretics and higher incidence of worsening renal function in patients with AHF.

Inflammatory Mechanisms of Cardiovascular Remodeling.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 82, 3, 629, 635, 2018年02月23日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Inflammation and fibrosis play an important role in the development and progression of cardiovascular diseases. Acute coronary syndrome (ACS) is caused by rupture of inflamed atherosclerotic plaque and subsequent atherothrombosis. Recent studies have shown that inflammatory markers such as C-reactive protein (CRP) can predict ACS development and have demonstrated the effectiveness of new therapeutic approaches targeting inflammation. Studies have also shown that an enhanced inflammatory response after myocardial infarction (MI) is associated with cardiac rupture, ventricular aneurysm formation, and exacerbation of left ventricular (LV) remodeling. Inflammation is a physiological reaction in which fibrosis is induced to facilitate the healing of tissue damage. However, when an excessive inflammatory response consisting mainly of monocytes/macrophages is induced by various factors, impaired reparative fibrosis and resulting pathological remodeling processes may occur. A similar phenomenon is observed in abdominal aortic aneurysm (AAA) expansion. In contrast, myocardial diseases such as inflammatory dilated cardiomyopathy (DCMI) and valvular diseases such as aortic valve stenosis (AS) are characterized by chronic inflammation mediated mainly by T lymphocytes and the associated enhancement of reactive fibrosis. Thus, inflammation can take 2 paths (the inhibition or promotion of fibrosis), depending on the phase of inflammation, inducing pathological cardiovascular remodeling. Elucidation of the regulatory mechanisms of inflammation and fibrosis will contribute to the development of new therapeutic approaches for cardiovascular diseases.

Diagnostic utility of cardiac troponin T level in patients with cardiac amyloidosis.
Seiji Takashio, Megumi Yamamuro, Yasuhiro Izumiya, Kyoko Hirakawa, Kyohei Marume, Masahiro Yamamoto, Mitsuharu Ueda, Taro Yamashita, Hatsue Ishibashi-Ueda, Satoshi Yasuda, Hisao Ogawa, Yukio Ando, Toshihisa Anzai, Kenichi Tsujita
ESC heart failure, 5, 1, 27, 35, 2018年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIM: The aim of this study was to evaluate the diagnostic utility of high-sensitivity cardiac troponin T (hs-cTnT) levels in discriminating cardiac amyloidosis from patients with cardiac hypertrophy caused by aetiologies other than cardiac amyloidosis. METHODS AND RESULTS: Serum hs-cTnT levels were measured in 96 patients with cardiac amyloidosis (light chain: 23, wild-type transthyretin amyloidosis: 40, and mutated transthyretin amyloidosis: 33), and 91 patients with other causes of cardiac hypertrophy who were confirmed to have no cardiac amyloidosis by endomyocardial biopsy (control group). The diagnostic utility and cut-off value of hs-cTnT were evaluated by receiver operating characteristic analysis. The median hs-cTnT levels were higher in cardiac amyloidosis than the control group [0.048 (0.029-0.073) vs. 0.016 (0.010-0.031) ng/mL; P < 0.001]. High levels of hs-cTnT were suggestive of cardiac amyloidosis (cut-off value: 0.0312 ng/mL, sensitivity: 0.74, specificity: 0.76, area under the curve: 0.788; 95% confidence interval: 0.723-0.854, P < 0.001), compared with brain natriuretic peptide and E/e' ratio. The hs-cTnT levels were also useful in differentiating each type of amyloidosis from the control group. Multivariate analysis identified log hs-cTnT as an independent diagnostic factor for cardiac amyloidosis (odds ratio: 2.22; 95% confidence interval: 1.30-3.80; P = 0.004). CONCLUSIONS: High serum levels of hs-cTnT are highly suggestive of cardiac amyloidosis, allowing its differentiation from cardiac hypertrophy of other aetiologies. Further refined diagnostic approaches that include imaging modalities and histopathological examination are needed for these patients to avoid underdiagnosis of cardiac amyloidosis.

Anticoagulation combined with antiplatelet therapy in patients with left ventricular thrombus after first acute myocardial infarction.
Naoki Maniwa, Masashi Fujino, Michikazu Nakai, Kunihiro Nishimura, Yoshihiro Miyamoto, Yu Kataoka, Yasuhide Asaumi, Yoshio Tahara, Michio Nakanishi, Toshihisa Anzai, Kengo Kusano, Takashi Akasaka, Yoichi Goto, Teruo Noguchi, Satoshi Yasuda
European heart journal, 39, 3, 201, 208, 2018年01月14日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Aims: There are limited data about the optimal anti-thrombotic therapy for preventing embolism while minimizing bleeding events in patients with first acute myocardial infarction (AMI) complicated by left ventricular thrombus (LVT). Methods and results: Among 2301 consecutive patients with AMI hospitalized between 2001 and 2014, we studied 1850 patients with first AMI who discharged alive to investigate clinical characteristics, incidence of systemic embolism (SE), and association between anticoagulation and embolic or bleeding events. Left ventricular thrombus was diagnosed by echocardiography, left ventriculography, or cardiac magnetic resonance imaging in 92 (5.0%) patients (62 ± 12 years). During a median follow-up period of 5.4 years (interquartile range 2.1-9.1 years), SE occurred in 15 of 92 patients with LVT (16.3%) and 51 of 1758 patients without LVT (2.9%), respectively. Kaplan-Meier analysis showed a significantly higher incidence of SE in the LVT group (log-rank test, P < 0.001). Multivariate analysis showed that LVT was an independent predictor of SE. Among the LVT patients treated with vitamin K antagonists (n = 84), we compared the patients with therapeutic range (TTR) ≥50% (n = 34) and those with TTR <50% (n = 50). Only one embolic event developed in the TTR ≥50% group and nine embolic events developed in the TTR <50% group (2.9% vs. 19%, P = 0.036). There was no difference in major bleeding events (TTR ≥50%; 9% vs. TTR <50%; 8%, P = 0.89). Conclusion: Appropriate anticoagulation therapy may decrease the incidence of embolic events without increasing the incidence of bleeding events in patients with first AMI complicated by LV thrombus.

Mortality after admission for heart failure in the UK compared with Japan.
Toshiyuki Nagai, Varun Sundaram, Kieran Rothnie, Jennifer Kathleen Quint, Ahmad Shoaib, Yasuyuki Shiraishi, Shun Kohsaka, Susan Piper, Theresa A McDonagh, Suzanna Marie C Hardman, Ayumi Goda, Atsushi Mizuno, Takashi Kohno, Alan S Rigby, Tsutomu Yoshikawa, Andrew L Clark, Toshihisa Anzai, John G F Cleland
Open heart, 5, 2, e000811, 2018年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Objective: Mortality amongst patients hospitalised for heart failure (HHF) in Western and Asian countries may differ, but this has not been investigated using individual patient-level data (IPLD). We sought to remedy this through rigorous statistical analysis of HHF registries and variable selection from a systematic literature review. Methods and results: IPLD from registries of HHF in Japan (n=3781) and the UK (n=894) were obtained. A systematic literature review identified 23 models for predicting outcome of HHF. Five variables appearing in 10 or more reports were strongly related to prognosis (systolic blood pressure, serum sodium concentration, age, blood urea nitrogen and creatinine). To compare mortality in the UK and Japan, variables were imputed in a propensity model using inverse probability of treatment weighting (IPTW) and IPTW with logistic regression (doubly robust IPTW). Overall, patients in the UK were sicker and in-patient and post-discharge mortalities were greater, suggesting that the threshold for hospital admission was higher. Covariate-adjusted in-hospital mortality was similar in the UK and Japan (IPTW OR: 1.14, 95% CI 0.70 to 1.86), but 180-day postdischarge mortality was substantially higher in the UK (doubly robust IPTW OR: 2.33, 95% CI 1.58 to 3.43). Conclusions: Despite robust methods to adjust for differences in patient characteristics and disease severity, HHF patients in the UK have roughly twice the mortality at 180 days compared with those in Japan. Similar analyses should be done using other data sets and in other countries to determine the consistency of these findings and identify factors that might inform healthcare policy and improve outcomes.

Decrease in exhaled hydrogen as marker of congestive heart failure.
Atsushi Shibata, Yasuo Sugano, Akito Shimouchi, Tetsuro Yokokawa, Naoya Jinno, Hideaki Kanzaki, Keiko Ohta-Ogo, Yoshihiko Ikeda, Hideshi Okada, Takeshi Aiba, Kengo Kusano, Mikiyasu Shirai, Hatsue Ishibashi-Ueda, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
Open heart, 5, 2, e000814, 2018年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Objective: Hydrogen excretion is thought to be related to systemic antioxidation activity. H2 selectively reduces the hydroxyl radical of free hydrogen (·OH), a highly cytotoxic form of reactive oxygen species, in cultured cells. Methods: We investigated whether exhaled H2 decreased during night sleep, reflected ·OH production and was associated with heart failure severity. We enrolled 108 patients with chronic heart failure (CHF) and 15 control participants without CHF. H2 concentration was measured by gas chromatography in exhaled breath collected before sleep and in the morning after overnight fasting. Overnight change in H2 concentration (ΔH2) was calculated. Mitochondrial morphology evaluated by transmission electron microscopy in endomyocardial biopsies collected from 18 patients with dilated cardiomyopathy. Results: ΔH2 was significantly lower in patients with CHF compared with controls (-4.3±1.0 vs 2.0±2.1 ppm, p=0.030) and was positively correlated with cardiac index (CI; r = -0.285, p=0.003). Patients with a ΔH2<0 ppm had a significantly lower CI compared with those who had a ΔH2>0 ppm (2.85±0.61 vs 3.24±0.65 L/min/m2, p=0.005). ΔH2 was negatively correlated with both the percentage of vacuole-containing mitochondria and indices of cristae remodelling (r = -0.61, p=0.007). Conclusions: Decrease in exhaled H2 during night sleep was associated with CHF severity. ΔH2 warrants investigation as marker of CHF severity.

Presence of increased inflammatory infiltrates accompanied by activated dendritic cells in the left atrium in rheumatic heart disease.
Mikio Shiba, Yasuo Sugano, Yoshihiko Ikeda, Hideshi Okada, Toshiyuki Nagai, Hatsue Ishibashi-Ueda, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
PloS one, 13, 9, e0203756, 2018年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Left atrial (LA) structural remodelling develops in rheumatic heart disease (RHD) according to the disease severity of the mitral valve and the presence of atrial fibrillation. Sustained active inflammation has been previously reported in the LA of patients with RHD, suggesting a direct role of cell-mediated immunity in the pathogenesis of LA remodelling. Dendritic cells (DCs) have a major antigen-presenting role, and are known as crucial modulators of innate and adaptive immunity. We investigated whether DCs are involved in the pathogenesis of LA remodelling in RHD. METHODS AND RESULTS: Immunohistochemical analyses were performed using antibodies to CD11c, CD209 and CD80 as markers of myeloid DCs, migratory-active DCs, mature DCs and infiltrated inflammatory cells including T lymphocytes (CD3) and M1 (CD68; pro-inflammatory profile) and M2 (CD163; pro-resolution profile) macrophages. Furthermore, tenascin-C, an extracellular matrix (ECM) protein that appears during ECM remodelling and inflammatory response, was examined. Infiltrated myeloid DCs, migratory-active DCs, mature DCs and other inflammatory infiltrates including T lymphocytes and M1 and M2 macrophages, were significantly higher in the RHD group than the non-RHD group. The positive area fraction for tenascin-C was significantly higher in the RHD group than in the non-RHD group. CONCLUSION: Our histological findings suggest that inflammation may persist long after a bout of rheumatic fever, ultimately leading to ECM remodelling. We identified and quantitatively assessed several subsets of DCs and other immunocompetent cells, and our results indicated that activation of DCs has some role in persistence of LA inflammation in patients with chronic RHD.

Effect of Mitral Valve Surgery in Patients With Dilated Cardiomyopathy and Severe Functional Mitral Regurgitation.
Hyemoon Chung, Makoto Amaki, Seiji Takashio, Hiroyuki Takahama, Takahiro Ohara, Takuya Hasegawa, Yasuo Sugano, Tomoyuki Fujita, Junjiro Kobayashi, Masanori Asakura, Hideaki Kanzaki, Toshihisa Anzai, Masafumi Kitakaze
Circulation journal : official journal of the Japanese Circulation Society, 82, 1, 131, 140, 2017年12月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Surgical treatment of functional mitral regurgitation (FMR) improves ventricular remodeling in patients with dilated cardiomyopathy (DCM). However, it is unclear whether surgical treatment improves long-term outcomes. We investigated the effects of mitral valve (MV) surgery in patients with DCM and FMR.Methods and Results:Of 525 patients with DCM hospitalized due to heart failure between January 1996 and September 2014, 70 who had severe FMR despite receiving optimal medical therapy were enrolled in the study. Of these patients, 16 underwent surgery for FMR (surgery group; repair=14, replacement=2); the remaining 54 who refused or decided not to undergo surgery were classified as the medication group. There were no differences in age, sex, medication, or echocardiographic parameters between the 2 groups (P>0.05). During the mean follow-up period of 53.6±43.6 months, the occurrence of clinical outcomes (i.e., all-cause death or left ventricular assist device implantation) was 54.3%; the occurrence of clinical outcomes was lower in the surgery group (P=0.008, log-rank test). Multivariate Cox regression analysis using clinical data revealed that MV surgery (hazard ratio [HR] 0.257, 95% confidence interval [CI] 0.103-0.640; P=0.004) and diabetes mellitus (HR 2.924, 95% CI 1.243-6.876; P=0.014) were independent predictors of clinical outcomes after adjusting for age and sex. CONCLUSIONS: Surgery for severe FMR provides better long-term outcomes in patients with DCM.

Transcatheter Aortic Valve Implantation for Degenerated 19-mm Aortic Bioprosthetic Valve.
Kizuku Yamashita, Tomoyuki Fujita, Satsuki Fukushima, Yusuke Shimahara, Yuta Kume, Yorihiko Matsumoto, Naonori Kawamoto, Tatsuro Hitsumoto, Nobuyasu Ito, Yasuhiro Hamatani, Atsushi Okada, Hiroyuki Takahama, Makoto Amaki, Takuya Hasegawa, Yasuo Sugano, Hideaki Kanzaki, Toshihisa Anzai, Satoshi Yasuda, Junjiro Kobayashi
Circulation journal : official journal of the Japanese Circulation Society, 82, 1, 289, 292, 2017年12月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The valve-in-valve procedure, in which a transcatheter heart valve (THV) is implanted over a prosthetic valve, has been shown to be safe and therapeutically effective, depending on the size of the replacement valve.Methods and Results:We report 3 cases of successful valve-in-valve procedure to replace a degenerated 19-mm stented prosthetic aortic valve. Balloon-expanding THVs were implanted: 20-mm in the 1st case and 23-mm in the next 2. Aortic stenosis was almost completely resolved in all patients, who recovered promptly and without cardiac adverse events. CONCLUSIONS: Using the valve-in-valve procedure for a 19-mm degenerated bioprosthesis was feasible and safe.

Coronary Artery Ectasia Predicts Future Cardiac Events in Patients With Acute Myocardial Infarction.
Takahito Doi, Yu Kataoka, Teruo Noguchi, Tatsuhiro Shibata, Takahiro Nakashima, Shoji Kawakami, Kazuhiro Nakao, Masashi Fujino, Toshiyuki Nagai, Tomoaki Kanaya, Yoshio Tahara, Yasuhide Asaumi, Etsuko Tsuda, Michikazu Nakai, Kunihiro Nishimura, Toshihisa Anzai, Kengo Kusano, Hiroaki Shimokawa, Yoichi Goto, Satoshi Yasuda
Arteriosclerosis, thrombosis, and vascular biology, 37, 12, 2350, 2355, LIPPINCOTT WILLIAMS & WILKINS, 2017年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Coronary artery ectasia (CAE) is an infrequently observed vascular phenotype characterized by abnormal vessel dilatation and disturbed coronary flow, which potentially promote thrombogenicity and inflammatory reactions. However, whether or not CAE influences cardiovascular outcomes remains unknown. APPROACH AND RESULTS: We investigated major adverse cardiac events (MACE; defined as cardiac death and nonfatal myocardial infarction [MI]) in 1698 patients with acute MI. The occurrence of MACE was compared in patients with and without CAE. CAE was identified in 3.0% of study subjects. During the 49-month observation period, CAE was associated with 3.25-, 2.71-, and 4.92-fold greater likelihoods of experiencing MACE (95% confidence interval [CI], 1.88-5.66; P<0.001), cardiac death (95% CI, 1.37-5.37; P=0.004), and nonfatal MI (95% CI, 2.20-11.0; P<0.001), respectively. These cardiac risks of CAE were consistently observed in a multivariate Cox proportional hazards model (MACE: hazard ratio, 4.94; 95% CI, 2.36-10.4; P<0.001) and in a propensity score-matched cohort (MACE: hazard ratio, 8.98; 95% CI, 1.14-71.0; P=0.03). Despite having a higher risk of CAE-related cardiac events, patients with CAE receiving anticoagulation therapy who achieved an optimal percent time in target therapeutic range, defined as ≥60%, did not experience the occurrence of MACE (P=0.03 versus patients with percent time in target therapeutic range <60% or without anticoagulation therapy). CONCLUSIONS: The presence of CAE predicted future cardiac events in patients with acute MI. Our findings suggest that acute MI patients with CAE are a high-risk subset who might benefit from a pharmacological approach to controlling the coagulation cascade.

Rationale and Design of Low-dose Administration of Carperitide for Acute Heart Failure (LASCAR-AHF).
Toshiyuki Nagai, Yasuyuki Honda, Hiroki Nakano, Satoshi Honda, Naotsugu Iwakami, Atsushi Mizuno, Nobuyuki Komiyama, Takafumi Yamane, Yutaka Furukawa, Tadayoshi Miyagi, Syuzo Nishihara, Nobuhiro Tanaka, Taichi Adachi, Toshimitsu Hamasaki, Yasuhide Asaumi, Yoshio Tahara, Takeshi Aiba, Yasuo Sugano, Hideaki Kanzaki, Teruo Noguchi, Kengo Kusano, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
Cardiovascular drugs and therapy, 31, 5-6, 551, 557, SPRINGER, 2017年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUNDS: Despite current therapies, acute heart failure (AHF) remains a major public health burden with high rates of in-hospital and post-discharge morbidity and mortality. Carperitide is a recombinantly produced intravenous formulation of human atrial natriuretic peptide that promotes vasodilation with increased salt and water excretion, which leads to reduction of cardiac filling pressures. A previous open-label randomized controlled study showed that carperitide improved long-term cardiovascular mortality and heart failure (HF) hospitalization for patients with AHF, when adding to standard therapy. However, the study was underpowered to detect a difference in mortality because of the small sample size. METHODS: Low-dose Administration of Carperitide for Acute Heart Failure (LASCAR-AHF) is a multicenter, randomized, open-label, controlled study designed to evaluate the efficacy of intravenous carperitide in hospitalized patients with AHF. Patients hospitalized for AHF will be randomly assigned to receive either intravenous carperitide (0.02 μg/kg/min) in addition to standard treatment or matching standard treatment for 72 h. The primary end point is death or rehospitalization for HF within 2 years. A total of 260 patients will be enrolled between 2013 and 2018. CONCLUSION: The design of LASCAR-AHF will provide data of whether carperitide reduces the risk of mortality and rehospitalization for HF in selected patients with AHF.

Cardiac Rehabilitation Increases Plasma Brain-Derived Neurotrophic Factor Levels in Patients With Heart Failure
Takashio Seiji, Goto Yoichi, Anzai Toshihisa, Tsujita Kenichi
CIRCULATION, 136, 2017年11月14日, ［査読有り］

Diagnostic Utility of Cardiac Troponin T Levels in Patients With Infiltrative Cardiomyopathy
Takashio Seiji, Izumiya Yasuhiro, Hirakawa Kyoko, Marume Kyohei, Yamamoto Masahiro, Ueda Mitsuharu, Yamashita Taro, Ishibashi-Ueda Hatsue, Yasuda Satoshi, Ando Yukio, Anzai Toshihisa, Tsujita Kenichi
CIRCULATION, 136, 2017年11月14日, ［査読有り］

Multimodality assessment of left ventricular dysfunction in Takayasu arteritis and familial hypercholesterolaemia.
Atsushi Okada, Hiroyuki Takahama, Masatsune Ogura, Yoshiaki Morita, Junichi Konma, Shuzo Yoshida, Shigeki Makino, Seiji Takashio, Makoto Amaki, Takahiro Ohara, Takuya Hasegawa, Yasuo Sugano, Hideaki Kanzaki, Mariko Harada-Shiba, Hatsue Ishibashi-Ueda, Satoshi Yasuda, Toshiaki Hanafusa, Toshihisa Anzai
ESC heart failure, 4, 4, 655, 659, 2017年11月, ［査読有り］, ［国際誌］
英語, Although left ventricular (LV) systolic dysfunction in patients suffering from Takayasu arteritis (TA) has been reported, little is known regarding the development of heart failure in these patients. We report a novel finding of active TA and familial hypercholesterolaemia presenting with severe LV dysfunction through multimodality assessments of LV systolic dysfunction.

Contrast-enhanced computed tomography with myocardial three-dimensional printing can guide treatment in symptomatic hypertrophic obstructive cardiomyopathy.
Yasuhiro Hamatani, Makoto Amaki, Hideaki Kanzaki, Kizuku Yamashita, Yasuteru Nakashima, Atsushi Shibata, Atsushi Okada, Hiroyuki Takahama, Takuya Hasegawa, Yusuke Shimahara, Yasuo Sugano, Tomoyuki Fujita, Isao Shiraishi, Satoshi Yasuda, Junjiro Kobayashi, Toshihisa Anzai
ESC heart failure, 4, 4, 665, 669, 2017年11月, ［査読有り］, ［国際誌］
英語, Both surgical myectomy and percutaneous transluminal septal myocardial ablation are effective treatments for drug-refractory symptomatic hypertrophic obstructive cardiomyopathy (HOCM). However, in some cases, it is not easy to elucidate the abnormal structure of left ventricular outflow obstruction to adopt these treatments. Here, we presented a young female patient with drug-refractory symptomatic HOCM. In this case, contrast-enhanced computed tomography enabled us to assess the suitability of percutaneous transluminal septal myocardial ablation. By creating three-dimensional printed models using computed tomography data, we could also visualize intracardiac structure and simulate the surgical procedure. A multimodality assessment strategy is useful for evaluating patients complicated with drug-refractory symptomatic HOCM.

What Should Be Generalized Diagnostic Markers for Peripartum Cardiomyopathy?
Ichiro Sakuma, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 81, 11, 1578, 1579, JAPANESE CIRCULATION SOC, 2017年10月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

Potential palliative care quality indicators in heart disease patients: A review of the literature.
Atsushi Mizuno, Mitsunori Miyashita, Akitoshi Hayashi, Fujimi Kawai, Koichiro Niwa, Akemi Utsunomiya, Shun Kohsaka, Takashi Kohno, Takeshi Yamamoto, Morimasa Takayama, Toshihisa Anzai
Journal of cardiology, 70, 4, 335, 341, ELSEVIER SCIENCE BV, 2017年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, In spite of the increasing interest in palliative care for heart disease, data on the detailed methods of palliative care and its efficacy specifically in heart disease are still lacking. A structured PubMed literature review revealed no quality indicators of palliative care in heart disease. Therefore, we performed a narrative overview of the potential quality indicators in heart disease by reviewing previous literature concerning quality indicators in cancer patients. We summarize seven potential categories of quality indicators in heart disease: (1) presence and availability of a palliative care unit, palliative care team, and outpatient palliative care; (2) human resources such as number of skilled staff; (3) infrastructure; (4) presence and frequency of documentation or family survey; (5) patient-reported outcome measure (PROM) data and disease-specific patient quality of life such as The Kansas City Cardiomyopathy Questionnaire (KCCQ); (6) questionnaires and interviews about the quality of palliative care after death, including bereaved family surveys; and (7) admission-related outcomes such as place of death and intensive care unit length of stay. Although detailed measurements of palliative care quality have not been validated in heart disease, many indicators developed in cancer patients might also be applicable to heart disease. This new categorization might be useful to determine quality indicators in heart disease patients.

Does the pathophysiology of heart failure prime the incidence of cancer?
Mari Sakamoto, Takuya Hasegawa, Masanori Asakura, Hideaki Kanzaki, Hiroyuki Takahama, Makoto Amaki, Naoki Mochizuki, Toshihisa Anzai, Toshimitsu Hamasaki, Masafumi Kitakaze
Hypertension research : official journal of the Japanese Society of Hypertension, 40, 9, 831, 836, NATURE PUBLISHING GROUP, 2017年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Both chronic heart failure (CHF) and cancer are among the most frequent causes of death in developed countries. Given that CHF activates neurohumoral factors, such as cytokines, the pathophysiology of CHF could prime the onset or progression of cancer. We consecutively enrolled 5238 patients with CHF who had been hospitalized in the Department of Cardiovascular Medicine in our institute between 2001 and 2013. We followed these patients until April 2015. We examined the cohort of patients from our hospital and compared it with a control cohort derived from the 2008 cancer database 'Monitoring of Cancer Incidence in Japan' from the National Cancer Center, Japan. The incidence of cancer in CHF patients (198 cases out of the 5238 patients) was approximately four times higher than that in control patients (2.27% vs 0.59%, P<0.0001; 95% confidence interval, 1.89-2.71). When we omitted the patients whose cancer diagnosis occurred prior to their diagnosis of CHF, we still observed a significantly higher incidence of cancer in patients with CHF than in controls. Based on our results, we suggest that there is a strong correlation between the pathophysiology of CHF and cancer. Given that CHF could prime the onset of cancers, we recommend that clinicians should be vigilant regarding cancer comorbidity in patients with CHF.

Earlier Right Ventricular Pacing in Cardiac Resynchronization Therapy for a Patient with Right Axis Deviation.
Yusuke Hattori, Kohei Ishibashi, Takashi Noda, Hideo Okamura, Hideaki Kanzaki, Toshihisa Anzai, Satoshi Yasuda, Kengo Kusano
Internal medicine (Tokyo, Japan), 56, 17, 2285, 2288, JAPAN SOC INTERNAL MEDICINE, 2017年09月01日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, We describe the case of a 37-year-old woman who presented with complete right bundle branch block and right axis deviation. She was admitted to our hospital due to severe heart failure and was dependent on inotropic agents. Cardiac resynchronization therapy was initiated but did not improve her condition. After the optimization of the pacing timing, we performed earlier right ventricular pacing, which led to an improvement of her heart failure. Earlier right ventricular pacing should be considered in patients with complete right bundle branch block and right axis deviation when cardiac resynchronization therapy is not effective.

Efficacy and Safety of an Orally Administered Selective Prostacyclin Receptor Agonist, Selexipag, in Japanese Patients With Pulmonary Arterial Hypertension.
Nobuhiro Tanabe, Satoshi Ikeda, Nobuhiro Tahara, Keiichi Fukuda, Masaru Hatano, Hiroshi Ito, Tomotaka Nakayama, Toshihisa Anzai, Akiyoshi Hashimoto, Teruo Inoue, Kouji Kajinami, Yasuki Kihara, Hideyuki Kinoshita, Koichiro Kuwahara, Toyoaki Murohara, Osamu Okazaki, Satoshi Sakai, Toru Satoh, Yutaka Takeda, Yasuchika Takeishi, Mitsugu Taniguchi, Hiroshi Watanabe, Takeshi Yamamoto, Keiko Yamauchi-Takihara, Koichiro Yoshioka, Shigetake Sasayama
Circulation journal : official journal of the Japanese Circulation Society, 81, 9, 1360, 1367, JAPANESE CIRCULATION SOC, 2017年08月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Selexipag is an orally available prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. In this open-label Phase II trial, the efficacy and safety of selexipag in Japanese patients with pulmonary arterial hypertension (PAH) is examined.Methods and Results:Selexipag was administered at 200 μg twice daily and titrated up to 1,600 μg by increments of 200 μg in 37 subjects to reach the individual maximum tolerated dose. At 16 weeks, in 33 patients comprising the per-protocol set, the pulmonary vascular resistance (PVR; primary endpoint) decreased from 683.2±237.3 to 560.3±238.7 dyn·s/cm5(P<0.0001). For the secondary endpoint, the 6-min walk distance (6MWD) increased from 445.0±102.2 to 459.1±112.8 m (P=0.0324); World Health Organization functional class improved in 4 patients (12.1%), and was maintained in 29 patients (87.9%). A decrease in PVR was also shown in patients treated with selexipag, on top of a phosphodiesterase inhibitor and endothelin receptor antagonist. Most of the commonly reported adverse events were consistent with those reported for other PGI2formulations. Thirty-four patients attained the individual maximum tolerated dose (maintenance dose). CONCLUSIONS: The efficacy and tolerability of selexipag in Japanese PAH patients was confirmed by improvement in pulmonary hemodynamics, exercise capacity, symptoms. Selexipag is an efficacious treatment option for Japanese PAH patients. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111532].).

Heart failure in patients with arrhythmogenic right ventricular cardiomyopathy: What are the risk factors?
Yoshitaka Kimura, Takashi Noda, Taka-Aki Matsuyama, Yosuke Otsuka, Tsukasa Kamakura, Mitsuru Wada, Kohei Ishibashi, Yuko Inoue, Koji Miyamoto, Hideo Okamura, Satoshi Nagase, Takeshi Aiba, Shiro Kamakura, Teruo Noguchi, Toshihisa Anzai, Kazuhiro Satomi, Yuko Wada, Seiko Ohno, Minoru Horie, Wataru Shimizu, Satoshi Yasuda, Hiroaki Shimokawa, Kengo Kusano
International journal of cardiology, 241, 288, 294, ELSEVIER IRELAND LTD, 2017年08月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: We previously demonstrated that heart failure (HF) was one of the major causes of death in arrhythmogenic right ventricular cardiomyopathy (ARVC). The purpose of this study was to elucidate the clinical impact and risk factors of HF in patients with ARVC. METHODS AND RESULTS: We evaluated cardiac adverse outcomes including HF in 113 consecutive patients with ARVC (85 men, mean age: 44±15years). During a median follow-up of 10.0years (interquartile range: 5.2 to 15.7years), 29 patients (26%) were hospitalized for progressive HF. The patients with one or more episodes of HF hospitalization had about a 10-fold increased incidence of cardiac death (14/29 [48%] vs. 4/84 [4.7%], p<0.0001). Left ventricular ejection fraction (LVEF) and right ventricular ejection fraction (RVEF) were significantly lower in the patients with HF hospitalization compared to the patients without HF hospitalization (LVEF, 45±15 vs. 54±13%, p=0.001; RVEF, 26±10 vs. 33±11%, p=0.003, respectively). Regarding the ECG findings, the prevalence of first-degree atrioventricular block (AVB, PR interval >200ms) and epsilon waves were significantly higher in patients with HF hospitalization than those without HF hospitalization (first-degree AVB, 14/29 [48%] vs. 11/84 [13%], p<0.0001; epsilon waves, 10/29 [34%] vs. 12/84 [14%], p=0.02). In multivariate analysis, first-degree AVB at baseline was the strongest independent risk factor for HF hospitalization in patients with ARVC (hazard ratio 4.24, 95% confidence interval 1.79-10.47, p=0.0011). CONCLUSION: HF hospitalization has a significant relation with malignant clinical course in ARVC patients. First-degree AVB was an independent determinant for increased risk of HF hospitalization.

Impact of decreased serum albumin levels on acute kidney injury in patients with acute decompensated heart failure: a potential association of atrial natriuretic peptide.
Yoichi Takaya, Fumiki Yoshihara, Hiroyuki Yokoyama, Hideaki Kanzaki, Masafumi Kitakaze, Yoichi Goto, Toshihisa Anzai, Satoshi Yasuda, Hisao Ogawa, Yuhei Kawano, Kenji Kangawa
Heart and vessels, 32, 8, 932, 943, SPRINGER, 2017年08月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Although hypoalbuminemia at admission is a risk for acute kidney injury (AKI) and mortality in patients with acute decompensated heart failure (ADHF), the clinical significance of decreased serum albumin levels (DAL) during ADHF therapy has not been elucidated. This study aimed to evaluate whether DAL was associated with AKI, and whether intravenous atrial natriuretic peptide (ANP) administration, which provides an effective treatment for ADHF but promotes albumin extravasation, was associated with DAL and AKI. A total of 231 consecutive patients with ADHF were enrolled. AKI was defined as ≥0.3 mg/dl absolute or 1.5-fold increase in serum creatinine levels within 48 h. AKI occurred in 73 (32%) of the 231 patients during ADHF therapy. The median value of decreases in serum albumin levels was 0.3 g/dl at 7 days after admission. When DAL was defined as ≥0.3 g/dl decrease in serum albumin levels, DAL occurred in 113 patients, and was independently associated with AKI. Of the 231 patients, 73 (32%) were treated with intravenous ANP. DAL occurred more frequently in patients receiving ANP than in those not receiving ANP (77 vs. 36%, p < 0.001), and ANP was independently associated with DAL. The incidence of AKI was higher in patients receiving ANP than in those not receiving ANP (48 vs. 24%, p < 0.001). ANP was independently associated with AKI. In conclusion, DAL is associated with AKI. Intravenous ANP administration may be one of the promoting factors of DAL, which leads to AKI, indicating a possible novel mechanism of AKI.

"Window Sliding" analysis combined with high-density and rapid electroanatomical mapping: its efficacy and the outcome of catheter ablation of atrial tachycardia.
Kosuke Nakasuka, Koji Miyamoto, Takashi Noda, Tsukasa Kamakura, Mitsuru Wada, Ikutaro Nakajima, Kohei Ishibashi, Yuko Inoue, Hideo Okamura, Satoshi Nagase, Takeshi Aiba, Shiro Kamakura, Wataru Shimizu, Teruo Noguchi, Toshihisa Anzai, Satoshi Yasuda, Nobuyuki Ohte, Kengo Kusano
Heart and vessels, 32, 8, 984, 996, SPRINGER, 2017年08月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Atrial tachycardia (AT) is a clinically challenging arrhythmia that can occur based on atrial substrates. Nowadays, a rapid construction of three-dimensional electroanatomical maps, which has an analysis function for complex arrhythmias, named 'Window Sliding' (WS) is available. However, little data has revealed the efficacy of this mapping strategy. The aim of this study was to investigate the efficacy of the WS analysis for AT treatments. All patients underwent electrophysiological studies during ATs and the characteristics of the ATs were analyzed using rapid high-density mapping followed by the WS analysis. RFA was then performed. Fifty-five ATs were identified in 34 patients (63 ± 17 year-old) and in 51 activation maps (cycle length, 322 ± 120 milliseconds) were successfully constructed with 644 ± 433 points per map during 5.3 ± 2.5 min. The types of detected ATs were macro-reentries around the mitral (8) and, tricuspid (12) valves, roof-dependent reentry (5), others (13), and focal patterns (13). Of those that underwent RFA, 46 (98%) were treated successfully. Two ATs were abandoned since their critical sites were close to the His bundle and sinoatrial node. During a mean follow-up period of 179 ± 176 days, 7 patients had documented recurrences of AT. This high-density mapping using the WS analysis was useful for creating the entire picture of the ATs in a short time, resulting in favorable RFA outcomes.

Prognostic impact of chronic total coronary occlusion on long-term outcomes in implantable cardioverter-defibrillator recipients with ischaemic heart disease.
Tatsuya Nishikawa, Masashi Fujino, Ikutaro Nakajima, Yasuhide Asaumi, Yu Kataoka, Toshihisa Anzai, Kengo Kusano, Teruo Noguchi, Yoichi Goto, Kunihiro Nishimura, Yoshihiro Miyamoto, Keisuke Kiso, Satoshi Yasuda
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, 19, 7, 1153, 1162, OXFORD UNIV PRESS, 2017年07月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Aims: The prognostic impact of chronic total coronary occlusion (CTO) on implantable cardioverter-defibrillator (ICD) recipients remains unclear. Methods and results: Eighty-four consecutive patients with ischaemic heart disease who received ICD therapy for primary or secondary prevention were analysed. We investigated all-cause mortality and major adverse cardiac events (MACEs) including cardiac death, appropriate device therapy, hospitalization for heart failure, and ventricular assist device implantation. Of the study patients (mean age 70 ± 8 years; 86% men), 34 (40%) had CTO. There were no significant differences in age, left ventricular ejection fraction (LVEF), New York Heart Association functional class III or IV status, and proportion who underwent secondary prevention between patients with CTO (CTO group) and without CTO (non-CTO group). During a median follow-up of 3.8 years (interquartile range 2.7-5.4 years), the CTO group tended to have a higher MACE rate (log-rank P = 0.054) than the non-CTO group. Within the CTO group, there was no difference in the MACE rate between patients with and without viable myocardium. In patients with ICD for secondary prevention (n = 47), 16 patients (34%) with CTO had a higher MACE rate than patients without CTO (log-rank P < 0.01). Cox proportional hazards regression analysis showed that the presence of CTO, but not LVEF, was associated with a higher MACE rate. Multivariate analysis showed that the presence of CTO was a predictor of MACE (P < 0.05). Conclusion: In patients with ischaemic heart disease receiving ICD implantation, the presence of CTO has an adverse impact on long-term prognosis, especially as secondary prevention.

Usefulness of the Direct and/or Total Bilirubin to Predict Adverse Outcomes in Patients With Acute Decompensated Heart Failure.
Atsushi Okada, Yasuo Sugano, Toshiyuki Nagai, Yasuyuki Honda, Naotsugu Iwakami, Hiroki Nakano, Seiji Takashio, Satoshi Honda, Yasuhide Asaumi, Takeshi Aiba, Teruo Noguchi, Kengo Kusano, Satoshi Yasuda, Toshihisa Anzai
The American journal of cardiology, 119, 12, 2035, 2041, EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC, 2017年06月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Abnormal liver function test results are often observed in acute decompensated heart failure (ADHF). However, the prognostic value of bilirubin fractionation has not been elucidated. The prognostic value of direct bilirubin (DB), in comparison with total bilirubin (TB), was examined in 556 consecutive patients with ADHF. Patients with elevated DB showed mostly similar patient characteristics including signs of elevated right-sided pressure (frequent hepatomegaly, jugular venous distention, dilated inferior vena cava, and elevated gamma-glutamyltransferase) and decreased cardiac output (cold extremities, decreased pulse pressure, and lower blood pressure) and other parameters of heart failure (HF) severity (increased plasma renin activity, decreased sodium, total cholesterol, and ejection fraction) to elevated TB; however, only patients with elevated DB showed a significant difference in the frequency of HF history and alkaline phosphatase value. Kaplan-Meier analysis showed that patients with elevated DB had a significantly higher rate of the composite end point of all-cause mortality or HF readmission (p = 0.021) compared with those with normal DB, whereas patients with elevated TB did not show a statistically significant difference compared with those with normal TB (NS). A multivariate Cox hazards model showed that DB was an independent predictor of adverse events (adjusted hazard ratio 1.052, 95% confidence interval 1.001 to 1.099, p = 0.034), whereas TB was not (adjusted hazard ratio 1.017, 95% confidence interval 0.985 to 1.046, p = 0.27). Adding DB to existing prognostic variables resulted in higher C-statistics than adding TB (C-statistics: 0.670 to 0.675, 0.670 to 0.674, respectively). In conclusion, elevated DB in ADHF was an independent prognostic predictor that was superior to TB. DB may be useful for further risk stratification in ADHF.

A Pathophysiological Role of Plasma Indoxyl Sulfate in Patients with Heart Failure
Miki Imazu, Hiroyuki Takahama, Kazuhiro Shindo, Takuya Hasegawa, Hideaki Kanzaki, Toshihisa Anzai, Hiroshi Asanuma, Toshisuke Morita, Masanori Asakura, Masafumi Kitakaze
INTERNATIONAL JOURNAL OF GERONTOLOGY, 11, 2, 62, 66, ELSEVIER TAIWAN, 2017年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: One of uremic toxins, indoxyl sulfate (IS), is associated with cardiovascular events. This study aimed to measure the plasma IS levels in patients with and without chronic heart failure (CHF).
Methods: We measured plasma IS levels in 49 patients with CHF and an estimated glomerular filtration rate (eGFR) of 40-60 ml/min/1.73 m(2) from our institute. These were compared with 31 healthy subjects without CHF (a control), but with comparable eGFR levels, from our resident cohort study. We also test the effect of AST-120 (the oral adsorbent) in 16 CHF patients.
Results: The plasma IS levels in 49 CHF patients increased (1.38 +/- 0.84 (SD) vs 0.12 +/- 0.07 mu g/ml (a control), p < 0.001), and fractional shortening (FS) levels were correlated with the plasma IS levels in these subjects. Second, in our database of the hospitalized CHF patients, we retrospectively reviewed the data for eight CHF patients with stage 3-5 chronic kidney disease (CKD) who received treatment with AST-120, before and one year after treatment, and compared these patients with eight sex-matched CHF patients with stage 3-5 CKD without AST-120. AST-120 decreased plasma IS levels and improved cardiac function.
Conclusions: Plasma IS levels increased in patients with CHF along with cardiac systolic dysfunction compared with those in healthy subjects, and AST-120 improved cardiac dysfunction in patients with CHF. Oral adsorbents may represent a novel treatment for CHF. Copyright (C) 2017, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC.

Clinical impact of the presence of macrophages in endomyocardial biopsies of patients with dilated cardiomyopathy.
Takafumi Nakayama, Yasuo Sugano, Tetsuro Yokokawa, Toshiyuki Nagai, Taka-Aki Matsuyama, Keiko Ohta-Ogo, Yoshihiko Ikeda, Hatsue Ishibashi-Ueda, Takeshi Nakatani, Nobuyuki Ohte, Satoshi Yasuda, Toshihisa Anzai
European journal of heart failure, 19, 4, 490, 498, WILEY, 2017年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Dilated cardiomyopathy (DCM) is the most common cardiomyopathy and causes left ventricular enlargement and contractile dysfunction, with a poor prognosis. The mechanisms underlying the disease process have not been precisely identified, but recent evidence has suggested that the activation of myocardial inflammation is involved in the deterioration associated with the condition. METHODS AND RESULTS: Biopsy samples from 182 consecutive DCM patients were immunohistochemically stained with antibodies specific to CD3 (T lymphocytes), CD68 (whole macrophages), and CD163 (M2 macrophages), and each type of infiltrating cell was counted. Masson's trichrome staining was used to determine the collagen area fraction (CAF) in each sample. Patients were followed up for 6.9 ± 2.4 years, and their clinical data were obtained for analysis. Median (interquartile range) numbers of myocardial CD3, CD68, and CD163-cell infiltrates were 8.1 (4.0-14.2)/mm2 , 22.3 (12.1-36.0)/mm2 , and 6.5 (2.0-14.0)/mm2 , respectively. Patients with higher counts of infiltrating CD3-, CD68-, and CD163-positive cells had significantly poorer outcomes (P = 0.007, P = 0.011, and P = 0.022, respectively). A high CD163-positive infiltrate count was independently associated with worse outcome in multivariate Cox regression analysis (hazard ratio 1.77, P = 0.004), and multivariate linear regression analysis revealed that the CD163 cell count was an independent determinant of CAF (P < 0.001). CONCLUSIONS: It was found that DCM with increased myocardial immune activation was associated with poor long-term outcome. The association between M2 macrophages and collagen formation suggests the phenotypic polarization of macrophages toward M2 may be associated with ventricular remodelling in DCM.

低体重は駆出率が保持された心不全における転帰の独立予測因子である JASPER試験からの報告(Underweight is an Independent Predictor of Outcomes in Heart Failure with Preserved Ejection Fraction: A Report from JASPER Study)　　　　　　　　　　　　　　　
Matsumoto Junichi, Kinugawa Shintaro, Fukushima Arata, Yokota Takashi, Yoshikawa Tsutomu, Saito Yoshihiko, Nagai Toshiyuki, Anzai Toshihisa
日本循環器学会学術集会抄録集, 81回, LBCS3, 6, (一社)日本循環器学会, 2017年03月
英語

Prognostic value of malnutrition assessed by Controlling Nutritional Status score for long-term mortality in patients with acute heart failure.
Naotsugu Iwakami, Toshiyuki Nagai, Toshiaki A Furukawa, Yasuo Sugano, Satoshi Honda, Atsushi Okada, Yasuhide Asaumi, Takeshi Aiba, Teruo Noguchi, Kengo Kusano, Hisao Ogawa, Satoshi Yasuda, Toshihisa Anzai
International journal of cardiology, 230, 529, 536, ELSEVIER IRELAND LTD, 2017年03月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The prognostic value of nutritional status is poorly understood and evidence-based nutritional assessment indices are required in acute heart failure (AHF). We investigated the prognostic value of malnutrition assessed by the Controlling Nutritional Status (CONUT) score (range 0-12, higher=worse, consisting of serum albumin, cholesterol and lymphocytes) in AHF patients. METHODS: The CONUT score was measured on admission in 635 consecutive AHF patients. The primary outcome was all-cause death. RESULTS: Median CONUT score was 3 (interquartile range 2 to 5). During the median follow-up of 324days, CONUT score was independently associated with death (HR 1.26, 95% CI 1.11-1.42, P<0.001) after adjustment for confounders in a multivariate Cox model. The CONUT score demonstrated the best C-statistic for predicting death (0.71) among other common nutritional markers in HF. Furthermore, addition of the CONUT score to an established risk prediction model from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure study significantly increased the C-statistic from 0.75 to 0.77 (P=0.02). The net reclassification improvement afforded by CONUT score was 21% for all-cause death, 27% for survival and 49% overall (P<0.001). CONCLUSION: Malnutrition assessed by the CONUT score on admission was an independent determinant of long-term death in AHF, and its prognostic value outweighed that of other nutritional indices. Moreover, addition of the score to the existing risk prediction model significantly increased the predictive ability for death, indicating beneficial clinical application of the CONUT score in AHF patients.

Impact of Elevated End-Diastolic Pulmonary Regurgitation Gradient on Worse Clinical Outcomes in Hospitalized Patients With Heart Failure.
Yasuyuki Honda, Toshiyuki Nagai, Yasuo Sugano, Satoshi Honda, Atsushi Okada, Yasuhide Asaumi, Takeshi Aiba, Teruo Noguchi, Kengo Kusano, Hisao Ogawa, Satoshi Yasuda, Toshihisa Anzai
The American journal of cardiology, 119, 4, 604, 610, EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC, 2017年02月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The echo Doppler end-diastolic pulmonary regurgitation (EDPR) gradient correlates well with catheter-derived pulmonary artery diastolic pressure. An elevated EDPR gradient is associated with worse clinical outcomes in patients with stable coronary artery disease. However, the prognostic significance of EDPR gradient in patients with heart failure (HF) is unclear. The aim of the present study was to investigate the prognostic impact of EDPR gradient in HF. We retrospectively examined 751 consecutive hospitalized patients with acute HF. Those with acute coronary syndrome or in-hospital death and those without accessible EDPR gradient data at discharge were excluded. Finally, 265 patients were examined and divided into 2 groups according to EDPR gradient (cutoff 9 mm Hg). Adverse events were defined as worsening HF and death. Patients with elevated EDPR gradient had higher B-type natriuretic peptide, lower age, and lower left ventricular ejection fraction at discharge than those with nonelevated EDPR gradient. During a median follow-up of 429 days, elevated EDPR gradient was independently associated with adverse events (hazard ratio 2.34, 95% CI 1.44 to 3.78, p <0.001) after adjustment for confounders. In conclusion, echo Doppler EDPR gradient might be a noninvasive predictor of clinical outcomes in hospitalized patients with HF.

Reply to "delirium in heart failure".
Satoshi Honda, Toshiyuki Nagai, Toshihisa Anzai
International journal of cardiology, 229, 133, 133, ELSEVIER IRELAND LTD, 2017年02月15日, ［査読有り］, ［国際誌］
英語

Use of serum fibroblast growth factor 23 vs. plasma B-type natriuretic peptide levels in assessing the pathophysiology of patients with heart failure.
Miki Imazu, Hiroyuki Takahama, Makoto Amaki, Yasuo Sugano, Takahiro Ohara, Takuya Hasegawa, Hideaki Kanzaki, Toshihisa Anzai, Naoki Mochizuki, Hiroshi Asanuma, Masanori Asakura, Masafumi Kitakaze
Hypertension research : official journal of the Japanese Society of Hypertension, 40, 2, 181, 188, NATURE PUBLISHING GROUP, 2017年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Recently, fibroblast growth factor 23 (FGF23), a phosphate-regulating hormone, has been linked to the pathophysiology of heart failure (HF), thus encouraging us to examine which hemodynamic abnormalities of HF are linked to either serum FGF23 or plasma B-type natriuretic peptide (BNP) levels. We measured both the serum FGF23 and plasma BNP levels in 154 consecutive prospectively enrolled hospitalized HF patients, with an estimated glomerular filtration rate >40 ml min-1 1.73 m-2, who underwent heart catheterizations and an echocardiogram. The serum FGF23 levels correlated with the diameter of the inferior vena cava and its respiratory changes, whereas the plasma BNP levels did not. Both the plasma BNP and serum FGF23 levels were moderately correlated with the mean pulmonary artery (PA) pressure and pulmonary capillary wedge (PCW) pressure. Interestingly, in patients with an above-median right-atrial (RA) pressure (4 mm Hg), FGF23 levels were correlated with both PA and PCW pressures, but the levels were not correlated in patients with a below-median RA pressure. In contrast, the plasma BNP levels were correlated with both PA and PCW pressures. Finally, serum FGF23 levels, compared with the plasma BNP levels, were more strongly associated with the clinical outcomes in patients with above-median RA pressure. These findings suggested that serum FGF23 levels are predominantly correlated with clinical outcomes, may serve as a biomarker for HF in patients with higher RA pressure, may provide beneficial information for patients with right-sided HF and may represent different clinical information than that provided only by plasma BNP levels.

Early development of acute kidney injury is an independent predictor of in-hospital mortality in patients with acute myocardial infarction.
Noriaki Moriyama, Masaharu Ishihara, Teruo Noguchi, Michio Nakanishi, Tetsuo Arakawa, Yasuhide Asaumi, Leon Kumasaka, Tomoaki Kanaya, Toshiyuki Nagai, Masashi Fujino, Satoshi Honda, Reiko Fujiwara, Toshihisa Anzai, Kengo Kusano, Yoichi Goto, Satoshi Yasuda, Shigeru Saito, Hisao Ogawa
Journal of cardiology, 69, 1, 79, 83, ELSEVIER SCIENCE BV, 2017年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Acute kidney injury (AKI) often occurs in patients with acute myocardial infarction (AMI), and is associated with adverse outcomes. However, it remains unclear how timing of AKI affects it. This study assessed impact of timing of AKI on prognosis after AMI. METHODS: This study consisted of 760 patients with AMI who were admitted within 48h after symptom onset. AKI was diagnosed as increase in creatinine ≥0.3mg/dl or ≥50% within any 48h after admission. Patients were classified into 3 groups according to the occurrence and timing of AKI: no-AKI, early-AKI (within 48h after admission) and late-AKI (>48h). Early-AKI was classified into transient early-AKI, defined as creatinine returning to the level below the criteria of AKI, and persistent early-AKI. RESULTS: Early-AKI occurred in 64 patients (9%) and late-AKI in 32 patients (4%). Patients with early-AKI had significantly higher mortality (35%) than those with late-AKI (7%, p<0.001) and no-AKI (3%, p<0.001). Multivariate analysis showed early-AKI was an independent predictor of in-hospital mortality (OR: 3.38, 95% CI: 1.30-8.76, p=0.013), but late-AKI was not. Among patients with early-AKI, mortality was significantly higher even if AKI was transient (23%, p<0.001). Patients with persistent early-AKI had the highest mortality (66%, p<0.001). CONCLUSIONS: Early-AKI was associated with worse outcome. Even if renal function once returned to baseline level, patients with early-AKI tended to be at high risk of mortality.

Persistent increase in cardiac troponin T at hospital discharge predicts repeat hospitalization in patients with acute decompensated heart failure.
Seiji Takashio, Toshiyuki Nagai, Yasuo Sugano, Satoshi Honda, Atsushi Okada, Yasuhide Asaumi, Takeshi Aiba, Teruo Noguchi, Kengo F Kusano, Hisao Ogawa, Satoshi Yasuda, Toshihisa Anzai
PloS one, 12, 4, e0173336, PUBLIC LIBRARY SCIENCE, 2017年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: High-sensitive cardiac troponin T (hsTnT) is a sensitive biomarker of myocardial damage and predictor of acute decompensated heart failure (ADHF). However, there is little information on changes over time in hsTnT level during ADHF management. The aim of this prospective study was to evaluate changes in hsTnT levels between admission and at discharge in patients with ADHF, and identify factors that determine such levels and their prognostic significance. METHODS AND RESULTS: We evaluated 404 ADHF patients with abnormal hsTnT levels (≥0.0135 ng/ml) on admission. The median (interquartile ranges) hsTnT levels on admission, at discharge, and percent changes in hsTnT levels were 0.038 (0.026 to 0.065), 0.032 (0.021 to 0.049) ng/ml, and -12.0 (-39.8 to 7.4) % respectively. The numbers of patients with falling (hsTnT decrease > -15%), stable (hsTnT change between -15 and +15%) and rising (hsTnT increase > +15%) hsTnT level at discharge were 190, 146, and 68, respectively. The percent change in B-type natriuretic peptide (BNP) levels was greater in the falling group, compared to the stable (p<0.001) and rising groups (p<0.001). Changes in hsTnT levels correlated significantly with changes in BNP levels (ρ = 0.22, p<0.001). Multivariate Cox regression analysis identified rising or stable hsTnT at discharge as a significant predictor of heart failure-related rehospitalization (hazard ratio: 1.69; 95% confidence interval: 1.06 to 2.70; p = 0.03). CONCLUSIONS: Persistent increase in hsTnT levels at discharge correlated with inadequate decrease of BNP levels, and was a predictor of poor clinical outcome, with repeat heart failure hospitalizations.

Immunohistochemical identification of Propionibacterium acnes in granuloma and inflammatory cells of myocardial tissues obtained from cardiac sarcoidosis patients.
Naoya Asakawa, Keisuke Uchida, Mamoru Sakakibara, Kazunori Omote, Keiji Noguchi, Yusuke Tokuda, Kiwamu Kamiya, Kanako C Hatanaka, Yoshihiro Matsuno, Shiro Yamada, Kyoko Asakawa, Yuichiro Fukasawa, Toshiyuki Nagai, Toshihisa Anzai, Yoshihiko Ikeda, Hatsue Ishibashi-Ueda, Masanori Hirota, Makoto Orii, Takashi Akasaka, Kenta Uto, Yasushige Shingu, Yoshiro Matsui, Shin-Ichiro Morimoto, Hiroyuki Tsutsui, Yoshinobu Eishi
PloS one, 12, 7, e0179980, PUBLIC LIBRARY SCIENCE, 2017年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Although rare, cardiac sarcoidosis (CS) is potentially fatal. Early diagnosis and intervention are essential, but histopathologic diagnosis is limited. We aimed to detect Propionibacterium acnes, a commonly implicated etiologic agent of sarcoidosis, in myocardial tissues obtained from CS patients. METHODS AND RESULTS: We examined formalin-fixed paraffin-embedded myocardial tissues obtained by surgery or autopsy and endomyocardial biopsy from patients with CS (n = 26; CS-group), myocarditis (n = 15; M-group), or other cardiomyopathies (n = 39; CM-group) using immunohistochemistry (IHC) with a P. acnes-specific monoclonal antibody. We found granulomas in 16 (62%) CS-group samples. Massive (≥14 inflammatory cells) and minimal (<14 inflammatory cells) inflammatory foci, respectively, were detected in 16 (62%) and 11 (42%) of the CS-group samples, 10 (67%) and 10 (67%) of the M-group samples, and 1 (3%) and 18 (46%) of the CM-group samples. P. acnes-positive reactivity in granulomas, massive inflammatory foci, and minimal inflammatory foci were detected in 10 (63%), 10 (63%), and 8 (73%) of the CS-group samples, respectively, and in none of the M-group and CM-group samples. CONCLUSIONS: Frequent identification of P. acnes in sarcoid granulomas of originally aseptic myocardial tissues suggests that this indigenous bacterium causes granuloma in many CS patients. IHC detection of P. acnes in massive or minimal inflammatory foci of myocardial biopsy samples without granulomas may be useful for differentiating sarcoidosis from myocarditis or other cardiomyopathies.

Risk factors for amiodarone-induced thyroid dysfunction in Japan.
Sayoko Kinoshita, Tomohiro Hayashi, Kyoichi Wada, Mikie Yamato, Takeshi Kuwahara, Toshihisa Anzai, Mai Fujimoto, Kouichi Hosomi, Mitsutaka Takada
Journal of arrhythmia, 32, 6, 474, 480, 2016年12月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Amiodarone is associated with a number of significant adverse effects, including elevated transaminase levels, pulmonary fibrosis, arrhythmia, and thyroid dysfunction. Although thyroid dysfunction is considered to be a common and potentially serious adverse effect of amiodarone therapy, the exact pathogenesis remains unknown because of its complex manifestations. Therefore, the prevalence of, and risk factors for, amiodarone-induced thyroid dysfunction in Japanese patients were investigated in the present study. METHODS: A retrospective analysis of patients treated with amiodarone between January 2012 and December 2013 was performed. A total of 317 patients with euthyroidism, or subclinical hyperthyroidism or hypothyroidism, were enrolled in this study. RESULTS: After being treated with amiodarone, 30 (9.5%) and 60 patients (18.9%) developed amiodarone-induced hyperthyroidism and amiodarone-induced hypothyroidism, respectively. Ten (33.3%) patients with amiodarone-induced hyperthyroidism and 40 (66.6%) with amiodarone-induced hypothyroidism were diagnosed within two years of the initiation of amiodarone therapy. Dilated cardiomyopathy (DCM) [Adjusted odds ratio (OR) 3.30 (95% confidence interval (CI): 1.26-8.90)], and cardiac sarcoidosis [Adjusted OR 6.47 (95% CI: 1.60-25.77)] were identified as predictors of amiodarone-induced hyperthyroidism. The baseline free thyroxine (T4) level [Adjusted OR 0.13 (95% CI: 0.03-0.68)], and thyroid-stimulating hormone (TSH) level [Adjusted OR1.47 (95% CI: 1.26-1.74)] were identified as predictors of amiodarone-induced hypothyroidism. CONCLUSION: DCM and cardiac sarcoidosis were identified as risk factors for amiodarone-induced hyperthyroidism. Risk factors for amiodarone-induced hypothyroidism included higher baseline TSH level and lower baseline free T4 level, suggesting that subclinical hypothyroidism may be a potential risk factor for the development of amiodarone-induced hypothyroidism.

Myocardial Immunocompetent Cells and Macrophage Phenotypes as Histopathological Surrogates for Diagnosis of Cardiac Sarcoidosis in Japanese.
Honda Y, Nagai T, Ikeda Y, Sakakibara M, Asakawa N, Nagano N, Nakai M, Nishimura K, Sugano Y, Ohta-Ogo K, Asaumi Y, Aiba T, Kanzaki H, Kusano K, Noguchi T, Yasuda S, Tsutsui H, Ishibashi-Ueda H, Anzai T
Journal of the American Heart Association, 5, 11, WILEY-BLACKWELL, 2016年11月17日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The histological diagnosis of cardiac sarcoidosis (CS) is based on the presence of myocardial granulomas; however, the sensitivity of endomyocardial biopsy is relatively low. We investigated whether immunocompetent cells including dendritic cells (DC) and macrophages in nongranuloma sections of endomyocardial biopsy samples could be histopathological surrogates for CS diagnosis. METHODS AND RESULTS: The numbers of DC and macrophages were investigated in 95 consecutive CS patients and 50 patients with nonischemic cardiomyopathy as controls. All patients underwent endomyocardial biopsy, and immunohistochemical staining was performed on all samples. We examined these immunocompetent cells in nongranuloma sections in CS patients diagnosed by the presence of myocardial granulomas (n=26) and in CS patients without myocardial granulomas diagnosed by the Japanese Ministry of Health Welfare 2007 criteria (n=65) or the Heart Rhythm Society 2014 criteria (n=26). In CS patients with and without myocardial granulomas, CD209+ DC and CD68+ macrophages were more frequently observed (P<0.01) and CD163+M2 macrophages were less frequently observed (P<0.01) in nongranuloma sections compared to controls. Furthermore, the combination of decreased CD163+M2/CD68+ macrophage ratio and increased number of CD209+ DC in nongranuloma sections of CS patients demonstrated high specificity (100%, 95% CI 92.7-100) for CS diagnosis with each diagnostic criteria and the presence of myocardial granulomas. CONCLUSIONS: Increased number of DC and decreased M2 among all macrophages in nongranuloma sections of myocardium showed high specificity for CS diagnosis, suggesting DC and macrophage phenotypes as histopathological surrogates for the diagnosis of CS.

Non-linear Equation using Plasma Brain Natriuretic Peptide Levels to Predict Cardiovascular Outcomes in Patients with Heart Failure.
Hiroki Fukuda, Hideaki Suwa, Atsushi Nakano, Mari Sakamoto, Miki Imazu, Takuya Hasegawa, Hiroyuki Takahama, Makoto Amaki, Hideaki Kanzaki, Toshihisa Anzai, Naoki Mochizuki, Akira Ishii, Hiroshi Asanuma, Masanori Asakura, Takashi Washio, Masafumi Kitakaze
Scientific reports, 6, 37073, 37073, NATURE PUBLISHING GROUP, 2016年11月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Brain natriuretic peptide (BNP) is the most effective predictor of outcomes in chronic heart failure (CHF). This study sought to determine the qualitative relationship between the BNP levels at discharge and on the day of cardiovascular events in CHF patients. We devised a mathematical probabilistic model between the BNP levels at discharge (y) and on the day (t) of cardiovascular events after discharge for 113 CHF patients (Protocol I). We then prospectively evaluated this model on another set of 60 CHF patients who were readmitted (Protocol II). P(t|y) was the probability of cardiovascular events occurring after >t, the probability on t was given as p(t|y) = -dP(t|y)/dt, and p(t|y) = pP(t|y) = αyβP(t|y), along with p = αyβ (α and β were constant); the solution was p(t|y) = αyβ exp(-αyβt). We fitted this equation to the data set of Protocol I using the maximum likelihood principle, and we obtained the model p(t|y) = 0.000485y0.24788 exp(-0.000485y0.24788t). The cardiovascular event-free rate was computed as P(t) = 1/60Σi=1,…,60 exp(-0.000485yi0.24788t), based on this model and the BNP levels yi in a data set of Protocol II. We confirmed no difference between this model-based result and the actual event-free rate. In conclusion, the BNP levels showed a non-linear relationship with the day of occurrence of cardiovascular events in CHF patients.

Prevalence, determinants, and prognostic significance of delirium in patients with acute heart failure.
Satoshi Honda, Toshiyuki Nagai, Yasuo Sugano, Atsushi Okada, Yasuhide Asaumi, Takeshi Aiba, Teruo Noguchi, Kengo Kusano, Hisao Ogawa, Satoshi Yasuda, Toshihisa Anzai
International journal of cardiology, 222, 521, 527, ELSEVIER IRELAND LTD, 2016年11月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Delirium is a serious syndrome in critically ill patients. However, the prognostic impact of delirium and its determinants in acute heart failure (AHF) patients have not been fully elucidated. METHODS: We examined 611 AHF patients who were admitted to our institution. Delirium was diagnosed based on the Intensive Care Delirium Screening Checklist (ICDSC). RESULTS: Delirium developed in 139 patients (23%) during hospitalization. Patients with delirium had higher incidence of non-cardiovascular death (p=0.046) and worsening heart failure (p<0.001) during hospitalization. Among patients who survived at discharge, the incidence of all-cause death, cardiovascular death and non-cardiovascular death after discharge were significantly higher in patients with delirium than those without (log-rank; p<0.001, p=0.001, p<0.001, respectively) during a median follow-up period of 335days. In multivariable model, the development of delirium was an independent determinant of worsening heart failure during hospitalization (OR: 2.44, 95% CI: 1.27-4.63) and all-cause death after discharge (HR: 2.38, 95% CI: 1.30-4.35). Furthermore, multivariate analysis indicated that history of cerebrovascular disease (OR: 2.13, 95% CI: 1.36-3.35), age (OR: 1.43, 95% CI: 1.15-1.80), log BNP (OR: 1.39, 95% CI: 1.09-1.79), serum albumin (OR: 0.84, 95% CI: 0.76-0.93) and blood glucose levels (OR: 1.03, 95% CI: 1.00-1.06) were independent determinants of delirium. CONCLUSION: In patients with AHF, the development of delirium was associated with poor clinical outcomes, suggesting the importance of early screening and careful monitoring of delirium in such patients.

Risk stratification based on nutritional screening on admission: Three-year clinical outcomes in hospitalized patients with acute heart failure syndrome.
Masashi Fujino, Hiroyuki Takahama, Toshimitsu Hamasaki, Kenichi Sekiguchi, Kengo Kusano, Toshihisa Anzai, Teruo Noguchi, Yoichi Goto, Masafumi Kitakaze, Hiroyuki Yokoyama, Hisao Ogawa, Satoshi Yasuda
Journal of cardiology, 68, 5, 392, 398, ELSEVIER SCIENCE BV, 2016年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Several blood tests are commonly used to assess nutritional status, including serum albumin levels (SAL) and lymphocyte counts (LC). The aim of this study is to investigate whether nutritional screening on admission can be used to determine risk levels for adverse clinical events in acute heart failure syndrome (AHFS) patients. METHODS: In 432 consecutive AHFS patients, we measured SAL and LC and prospectively followed the patients for their combined clinical events (all-cause death and re-hospitalization for heart failure) for three years from admission. The classification and regression tree (CART) tool identified the cut-off criteria for SAL and LC to differentiate among patients with different risks of clinical events as 3.5g/dl and 963/mm3, respectively. RESULTS: The CART tool classified 15.5% patients as high risk, 15.7% as intermediate risk, and 68.8% as low risk. The CART for nutritional status (CART-NS) values were strongly correlated with combined clinical events [hazard ratio of 2.13 (low vs high risk), 95% confidence interval of 1.42-3.16, p<0.001], even after adjusting for plasma brain natriuretic peptide levels. The CART-NS analysis improved the specificity (89.5%) of predictions of clinical outcomes with the comparable sensitivity (36.3%) compared with the use of a single criterion (SAL <3.5g/dl: 70.2, 42.4% or LC <963/mm3: 73.4, 41.7%, respectively). CONCLUSION: A substantial proportion of AHFS patients are at risk of malnutrition, and this risk is associated with poor clinical outcomes. We demonstrate that this algorithm for nutritional screening, even in emergency clinical settings, can determine risk levels for further adverse events in AHFS patients.

The Current Status of Cardiovascular Medicine in Japan - Analysis of a Large Number of Health Records From a Nationwide Claim-Based Database, JROAD-DPC.
Satoshi Yasuda, Kazuhiro Nakao, Kunihiro Nishimura, Yoshihiro Miyamoto, Yoko Sumita, Toshiaki Shishido, Toshihisa Anzai, Hiroyuki Tsutsui, Hiroshi Ito, Issei Komuro, Yoshihiko Saito, Hisao Ogawa
Circulation journal : official journal of the Japanese Circulation Society, 80, 11, 2327, 2335, JAPANESE CIRCULATION SOC, 2016年10月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Since cardiovascular disease accounts for one-quarter of deaths in the Japanese population, we developed a nationwide database using the administrative case-mix Diagnostic Procedure Combination (DPC) system (ie, theJapaneseRegistryOfAll cardiac and vascularDiseases (JROAD)-DPC) to reveal the current status of cardiovascular medicine in Japan.Methods and Results:The JROAD-DPC database included 704,593 health records' data of 2012 from 610 certificated hospitals of the Japanese Circulation Society. The 35,824 patients with acute myocardial infarction (AMI) and 108,665 patients with heart failure (HF) were admitted to hospitals. Increased hospital case volume was associated with reduced in-hospital mortality rates for both AMI and HF (P for trend <0.001). Although there was little variation among AMI patients in terms of aspirin use at discharge (median prescription rate, 83.0%; interquartile range [IQR], 76.9-88.0%), there were wide variations in the proportions of patients prescribed β-blockers (BB) and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin-receptor blockers (ARB) at discharge (BB, 41.4%, IQR 27.6-55.7%; ACEI/ARB, 52.0%, IQR 40.3-62.3%). In patients with HF, there were between-hospital variations in medications at discharge (BB, 38.1%, IQR, 27.8-47.6%; ACEI/ARB, 41.0%, IQR 31.7-49.1%). CONCLUSIONS: A nationwide administrative database of patients with cardiovascular diseases (JROAD-DPC) provided useful information that will contribute to improved quality of medical care, especially in the aging society of Japan, where HF has become an important health problem. (Circ J 2016; 80: 2327-2335).

Potentially Lethal Ventricular Arrhythmias and Heart Failure in Arrhythmogenic Right Ventricular Cardiomyopathy: What Are the Differences Between Men and Women?
Kimura Y, Noda T, Otsuka Y, Wada M, Nakajima I, Ishibashi K, Miyamoto K, Okamura H, Aiba T, Kamakura S, Noguchi T, Anzai T, Satomi K, Ogawa H, Yasuda S, Kusano KF
JACC. Clinical electrophysiology, 2, 5, 546, 555, 2016年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: The aim of this study was to assess sex-related differences in sporadic cases of arrhythmogenic right ventricular cardiomyopathy (ARVC). BACKGROUND: Previous studies have suggested male predominance in ARVC. However, the impact of sex on the heterogeneous clinical profile and prognosis of ARVC were not fully recognized. METHODS: The study population included 110 patients with ARVC who fulfilled the revised Task Force criteria (median age 48 years [interquartile range (IQR): 36 to 57 years]). All patients were sporadic cases without family history of ARVC. Male patients had a 3:1 predominance (75%). Ninety-seven patients (88%) were considered to have "definite" ARVC based on revised Task Force criteria. RESULTS: At the initial evaluation, there were no significant sex-related differences in age, 12-lead electrocardiogram findings, late potentials by signal-averaged electrocardiogram, left ventricular ejection fraction, or right ventricular ejection fraction. During a median follow-up of 10.0 years (IQR: 5.2 to 15.6 years), 18 patients died from cardiac causes. Kaplan-Meier analysis, considering patients' lives since birth, revealed that male patients had a significantly higher risk of ventricular tachycardia/ventricular fibrillation than did female patients (56% vs. 90%, p = 0.02), whereas female patients had a significantly higher risk of heart failure (HF) death or heart transplantation (22% vs. 5%, p = 0.002). On multivariate Cox regression analysis, female sex was an independent risk factor for HF death or heart transplantation due to HF (hazard ratio: 6.29, 95% confidence interval: 1.29 to 40.2; p = 0.02). CONCLUSIONS: Among patients with sporadic ARVC, men had a significantly higher risk of ventricular tachycardia/ventricular fibrillation, whereas women had a significantly higher risk of HF death or heart transplantation due to HF.

Diagnostic Value of Right Ventricular Dysfunction in Tachycardia-Induced Cardiomyopathy Using Cardiac Magnetic Resonance Imaging.
Atsushi Okada, Ikutaro Nakajima, Yoshiaki Morita, Yuko Y Inoue, Tsukasa Kamakura, Mitsuru Wada, Kohei Ishibashi, Koji Miyamoto, Hideo Okamura, Satoshi Nagase, Takashi Noda, Takeshi Aiba, Shiro Kamakura, Toshihisa Anzai, Teruo Noguchi, Satoshi Yasuda, Kengo Kusano
Circulation journal : official journal of the Japanese Circulation Society, 80, 10, 2141, 8, JAPANESE CIRCULATION SOC, 2016年09月23日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Predicting tachycardia-induced cardiomyopathy (TIC) in patients presenting with left ventricular (LV) dysfunction and tachyarrhythmias remains challenging. We assessed the diagnostic value of early right ventricular (RV) dysfunction to predict TIC using cardiac magnetic resonance (CMR) imaging. METHODS AND RESULTS: A total of 102 consecutive patients with newly diagnosed LV dysfunction and atrial tachyarrhythmias were examined. Patients whose LV ejection fraction (EF) improved to ≥50% during a 1-year follow-up were diagnosed with TIC, and with dilated cardiomyopathy (DCM) in those whose did not improve. CMR was performed at a median of 23 days after admission, and the TIC and DCM patients exhibited different distributions of EF and end-diastolic volume (EDV) between the LV and RV (both P<0.001, ANCOVA). TIC patients had significantly lower RVEF/LVEF ratio (1.01±0.23 vs. 1.36±0.31, P<0.001) and higher RVEDV/LVEDV ratio (0.96±0.21 vs. 0.73±0.19, P<0.001) compared with DCM patients, suggesting that RV systolic dysfunction and RV dilatation were observed in TIC. In the multivariate analysis, age, RVEF/LVEF ratio, and RVEDV/LVEDV ratio were significant predictors of TIC, and RVEF/LVEF ratio of <1.05 most highly predicted TIC with a sensitivity of 69.1% and specificity of 91.5% (area under the curve 0.860). CONCLUSIONS: Among patients with newly diagnosed LV dysfunction and atrial tachyarrhythmias, age and coexistence of RV dysfunction was a strong predictor of TIC. (Circ J 2016; 80: 2141-2148).

Validation of the Coronary Artery Bypass Graft SYNTAX Score (Synergy Between Percutaneous Coronary Intervention With Taxus) as a Prognostic Marker for Patients With Previous Coronary Artery Bypass Graft Surgery After Percutaneous Coronary Intervention.
Tadayoshi Miyagi, Yasuhide Asaumi, Kunihiro Nishimura, Takahiro Nakashima, Hiroki Sakamoto, Kazuhiro Nakao, Tomoaki Kanaya, Toshiyuki Nagai, Yuji Shimabukuro, Yoshihiro Miyamoto, Tomoyuki Fujita, Kengo Kusano, Toshihisa Anzai, Junjirou Kobayashi, Teruo Noguchi, Hisao Ogawa, Satoshi Yasuda
Circulation. Cardiovascular interventions, 9, 9, LIPPINCOTT WILLIAMS & WILKINS, 2016年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The efficacy and prognosis of percutaneous coronary intervention (PCI) as secondary revascularization in patients with previous coronary artery bypass graft surgery remain uncertain. METHODS AND RESULTS: We retrospectively evaluated 434 consecutive patients with previous coronary artery bypass graft surgery hospitalized for PCI between 2004 and 2011 (men 84%, age 71 (interquartile range, 66-76) years) and calculated the coronary artery bypass graft Synergy Between Percutaneous Coronary Intervention With Taxus score (CSS) before (baseline CSS) and after PCI (post-PCI CSS). Patients were divided into 2 groups based on median post-PCI CSS: low-score (≤23; n=217) and high-score groups (>23; n=217). Major adverse cardiovascular events (MACE) were defined as the composite of cardiovascular death, myocardial infarction, and unplanned repeat revascularization for myocardial ischemia. The median baseline and post-PCI CSS were 30 (interquartile range, 21-40) and 23 (interquartile range, 14.5-33.5), respectively. During a median follow-up of 69 months, the prevalence of MACE and cardiac death differed significantly between the 2 post-PCI CSS groups (MACE: low, 13.8%; high, 28.6%; P<0.001; cardiac death: low, 6.2%; high, 16.7%; P=0.002). In multivariable analysis, the high post-PCI CSS divided by the median was associated with substantially greater cumulative MACE (hazard ratio, 2.09; 95% confidence interval, 1.31-3.34; P=0.002) and cardiac death (hazard ratio, 2.02; 95% confidence interval, 1.03-3.98; P=0.042) compared with the low post-PCI CSS. Net reclassification improvement analysis revealed that post-PCI CSS resulted in significantly improved prediction of MACE and cardiac death compared with baseline CSS. CONCLUSIONS: In this external validation study, the CSS was a potential prognostic factor after subsequent PCI, even for previous coronary artery bypass graft surgery patients.

Subclinical hypothyroidism is an independent predictor of adverse cardiovascular outcomes in patients with acute decompensated heart failure.
Tomohiro Hayashi, Takuya Hasegawa, Hideaki Kanzaki, Akira Funada, Makoto Amaki, Hiroyuki Takahama, Takahiro Ohara, Yasuo Sugano, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
ESC heart failure, 3, 3, 168, 176, 2016年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Altered thyroid hormone metabolism characterized by a low triiodothyronine (T3), so-called low-T3 syndrome, is a common finding in patients with severe systemic diseases. Additionally, subclinical thyroid dysfunction, defined as abnormal thyroid stimulating hormone (TSH) and normal thyroxine (T4), causes left ventricular dysfunction. Our objective was to identify the prevalence and prognostic impact of low-T3 syndrome and subclinical thyroid dysfunction in patients with acute decompensated heart failure (ADHF). METHODS AND RESULTS: We examined 274 ADHF patients who were not receiving thyroid medication or amiodarone on admission (70 ± 15 years, 156 male), who underwent thyroid function tests. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L; subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L; and subclinical hyperthyroidism as TSH < 0.45 mIU/L, with normal free T4 level for the last two. Additionally, low-T3 syndrome was defined as free T3 < 4.0 pmol/L among euthyroidism subjects. On admission, 188 patients (69%) showed euthyroidism, 58 (21%) subclinical hypothyroidism, 5 (2%) subclinical hyperthyroidism, and 95 (35%) low-T3 syndrome. Cox proportional hazards models revealed that higher TSH, but not free T3 and free T4, was independently associated with composite cardiovascular events, including cardiac death and re-hospitalization for heart failure. Indeed, subclinical hypothyroidism was an independent predictor (hazard ratio: 2.31; 95% confidence interval: 1.44 to 3.67; P < 0.001), whereas low-T3 syndrome and subclinical hyperthyroidism were not. CONCLUSIONS: Subclinical hypothyroidism on admission was an independent predictor of adverse cardiovascular outcomes in ADHF patients, suggesting a possible interaction between thyroid dysfunction and the pathophysiology of ADHF.

Usefulness of Geriatric Nutritional Risk Index for Assessing Nutritional Status and Its Prognostic Impact in Patients Aged ≥65 Years With Acute Heart Failure.
Honda Y, Nagai T, Iwakami N, Sugano Y, Honda S, Okada A, Asaumi Y, Aiba T, Noguchi T, Kusano K, Ogawa H, Yasuda S, Anzai T, NaDEF investigators
The American journal of cardiology, 118, 4, 550, 5, EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC, 2016年08月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Malnutrition is becoming one of the most important determinants of worse clinical outcomes in patients with acute heart failure (AHF). However, appropriate tools for evaluating the nutritional status in patients aged ≥65 years with AHF remain unclear. We examined 490 consecutive patients aged ≥65 years with AHF. They were divided into 2 groups according to Geriatric Nutritional Risk Index (GNRI; cut-off value = 92). During a median period of 189 days, the mortality rate was significantly higher in the lower GNRI group than the higher GNRI group (p <0.001). In multivariate analyses, lower GNRI was an independent determinant of adverse events (HR 0.92, 95% CI 0.88 to 0.95, p <0.001). The GNRI showed the best prognostic value (C-statistic: 0.70) among other nutritional indexes. Adding GNRI to an existing outcome prediction model for mortality in AHF significantly increased the C-statistic from 0.68 to 0.74 (p = 0.017). The net reclassification improvement afforded by GNRI was 60% overall, 27% for events, and 33% for nonevents (p <0.001). In conclusion, lower GNRI on admission was independently associated with worse clinical outcomes in patients aged ≥65 years with AHF, and it was superior to other nutritional parameters. Furthermore, the assessment of nutritional status using GNRI is very helpful for risk stratification.

Impact of B-type natriuretic peptide (BNP) on development of atrial fibrillation in people with Type 2 diabetes
I. Kishimoto, H. Makino, Y. Ohata, T. Tamanaha, M. Tochiya, K. Kusano, T. Anzai, K. Toyoda, S. Yasuda, K. Minematsu, H. Ogawa
Diabetic Medicine, 33, 8, 1118, 1124, 2016年08月01日
研究論文（学術雑誌）, Aims: To examine if a simple biomarker can identify people with diabetes who are at high risk of atrial fibrillation. Methods: A retrospective cohort study was conducted at a single centre in people with Type 2 diabetes referred to our department between January 2000 and December 2007. In 517 consecutive people without any history, signs or symptoms of atrial fibrillation at baseline, the association between baseline B-type natriuretic peptide level and future atrial fibrillation incidence was examined, with adjustments for other potentially confounding factors. Results: A total of 28 people were diagnosed with new-onset atrial fibrillation during a median 6-year follow-up. When people were categorized into three groups according to B-type natriuretic peptide clinical thresholds (20 and 100 pg/ml), hazard ratios for the development of atrial fibrillation in the middle and highest B-type natriuretic peptide groups were 2.8 and 9.4, respectively, compared with the lowest B-type natriuretic peptide group. Time-dependent receiver-operating curve analysis identified a threshold for B-type natriuretic peptide to detect atrial fibrillation development of 52.8 pg/ml (sensitivity 75.2%, specificity 68.8%). The B-type natriuretic peptide predictive value was independent of and similar to that of left atrial size and ventricular dimension. Conclusion: In people with Type 2 diabetes, high baseline B-type natriuretic peptide levels were significantly associated with future atrial fibrillation development.

[NYHA functional classification and AHA/ACC Stages for heart failure management].
Nagai T, Anzai T
Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology, 74 Suppl 6, 340, 344, 2016年08月, ［査読有り］

[NYHA functional classification and AHA/ACC Stages for heart failure management].
Toshiyuki Nagai, Toshihisa Anzai
Nihon rinsho. Japanese journal of clinical medicine, 74 Suppl 6, 340, 4, 2016年08月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）

Larger low voltage zone in endocardial unipolar map compared with that in epicardial bipolar map indicates difficulty in eliminating ventricular tachycardia by catheter ablation.
Koji Miyamoto, Takashi Noda, Kazuhiro Satomi, Mitsuru Wada, Ikutaro Nakajima, Kohei Ishibashi, Hideo Okamura, Teruo Noguchi, Toshihisa Anzai, Satoshi Yasuda, Hisao Ogawa, Wataru Shimizu, Takeshi Aiba, Shiro Kamakura, Kengo Kusano
Heart and vessels, 31, 8, 1337, 46, SPRINGER, 2016年08月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Patients with ischemic and non-ischemic cardiomyopathy often have substrate for ventricular tachycardia (VT) in the endocardium (ENDO), epicardium (EPI), and/or intramural. Although it has been reported that the ENDO unipolar (UNI) voltage map is useful in detecting EPI substrate, its feasibility to detect intramural scarring and its usefulness in radiofrequency catheter ablation (RFCA) remain unclear. To assess the relationship between the left ventricle (LV) ENDO UNI voltage map and the LV EPI bipolar (BIP) voltage map, and to determine the usefulness of the ENDO UNI voltage map to guide RFCA for VT in patients with cardiomyopathy undergoing combined ENDO- and EPI RFCA. Eleven patients with VT undergoing detailed ENDO and EPI electroanatomical mapping of the LV were included (mean age 59 ± 11 years, 9 men). We assessed the value of the LV ENDO UNI voltage map in identifying EPI and/or intramural substrate in these 11 patients with non-ischemic or ischemic cardiomyopathy. The underlying heart disease was dilated cardiomyopathy in 4 patients, cardiac sarcoidosis in 3, hypertrophic cardiomyopathy in 2, and ischemic heart disease in 2 patients. The mean LV ejection fraction was 24 ± 7 %. The low voltage zone (LVZ) was defined as <1.5 mV for LV ENDO BIP electrograms (EGMs), <8.3 mV for LV ENDO UNI EGMs, and <1.0 mV for LV EPI BIP EGMs. The surface area of each LVZ was measured. We also measured the LVZ of the spatial overlap between ENDO UNI and EPI BIP voltage maps using the transparency mode on CARTO software. We performed RFCA at the ENDO and EPI based on activation and/or substrate maps, targeting the LVZ and/or abnormal EGMs. The LVZ was present in the LV ENDO BIP voltage map in 10 of 11 patients (42 ± 33 cm(2)), and in the LV ENDO UNI voltage map in 10 of 11 patients (72 ± 45 cm(2)). The LVZ was present in the EPI BIP voltage map in 9 of 11 patients (70 ± 61 cm(2)), and the LVZ in the ENDO UNI voltage map was also seen in all 9 patients. The location of the LVZ in the EPI BIP map matched that in 45 ± 28 % of ENDO UNI voltage maps. The LVZ in the ENDO UNI voltage map was larger than that in the EPI BIP voltage map in 6 of 11 patients, and RFCA failed in 5 of these 6 patients. In the remaining 5 patients with a smaller LVZ in the ENDO UNI voltage map compared with the EPI BIP voltage map or no LVZ both at ENDO UNI and EPI BIP voltage map, VT was successfully eliminated in 4 of 5 patients. The LV ENDO UNI voltage map is useful in detecting EPI substrate in patients with cardiomyopathy. A larger LVZ in the ENDO UNI voltage map compared to that in the EPI BIP voltage map may indicate the presence of intramural substrate, which leads to difficulty in eliminating VT, even with combined ENDO- and EPI RFCA.

Impact of renal function deterioration on adverse events during anticoagulation therapy using non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
Koji Miyamoto, Takeshi Aiba, Shoji Arihiro, Makoto Watanabe, Yoshihiro Kokubo, Kohei Ishibashi, Sayako Hirose, Mitsuru Wada, Ikutaro Nakajima, Hideo Okamura, Takashi Noda, Kazuyuki Nagatsuka, Teruo Noguchi, Toshihisa Anzai, Satoshi Yasuda, Hisao Ogawa, Shiro Kamakura, Wataru Shimizu, Yoshihiro Miyamoto, Kazunori Toyoda, Kengo Kusano
Heart and vessels, 31, 8, 1327, 36, SPRINGER, 2016年08月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Renal function is crucial for patients with non-valvular atrial fibrillation (NVAF) using non-vitamin K antagonist oral anticoagulants (NOAC). The incidence of renal function deterioration during anticoagulation therapy and its impact of adverse events are unknown. In 807 consecutive NVAF patients treated with NOAC and with estimated creatinine clearance (eCCr) ≥ 50 ml/min (mean age 68 ± 11 years, mean CHADS2 score = 1.8 ± 1.4, CHA2DS2-VASc score = 2.8 ± 1.8, HAS-BLED score = 1.7 ± 1.1), we analyzed the time course of renal function and clinical outcomes, and compared these with the data of general Japanese inhabitants from the Suita Study (n = 2140). Of the 807 patients, 751 (93 %) maintained eCCr ≥ 50 ml/min (group A) whereas the remaining 56 (7 %) fell into the eCCr < 50 ml/min (group B) during the 382 ± 288 days of follow-up. Multivariate logistic regression analysis revealed that advanced age, lower body weight, and congestive heart failure were independent predictors for renal function deterioration in patients with eCCr ≥ 50 ml/min at baseline. Major and/or minor bleedings were more commonly observed in group B than in group A (21 vs. 8 %; P = 0.0004). The CHADS2, CHA2DS2-VASc, and HAS-BLED scores were also significant predictors of renal function deterioration (P < 0.0001). The incidences of renal function deterioration were 1.4, 3.4, 10.5 and 11.7 % in patients with CHADS2 score of 0, 1, 2 and ≥3, respectively. As to CHA2DS2-VASc score, renal function deterioration occurred in 0, 1.7, 9.8 and 15.0 % with a score of 0, 1-2, 3-4 and ≥5, respectively. In the Suita Study of the general population, on the other hand, 122 of 2140 participants with eCCr ≥ 50 ml/min at baseline (5.7 %) fell into the eCCr < 50 ml/min during about 2 years. The incidence of renal function deterioration increased with the CHADS2 score in the general population as well as in our patients. Renal function deterioration was not uncommon and was associated with more frequent adverse events including major bleeding in NVAF patients with anticoagulation therapy. CHADS2, CHA2DS2-VASc, and HAS-BLED scores may be useful as an index of predicting renal function deterioration.

Inflammatory dilated cardiomyopathy　　　　　　　　　　　　　　　
Yasuo Sugano, Toshihisa Anzai
Respiration and Circulation, 64, 7, 655, 661, Igaku-Shoin Ltd, 2016年07月01日
日本語, 研究論文（学術雑誌）

Novel chemiluminescent enzyme immunoassays for individual quantification of three endogenous molecular forms of atrial natriuretic peptide in human plasma.
Nagai-Okatani C, Kangawa K, Takashio S, Takahama H, Hayashi T, Anzai T, Minamino N
The Journal of Applied Laboratory Medicine, 1, 1, 47, 59, 2016年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are cardiac peptide hormones with pivotal roles in maintaining cardiovascular homeostasis. BNP and its precursor fragment are accepted as gold standard markers for heart failure (HF). Human ANP is present in the atria of the heart and plasma as 3 endogenous molecular forms designated α-ANP, β-ANP, and proANP. A previous study indicated that the ratios of these 3 ANP forms are altered in the plasma of HF patients. The purpose of our study was to establish immunoassays for quantifying the individual ANP forms to collect clinical information. METHODS: We developed 3 plate-based chemiluminescent enzyme immunoassays (CLEIAs) for measuring total ANP (i.e., sum of α-ANP, β-ANP, and proANP), β-ANP, and proANP levels. To minimize background signals, we added single-step PEGylation targeting the immobilized antibody in the conventional plate-based sandwich CLEIA procedure. RESULTS: CLEIAs with PEGylation showed sensitivity, specificity, reproducibility, and accuracy satisfying clinical requirements. Two of the CLEIAs enabled direct measurement in plasma samples. During treatments, acute decompensated HF patients exhibited marked decreases in plasma β-ANP levels but moderate decreases in plasma proANP level. The plasma ratios of α-ANP/total ANP and proANP/total ANP in acute decompensated HF patients were maintained, whereas the β-ANP/total ANP ratio was significantly decreased at discharge. CONCLUSIONS: The combination of the 3 CLEIAs enabled accurate quantification of α-ANP, β-ANP, and proANP, even in plasma samples, and indicated the potential of β-ANP and proANP as circulating biomarkers for HF, with different characteristics from that of BNP.

Renovascular heart failure: heart failure in patients with atherosclerotic renal artery disease.
Osami Kawarada, Satoshi Yasuda, Teruo Noguchi, Toshihisa Anzai, Hisao Ogawa
Cardiovascular intervention and therapeutics, 31, 3, 171, 82, 2016年07月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Atherosclerotic renal artery disease presents with a broad spectrum of clinical features, including heart failure as well as hypertension, and renal failure. Although recent randomized controlled trials failed to demonstrate renal artery stenting can reduce blood pressure or the number of cardiovascular or renal events more so than medical therapy, increasing attention has been paid to flash pulmonary edema and congestive heart failure associated with atherosclerotic renal artery disease. This clinical entity "renovascular heart failure" is diagnosed retrospectively. Given the increasing global burden of heart failure, this review highlights the background and catheter-based therapeutic aspects for renovascular heart failure.

Prognostic significance of endogenous erythropoietin in long-term outcome of patients with acute decompensated heart failure.
Toshiyuki Nagai, Kunihiro Nishimura, Takehiro Honma, Aya Higashiyama, Yasuo Sugano, Michikazu Nakai, Satoshi Honda, Naotsugu Iwakami, Atsushi Okada, Shoji Kawakami, Tomoaki Kanaya, Yasuhide Asaumi, Takeshi Aiba, Yoko Nishida, Yoshimi Kubota, Daisuke Sugiyama, Tomonori Okamura, Teruo Noguchi, Kengo Kusano, Hisao Ogawa, Satoshi Yasuda, Toshihisa Anzai
European journal of heart failure, 18, 7, 803, 13, WILEY-BLACKWELL, 2016年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Although previous reports suggest that an elevated endogenous erythropoietin (EPO) level is associated with worse clinical outcomes in chronic heart failure (HF) patients, the prognostic implication of EPO in patients with acute decompensated HF (ADHF) and underlying mechanisms of the high EPO level in severe HF patients who have a poor prognosis remain unclear. METHODS AND RESULTS: We examined 539 consecutive ADHF patients with EPO measurement on admission from our registry. During a median follow-up period of 329 days, a higher EPO level on admission was independently associated with worse clinical outcomes [hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.06-1.48, P = 0.008], and haemoglobin level was the strongest determinant of EPO level (P < 0.001), whereas estimated glomerular filtration rate (eGFR) was not significant in multivariate regression analysis. In the anaemic subgroup of 318 patients, a higher EPO level than expected on the basis of their haemoglobin level was related to increased adverse events (HR 1.63, 95% CI 1.05-2.49, P = 0.028). Moreover, estimated plasma volume excess rate was positively associated with EPO level (P = 0.003), and anaemic patients with a higher than expected EPO level tended to have a higher estimated plasma volume excess rate and plasma lactate level, and lower systemic oxygen saturation level with the preservation of the reticulocyte production index than those with a lower than expected EPO level. CONCLUSION: A high EPO level predicts long-term worse clinical outcomes in ADHF patients, independent of anaemia and impaired renal function. Anaemia and hypoxia due to severe congestion may synergistically contribute to a high EPO level in high-risk HF patients.

The predictability of renin-angiotensin-aldosterone system factors for clinical outcome in patients with acute decompensated heart failure.
Yasuki Nakada, Hiroyuki Takahama, Hideaki Kanzaki, Yasuo Sugano, Takuya Hasegawa, Takahiro Ohara, Makoto Amaki, Akira Funada, Akemi Yoshida, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
Heart and vessels, 31, 6, 925, 31, SPRINGER, 2016年06月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Although counter-regulation between B-type natriuretic peptide (BNP) levels and renin-angiotensin-aldosterone system (RAAS) activation in heart failure (HF) has been suggested, whether the regulation is preserved in acute decompensated heart failure (ADHF) patients remains unclear. This study aimed to determine: (1) the relationship between RAAS activation and clinical outcomes in ADHF patients, and (2) the relationships between plasma BNP levels and degrees of activation in RAAS factors. This study included ADHF patients (n = 103, NYHA3-4, plasma BNP > 200 pg/ml). We studied the predictability of RAAS factors for cardiovascular events and the relationships between plasma BNP levels and the degrees of activation in RAAS factors, which were evaluated by plasma renin activity (PRA) and aldosterone concentration (PAC). PRA was a strong predictor of cardiovascular (CV) events over 1 year, even after accounting for plasma BNP levels (hazard ratio (HR): 1.04, CI [1.02-1.06], p < 0.01) and medication such as RAAS blockers (HR: 1.03, CI [1.01-1.05], p < 0.01), whereas PAC was borderline-significant (univariate analysis, p = 0.06). Cut-off value of PRA (5.3 ng/ml/h) was determined by AUC curve. Of the enrolled patients, higher PRA was found in 40 % of them. Although no correlation between the plasma BNP levels and PRA was found (p = 0.36), after adjusting for hemodynamic parameters, eGFR and medication, a correlation was found between them (p = 0.01). Elevated RAAS factors were found in a substantial number of ADHF patients with high plasma BNP levels in the association with hemodynamic state, which predicts poor clinical outcomes. The measurements of RAAS factors help to stratify ADHF patients at risk for further CV events.

Prognostic significance of late gadolinium enhancement quantification in cardiac magnetic resonance imaging of hypertrophic cardiomyopathy with systolic dysfunction.
Akira Funada, Hideaki Kanzaki, Teruo Noguchi, Yoshiaki Morita, Yasuo Sugano, Takahiro Ohara, Takuya Hasegawa, Hiromi Hashimura, Hatsue Ishibashi-Ueda, Masafumi Kitakaze, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
Heart and vessels, 31, 5, 758, 70, SPRINGER, 2016年05月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Hypertrophic cardiomyopathy (HCM) with systolic dysfunction carries a poor prognosis. Although late gadolinium enhancement (LGE) on cardiac magnetic resonance is associated with adverse cardiac events in HCM and is inversely related to left ventricular ejection fraction (LVEF), it is unknown whether LGE or LVEF more accurately predicts adverse cardiac events in HCM with systolic dysfunction. We retrospectively assessed the extent of LGE with a threshold of 6 standard deviations in 46 consecutive HCM patients with systolic dysfunction defined as LVEF <50 % (average 35 ± 12 %) who underwent cardiac magnetic resonance (35 males, mean age 59 ± 14 years). They were followed up over 1755 ± 594 days. The composite adverse cardiac events end point included cardiovascular death, lethal arrhythmia, cardioembolic stroke, and unplanned heart failure hospitalization. LGE was detected in all patients, and the mean extent was 30 ± 15 %. Twenty-nine patients developed adverse cardiac events. Multivariate Cox proportional hazard analysis revealed the extent of LGE as a good independent predictor of adverse cardiac events. Risk increased with the extent of LGE (hazard ratio = 1.62/10 % increase in LGE, 95 % confidence interval = 1.23-2.15, p < 0.001). LVEF was inversely related to the extent of LGE (r = -0.44; p = 0.002) and was also an independent predictor of adverse cardiac events. Risk decreased with LVEF (hazard ratio = 0.68/10 % increase in LVEF, 95 % confidence interval = 0.51-0.91, p = 0.010). The Akaike information criterion evaluating the fit of a model demonstrated that the extent of LGE was a better independent predictor of MACE than LVEF (Akaike information criterion = 172.20 and 178.09, respectively).The extent of LGE was a good independent predictor of adverse cardiac events and reflected mortality and morbidity more precisely than LVEF in HCM with systolic dysfunction.

Erratum to: Prognostic significance of late gadolinium enhancement quantification in cardiac magnetic resonance imaging of hypertrophic cardiomyopathy with systolic dysfunction.
Akira Funada, Hideaki Kanzaki, Teruo Noguchi, Yoshiaki Morita, Yasuo Sugano, Takahiro Ohara, Takuya Hasegawa, Hiromi Hashimura, Hatsue Ishibashi-Ueda, Masafumi Kitakaze, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
Heart and vessels, 31, 5, 771, 772, SPRINGER, 2016年05月, ［査読有り］, ［国内誌］
英語

Exhaled Acetone Concentration Is Related to Hemodynamic Severity in Patients With Non-Ischemic Chronic Heart Failure.
Tetsuro Yokokawa, Yasuo Sugano, Akito Shimouchi, Atsushi Shibata, Naoya Jinno, Toshiyuki Nagai, Hideaki Kanzaki, Takeshi Aiba, Kengo Kusano, Mikiyasu Shirai, Yasuchika Takeishi, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 80, 5, 1178, 86, JAPANESE CIRCULATION SOC, 2016年04月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: We hypothesized that exhaled acetone concentration (EAC), reflecting altered blood ketone body metabolism and increased acetone exhaust because of pulmonary congestion in heart failure (HF), would correlate with hemodynamic parameters in patients with non-ischemic chronic HF. METHODS AND RESULTS: We prospectively enrolled 102 non-ischemic HF patients with New York Heart Association (NYHA) class I-III. Exhaled breath was collected after an overnight fast. Echocardiography and cardiac catheterization were performed in all patients. We also enrolled 17 control patients without HF. EAC in the HF patients was significantly higher than that in the control patients (median EAC; 0.53 vs. 0.38 ppm, P=0.012). EAC positively correlated with blood total ketone bodies (r=0.454, P<0.001), NYHA class (r=0.489, P<0.001), and plasma B-type natriuretic peptide (r=0.316, P=0.001). Right heart catheterization revealed that EAC significantly correlated with pulmonary capillary wedge pressure (PCWP, r=0.377, P<0.001). Receiver-operating characteristic analysis revealed that EAC >1.05 ppm was associated with PCWP ≥18 mmHg (area under the curve [AUC] 0.726, sensitivity 50%, specificity 89%). EAC was shown to be a comparable diagnostic biomarker for HF to BNP (AUC 0.760, sensitivity 80%, specificity 70%). CONCLUSIONS: EAC may be a novel noninvasive biomarker that correlates hemodynamic severity in non-ischemic chronic HF. (Circ J 2016; 80: 1178-1186).

Rationale and design of a randomized trial to test the safety and non-inferiority of canagliflozin in patients with diabetes with chronic heart failure: the CANDLE trial.
Atsushi Tanaka, Teruo Inoue, Masafumi Kitakaze, Jun-Ichi Oyama, Masataka Sata, Isao Taguchi, Wataru Shimizu, Hirotaka Watada, Hirofumi Tomiyama, Junya Ako, Yasushi Sakata, Toshihisa Anzai, Masaaki Uematsu, Makoto Suzuki, Kazuo Eguchi, Akira Yamashina, Yoshihiko Saito, Yasunori Sato, Shinichiro Ueda, Toyoaki Murohara, Koichi Node
Cardiovascular diabetology, 15, 57, 57, BIOMED CENTRAL LTD, 2016年04月04日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Because type 2 diabetes mellitus is associated strongly with an increased risk of cardiovascular diseases, the number of patients with diabetes with chronic heart failure is increasing steadily. However, clinical evidence of therapeutic strategies in such patients is still lacking. A recent randomized, placebo-controlled trial in patients with type 2 diabetes with high cardiovascular risk demonstrated that the SGLT2 inhibitor, empagliflozin, reduced the incidence of hospitalization for heart failure. Because SGLT2 inhibitors cause a reduction in body weight and blood pressure in addition to improving glycemic control, they have the potential to exert beneficial effects on the clinical pathophysiology of heart failure. The aim of the ongoing CANDLE trial is to test the safety and non-inferiority of canagliflozin, another SGLT2 inhibitor, compared with glimepiride, a sulfonylurea agent, in patients with type 2 diabetes mellitus and chronic heart failure. METHODS: A total of 250 patients with type 2 diabetes who are drug-naïve or taking any anti-diabetic agents and suffering from chronic heart failure with a New York Heart Association classification I to III will be randomized centrally into either canagliflozin or glimepiride groups (1: 1) using the dynamic allocation method stratified by age (<65, ≥65 year), HbA1c level (<6.5, ≥6.5 %), and left ventricular ejection fraction (<40, ≥40 %). After randomization, all the participants will be given the add-on study drug for 24 weeks in addition to their background therapy. The primary endpoint is the percentage change from baseline in NT-proBNP after 24 weeks of treatment. The key secondary endpoints after 24 weeks of treatment are the change from baseline in glycemic control, blood pressure, body weight, lipid profile, quality of life score related to heart failure, and cardiac and renal function. DISCUSSION: The CANDLE trial is the first to assess the safety and non-inferiority of canagliflozin in comparison with glimepiride in patients with type 2 diabetes with chronic heart failure. This trial has the potential to evaluate the clinical safety and efficacy of canagliflozin on heart failure. Trial registration Unique trial Number, UMIN000017669.

Significance of myocardial tenascin-C expression in left ventricular remodelling and long-term outcome in patients with dilated cardiomyopathy.
Tetsuro Yokokawa, Yasuo Sugano, Takafumi Nakayama, Toshiyuki Nagai, Taka-Aki Matsuyama, Keiko Ohta-Ogo, Yoshihiko Ikeda, Hatsue Ishibashi-Ueda, Takeshi Nakatani, Satoshi Yasuda, Yasuchika Takeishi, Hisao Ogawa, Toshihisa Anzai
European journal of heart failure, 18, 4, 375, 85, WILEY-BLACKWELL, 2016年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIM: Dilated cardiomyopathy (DCM) has a variety of causes, and no useful approach to predict left ventricular (LV) remodelling and long-term outcome has yet been established. Myocardial tenascin-C (TNC) is known to appear under pathological conditions, possibly to regulate cardiac remodelling. The aim of this study was to clarify the significance of myocardial TNC expression in LV remodelling and the long-term outcome in DCM. METHODS AND RESULTS: One hundred and twenty-three consecutive DCM patients who underwent endomyocardial biopsy for initial diagnosis were studied. Expression of TNC in biopsy sections was analysed immunohistochemically to quantify the ratio of the TNC-positive area to the whole myocardial tissue area (TNC area). Clinical parameters associated with TNC area were investigated. The patients were divided into two groups based on receiver operating characteristic analysis of TNC area to predict death: high TNC group with TNC area ≥2.3% (22 patients) and low TNC group with TNC area <2.3% (101 patients). High TNC was associated with diabetes mellitus. Comparing echocardiographic findings between before and 9 months after endomyocardial biopsy, the low TNC group was associated with decreased LV end-diastolic diameter and increased LV ejection fraction, whereas the high TNC group was not. Survival analysis revealed a worse outcome in the high TNC group than in the low TNC group (P < 0.001). Multivariable Cox regression analysis revealed that TNC area was independently associated with poor outcome (HR = 1.347, P = 0.032). CONCLUSIONS: Increased myocardial TNC expression was associated with worse LV remodeling and long-term outcome in DCM.

Practical applicability of landiolol, an ultra-short-acting β1-selective blocker, for rapid atrial and ventricular tachyarrhythmias with left ventricular dysfunction.
Wada Y, Aiba T, Tsujita Y, Itoh H, Wada M, Nakajima I, Ishibashi K, Okamura H, Miyamoto K, Noda T, Sugano Y, Kanzaki H, Anzai T, Kusano K, Yasuda S, Horie M, Ogawa H
Journal of arrhythmia, 32, 2, 82, 8, 2016年04月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Landiolol effectively controls rapid heart rate in atrial fibrillation or flutter (AF/AFL) patients with left ventricular (LV) dysfunction. However, predicting landiolol Responders and Non-Responders and patients who will experience adverse effects remains a challenge. The aim of this study was to clarify the potential applicability of landiolol for rapid AF/AFL and refractory ventricular tachyarrhythmias (VTs) in patients with heart failure. METHODS: A total of 39 patients with AF/AFL with ventricular response ≥120 bpm and 12 VTs were retrospectively enrolled. Landiolol Responders for rapid AF/AFL were defined as patients whose ventricular response was suppressed to less than 110 bpm or decreased by ≥20% from the initial heart rate after administration of landiolol. Responders for VTs were defined as patients with no recurrent VTs during the 24 h after the initiation of landiolol. RESULTS: For AF/AFL, 29 patients (74%) were Responders. In nine patients (31%), AF was spontaneously terminated after starting landiolol. Eight Non-Responders (80%) needed to have AF terminated by cardioversion. Left ventricular ejection fraction (LVEF) at baseline was significantly associated with landiolol efficacy. For VTs, seven patients (58%) were Responders, and smaller LV diastolic and systolic diameters were associated with landiolol efficacy. Hypotension after landiolol treatment occurred in 5 of 51 patients, and lower LV systolic function was associated with the development of adverse events. CONCLUSIONS: Landiolol is effective in patients with heart failure not only due to rapid AF/AFL but also due to VTs. However, preserved LVEF is important for efficacy and safety in landiolol treatment.

Effect of Discontinuation of Prednisolone Therapy on Risk of Cardiac Mortality Associated With Worsening Left Ventricular Dysfunction in Cardiac Sarcoidosis.
Toshiyuki Nagai, Nobutaka Nagano, Yasuo Sugano, Yasuhide Asaumi, Takeshi Aiba, Hideaki Kanzaki, Kengo Kusano, Teruo Noguchi, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
The American journal of cardiology, 117, 6, 966, 71, EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC, 2016年03月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Prednisolone (PSL) therapy is the gold standard treatment in patients with cardiac sarcoidosis (CS). However, clinicians often have difficulty in deciding whether to discontinue PSL therapy in long-term management. Sixty-one consecutive patients with CS were divided into 2 groups based on the discontinuation of PSL during the median follow-up period of 9.9 years. PSL was discontinued in 12 patients because of improvement of clinical findings. There were no significant differences between the 2 groups in age, gender, left ventricular ejection fraction (LVEF), findings of imaging techniques, incidence of fatal arrhythmias and heart failure, and dose of PSL. After discontinuation of PSL, 5 patients had cardiac death, and discontinuation of PSL was significantly associated with higher cardiac mortality compared with continuation (p = 0.035). Although patients with discontinuation had improvement of LVEF after PSL treatment, LVEF decreased after discontinuation of PSL. Furthermore, discontinuation of PSL was associated with greater percent decrease in LVEF compared with continuation (p = 0.037) during the follow-up period. In conclusion, in the long-term management of patients with CS, discontinuation of PSL was associated with poor clinical outcomes and decreased LVEF, suggesting the importance of PSL maintenance therapy.

Intracardiac echocardiography to diagnose pannus formation after aortic valve replacement.
Yoshiya Yamamoto, Takahiro Ohara, Akira Funada, Hiroyuki Takahama, Makoto Amaki, Takuya Hasegawa, Yasuo Sugano, Hideaki Kanzaki, Toshihisa Anzai
Journal of echocardiography, 14, 1, 39, 41, 2016年03月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 66-year-old female, under regular follow-up for 20 years after aortic valve replacement (19-mm Carbomedics), presented dyspnea on effort and hypotension during hemodialysis. A transthoracic echocardiogram showed elevation of transvalvular velocity up to 4 m/s, but the structure around the aortic prosthesis was difficult to observe due to artifacts. Fluoroscopy revealed normal motion of the leaflets of the mechanical valve. Intracardiac echocardiography (ICE) revealed a pannus-like structure in the left ventricular outflow tract. Transesophageal echocardiogram also revealed this structure. ICE can visualize structural abnormalities around a prosthetic valve after cardiac surgery even in patients in whom conventional imaging modalities failed.

[Valvular Heart Disease: Current Treatment and Future Perspectives. Editorial: Paradigm shift and future aspect of the treatment of valvular heart disease].
Toshihisa Anzai
Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine, 105, 2, 181, 3, 2016年02月10日, ［査読有り］, ［国内誌］
日本語

Response to Letter Regarding Article, "Prevalence, Clinical Features, and Prognosis of Acute Myocardial Infarction Attributable to Coronary Artery Embolism".
Teruo Noguchi, Satoshi Yasuda, Tatsuhiro Shibata, Shoji Kawakami, Tomotaka Tanaka, Yasuhide Asaumi, Tomoaki Kanaya, Toshiyuki Nagai, Kazuhiro Nakao, Masashi Fujino, Kazuyuki Nagatsuka, Hatsue Ishibashi-Ueda, Kunihiro Nishimura, Yoshihiro Miyamoto, Kengo Kusano, Toshihisa Anzai, Yoichi Goto, Hisao Ogawa
Circulation, 133, 5, e379, E379, LIPPINCOTT WILLIAMS & WILKINS, 2016年02月02日, ［査読有り］, ［国際誌］
英語

A case of acute decompensated heart failure evaluated by series of exhaled acetone concentrations as noninvasive biomarker of heart failure severity.
Tetsuro Yokokawa, Yasuo Sugano, Akito Shimouchi, Atsushi Shibata, Takafumi Nakayama, Takahiro Ohara, Naoya Jinno, Hideaki Kanzaki, Toshihisa Anzai
International journal of cardiology, 204, 112, 3, ELSEVIER IRELAND LTD, 2016年02月01日, ［査読有り］, ［国際誌］
英語

Impact of onset time of acute kidney injury on outcomes in patients with acute decompensated heart failure.
Yoichi Takaya, Fumiki Yoshihara, Hiroyuki Yokoyama, Hideaki Kanzaki, Masafumi Kitakaze, Yoichi Goto, Toshihisa Anzai, Satoshi Yasuda, Hisao Ogawa, Yuhei Kawano
Heart and vessels, 31, 1, 60, 5, SPRINGER, 2016年01月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Since acute kidney injury (AKI) is not always related to mortality in patients with acute decompensated heart failure (ADHF), the aim of this study was to focus on onset time of AKI and its clinical importance. A total of 371 ADHF patients were included. The impact of AKI (≥ 0.3 mg/dl or 1.5-fold increase in serum creatinine level within 48 h) with early onset (≤ 4 days from admission) or late onset (≥ 5 days from admission) was assessed. AKI occurred in 99 patients, who were divided into two groups according to the median onset time of AKI: 50 with early onset of AKI and 49 with late onset of AKI. The maximum increase in serum creatinine level from admission was greater in patients with late onset of AKI than in patients with early onset of AKI (p = 0.012). Patients with late onset of AKI had a higher 12-month mortality rate than that in patients with early onset of AKI (log-rank test, p = 0.014). Late onset of AKI was an independent predictor of mortality (hazard ratio: 3.39, 95 % confidence interval: 1.84-6.18, p < 0.001). Late onset of AKI was associated with high blood urea nitrogen level at admission and intravenous administration of dobutamine. In conclusion, late onset of AKI related to high blood urea nitrogen level and intravenous administration of dobutamine, but not early onset of AKI, is linked to high mortality rate. Onset time of AKI may be useful for risk stratification of mortality in ADHF patients developing AKI.

Prognostic Impact of Functional Mitral Regurgitation in Patients Admitted With Acute Decompensated Heart Failure.
Yuko Wada, Takahiro Ohara, Akira Funada, Takuya Hasegawa, Yasuo Sugano, Hideaki Kanzaki, Hiroyuki Yokoyama, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 80, 1, 139, 47, JAPANESE CIRCULATION SOC, 2016年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Functional mitral regurgitation (FMR) is a common complication of heart failure (HF) and worsens in acute decompensation. It is unclear whether FMR on admission or discharge determines the outcome. This study aimed to elucidate the prognostic significance of FMR on admission or discharge in patients admitted with acute decompensated HF. METHODS AND RESULTS: From 2006 to 2009, 349 patients admitted with acute decompensated HF were enrolled. They were followed with the composite endpoint of all-cause death and hospitalization for HF; 74 (21%) died and 113 (32%) developed the composite endpoint during 2.1±1.3 years. Moderate/severe FMR at discharge was associated with the composite endpoint (P=0.001), whereas that on admission was not. Multivariate Cox proportional hazard analysis showed that moderate/severe FMR (hazard ratio [95% confidence interval] =1.70 [1.03-2.73] P=0.04), logBNP, and NYHA class III/IV at discharge were independent determinants of the outcome. Moderate/severe FMR at discharge with BNP ≥200 pg/ml was prognostic, but BNP <200 pg/ml was no longer prognostic. CONCLUSIONS: Residual moderate/severe FMR after medical therapy for acute decompensated HF was associated with poor outcome, suggesting a potential target for further treatment of HF.

Pronounced Shortening of QT Interval With Mexiletine Infusion Test in Patients With Type 3 Congenital Long QT Syndrome.
Moritoshi Funasako, Takeshi Aiba, Kohei Ishibashi, Ikutaro Nakajima, Koji Miyamoto, Yuko Inoue, Hideo Okamura, Takashi Noda, Shiro Kamakura, Toshihisa Anzai, Teruo Noguchi, Satoshi Yasuda, Yoshihiro Miyamoto, Kengo Fukushima Kusano, Hisao Ogawa, Wataru Shimizu
Circulation journal : official journal of the Japanese Circulation Society, 80, 2, 340, 5, JAPANESE CIRCULATION SOC, 2016年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Mexiletine is often used for medical therapy in LQT3 patients, however, the usefulness of mexiletine infusion test for LQT3 patients has not been reported. The aim of this study was to evaluate the usefulness of mexiletine infusion test for detecting LQT3 patients. METHODS AND RESULTS: We analyzed response in 12-lead electrocardiogram parameters measured in II or V5 to i.v. mexiletine infusion (2 mg/kg) during sinus rhythm among 31 genotype-positive LQT patients (29 ± 18 years, 12 male). Change in QTc interval after mexiletine was compared between LQT3 (n=15, 24 ± 21 years, 9 male) and other LQT patients (4 LQT1 and 12 LQT2; 34 ± 14 years, 3 male). Baseline RR, QT, and QTc interval were not different between the 2 groups (981 ± 182 vs. 1,023 ± 192 ms; 550 ± 94 vs. 524 ± 75 ms; 556 ± 66 vs. 520 ± 62 ms, respectively). While QTc interval was shortened with mexiletine in both groups (P<0.0001 vs. baseline), degree of QTc shortening (∆QTc) was significantly larger in LQT3 than in LQT1/LQT2 patients (99 ± 39 vs. 48 ± 32 ms; P=0.0004). The sensitivity, specificity and predictive accuracy of mexiletine infusion test for differentiating LQT3 from LQT1/LQT2 were 86.7%, 81.3% and 81.3%, respectively, and the optimal cut-off for ∆QTc was 69 ms on receiver operating characteristic analysis. No pro-arrhythmic event was observed. CONCLUSIONS: Pronounced shortening of QT interval with mexiletine may facilitate genetic testing in patients with LQT3 syndrome.

First Case Report of the Antemortem Diagnosis of Nonbacterial Thrombotic Endocarditis of a Mechanical Prosthetic Valve.
Hideki Yasutake, Yasuo Sugano, Yoshihiko Ikeda, Takahiro Ohara, Takuya Hasegawa, Hideaki Kanzaki, Toshihisa Anzai
Internal medicine (Tokyo, Japan), 55, 3, 255, 7, JAPAN SOC INTERNAL MEDICINE, 2016年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 67-year-old man with a history of aortic mechanical valve replacement exhibited an abnormal mass on the sewing ring of the prosthesis on echocardiography. Despite receiving strong anticoagulation, he developed acute cerebral infarction due to the formation of emboli resulting from the thrombus and underwent urgent re-aortic valve replacement. Based on the microscopic findings of the resected mass, he was finally diagnosed as having nonbacterial thrombotic endocarditis (NBTE) of the mechanical prosthetic valve, which was thought to be associated with colorectal cancer. We herein report the first known case of an antemortem diagnosis of NBTE on a mechanical heart valve.

Prognostic Value of Prothrombin Time International Normalized Ratio in Acute Decompensated Heart Failure - A Combined Marker of Hepatic Insufficiency and Hemostatic Abnormality.
Atsushi Okada, Yasuo Sugano, Toshiyuki Nagai, Seiji Takashio, Satoshi Honda, Yasuhide Asaumi, Takeshi Aiba, Teruo Noguchi, Kengo F Kusano, Hisao Ogawa, Satoshi Yasuda, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 80, 4, 913, 23, JAPANESE CIRCULATION SOC, 2016年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: There are limited studies regarding the prognostic value of coagulation abnormalities in heart failure patients. The clinical significance of prothrombin time international normalized ratio (INR), a widely accepted marker assessing coagulation abnormalities, in acute decompensated heart failure (ADHF) remains unclear. METHODS AND RESULTS: Among 561 consecutive patients admitted for ADHF, INR was assessed in 294 patients without prior anticoagulation therapy, acute coronary syndrome, liver disease, or overt disseminated intravascular coagulation. Increased INR on admission was positively associated with increased levels of thrombin-antithrombin complex, C-reactive protein, total bilirubin, γ-glutamyl transpeptidase, inferior vena cava diameter, tricuspid regurgitation severity, markers of neurohormonal activation, and also negatively associated with decreased albumin, cholinesterase, and total cholesterol. In contrast, there was no significant association with left ventricular ejection fraction, serum sodium or blood urea nitrogen. Multivariate analysis showed that increased INR was independently associated with increased all-cause mortality (hazard ratio 1.89 per 0.1 increase, 95% confidence interval 1.14-3.13, P=0.013) during the median follow up of 284 days. Increased INR also had a higher prognostic value compared to risk score models including the Model for End-Stage Liver Disease (MELD) score or the MELD excluding INR (MELD-XI) score. CONCLUSIONS: Increased INR is an independent predictor of all-cause mortality in ADHF patients without anticoagulation, reflecting coagulation abnormalities and hepatic insufficiency, possibly through systemic inflammation, neurohormonal activation and venous congestion.

Prosthetic Valve Dysfunction 35 Years after Mitral Valve Replacement with a Starr-Edwards Caged-disc Valve.
Tetsuro Yokokawa, Takahiro Ohara, Seiji Takashio, Mari Sakamoto, Yuko Wada, Kenji Nakamura, Hiroyuki Takahama, Makoto Amaki, Takuya Hasegawa, Yasuo Sugano, Hideaki Kanzaki, Satoshi Yasuda, Hisao Ogawa, Tomoyuki Fujita, Junjiro Kobayashi, Yoko Okamoto, Taka-Aki Matsuyama, Hatsue Ishibashi-Ueda, Toshihisa Anzai
Internal medicine (Tokyo, Japan), 55, 5, 479, 83, JAPAN SOC INTERNAL MEDICINE, 2016年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 49-year-old man was admitted to our hospital with a chief complaint of dyspnea. He had a history of mitral valve replacement (MVR) with a Starr-Edwards (SE) caged-disc valve at the age of 14. Echocardiography revealed elevated trans-valvular pressure gradient of the mitral prosthetic valve with neither disk motion abnormality nor abnormal structure. Catheterization confirmed an elevation of the mean diastolic gradient of the mitral valve to 12.3 mmHg. Re-MVR was performed, and abnormal tissue attached to the cage of the valve and proliferating beneath the valve was observed. Histologic examination revealed them as fibrinous tissue and mild pannus proliferation, respectively. This rare case report focuses on long-term follow-up and the complication of a SE caged-disc valve. A SE caged-disc valve may become stenotic, only detected with a trans-valvular pressure gradient without any disk motion abnormality or abnormal structure during a prolonged follow-up period.

Pathohistological Evidence of Smoldering Inflammation in Rheumatic Heart Disease with Massive Left Atrial Calcification.
Mikio Shiba, Yasuo Sugano, Yoshihiko Ikeda, Hatsue Ishibashi-Ueda, Takahiro Ohara, Takuya Hasegawa, Hideaki Kanzaki, Toshihisa Anzai
Internal medicine (Tokyo, Japan), 55, 7, 751, 4, JAPAN SOC INTERNAL MEDICINE, 2016年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 74-year-old man, who had a history of a mitral valve replacement for rheumatic heart disease (RHD) 30 years previously, was admitted with progressive heart failure. Massive calcification was observed around the left atrium on multidetector CT, in addition to a late gadolinium enhancement (LGE)-positive layer adjacently outside of the calcification on MRI. He underwent a second mitral valve replacement for the prosthetic valve failure. Pathohistological analyses of a tissue section of the left atrial wall from a surgical specimen revealed lymphocyte and macrophage infiltration that coincided with the LGE-positive layer on MRI, suggesting the existence of sustained active inflammation even after the long period of RHD.

Pathological Investigation of Congenital Bicuspid Aortic Valve Stenosis, Compared with Atherosclerotic Tricuspid Aortic Valve Stenosis and Congenital Bicuspid Aortic Valve Regurgitation.
Yasuhiro Hamatani, Hatsue Ishibashi-Ueda, Toshiyuki Nagai, Yasuo Sugano, Hideaki Kanzaki, Satoshi Yasuda, Tomoyuki Fujita, Junjiro Kobayashi, Toshihisa Anzai
PloS one, 11, 8, e0160208, PUBLIC LIBRARY SCIENCE, 2016年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Congenital bicuspid aortic valve (CBAV) is the main cause of aortic stenosis (AS) in young adults. However, the histopathological features of AS in patients with CBAV have not been fully investigated. METHODS AND RESULTS: We examined specimens of aortic valve leaflets obtained from patients who had undergone aortic valve re/placement at our institution for severe AS with CBAV (n = 24, CBAV-AS group), severe AS with tricuspid aortic valve (n = 24, TAV-AS group), and severe aortic regurgitation (AR) with CBAV (n = 24, CBAV-AR group). We compared the histopathological features among the three groups. Pathological features were classified using semi-quantitative methods (graded on a scale 0 to 3) by experienced pathologists without knowledge of the patients' backgrounds. The severity of inflammation, neovascularization, and calcium and cholesterol deposition did not differ between the CBAV-AS and TAV-AS groups, and these four parameters were less marked in the CBAV-AR group than in the CBAV-AS (all p<0.01). Meanwhile, the grade of valvular fibrosis was greater in the CBAV-AS group, compared with the TAV-AS and CBAV-AR groups (both p<0.01). In AS patients, thickness of fibrotic lesions was greater on the aortic side than on the ventricular side (both p<0.01). Meanwhile, thickness of fibrotic lesions was comparable between the aortic and ventricular sides in CBAV-AR patients (p = 0.35). CONCLUSIONS: Valvular fibrosis, especially on the aortic side, was greater in patients with CBAV-AS than in those without, suggesting a difference in the pathogenesis of AS between CBAV and TAV.

Circulating Omega-6, But Not Omega-3 Polyunsaturated Fatty Acids, Are Associated with Clinical Outcomes in Patients with Acute Decompensated Heart Failure.
Toshiyuki Nagai, Yasuyuki Honda, Yasuo Sugano, Kunihiro Nishimura, Michikazu Nakai, Satoshi Honda, Naotsugu Iwakami, Atsushi Okada, Yasuhide Asaumi, Takeshi Aiba, Teruo Noguchi, Kengo Kusano, Hisao Ogawa, Satoshi Yasuda, Toshihisa Anzai
PloS one, 11, 11, e0165841, PUBLIC LIBRARY SCIENCE, 2016年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Circulating polyunsaturated fatty acid (PUFA) levels are associated with clinical outcomes in cardiovascular diseases including coronary artery disease and chronic heart failure (HF). However, their clinical implications in acute decompensated HF (ADHF) remain unclear. The aim of this study was to investigate the clinical roles of circulating PUFAs in patients with ADHF. METHODS: Circulating levels of PUFAs, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA) and dihomo-gamma linoleic acid (DGLA), were measured on admission in 685 consecutive ADHF patients. Adverse events were defined as all-cause death and worsening HF. RESULTS: During a median follow-up period of 560 days, 262 (38.2%) patients had adverse events. Although patients with adverse events had lower n-6 PUFA (AA + DGLA) level than those without, n-3 PUFA (EPA + DHA) level was comparable between the groups. Kaplan-Meier analyses showed that lower n-6 PUFA level on admission was significantly associated with the composite of all-cause death and worsening HF, all-cause death, cardiovascular death and worsening HF (p < 0.001, p = 0.005, p = 0.021, p = 0.019, respectively). In a multivariate Cox model, lower n-6 PUFA level was independently associated with increased risk of adverse events (HR 0.996, 95% CI: 0.993-0.999, p = 0.027). CONCLUSIONS: Lower n-6 but not n-3 PUFA level on admission was significantly related to worse clinical outcomes in ADHF patients. Measurement of circulating n-6 PUFA levels on admission might provide information for identifying high risk ADHF patients.

Azilsartan, but not Candesartan Improves Left Ventricular Diastolic Function in Patients with Hypertension and Heart Failure
Mari Sakamoto, Masanori Asakura, Atsushi Nakano, Hideaki Kanzaki, Yasuo Sugano, Makoto Amaki, Takahiro Ohara, Takuya Hasegawa, Toshihisa Anzai, Masafumi Kitakaze
INTERNATIONAL JOURNAL OF GERONTOLOGY, 9, 4, 201, 205, ELSEVIER TAIWAN, 2015年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Diastolic dysfunction is a major cause of heart failure (HF) with a preserved ejection fraction (HFpEF); however, there is no clear strategy for treating diastolic dysfunction. Myocardial and vascular abnormalities may cause HFpEF, which indicates that correcting both abnormalities may specifically improve the severity of diastolic dysfunction. Candesartan primarily affects the myocardium, but azilsartan affects the myocardium and the aortic vasculature. This study was undertaken to test the hypothesis that azilsartan, but not candesartan, improves left ventricular (LV) diastolic dysfunction in patients with hypertension and HFpEF.
Methods: Among patients with HF in our database, the patients who received azilsartan or candesartan were retrospectively screened. Fifteen patients treated with azilsartan were identified, and sex-matched patients who received candesartan were blindly selected.
Results: At baseline, there were no significant differences between the two groups in clinical findings, echocardiographic parameters, and plasma brain natriuretic peptide levels. At 3-6 months, blood pressure decreased to similar levels in both groups. However, the early LV filling velocity/early diastolic velocity (E/e') ratio decreased in the azilsartan group (13.0 +/- 4.2 vs. 10.9 +/- 3.2, p = 0.03), but remained unchanged in the candesartan group (12.0 +/- 3.6 vs. 12.5 +/- 5.0, p = 0.58; for interaction, p = 0.04). Other echocardiographic parameters were unaltered by azilsartan or candesartan.
Conclusion: Azilsartan improves diastolic function in HF patients with hypertension, and it may be the preferred option over other angiotensin II receptor blockers in patients with HFpEF. Copyright (C) 2015, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC. All rights reserved.

Improvement of left ventricular filling and pulmonary artery pressure following unilateral renal artery total occlusion stenting in a patient with recurrent congestive heart failure complicated by renovascular hypertension and renal failure.
Osami Kawarada, Ryota Kitajima, Yasuo Sugano, Teruo Noguchi, Toshihisa Anzai, Hisao Ogawa, Satoshi Yasuda
ESC heart failure, 2, 4, 160, 163, 2015年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Recurrent congestive heart failure related to renal artery disease is an important clinical entity that is typically observed in bilateral renal artery stenosis or solitary functioning kidney. However, the relationship between heart failure and unilateral renal artery disease, especially that with total occlusion, remains unclear. We report a successful management by unilateral renal artery total occlusion stenting with an evidence of improvement of left ventricular filling and pulmonary artery pressure in case of a patient suffering from medical therapy resistant recurrent congestive heart failure with preserved ejection fraction.

Active cardiac sarcoidosis in a patient with adult-onset Kawasaki disease.
Noriaki Moriyama, Takahiro Ohara, Hideaki Kanzaki, Etsuko Tsuda, Masaharu Ishihara, Toshihisa Anzai
Journal of cardiology cases, 12, 3, 68, 71, 2015年09月, ［査読有り］, ［国内誌］
英語, Adult-onset Kawasaki disease is a rare condition. Cardiac sarcoidosis is an uncommon cardiomyopathy which is characterized by progressive cardiac dysfunction, and abnormality on electrocardiography and morphological aberration of the heart. We report a first case of a combination of these rare conditions. The patient was initially diagnosed with Kawasaki disease based on the coronary artery aneurysms and a past medical history at the age of 20 years which was typical of Kawasaki disease. Decades later, he developed progressive cardiac dysfunction and a sudden-onset atrioventricular block. Laboratory and imaging results revealed severe myocardial damage and inflammation which were unexplainable by coronary artery ischemia. We diagnosed him with cardiac sarcoidosis based on a Japanese guideline to diagnose cardiac sarcoidosis. A cardiac resynchronization therapy defibrillator was implanted and he received oral steroid therapy. This rare combination of adult-onset Kawasaki disease and cardiac sarcoidosis may suggest the causative association of these conditions. .

Prevalence, Clinical Features, and Prognosis of Acute Myocardial Infarction Attributable to Coronary Artery Embolism.
Tatsuhiro Shibata, Shoji Kawakami, Teruo Noguchi, Tomotaka Tanaka, Yasuhide Asaumi, Tomoaki Kanaya, Toshiyuki Nagai, Kazuhiro Nakao, Masashi Fujino, Kazuyuki Nagatsuka, Hatsue Ishibashi-Ueda, Kunihiro Nishimura, Yoshihiro Miyamoto, Kengo Kusano, Toshihisa Anzai, Yoichi Goto, Hisao Ogawa, Satoshi Yasuda
Circulation, 132, 4, 241, 50, LIPPINCOTT WILLIAMS & WILKINS, 2015年07月28日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Coronary artery embolism (CE) is recognized as an important nonatherosclerotic cause of acute myocardial infarction. Its prevalence, clinical features, and prognosis remain insufficiently characterized. METHODS AND RESULTS: We screened 1776 consecutive patients who presented with de novo acute myocardial infarction between 2001 and 2013. CE was diagnosed based on criteria encompassing histological, angiographic, and other diagnostic imaging findings. The prevalence, clinical characteristics, treatment strategies, in-hospital outcomes, and long-term risk of CE recurrence or major adverse cardiac and cerebrovascular events (cardiac death, fatal arrhythmia, or recurrent thromboembolism) were evaluated. The prevalence of CE was 2.9% (n=52), including 8 (15%) patients with multivessel CE. Atrial fibrillation was the most common cause (n=38, 73%). Only 39% of patients with CE were treated with vitamin K antagonists, and the median international normalized ratio was 1.42 (range, 0.95-1.80). Eighteen of the 30 CE patients with nonvalvular atrial fibrillation had a CHADS2 score of 0 or 1. When those patients were reevaluated using CHA2DS2-VASc, 61% were reassigned to a higher risk category. During a median follow-up of 49 months, CE and thromboembolism recurred in 5 atrial fibrillation patients. The 5-year rate of major adverse cardiac and cerebrovascular events was 27.1%. In the propensity score-matched cohorts (n=45 each), Kaplan-Meier analysis showed a significantly higher incidence of cardiac death in the CE group than in the non-CE group (hazard ratio, 9.29; 95% confidence interval, 1.13-76.5; P<0.001). CONCLUSIONS: Atrial fibrillation is the most frequent cause of CE. Patients with CE represent a high-risk subgroup of patients with acute myocardial infarction and require close follow-up.

Significance of low plasma levels of brain-derived neurotrophic factor in patients with heart failure.
Seiji Takashio, Seigo Sugiyama, Megumi Yamamuro, Hiroyuki Takahama, Tomohiro Hayashi, Yasuo Sugano, Yasuhiro Izumiya, Seiji Hokimoto, Naoto Minamino, Satoshi Yasuda, Toshihisa Anzai, Hisao Ogawa
The American journal of cardiology, 116, 2, 243, 9, EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC, 2015年07月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which regulates neuronal differentiation and functions. Low levels of BDNF are because of psychological stress and potentially play a role in the pathogenesis of depression and cognition disorders. Because psychological stress and depression are associated with increased risk of heart failure (HF), the pathogenic link between HF and psychological status has attracted clinical attention. We hypothesized that plasma BDNF levels might be decreased in patients with HF and that BDNF could be a key factor associated with HF. We evaluated plasma BDNF levels in 242 patients with HF and 80 subjects without HF who are age and gender matched. Plasma BDNF levels were significantly lower in patients with HF (3,712 pg/ml [2,124 to 6,180]) than those without HF (7,247 pg/ml [5,388 to 9,255], p <0.001) and lower in patients with HF with the New York Heart Association functional class III than class I (p = 0.01) and class II (p <0.001). Log BDNF levels correlated negatively with log B-type natriuretic peptide (r = -0.203, p = 0.03) in patients with HF. Of 61 acute decompensated patients with HF, plasma BDNF levels were significantly higher at discharge (4,194 pg/ml [2,356 to 6,916]) compared with those at admission (2,749 pg/ml [1,380 to 4,161], p = 0.003). Multivariate logistic regression analysis identified log BDNF level as a significant correlate with the presence of HF (odds ratio 0.82; 95% confidence interval 0.76 to 0.91, p <0.001). In conclusion, plasma BDNF levels were decreased in patients with HF and associated with HF severity. BDNF could be a potentially clinically useful biomarker of HF reflecting possible cardio-neuronal linkage.

Late aneurysm formation of Valsalva sinus after aortic valve replacement due to Takayasu's arteritis.
Akira Funada, Hideaki Kanzaki, Nobutaka Nagano, Yasuo Sugano, Takahiro Ohara, Takuya Hasegawa, Hatsue Ishibashi-Ueda, Masafumi Kitakaze, Toshihisa Anzai
Heart and vessels, 30, 4, 558, 62, SPRINGER, 2015年07月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Takayasu's arteritis (TA) is an inflammatory disease of unknown etiology involving the aorta and its branches, and also causes aortic regurgitation (AR). One of the most serious but rare complications after aortic valve replacement (AVR) in TA is aneurysm formation of the sinus of Valsalva. A 64-year-old woman had undergone AVR with a prosthetic valve for AR due to TA 4 years earlier and had received an implanted permanent pacemaker for complete atrioventricular block (AVB) 2 years later. Aortography 4 years postoperatively demonstrated aneurysm formation (47 mm in diameter) at the sinus of Valsalva although preoperative aortography showed severe AR without dilatation of the sinus of Valsalva. We recommended reoperation for the aneurysm but the patient refused. The perioperative histopathological examination revealed extensive destruction of the medial elastic fibers. Both the fragility of the sinus of Valsalva and the residual inflammation could have caused the patient's aneurysm formation. Moreover, extension of TA into the ventricular septum or mechanical compression of the aneurysm against the conduction system might have caused her progressive AVB. Close and lifelong follow-up for patients with TA regarding development of aneurysm after surgical treatment is indispensable when fragility of the aortic root had been confirmed.

Prognostic impact of blood pressure response plus gadolinium enhancement in dilated cardiomyopathy.
Emi Tateishi, Teruo Noguchi, Yoichi Goto, Yoshiaki Morita, Hatsue Ishibashi-Ueda, Naoaki Yamada, Hideaki Kanzaki, Kunihiro Nishimura, Yoshihiro Miyamoto, Toshihisa Anzai, Hisao Ogawa, Satoshi Yasuda
Heart (British Cardiac Society), 101, 10, 774, 80, BMJ PUBLISHING GROUP, 2015年05月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Late gadolinium enhancement (LGE) is not necessarily ideal for detecting diffuse myocardial fibrosis in idiopathic dilated cardiomyopathy (DCM). Since systolic blood pressure response (SBPR) during exercise has been proposed to reflect cardiac pump reserve in patients with heart failure, we wished to determine whether LGE plus SBPR is a better prognostic factor in patients with DCM. METHODS: LGE and cardiopulmonary exercise testing results in consecutive 207 patients with DCM were examined. Patients were divided into four groups according to the presence or absence of LGE and the SBPR cut-off value of +40 mm Hg according to receiver operating characteristic curve analysis: LGE-positive+SBPR <40 mm Hg (n=65), LGE-positive+SBPR ≥40 mm Hg (n=40), LGE-negative+SBPR <40 mm Hg (n=33) and LGE-negative+SBPR ≥40 mm Hg (n=69). The composite end point was cardiac death, cardiac transplantation, LV assist device implantation, life-threatening arrhythmia or heart failure. RESULTS: Forty-two (20%) patients developed the composite end point, with rates of 35%, 20%, 21% and 6% in patients with LGE-positive+SBPR <40 mm Hg, LGE-positive+SBPR ≥40 mm Hg, LGE-negative+SBPR <40 mm Hg and LGE-negative+SBPR ≥40 mm Hg status, respectively. Multivariable Cox regression analysis identified LGE-positive and SBPR <40 mm Hg as a significant independent predictor of cardiac events (HR 2.08, 95% CI 1.06 to 4.11, p=0.034). Of note, there was no significant difference in the cardiac event-free survival rate between the LGE-positive+SBPR ≥40 mm Hg and LGE-negative+SBPR <40 mm Hg groups (p=0.736). CONCLUSIONS: The combination of LGE and SBPR provides more clinically relevant information for assessing the risk of cardiac events in patients with DCM than LGE status alone.

Efficacy and safety of flecainide for ventricular arrhythmias in patients with Andersen-Tawil syndrome with KCNJ2 mutations.
Koji Miyamoto, Takeshi Aiba, Hiromi Kimura, Hideki Hayashi, Seiko Ohno, Chie Yasuoka, Yoshihito Tanioka, Takeshi Tsuchiya, Yoko Yoshida, Hiroshi Hayashi, Ippei Tsuboi, Ikutaro Nakajima, Kohei Ishibashi, Hideo Okamura, Takashi Noda, Masaharu Ishihara, Toshihisa Anzai, Satoshi Yasuda, Yoshihiro Miyamoto, Shiro Kamakura, Kengo Kusano, Hisao Ogawa, Minoru Horie, Wataru Shimizu
Heart rhythm, 12, 3, 596, 603, ELSEVIER SCIENCE INC, 2015年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Andersen-Tawil syndrome (ATS) is an autosomal dominant genetic or sporadic disorder characterized by ventricular arrhythmias (VAs), periodic paralyses, and dysmorphic features. The optimal pharmacological treatment of VAs in patients with ATS remains unknown. OBJECTIVE: We evaluated the efficacy and safety of flecainide for VAs in patients with ATS with KCNJ2 mutations. METHODS: Ten ATS probands (7 females; mean age 27 ± 11 years) were enrolled from 6 institutions. All of them had bidirectional VAs in spite of treatment with β-blockers (n = 6), but none of them had either aborted cardiac arrest or family history of sudden cardiac death. Twenty-four-hour Holter recording and treadmill exercise test (TMT) were performed before (baseline) and after oral flecainide therapy (150 ± 46 mg/d). RESULTS: Twenty-four-hour Holter recordings demonstrated that oral flecainide treatment significantly reduced the total number of VAs (from 38,407 ± 19,956 to 11,196 ± 14,773 per day; P = .003) and the number of the longest ventricular salvos (23 ± 19 to 5 ± 5; P = .01). At baseline, TMT induced nonsustained ventricular tachycardia (n = 7) or couplets of premature ventricular complex (n = 2); treatment with flecainide completely (n = 7) or partially (n = 2) suppressed these exercise-induced VAs (P = .008). In contrast, the QRS duration, QT interval, and U-wave amplitude of the electrocardiogram were not altered by flecainide therapy. During a mean follow-up of 23 ± 11 months, no patients developed syncope or cardiac arrest after oral flecainide treatment. CONCLUSION: This multicenter study suggests that oral flecainide therapy is an effective and safe means of suppressing VAs in patients with ATS with KCNJ2 mutations, though the U-wave amplitude remained unchanged by flecainide.

Role of non-electrocardiogram-gated contrast-enhanced computed tomography in the diagnosis of acute coronary syndrome.
Yoshinori Mano, Toshihisa Anzai, Akihiro Yoshizawa, Yuji Itabashi, Takahiro Ohki
Heart and vessels, 30, 1, 1, 8, SPRINGER, 2015年01月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Non-electrocardiogram-gated contrast-enhanced computed tomography (non-ECG-gated CT) is available in most hospitals where patients with chest and/or back pain are admitted to the emergency department. Although it has been established as the initial diagnostic imaging modality for acute aortic dissection (AAD) and pulmonary thromboembolism (PE), its diagnostic ability for acute coronary syndrome (ACS) in the emergency department has not been elucidated. We retrospectively investigated 154 consecutive patients who required non-ECG-gated CT to differentiate AAD and PE in the emergency department, but had no evidence of them on CT. Furthermore, a subanalysis was performed in the patients who were subsequently suspected of ACS and underwent emergent invasive coronary angiography followed by CT. We evaluated left ventricular enhancement to detect myocardial perfusion deficit by calculating Hounsfield units, and the results were compared with ultimate diagnoses and angiography findings. A perfusion deficit was detected in 43 patients, among whom 26 were ultimately diagnosed with acute myocardial infarction (AMI); 24 patients required emergent revascularization. The subanalysis indicated that perfusion abnormalities corresponded with the territory of the culprit artery in all except one patient. In the remaining 111 patients without perfusion deficit, only two required emergent revascularization, and their levels of creatine kinase MB were not elevated. The sensitivity, specificity, and positive and negative predictive values of non-ECG-gated CT in predicting AMI/emergent revascularization were 93 %, 87 %, 61 %, and 98 %/92 %, 85 %, 56 %, and 98 %, respectively. Non-ECG-gated CT facilitates the diagnosis of ACS and the decision on emergent catheterization, providing information on the ischemic myocardial area by detection of a localized decrease in left ventricular enhancement.

Non-contrast T1-weighted magnetic resonance imaging at 3.0 Tesla in a patient undergoing elective percutaneous coronary intervention – clinical and pathological significance of high-intensity plaque.
Asaumi Y, Noguchi T, Morita Y, Matsuyama TA, Otsuka F, Fujiwara R, Kanaya T, Nagai T, Higashi M, Kusano K, Anzai T, Ishibashi-Ueda H, Ogawa H, Yasuda S
Circulation journal : official journal of the Japanese Circulation Society, 79, 1, 218, 20, JAPANESE CIRCULATION SOC, 2015年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

Does major noncardiac surgery accelerate the progression of aortic stenosis? - Role of inflammation.
Makoto Amaki, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 79, 4, 766, 7, JAPANESE CIRCULATION SOC, 2015年, ［査読有り］, ［国内誌］
英語

Risk Stratification of Acute Kidney Injury Using the Blood Urea Nitrogen/Creatinine Ratio in Patients With Acute Decompensated Heart Failure.
Yoichi Takaya, Fumiki Yoshihara, Hiroyuki Yokoyama, Hideaki Kanzaki, Masafumi Kitakaze, Yoichi Goto, Toshihisa Anzai, Satoshi Yasuda, Hisao Ogawa, Yuhei Kawano
Circulation journal : official journal of the Japanese Circulation Society, 79, 7, 1520, 5, JAPANESE CIRCULATION SOC, 2015年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Risk stratification of acute kidney injury (AKI) is important for acute decompensated heart failure (ADHF). The aim of this study was to determine whether clinical markers, such as the blood urea nitrogen/creatinine ratio (BUN/Cr) or BUN or creatinine values alone, stratify the risk of AKI for mortality. METHODS AND RESULTS: In all, 371 consecutive ADHF patients were enrolled in the study. AKI was defined as serum creatinine ≥0.3 mg/dl or a 1.5-fold increase in serum creatinine levels within 48 h. During ADHF therapy, AKI occurred in 99 patients; 55 patients died during the 12-month follow-up period. Grouping patients according to AKI and a median BUN/Cr at admission of 22.1 (non-AKI+low BUN/Cr, non-AKI+high BUN/Cr, AKI+low BUN/Cr, and AKI+high BUN/Cr groups) revealed higher mortality in the AKI+high BUN/Cr group (log-rank test, P<0.001). Cox's proportional hazard analysis revealed an association between AKI+high BUN/Cr and mortality, whereas the association with AKI+low BUN/Cr did not reach statistical significance. When patients were grouped according to AKI and median BUN or creatinine values at admission, AKI was associated with mortality, regardless of BUN or creatinine. CONCLUSIONS: The combination of AKI and elevated BUN/Cr, but not BUN or creatinine individually, is linked with an increased risk of mortality in ADHF patients, suggesting that the BUN/Cr is useful for risk stratification of AKI.

Effect of Corticosteroid Therapy on Long-Term Clinical Outcome and Left Ventricular Function in Patients With Cardiac Sarcoidosis.
Toshiyuki Nagai, Nobutaka Nagano, Yasuo Sugano, Yasuhide Asaumi, Takeshi Aiba, Hideaki Kanzaki, Kengo Kusano, Teruo Noguchi, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 79, 7, 1593, 600, JAPANESE CIRCULATION SOC, 2015年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Cardiac involvement is the worst prognostic determinant in patients with sarcoidosis, but the long-term prognostic significance of corticosteroid therapy for cardiac sarcoidosis (CS) remains unclear. METHODS AND RESULTS: We examined 83 consecutive patients diagnosed with CS. Patients were divided into 2 groups based on the presence or absence of corticosteroid therapy at diagnosis. Patients with corticosteroid therapy had lower age and higher rate of positive findings in the myocardium on gallium scintigraphy (Ga) at diagnosis than those without. LVEF, biomarkers, and use of cardiovascular medication were similar between the 2 groups. During the follow-up (7.6±4.4 years), corticosteroid therapy was associated with fewer long-term adverse events (overall, P=0.005; cardiac death, P=0.92; symptomatic arrhythmias, P=0.89; heart failure admission, P<0.0001) and a greater % increase in LVEF than those without (7.9±36.3% vs. -16.7±34.8%, P=0.03). On Cox proportional hazards modeling, corticosteroid therapy (HR, 0.41; 95% CI: 0.20-0.89) was an independent determinant of long-term adverse event-free survival, but age, sex, LVEF, and Ga findings were not. CONCLUSIONS: Corticosteroid therapy might have a beneficial effect on long-term clinical outcome in CS patients, particularly by reduction of heart failure admission and retarding the progression of LV systolic dysfunction.

Association Between Basal Thinning of Interventricular Septum and Adverse Long-Term Clinical Outcomes in Patients With Cardiac Sarcoidosis.
Nobutaka Nagano, Toshiyuki Nagai, Yasuo Sugano, Yoshiaki Morita, Yasuhide Asaumi, Takeshi Aiba, Hideaki Kanzaki, Kengo Kusano, Teruo Noguchi, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 79, 7, 1601, 8, JAPANESE CIRCULATION SOC, 2015年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Basal thinning of the interventricular septum (IVS) is an important diagnostic feature of cardiac sarcoidosis (CS), but its long-term prognostic significance remains unclear. METHODS AND RESULTS: We examined 74 consecutive patients who were diagnosed with CS. Basal IVS thickness at a point located 10 mm from the aortic annulus was measured. IVS thickness at the left ventricular minor axis level (IVS) was also measured according to the recommended procedure of the American Society of Echocardiography. Patients were divided into 2 groups based on the presence or absence of basal IVS thinning, which was defined as basal IVS ≤4 mm and/or basal IVS/IVS ratio ≤0.6. Basal IVS thinning was observed in 21 patients and was associated with greater long-term adverse events during follow-up (5.1±2.5 years), although the baseline characteristics were comparable between groups (overall, P<0.01; all-cause death, P=0.53; symptomatic arrhythmias, P<0.01; heart failure admission, P=0.027). Multivariate analysis showed basal IVS thinning was an independent determinant of long-term adverse events (hazard ratio 2.86, 95% confidence interval 1.31-6.14) even after adjustment for existing prognostic variables. CONCLUSIONS: The presence of basal IVS thinning at the time of CS diagnosis was associated with poor long-term clinical outcomes, suggesting its prognostic significance in patients with CS.

Clinical and Pathological Impact of Tissue Fibrosis on Lethal Arrhythmic Events in Hypertrophic Cardiomyopathy Patients With Impaired Systolic Function.
Yuko Wada, Takeshi Aiba, Taka-aki Matsuyama, Ikutaro Nakajima, Kohei Ishibashi, Koji Miyamoto, Yuko Yamada, Hideo Okamura, Takashi Noda, Kazuhiro Satomi, Yoshiaki Morita, Hideaki Kanzaki, Kengo Kusano, Toshihisa Anzai, Shiro Kamakura, Hatsue Ishibashi-Ueda, Wataru Shimizu, Minoru Horie, Satoshi Yasuda, Hisao Ogawa
Circulation journal : official journal of the Japanese Circulation Society, 79, 8, 1733, 41, JAPANESE CIRCULATION SOC, 2015年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The natural history of hypertrophic cardiomyopathy (HCM) varies from an asymptomatic benign course to a poor prognosis. Myocardial fibrosis may play a critical role in ventricular tachyarrhythmias (VT/VF); however, the clinical significance of tissue fibrosis by right ventricular (RV) biopsy in the long-term prognosis of HCM patients remains unclear. METHODS AND RESULTS: We enrolled 185 HCM patients (mean age, 57±14 years). The amount of fibrosis (%area) was quantified using a digital microscope. Hemodynamic, echocardiographic, and electrophysiologic parameters were also evaluated. Patients with severe fibrosis had longer QRS duration and positive late potential (LP) on signal-averaged ECG, resulting in a higher incidence of VT/VF. At the 5±4 year follow-up, VT/VF occurred in 31 (17%) patients. Multivariate Cox regression analysis revealed that tissue fibrosis (hazard ratio (HR): 1.65; P=0.003 per 10% increase), lower left ventricular ejection fraction (HR: 0.64; P=0.001 per 10% increase), and positive SAECG (HR: 3.14; P=0.04) led to a greater risk of VT/VF. The combination of tissue fibrosis severity and lower left ventricular ejection fraction could be used to stratify the risk of lethal arrhythmic events in HCM patients. CONCLUSIONS: Myocardial fibrosis in RV biopsy samples may contribute to abnormal conduction delay and spontaneous VT/VF, leading to a poor prognosis in HCM patients.

Time-Course Changes of Cardiac-Specific Inflammation in a Patient With Left Ventricular Calcified Amorphous Tumor.
Hiroki Yasui, Hiroyuki Takahama, Hideaki Kanzaki, Hatsue Ishibashi-Ueda, Naomi Morita, Yasuo Sugano, Takuya Hasegawa, Takahiro Ohara, Makoto Amaki, Akira Funada, Yasushi Yoshikawa, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 79, 9, 2069, 71, JAPANESE CIRCULATION SOC, 2015年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

Isolated Septal Branch Myocardial Infarction Due to Coronary Spasm Mimicking Non-Ischemic Late Gadolinium Enhancement Pattern on Cardiac Magnetic Resonance Imaging.
Naotsugu Iwakami, Teruo Noguchi, Yoshihiko Ikeda, Emi Tateishi, Yoshiaki Morita, Hideaki Kanzaki, Mitsuhiko Takewa, Toshihisa Anzai, Hisao Ogawa, Satoshi Yasuda
Circulation journal : official journal of the Japanese Circulation Society, 79, 10, 2280, 2, JAPANESE CIRCULATION SOC, 2015年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

Intensity of statin therapy and new hospitalizations for heart failure in patients with type 2 diabetes.
Ichiro Kishimoto, Hisashi Makino, Yoko Ohata, Tamiko Tamanaha, Mayu Tochiya, Toshihisa Anzai, Kengo Kusano, Teruo Noguchi, Satoshi Yasuda, Hisao Ogawa
BMJ open diabetes research & care, 3, 1, e000137, 2015年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: To examine a relationship between statin intensity and heart failure (HF) incidence in diabetes. RESEARCH DESIGN AND METHODS: We performed a retrospective cohort study of patients with type 2 diabetes (n=600; age, 66.3 years; men, 68%). Patients were categorized into three groups by baseline statin treatments-moderate-intensity, low-intensity, or no statin-and the independent association between the statin category and HF hospitalization during follow-up was examined. RESULTS: Over the course of the median 6-year follow-up, 17.7% of the patients were hospitalized for HF. Cox regression analysis revealed a significant association between the baseline statin category and HF incidence (p=0.002), independently of age, sex, hypertension, B-type natriuretic peptide, glycated hemoglobin, estimated glomerular filtration rate, and low-density lipoprotein (LDL) cholesterol levels. The moderate-intensity statin group had a significantly lower risk for HF than the low-intensity statin group with an adjusted HR of 0.31 (95% CI 0.13 to 0.65, p=0.0014). Interestingly, among patients with prevalent coronary artery diseases (CAD) and with baseline LDL controlled to less than 100 mg/dL, the frequency of HF was still significantly lower in the moderate-intensity group than in the low-intensity group or the no statin group. The effect of baseline statin category on HF was independent of incident CAD events during follow-up. CONCLUSIONS: In type 2 diabetes, moderate-intensity statins, in comparison to low-intensity or no statin, were associated with lower HF incidence independently of LDL levels or of CAD events.

Impact of acute and chronic hyperglycemia on in-hospital outcomes of patients with acute myocardial infarction.
Masashi Fujino, Masaharu Ishihara, Satoshi Honda, Shoji Kawakami, Takafumi Yamane, Toshiyuki Nagai, Kazuhiro Nakao, Tomoaki Kanaya, Leon Kumasaka, Yasuhide Asaumi, Tetsuo Arakawa, Yoshio Tahara, Michio Nakanishi, Teruo Noguchi, Kengo Kusano, Toshihisa Anzai, Yoichi Goto, Satoshi Yasuda, Hisao Ogawa
The American journal of cardiology, 114, 12, 1789, 93, EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC, 2014年12月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, This study was undertaken to assess the impact of acute hyperglycemia (acute-HG) and chronic hyperglycemia (chronic-HG) on short-term outcomes in patients with acute myocardial infarction (AMI). This study consisted of 696 patients with AMI. Acute-HG was defined as admission plasma glucose ≥200 mg/dl and chronic-HG as hemoglobin A1c ≥6.5%. Acute-HG was associated with higher peak serum creatine kinase (4,094 ± 4,594 vs 2,526 ± 2,227 IU/L, p <0.001) and in-hospital mortality (9.8% vs 1.6%, p <0.001). On the contrary, there was no significant difference in peak creatine kinase (2,803 ± 2,661 vs 2,940 ± 3,181 IU/L, p = 0.59) and mortality (3.3 vs 3.7%, p = 0.79) between patients with chronic-HG and those without. Multivariate analysis showed that admission plasma glucose was an independent predictor of in-hospital mortality (odds ratio 1.15, 95% confidence interval 1.05 to 1.27, p <0.001), but hemoglobin A1c was not. When only patients with acute-HG were analyzed, chronic-HG was associated with a significantly smaller infarct size (3,221 ± 3,001 vs 5,904 ± 6,473 IU/L, p <0.001) and lower in-hospital mortality (5.5 vs 18.9%, p = 0.01). In conclusion, these results suggested that acute-HG, but not chronic-HG, was associated with adverse short-term outcomes after AMI. Paradoxically, in patients with acute-HG, chronic-HG might abate the adverse effects of acute-HG.

Pathophysiological impact of serum fibroblast growth factor 23 in patients with nonischemic cardiac disease and early chronic kidney disease.
Miki Imazu, Hiroyuki Takahama, Hiroshi Asanuma, Akira Funada, Yasuo Sugano, Takahiro Ohara, Takuya Hasegawa, Masanori Asakura, Hideaki Kanzaki, Toshihisa Anzai, Masafumi Kitakaze
American journal of physiology. Heart and circulatory physiology, 307, 10, H1504-11, H1511, AMER PHYSIOLOGICAL SOC, 2014年11月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Although the important role of fibroblast growth factor (FGF)23 on cardiac remodeling has been suggested in advanced chronic kidney disease (CKD), little is known about serum (s)FGF23 levels in patients with heart failure (HF) due to nonischemic cardiac disease (NICD) and early CKD. The present study aimed to investigate sFGF23 levels in NICD patients and identify the responsible factors for the elevation of sFGF23 levels. We prospectively measured sFGF23 levels in consecutive hospitalized NICD patients with early CKD (estimated glomerular filtration rate ≥ 40 ml·min(-1)·1.73 m(-2)) and analyzed the data of both echocardiography and right heart catheterization. Of the 156 NICD patients (estimated glomerular filtration rate range: 41-128 ml·min(-1)·1.73 m(-2)), the most severe HF symptom (New York Heart Association class III-IV, 53% vs. 33%, P = 0.015) was found in the above median sFGF23 (39.1 pg/ml) group compared with the below median sFGF23 group. sFGF23 levels were higher in patients with HF hospitalization history compared with those without HF [median: 46.8 (interquartile range: 38.8-62.7) vs. 34.7 (interquartile range: 29.6-42.4) pg/ml, P < 0.0001]. In the multivariate analysis, HF hospitalization was independently related to elevated sFGF23 levels (P = 0.022). Both systolic dysfunction and high plasma aldosterone concentration were identified as predictors of high sFGF23 levels (P < 0.05). Among the neurohormonal parameters, elevated sFGF23 levels were the only factor to predict a declining left ventricular ejection fraction (P = 0.001). These findings suggest that the progression of HF per se contributes to the elevation of sFGF23 levels even in the early stages of CKD, which leads to further myocardial dysfunction, potentially creating a vicious cycle.

Trends in the clinical and pathological characteristics of cardiac rupture in patients with acute myocardial infarction over 35 years.
Satoshi Honda, Yasuhide Asaumi, Takafumi Yamane, Toshiyuki Nagai, Tadayoshi Miyagi, Teruo Noguchi, Toshihisa Anzai, Yoichi Goto, Masaharu Ishihara, Kunihiro Nishimura, Hisao Ogawa, Hatsue Ishibashi-Ueda, Satoshi Yasuda
Journal of the American Heart Association, 3, 5, e000984, WILEY-BLACKWELL, 2014年10月20日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: There is little known about whether the clinical and pathological characteristics and incidence of cardiac rupture (CR) in patients with acute myocardial infarction (AMI) have changed over the years. METHODS AND RESULTS: The incidence and clinical characteristics of CR were investigated in patients with AMI, who were divided into 3 cohorts: 1977-1989, 1990-2000, and 2001-2011. Of a total of 5699 patients, 144 were diagnosed with CR and 45 survived. Over the years, the incidence of CR decreased (1977-1989, 3.3%; 1990-2000, 2.8%; 2001-2011, 1.7%; P=0.002) in association with the widespread adoption of reperfusion therapy. The mortality rate of CR decreased (1977-1989, 90%; 1990-2000, 56%; 2001-2011, 50%; P=0.002) in association with an increase in the rate of emergent surgery. In multivariable analysis, first myocardial infarction, anterior infarct, female sex, hypertension, and age >70 years were significant risk factors for CR, whereas impact of hypertension on CR was weaker from 2001 to 2011. Primary percutaneous coronary intervention (PPCI) was a significant protective factor against CR. In 64 autopsy cases with CR, myocardial hemorrhage occurred more frequently in those who underwent PPCI or fibrinolysis than those who did not receive reperfusion therapy (no reperfusion therapy, 18.0%; fibrinolysis, 71.4%; PPCI, 83.3%; P=0.001). CONCLUSIONS: With the development of medical treatment, the incidence and mortality rate of CR have decreased. However, first myocardial infarction, anterior infarct, female sex, and old age remain important risk factors for CR. Adjunctive cardioprotection against reperfusion-induced myocardial hemorrhage is emerging in the current PPCI era.

Incidence and prognostic significance of myocardial late gadolinium enhancement in patients with sarcoidosis without cardiac manifestation.
Toshiyuki Nagai, Shun Kohsaka, Shigeo Okuda, Toshihisa Anzai, Koichiro Asano, Keiichi Fukuda
Chest, 146, 4, 1064, 1072, AMER COLL CHEST PHYSICIANS, 2014年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Cardiac death is the leading cause of mortality associated with sarcoidosis in Japan. However, the involvement of sarcoidosis infiltration often remains undetected. Recently, late gadolinium enhancement with cardiovascular MRI (LGE-CMR) imaging has been introduced for the detection of myocardial infiltrative disease, as it enables the detection of even minor myocardial damage. We investigated the incidence and prognostic value of LGE-CMR in patients with extracardiac sarcoidosis without cardiac manifestations. METHODS: Sixty-one consecutive patients who met the histologic and clinical criteria for sarcoidosis, and who did not have signs or symptoms of cardiovascular involvement, were prospectively recruited. LGE-CMR was performed at the time of enrollment, and patients were classified into positive or negative late gadolinium enhancement groups based on the findings. The study end point was a composite of all-cause death, symptomatic arrhythmia, and heart failure necessitating admission. RESULTS: Patients were predominantly middle aged (57 ± 15 years) and female (66%), and most had stable disease activity that did not require treatment with immunosuppressants. LGE-CMR detected cardiac involvement in eight patients (13%). Interventricular septal thinning detected by echocardiography was an independent predictor of LGE-CMR-detected cardiac involvement. During the follow-up period of 50 ± 12 months, no significant difference in adverse events was noted between patients in the LGE-CMR-positive and LGE-CMR-negative groups. CONCLUSIONS: LGE-CMR detected cardiac involvement in 13% of patients with sarcoidosis without cardiac manifestation, but both patients with and without LGE had relatively low event rates. TRIAL REGISTRY: Japan Primary Registries Network; No.: UMIN000001549; URL: www.umin.ac.jp.

Development of a web system to support the management of chronic heart failure patients for use in disaster-stricken areas
Shoko Tani, Yoshihiro Miyamoto, Toshihisa Anzai, Shigeki Kuwata, Takeshi Kuwahara, Yasuo Sugano, Toshinari Nakao, Kiyokazu Kawakami, Naoko Ueno, Hiroshi Inada, Kazuo Nakazawa
Transactions of Japanese Society for Medical and Biological Engineering, 52, 259, O-260, Japan Soc. of Med. Electronics and Biol. Engineering, 2014年08月17日, ［査読有り］
日本語, 研究論文（学術雑誌）, The authors aim to address self-management support of chronic heart failure (CHF) patients who are treated in the temporary housings of disaster-stricken areas. We develop a web management system to collect lifestyle information from patients with mild to moderately-severe CHF. Patients can enter information on their lifestyle and medication. They send their information to the web server of the medical institution using a tablet PC. We present the basic health conditions that are essential for patient management of CHF. We then examine the functions required to implement this system. Based on the results of these investigations, we designed an input interface and created a program that the patients can use to manage their prescription medicine, their weight and other items. Our system is expected to increase the ease of information collection, which is an important part of managing patients with CHF. We plan to validate this system in a clinical.

Extensive late gadolinium enhancement on cardiovascular magnetic resonance predicts adverse outcomes and lack of improvement in LV function after steroid therapy in cardiac sarcoidosis.
Takayuki Ise, Takuya Hasegawa, Yoshiaki Morita, Naoaki Yamada, Akira Funada, Hiroyuki Takahama, Makoto Amaki, Hideaki Kanzaki, Hideo Okamura, Shiro Kamakura, Wataru Shimizu, Toshihisa Anzai, Masafumi Kitakaze
Heart (British Cardiac Society), 100, 15, 1165, 72, BMJ PUBLISHING GROUP, 2014年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Gadolinium-enhanced cardiovascular magnetic resonance is an emerging tool for the diagnosis of cardiac sarcoidosis (CS); however, the correlations between extent of late gadolinium enhancement (LGE) and efficacy of steroid therapy and adverse outcomes in patients with CS remain unclear. OBJECTIVE: We aimed to clarify the prognostic impact of extent of LGE in patients with CS. METHODS: Before the start of steroid therapy, 43 consecutive LGE-positive patients with CS were divided into two groups based on the extent of LGE by a median value: small-extent LGE (LGE mass <20% of LV mass; n=21) and large-extent LGE (LGE mass ≥20% of LV mass; n=22). We examined the correlations between extent of LGE and outcomes after steroid therapy. RESULTS: Among the 6 patients who died from heart disorders, 11 patients who were hospitalised because of heart failure and 6 patients who suffered life-threatening arrhythmia during the follow-up period, large-extent LGE predicted higher incidences of cardiac mortality and hospitalisation for heart failure. Multivariate Cox regression analysis showed that large-extent LGE was independently associated with combined adverse outcomes including cardiac death, hospitalisation for heart failure, and life-threatening arrhythmias. In the small-extent LGE group, LV end-diastolic volume index significantly decreased and LVEF significantly increased after steroid therapy, whereas in the large-extent LGE group, neither LV volume nor LVEF changed substantially. CONCLUSIONS: Large-extent LGE correlates with absence of LV functional improvement and high incidence of adverse outcomes in patients with CS after steroid therapy.

Decreased myocardial dendritic cells is associated with impaired reparative fibrosis and development of cardiac rupture after myocardial infarction in humans.
Toshiyuki Nagai, Satoshi Honda, Yasuo Sugano, Taka-aki Matsuyama, Keiko Ohta-Ogo, Yasuhide Asaumi, Yoshihiko Ikeda, Kengo Kusano, Masaharu Ishihara, Satoshi Yasuda, Hisao Ogawa, Hatsue Ishibashi-Ueda, Toshihisa Anzai
Journal of the American Heart Association, 3, 3, e000839, WILEY-BLACKWELL, 2014年06月03日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Dendritic cells (DC) play pivotal roles in regulating the immune system and inflammatory response. We previously reported DC infiltration in the infarcted heart and its immunoprotective roles in the post-infarction healing process after experimental myocardial infarction (MI). However, its clinical significance has not been determined. METHODS AND RESULTS: The degree of DC infiltration and its correlation with the post-infarction healing process in the human infarcted heart were investigated in 24 autopsy subjects after ST-elevation MI. Patients were divided into two groups according to the presence (n=13) or absence (n=11) of cardiac rupture. The numbers of infiltrated DC and macrophages and the extent of fibrosis in the infarcted area were examined. In the rupture group, CD68(+) macrophage infiltration was increased and CD209(+) DC, and CD11c(+) DC infiltration and the extent of reparative fibrosis were decreased compared with the non-rupture group, under matched baseline characteristics including the time from onset to death and use of revascularization. Furthermore, there was a significant positive correlation between the number of infiltrating CD209(+) DC, and CD11c(+) DC and the extent of reparative fibrosis. CONCLUSIONS: Decreased number of DC in human-infarcted myocardial tissue was associated with increased macrophage infiltration, impaired reparative fibrosis, and the development of cardiac rupture after MI. These findings suggest a protective role of DC in post-MI inflammation and the subsequent healing process.

Hemoglobin A1c predicts heart failure hospitalization independent of baseline cardiac function or B-type natriuretic peptide level.
Ichiro Kishimoto, Hisashi Makino, Yoko Ohata, Tamiko Tamanaha, Mayu Tochiya, Akiko Kada, Masaharu Ishihara, Toshihisa Anzai, Wataru Shimizu, Satoshi Yasuda, Hisao Ogawa
Diabetes research and clinical practice, 104, 2, 257, 65, ELSEVIER IRELAND LTD, 2014年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Diabetes is a major risk factor for heart failure (HF). We examined whether baseline HbA1c level predicts HF incidence independent of other HF risk factors, including baseline cardiac structural and functional abnormalities. METHODS: In patients with type 2 diabetes, multivariable Cox regression models were constructed to examine the independent association between baseline HbA1c and future HF hospitalization. RESULTS: In 608 subjects (mean age, 66.5 years; men, 68%; mean HbA1c, 9.1% (76 mmol/mol)), 92 were hospitalized for HF during a median follow-up of 6 years. For a 1% (11 mmol/mol) increase in baseline HbA1c, the hazard ratio for HF was 1.23 (95% confidence interval, 1.1-1.7, p<0.001) with adjustment for age, sex, body mass index, blood pressure and plasma B-type natriuretic peptide (BNP) level. The effect of HbA1c on HF was independent of baseline left ventricular (LV) ejection fraction, the ratio of peak early to late diastolic filling velocity, and prevalent/incident coronary heart disease (CHD), and was more evident in patients with enlarged LV, decreased systolic function, prevalent CHD, or prevalent HF. CONCLUSION: In patients with type 2 diabetes, HbA1c significantly predicts future HF hospitalization independent of baseline BNP level or echocardiographic parameters.

Electrocardiographic predictors of response to cardiac resynchronization therapy in patients with intraventricular conduction delay.
Yoichi Takaya, Takashi Noda, Ikutaro Nakajima, Yuko Yamada, Koji Miyamoto, Hideo Okamura, Kazuhiro Satomi, Takeshi Aiba, Kengo F Kusano, Hideaki Kanzaki, Toshihisa Anzai, Masaharu Ishihara, Satoshi Yasuda, Hisao Ogawa, Shiro Kamakura, Wataru Shimizu
Circulation journal : official journal of the Japanese Circulation Society, 78, 1, 71, 7, JAPANESE CIRCULATION SOC, 2014年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Little is known about predictors of response to cardiac resynchronization therapy (CRT) in patients with intraventricular conduction delay (IVCD). The purpose of this study was to investigate the benefits of CRT and significant variables on surface electrocardiogram (ECG) to predict response to CRT in those patients. METHODS AND RESULTS: Among the cohort of 152 CRT patients, 40 patients with IVCD were evaluated. Sixteen patients (40%) were responders. At baseline, responders had a wider QRS duration (158±18 vs. 144±18ms, P=0.02) and a higher frequency of left axis deviation (LADEV; 75% vs. 29%, P=0.004) compared with non-responders. After CRT, greater shortening of QRS duration (ΔQRS; 26±24 vs. 7±24ms, P=0.02), axis shift from LADEV to right axis deviation (RADEV; 69% vs. 13%, P<0.001), and both rightward forces in lead I and anterior forces in V1 (56% vs. 13%, P=0.003) were found more frequently in responders. Multivariable logistic regression analysis showed that LADEV at baseline, or ΔQRS and axis shift from LADEV to RADEV after CRT were independent predictors of response to CRT. CONCLUSIONS: Patients with IVCD may not respond to CRT, but LADEV at baseline and reversal of ventricular activation after CRT on surface ECG could be important to predict response to CRT.

Admission hyperglycemia is an independent predictor of acute kidney injury in patients with acute myocardial infarction.
Noriaki Moriyama, Masaharu Ishihara, Teruo Noguchi, Michio Nakanishi, Tetsuo Arakawa, Yasuhide Asaumi, Leon Kumasaka, Tomoaki Kanaya, Tadayoshi Miyagi, Toshiyuki Nagai, Takafumi Yamane, Masashi Fujino, Satoshi Honda, Reiko Fujiwara, Toshihisa Anzai, Kengo Kusano, Yoichi Goto, Satoshi Yasuda, Hisao Ogawa
Circulation journal : official journal of the Japanese Circulation Society, 78, 6, 1475, 80, JAPANESE CIRCULATION SOC, 2014年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Acute kidney injury (AKI) and acute hyperglycemia are associated with unfavorable outcomes. The impact of acute hyperglycemia on the development of AKI after acute myocardial infarction (AMI), however, remains unclear. This study was undertaken to assess the relationship between admission glucose and incidence of AKI after AMI. METHODS AND RESULTS: This study consisted of 760 patients with AMI admitted to the National Cerebral and Cardiovascular Center within 48h after symptom onset. Blood sample was obtained on admission and repeated sampling was done at least every 1 or 2 days during the first week. AKI was diagnosed as increase in serum creatinine ≥0.3mg/dl or ≥50% within any 48h. Ninety-six patients (13%) had AKI during hospitalization for AMI, and these patients had higher in-hospital mortality than those without AKI (25% vs. 3%, P<0.001). Patients with AKI had higher plasma glucose (PG) on admission than those without (222±105mg/dl vs. 166±69mg/dl, P<0.001). The incidence of AKI increased as admission PG rose: 7% with PG <120mg/dl; 9% with PG 120-160mg/dl; 11% with PG 160-200mg/dl; and 28% with PG >200mg/dl (P<0.01). On multivariate analysis admission PG was an independent predictor of AKI (odds ratio, 1.10; 95% confidence interval: 1.03-1.18, P=0.02). CONCLUSIONS: Admission hyperglycemia might have contributed to the development of AKI in patients with AMI.

Massive mobile thrombus in the left ventricle due to Löffler endocarditis complicated with dilated cardiomyopathy.
Nakashima T, Funada A, Kanzaki H, Sugano Y, Ohara T, Hasegawa T, Ishibashi-Ueda H, Kitakaze M, Anzai T
Circulation journal : official journal of the Japanese Circulation Society, 78, 8, 1992, 4, JAPANESE CIRCULATION SOC, 2014年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

Electrocardiographic predictors of response to cardiac resynchronization therapy in patients with intraventricular conduction delay.
Yoichi Takaya, Takashi Noda, Ikutaro Nakajima, Yuko Yamada, Koji Miyamoto, Hideo Okamura, Kazuhiro Satomi, Takeshi Aiba, Kengo F Kusano, Hideaki Kanzaki, Toshihisa Anzai, Masaharu Ishihara, Satoshi Yasuda, Hisao Ogawa, Shiro Kamakura, Wataru Shimizu
Circulation journal : official journal of the Japanese Circulation Society, 78, 1, 71, 7, JAPANESE CIRCULATION SOC, 2014年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Little is known about predictors of response to cardiac resynchronization therapy (CRT) in patients with intraventricular conduction delay (IVCD). The purpose of this study was to investigate the benefits of CRT and significant variables on surface electrocardiogram (ECG) to predict response to CRT in those patients. METHODS AND RESULTS: Among the cohort of 152 CRT patients, 40 patients with IVCD were evaluated. Sixteen patients (40%) were responders. At baseline, responders had a wider QRS duration (158±18 vs. 144±18ms, P=0.02) and a higher frequency of left axis deviation (LADEV; 75% vs. 29%, P=0.004) compared with non-responders. After CRT, greater shortening of QRS duration (ΔQRS; 26±24 vs. 7±24ms, P=0.02), axis shift from LADEV to right axis deviation (RADEV; 69% vs. 13%, P<0.001), and both rightward forces in lead I and anterior forces in V1 (56% vs. 13%, P=0.003) were found more frequently in responders. Multivariable logistic regression analysis showed that LADEV at baseline, or ΔQRS and axis shift from LADEV to RADEV after CRT were independent predictors of response to CRT. CONCLUSIONS: Patients with IVCD may not respond to CRT, but LADEV at baseline and reversal of ventricular activation after CRT on surface ECG could be important to predict response to CRT.

Significance of AT1 receptor independent activation of mineralocorticoid receptor in murine diabetic cardiomyopathy.
Yuji Nagatomo, Tomomi Meguro, Hiroyuki Ito, Kimi Koide, Toshihisa Anzai, Keiichi Fukuda, Satoshi Ogawa, Tsutomu Yoshikawa
PloS one, 9, 3, e93145, PUBLIC LIBRARY SCIENCE, 2014年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Diabetes mellitus (DM) has deleterious influence on cardiac performance independent of coronary artery disease and hypertension. The objective of the present study was to investigate the role of the renin-angiotensin-aldosterone system, especially angiotensin II type 1a receptor (AT1aR) and mineralocorticoid receptor (MR) signaling, in left ventricular (LV) dysfunction induced by diabetes mellitus (DM). METHODS AND RESULTS: DM was induced by intraperitoneal injection of streptozotocin (200 mg/kg BW) in wild-type (WT) or AT1aR knockout (KO) male mice, and they were bred during 6 or 12 weeks. Some KO mice were administered the MR antagonist eplerenone (100 mg/kg body weight). At 6 weeks, LV diastolic function was impaired in WT-DM, but preserved in KO-DM. At that time point MR mRNA expression was upregulated, NADPH oxidase subunit (p47phox) and glutathione peroxidase (GPx1) mRNA expression were upregulated, the staining intensities of LV tissue for 4-hydroxy-2-nonenal was stronger in immunohistochemistry, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) positive cells was increased, Bcl-2 protein expression was significantly downregulated, and the expression of SERCA2a and phosphorylated phospholamban was depressed in WT-DM, while these changes were not seen in KO-DM. At 12 weeks, however, these changes were also noted in KO-DM. Eplerenone arrested those changes. The plasma aldosterone concentration was elevated in WT-DM but not in KO-DM at 6 weeks. It showed 3.7-fold elevation at 12 weeks even in KO-DM, which suggests "aldosterone breakthrough" phenomenon. However, the aldosterone content in LV tissue was unchanged in KO-DM. CONCLUSIONS: DM induced diastolic dysfunction was observed even in KO at 12 weeks, which was ameliorated by minelarocorticoid receptor antagonist, eplerenone. AT1-independent MR activation in the LV might be responsible for the pathogenesis of diabetic cardiomyopathy.

Admission hyperglycemia is an independent predictor of acute kidney injury in patients with acute myocardial infarction.
Noriaki Moriyama, Masaharu Ishihara, Teruo Noguchi, Michio Nakanishi, Tetsuo Arakawa, Yasuhide Asaumi, Leon Kumasaka, Tomoaki Kanaya, Tadayoshi Miyagi, Toshiyuki Nagai, Takafumi Yamane, Masashi Fujino, Satoshi Honda, Reiko Fujiwara, Toshihisa Anzai, Kengo Kusano, Yoichi Goto, Satoshi Yasuda, Hisao Ogawa
Circulation journal : official journal of the Japanese Circulation Society, 78, 6, 1475, 80, JAPANESE CIRCULATION SOC, 2014年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Acute kidney injury (AKI) and acute hyperglycemia are associated with unfavorable outcomes. The impact of acute hyperglycemia on the development of AKI after acute myocardial infarction (AMI), however, remains unclear. This study was undertaken to assess the relationship between admission glucose and incidence of AKI after AMI. METHODS AND RESULTS: This study consisted of 760 patients with AMI admitted to the National Cerebral and Cardiovascular Center within 48h after symptom onset. Blood sample was obtained on admission and repeated sampling was done at least every 1 or 2 days during the first week. AKI was diagnosed as increase in serum creatinine ≥0.3mg/dl or ≥50% within any 48h. Ninety-six patients (13%) had AKI during hospitalization for AMI, and these patients had higher in-hospital mortality than those without AKI (25% vs. 3%, P<0.001). Patients with AKI had higher plasma glucose (PG) on admission than those without (222±105mg/dl vs. 166±69mg/dl, P<0.001). The incidence of AKI increased as admission PG rose: 7% with PG <120mg/dl; 9% with PG 120-160mg/dl; 11% with PG 160-200mg/dl; and 28% with PG >200mg/dl (P<0.01). On multivariate analysis admission PG was an independent predictor of AKI (odds ratio, 1.10; 95% confidence interval: 1.03-1.18, P=0.02). CONCLUSIONS: Admission hyperglycemia might have contributed to the development of AKI in patients with AMI.

Massive mobile thrombus in the left ventricle due to Löffler endocarditis complicated with dilated cardiomyopathy.
Nakashima T, Funada A, Kanzaki H, Sugano Y, Ohara T, Hasegawa T, Ishibashi-Ueda H, Kitakaze M, Anzai T
Circulation journal : official journal of the Japanese Circulation Society, 78, 8, 1992, 4, JAPANESE CIRCULATION SOC, 2014年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

Left circumflex coronary artery is protected against no-reflow phenomenon following percutaneous coronary intervention for coronary artery disease.
Toshiyuki Nagai, Takuro Hirano, Mayumi Tsunoda, Haruhiko Hosaka, Yoshikazu Kishino, Takaharu Katayama, Keisuke Matsumura, Takashi Miyagawa, Shun Kohsaka, Toshihisa Anzai, Keiichi Fukuda, Masahiro Suzuki
Heart and vessels, 28, 5, 559, 65, SPRINGER, 2013年09月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Despite the positive impact of percutaneous coronary intervention (PCI) on reducing mortality, a small percentage of patients experience poor myocardial reperfusion following PCI. However, factors associated with no-reflow remain unclear. We investigated clinical factors associated with no-reflow following PCI for coronary artery disease (CAD). We retrospectively analyzed 1622 consecutive CAD patients who underwent PCI over a 5-year period at our institution. Patients were divided into two groups according to the presence (n = 31) or absence (n = 1591) of no-reflow, defined as Thrombolysis in Myocardial Infarction flow grade <3 after PCI. No significant differences in patient characteristics or PCI strategy were seen between the no-reflow and normal flow groups. The incidence of no-reflow was significantly lower in the left circumflex artery (LCx) than in the left anterior descending artery (LAD) (P = 0.0015), with no differences in characteristics or PCI strategy between these two target vessels. Multivariate analysis revealed that involvement of the LCx was an independent protective factor against no-reflow (odds ratio 0.14, 95 % confidence interval 0.02-0.98, P = 0.044). In conclusion, LCx as the target vessel was protective against no-reflow compared with LAD following PCI for CAD. Our results suggest that embolic protection devices may be unnecessary in CAD patients with involvement of LCx.

Eicosapentaenoic acid suppresses adverse effects of C-reactive protein overexpression on pressure overload-induced cardiac remodeling.
Toshiyuki Nagai, Toshihisa Anzai, Yoshinori Mano, Hidehiro Kaneko, Atsushi Anzai, Yasuo Sugano, Yuichiro Maekawa, Toshiyuki Takahashi, Tsutomu Yoshikawa, Keiichi Fukuda
Heart and vessels, 28, 3, 404, 11, SPRINGER, 2013年05月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Serum C-reactive protein (CRP) elevation is associated with poor clinical outcome in patients with heart failure (HF). We previously reported that CRP exacerbates the development of pressure overload-induced cardiac remodeling through an enhanced inflammatory response and oxidative stress. In the present study, we examined the effect of eicosapentaenoic acid (EPA), a suppressor of inflammatory response and oxidative stress, on pressure overload-induced cardiac remodeling. Transverse aortic constriction (TAC) was performed on transgenic mice overexpressing CRP (CRPtg) and nontransgenic littermates (TAC/CON). CRPtg with TAC operation were randomly assigned to be fed a standard diet (TAC/CRPtg) or an EPA-enriched diet (7 % of total energy) (TAC/CRPtg/EPA). Myocardial mRNA level of transforming growth factor-β1, proinflammatory cytokines, and oxidative stress markers were increased in TAC/CRPtg in comparison with TAC/CON 1 and 4 weeks after the operation. These parameters were significantly suppressed in TAC/CRPtg/EPA compared with TAC/CRPtg. In addition, after 4 weeks of EPA treatment, as compared with TAC/CRPtg, TAC/CRPtg/EPA mice demonstrated reduced heart and lung weights, increased left ventricular fractional shortening, and decreased left ventricular end-diastolic pressure, together with decreased cardiac hypertrophy, fibrosis, and improved cardiac function. In conclusion, the anti-inflammatory and antioxidative properties of EPA may make it an effective therapeutic strategy for adverse cardiac remodeling associated with CRP overexpression.

Post-infarction inflammation and left ventricular remodeling: a double-edged sword.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 77, 3, 580, 7, 2013年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, After myocardial infarction (MI), inflammatory cells such as neutrophils, followed by monocytes and macrophages, infiltrate and phagocytose the necrotic tissues, as well as secreting a variety of inflammatory cytokines. The vulnerable myocardium, which consists of necrotic tissue and inflammatory cells, is susceptible to wall stress, resulting in infarct expansion. Subacute cardiac rupture is an extreme form of infarct expansion, whereas ventricular aneurysm is its chronic form and a trigger for subsequent left ventricular (LV) remodeling. Although post-infarction inflammation is essential for the healing process, excessive inflammation could play an important role in the development of LV remodeling. Increase in the C-reactive protein level, which reflects myocardial inflammation, is reported to be a useful predictive marker for cardiac rupture, ventricular aneurysm and LV remodeling. In addition, an increase in peripheral monocyte count is associated with a poor outcome after MI, and an animal study has demonstrated that granulocyte/macrophage-colony stimulating factor induction causes excessive macrophage infiltration in the infarcted area and worsening of LV remodeling. Recently, it was also found that dendritic cells play an important role in controlling excessive inflammation caused by monocytes/macrophages. Thus, inflammation that develops after MI is a double-edged sword, and how to control inflammation to suppress pathological remodeling is an important issue to be considered in developing new treatment for heart failure.

Extent of heart rate reduction during hospitalization using beta-blockers, not the achieved heart rate itself at discharge, predicts the clinical outcome in patients with acute heart failure syndromes.
Hiroyuki Takahama, Hiroyuki Yokoyama, Akiko Kada, Kenichi Sekiguchi, Masashi Fujino, Akira Funada, Makoto Amaki, Takuya Hasegawa, Masanori Asakura, Hideaki Kanzaki, Toshihisa Anzai, Masafumi Kitakaze
Journal of cardiology, 61, 1, 58, 64, 2013年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIM: It has been uncertain whether patients with acute heart failure syndromes (AHFSs) benefit from a lower heart rate (HR) itself or from treatment for heart failure (HF) that reduces sympathetic tone with consequent HR reduction (HRR). The present study investigated the influence of HRR during hospitalization on the prognosis of AHFS patients. METHODS AND RESULTS: In 421 AHFS patients, we analyzed the relationship between HRR during hospitalization and the prognosis after discharge. During a mean follow-up period of 1.9 years, 76 and 55 patients died or were re-hospitalized for HF, respectively. Although HR at discharge did not influence cardiac events (hazard ratio [HR]: 1.00 [95% CI; 0.99-1.02], p=0.22), the extent of HRR was a predictor of cardiac events (HR: 0.89 [0.84-0.96], p<0.001). Kaplan-Meier analysis revealed that the cardiac event rate of the HRR-positive group (≥ 27 bpm reduction of HR from 114 ± 24 at admission to 65 ± 11 bpm at discharge) was significantly lower than that of the HRR-negative group (≤ 26 bpm (=median value) reduction of HR from 74 ± 14 to 71 ± 14 bpm). In the HRR-positive group, the cardiac event rate was significantly lower in patients receiving beta-blockers. Furthermore, the extent of HR change was an important predictor of cardiac events among other markers, compared with the change in systolic blood pressure or B-type natriuretic peptide. CONCLUSION: The HR itself at discharge was not associated with the prognosis, but the extent of HRR achieved by treatment of HF with beta-blockers was a strong predictor for the clinical outcome in AHFS patients.

Post-infarction inflammation and left ventricular remodeling: a double-edged sword.
Toshihisa Anzai
Circulation journal : official journal of the Japanese Circulation Society, 77, 3, 580, 7, JAPANESE CIRCULATION SOC, 2013年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, After myocardial infarction (MI), inflammatory cells such as neutrophils, followed by monocytes and macrophages, infiltrate and phagocytose the necrotic tissues, as well as secreting a variety of inflammatory cytokines. The vulnerable myocardium, which consists of necrotic tissue and inflammatory cells, is susceptible to wall stress, resulting in infarct expansion. Subacute cardiac rupture is an extreme form of infarct expansion, whereas ventricular aneurysm is its chronic form and a trigger for subsequent left ventricular (LV) remodeling. Although post-infarction inflammation is essential for the healing process, excessive inflammation could play an important role in the development of LV remodeling. Increase in the C-reactive protein level, which reflects myocardial inflammation, is reported to be a useful predictive marker for cardiac rupture, ventricular aneurysm and LV remodeling. In addition, an increase in peripheral monocyte count is associated with a poor outcome after MI, and an animal study has demonstrated that granulocyte/macrophage-colony stimulating factor induction causes excessive macrophage infiltration in the infarcted area and worsening of LV remodeling. Recently, it was also found that dendritic cells play an important role in controlling excessive inflammation caused by monocytes/macrophages. Thus, inflammation that develops after MI is a double-edged sword, and how to control inflammation to suppress pathological remodeling is an important issue to be considered in developing new treatment for heart failure.

Titration of β-blockers for patients with heart failure.
Anzai T
Circulation journal : official journal of the Japanese Circulation Society, 77, 4, 902, 3, 2013年, ［査読有り］, ［国内誌］
英語

A successful case of percutaneous transluminal septal myocardial ablation for mitral regurgitation that emerged following mitral valve repair surgery.
Tomohiro Hayashi, Makoto Amaki, Hideaki Kanzaki, Akira Funada, Yasuo Sugano, Takahiro Ohara, Hiroyuki Takahama, Takuya Hasegawa, Masafumi Kitakaze, Toshihisa Anzai
Internal medicine (Tokyo, Japan), 52, 24, 2765, 9, 2013年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 70-year-old man complaining of exertional dyspnea was referred to our hospital for recurrence of mitral regurgitation (MR) after mitral valve repair. Echocardiography revealed the presence of a bulging subaortic septum with flow acceleration in the left ventricular outflow tract (LVOT) and systolic anterior motion of the mitral valve with moderate MR, consistent with LVOT obstruction. Since medical therapy was not sufficiently effective, we performed percutaneous transluminal septal myocardial ablation (PTSMA). After the procedure, the MR resolved, with a reduced LVOT pressure gradient. The patient's symptoms improved. PTSMA was effective for the treatment of MR that emerged after mitral valve repair.

Eosinophilia associated with dobutamine allergy causes eosinophilic endomyocarditis confirmed by serial endomyocardial biopsies.
Moritoshi Funasako, Akira Funada, Hideaki Kanzaki, Hiroyuki Takahama, Makoto Amaki, Takuya Hasegawa, Yoshihiko Ikeda, Hatsue Ishibashi-Ueda, Toshihisa Anzai, Masafumi Kitakaze
Journal of cardiology cases, 6, 6, e179-e182, e182, 2012年12月, ［査読有り］, ［国内誌］
英語, We report a case of eosinophilic endomyocarditis caused by eosinophilia due to dobutamine allergy and successfully treated by a short-term and medium-dose steroid administration. Serial endomyocardial biopsies were useful for early diagnosis and evaluation of the effect of the treatment. Eosinophilic endomyocarditis due to dobutamine allergy is a rare entity; however, because of the high utilization rate of dobutamine in patients with low output heart failure, it is important to recognize that additional deterioration of cardiac function caused by eosinophilic endomyocarditis makes prognosis poor and early intervention is necessary. .

High-mobility group box 1 protein blockade suppresses development of abdominal aortic aneurysm.
Takashi Kohno, Toshihisa Anzai, Hidehiro Kaneko, Yasuo Sugano, Hideyuki Shimizu, Masayuki Shimoda, Taku Miyasho, Minoru Okamoto, Hiroshi Yokota, Shingo Yamada, Tsutomu Yoshikawa, Yasunori Okada, Ryohei Yozu, Satoshi Ogawa, Keiichi Fukuda
Journal of cardiology, 59, 3, 299, 306, ELSEVIER IRELAND LTD, 2012年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Abdominal aortic aneurysm (AAA) expansion is characterized by chronic inflammatory cell infiltration and extracellular matrix degradation. High-mobility group box 1 protein (HMGB1) is one of the damage-associated molecular pattern molecules derived from injured/necrotic and activated inflammatory cells. We investigated the expression of HMGB1 in human AAA and mouse experimental AAA. Then, we evaluated the effect of HMGB1 blockade on AAA formation in the mouse model. METHODS AND RESULTS: Human AAA samples showed increased HMGB1 expression compared with normal aortic wall. In a mouse CaCl(2)-induced AAA model, the expression of HMGB1 was increased compared with that in sham, and was positively correlated with matrix metalloproteinase (MMP)-2 and MMP-9 activity. We administered neutralizing anti-HMGB1 antibody (AAA/anti-H) or control antibody (AAA/C) to AAA mice subcutaneously every 3 days for 6 weeks. Treatment with neutralizing anti-HMGB1 antibody suppressed AAA formation, and attenuated elastin fragmentation. HMGB1 blockade markedly reduced the number of macrophages and MMP-2 and MMP-9 activity in aneurysmal tissue. The mRNA level of tumor necrosis factor-α and CD68 in the aorta was reduced in AAA/anti-H compared with AAA/C. CONCLUSIONS: Elevation of HMGB1 level in aneurysmal tissue was observed in human AAA and mouse experimental AAA. HMGB1 blockade in a mouse AAA model reduced AAA progression, in association with reduced infiltration of macrophages and MMPs activity. These findings suggest a significant role for HMGB1 in the pathogenesis of AAA.

Effect of preoperative evaluation by multidetector computed tomography in percutaneous coronary interventions of chronic total occlusions.
Koji Ueno, Akio Kawamura, Takeshi Onizuka, Takashi Kawakami, Yuji Nagatomo, Kentaro Hayashida, Shinsuke Yuasa, Yuichiro Maekawa, Toshihisa Anzai, Masahiro Jinzaki, Sachio Kuribayashi, Satoshi Ogawa
International journal of cardiology, 156, 1, 76, 9, ELSEVIER IRELAND LTD, 2012年04月05日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The prevalence of success of percutaneous coronary interventions (PCIs) of chronic total occlusions (CTOs) remains relatively low. We determined the effect of preoperative multidetector computed tomography coronary angiography (CTCA) in PCIs of CTOs. METHODS: The study population was 100 consecutive patients who underwent PCIs of CTOs from January 2005 to December 2007 at Keio University School of Medicine. They were divided into two groups according to the absence (non-CT group, n=60) or presence (CT group, n=40) of preoperative CTCA. The effect of preoperative CTCA was assessed in the prevalence of success of the procedure, prevalence of complications, irradiation time, and the dose of contrast agents. RESULTS: The prevalence of procedural success was similar in both groups (non-CT group vs CT group 80.0% vs 77.5%, p=0.76). Irradiation time and the dose of contrast agents were also similar between these groups. The prevalence of complications was significantly reduced in the CT group (23.3% vs 7.5%, p=0.039), especially coronary perforations, which required treatment only in the non-CT group (10.0% vs 0.0%, p=0.039). Multiple logistic regression analysis revealed that use of a rotablator (odds ratio [OR]: 4.40, 95% confidence interval [CI]: 1.19-16.27, p=0.027) and absence of preoperative CTCA (OR: 4.26, 95% CI: 1.04-17.49, p=0.044) were independent determinants of complications. CONCLUSION: Preoperative CTCA does not affect the prevalence of procedural success, irradiation time and the dose of contrast agents, but may be useful to reduce the prevalence of complications during PCIs of CTOs.

Regulatory role of dendritic cells in postinfarction healing and left ventricular remodeling.
Atsushi Anzai, Toshihisa Anzai, Shigenori Nagai, Yuichiro Maekawa, Kotaro Naito, Hidehiro Kaneko, Yasuo Sugano, Toshiyuki Takahashi, Hitoshi Abe, Satsuki Mochizuki, Motoaki Sano, Tsutomu Yoshikawa, Yasunori Okada, Shigeo Koyasu, Satoshi Ogawa, Keiichi Fukuda
Circulation, 125, 10, 1234, 45, LIPPINCOTT WILLIAMS & WILKINS, 2012年03月13日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Inflammation and immune responses are integral components in the healing process after myocardial infarction. We previously reported dendritic cell (DC) infiltration in the infarcted heart; however, the precise contribution of DC in postinfarction healing is unclear. METHODS AND RESULTS: Bone marrow cells from CD11c-diphtheria toxin receptor/green fluorescent protein transgenic mice were transplanted into lethally irradiated wild-type recipient mice. After reconstitution of bone marrow-derived cells, the recipient mice were treated with either diphtheria toxin (DC ablation) or vehicle (control), and myocardial infarction was created by left coronary ligation. CD11c(+) green fluorescent protein-positive DCs expressing CD11b and major histocompatibility complex class II were recruited into the heart, peaking on day 7 after myocardial infarction in the control group. Mice with DC ablation for 7 days showed deteriorated left ventricular function and remodeling. The DC-ablated group demonstrated enhanced and sustained expression of inflammatory cytokines such as interleukin-1β, interleukin-18, and tumor necrosis factor-α, prolonged extracellular matrix degradation associated with a high level of matrix metalloproteinase-9 activity, and diminished expression level of interleukin-10 and endothelial cell proliferation after myocardial infarction compared with the control group. In vivo analyses revealed that DC-ablated infarcts had enhanced monocyte/macrophage recruitment. Among these cells, marked infiltration of proinflammatory Ly6C(high) monocytes and F4/80(+) CD206(-) M1 macrophages and, conversely, impaired recruitment of anti-inflammatory Ly6C(low) monocytes and F4/80(+) CD206(+) M2 macrophages in the infarcted myocardium were identified in the DC-ablated group compared with the control group. CONCLUSIONS: These results suggest that the DC is a potent immunoprotective regulator during the postinfarction healing process via its control of monocyte/macrophage homeostasis.

Low incidence of catheter-related complications in patients with advanced pulmonary arterial hypertension undergoing continuous epoprostenol infusion.
Toshiyuki Nagai, Shun Kohsaka, Toshihisa Anzai, Tsutomu Yoshikawa, Keiichi Fukuda, Toru Sato
Chest, 141, 1, 272, 273, AMER COLL CHEST PHYSICIANS, 2012年01月, ［査読有り］, ［国際誌］
英語

Significance of electrocardiographic right ventricular hypertrophy in patients with pulmonary hypertension with or without right ventricular systolic dysfunction.
Toshiyuki Nagai, Shun Kohsaka, Mitsushige Murata, Shigeo Okuda, Toshihisa Anzai, Keiichi Fukuda, Toru Satoh
Internal medicine (Tokyo, Japan), 51, 17, 2277, 83, JAPAN SOC INTERNAL MEDICINE, 2012年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: We sought to determine the value of electrocardiographic right ventricular hypertrophy (ECG-RVH) in pulmonary hypertension (PH) patients with right ventricular systolic dysfunction defined by cardiac magnetic resonance (CMR-RVSD). PATIENTS: A total of 31 consecutive patients with PH with a mean pulmonary arterial pressure of >25 mmHg underwent both ECG and CMR studies. Patients were divided into 2 groups according to the presence of RVSD, defined as a RV ejection fraction <35%. Logistic regression modeling was performed to define the association between ECG-RVH and CMR-RVSD. RESULTS: About half of the patients had RVSD (n=15 ; 48%). The R to S wave ratio (p=0.01) or incidence of qR pattern (p=0.002) in lead V(1) was significantly greater in patients with PH complicated by RVSD than in those without RVSD. These 2 patterns were significant predictors of RVSD [odds ratio (OR), 19.3 for qR; OR, 14.0 for R/S>1] and when each of these ECG findings was assigned with a point proportional to OR (score of 2 for qR in lead V(1) and score of 1 for R/S>1 in lead V(1)), the incidence of RVSD increased by the total ECG score. CONCLUSION: The combination of ECG-RVH findings, especially in lead V(1), predicts the presence of RVSD defined by CMR. ECG might be a useful tool for estimating the presence of RVSD in patients with PH.

Dendritic Cell is an Immunoprotective Regulator in Post-Infarction Healing and Left Ventricular Remodeling
Atsushi Anzai, Toshihisa Anzai, Shigenori Nagai, Yuichiro Maekawa, Motoaki Sano, Tsutomu Yoshikawa, Shigeo Koyasu, Satoshi Ogawa, Keiichi Fukuda
CIRCULATION, 124, 21, LIPPINCOTT WILLIAMS & WILKINS, 2011年11月, ［査読有り］
英語

[Ivabradine (pure heart-rate-lowering agent)].
Toshihisa Anzai
Nihon rinsho. Japanese journal of clinical medicine, 69 Suppl 9, 412, 6, 2011年11月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）

Tumor necrosis factor-α converting enzyme is a key mediator of abdominal aortic aneurysm development.
Kaneko H, Anzai T, Horiuchi K, Kohno T, Nagai T, Anzai A, Takahashi T, Sasaki A, Shimoda M, Maekawa Y, Shimizu H, Yoshikawa T, Okada Y, Yozu R, Fukuda K
Atherosclerosis, 218, 2, 470, 8, ELSEVIER IRELAND LTD, 2011年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Tumor necrosis factor (TNF)-α is known to be elevated in plasma and the aorta in abdominal aortic aneurysm (AAA) patients. We sought to clarify the role of TNF-α converting enzyme (Tace), which cleaves the transmembrane precursor of TNF-α, in AAA development. METHODS: We obtained aortic sample of AAA during surgical operation to assess the histological features and protein expression of human AAA. AAA was induced in mice with temporal systemic deletion of Tace by the inducible Mx-1 Cre transgene (TaceMx1) and in wild-type littermates (CON) by periaortic application of CaCl(2) (AAA/TaceMx1, AAA/CON). RESULTS: Tace expression was increased in human AAA samples as compared with normal aorta. Six weeks postoperatively, aortic diameter in AAA/TaceMx1 was decreased than in AAA/CON in association with attenuated TNF-α expression and extracellular matrix disruption. Increased activities of matrix metalloproteinase (MMP)-9 and MMP-2, numbers of Mac-2-positive macrophages, CD3-positive T lymphocytes and CD31-positive vessels in periaortic tissues, mRNA expression of CD68, monocyte chemotactic protein-1, TNF-α, vascular endothelial growth factor-A, p47 and glutathione peroxidases, and protein expression of phospho-c-Jun N-terminal kinase in AAA were all attenuated by Tace deletion. Protein expression of transforming growth factor (TGF)-β1 was upregulated by Tace deletion in sham-operated mice. TGF-β1 expression was further increased in AAA/TaceMx1. CONCLUSIONS: Tace was overexpressed in the aortic wall in human and experimental AAA. Temporal systemic deletion of Tace prevented AAA development in association with attenuating inflammation, oxidative stress, neoangiogenesis and extracellular matrix disruption, suggesting a crucial role of Tace in AAA development.

[Beta-blocker].
Toshihisa Anzai
Nihon rinsho. Japanese journal of clinical medicine, 69 Suppl 7, 445, 9, 2011年09月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）

Human C-reactive protein exacerbates metabolic disorders in association with adipose tissue remodelling.
Hidehiro Kaneko, Toshihisa Anzai, Toshiyuki Nagai, Atsushi Anzai, Toshiyuki Takahashi, Yoshinori Mano, Kohkichi Morimoto, Yuichiro Maekawa, Hiroshi Itoh, Tsutomu Yoshikawa, Satoshi Ogawa, Keiichi Fukuda
Cardiovascular research, 91, 3, 546, 55, OXFORD UNIV PRESS, 2011年08月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: C-reactive protein (CRP) expression is increased with metabolic alterations. We sought to clarify the effect of CRP on the development of obesity-induced metabolic disorders using human CRP-overexpressing transgenic mice (CRPTG). METHODS AND RESULTS: CRPTG and their non-transgenic littermates (CON) were fed a standard diet (STD) or a high-fat diet (HFD) from 6 weeks of age. Oral glucose tolerance and intraperitoneal insulin tolerance tests 12 weeks after starting the diets showed deterioration of glucose tolerance and insulin sensitivity in HFD/CRPTG compared with HFD/CON. Hepatocellular ballooning, oil droplets, and peri-sinusoidal fibrosis were more prominent in HFD/CRPTG than in HFD/CON. In HFD/CRPTG, hepatic triglyceride content was higher and serum adiponectin levels lower than in HFD/CON. Epididymal adipose tissue mRNA expression of mucin-like, hormone receptor-like 1, monocyte chemotactic protein-1, and tumour necrosis factor-α in HFD/CRPTG was up-regulated compared with that in HFD/CON. Immunohistochemical staining of epididymal adipose tissue showed that the number of Mac-3(+) macrophages was higher in HFD/CRPTG than in HFD/CON. CONCLUSION: Human CRP overexpression facilitated the development of insulin resistance and hepatosteatosis with HFD in association with adiponectin down-regulation and enhancement of macrophage infiltration and expression of pro-inflammatory cytokines in epididymal adipose tissue, suggesting its pathogenic role in the development of obesity-induced metabolic disorders.

Resveratrol prevents the development of abdominal aortic aneurysm through attenuation of inflammation, oxidative stress, and neovascularization.
Hidehiro Kaneko, Toshihisa Anzai, Maho Morisawa, Takashi Kohno, Toshiyuki Nagai, Atsushi Anzai, Toshiyuki Takahashi, Masayuki Shimoda, Aya Sasaki, Yuichiro Maekawa, Koichi Yoshimura, Hiroki Aoki, Kazuo Tsubota, Tsutomu Yoshikawa, Yasunori Okada, Satoshi Ogawa, Keiichi Fukuda
Atherosclerosis, 217, 2, 350, 7, ELSEVIER IRELAND LTD, 2011年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: We sought to examine the effect of resveratrol (3,4',5-trihydroxy-trans-stilbene), a plant-derived polyphenolic compound, on the development of abdominal aortic aneurysm (AAA). METHODS: AAA was induced in mice by periaortic application of CaCl(2). NaCl (0.9%)-applied mice were used as a sham group. Mice were treated with intraperitoneal injection of PBS (Sham/CON, AAA/CON, n=30 for each) or resveratrol (100 mg/kg/day) (AAA/RSVT, n=30). Six weeks after the operation, aortic tissue was excised for further examinations. RESULTS: Aortic diameter was enlarged in AAA/CON compared with Sham/CON. Resveratrol treatment reduced the aneurysm size and inflammatory cell infiltration in the aortic wall compared with AAA/CON. Elastica Van Gieson staining showed destruction of the wavy morphology of the elastic lamellae in AAA/CON, while it was preserved in AAA/RSVT. The increased mRNA expression of monocyte chemotactic protein-1, tumor necrosis factor-α, intercellular adhesion molecule-1, CD68, vascular endothelial growth factor-A, p47, glutathione peroxidase (GPX)1 and GPX3 were attenuated by resveratrol treatment (all p<0.05). Administration of resveratrol decreased protein expression of phospho-p65 in AAA. The increased 8-hydroxy-2'-deoxyguanosine-positive cell count and 4-hydroxy-2-nonenal-positive cell count in AAA were also reduced by resveratrol treatment. Zymographic activity of matrix metalloproteinase (MMP)-9 and MMP-2 was lower in AAA/RSVT compared with AAA/CON (both p<0.05). Compared with AAA/CON, Mac-2(+) macrophages and CD31(+) vessels in the aortic wall were decreased in AAA/RSVT (both p<0.05). CONCLUSION: Treatment with resveratrol in mice prevented the development of CaCl(2)-induced AAA, in association with reduced inflammation, oxidative stress, neoangiogenesis, and extracellular matrix disruption. These findings suggest therapeutic potential of resveratrol for AAA.

Role of vascular endothelial growth factor-A in development of abdominal aortic aneurysm.
Hidehiro Kaneko, Toshihisa Anzai, Toshiyuki Takahashi, Takashi Kohno, Masayuki Shimoda, Aya Sasaki, Hideyuki Shimizu, Toshiyuki Nagai, Yuichiro Maekawa, Koichi Yoshimura, Hiroki Aoki, Tsutomu Yoshikawa, Yasunori Okada, Ryohei Yozu, Satoshi Ogawa, Keiichi Fukuda
Cardiovascular research, 91, 2, 358, 67, OXFORD UNIV PRESS, 2011年07月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Increased angiogenesis, chronic inflammation, and extracellular matrix degradation are the major pathological features of abdominal aortic aneurysm (AAA). We sought to elucidate the role of vascular endothelial growth factor (VEGF)-A, a potent angiogenic and proinflammatory factor, in the development of AAA. METHODS AND RESULTS: Human AAA samples showed increased VEGF-A expression, neovascularization, and macrophage infiltration compared with normal aortic walls. AAA was induced in mice by periaortic application of CaCl(2). AAA mice were treated with soluble VEGF-A receptor (sFlt)-1 or phosphate-buffered saline and sacrificed 6 weeks after the operation. Treatment with sFlt-1 resulted in reduced aneurysm size, restored wavy structure of the elastic lamellae, reduced Mac-2(+) monocytes/macrophages, CD3(+) T-lymphocytes, and CD31(+) vessels, and attenuated matrix metalloproteinase (MMP)-2 and 9 activity in periaortic tissue of AAA. Increased aortic mRNA expression of monocyte chemotactic protein-1, tumour necrosis factor-α, and intercellular adhesion molecule-1 in AAA was attenuated by sFlt-1 treatment. CONCLUSION: VEGF-A was overexpressed in the aortic wall of human and experimental AAA. Treatment with sFlt-1 inhibited AAA development in mice, in association with reduced neoangiogenesis, infiltration of inflammatory cells, MMP activity, and extracellular matrix degradation. These findings suggest a crucial role of VEGF-A in the development of AAA.

Impact of serum high-mobility group box 1 protein elevation on oxygenation impairment after thoracic aortic aneurysm repair.
Takashi Kohno, Toshihisa Anzai, Hideyuki Shimizu, Hidehiro Kaneko, Yasuo Sugano, Shingo Yamada, Tsutomu Yoshikawa, Akitoshi Ishizaka, Ryohei Yozu, Satoshi Ogawa
Heart and vessels, 26, 3, 306, 12, SPRINGER, 2011年05月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, High-mobility group box 1 protein (HMGB1) is a late mediator of inflammatory responses that can cause acute lung injury. We examined the significance of serum HMGB1 elevation in the development of systemic inflammatory response syndrome (SIRS) and lung oxygenation impairment (LOI) after thoracic aortic aneurysm (TAA) repair. Serial measurements of the serum HMGB1 level and SIRS score for 7 days after surgery were determined in 20 patients with TAA who underwent surgical repair. Arterial oxygen tension was measured serially for at least 4 days after surgery, and LOI was defined as the lowest PaO(2)/FiO(2) ratio ≤ 200 mmHg. The serum HMGB1 level was markedly increased after surgery, peaking on day 2, and remained significantly elevated on day 7. Peak HMGB1 level positively correlated with SIRS duration and the cumulative SIRS score during postoperative days 1-7 (P = 0.0013 and P = 0.0004, respectively). Peak HMGB1 level and cumulative SIRS score were higher in patients with LOI than in those without (P = 0.01 and P = 0.044, respectively). Peak HMGB1 level was negatively correlated with the lowest PaO(2)/FiO(2) ratio (P = 0.0077) and positively correlated with postoperative length of hospitalization (P = 0.042). A greater serum HMGB1 elevation after TAA repair was associated with more severe SIRS and a higher incidence of LOI. HMGB1 might play a key role in the pathogenesis of SIRS and LOI after surgical TAA repair.

Can intravascular ultrasound guidance modify the efficacy of drug-eluting stent over bare-metal stent in an aorto-ostial lesion?
Teruo Okabe, Akio Kawamura, Yuichiro Maekawa, Toshihisa Anzai, Shiro Iwanaga, Tsutomu Yoshikawa, Satoshi Ogawa
Cardiovascular Revascularization Medicine, 12, 2, 105, 110, 2011年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Purpose: We compared the efficacy of drug-eluting stents (DESs) versus bare-metal stents (BMSs) in de novo and native aorto-ostial lesions (AOLs) guided by intravascular ultrasound (IVUS). Method: Thirty-eight patients underwent DES implantation for 38 AOLs
35 with sirolimus-eluting stents, and three with paclitaxel-eluting stents (DES group). The control group was composed of 40 AOLs treated by BMS. The incidence of the primary composite end point of all-cause mortality, Q-wave myocardial infarction and target vessel revascularization (TVR) as TVR-major adverse cardiac event (TVR-MACE) was evaluated during a 1-year follow-up. Clinical and IVUS parameters were compared between the DES and BMS groups, and Cox hazards model was used to calculate hazard ratios of several factors for the 1-year TVR-MACE. Results: Although the vessel, plaque, and stent volumes were significantly larger after the procedures in the DES group owing to longer lesions (18.3±5.1 vs. 13.2±5.9 mm, P<
001), the stent volume index (10.8±2.6 vs. 12.4±3.3, P=024) was much smaller than that in the BMS group. During the 1-year follow-up, there were 13 TVR-MACEs in all patients (13% in DES vs. 20% in BMS, P=4 by Kaplan-Meier analysis). The Cox hazards model did not indicate any specific unfavorable factor for the 1-year TVR-MACE. Conclusions: The present study showed equality between DES and BMS on de novo and native AOLs about the 1-year TVR-MACE rate, even though a DES was used in longer and bulkier lesions as compared to BMS. © 2011 Elsevier Inc.

C-reactive protein overexpression exacerbates pressure overload-induced cardiac remodeling through enhanced inflammatory response.
Toshiyuki Nagai, Toshihisa Anzai, Hidehiro Kaneko, Yoshinori Mano, Atsushi Anzai, Yuichiro Maekawa, Toshiyuki Takahashi, Tomomi Meguro, Tsutomu Yoshikawa, Keiichi Fukuda
Hypertension (Dallas, Tex. : 1979), 57, 2, 208, 15, LIPPINCOTT WILLIAMS & WILKINS, 2011年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Serum C-reactive protein (CRP) elevation predicts the development of heart failure in patients with hypertension. CRP activates macrophages and enhances oxidative stress. We hypothesize that CRP itself has a pathogenic role in the development of pressure overload-induced cardiac remodeling. Transgenic mice with human CRP overexpression (CRPtg) and nontransgenic littermates (CON) were subjected to transverse aortic constriction (TAC/CRPtg and TAC/CON) or sham operation (Sham/CRPtg and Sham/CON). One week after operation, in TAC/CRPtg, myocardial mRNA levels of interleukin (IL)-6, CD68, glutathione peroxidase-3 (GPx3), 47-kDa α-subunit of nicotinamide adenine dinucleotide phosphate oxidase (p47(phox)), and collagen-I, the number of infiltrating Mac-2-positive macrophages, nuclear localization of phosphorylated NF-κB/p65 (p-p65) in cardiomyocytes, nuclear NF-κB-DNA-binding activity, and reactive oxygen species (ROS) content were increased compared to those in TAC/CON. Cardiac fibrosis was more prominent in TAC/CRPtg compared to TAC/CON. Four weeks after operation, heart and lung weights, cardiomyocyte cross-sectional area, and the extent of cardiac fibrosis were greater in TAC/CON than in Sham/CON, and these differences were further augmented in TAC/CRPtg compared to TAC/CON. Left ventricular (LV) fractional shortening was less and LV end-diastolic pressure was higher in TAC/CRPtg than in TAC/CON. Myocardial mRNA levels of angiotensin type 1 receptor, atrial natriuretic factor, IL-6, GPx3, p47(phox), collagen-I, and transforming growth factor (TGF)-β1, the protein level of TGF-β1, and the numbers of Mac-2-positive macrophages and p-p65-positive cells were higher in TAC/CRPtg than in TAC/CON. In conclusion, CRP itself may have a pathogenic role in the development of pressure overload-induced cardiac remodeling, possibly through enhanced inflammation and oxidative stress.

Overexpression of human C-reactive protein exacerbates left ventricular remodeling in diabetic cardiomyopathy.
Yoshinori Mano, Toshihisa Anzai, Hidehiro Kaneko, Yuji Nagatomo, Toshiyuki Nagai, Atsushi Anzai, Yuichiro Maekawa, Toshiyuki Takahashi, Tomomi Meguro, Tsutomu Yoshikawa, Keiichi Fukuda
Circulation journal : official journal of the Japanese Circulation Society, 75, 7, 1717, 27, JAPANESE CIRCULATION SOC, 2011年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: C-reactive protein (CRP) is known to be a pathogenic agent in the cardiovascular system. However, the effect of CRP on heart failure has not been elucidated. The effect of human CRP on cardiac dysfunction induced by diabetes mellitus (DM) using human CRP-overexpressing transgenic mice (CRP-Tg) was examined. METHODS AND RESULTS: DM was induced in male wild-type mice (Wt/DM) and CRP-Tg (CRP/DM) by an injection of streptozotocin. Non-diabetic wild-type mice (Wt/Con) and CRP-Tg (CRP/Con) served as controls. Echocardiography and hemodynamic measurements 6 weeks after injection showed lower fractional shortening and left ventricular (LV) dP/dt max in CRP/DM compared with Wt/DM. Myocardial mRNA levels of interleukin-6, tumor necrosis factor-α, plasminogen activator inhibitor-1, angiotensin type 1 receptor, angiotensinogen, NADPH oxidase subunits (p47(phox), gp91(phox)), glutathione peroxidase-3. and connective tissue growth factor were increased in CRP/DM compared with Wt/DM. Nuclear staining of 8-hydroxydeoxyguanosine was also increased in CRP/DM compared with Wt/DM. CRP/DM was associated with increased terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling positive cells and a higher ratio of Bax/Bcl-2 proteins compared with Wt/DM. The extent of cardiac fibrosis assessed by Sirius red staining and immunohistochemical staining for collagen type 1 was significantly increased in CRP/DM compared with Wt/DM. CONCLUSIONS: Overexpression of human CRP exacerbates LV dysfunction and remodeling in diabetic cardiomyopathy, possibly through enhancement of the inflammation, renin-angiotensin system, and oxidative stress.

Tumor necrosis factor-α converting enzyme inactivation ameliorates high-fat diet-induced insulin resistance and altered energy homeostasis.
Kaneko H, Anzai T, Horiuchi K, Morimoto K, Anzai A, Nagai T, Sugano Y, Maekawa Y, Itoh H, Yoshikawa T, Okada Y, Ogawa S, Fukuda K
Circulation journal : official journal of the Japanese Circulation Society, 75, 10, 2482, 90, JAPANESE CIRCULATION SOC, 2011年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Tumor necrosis factor (TNF)-α, which is released as a soluble form by ectodomain shedding of TNF-α converting enzyme (Tace), is known to play a pivotal role in obesity-induced insulin resistance. The role of Tace in obesity-induced metabolic disorders was to be clarified in this study. METHODS AND RESULTS: Transgenic mice with temporal systemic Tace deletion (TaceMx1) and their non-transgenic littermates (CON) were fed a standard diet or a high-fat diet (HFD) from 6 weeks of age. The increased body, liver and epididymal adipose tissue (EAT) weights, systolic blood pressure, and fasting glucose and lipid levels and decreased serum adiponectin level 12 weeks after starting a HFD were suppressed by Tace inactivation. A HFD/TaceMx1 showed ameliorated glucose tolerance and insulin sensitivity compared with HFD/CON. Indirect calorimetry showed that energy expenditure and oxidation of both fat and carbohydrate were higher in HFD/TaceMx1 than HFD/CON. Marked hepatosteatosis, increased triglyceride content and TNF-α expression in liver, and increased adipocyte size, macrophage infiltration and TNF-α and monocyte chemoattractant protein-1 expression in EAT induced by a HFD were attenuated in HFD/TaceMx1. CONCLUSIONS: Inactivation of Tace suppressed HFD-induced obesity, insulin resistance, hepatosteatosis and adipose tissue remodeling in association with increased energy expenditure, suggesting an important role of Tace in the development of obesity-induced metabolic disorders.

Overexpression of human C-reactive protein exacerbates left ventricular remodeling in diabetic cardiomyopathy.
Yoshinori Mano, Toshihisa Anzai, Hidehiro Kaneko, Yuji Nagatomo, Toshiyuki Nagai, Atsushi Anzai, Yuichiro Maekawa, Toshiyuki Takahashi, Tomomi Meguro, Tsutomu Yoshikawa, Keiichi Fukuda
Circulation journal : official journal of the Japanese Circulation Society, 75, 7, 1717, 27, JAPANESE CIRCULATION SOC, 2011年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: C-reactive protein (CRP) is known to be a pathogenic agent in the cardiovascular system. However, the effect of CRP on heart failure has not been elucidated. The effect of human CRP on cardiac dysfunction induced by diabetes mellitus (DM) using human CRP-overexpressing transgenic mice (CRP-Tg) was examined. METHODS AND RESULTS: DM was induced in male wild-type mice (Wt/DM) and CRP-Tg (CRP/DM) by an injection of streptozotocin. Non-diabetic wild-type mice (Wt/Con) and CRP-Tg (CRP/Con) served as controls. Echocardiography and hemodynamic measurements 6 weeks after injection showed lower fractional shortening and left ventricular (LV) dP/dt max in CRP/DM compared with Wt/DM. Myocardial mRNA levels of interleukin-6, tumor necrosis factor-α, plasminogen activator inhibitor-1, angiotensin type 1 receptor, angiotensinogen, NADPH oxidase subunits (p47(phox), gp91(phox)), glutathione peroxidase-3. and connective tissue growth factor were increased in CRP/DM compared with Wt/DM. Nuclear staining of 8-hydroxydeoxyguanosine was also increased in CRP/DM compared with Wt/DM. CRP/DM was associated with increased terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling positive cells and a higher ratio of Bax/Bcl-2 proteins compared with Wt/DM. The extent of cardiac fibrosis assessed by Sirius red staining and immunohistochemical staining for collagen type 1 was significantly increased in CRP/DM compared with Wt/DM. CONCLUSIONS: Overexpression of human CRP exacerbates LV dysfunction and remodeling in diabetic cardiomyopathy, possibly through enhancement of the inflammation, renin-angiotensin system, and oxidative stress.

Tumor necrosis factor-α converting enzyme inactivation ameliorates high-fat diet-induced insulin resistance and altered energy homeostasis.
Kaneko H, Anzai T, Horiuchi K, Morimoto K, Anzai A, Nagai T, Sugano Y, Maekawa Y, Itoh H, Yoshikawa T, Okada Y, Ogawa S, Fukuda K
Circulation journal : official journal of the Japanese Circulation Society, 75, 10, 2482, 90, JAPANESE CIRCULATION SOC, 2011年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Tumor necrosis factor (TNF)-α, which is released as a soluble form by ectodomain shedding of TNF-α converting enzyme (Tace), is known to play a pivotal role in obesity-induced insulin resistance. The role of Tace in obesity-induced metabolic disorders was to be clarified in this study. METHODS AND RESULTS: Transgenic mice with temporal systemic Tace deletion (TaceMx1) and their non-transgenic littermates (CON) were fed a standard diet or a high-fat diet (HFD) from 6 weeks of age. The increased body, liver and epididymal adipose tissue (EAT) weights, systolic blood pressure, and fasting glucose and lipid levels and decreased serum adiponectin level 12 weeks after starting a HFD were suppressed by Tace inactivation. A HFD/TaceMx1 showed ameliorated glucose tolerance and insulin sensitivity compared with HFD/CON. Indirect calorimetry showed that energy expenditure and oxidation of both fat and carbohydrate were higher in HFD/TaceMx1 than HFD/CON. Marked hepatosteatosis, increased triglyceride content and TNF-α expression in liver, and increased adipocyte size, macrophage infiltration and TNF-α and monocyte chemoattractant protein-1 expression in EAT induced by a HFD were attenuated in HFD/TaceMx1. CONCLUSIONS: Inactivation of Tace suppressed HFD-induced obesity, insulin resistance, hepatosteatosis and adipose tissue remodeling in association with increased energy expenditure, suggesting an important role of Tace in the development of obesity-induced metabolic disorders.

Increased C-reactive protein expression exacerbates left ventricular dysfunction and remodeling after myocardial infarction.
Toshiyuki Takahashi, Toshihisa Anzai, Hidehiro Kaneko, Yoshinori Mano, Atsushi Anzai, Toshiyuki Nagai, Takashi Kohno, Yuichiro Maekawa, Tsutomu Yoshikawa, Keiichi Fukuda, Satoshi Ogawa
American journal of physiology. Heart and circulatory physiology, 299, 6, H1795-804, H1804, AMER PHYSIOLOGICAL SOC, 2010年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We previously reported serum C-reactive protein (CRP) elevation after acute myocardial infarction (MI) to be associated with adverse outcomes including cardiac rupture, left ventricular (LV) remodeling, and cardiac death. Experimental studies have indicated that CRP per se has various biological actions including proinflammatory and proapoptotic effects, suggesting a pathogenic role of CRP in the post-MI remodeling process. We tested the hypothesis that increased CRP expression would exacerbate adverse LV remodeling after MI via deleterious effects of CRP. Transgenic mice with human CRP expression (CRP-Tg) and their transgene-negative littermates (control) underwent left coronary artery ligation. There was no apparent difference in phenotypic features between CRP-Tg and control mice before MI. Although mortality and infarct size were similar in the two groups, CRP-Tg mice showed more LV dilation and worse LV function with more prominent cardiomyocyte hypertrophy and fibrosis in the noninfarcted regions after MI than controls. Histological evaluation conducted 1 wk post-MI revealed a higher rate of apoptosis and more macrophage infiltration in the border zones of infarcted hearts from CRP-Tg mice in relation to increased monocyte chemotactic protein (MCP)-1 expression and matrix metalloproteinase (MMP)-9 activity. Increased CRP expression exacerbates LV dysfunction and promotes adverse LV remodeling after MI in mice. The deleterious effect of CRP on post-MI LV remodeling may be associated with increased apoptotic rates, macrophage infiltration, MCP-1 expression, and MMP-9 activity in the border zone.

Re-elevation of D-dimer as a predictor of re-dissection and venous thromboembolism after Stanford type B acute aortic dissection.
Yusuke Jo, Toshihisa Anzai, Koji Ueno, Hidehiro Kaneko, Takashi Kohno, Yasuo Sugano, Yuichiro Maekawa, Tsutomu Yoshikawa, Hideyuki Shimizu, Ryohei Yozu, Satoshi Ogawa
Heart and vessels, 25, 6, 509, 14, SPRINGER, 2010年11月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, D-dimer measurement is a useful complementary initial diagnostic marker in patients with acute aortic dissection (AAD). However, it has not been clarified whether serial measurements of D-dimer are useful during in-hospital management of Stanford type B AAD. We studied 30 patients who were admitted with diagnosis of Stanford type B AAD and treated conservatively. D-dimer was serially measured on admission and then every 5 days during hospitalization. Patients were divided into two groups according to the presence or absence of re-elevation of D-dimer during hospitalization, in which D-dimer transition were biphasic and latter peak >10.0 μg/ml. Re-elevation of D-dimer was observed in 17 patients. There were no differences in atherosclerotic risk factors, blood pressure on admission, D-dimer level on admission, extent of AAD, and false lumen patency. Patients with re-elevation of D-dimer showed higher incidence of re-dissection and/or venous thromboembolism (VTE). Peak D-dimer level in patients with re-dissection and/or VTE was significantly higher than that without these complications (p = 0.005). In conclusion, serial measurements of D-dimer are useful for early detection of re-dissection or VTE in patients with Stanford type B AAD, which may contribute to the prevention of disastrous consequences such as pulmonary embolism and extension of AAD.

Impact of systemic acidosis on the development of malignant ventricular arrhythmias after reperfusion therapy for ST-elevation myocardial infarction.
Toshiyuki Nagai, Toshihisa Anzai, Hidehiro Kaneko, Atsushi Anzai, Yoshinori Mano, Yuji Nagatomo, Shun Kohsaka, Yuichiro Maekawa, Akio Kawamura, Tsutomu Yoshikawa, Satoshi Ogawa
Circulation journal : official journal of the Japanese Circulation Society, 74, 9, 1808, 14, JAPANESE CIRCULATION SOC, 2010年09月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The aim of the present study was to examine the effect of systemic acidosis on the development of malignant ventricular arrhythmias, including sustained ventricular tachycardia and ventricular fibrillation (VT/VF), after reperfused ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: A total of 157 consecutive patients with a reperfused STEMI were examined. Patients were divided into 2 groups according to the presence or absence of systemic acidosis, defined as arterial blood pH <7.40 on admission. Serum creatine kinase and C-reactive protein (CRP) levels were serially measured. Systemic acidosis was observed in 53 patients (34%). There was no significant difference in coronary risk factors and arrival time from onset between the 2 groups. Estimated glomerular filtration rate (eGFR) on admission was lower in patients with acidosis than in those without (P=0.001). Patients with acidosis had a higher incidence of VT/VF (26% vs 4%, P<0.0001), especially within 48 h after STEMI (23% vs 3%, P=0.0002), than those without. The peripheral white blood cell count on admission was higher in patients with than in those without acidosis. Multivariate analysis showed that systemic acidosis was a strong independent predictor of VT/VF (relative risk =8.79, P=0.002) among variables including prior MI and eGFR <60 ml . min(-1) . 1.73 m(-2). CONCLUSIONS: Systemic acidosis was a significant determinant of VT/VF after reperfused STEMI and was associated with elevated serum CRP level. Systemic acidosis and subsequent inflammation after ischemia reperfusion may play an important role in the development of VT/VF.

Impact of systemic acidosis on the development of malignant ventricular arrhythmias after reperfusion therapy for ST-elevation myocardial infarction.
Toshiyuki Nagai, Toshihisa Anzai, Hidehiro Kaneko, Atsushi Anzai, Yoshinori Mano, Yuji Nagatomo, Shun Kohsaka, Yuichiro Maekawa, Akio Kawamura, Tsutomu Yoshikawa, Satoshi Ogawa
Circulation journal : official journal of the Japanese Circulation Society, 74, 9, 1808, 14, JAPANESE CIRCULATION SOC, 2010年09月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The aim of the present study was to examine the effect of systemic acidosis on the development of malignant ventricular arrhythmias, including sustained ventricular tachycardia and ventricular fibrillation (VT/VF), after reperfused ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: A total of 157 consecutive patients with a reperfused STEMI were examined. Patients were divided into 2 groups according to the presence or absence of systemic acidosis, defined as arterial blood pH <7.40 on admission. Serum creatine kinase and C-reactive protein (CRP) levels were serially measured. Systemic acidosis was observed in 53 patients (34%). There was no significant difference in coronary risk factors and arrival time from onset between the 2 groups. Estimated glomerular filtration rate (eGFR) on admission was lower in patients with acidosis than in those without (P=0.001). Patients with acidosis had a higher incidence of VT/VF (26% vs 4%, P<0.0001), especially within 48 h after STEMI (23% vs 3%, P=0.0002), than those without. The peripheral white blood cell count on admission was higher in patients with than in those without acidosis. Multivariate analysis showed that systemic acidosis was a strong independent predictor of VT/VF (relative risk =8.79, P=0.002) among variables including prior MI and eGFR <60 ml . min(-1) . 1.73 m(-2). CONCLUSIONS: Systemic acidosis was a significant determinant of VT/VF after reperfused STEMI and was associated with elevated serum CRP level. Systemic acidosis and subsequent inflammation after ischemia reperfusion may play an important role in the development of VT/VF.

Differential effects of carvedilol and metoprolol on renal function in patients with heart failure.
Hiroyuki Ito, Yuji Nagatomo, Takashi Kohno, Toshihisa Anzai, Tomomi Meguro, Satoshi Ogawa, Tsutomu Yoshikawa
Circulation journal : official journal of the Japanese Circulation Society, 74, 8, 1578, 83, JAPANESE CIRCULATION SOC, 2010年08月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The aim of the present study was to verify the effects of beta-blockers on renal function in patients with heart failure (HF). METHODS AND RESULTS: A total of 40 patients with HF (New York Heart Association class, II-III) were enrolled, who had beta-blocker therapy initiated with carvedilol (n=23) or metoprolol (n=17). The changes in renal and cardiac function were retrospectively analyzed over 16 weeks. The study population was divided into 2 groups according to the median baseline (65.9 ml/min) of estimated glomerular filtration rate (eGFR) calculated by the Modification of Diet in Renal Disease formula. eGFR significantly decreased in the higher eGFR group (P=0.04), but did not in the lower eGFR group. Left ventricular ejection fraction significantly increased in both groups with lower eGFR (P=0.01) and higher eGFR (P<0.01). There was an interaction between plasma norepinephrine concentration and eGFR in terms of beta-blocker treatment (P=0.02, ANOVA). eGFR significantly decreased in patients who received metoprolol (from 75.7+/-33.5 to 59.5+/-20.0 mlxmin(-1).1.73 m(-2), P<0.01), but did not change in those who received carvedilol (from 67.1+/-27.7 mlxmin(-1).1.73 m(-2) to 65.6+/-23.2 mlxmin(-1).1.73 m(-2)). CONCLUSIONS: Beta-blockers preserved renal function in HF patients with lower baseline eGFR, but not in those with higher baseline eGFR. Carvedilol may be preferable to metoprolol to prevent the development of chronic kidney disease during beta-blocker therapy for HF.

Differential effects of carvedilol and metoprolol on renal function in patients with heart failure.
Hiroyuki Ito, Yuji Nagatomo, Takashi Kohno, Toshihisa Anzai, Tomomi Meguro, Satoshi Ogawa, Tsutomu Yoshikawa
Circulation journal : official journal of the Japanese Circulation Society, 74, 8, 1578, 83, JAPANESE CIRCULATION SOC, 2010年08月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The aim of the present study was to verify the effects of beta-blockers on renal function in patients with heart failure (HF). METHODS AND RESULTS: A total of 40 patients with HF (New York Heart Association class, II-III) were enrolled, who had beta-blocker therapy initiated with carvedilol (n=23) or metoprolol (n=17). The changes in renal and cardiac function were retrospectively analyzed over 16 weeks. The study population was divided into 2 groups according to the median baseline (65.9 ml/min) of estimated glomerular filtration rate (eGFR) calculated by the Modification of Diet in Renal Disease formula. eGFR significantly decreased in the higher eGFR group (P=0.04), but did not in the lower eGFR group. Left ventricular ejection fraction significantly increased in both groups with lower eGFR (P=0.01) and higher eGFR (P<0.01). There was an interaction between plasma norepinephrine concentration and eGFR in terms of beta-blocker treatment (P=0.02, ANOVA). eGFR significantly decreased in patients who received metoprolol (from 75.7+/-33.5 to 59.5+/-20.0 mlxmin(-1).1.73 m(-2), P<0.01), but did not change in those who received carvedilol (from 67.1+/-27.7 mlxmin(-1).1.73 m(-2) to 65.6+/-23.2 mlxmin(-1).1.73 m(-2)). CONCLUSIONS: Beta-blockers preserved renal function in HF patients with lower baseline eGFR, but not in those with higher baseline eGFR. Carvedilol may be preferable to metoprolol to prevent the development of chronic kidney disease during beta-blocker therapy for HF.

Prognostic significance of acute kidney injury after reperfused ST-elevation myocardial infarction: synergistic acceleration of renal dysfunction and left ventricular remodeling.
Atsushi Anzai, Toshihisa Anzai, Kotaro Naito, Hidehiro Kaneko, Yoshinori Mano, Yusuke Jo, Yuji Nagatomo, Yuichiro Maekawa, Akio Kawamura, Tsutomu Yoshikawa, Satoshi Ogawa
Journal of cardiac failure, 16, 5, 381, 9, CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2010年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Acute kidney injury (AKI) after myocardial infarction is associated with poor clinical outcome. However, mechanisms of the adverse effect of AKI on clinical outcome after reperfused ST-elevation myocardial infarction (STEMI) have not been fully elucidated. METHODS AND RESULTS: We examined 141 consecutive patients with reperfused first anterior STEMI. AKI was defined as an increase in serum creatinine of >or=0.3mg/dL within 48hours after admission. Patients with AKI had higher incidence of in-hospital cardiac death (P=.0004) and major adverse cardiac events (MACE, P=.020) during a mean of 39+/-40 (range, 1 to 96) months than those without, in association with adverse left ventricular (LV) remodeling. White blood cell count on admission and peak C-reactive protein were higher in patients with than those without AKI. Plasma norepinephrine on admission, interleukin-6, brain natriuretic peptide, and malondialdehyde-modified low-density lipoprotein 2 weeks after STEMI were higher in patients with AKI than those without AKI. Cox proportional hazards model analysis revealed AKI was an independent predictor of MACE (hazard ratio=2.38, P=.019). CONCLUSIONS: AKI was a strong predictor of MACE in association with adverse LV remodeling. Enhanced inflammatory response, oxidative stress, and neurohormonal activation may synergistically accelerate renal dysfunction and LV remodeling after STEMI.

Elevated troponin T on discharge predicts poor outcome of decompensated heart failure.
Kimi Koide, Tsutomu Yoshikawa, Yuji Nagatomo, Shun Kohsaka, Toshihisa Anzai, Tomomi Meguro, Satoshi Ogawa
Heart and vessels, 25, 3, 217, 22, SPRINGER, 2010年05月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Persistent elevation of cardiac troponin T (cTnT) predicts an adverse clinical outcome in patients with chronic heart failure (HF), but the underlying mechanisms remain to be determined. We investigated the association between predischarge cTnT elevation and coexistent pathophysiology in patients with decompensated HF. Plasma cTnT levels were determined before discharge in 170 patients with decompensated HF. We divided the patients into a group that was positive for cTnT [cTnT(+) group, n = 40] and a group that was negative for cTnT [cTnT(-) group, n = 130]. Multivariate analysis showed that use of beta-blocker therapy (odds ratio [OR] = 0.236, P = 0.003), an elevated high-sensitivity C-reactive protein (hsCRP) level (OR = 3.731, P = 0.006), a high brain natriuretic peptide (BNP) level (OR = 3.570, P = 0.007), diabetes (OR = 3.090, P = 0.018), and anemia (OR = 2.330, P = 0.047) were independently associated with cTnT positivity. During a mean follow-up period of 441 days after discharge, total mortality (P < 0.001), cardiac death (P < 0.001), and exacerbation of HF requiring hospitalization (P = 0.007) were all more common in the cTnT(+) group than in the cTnT(-) group. Cox proportional hazards analysis showed that cTnT positivity was an independent predictor of total mortality (hazard ratio = 5.008, P = 0.004) in an age- and gender-matched model. Elevation of cTnT during convalescence was associated with lack of beta-blocker therapy, a high hsCRP level at discharge, a high BNP level at discharge, diabetes, and anemia, and a worse clinical outcome in patients with decompensated HF.

Impact of high-density lipoprotein cholesterol level in patients with variant angina pectoris.
Yasuo Sugano, Toshihisa Anzai, Takashi Yagi, Shigetaka Noma
International journal of cardiology, 140, 2, 175, 81, ELSEVIER IRELAND LTD, 2010年04月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: It is generally considered that patients with variant angina pectoris (VAP) have a potential disturbance in the coronary endothelium. High-density lipoprotein (HDL) has been shown to mediate vasodilation as a result of its endothelium-enhancing property; however, the significance of low HDL in patients with VAP has not been clarified. We sought to determine the association between a low level of high-density lipoprotein cholesterol (HDL-C) and VAP. METHODS: We examined a total of 174 consecutive patients who were suspected of having VAP and underwent spasm provocation test by direct injection of acetylcholine into the coronary arteries. One hundred and three patients (59%) were consequently diagnosed as having VAP. Serum HDL-C, fasting plasma glucose (FPG), and glycohemoglobin levels were measured in all patients. RESULTS: HDL-C in quartiles showed a significant negative correlation with the presence of VAP. Multivariate analysis revealed that the lowest HDL-C quartile (<43 mg/dl), as well as cigarette smoking and impaired fasting glucose/diabetes mellitus, was an independent determinant of VAP (odds ratio=3.39, P=0.010). Patients in the highest FPG quartile (> or =106 mg/dl) or with cigarette smoking habit in combination with the lowest HDL-C quartile showed an increased risk for VAP (relative risk=2.01 and 1.88, respectively). CONCLUSIONS: A low level of HDL-C is an independent determinant for VAP. Endothelial dysfunction caused by a low HDL state may play a role in the development of VAP.

Persistent Angiotensin II Independent Activation of Mineralocorticoid Receptor Signaling is Associated With the Deterioration of Cardiac Function Induced by Chronic Diabetes Mellitus
Yuji Nagatomo, Tomomi Meguro, Hiroyuki Ito, Kimi Koide, Toshihisa Anzai, Satoshi Ogawa, Tsutomu Yoshikawa
CIRCULATION, 120, 18, S782, S782, LIPPINCOTT WILLIAMS & WILKINS, 2009年11月, ［査読有り］
英語

Role of ischemic preconditioning and inflammatory response in the development of malignant ventricular arrhythmias after reperfused ST-elevation myocardial infarction.
Hidehiro Kaneko, Toshihisa Anzai, Kotaro Naito, Takashi Kohno, Yuichiro Maekawa, Toshiyuki Takahashi, Akio Kawamura, Tsutomu Yoshikawa, Satoshi Ogawa
Journal of cardiac failure, 15, 9, 775, 81, CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2009年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Sustained ventricular tachycardia and ventricular fibrillation (VT/VF) are major complications of ST-elevation myocardial infarction (STEMI), even in the era of reperfusion therapy. We sought to clarify the determinants of VT/VF after reperfused STEMI. METHODS AND RESULTS: Consecutive STEMI patients treated with primary percutaneous coronary intervention (n=457) were divided into 2 groups by the presence or absence of VT/VF during hospitalization. Serum C-reactive protein (CRP) level and peripheral white blood cell (WBC) count were serially measured. VT/VF was observed in 54 patients (12%). Prior infarction was more common and preinfarction angina was less in patients with VT/VF than those without. Peak CRP level (P < .0001), WBC count on admission (P=.008), and maximum WBC count (P=.0014) were higher in patients with VT/VF than those without. VT/VF, especially VT/VF later than 48 hours after onset, was associated with greater left ventricular (LV) dimension during convalescence. Kaplan-Meier curves and log-rank test revealed VT/VF to be a significant determinant of long-term major adverse cardiac events. Multivariate analysis revealed that prior infarction, absence of preinfarction angina, and peak CRP >or=10mg/dL were independent determinants of VT/VF. CONCLUSIONS: Lack of ischemic preconditioning, enhanced inflammatory response, and subsequent LV dysfunction are related to the development of VT/VF after STEMI.

Increased epicardial fat volume quantified by 64-multidetector computed tomography is associated with coronary atherosclerosis and totally occlusive lesions.
Koji Ueno, Toshihisa Anzai, Masahiro Jinzaki, Minoru Yamada, Yusuke Jo, Yuichiro Maekawa, Akio Kawamura, Tsutomu Yoshikawa, Yutaka Tanami, Kozo Sato, Sachio Kuribayashi, Satoshi Ogawa
Circulation journal : official journal of the Japanese Circulation Society, 73, 10, 1927, 33, JAPANESE CIRCULATION SOC, 2009年10月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The relationship between the epicardial fat volume measured by 64-slice multidetector computed tomography (MDCT) and the extension and severity of coronary atherosclerosis was investigated. METHODS AND RESULTS: Both MDCT and conventional coronary angiography (CAG) were performed in 71 consecutive patients who presented with effort angina. The volume of epicardial adipose tissue (EAT) was measured by MDCT. The severity of coronary atherosclerosis was assessed by evaluating the extension of coronary plaques in 790 segments using MDCT data, and the percentage diameter stenosis in 995 segments using CAG data. The estimated volume of EAT indexed by body surface area was defined as VEAT. Increased VEAT was associated with advanced age, male sex, degree of metabolic alterations, a history of acute coronary syndrome (ACS) and the presence of total occlusions, and showed positive correlation with the stenosis score (r=0.28, P=0.02) and the atheromatosis score (r=0.67, P<0.0001) of the coronary arteries. Multiple logistic regression analysis revealed an increased VEAT (>or=50 cm(3)/m(2)) to be the strongest independent determinant of the presence of total occlusions (odds ratio 4.64, P=0.02). CONCLUSIONS: VEAT correlates with the degree of metabolic alterations and coronary atheromatosis. Excessive accumulation of EAT might contribute to the development of ACS and coronary total occlusions.

Increased epicardial fat volume quantified by 64-multidetector computed tomography is associated with coronary atherosclerosis and totally occlusive lesions.
Koji Ueno, Toshihisa Anzai, Masahiro Jinzaki, Minoru Yamada, Yusuke Jo, Yuichiro Maekawa, Akio Kawamura, Tsutomu Yoshikawa, Yutaka Tanami, Kozo Sato, Sachio Kuribayashi, Satoshi Ogawa
Circulation journal : official journal of the Japanese Circulation Society, 73, 10, 1927, 33, JAPANESE CIRCULATION SOC, 2009年10月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The relationship between the epicardial fat volume measured by 64-slice multidetector computed tomography (MDCT) and the extension and severity of coronary atherosclerosis was investigated. METHODS AND RESULTS: Both MDCT and conventional coronary angiography (CAG) were performed in 71 consecutive patients who presented with effort angina. The volume of epicardial adipose tissue (EAT) was measured by MDCT. The severity of coronary atherosclerosis was assessed by evaluating the extension of coronary plaques in 790 segments using MDCT data, and the percentage diameter stenosis in 995 segments using CAG data. The estimated volume of EAT indexed by body surface area was defined as VEAT. Increased VEAT was associated with advanced age, male sex, degree of metabolic alterations, a history of acute coronary syndrome (ACS) and the presence of total occlusions, and showed positive correlation with the stenosis score (r=0.28, P=0.02) and the atheromatosis score (r=0.67, P<0.0001) of the coronary arteries. Multiple logistic regression analysis revealed an increased VEAT (>or=50 cm(3)/m(2)) to be the strongest independent determinant of the presence of total occlusions (odds ratio 4.64, P=0.02). CONCLUSIONS: VEAT correlates with the degree of metabolic alterations and coronary atheromatosis. Excessive accumulation of EAT might contribute to the development of ACS and coronary total occlusions.

Differential Effects of Carvedilol and Metoprolol on Renal Function in Patients With Heart Failure
Hiroyuki Ito, Yuji Nagatomo, Takashi Kohno, Toshihisa Anzai, Tomomi Meguro, Satoshi Ogawa, Tsutomu Yoshikawa
JOURNAL OF CARDIAC FAILURE, 15, 7, S160, S160, CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2009年09月, ［査読有り］
英語

Persistent Angiotensin II-independent Activation of Mineralocorticoid Receptor Signaling is Associated With the Cardiac Dysfunction Induced by Long-term Diabetes Mellitus
Yuji Nagatomo, Tomomi Meguro, Hiroyuki Ito, Kimi Koide, Toshihisa Anzai, Satoshi Ogawa, Tsutomu Yoshikawa
JOURNAL OF CARDIAC FAILURE, 15, 7, S168, S169, CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2009年09月, ［査読有り］
英語

Diagnostic Accuracy of Angiographic View Image for the Detection of Coronary Artery Stenoses by 64-Detector Row CT - A Pilot Study Comparison With Conventional Post-Processing Methods and Axial Images Alone
Masahiro Jinzaki, Kozo Sato, Yutaka Tanami, Minoru Yamada, Toshihisa Anzai, Akio Kawamura, Koji Ueno, Sachio Kuribayashi
CIRCULATION JOURNAL, 73, 4, 691, 698, JAPANESE CIRCULATION SOC, 2009年04月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: The angiographic view (AGV) image is a new post-processing method that is similar to conventional coronary angiography (CAG). The purpose of this study was to evaluate its accuracy for coronary stenosis detection by 64-detector row computed tomography (CT).
Methods and Results: CT evaluation results of 17 patients were compared with the results of invasive CAG on a coronary segment basis concerning the presence of stenoses >50% diameter reduction. All images of the 3 viewing methods (combination of conventional methods, AGV image alone, and axial images alone) were evaluated in consensus by 3 cardiovascular radiologists. Among 196 assessable segments, invasive CAG showed significant coronary artery stenoses in 44 segments. 43 of 44 lesions were detected with the AGV image, and absence of significant stenosis was correctly identified in 135 of 152 segments (sensitivity 98%; specificity 89%; accuracy 91%; positive predictive value 72%, negative predictive value 99%). The sensitivity of the AGV image was the same as that of conventional methods (98%). There was no significant difference in accuracy between the AGV image (91%) and conventional methods (94%). The accuracy of the AGV image was significantly higher than the axial images alone (78%).
Conclusions: AGV image shows promise as a post-processing method for identifying coronary artery stenosis with high accuracy. (Circ J 2009;73:691-698)

Diagnostic accuracy of angiographic view image for the detection of coronary artery stenoses by 64-detector row CT: a pilot study comparison with conventional post-processing methods and axial images alone.
Masahiro Jinzaki, Kozo Sato, Yutaka Tanami, Minoru Yamada, Toshihisa Anzai, Akio Kawamura, Koji Ueno, Sachio Kuribayashi
Circulation journal : official journal of the Japanese Circulation Society, 73, 4, 691, 8, JAPANESE CIRCULATION SOC, 2009年04月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The angiographic view (AGV) image is a new post-processing method that is similar to conventional coronary angiography (CAG). The purpose of this study was to evaluate its accuracy for coronary stenosis detection by 64-detector row computed tomography (CT). METHODS AND RESULTS: CT evaluation results of 17 patients were compared with the results of invasive CAG on a coronary segment basis concerning the presence of stenoses>50% diameter reduction. All images of the 3 viewing methods (combination of conventional methods, AGV image alone, and axial images alone) were evaluated in consensus by 3 cardiovascular radiologists. Among 196 assessable segments, invasive CAG showed significant coronary artery stenoses in 44 segments. 43 of 44 lesions were detected with the AGV image, and absence of significant stenosis was correctly identified in 135 of 152 segments (sensitivity 98%; specificity 89%; accuracy 91%; positive predictive value 72%, negative predictive value 99%). The sensitivity of the AGV image was the same as that of conventional methods (98%). There was no significant difference in accuracy between the AGV image (91%) and conventional methods (94%). The accuracy of the AGV image was significantly higher than the axial images alone (78%). CONCLUSIONS: AGV image shows promise as a post-processing method for identifying coronary artery stenosis with high accuracy.

A pilot study on the role of autoantibody targeting the beta1-adrenergic receptor in the response to beta-blocker therapy for congestive heart failure.
Yuji Nagatomo, Tsutomu Yoshikawa, Takashi Kohno, Akihiro Yoshizawa, Akiyasu Baba, Toshihisa Anzai, Tomomi Meguro, Toru Satoh, Satoshi Ogawa
Journal of cardiac failure, 15, 3, 224, 32, CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2009年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Autoantibodies directed against the beta1-adrenergic receptor exert agonist-like actions by inducing receptor uncoupling and cause myocardial damage as well as fatal ventricular arrhythmias. Previous studies have shown that beta-blockers can modulate these actions of the autoantibodies. We investigated the influence of such autoantibodies in patients with congestive heart failure (CHF) receiving beta-blocker therapy. METHODS AND RESULTS: Eighty-two CHF patients were randomly assigned to treatment with metoprolol or carvedilol for 16 weeks. Autoantibodies were detected in 20 patients (24%) by enzyme-linked immunosorbent assay. Left ventricular function in response to beta-blocker therapy did not differ significantly by the presence of the autoantibody in global analysis. However, changes of the left ventricular end-diastolic dimension (P = .04), end-systolic dimension (P < .01), and ejection fraction on radionuclide ventriculography (P = .02) were significantly larger in autoantibody-positive patients than antibody-negative patients. Changes in the plasma level of brain natriuretic peptide tended to be larger in autoantibody-positive patients (P = .09). The increase of heart rate normalized by the increase of plasma norepinephrine during exercise (an index of adrenergic responsiveness) showed a greater decrease in autoantibody-positive patients than autoantibody-negative patients (P = .035). CONCLUSION: Our data suggest that beta-blocker therapy might be more effective in CHF patients with autoantibodies targeting the beta1-adrenergic receptor.

Role of high-mobility group box 1 protein in post-infarction healing process and left ventricular remodelling.
Takashi Kohno, Toshihisa Anzai, Kotaro Naito, Taku Miyasho, Minoru Okamoto, Hiroshi Yokota, Shingo Yamada, Yuichiro Maekawa, Toshiyuki Takahashi, Tsutomu Yoshikawa, Akitoshi Ishizaka, Satoshi Ogawa
Cardiovascular research, 81, 3, 565, 73, OXFORD UNIV PRESS, 2009年02月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: High-mobility group box 1 protein (HMGB1) is one of the recently defined damage-associated molecular pattern molecules derived from necrotic cells and activated macrophages. We investigated clinical implications of serum HMGB1 elevation in patients with acute myocardial infarction (MI). Then, we evaluated the effect of HMGB1 blockade on post-MI left ventricular (LV) remodelling in a rat MI model. METHODS AND RESULTS: Serum HMGB1 levels were examined in patients with ST-elevation MI (n = 35). A higher peak serum HMGB1 level was associated with pump failure, cardiac rupture, and in-hospital cardiac death. Then, an experimental MI model was induced in male Wistar rats. The mRNA and protein expression of HMGB1 were increased in the infarcted area compared with those values observed in sham-operated rats. We administered neutralizing anti-HMGB1 antibody (MI/anti-H) or control antibody (MI/C) to MI rats subcutaneously for 7 days. The mRNA levels of tumour necrosis factor-alpha and interleukin-1beta and the number of macrophages in the infarcted area were reduced on day 3 in MI/anti-H rats compared with MI/C rats. Interestingly, HMGB1 blockade resulted in thinning and expansion of the infarct scar and marked hypertrophy of the non-infarcted area on day 14. CONCLUSION: Elevated serum HMGB1 levels were associated with adverse clinical outcomes in patients with MI. However, HMGB1 blockade in a rat MI model aggravated LV remodelling, possibly through impairment of the infarct-healing process. HMGB1, a novel predictor of adverse clinical outcomes after MI, may have an essential role in the appropriate healing process after MI.

Diagnostic capacity of 64-slice multidetector computed tomography for acute coronary syndrome in patients presenting with acute chest pain.
Koji Ueno, Toshihisa Anzai, Masahiro Jinzaki, Minoru Yamada, Takashi Kohno, Akio Kawamura, Tsutomu Yoshikawa, Sachio Kuribayashi, Satoshi Ogawa
Cardiology, 112, 3, 211, 8, KARGER, 2009年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND/AIMS: Early evaluations of patients presenting with acute chest pain remain difficult. We examined the diagnostic capacity of multidetector computed tomography (MDCT) for acute coronary syndrome (ACS) in patients presenting with acute chest pain. METHODS/RESULTS: We examined 36 consecutive patients presenting with acute chest pain with neither diagnostic ECG changes nor elevated biomarkers. 64-slice MDCT was performed, and we evaluated the presenceof significant coronaryartery stenosis (>50% reduction in lumen diameter). Significant stenosis was detected in 15 patients by MDCT. Among them, 11 patients were diagnosed as having ACS based on the findings of coronary angiography or myocardial perfusion single photon emission computed tomography (positive predictive value 73%). All 21 patients without significant stenosis by MDCT, except only one, were regarded as not having ACS (negative predictive value 95%). Sensitivity and specificity were 92 and 83%, respectively. In patients without a history of coronary artery disease (CAD), both the specificity and positive predictive value improved to 100% (sensitivity 90%; negative predictive value 95%). In patients with neither a history of CAD nor coronary calcification, the diagnostic accuracy of MDCT was 100%. CONCLUSIONS: MDCT has high diagnostic capacity for the early evaluation of ACS, especially in patients without a history of CAD or coronary calcification.

Extrinsic compression of the left main coronary artery by atrial septal defect.
Yusuke Jo, Akio Kawamura, Masahiro Jinzaki, Takashi Kohno, Toshihisa Anzai, Shiro Iwanaga, Kiyokazu Kokaji, Tsutomu Yoshikawa, Ryohei Yozu, Sachio Kuribayashi, Satoshi Ogawa
The Annals of thoracic surgery, 86, 6, 1987, 9, ELSEVIER SCIENCE INC, 2008年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, On rare occasions, extrinsic compression of the coronary artery can cause significant stenosis. We report a 42-year-old woman who was referred to our hospital for surgical repair of atrial septal defect. Cardiac 64-slice multi-detector computed tomography before the operation revealed the extrinsic compression of the proximal left main coronary artery by the marked dilatation of pulmonary trunk. The patient eventually underwent atrial septal defect closure and coronary artery bypass simultaneously. Four months after the operation, multi-detector computed tomographic scan revealed reduction of pulmonary trunk diameter and resolution of left main coronary artery narrowing.

Impact of chronic kidney disease on postinfarction inflammation, oxidative stress, and left ventricular remodeling.
Kotaro Naito, Toshihisa Anzai, Tsutomu Yoshikawa, Atsushi Anzai, Hidehiro Kaneko, Takashi Kohno, Toshiyuki Takahashi, Akio Kawamura, Satoshi Ogawa
Journal of cardiac failure, 14, 10, 831, 8, CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2008年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Patients with chronic kidney disease (CKD) have poor clinical outcomes after myocardial infarction (MI). However, the precise mechanisms are unclear. We sought to determine the prognostic significance of CKD in patients with MI in relation to left ventricular (LV) remodeling. METHODS AND RESULTS: We examined 120 consecutive patients with a reperfused first anterior ST-elevation MI. Patients were divided into 2 groups according to the presence or absence of CKD, defined as estimated glomerular filtration rates <60 mL x min x 1.73 m2. Patients with CKD had a higher incidence of in-hospital cardiac death and readmission for heart failure during follow-up, in association with a greater LV volume and lower LV ejection fraction 2 weeks after MI compared with those without CKD. Cox proportional hazards model analysis revealed that CKD was an independent predictor of major adverse cardiac events (hazard ratio=3.13, P=.001). Plasma interleukin-6 on admission, and peak serum C-reactive protein, and malondialdehyde-modified low-density lipoprotein levels during convalescence, were higher in patients with CKD than in those without. CONCLUSIONS: Patients with CKD had poorer clinical outcomes and accelerated infarct expansion in association with enhanced inflammation and oxidative stress, as compared with non-CKD patients, suggesting a major impact of CKD in the development of LV remodeling after MI.

Differential effects of GM-CSF and G-CSF on infiltration of dendritic cells during early left ventricular remodeling after myocardial infarction.
Kotaro Naito, Toshihisa Anzai, Yasuo Sugano, Yuichiro Maekawa, Takashi Kohno, Tsutomu Yoshikawa, Kenjiro Matsuno, Satoshi Ogawa
Journal of immunology (Baltimore, Md. : 1950), 181, 8, 5691, 701, AMER ASSOC IMMUNOLOGISTS, 2008年10月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Several lines of evidence suggest that the immune activation after myocardial infarction (MI) induces secondary myocardial injury. Although dendritic cells (DC) are potent regulators of immunity, their role in MI is still undetermined. We investigated the effect of DC modulation by CSF on left ventricular (LV) remodeling after MI. MI was induced by ligation of the left coronary artery in male Wistar rats. G-CSF (20 microg/kg/day, MI-G, n = 33), a GM-CSF inducer (romurtide, 200 microg/kg/day, MI-GM, n = 28), or saline (MI-C, n = 55) was administered for 7 days. On day 14, MI-G animals had higher LV max dP/dt and smaller LV dimensions, whereas MI-GM animals had lower LV max dP/dt and larger LV dimensions than did MI-C animals, despite similar infarct size. In MI-C, OX62(+) DC infiltrated the infarcted and border areas, peaking on day 7. Bromodeoxyuridine-positive DC were observed in the border area during convalescence. Infiltration by DC was decreased in MI-G animals and increased in MI-GM animals compared with MI-C (p < 0.05). In the infarcted area, the heat shock protein 70, TLR2 and TLR4, and IFN-gamma expression were reduced in MI-G, but increased in MI-GM in comparison with those in MI-C animals. IL-10 expression was higher in MI-G and lower in MI-GM than in MI-C animals. In conclusion, G-CSF improves and GM-CSF exacerbates early postinfarction LV remodeling in association with modulation of DC infiltration. Suppression of DC-mediated immunity could be a new strategy for the treatment of LV remodeling after MI.

Angiotensin-receptor blockade reduces border zone myocardial monocyte chemoattractant protein-1 expression and macrophage infiltration in post-infarction ventricular remodeling.
Takashi Kohno, Toshihisa Anzai, Kotaro Naito, Yasuo Sugano, Yuichiro Maekawa, Toshiyuki Takahashi, Tsutomu Yoshikawa, Satoshi Ogawa
Circulation journal : official journal of the Japanese Circulation Society, 72, 10, 1685, 92, JAPANESE CIRCULATION SOC, 2008年10月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is a key mediator of left ventricular (LV) remodeling during the early phase of myocardial infarction (MI). The hypothesis tested was that myocardial MCP-1 expression would increase during the chronic phase of MI and an angiotensin-II type 1 receptor blocker (ARB) would attenuate macrophage infiltration through decreased myocardial MCP-1 expression. METHODS AND RESULTS: MI was produced by ligation of the left coronary artery in Wistar rats, which were then randomized to treatment with vehicle (MI/C), candesartan (10 mg.kg(-1).day(-1)) for 6 weeks (MI/ARB0-6W), or candesartan for 2 weeks, starting 4 weeks after MI (MI/ARB4-6W). LV systolic and end-diastolic pressures 6 weeks after MI were decreased in MI/ARB0-6W compared with MI/C or MI/ARB4-6W, however, there were no differences in other hemodynamic or echocardiographic parameters among infarcted rat groups. Both long- and short-term treatments with ARB similarly reduced mRNA expressions of MCP-1, transforming growth factor-beta1, and procollagen type I and III, macrophage infiltration, and myocardial fibrosis in the border zone. CONCLUSIONS: In post-MI heart failure, ARB attenuated MCP-1 expression and macrophage infiltration in the border zone, resulting in less myocardial fibrosis. ARB may exert its beneficial effect, at least in part, by inhibiting myocardial macrophage-related inflammation.

Angiotensin-receptor blockade reduces border zone myocardial monocyte chemoattractant protein-1 expression and macrophage infiltration in post-infarction ventricular remodeling
Takashi Kohno, Toshihisa Anzai, Kotaro Naito, Yasuo Sugano, Yuichiro Maekawa, Toshiyuki Takahashi, Tsutomu Yoshikawa, Satoshi Ogawa
CIRCULATION JOURNAL, 72, 10, 1685, 1692, JAPANESE CIRCULATION SOC, 2008年10月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Background Monocyte chernoattractant protein-1 (MCP-1) is a key mediator of left ventricular (LV) remodeling during the early phase of myocardial infarction (MI). The hypothesis tested was that myocardial MCP-1 expression would increase during the chronic phase of MI and in angiotensin-II type 1 receptor blocker (ARB) would attenuate macrophage infiltration through decreased myocardial MCP-1 expression.
Methods and Results MI was produced by ligation of the left coronary artery in Wistar rats, which were then randomized to treatment with vehicle (MI/C), candesartan (10 mg.kg(-1).day(-1)) for 6 weeks (MI/ARB0-6W), or candesartan for 2 weeks, starting 4 weeks after MI (MI/ARB4-6W). LV systolic and end-diastolic pressures 6 weeks after MI were decreased in MI/ARB0-6W compared with MI/C or MI/ARB4-6W, however, there were no differences in other hemodynamic or echocardiographic parameters among infarcted rat groups. Both long- and short-term treatments with ARB similarly reduced mRNA expressions of MCP-1, transforming growth factor-31. and procollagen type I and III, macrophage infiltration, and myocardial fibrosis in the border zone.
Conclusions In post-MI heart failure, ARB attenuated MCP-1 expression and macrophage infiltration in the border zone. resulting in less myocardial macrophage-related inflammation.

Angiotensin II independent mineralocorticoid receptor activation in heart failure models
Tomomi Meguro, Yuji Nagato, Kimi Koide, Hiroyuki Ito, Toshihisa Anzai, Satoshi Ogawa, Tsutomu Yoshikawa
JOURNAL OF CARDIAC FAILURE, 14, 7, S147, S147, CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2008年09月, ［査読有り］
英語

Effect of human C-reactive protein on cardiac function and angiotensin 2 signaling in diabetic cardiomyopathy
Yoshinori Mano, Toshihisa Anzai, Toshiyuki Takahashi, Yuji Nagatomo, Kimi Koide, Hidehiro Kaneko, Tomomi Meguro, Tsutomu Yoshikawa, Satoshi Ogawa
JOURNAL OF CARDIAC FAILURE, 14, 7, S170, S170, CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2008年09月, ［査読有り］
英語

Persistent elevation in troponin T level during convalescence is associated with inflammatory response in patients with decompensated heart failure
Kimi Koide, Tsutomu Yoshikawa, Yuji Nagatomo, Toshihisa Anzai, Tomomi Meguro, Satoshi Ogawa
JOURNAL OF CARDIAC FAILURE, 14, 7, S171, S171, CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2008年09月, ［査読有り］
英語

Use of renin-angiotensin inhibitors at discharge in patients hospitalized for heart failure is associated with improved survival
Yusuke Yoshimatsu, Shun Kohsaka, Kimi Koide, Yuji Nagatomo, Hiroyuki Ito, Tomomi Meguro, Toshihisa Anzai, Satoshi Ogawa, Tsutomu Yoshikawa
JOURNAL OF CARDIAC FAILURE, 14, 7, S173, S173, CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2008年09月, ［査読有り］
英語

Impact of optimal medical therapy at discharge in patients with heart failure: Characteristics and long-term outcome
Shuhei Ito, Shun Kohsaka, Kipvii Koide, Yuji Nagatomo, Hiroyuki Ito, Tomomi Meguro, Toshihisa Anzai, Satoshi Ogawa, Tsutomu Yoshikaa
JOURNAL OF CARDIAC FAILURE, 14, 7, S173, S173, CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2008年09月, ［査読有り］
英語

Differential effects of carvedilol and metoprolol on renal function in patients with heart failure
Hiroyuki Ito, Yuji Nagatomo, Takashi Kohno, Toshihisa Anzai, Tomomi Meguro, Satoshi Ogawa, Tsutomu Ycshikawa
JOURNAL OF CARDIAC FAILURE, 14, 7, S174, S174, CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2008年09月, ［査読有り］
英語

Early use of beta-blockers attenuates systemic inflammatory response and lung oxygenation impairment after distal type acute aortic dissection.
Yusuke Jo, Toshihisa Anzai, Yasuo Sugano, Kotaro Naito, Koji Ueno, Takashi Kohno, Tsutomu Yoshikawa, Satoshi Ogawa
Heart and vessels, 23, 5, 334, 40, SPRINGER, 2008年09月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, We have reported that serum C-reactive protein (CRP) elevation is an independent predictor of lung oxygenation impairment (LOI) after distal type acute aortic dissection (AAD). Systemic activation of the inflammatory system after aortic injury may play a role in the development of LOI. The aim of this study is to clarify the effect of beta-blockers on systemic inflammation and the development of LOI after distal type AAD. A total of 49 patients, who were admitted with distal type AAD and treated conservatively, were examined. White blood cell (WBC) count, serum CRP level, and arterial blood gases were measured serially. Forty patients received beta-blocker treatment within 24 h of the onset, while 9 patients received no beta-blocker treatment. Maximum WBC count, maximum CRP level, lowest PaO(2)/FiO(2) (P/F) ratio, and patient background were compared between the two groups. There was no difference between the groups according to age, sex, coronary risk factors, blood pressure, serum level of CRP, WBC count, and oxygenation index on admission. Beta-blocker treatment was associated with lower maximum WBC count (P = 0.0028) and lower maximum serum CRP level (P = 0.0004). The minimum P/F ratio was higher in patients with beta-blocker treatment than in those without (P = 0.0076). Multivariate analysis revealed that administration of a beta-blocker was an independent negative determinant of LOI (P/F ratio < or = 200 mmHg). In conclusion, early use of beta-blockers prevented excessive inflammation and LOI after distal type AAD, suggesting a pleiotropic effect of beta-blockers on the inflammatory response after AAD.

Overview image of the lumen and vessel wall in coronary CT angiography.
Masahiro Jinzaki, Minoru Yamada, Kozo Sato, Yutaka Tanami, Toshihisa Anzai, Kosuke Sasaki, Sachio Kuribayashi
Circulation journal : official journal of the Japanese Circulation Society, 72, 4, 671, 3, JAPANESE CIRCULATION SOC, 2008年04月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: There is no post-processing technique that can display an overview image of the lumen and vessel wall of a whole heart in one image. A merging coronary lumen view (Angiographic View) with a plaque image can provide a single, comprehensive image of plaque distribution. METHODS AND RESULTS: A color-coded plaque image is assigned to different computed tomography attenuation ranges in the coronary artery to visualize plaques. This plaque image is re-formatted into a maximum intensity projection image and loaded onto the Angiographic View image. CONCLUSIONS: The integrated image of the coronary lumen and vessel wall of a whole heart is feasible. This image (Plaque-loaded Angiographic View) will give effective information in explaining the distribution of coronary lesions in patients as well as providing opportunities to discuss treatment strategies.

Comparison of the effects of carvedilol and metoprolol on exercise ventilatory efficiency in patients with congestive heart failure.
Masaharu Kataoka, Toru Satoh, Tsutomu Yoshikawa, Iwao Nakamura, Takashi Kohno, Akihiro Yoshizawa, Toshihisa Anzai, Satoshi Ogawa
Circulation journal : official journal of the Japanese Circulation Society, 72, 3, 358, 63, JAPANESE CIRCULATION SOC, 2008年03月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The slope of the relationship between ventilation and carbon dioxide production (VE/VCO2 slope), obtained during symptom-limited ramp exercise testing, reflects exercise ventilatory efficiency. Importantly, the VE/VCO2 slope is related to prognosis in patients with congestive heart failure (CHF). The aim of the present study was to determine the relationship between the institution of beta-blockers, carvedilol or metoprolol, and the VE/VCO2 slope during exercise in patients with CHF. METHODS AND RESULTS: Fifty-seven patients with New York Heart Association functional class II or III with a radionuclide left ventricular ejection fraction (LVEF) of less than 40% received carvedilol or metoprolol in a randomized fashion. The VE/VCO2 slope, LVEF and plasma brain natriuretic peptide (BNP) concentration were determined before and after 16 weeks of treatment. LVEF improved (p<0.01), but the VE/VCO2 slope and BNP did not. A significant improvement in the VE/VCO2 slope was observed in patients with LVEF <29% or BNP >63 pg/ml (respective baseline median values) (p<0.05, p<0.05). In patients with BNP >63 pg/ml, the improvement effect on the VE/VCO2 slope with carvedilol was significantly greater than that with metoprolol (p<0.05) and a significant improvement in the VE/VCO2 slope was observed only in those who took carvedilol (p<0.01). CONCLUSIONS: The VE/VCO2 slope was not improved after beta-blocker therapy in any of the patients. However, it did improve in patients with a lower LVEF or higher BNP level at baseline, and carvedilol was more effective than metoprolol in improving the VE/VCO2 slope in patients with higher BNP levels at baseline.

Erratum: A 19-year-old man with myocardial infarction and sitosterolemia (Internal Medicine (2003) vol. 42 (7) (591))
Takaharu Katayama, Toru Satoh, Takashi Yagi, Nobuyoshi Hirose, Yasuo Kuita, Toshihisa Anzai, Yasushi Asakura, Tsutomu Yoshikawa, Hideo Mitamura, Satoshi Ogawa
Internal Medicine, 47, 3, 191, 2008年02月01日, ［査読有り］
英語, 研究論文（学術雑誌）

Genetic ablation of angiotersin II type 1a receptor has a beneficial effect on diabetes-induced cardiomyopathy by expressing heat shock proteins and by inhibiting apoptosis
Yuji Nagatomo, Tomomi Meguro, Kimi Koide, Toshihisa Anzai, Satoshi Ogawa, Tsutomu Yoshikawa
CIRCULATION, 116, 16, 310, 310, LIPPINCOTT WILLIAMS & WILKINS, 2007年10月, ［査読有り］
英語

Effects of beta-blocker therapy on high sensitivity c-reactive protein, oxidative stress, and cardiac function in patients with congestive heart failure.
Yuji Nagatomo, Tsutomu Yoshikawa, Takashi Kohno, Akihiro Yoshizawa, Toshihisa Anzai, Tomomi Meguro, Toru Satoh, Satoshi Ogawa
Journal of cardiac failure, 13, 5, 365, 71, CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2007年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: It is uncertain whether beta-blocker therapy affects serum C-reactive protein (CRP) level in patients with congestive heart failure (CHF). We attempted to determine if beta-blocker therapy decreases serum CRP production and to correlate the production with biomarkers and cardiac function in such patients. METHODS AND RESULTS: Fifty-two patients with mild to moderate CHF with a left ventricular ejection fraction (EF) <40% were enrolled. They were randomly assigned to metoprolol or carvedilol treatment groups. The CRP concentration decreased significantly in patients with higher baseline CRP concentration, but not in those with lower baseline CRP concentrations. There was an inverse correlation between DeltaCRP and DeltaEF 16 weeks after the start of beta-blocker therapy for patients with higher baseline CRP concentrations. In patients with higher baseline concentrations, CRP decreased in patients who received carvedilol, but not in those who received metoprolol. Plasma lipid peroxide (LPO) concentration significantly decreased, and there was an inverse correlation between DeltaCRP and DeltaLPO 16 weeks after the start of therapy. CONCLUSIONS: Administration of beta-blockers is associated with attenuation of inflammatory marker in certain patients with CHF. The antioxidant effects of beta-blockers, especially carvedilol, may play a role in mediating the phenomenon.

Increased body temperature after reperfused acute myocardial infarction is associated with adverse left ventricular remodeling.
Kotaro Naito, Toshihisa Anzai, Tsutomu Yoshikawa, Yuichiro Maekawa, Yasuo Sugano, Takashi Kohno, Keitaro Mahara, Teruo Okabe, Yasushi Asakura, Satoshi Ogawa
Journal of cardiac failure, 13, 1, 25, 33, CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2007年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Fever is frequently observed in patients with acute myocardial infarction (AMI); however, its prognostic significance remains to be determined. We sought to determine the prognostic significance of increased body temperature (BT) after AMI. METHODS AND RESULTS: We examined 156 consecutive patients with reperfused first anterior AMI. Axillary BT was serially measured every 6 hours for a week. Patients were divided into quartiles by peak BT from the lowest to highest levels. Peak BT within the first week showed a significant positive correlation with peak C-reactive protein level (P < .0001), but not with peak creatine kinase level. There were positive correlations of peak BT with the incidence of pump failure (P = .022), left ventricular (LV) aneurysm (P = .029), and readmission for heart failure (P = .006). Higher peak BT was associated with greater LV end-diastolic volume (P = .031), greater end-systolic volume (P = .008), and lower LV ejection fraction (P = .014) 2 weeks after AMI. Multiple logistic regression analyses revealed that peak BT quartile was an independent predictor of in-hospital cardiac events (odds ratio = 1.61/quartile, P = .008). Furthermore, peak BT quartile was a significant predictor of readmission for heart failure by Cox proportional hazard model analysis (P = .048). CONCLUSIONS: Increased BT after AMI was associated with a worse clinical outcome and infarct expansion, suggesting a relationship between systemic inflammatory response and LV remodeling.

Impact of serum C-reactive protein elevation on the left ventricular spherical change and the development of mitral regurgitation after anterior acute myocardial infarction.
Takashi Kohno, Toshihisa Anzai, Kotaro Naito, Yohei Ohno, Hidehiro Kaneko, Hui-Chong Li, Yasuo Sugano, Yuichiro Maekawa, Shiro Iwanaga, Yasushi Asakura, Tsutomu Yoshikawa, Satoshi Ogawa
Cardiology, 107, 4, 386, 94, KARGER, 2007年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND/AIMS: Mitral regurgitation (MR) is frequently observed in patients with acute myocardial infarction (AMI), and is known to convey an adverse prognosis. We sought to clarify the relationship between MR and left ventricular (LV) remodeling, in association with serum C-reactive protein (CRP) elevation. METHODS/RESULTS: A total of 181 patients with first anterior ST-elevation AMI were examined. MR was detected in 68 patients by color Doppler echocardiography 2 weeks after AMI, and the patients with MR were associated with higher incidence of readmission for heart failure. Serum CRP was serially measured, and the peak serum CRP level was markedly increased in patients with MR compared with those without MR. Multiple logistic regression analysis showed that peak CRP tertile was an independent determinant of MR after AMI (p < 0.0001). In the substudy, the increases in LV end-diastolic volume and sphericity index were higher in patients with MR than in those without MR. CONCLUSIONS: MR during the early phase of anterior AMI was associated with LV spherical change and late-phase heart failure, in association with increased serum CRP level. These findings suggest an important role of the inflammatory response in the development of ischemic MR and LV remodeling.

Novel method of displaying coronary CT angiography: Angiographic view.
Masahiro Jinzaki, Kozo Sato, Yutaka Tanami, Minoru Yamada, Sachio Kuribayashi, Toshihisa Anzai, Yasushi Asakura, Satoshi Ogawa
Circulation journal : official journal of the Japanese Circulation Society, 70, 12, 1661, 2, JAPANESE CIRCULATION SOCIETY, 2006年12月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Background A method of displaying coronary computed tomography (CT) angiography, which enables evaluation of coronary artery disease (CAD) with fewer images and is understandable to the third person, is preferable. Methods and Results A maximum intensity projection image was created in which contrast media in the ventricles is eliminated, enabling an overview of CAD in a single 3-dimensional (D) image that can be rotated to be viewed at various angles and is easily understood by a third person. Conclusions A novel method of displaying coronary CT angiography in a single 3-D image has been developed and we believe it should become available for many workstations.

Genetic ablation of angiotensin II type1a receptor ameliorates cardiac diastolic dysfunction induced by diabetes mellitus through the improvement of calcium handling
Yuji Nagatomo, Tomomi Meguro, Hitomi Saito, Jun Katada, Toshihisa Anzai, Satoshi Ogawa, Tsutomu Yosikawa
CIRCULATION, 114, 18, 151, 151, LIPPINCOTT WILLIAMS & WILKINS, 2006年10月, ［査読有り］
英語

Presence of autoantibody directed against ss-adrenergic receptors is associated with amelioration of cardiac dysfunction during ss-blocker therapy for congestive heart failure
Yuji Nagatomo, Tsutomu Yosikawa, Takashi Kohno, Akihiro Yoshizawa, Akiyasu Baba, Toshihisa Anzai, Tomomi Meguro, Toru Sato, Satoshi Ogawa
CIRCULATION, 114, 18, 667, 667, LIPPINCOTT WILLIAMS & WILKINS, 2006年10月, ［査読有り］
英語

Presence of autoantibody against b1-adrenergic receptors is associated with amelioration of cardiac function during b-blocker therapy for congestive heart failure
Yuji Nagatomo, Tsutomu Yoshikawa, Takashi Kohno, Akihiro Yoshizawa, Akiyasu Baba, Toshihisa Anzai, Tomomi Meguro, Toru Sato, Satoshi Ogawa
JOURNAL OF CARDIAC FAILURE, 12, 8, S172, S172, CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS, 2006年10月, ［査読有り］
英語

Mineralocorticoid receptor blockade arrests pressure overload-induced left ventricular hypertrophy and preserves cardiac function in angiotensin II type 1a receptor knockout mice
Tomomi Meguro, Tsutomu Yoshikawa, Jun Katada, Hitomi Saito, Toshihisa Anzai, Yuji Nagatomo, Satoshi Ogawa
CIRCULATION, 114, 18, 150, 150, LIPPINCOTT WILLIAMS & WILKINS, 2006年10月, ［査読有り］
英語

Antigen-specific effects of autoantibodies against sarcolemmal Na-K-ATPase pump in immunized cardiomyopathic rabbits.
Akiyasu Baba, Tsutomu Yoshikawa, Michikado Iwata, Toshihisa Anzai, Iwao Nakamura, Yumiko Wainai, Satoshi Ogawa, Michael Fu
International journal of cardiology, 112, 1, 15, 20, ELSEVIER IRELAND LTD, 2006年09月10日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: We examine antigen-specific actions of autoantibodies directed against sarcolemmal Na-K-ATPase. BACKGROUND: Autoantibodies against some receptors or pumps were detected in patients with dilated cardiomyopathy. Although immunoglobulin adsorption therapy improved cardiac function in such patients, direct pathogenic effects of autoantibodies remain to be proven. METHODS: Japanese white rabbits were immunized once a month with purified Na-K-ATPase (NKA rabbits, n=10) or a synthetic peptide corresponding to the second extracellular loop of beta1-adrenergic receptors (beta rabbits, n=10), respectively. Control rabbits (n=10) received vehicle in the same manner. RESULTS: At 6 months, cardiac hypertrophy along with increased left ventricular end-diastolic pressure was observed in both NKA and beta rabbits, and inhibitory G protein level increased in both NKA and beta rabbits. Histological findings showed similar myocyte hypertrophy and interstitial fibrosis in both rabbits. Enzymatic activities of Na-K-ATPase were lower in NKA rabbits than in other groups. Immunoblotting showed that alpha3-isoform of Na-K-ATPase was selectively reduced in myocardium from NKA rabbits. CONCLUSIONS: Our present findings suggested that isoform-specific alterations of myocardial Na-K-ATPase activity were induced by immunizing rabbits. This was not secondary change due to cardiac hypertrophy. Thus, autoantibodies against sarcolemmal Na-K-ATPase have antigen-specific effect on the heart in vivo.

心筋症の診断と治療 up to date 液性免疫異常からみた心筋症の診断と治療　　　　　　　　　　　　　　　
馬場 彰泰, 吉川 勉, 長友 祐司, 栗田 康生, 内藤 広太郎, 吉澤 彰宏, 家田 真樹, 安斎 俊久, 島田 恵, 松原 隆, 赤石 誠, 朝倉 靖, 岩永 史郎, 熊谷 裕生, 小川 聡
Journal of Cardiology, 48, Suppl.I, 154, 154, (一社)日本心臓病学会, 2006年09月, ［査読有り］
日本語

Aging adversely affects postinfarction inflammatory response and early left ventricular remodeling after reperfused acute anterior myocardial infarction.
Keitaro Mahara, Toshihisa Anzai, Tsutomu Yoshikawa, Yuichiro Maekawa, Teruo Okabe, Yasushi Asakura, Toru Satoh, Hideo Mitamura, Masahiro Suzuki, Akira Murayama, Satoshi Ogawa
Cardiology, 105, 2, 67, 74, KARGER, 2006年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND AIMS: We have demonstrated that an increased peak serum C-reactive protein (CRP) level after acute myocardial infarction (AMI) was a major predictor of left ventricular (LV) remodeling. We sought to clarify the effect of aging on the postinfarction inflammatory response and LV remodeling. METHODS: We studied 102 patients who underwent primary angioplasty for a first anterior Q-wave AMI. Serum CRP levels, plasma neurohormones and interleukin-6 (IL-6) levels, and LV volume by left ventriculography were serially measured. Patients were divided into two groups according to their age (>or=70 years, n=33; <70 years, n=69). RESULTS: There was no difference in use of cardiovascular drugs and coronary angiographic findings. Older patients had a greater increase in LV end-diastolic volume during 2 weeks after AMI (p=0.0007) and a higher peak CRP level (12.4+/-7.3 vs. 5.5+/-4.2 mg/dl, p<0.0001), although peak CK level was comparable between the two groups. Plasma atrial natriuretic peptide, brain natriuretic peptide and IL-6 levels were higher in older patients at 2 weeks and 6 months after AMI. CONCLUSIONS: Augmented and prolonged activation of the inflammatory system after AMI was observed in older patients, in association with exaggerated LV remodeling. Aging may adversely affect LV remodeling through modification of the inflammatory response after AMI.

Carvedilol exerts more potent antiadrenergic effect than metoprolol in heart failure.
Takashi Kohno, Tsutomu Yoshikawa, Akihiro Yoshizawa, Iwao Nakamura, Toshihisa Anzai, Toru Satoh, Satoshi Ogawa
Cardiovascular drugs and therapy, 19, 5, 347, 55, SPRINGER, 2005年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: It is still uncertain whether or not there is a difference between metoprolol and carvedilol for the treatment of congestive heart failure. We attempted to determine the difference between the two beta-blockers in terms of their antiadrenergic effect during exercise in patients with heart failure and their efficacy based on the baseline plasma brain natriuretic peptide concentration. METHODS: Fifty-three patients with mild to moderate heart failure with a radionuclide left ventricular ejection fraction <40% received open label metoprolol or carvedilol in a randomized fashion. The increase in the heart rate normalized to the increase in the plasma norepinephrine concentration during exercise, was calculated as an index of adrenergic responsiveness during exercise. RESULTS: The increase in heart rate normalized by the increase in plasma norepinephrine concentration, decreased after the initiation of beta-blockers in the carvedilol group, but not in the metoprolol group. The change in cardiac function was more favorable for carvedilol than metoprolol in patients who exhibited a higher baseline brain natriuretic peptide concentration. CONCLUSIONS: Carvedilol exerts a more potent antiadrenergic effect than metoprolol during stress in patients with mild to moderate heart failure. Carvedilol appears to be more efficacious than metoprolol in patients who exhibit higher baseline brain natriuretic peptide concentrations. These differences should be kept in mind when selecting appropriate pharmacologic agents in the treatment of heart failure.

Serum C-reactive protein elevation predicts poor clinical outcome in patients with distal type acute aortic dissection: association with the occurrence of oxygenation impairment.
Yasuo Sugano, Toshihisa Anzai, Tsutomu Yoshikawa, Toru Satoh, Shiro Iwanaga, Takeharu Hayashi, Yuichiro Maekawa, Hideyuki Shimizu, Ryohei Yozu, Satoshi Ogawa
International journal of cardiology, 102, 1, 39, 45, ELSEVIER IRELAND LTD, 2005年06月22日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Acute aortic dissection (AAD) is sometimes complicated by respiratory failure due to severe lung oxygenation impairment. Systemic activation of inflammatory system after aortic injury may play some roles in the development of this complication. The aim of this study was to determine the significance of serum C-reactive protein (CRP) elevation in the development of oxygenation impairment and clinical outcome with distal type AAD. METHODS AND RESULTS: A total of 61 patients, who were admitted with distal type AAD within 24 h from the onset, were examined. Serum CRP levels, white blood cell (WBC) counts and body temperature were measured serially for at least 4 days. Oxygenation impairment, defined as the lowest PaO2/FIO2 ratio < or = 200 mmHg, was noted in 31 patients (51%). In patients with oxygenation impairment, peak CRP levels (20.7+/-7.9 vs. 12.7+/-3.8 mg/dl, P < 0.001), peak WBC counts (14,600+/-3600 vs. 11,800+/-4300/mm3, P = 0.008) and body temperature (38.4+/-0.5 vs. 38.0+/-0.6 degrees C, P = 0.004) were significantly higher than those without. Peak CRP level was inversely correlated with the lowest PaO2/FIO2 (P < 0.001). Patients who underwent urgent surgical treatment and/or died in the hospital had higher peak CRP levels (25.1+/-12.3 vs. 16.1+/-7.4 mg/dl, P = 0.010) than those who did not. Multivariate analysis revealed that a peak CRP level > or = 15 mg/dl (relative risk = 12.6, P < 0.001) was an independent determinant of the development of oxygenation impairment. CONCLUSION: The greater serum CRP elevation after distal type AAD was associated with a higher incidence of oxygenation impairment and poor clinical outcome. Systemic activation of the inflammatory system after aortic injury may play an important role in the development of oxygenation impairment.

Persistent cardiac aldosterone synthesis in angiotensin II type 1A receptor-knockout mice after myocardial infarction.
Jun Katada, Tomomi Meguro, Hitomi Saito, Akira Ohashi, Toshihisa Anzai, Satoshi Ogawa, Tsutomu Yoshikawa
Circulation, 111, 17, 2157, 64, LIPPINCOTT WILLIAMS & WILKINS, 2005年05月03日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The renin-angiotensin-aldosterone system is implicated in the pathogenesis of heart failure. Pharmacological blockade of angiotensin II (Ang II)-dependent signaling is clinically effective in reducing cardiovascular events after myocardial infarction (MI) but still fails to completely prevent remodeling. The molecular basis underlying this Ang II-independent remodeling is unclear. METHODS AND RESULTS: Acute MI was induced by coronary ligation in wild-type (WT) and angiotensin II type IA receptor-knockout (AT1A-KO) mice. Left ventricular (LV) geometry, hemodynamics, and cardiac gene expression were evaluated on day 28. Severe LV remodeling and resultant cardiac dysfunction were observed in WT mice, whereas less marked, but still significant, LV remodeling and cardiac dysfunction were induced in AT1A-KO mice. Gene expression levels of aldosterone synthase and the cardiac aldosterone content were both elevated in the MI hearts, even in AT1A-KO mice. In AT1A-KO mice treated with spironolactone (20 mg/kg per day), LV remodeling, cardiac dysfunction, and cardiac gene expression of collagens and natriuretic peptides were almost normalized. CONCLUSIONS: Our results indicate that genetic blockade of AT1A signaling fails to arrest aldosterone production in cardiac tissues and that cardiac aldosterone plays a critical role in post-MI LV remodeling. The results suggest that spironolactone could be potentially effective in patients with MI, when used in combination with renin-angiotensin system blockade, by blocking the actions of aldosterone produced by Ang II-independent mechanisms.

Oral sildenafil improves primary pulmonary hypertension refractory to epoprostenol.
Masaharu Kataoka, Toru Satoh, Tomohiro Manabe, Toshihisa Anzai, Tsutomu Yoshikawa, Hideo Mitamura, Satoshi Ogawa
Circulation journal : official journal of the Japanese Circulation Society, 69, 4, 461, 5, JAPANESE CIRCULATION SOCIETY, 2005年04月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Epoprostenol (prostaglandin I(2)) has become recognized as a therapeutic breakthrough that can improve hemodynamics and survival in patients with primary pulmonary hypertension (PPH). However, a significant number of patients have PPH that is refractory to epoprostenol, and lung transplantation has been the only remaining treatment option. METHODS AND RESULTS: The study subjects included 20 consecutive patients with PPH (mean pulmonary arterial pressure: 65+/-15 mmHg) who had received epoprostenol for more than 12 months. The patients were divided into 2 groups; responders and non-responders. In the non-responders, New York Heart Association (NYHA) functional class did not improve and mean right atrial pressure (mRA) increased to 8 mmHg or more, and additional sildenafil, a phosphodiesterase-5 inhibitor, was started. Six patients were included in the non-responders, whose mRA was 9+/-5 mmHg before and significantly increased to 13+/-3 mmHg after epoprostenol administration (p < 0.05). One patient died and the other 5 patients received oral sildenafil. The mRA of 12+/-4 mmHg (value before sildenafil) improved to 8+/-5 mmHg after sildenafil administration. Three patients were classified in the NYHA functional class 4 and improved to class 3, and 2 patients were in class 3 and remained in the same class after the addition of sildenafil. CONCLUSIONS: In patients with severe PPH refractory to epoprostenol treatment, additional oral sildenafil can improve pulmonary hemodynamics and symptoms. The combination therapy of epoprostenol and sildenafil is a new medical treatment to attempt before progressing to lung transplantation for patients with PPH refractory to epoprostenol.

Granulocyte colony-stimulating factor attenuates early ventricular expansion after experimental myocardial infarction.
Yasuo Sugano, Toshihisa Anzai, Tsutomu Yoshikawa, Yuichiro Maekawa, Takashi Kohno, Keitaro Mahara, Kotaro Naito, Satoshi Ogawa
Cardiovascular research, 65, 2, 446, 56, OXFORD UNIV PRESS, 2005年02月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: In the early phase after transmural myocardial infarction (MI), the infarcted myocardium undergoes replacement by scar tissue, which is essential for preserving the structural integrity of the infarcted tissue. Transforming growth factor (TGF)-beta1, which is known as a fibrotic cytokine, plays a pivotal role in the reparative fibrosis after MI. It is reported that granulocyte colony-stimulating factor (G-CSF) can accelerate wound healing. The aim of our study was to investigate the effect of G-CSF on early ventricular expansion after MI. METHODS: MI was induced by ligation of the left coronary artery in male Wistar rats. G-CSF (20 microg/kg/day, MI-GCSF) or saline (MI-saline) was injected subcutaneously 3 h after MI and every 24 h thereafter for 7 days. Hemodynamic and echocardiographic studies were performed at 14 days. Expression of TGF-beta1 and procollagen type I and type III mRNA in both the infarcted and noninfarcted areas was studied by quantitative RT-PCR at 1, 3, 7, and 14 days after MI. Histological studies were performed at 7 days. RESULTS: MI-GCSF had higher LV max dP/dt, lower LV end-diastolic pressure, and smaller LV end-diastolic and end-systolic dimensions compared to MI-saline. Infarct size was not different between MI-GCSF and MI-saline. Expression of TGF-beta1 mRNA in the infarcted area at 3 days was significantly higher in MI-GCSF than in MI-saline. Expression of procollagen type I and type III mRNA in the infarcted area at 3 days was higher in MI-GCSF compared to MI-saline, and the peak mRNA levels were earlier in MI-GCSF. In the noninfarcted area, there was no difference in TGF-beta1 mRNA expression between MI-GCSF and MI-saline. Histologically, collagen accumulation in the infarcted area at 7 days was more prominent in MI-GCSF than in MI-saline. CONCLUSION: G-CSF treatment improves early post-infarct ventricular expansion through promotion of reparative collagen synthesis in the infarcted area, suggesting some beneficial effect of G-CSF on the infarct healing process.

Relation of stent overexpansion to the angiographic no-reflow phenomenon in intravascular ultrasound-guided stent implantation for acute myocardial infarction.
Yuichiro Maekawa, Yasushi Asakura, Toshihisa Anzai, Shiro Ishikawa, Teruo Okabe, Tsutomu Yoshikawa, Satoshi Ogawa
Heart and vessels, 20, 1, 13, 8, SPRINGER, 2005年02月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, The angiographic no-reflow phenomenon is observed in some patients during stent implantation for acute myocardial infarction (AMI). We attempted to clarify the influence of stent overexpansion and plaque morphology on the angiographic no-reflow phenomenon in AMI patients who underwent intravascular ultrasound (IVUS)-guided stent implantation. We assessed the thrombolysis in myocardial infarction (TIMI) flow grade in the coronary angiographic findings, and quantitative and qualitative IVUS findings, in a total of 90 patients who underwent IVUS-guided stenting for AMI. The patients were divided into two groups according to the stent-to-artery ratio: overexpansion group (ratio > or =1.2) and non-overexpansion group (ratio <1.2). Angiographic no-reflow (defined as TIMI flow grade <3) in stent implantation was observed in 15 patients (17%). Angiographic no-reflow was more frequently observed in the overexpansion group than in the non-overexpansion group (32% vs 11%, P = 0.0312). Patients with no-reflow had more lipid pool-like images or fissure/dissection than those without. In the overexpansion group, a lipid pool-like image and fissure/dissection were more frequently observed in patients with no-reflow. The rate of target lesion revascularization (TLR) in the overexpansion group was significantly lower than that in the non-overexpansion group during the follow-up period (10% vs 18%, P = 0.0476), but the incidence of pump failure in the overexpansion group was higher than that in the non-overexpansion group during the hospital course (28% vs 14%, P = 0.0358). Stent overexpansion in AMI patients is related to a higher incidence of angiographic no-reflow, especially if the lesion has a lipid pool-like image or fissure/dissection, although there is a tendency for lower TLR.

Effect of granulocyte-macrophage colony-stimulating factor inducer on left ventricular remodeling after acute myocardial infarction.
Yuichiro Maekawa, Toshihisa Anzai, Tsutomu Yoshikawa, Yasuo Sugano, Keitaro Mahara, Takashi Kohno, Toshiyuki Takahashi, Satoshi Ogawa
Journal of the American College of Cardiology, 44, 7, 1510, 20, ELSEVIER SCIENCE INC, 2004年10月06日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: We sought to determine the influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) induction on post-myocardial infarction (MI) remodeling, especially in relation to the inflammatory response and myocardial fibrosis. BACKGROUND: Granulocyte-macrophage colony-stimulating factor modifies wound healing by promoting monocytopoiesis and infiltration of monocytes and macrophages into injured tissue; however, the effect of GM-CSF induction on the infarct healing process and myocardial fibrosis is unclear. METHODS: A model of MI was produced in Wistar rats by ligation of the left coronary artery. The MI animals were randomized to receive GM-CSF inducer (romurtide 200 microg/kg/day for 7 consecutive days) (MI/Ro) or saline (MI/C). RESULTS: Echocardiographic and hemodynamic studies on day 14 revealed increased left ventricular (LV) end-diastolic dimension, decreased fractional shortening, elevated LV end-diastolic pressure, and decreased LV maximum rate of isovolumic pressure development in MI/Ro compared with MI/C. Immunoblotting showed that expression of transforming growth factor (TGF)-beta1 in the infarcted site on day 3 after MI was decreased in MI/Ro compared with MI/C. In the infarcted site, TGF-beta1, collagen type I and type III messenger ribonucleic acid (mRNA) expression on day 3, and collagen content on day 7 were reduced in MI/Ro compared with MI/C, in association with marked infarct expansion. In MI/Ro, monocyte chemoattractant protein-1 mRNA level and the degree of infiltration of monocyte-derived macrophages (ED-1-positive)were greater in the infarcted site on day 7 than those in MI/C. CONCLUSIONS: The GM-CSF induction by romurtide facilitated infarct expansion in association with the promotion of monocyte recruitment and inappropriate collagen synthesis in the infarcted region during the early phase of MI.

Marked improvement with sildenafil in a patient with primary pulmonary hypertension unresponsive to epoprostenol.
Masaharu Kataoka, Toru Satoh, Tomohiro Manabe, Toshihisa Anzai, Tsutomu Yoshikawa, Hideo Mitamura, Satoshi Ogawa
Internal medicine (Tokyo, Japan), 43, 10, 945, 50, JAPAN SOC INTERNAL MEDICINE, 2004年10月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, We report a 48-year-old woman with right heart failure due to primary pulmonary hypertension. Continuous infusion of epoprostenol (prostaglandin I2) for 1.5 years failed to control her condition, but she was later successfully treated with additional sildenafil for a few months. Her mean pulmonary artery pressure was originally 57 mmHg, increased to 62 mmHg with epoprostenol, and decreased to 45 mmHg with sildenafil. Additional sildenafil may be an effective and life-saving agent in patients with primary pulmonary hypertension who show a poor response to epoprostenol, which is considered to be very powerful medical treatment for the disease.

Angiotensin receptor blockade improves myocardial beta-adrenergic receptor signaling in postinfarction left ventricular remodeling: a possible link between beta-adrenergic receptor kinase-1 and protein kinase C epsilon isoform.
Toshiyuki Takahashi, Toshihisa Anzai, Tsutomu Yoshikawa, Yuichiro Maekawa, Keitaro Mahara, Michikado Iwata, H Kirk Hammond, Satoshi Ogawa
Journal of the American College of Cardiology, 43, 1, 125, 32, ELSEVIER SCIENCE INC, 2004年01月07日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: We tested the hypothesis that angiotensin II type 1 receptor blocker (ARB) may improve beta-adrenergic receptor (AR) coupling in heart failure (HF) after myocardial infarction (MI). BACKGROUND: Beta-AR desensitization is one of the mechanisms underlying the transition from compensated to decompensated HF. Beta-adrenergic receptor kinase-1 (ARK1), which can be induced by protein kinase C (PKC) in vitro, is activated in the failing myocardium, resulting in beta-AR uncoupling. METHODS: Models of MI in rats were produced by ligation of left coronary artery. Four weeks after surgery, they were randomized to vehicle (MI/control [C]) or candesartan (10 mg/kg/day) treatment (MI/ARB). Sham-operated rats, or shams, served as controls. RESULTS: After two weeks of treatment, echocardiography and hemodynamics showed that the left ventricular (LV) dimension increased and that the percent of fractional shortening and maximum rate of rise in left ventricular pressure (dP/dt) decreased in MI rats compared with shams. There were no differences in these indexes between MI/C and MI/ARB. An increase in maximum dP/dt under isoproterenol (ISO) stimulation was attenuated in MI/C but improved in MI/ARB. Reductions in the percentage of high-affinity sites of beta-AR and ISO-stimulated cyclic adenosine monophosphate production in noninfarcted myocardium were also improved by ARB treatment. Up-regulation of beta-ARK1 and PKC-epsilon isoform protein levels and activation of PKC in noninfarcted myocardium from MI/C were both inhibited by ARB treatment. CONCLUSIONS: Treatment with ARB during the chronic phase of MI improved beta-AR coupling in noninfarcted myocardium without affecting basal LV function. Cross-talk between beta-AR and angiotensin signaling through beta-ARK1 and PKC-epsilon may be responsible for the phenomenon.

Serum C-reactive protein elevation in left ventricular remodeling after acute myocardial infarction--role of neurohormones and cytokines.
Toshiyuki Takahashi, Toshihisa Anzai, Tsutomu Yoshikawa, Yuichiro Maekawa, Yasushi Asakura, Toru Satoh, Hideo Mitamura, Satoshi Ogawa
International journal of cardiology, 88, 2-3, 257, 65, ELSEVIER SCI IRELAND LTD, 2003年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: We previously reported that increased peak serum C-reactive protein (CRP) level after acute myocardial infarction (AMI) was a major predictor of cardiac rupture and long-term outcome. The aim of this study was to clarify the role of serum CRP elevation as a possible marker of left ventricular (LV) remodeling after AMI. METHODS: We prospectively studied 31 patients who underwent primary angioplasty for a first anterior Q-wave AMI. Peak serum CRP level was determined by serial measurements after admission. LV volume and the plasma levels of various neurohormones and cytokines were measured on admission, and 2 weeks and 6 months after AMI. RESULTS: Patients with higher peak CRP levels (above the median) had a greater increase in LV end-diastolic volume during 2 weeks after AMI (+21+/-14 vs. +5+/-6 ml/m(2), P=0.001) and a lower ejection fraction (45+/-11 vs. 53+/-7%, P=0.02) than those with lower CRP levels, associated with a higher incidence of pump failure, atrial fibrillation, and LV aneurysm. Plasma levels of norepinephrine, brain natriuretic peptide, and interleukin-6 2 weeks after AMI were higher in the high CRP group than in the low CRP group. CONCLUSIONS: Increased peak serum CRP level was associated with a greater increase in LV volume after anterior AMI. Plasma norepinephrine and interleukin-6 levels were increased in patients with higher CRP levels, suggesting a possible role of sympathetic activation and enhanced immune response in the development of LV remodeling after AMI.

Serum C-reactive protein elevation in left ventricular remodeling after acute myocardial infarction--role of neurohormones and cytokines.
Toshiyuki Takahashi, Toshihisa Anzai, Tsutomu Yoshikawa, Yuichiro Maekawa, Yasushi Asakura, Toru Satoh, Hideo Mitamura, Satoshi Ogawa
International journal of cardiology, 88, 2-3, 257, 65, ELSEVIER SCI IRELAND LTD, 2003年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: We previously reported that increased peak serum C-reactive protein (CRP) level after acute myocardial infarction (AMI) was a major predictor of cardiac rupture and long-term outcome. The aim of this study was to clarify the role of serum CRP elevation as a possible marker of left ventricular (LV) remodeling after AMI. METHODS: We prospectively studied 31 patients who underwent primary angioplasty for a first anterior Q-wave AMI. Peak serum CRP level was determined by serial measurements after admission. LV volume and the plasma levels of various neurohormones and cytokines were measured on admission, and 2 weeks and 6 months after AMI. RESULTS: Patients with higher peak CRP levels (above the median) had a greater increase in LV end-diastolic volume during 2 weeks after AMI (+21+/-14 vs. +5+/-6 ml/m(2), P=0.001) and a lower ejection fraction (45+/-11 vs. 53+/-7%, P=0.02) than those with lower CRP levels, associated with a higher incidence of pump failure, atrial fibrillation, and LV aneurysm. Plasma levels of norepinephrine, brain natriuretic peptide, and interleukin-6 2 weeks after AMI were higher in the high CRP group than in the low CRP group. CONCLUSIONS: Increased peak serum CRP level was associated with a greater increase in LV volume after anterior AMI. Plasma norepinephrine and interleukin-6 levels were increased in patients with higher CRP levels, suggesting a possible role of sympathetic activation and enhanced immune response in the development of LV remodeling after AMI.

【21世紀の心不全治療の展望】免疫学的アプローチによる心不全治療
吉川 勉, 馬場 彰泰, 安斉 俊久
呼吸と循環, 50, 10, 999, 1006, (株)医学書院, 2002年10月, ［査読有り］
日本語

Effect of preinfarction angina pectoris on ST-segment resolution after primary coronary angioplasty for acute myocardial infarction.
Toshiyuki Takahashi, Toshihisa Anzai, Tsutomu Yoshikawa, Yuichiro Maekawa, Yasushi Asakura, Toru Satoh, Hideo Mitamura, Satoshi Ogawa
The American journal of cardiology, 90, 5, 465, 9, EXCERPTA MEDICA INC, 2002年09月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The presence of preinfarction angina has been shown to exert a favorable effect on left ventricular function after acute myocardial infarction (AMI). Whether or not preinfarction angina is beneficial for myocardial tissue reperfusion, however, remains to be determined. We sought to evaluate the influence of preinfarction angina on resolution of ST-segment elevation, which could be affected by microcirculatory damage after recanalization therapy. We studied 96 patients with a first AMI in whom Thrombolysis In Myocardial Infarction (TIMI)-3 flow in the infarct-related artery was established by primary angioplasty. Percent reduction in the sum of ST elevation from baseline to 1 hour after angioplasty (percent delta summation operator ST) was examined. Poor ST resolution, defined as percent delta summation operator ST <50%, was observed in 25 patients, who had a worse clinical outcome, larger infarct size, and poorer left ventricular function. On multivariate analysis, the absence of preinfarction angina, as well as anterior wall infarction, were major independent predictors of poor ST resolution, whereas age, sex, coronary risk factors, ischemic time, Killip class on admission, multivessel disease, initial TIMI flow grade, and extent of collaterals were not significant. Patients with preinfarction angina had a greater degree of ST-segment resolution than those without angina (71 +/- 21% vs 49 +/- 43%, p = 0.02). Additional ST elevation after reperfusion was noted exclusively in patients without preinfarction angina (p = 0.02). Preinfarction angina is associated with a greater degree of ST-segment resolution in patients with TIMI-3 flow after primary angioplasty, suggesting a protective effect of preinfarction angina against microcirculatory damage after reperfusion.

右房内血栓,回盲部潰瘍を伴ったBehcet病の一例
吉澤 彰宏, 松下 健一, 佐藤 徹, 栗田 康生, 安斎 俊久, 岩永 史郎, 吉川 勉, 三田村 秀雄, 小川 聡, 四津 良平
Circulation Journal, 66, Suppl.II, 890, 890, (一社)日本循環器学会, 2002年04月
日本語

梅毒性大動脈炎による重症大動脈弁逆流(AR)の一例
菊池 真大, 杵渕 修, 佐藤 徹, 前川 裕一郎, 栗田 康生, 安斎 俊久, 岩永 史郎, 吉川 勉, 三田村 秀雄, 小川 聡
Circulation Journal, 66, Suppl.II, 906, 906, (一社)日本循環器学会, 2002年04月
日本語

Prognostic significance of peripheral monocytosis after reperfused acute myocardial infarction:a possible role for left ventricular remodeling.
Yuichiro Maekawa, Toshihisa Anzai, Tsutomu Yoshikawa, Yasushi Asakura, Toshiyuki Takahashi, Shiro Ishikawa, Hideo M