Updated on 2025/05/30

Information

 

写真a

 
MATSUSHIMA SHOUJI
 
Organization
Kyushu University Hospital Angiocardiology Lecturer
School of Medicine Department of Medicine(Concurrent)
Title
Lecturer
Contact information
メールアドレス
Tel
0926425360
Profile
1.心不全・心筋症に関する基礎研究 2.心不全・心筋症の臨床研究 3.循環器疾患の診療 4.循環器領域の教育
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Degree

  • M.D., Ph.D. ( 2007.3 Kyushu University )

Research Interests・Research Keywords

  • Research theme: 1.Basic research of pathophysiology of heart failure 2.Clinical research of heart failure and cardiomyopathy 3. Omics analysis

    Keyword: heart failure, cardiomyophaty

    Research period: 2022.4 - 2025.3

  • Research theme: 1. Organella regulation in cardiac remodeling 2. Post-translational modification of proteins in cardiac remodeling

    Keyword: mitochondria, heart failure

    Research period: 2021.4 - 2022.3

  • Research theme: 1.Cardiac remodeling and organella regulation 2.Novel mechanism of protein post-translational modification in cardiac remodeling

    Keyword: Cardiac remodeling

    Research period: 2020.4 - 2020.3

  • Research theme: 1.The regulatory mechanism of organella function 2.The role of post-translational modification and its regulatory mechanism

    Keyword: Cardiac remodeling

    Research period: 2019.4 - 2020.3

  • Research theme: 1. ER stress in cardiac remodeling 2. MAM and heart failure 3. O'GacNacylation in cardiac remodeling

    Keyword: Cardiac remodeling

    Research period: 2018.4 - 2019.3

  • Research theme: 1.A novel regulatory mechanism of ER stress in cardiac remodeling 2.The role of MAM in heart failure 3. The role of O'GlucNAcylation in cardiac remodeling

    Keyword: Heart failure

    Research period: 2017.4 - 2020.3

  • Research theme: 1. The role of oxidative stress in cardiac remodelign and failure 2. Clinical feature of dilated phase of hypertrophic cardiomyopathy 3. Mechanism of mitochondrial quality control in heart failure 4. Eluciation of novel target and mechanism of cardiac remodeling

    Keyword: Heart failure, oxidative stress, mitochondria

    Research period: 2016.4 - 2017.3

Awards

  • 第12回日本心不全学会学術賞

    2024.10   日本心不全学会  

  • 日本心臓財団拡張型心筋症研究奨励賞

    2019.3   日本心臓財団   日本心臓財団拡張型心筋症研究奨励賞

  • 第11回Vascular Biology Innovation Conference 最優秀賞

    2016.8   応用酵素協会   FynによるNox4の新たな制御機構の解明に関する研究に対して

Papers

  • A Case of Severe COVID-19-related Pneumonia Seven Years after Heart Transplantation

    Taniguchi, G; Matsushima, S; Fujino, T; Hashimoto, T; Shinohara, K; Kisanuki, H; Misumi, K; Katsuki, S; Shiose, A; Abe, K

    INTERNAL MEDICINE   2025.4   ISSN:0918-2918 eISSN:1349-7235

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  • Triglyceride/high density lipoprotein cholesterol index and future cardiovascular events in diabetic patients without known cardiovascular disease

    Nakashima, R; Ikeda, S; Shinohara, K; Matsumoto, S; Yoshida, D; Ono, Y; Nakashima, H; Miyamoto, R; Matsushima, S; Kishimoto, J; Itoh, H; Komuro, I; Tsutsui, H; Abe, K

    SCIENTIFIC REPORTS   15 ( 1 )   9217   2025.3   ISSN:2045-2322

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    The triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) index, calculated as TG divided by HDL-C, has been suggested as a predictor of cardiovascular disease (CVD). We investigated the association between the TG/HDL-C index and CVD events in type 2 diabetes mellitus (T2DM) patients with retinopathy and hyperlipidemia but no known CVD, enrolled in the EMPATHY study, which compared intensive and standard statin therapy (targeting LDL-C levels < 70 mg/dL and ≥ 100 to < 120 mg/dL, respectively). A total of 4665 patients were divided into high (TG/HDL-C ≥ 2.5, n = 2013) and low (TG/HDL-C < 2.5, n = 2652) TG/HDL-C index groups. During a median follow-up of 36.8 months, 260 CVD events occurred. The high TG/HDL-C index group had higher CVD risk than the low group (HR 1.89, 95% CI 1.45–2.47, p < 0.001). This association remained consistent across subgroups. A trend toward interaction between TG/HDL-C index and statin treatment allocation for CVD risk was observed (p for interaction = 0.062). Intensive statin treatment reduced CVD risk in the high TG/HDL-C group but not in the low group. In conclusion, a TG/HDL-C index ≥ 2.5 was associated with higher CVD risk in T2DM patients with retinopathy and hyperlipidemia without a history of CVD. The TG/HDL-C index may identify patients who benefit from intensive statin treatment.

    DOI: 10.1038/s41598-025-92933-6

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  • Establishment of a HFpEF model using female Dahl salt-sensitive rats: a valuable tool for elucidating the pathophysiology of HFpEF in women

    Nakashima, H; Shinohara, K; Matsumoto, S; Nakashima, R; Yoshida, D; Ono, Y; Miyamoto, R; Ikeda, S; Matsushima, S; Hashimoto, T; Katsuki, S; Ikeda, M; Yoshida, K; Kinugawa, S; Abe, K

    HYPERTENSION RESEARCH   48 ( 2 )   672 - 680   2025.2   ISSN:0916-9636 eISSN:1348-4214

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    The pathogenesis of heart failure with preserved ejection fraction (HFpEF) remains unclear, and effective treatments are limited. HFpEF is more prevalent in females, indicating potential gender differences in its pathogenesis. However, no female HFpEF model animals have been established. Hypertension is a major contributor to HFpEF, and sympathetic activation is thought to play a role in both conditions. This study aimed to establish a female HFpEF model using hypertensive Dahl salt-sensitive rats and to assess the presence of sympathetic activation. Seven-week-old female Dahl salt-sensitive rats were fed an 8% high-salt diet (HS group, n = 6), while a low-salt diet group (LS group, n = 9) served as controls. The HS group exhibited increased systolic blood pressure and heart rate. Echocardiography revealed an increased left ventricular (LV) wall thickness, a decreased E/A ratio, and an increased E/e’ ratio, all indicative of diastolic dysfunction without reduced LV ejection fraction. Additionally, the HS group showed elevated LV end-diastolic pressure, LV weight, and lung weight, along with histological cardiomyocyte hypertrophy and interstitial fibrosis. Gene expression markers for cardiac hypertrophy and fibrosis were also increased. Renal function was significantly impaired, and plasma norepinephrine levels were elevated, consistent with heightened pre-sympathetic neuronal activity in the brain. In conclusion, high salt loading from 7 weeks of age in female Dahl salt-sensitive rats induced hypertensive HFpEF phenotypes with LV hypertrophy and fibrosis, and sympathetic activation by 16 to 19 weeks of age. This model provides a valuable tool for studying HFpEF pathophysiology in women. (Figure presented.)

    DOI: 10.1038/s41440-024-02025-7

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  • Prognostic impact of moderate to severe anemia associated with renal dysfunction in patients with heart failure

    Noda, E; Matsushima, S; Hashimoto, T; Tsutsui, Y; Misumi, K; Enzan, N; Yoshida, K; Shinohara, K; Fujino, T; Katsuki, S; Sakamoto, T; Hosokawa, K; Kinugawa, S; Abe, K

    SCIENTIFIC REPORTS   15 ( 1 )   3918   2025.1   ISSN:2045-2322

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    Moderate/severe anemia [hemoglobin (Hb) < 10 g/dL] is recommended to be treated in patients with renal anemia. However, the optimal therapeutic target for Hb levels in patients with heart failure (HF) is unknown. This study aimed to investigate the impact of severity of anemia, especially moderate/severe anemia, associated with renal dysfunction (RD: eGFR < 60 mL/min/1.73 m2) in HF patients. We analyzed 1,608 HF patients from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) database. Patients were classified based on the severity of admission anemia in the presence/absence of RD. Patients with RD and anemia were older, more likely to be female, and had a history of HF admission. The composite outcome was higher in RD and moderate/severe anemia (adjusted hazard ratio:2.120, 95% CI:1.559–2.881, p < 0.001) compared to RD and non/mild anemia (Hb ≥ 10 g/dL), non-RD and moderate/severe anemia, and non-RD and non/mild anemia (reference). During hospitalization, 6% and 10% of patients had improving and worsening RD and/or moderate/severe anemia, respectively. These status changes were associated with the post-discharge outcomes in HF patients. Moderate/severe anemia has a prognostic impact in HF patients with RD and may be an appropriate therapeutic target in HF.

    DOI: 10.1038/s41598-025-87650-z

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  • Clinical characteristics and predictive biomarkers of intensive care unit-acquired weakness in patients with cardiogenic shock requiring mechanical circulatory support

    Higuchi, T; Ide, T; Fujino, T; Tohyama, T; Nagatomi, Y; Nezu, T; Ikeda, M; Hashimoto, T; Matsushima, S; Shinohara, K; Nishihara, M; Iyonaga, T; Akahoshi, T; Ushijima, T; Shiose, A; Kinugawa, S; Tsutsui, H; Abe, K

    SCIENTIFIC REPORTS   15 ( 1 )   3535   2025.1   ISSN:2045-2322

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    Intensive care unit-acquired weakness (ICU-AW) is recognized as newly-acquired bilateral muscle weakness, which is a complication of critical illness in the ICU; however, there are no reports on the pathogenesis and early predictors of ICU-AW specifically associated with cardiogenic shock (CS). Therefore, this study aimed to investigate the clinical characteristics of ICU-AW in patients with CS requiring mechanical circulatory support (MCS). This study was a single-center, prospective, and observational study. Patients aged 16 years and older who underwent MCS for CS were included. ICU-AW was diagnosed based on Medical Research Council (MRC) score after awakening. The ICU-AW group included patients with the MRC score < 48 points, and the non-ICU-AW group included those with ≥ 48 points. Twenty-eight cases were enrolled on admission and MRC score was evaluated in 23 cases after awakening. Eleven patients were included in the non-ICU-AW group and 12 patients (52%) were in the ICU-AW group. The ICU-AW group showed a higher prevalence of extracorporeal membrane oxygenation and ventilator use. Creatine kinase, troponin T, interleukin (IL)-15 levels on admission were significantly higher, whereas hemoglobin and albumin levels were significantly lower in the ICU-AW group. A strong negative correlation was observed between the initial MRC scores and IL-15 levels. ICU-AW occurred 52% of patients with CS using MCS, indicating the significance of recognizing and managing this complication for those patients. In addition, IL-15 can be a potential biomarker for the early prediction of ICU-AW.

    DOI: 10.1038/s41598-025-87381-1

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  • Deep learning model to diagnose cardiac amyloidosis from haematoxylin/eosin-stained myocardial tissue.

    Tohyama T, Iwasaki T, Ikeda M, Katsuki M, Watanabe T, Misumi K, Shinohara K, Fujino T, Hashimoto T, Matsushima S, Ide T, Kishimoto J, Todaka K, Oda Y, Abe K

    European heart journal. Imaging methods and practice   3 ( 1 )   qyae141   2025.1

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    DOI: 10.1093/ehjimp/qyae141

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  • Validation of Guideline Recommendation on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy

    Amano M., Kitaoka H., Yoshikawa Y., Sakata Y., Dohi K., Tokita Y., Kato T., Matsushima S., Kitai T., Okada A., Furukawa Y., Tamura T., Hayashida A., Abe H., Ando K., Yuda S., Inoko M., Kadota K., Abe Y., Iwakura K., Kitamura T., Masuda J., Ohara T., Omura T., Tanigawa T., Nakamura K., Nishimura K., Izumi C., Kubo T., Sugiura K., Taneike R., Takeda Y., Moriwaki K., Okamoto R., Takano H., Imori Y., Shiomi H., Obayashi Y., Okada T., Shigeno R., Hashimoto T., Kinugwa S., Tamaki Y., Hamaguchi Y., Nakamura M., Ueda Y., Ishizu K., Kitano M., Hamaguchi T., Ono S., Matsumura Y., Watanabe K., Sato Y., Koji T., Kobayashi S.

    JACC: Heart Failure   2025   ISSN:22131779

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    Background: To prevent sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM), the HCM Risk-SCD calculator and guideline recommendations are used to aid decision making for implantable cardioverter-defibrillator placement. Objectives: The aim of this study was to assess the clinical profiles and occurrence of SCD by phenotypes of HCM and validate the performance of the current guidelines from a large-scale Japanese multicenter registry. Methods: This was a retrospective, multicenter, observational, longitudinal cohort study that enrolled 3,611 consecutive patients with HCM. The primary endpoint was a composite of SCD or an equivalent event. Results: The 5-year cumulative incidence of SCD events was markedly high in patients with end-stage HCM, defined by ejection fraction <50% (18.5%), followed by midventricular obstruction and nonobstructive HCM (6.9% and 4.7%). The 5-year cumulative incidence rates of SCD events for each recommendation class by the 2 guidelines were as follows: with the 2024 ACC (American College of Cardiology)/AHA (American Heart Association) guidelines, 23.8%, 7.2%, 5.7%, and 2.3% for Classes 1, 2a, 2b, and 3, respectively, and with the 2023 ESC (European Society of Cardiology) guidelines, 23.8%, 2.9%, 9.3%, and 2.6%, respectively. The 5-year risk was not well stratified between Classes 2a and 2b with the 2024 ACC/AHA guidelines (P = 0.101), and the event rate was even reversed with the 2023 ESC guidelines (P = 0.545). Conclusions: Among HCM phenotypes, the prognosis of patients with end-stage HCM was markedly worse. The 2024 ACC/AHA and 2023 ESC guidelines well stratified SCD risk in patients with HCM; the 2024 ACC/AHA guidelines seemed to better stratify SCD risk between Classes 2a and 2b compared with the 2023 ESC guidelines.

    DOI: 10.1016/j.jchf.2024.12.006

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  • Clinical and pathological characteristics of immune checkpoint inhibitor-related fulminant myocarditis

    Izumi, R; Hashimoto, T; Kisanuki, H; Ikuta, K; Otsuru, W; Asakawa, S; Yamamoto, S; Misumi, K; Fujino, T; Shinohara, K; Matsushima, S; Hosokawa, K; Katsuki, S; Mori, T; Hashisako, M; Tateishi, Y; Iwasaki, T; Oda, Y; Kinugawa, S; Abe, K

    CARDIO-ONCOLOGY   10 ( 1 )   82   2024.11   eISSN:2057-3804

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    The advent of immune checkpoint inhibitors (ICIs) has significantly improved cancer treatment. With the increasing use of ICIs, ICI-related myocarditis has been recognized. However, an evidence-based therapeutic strategy has not been established because of the limited knowledge on ICI-related myocarditis. Here, we present four cases of ICI-related fulminant myocarditis (FM). Three of the four cases resulted in fatal outcomes despite aggressive treatment with mechanical circulatory support and immunosuppressive therapy with corticosteroids. Given the poor prognosis of ICI-FM, the establishment of rapid and adequate therapeutic interventions on the basis of clinical and pathological evaluation is imperative.

    DOI: 10.1186/s40959-024-00288-0

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  • Effectiveness of Vericiguat on right ventricle to pulmonary artery uncoupling associated with heart failure with reduced ejection fraction

    Hashimoto, T; Yoshitake, T; Suenaga, T; Yamamoto, S; Fujino, T; Shinohara, K; Matsushima, S; Ide, T; Kinugawa, S; Abe, K

    INTERNATIONAL JOURNAL OF CARDIOLOGY   415   132441   2024.11   ISSN:0167-5273 eISSN:1874-1754

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    Backgrounds: A soluble guanylyl cyclase stimulator vericiguat has been shown to reduce cardiovascular mortality or hospitalization for heart failure in patients with worsening heart failure in the VICTORIA study. However, little is known about the effects of vericiguat on biventricular structure and function. Methods and results: A retrospective analysis of 63 consecutive patients with heart failure with reduced ejection fraction (HFrEF) who were treated with vericiguat was performed. Clinical data and echocardiographic parameters were compared between baseline and follow-up after the initiation of vericiguat. The median follow-up duration was 266 days. Treatment with vericiguat significantly reduced the plasma BNP levels (log-transformed) compared to baseline (2.46 ± 0.51 vs. 2.14 ± 0.58, p < 0.0001). Left ventricular end-diastolic volume index and left ventricular end-systolic volume index were significantly reduced (LVEDVI, 113.5 ± 46.3 vs. 103.6 ± 51.0, p = 0.0056; LVESVI, 82.0 ± 41.9 vs. 72.8 ± 44.7, p = 0.0077; respectively). The tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) ratio, an indicator of right ventricle-pulmonary artery (RV-PA) coupling, increased significantly after the treatment (0.56 ± 0.29 vs. 0.92 ± 1.09, p < 0.0001). Univariate and multivariate analyses showed that the treatment effects of vericiguat on BNP levels, LV reverse remodeling, and RV-PA coupling were not correlated with the achievement of the quadruple therapy with beta-blockers, renin-angiotensin system inhibitors, mineralocorticoid inhibitors, and sodium-glucose cotransporter-2 inhibitors, nor with worsening heart failure (WHF). Conclusion: Treatment with vericiguat improved adverse LV remodeling and RV-PA uncoupling in HFrEF patients. These effects were independent of WHF and achieving the quadruple therapy. Patients with HFrEF may benefit from early initiation of vericiguat to prevent biventricular adverse remodeling.

    DOI: 10.1016/j.ijcard.2024.132441

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  • A Case of Cardiogenic Shock due to Propionic Acidemia-Associated Cardiomyopathy Successfully Treated with a Combination of Mechanical Circulatory Support and Medical Therapy

    Ishikawa, Y; Fujino, T; Hashimoto, T; Shinohara, K; Matsushima, S; Fuke, Y; Ushijima, T; Sonoda, H; Nakashima, Y; Mushimoto, Y; Ishii, K; Ide, T; Tsutsui, H; Kinugawa, S; Shiose, A; Abe, K

    INTERNATIONAL HEART JOURNAL   65 ( 6 )   1172 - 1176   2024.11   ISSN:1349-2365 eISSN:1349-3299

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    An 18-year-old man experienced refractory cardiogenic shock due to dilated cardiomyopathy of unknown aetiology, and was referred to our hospital to undergo a paracorporeal left ventricular assist device (LVAD) im-plantation. After surgery, the patient lost consciousness, with subsequent head computed tomography revealing low-density areas in the bilateral basal ganglia. Metabolic acidosis and hyperammonaemia also appeared. Metabolic evaluation and genetic tests led to a diagnosis of propionic acidemia. Following appropriate management of heart failure and propionic acidemia, his neurological and cardiac functions gradually recovered, and the paracorporeal LVAD was successfully explanted. Dilated cardiomyopathy and heart failure are rare manifestations of adult-onset propionic acidemia. This is the first reported case of cardiogenic shock due to propionic acidemia-associated cardiomyopathy successfully treated with a combination of mechanical circulatory support and medical therapy for heart failure and propionic acidemia.

    DOI: 10.1536/ihj.24-364

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  • Different Impact of Immunosuppressive Therapy on Cardiac Outcomes in Systemic Versus Isolated Cardiac Sarcoidosis.

    Masunaga T, Hashimoto T, Fujino T, Ohtani K, Ishikawa Y, Yoshitake T, Shinohara K, Matsushima S, Ide T, Yamasaki Y, Isoda T, Baba S, Ishigami K, Tsutsui H, Kinugawa S

    International heart journal   65 ( 5 )   856 - 865   2024.9   ISSN:1349-2365 eISSN:1349-3299

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    Isolated cardiac sarcoidosis (iCS) is increasingly recognized; however, its prognosis and the efficacy of immunosuppressive therapy remain undetermined. We aimed to compare the prognosis of iCS and systemic sarcoidosis including cardiac involvement (sCS) under immunosuppressive therapy. We retrospectively reviewed the clinical data of 42 patients with sCS and 30 patients with iCS diagnosed at Kyushu University Hospital from 2004 through 2022. We compared the characteristics and the rate of adverse cardiac events including cardiac death, fatal ventricular tachyarrhythmia, and heart failure hospitalization between the 2 groups. The median follow-up time was 1535 [interquartile range, 630-2555] days, without a significant difference between the groups. There were no significant differences in gender, NYHA class, or left ventricular ejection fraction. Immunosuppressive agents were administered in 86% of sCS and in 73% of iCS patients (P = 0.191). When analyzed only with patients receiving immunosuppressive therapy (sCS, n = 36; iCS, n = 21), the cardiac event-free survival was significantly lower in iCS than sCS (37% versus 79%, P = 0.002). Myocardial LGE content at the initial diagnosis was comparable in both groups. The disease activity was serially evaluated in 26 sCS and 16 iCS patients by quantitative measures of FDG-PET including cardiac metabolic volume and total lesion glycolysis, representing 3-dimensional distribution and intensity of inflammation in the entire heart. Although iCS patients had lower baseline disease activity than sCS patients, immunosuppressive therapy did not attenuate disease activity in iCS in contrast to sCS. iCS showed a poorer response to immunosuppressive therapy and a worse cardiac prognosis compared to sCS despite lower baseline disease activity.

    DOI: 10.1536/ihj.24-166

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  • Right Ventricular to Pulmonary Artery Uncoupling Is Associated With Impaired Exercise Capacity in Patients With Transthyretin Cardiac Amyloidosis.

    Hashimoto T, Ikuta K, Yamamoto S, Yoshitake T, Suenaga T, Nakashima S, Kai T, Misumi K, Fujino T, Shinohara K, Matsushima S, Atsumi R, Isoda T, Kinugawa S, Abe K

    Circulation journal : official journal of the Japanese Circulation Society   89 ( 1 )   31 - 40   2024.9   ISSN:1346-9843 eISSN:1347-4820

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    Background: Exercise capacity is related to mortality and morbidity in heart failure (HF) patients. Determinants of exercise capacity in transthyretin cardiac amyloidosis (ATTR-CA) have not been established. Methods and Results: This single-center study retrospectively evaluated ATTR-CA patients and patients with non-amyloidosis HF with preserved/mildly reduced ejection fraction (HFpEF/HFmrEF) (n=32 and n=51, respectively). In the ATTR-CA group, the median age was 75.5 years (interquartile range [IQR] 71.3–78.8 years), 90.6% were male, and the median left ventricular (LV) ejection fraction was 53.5% (IQR 41.4–65.6%). Cardiopulmonary exercise tests revealed a median peak oxygen consumption and anaerobic threshold of 15.9 (IQR 11.6–17.4) and 10.6 (IQR 8.5–12.0] mL/min/kg, respectively, and ventilatory efficiency (minute ventilation/ carbon dioxide production [V̇ E/V̇ CO2] slope) of 35.5 (IQR 32.0–42.5). Among exercise variables, V̇ E/V̇ CO2 slope has the greatest prognostic value. Univariate analysis revealed a significant correlation between V̇ E/V̇ CO2 slope and age, LV global longitudinal strain, tricuspid annular plain systolic excursion/pulmonary arterial systolic pressure (TAPSE/PASP) ratio, and mixed venous oxygen saturation. In multivariate analyses, the TAPSE/PASP ratio was an independent predictor of V̇ E/V̇ CO2 slope (95% confidence interval −44.5, −10.8; P=0.0067). In non-amyloidosis HFpEF/HFmrEF patients, the TAPSE/PASP ratio was not independently correlated with V̇ E/V̇ CO2 slope. Conclusions: Right ventricular–pulmonary artery coupling estimated by the TAPSE/PASP ratio determines exercise capacity in ATTR-CA patients. This highlights the importance of early therapeutic intervention against underappreciated right ventricular dysfunction associated with ATTR-CA.

    DOI: 10.1253/circj.CJ-24-0402

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  • Association of Multiple Nonhypertrophic Cardiomyopathy-Related Genetic Variants and Outcomes in Patients With Hypertrophic Cardiomyopathy.

    Hiruma T, Inoue S, Dai Z, Nomura S, Kubo T, Sugiura K, Suzuki A, Kashimura T, Matsushima S, Yamada T, Tobita T, Katoh M, Ko T, Ito M, Ishida J, Amiya E, Hatano M, Takeda N, Takimoto E, Akazawa H, Morita H, Yamaguchi J, Inomata T, Tsutsui H, Kitaoka H, Aburatani H, Takeda N, Komuro I

    JACC. Heart failure   12 ( 12 )   2041 - 2052   2024.9   ISSN:2213-1779 eISSN:2213-1787

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    Background: Approximately 10% of hypertrophic cardiomyopathy (HCM) patients have left ventricular systolic dysfunction (end-stage HCM) leading to severe heart-failure; however, risk stratification to identify patients at risk of progressing to end-stage HCM remains insufficient. Objectives: In this study, the authors sought to elucidate whether the coexistence of other cardiovascular disease (CVD)–related variants is associated with progression to end-stage HCM in patients with HCM harboring pathogenic or likely pathogenic (P/LP) sarcomeric variants. Methods: The authors performed genetic analysis of 83 CVD-related genes in HCM patients from a Japanese multicenter cohort. P/LP variants in 8 major sarcomeric genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, and ACTC1) definitive for HCM were defined as “sarcomeric variants.” In addition, P/LP variants associated with other CVDs, such as dilated cardiomyopathy and arrhythmogenic cardiomyopathy, were referred to as “other CVD-related variants.” Results: Among 394 HCM patients, 139 carried P/LP sarcomeric variants: 11 (7.9%) carried other CVD-related variants, 6 (4.3%) multiple sarcomeric variants, and 122 (87.8%) single sarcomeric variants. In a multivariable Cox regression analysis, presence of multiple sarcomeric variants (adjusted HR [aHR]: 3.35 [95% CI: 1.25-8.95]; P = 0.016) and coexistence of other CVD-related variants (aHR: 2.80 [95% CI: 1.16-6.78]; P = 0.022) were independently associated with progression to end-stage HCM. Coexisting other CVD-related variants were also associated with heart failure events (aHR: 2.75 [95% CI: 1.27-5.94]; P = 0.010). Conclusions: Approximately 8% of sarcomeric HCM patients carried other CVD-related variants, which were associated with progression to end-stage HCM and heart failure events. Comprehensive surveillance of CVD-related variants within sarcomeric HCM patients contributes to risk stratification and understanding of mechanisms underlying end-stage HCM.

    DOI: 10.1016/j.jchf.2024.08.005

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  • Association Between Clonal Hematopoiesis and Left Ventricular Reverse Remodeling in Nonischemic Dilated Cardiomyopathy

    Inoue, S; Ko, T; Shindo, A; Nomura, S; Yamada, T; Jimba, T; Dai, ZH; Nakao, H; Suzuki, A; Kashimura, T; Iwahana, T; Goto, K; Matsushima, S; Ishida, J; Amiya, E; Zhang, B; Kubota, M; Sawami, K; Heryed, T; Yamada, S; Katoh, M; Katagiri, M; Ito, M; Nayakama, Y; Fujiu, K; Hatano, M; Takeda, N; Takimoto, E; Akazawa, H; Morita, H; Yamaguchi, J; Inomata, T; Kobayashi, Y; Minamino, T; Tsutsui, H; Kurokawa, M; Aiba, A; Aburatani, H; Komuro, I

    JACC-BASIC TO TRANSLATIONAL SCIENCE   9 ( 8 )   956 - 967   2024.8   ISSN:2452-302X

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    Although clonal hematopoiesis of indeterminate potential (CHIP) is an adverse prognostic factor for atherosclerotic disease, its impact on nonischemic dilated cardiomyopathy (DCM) is elusive. The authors performed whole-exome sequencing and deep target sequencing among 198 patients with DCM and detected germline mutations in cardiomyopathy-related genes and somatic mutations in CHIP driver genes. Twenty-five CHIP driver mutations were detected in 22 patients with DCM. Ninety-two patients had cardiomyopathy-related pathogenic mutations. Multivariable analysis revealed that CHIP was an independent risk factor of left ventricular reverse remodeling, irrespective of known prognostic factors. CHIP exacerbated cardiac systolic dysfunction and fibrosis in a DCM murine model. The identification of germline and somatic mutations in patients with DCM predicts clinical prognosis.

    DOI: 10.1016/j.jacbts.2024.04.010

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  • Esaxerenone: blood pressure reduction and cardiorenal protection without reflex sympathetic activation in salt-loaded stroke-prone spontaneously hypertensive rats

    Ikeda, S; Shinohara, K; Kashihara, S; Matsumoto, S; Yoshida, D; Nakashima, R; Ono, Y; Matsushima, S; Tsutsui, H; Kinugawa, S

    HYPERTENSION RESEARCH   47 ( 8 )   2133 - 2143   2024.8   ISSN:0916-9636 eISSN:1348-4214

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    Mineralocorticoid receptor (MR) is involved in the mechanisms of blood pressure elevation, organ fibrosis, and inflammation. MR antagonists have been used in patients with hypertension, heart failure, or chronic kidney disease. Esaxerenone, a recently approved MR blocker with a nonsteroidal structure, has demonstrated a strong blood pressure-lowering effect. However, blood pressure reduction may lead to sympathetic activation through the baroreflex. The effect of esaxerenone on the sympathetic nervous system remains unclear. We investigated the effect of esaxerenone on organ damage and the sympathetic nervous system in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP), a well-established model of essential hypertension with sympathoexcitation and organ damage. Three-week administration of esaxerenone or hydralazine successfully attenuated the blood pressure elevation. Both esaxerenone and hydralazine comparably suppressed left ventricular hypertrophy and urinary albumin excretion. However, renal fibrosis and glomerular sclerosis were suppressed by esaxerenone but not hydralazine. Furthermore, plasma norepinephrine level, a parameter of systemic sympathetic activity, was significantly increased by hydralazine but not by esaxerenone. Consistent with these findings, the activity of the control centers of sympathetic nervous system, the parvocellular region of the paraventricular nucleus in the hypothalamus and the rostral ventrolateral medulla, was enhanced by hydralazine but remained unaffected by esaxerenone. These results suggest that esaxerenone effectively lowers blood pressure without inducing reflex sympathetic nervous system activation. Moreover, the organ-protective effects of esaxerenone appear to be partially independent of its blood pressure-lowering effect. In conclusion, esaxerenone demonstrates a blood pressure-lowering effect without concurrent sympathetic activation and exerts organ-protective effects in salt-loaded SHRSP. (Figure presented.)

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  • Management and outcomes of heart failure hospitalization among older adults in the United States and Japan

    Bates, BA; Enzan, N; Tohyama, T; Gandhi, P; Matsushima, S; Tsutsui, H; Setoguchi, S; Ide, T

    ESC HEART FAILURE   11 ( 5 )   3395 - 3405   2024.7   ISSN:2055-5822

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    Aims: Despite advances in therapies, the disease burden of heart failure (HF) has been rising globally. International comparisons of HF management and outcomes may reveal care patterns that improve outcomes. Accordingly, we examined clinical management and patient outcomes in older adults hospitalized for acute HF in the United States (US) and Japan. Methods: We identified patients aged >65 who were hospitalized for HF in 2013 using US Medicare data and the Japanese Registry of Acute Decompensated Heart Failure (JROADHF). We described patient characteristics, management, and healthcare utilization and compared outcomes using multivariable Cox regression during and after HF hospitalization. Results: Among 11 193 Japanese and 120 289 US patients, age and sex distributions were similar, but US patients had higher comorbidity rates. The length of stay was longer in Japan (median 18 vs. 5 days). While Medicare patients had higher use of implantable cardioverter defibrillator or cardiac resynchronization therapy during hospitalization (1.32% vs. 0.6%), Japanese patients were more likely to receive cardiovascular medications at discharge and to undergo cardiac rehabilitation within 3 months of HF admission (31% vs. 1.6%). Physician follow-up within 30 days was higher in Japan (77% vs. 57%). Cardiovascular readmission, cardiovascular mortality and all-cause mortality were 2.1–3.7 times higher in the US patients. The per-day cost of hospitalization was lower in Japan ($516 vs. $1323). Conclusions: We observed notable differences in the management, outcomes and costs of HF hospitalization between the US and Japan. Large differences in length of hospitalization, cardiac rehabilitation rate and outcomes warrant further research to determine the optimal length of stay and assess the benefits of inpatient cardiac rehabilitation to reduce rehospitalization and mortality.

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  • Hemoglobin Level Can Predict Heart Failure Hospitalization in Patients with Advanced Heart Failure Awaiting Heart Transplantation without Inotropes or Mechanical Circulatory Support

    Suenaga, T; Fujino, T; Hashimoto, T; Ishikawa, Y; Shinohara, K; Matsushima, S; Komman, H; Toyosawa, M; Ide, T; Tsutsui, H; Shiose, A; Kinugawa, S

    INTERNATIONAL HEART JOURNAL   65 ( 4 )   667 - 675   2024.7   ISSN:1349-2365 eISSN:1349-3299

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    Although anemia is a common comorbidity that often coexists with heart failure (HF), its clinical impact in patients with advanced HF remains unclear. We investigated the impact of hemoglobin levels on clinical outcomes in patients with advanced HF listed for heart transplantation without intravenous inotropes or mechanical circulatory support. We retrospectively reviewed the clinical data of patients listed for heart transplantation at our institute who did not receive intravenous inotropes or mechanical circulatory support between 2011 and 2022. We divided the patients into those with hemoglobin levels lower or higher than the median value and compared the composite of all-cause death and HF hospitalization within 1 year from the listing date. We enrolled consecutive 38 HF patients (27 males, 49.1 ± 10.8 years old). The median hemoglobin value at the time of listing for heart transplantation was 12.9 g/dL, and 66.7% of the patients had iron deficiency. None of the patients in either group died within 1 year. The HF hospitalization-free survival rate was significantly lower in the lower hemoglobin group (40.9% versus 81.9% at 1 year, P = 0.020). Multivariate Cox proportional hazards model analysis showed that hemoglobin as a continuous variable was an independent predictor for HF hospitalization (odds ratio 0.70, 95% confidence interval 0.49-0.97, P = 0.030). Hemoglobin level at the time of listing for heart transplantation was a predictor of hospitalization in heart-transplant candidates without intravenous inotropes or mechanical circulatory support.

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  • Atrial fibrillation type and long-term clinical outcomes in hospitalized patients with heart failure: insight from JROADHF

    Hamatani, Y; Enzan, N; Iguchi, M; Yoshizawa, T; Kawaji, T; Ide, T; Tohyama, T; Matsushima, S; Abe, M; Tsutsui, H; Akao, M

    EUROPEAN HEART JOURNAL-QUALITY OF CARE AND CLINICAL OUTCOMES   10 ( 3 )   193 - 202   2024.5   ISSN:2058-5225 eISSN:2058-1742

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    Aims: Atrial fibrillation (AF) type (paroxysmal, persistent, or permanent) is important in determining therapeutic management; however, clinical outcomes by AF type are largely unknown for hospitalized patients with heart failure (HF). Methods and results: The Japanese Registry Of Acute Decompensated Heart Failure is a retrospective, multicenter, and nationwide registry of patients hospitalized for acute HF in Japan. Follow-up data were collected up to 5 years after hospitalization. Patients were divided based on diagnosis and AF type into 3 groups [without AF, paroxysmal AF, and sustained AF (defined as a composite of persistent and permanent AF)], and compared the backgrounds and outcomes between the groups. Of 12 895 hospitalized HF patients [mean age: 78 ± 13 years, female: 6077 (47%), and mean left ventricular ejection fraction: 47 ± 17%], 1725 had paroxysmal AF, and 3672 had sustained AF. Compared with patients without AF, sustained AF had a higher risk of the primary composite endpoint of cardiovascular (CV) death or HF hospitalization [hazard ratio (HR): 1.09, 95% confidence interval (CI): 1.01-1.17; P = 0.03], mainly driven by HF hospitalization [HR: 1.16, 95% CI: 1.06-1.26; P < 0.001], whereas the corresponding risk for the primary endpoint in patients with paroxysmal AF was not elevated (HR: 1.03, 95% CI: 0.94-1.13; P = 0.53) after adjustment by multivariable Cox regression analysis. These results were consistent among the subgroups of patients with reduced or preserved ejection fraction (interaction P = 0.74). Conclusion: Among hospitalized patients with HF, sustained AF, but not paroxysmal AF, was significantly associated with a higher risk for CV death or HF hospitalization, indicating the importance of accounting for AF type in HF patients.

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  • LONG-TERM PROGNOSTIC IMPACT OF IN-HOSPITAL SERUM ALBUMIN CONCENTRATION CHANGES IN PATIENTS HOSPITALIZED FOR HEART FAILURE: INSIGHTS FROM THE JAPANESE REGISTRY OF ACUTE DECOMPENSATED HEART FAILURE (JROADHF) STUDY

    Fukino, K; Miyata, S; Ide, T; Matsushima, S; Tohyama, T; Enzan, N; Tsutsui, H; Nakamura, F

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   83 ( 13 )   534 - 534   2024.4   ISSN:0735-1097 eISSN:1558-3597

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  • <SUP>18</SUP>F-Fluorodeoxyglucose Positron Emission Tomography Can be a Novel Diagnostic Tool for Detecting Acute Cellular Rejection Following Heart Transplantation

    Yoshitake, T; Fujino, T; Yamamoto, S; Hashimoto, T; Suenaga, T; Shinohara, K; Matsushima, S; Kitamura, Y; Komman, H; Toyosawa, M; Ide, T; Shiose, A; Kinugawa, S

    JOURNAL OF HEART AND LUNG TRANSPLANTATION   43 ( 4 )   S206 - S206   2024.4   ISSN:1053-2498 eISSN:1557-3117

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  • Overview of the 87th Annual Scientific Meeting of the Japanese Circulation Society (JCS2023) ― New Challenge With Next Generation ―

    Matoba, T; Nakano, Y; Katsuki, S; Ide, T; Matsushima, S; Fujino, T; Hashimoto, T; Shinohara, K; Abe, K; Hosokawa, K; Sakamoto, T; Sakamoto, I; Kakino, T; Ishikita, A; Nishizaki, A; Sakamoto, K; Takase, S; Nagayama, T; Tohyama, T; Nagata, T; Kinugawa, S; Tsutsui, H

    CIRCULATION JOURNAL   88 ( 4 )   615 - 619   2024.4   ISSN:1346-9843 eISSN:1347-4820

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    The 87th Annual Meeting of the Japanese Circulation Society (JCS2023) was held in March 2023 in Fukuoka, Japan, marking the first in-person gathering after the COVID-19 pandemic. With the theme of “New Challenge With Next Generation” the conference emphasized the development of future cardiovascular leaders and technologies such as artificial intelligence (AI). Notable sessions included the Mikamo Lecture on heart failure and the Mashimo Lecture on AI in medicine. Various hands-on sessions and participatory events were well received, promoting learning and networking. Post-event surveys showed high satisfaction among participants, with positive feedback on face-to-face interactions and the overall experience. JCS2023, attended by 17,852 participants, concluded successfully, marking a significant milestone in post-pandemic meetings, and advancing cardiovascular medicine.

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  • Development of deep-learning models for real-time anaerobic threshold and peak VO<sub>2</sub> prediction during cardiopulmonary exercise testing

    Watanabe, T; Tohyama, T; Ikeda, M; Fujino, T; Hashimoto, T; Matsushima, S; Kishimoto, J; Todaka, K; Kinugawa, S; Tsutsui, H; Ide, T

    EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY   31 ( 4 )   448 - 457   2024.3   ISSN:2047-4873 eISSN:2047-4881

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    Aims Exercise intolerance is a clinical feature of patients with heart failure (HF). Cardiopulmonary exercise testing (CPET) is the first-line examination for assessing exercise capacity in patients with HF. However, the need for extensive experience in assessing anaerobic threshold (AT) and the potential risk associated with the excessive exercise load when measuring peak oxygen uptake (peak VO2) limit the utility of CPET. This study aimed to use deep-learning approaches to identify AT in real time during testing (defined as real-time AT) and to predict peak VO2 at real-time AT. Methods and results This study included the time-series data of CPET recorded at the Department of Cardiovascular Medicine, Kyushu University Hospital. Two deep neural network models were developed to: (i) estimate the AT probability using breath-by-breath data and (ii) predict peak VO2 using the data at the real-time AT. The eligible CPET contained 1472 records of 1053 participants aged 18–90 years and 20% were used for model evaluation. The developed model identified real-time AT with 0.82 for correlation coefficient (Corr) and 1.20 mL/kg/min for mean absolute error (MAE), and the corresponding AT time with 0.86 for Corr and 0.66 min for MAE. The peak VO2 prediction model achieved 0.87 for Corr and 2.25 mL/kg/min for MAE. Conclusion Deep-learning models for real-time CPET analysis can accurately identify AT and predict peak VO2. The developed models can be a competent assistant system to assess a patient’s condition in real time, expanding CPET utility.

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  • Evaluation of the A<sub>2</sub>B Score for Prediction of Survival in Patients With Heart Failure in a Nationwide Cohort in Japan

    Kyodo, A; Nakada, Y; Nogi, M; Nogi, K; Ishihara, S; Ueda, T; Tohyama, T; Enzan, N; Ide, T; Matsushima, S; Tsutsui, H; Saito, Y

    JOURNAL OF THE AMERICAN HEART ASSOCIATION   13 ( 4 )   e031104   2024.2   eISSN:2047-9980

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    BACKGROUND: Although a tool for sharing patient prognosis among all medical staff is desirable in heart failure (HF) cases, only a few simple HF prognostic scores are available. We previously presented the A2 B score, a simple user-friendly HF risk score, and validated it in a small single-center cohort. In the present study, we validated it in a larger nationwide cohort. METHODS AND RESULTS: We examined the 2-year mortality in relation to the A2 B scores in 3483 patients from a Japanese nationwide cohort and attempted to stratify their prognoses according to the scores. The A2 B score was determined by assign-ing points for age, anemia, and brain natriuretic peptide (BNP) level at discharge: age (<65 years, 0; 65–74 years, 1; ≥75 years, 2), anemia (hemoglobin ≥12 g/dL, 0; 10–11.9 g/dL, 1; <10 g/dL, 2), and BNP (<200 pg/mL, 0; 200–499 pg/mL, 1; ≥500 pg/mL, 2). Hemoglobin and BNP levels were applied to the data at discharge. The 2-year survival rates for A2 B scores 1, 2, 3, 4, 5, and 6 were 94.1%, 83.2%, 74.1%, 63.5%, 51.6%, and 41.5%, respectively; the mortality rate increased by ≈10% for each point increase (c-index, 0.702). The A2 B score was applicable in HF cases with reduced or preserved ejection fraction and remained useful when BNP was substituted with N-terminal proBNP (c-index, 0.749, 0.676, and 0.682, respectively). CONCLUSIONS: The A2 B score showed a good prognostic value for HF in a large population even when BNP was replaced with N-terminal proBNP.

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  • Association of baseline electrocardiographic left ventricular hypertrophy with future renal function decline in the general population

    Ikeda, S; Shinohara, K; Tagawa, K; Tohyama, T; Kishimoto, J; Kazurayama, M; Tanaka, S; Yamaizumi, M; Nagayoshi, H; Toyama, K; Matsushima, S; Tsutsui, H; Kinugawa, S

    SCIENTIFIC REPORTS   14 ( 1 )   301   2024.1   ISSN:2045-2322

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    Electrocardiographic left ventricular hypertrophy (LVH) could predict adverse renal outcomes in patients with hypertension. This study aimed to investigate the association between electrocardiographic LVH and future decline in renal function in the general population using a dataset of population-based health checkups from 2010 to 2019 including 19,825 participants. Electrocardiographic LVH was defined according to the Minnesota code. Renal function decline was defined as a decrease of ≥ 25% in the estimated glomerular filtration rate from baseline to < 60 mL/min/1.73 m2. Electrocardiographic LVH was found in 1263 participants at the baseline visit. The mean follow-up period was 3.4 ± 1.9 years. The incidence rates of renal function decline were 0.30 and 0.78 per 100 person-years in the non-LVH group and LVH groups, respectively. Electrocardiographic LVH was associated with the risk for renal function decline in the adjusted analysis (hazard ratio 1.69, 95% confidence interval 1.14–2.50, P = 0.009). This association was comparable across subgroups stratified by age, sex, body mass index, diagnosed hypertension, systolic blood pressure, hemoglobin A1c, and urinary protein. This study underscores the usefulness of electrocardiographic LVH to detect high-risk individuals for renal function decline in the setting of health checkups in the general population.

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  • Deferasirox Targeting Ferroptosis Synergistically Ameliorates Myocardial Ischemia Reperfusion Injury in Conjunction With Cyclosporine A

    Ishimaru, K; Ikeda, M; Miyamoto, HD; Furusawa, S; Abe, K; Watanabe, M; Kanamura, T; Fujita, S; Nishimura, R; Toyohara, T; Matsushima, S; Koumura, T; Yamada, K; Imai, H; Tsutsui, H; Ide, T

    JOURNAL OF THE AMERICAN HEART ASSOCIATION   13 ( 1 )   e031219   2024.1   eISSN:2047-9980

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    BACKGROUND: Ferroptosis, an iron-dependent form of regulated cell death, is a major cell death mode in myocardial ischemia reperfusion (I/R) injury, along with mitochondrial permeability transition-driven necrosis, which is inhibited by cyclosporine A (CsA). However, therapeutics targeting ferroptosis during myocardial I/R injury have not yet been developed. Hence, we aimed to investigate the therapeutic efficacy of deferasirox, an iron chelator, against hypoxia/reoxygenation-induced ferroptosis in cultured cardiomyocytes and myocardial I/R injury. METHODS AND RESULTS: The effects of deferasirox on hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis were examined in cultured cardiomyocytes. In a mouse model of I/R injury, the infarct size and adverse cardiac remodeling were examined after treatment with deferasirox, CsA, or both in combination. Deferasirox suppressed hypoxia-or hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis in cultured cardiomyocytes. Deferasirox treatment reduced iron levels in the endoplasmic reticulum and prevented increases in lipid peroxidation and ferroptosis in the I/R-injured myocardium 24 hours after I/R. Deferasirox and CsA independently reduced the infarct size after I/R injury to a similar degree, and combination therapy with deferasirox and CsA synergistically reduced the infarct size (infarct area/area at risk; control treatment: 64±2%; deferasirox treatment: 48±3%; CsA treatment: 48±4%; deferasirox+CsA treatment: 37±3%), thereby ameliorating adverse cardiac remodeling on day 14 after I/R. CONCLUSIONS: Combination therapy with deferasirox and CsA may be a clinically feasible and effective therapeutic approach for limiting I/R injury and ameliorating adverse cardiac remodeling after myocardial infarction.

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  • Cardiac Autoantibodies Against Cardiac Troponin I in Post-Myocardial Infarction Heart Failure: Evaluation in a Novel Murine Model and Applications in Therapeutics

    Furusawa, S; Ikeda, M; Ide, T; Kanamura, T; Miyamoto, HD; Abe, K; Ishimaru, K; Watanabe, M; Tsutsui, Y; Miyake, R; Fujita, S; Tohyama, T; Matsushima, S; Baba, Y; Tsutsui, H

    CIRCULATION-HEART FAILURE   16 ( 10 )   895 - 908   2023.10   ISSN:1941-3289 eISSN:1941-3297

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    BACKGROUND: Cardiac autoantibodies (cAAbs) are involved in the progression of adverse cardiac remodeling in heart failure (HF). However, our understanding of cAAbs in HF is limited owing to the absence of relevant animal models. Herein, we aimed to establish and characterize a murine model of cAAb-positive HF after myocardial infarction (MI), thereby facilitating the development of therapeutics targeting cAAbs in post-MI HF. METHODS: MI was induced in BALB/c mice. Plasma cAAbs were evaluated using modified Western blot-based methods. Prognosis, cardiac function, inflammation, and fibrosis were compared between cAAb-positive and cAAb-negative MI mice. Rapamycin was used to inhibit cAAb production. RESULTS: Common cAAbs in BALB/c MI mice targeted cTnI (cardiac troponin I). Herein, 71% (24/34) and 44% (12/27) of the male and female MI mice, respectively, were positive for cAAbs against cTnI (cTnIAAb). Germinal centers were formed in the spleens and mediastinal lymph nodes of cTnIAAb-positive MI mice. cTnIAAb-positive MI mice showed progressive cardiac remodeling with a worse prognosis (P=0.014, by log-rank test), which was accompanied by cardiac inflammation, compared with that in cTnIAAb-negative MI mice. Rapamycin treatment during the first 7 days after MI suppressed cTnIAAb production (cTnIAAb positivity, 59% [29/49] and 7% [2/28] in MI mice treated with vehicle and rapamycin, respectively; P<0.001, by Pearson χ2 test), consequently improving the survival and ameliorating cardiac inflammation, cardiac remodeling, and HF in MI mice. CONCLUSIONS: The present post-MI HF model may accelerate our understanding of cTnIAAb and support the development of therapeutics against cTnIAAbs in post-MI HF.

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  • Regional Variation in the Clinical Practice and Prognosis in Patients With Heart Failure With Reduced Ejection Fraction in Japan ― A Report From the Japanese Registry of Acute Decompensated Heart Failure (JROADHF)

    Sato, Y; Yoshihisa, A; Ide, T; Tohyama, T; Enzan, N; Matsushima, S; Tsutsui, H; Takeishi, Y

    CIRCULATION JOURNAL   87 ( 10 )   1380 - +   2023.10   ISSN:1346-9843 eISSN:1347-4820

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    Background: The present study aimed to clarify the regional variations in clinical practice and the prognosis of patients with heart failure with reduced ejection fraction (HFrEF) in Japan using the Japanese Registry of Acute Decompensated Heart Failure (JROADHF). Methods and Results: We recruited data of hospitalized patients with HFrEF (n=4, 329) from the JROADHF. The patients were divided into 6 groups based on the region of Japan where they were hospitalized: Hokkaido-Tohoku (n=504), Kanto (n=958), Chubu (n=779), Kinki (n=902), Chugoku-Shikoku (n=446), and Kyushu (n=740). We compared the patients' characteristics, including etiology of HF and prognosis after discharge. The age of the patients was lowest in the Kanto and Kinki regions. In contrast, there were no differences in the prevalence of comorbidities, levels of B-type natriuretic peptide, or left ventricular EF among the 6 groups. Post-discharge cardiospecific prognosis, specifically, the composite of cardiac death or HF hospitalization, cardiac death, and HF hospitalization, was comparable among the 6 regions. Conclusions: There were no differences in cardiospecific prognosis in patients with HFrEF among the 6 regions in Japan.

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  • Efficacy of Early Catheter Ablation for Atrial Fibrillation After Admission for Heart Failure

    Sakamoto, K; Tohyama, T; Ide, T; Mukai, Y; Enzan, N; Nagata, T; Ikeda, M; Takase, S; Nagayama, T; Fujino, T; Matsushima, S; Tsutsui, H

    JACC-CLINICAL ELECTROPHYSIOLOGY   9 ( 9 )   1948 - 1959   2023.9   ISSN:2405-500X eISSN:2405-5018

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    Background: Advances in catheter ablation (CA) for atrial fibrillation (AF) have improved the prognosis of patients with heart failure (HF) and AF. However, its optimal timing remains to be fully elucidated. Objectives: The aim of this study was to investigate the prognostic impact of early CA in patients with HF and AF hospitalized for worsening HF. Methods: From JROADHF (Japanese Registry of Acute Decompensated Heart Failure) (n = 13,238), patients with HF and AF who underwent CA within 90 days after admission for HF (early CA; n = 103) and those who did not (control; n = 2,683) were identified. Mortality was compared between these groups in the crude cohort, as well as in the propensity-matched cohort (n = 83 in each group). Results: In the crude cohort, all-cause mortality was significantly lower in the early CA group than in the control group (log-rank P < 0.001; HR: 0.38; 95% CI: 0.24-0.60). In the matched cohort, all-cause mortality was likewise significantly lower in the early CA group (log-rank P = 0.014; HR: 0.47; 95% CI: 0.25-0.88). Cardiovascular death and HF mortality were significantly lower in both cohorts (crude: Gray’ test: P < 0.001 and P = 0.005; subdistribution HR: 0.28 [95% CI: 0.13-0.63] and HR: 0.31 [95% CI: 0.13-0.75]; matched: Gray's test: P = 0.006 and P = 0.017; subdistribution HR: 0.24 [95% CI: 0.08-0.70] and HR: 0.28 [95% CI: 0.09-0.84], respectively). Conclusions: In a nationwide representative real-world cohort, CA for AF within 90 days after admission for HF was associated with improved long-term outcomes, including cardiovascular and HF death in patients with HF and AF.

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  • IFN-g-STAT1-ERK Pathway Mediates Protective Effects of Invariant Natural Killer T Cells Against Doxorubicin-Induced Cardiomyocyte Death

    Sada, M; Matsushima, S; Ikeda, M; Ikeda, S; Okabe, K; Ishikita, A; Tadokoro, T; Enzan, N; Yamamoto, T; Miyamoto, HD; Tsutsui, Y; Miyake, R; Setoyama, D; Kang, D; Ide, T; Tsutsui, H

    JACC-BASIC TO TRANSLATIONAL SCIENCE   8 ( 8 )   992 - 1007   2023.8   ISSN:2452-302X

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    Doxorubicin (DOX)-induced cardiomyopathy has poor prognosis, and myocardial inflammation is intimately involved in its pathophysiology. The role of invariant natural killer T (iNKT) cells has not been fully determined in this disease. We here demonstrated that activation of iNKT cells by α-galactosylceramide (GC) attenuated DOX-induced cardiomyocyte death and cardiac dysfunction. αGC increased interferon (IFN)-γ and phosphorylation of signal transducers and activators of transcription 1 (STAT1) and extracellular signal-regulated kinase (ERK). Administration of anti-IFN-γ neutralizing antibody abrogated the beneficial effects of αGC on DOX-induced cardiac dysfunction. These findings emphasize the protective role of iNKT cells in DOX-induced cardiomyopathy via the IFN-γ-STAT1-ERK pathway.

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  • An increasing trend of gastric cancer deaths and inadequate preventive measures in elderly adults

    Matsushima, R; Matsushima, S; Kobayashi, M; Fujimori, K; Sakamoto, N; Asaka, M

    HELICOBACTER   28 ( 4 )   e12988   2023.8   ISSN:1083-4389 eISSN:1523-5378

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    Background: Japan became the world's first country to cover Helicobacter pylori eradication for chronic gastritis under its National Health Insurance (NHI) system in February 2013. Thereafter, H. pylori eradication dramatically increased and gastric cancer deaths began to decrease in Japan. However, the details of gastric cancer deaths and its prevention in the very elderly have not been fully elucidated. Methods: We analyzed the temporal trend of gastric cancer deaths referencing data from Ministry of Health, Labour and Welfare reports and “Cancer Statistics in Japan–2021” and assessed the numbers of H. pylori test and gastric cancer screening using a national database and a report of cancer screening in Shimane Prefecture, respectively. Results: Although gastric cancer deaths in total population have clearly decreased since 2013, those in people aged 80 years and older are still increasing. People aged 80 years and older represent 9% of the total population and accounted for half of all gastric cancer deaths in 2020. The numbers of H. pylori eradication and gastric cancer screening in people aged 80 years and older were 25% and 25% of those in other generations, respectively. Conclusion: In spite of a dramatic increase in H. pylori eradication and a clear decrease in gastric cancer deaths in Japan, gastric cancer deaths in people aged 80 years and older are increasing. This might be due to fewer H. pylori eradication in the elderly than in other generations, indicating the difficulty of gastric cancer prevention in the very elderly.

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  • Prevalence, characteristics and cardiovascular and non-cardiovascular outcomes in patients with heart failure with supra-normal ejection fraction: Insight from the JROADHF study

    Horiuchi, Y; Asami, M; Ide, T; Yahagi, K; Komiyama, K; Yuzawa, H; Tanaka, J; Aoki, J; Matsushima, S; Tohyama, T; Enzan, N; Tsutsui, H; Tanabe, K

    EUROPEAN JOURNAL OF HEART FAILURE   25 ( 7 )   989 - 998   2023.7   ISSN:1388-9842 eISSN:1879-0844

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    Aims: We aimed to investigate the characteristics and prognosis of patients with heart failure (HF) with supra-normal ejection fraction (HFsnEF) compared to HF with normal ejection fraction (HFnEF). Methods and results: Among 11 573 patients enrolled in the nationwide registry of hospitalized patients with HF in Japan, 1943 patients (16.8%) were classified as HFsnEF (left ventricular ejection fraction [LVEF] >65%), 3277 (28.3%) as HFnEF (50% ≤ LVEF ≤65%), 2024 (17.5%) as HF with mildly reduced ejection fraction (40% ≤ LVEF <50%) and 4329 (37.4%) as HF with reduced ejection fraction (LVEF <40%). Patients with HFsnEF were older, more likely to be women, had lower natriuretic peptide values, and had smaller left ventricles than those with HFnEF. The primary endpoint, the composite of cardiovascular death or HF readmission, did not differ between HFsnEF (802/1943, 41.3%) and HFnEF (1413/3277, 43.1%) during a median follow-up period of 870 days (hazard ratio [HR] 0.96, 95% confidence interval 0.88–1.05, p = 0.346). The incidence of secondary outcomes, including all-cause, cardiovascular, and non-cardiovascular deaths and HF readmission, did not differ between HFsnEF and HFnEF. In the multivariable Cox regression analysis, HFsnEF compared to HFnEF was associated with a lower adjusted HR for HF readmission but not with the primary and other secondary endpoints. HFsnEF was associated with a higher HR for the composite endpoint and all-cause death in women, and a higher HR for all-cause death in patients with renal dysfunction. Conclusions: Heart failure with supra-normal ejection fraction is a common and distinctive phenotype, and has different characteristics and prognoses from HFnEF.

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  • Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis. Invited Reviewed International journal

    Abe K, Ikeda M, Ide T, Tadokoro T, Miyamoto HD, Furusawa S, Tsutsui Y, Miyake R, Ishimaru K, Watanabe M, Matsushima S, Koumura T, Yamada KI, Imai H, Tsutsui H

    Sci Signal   2023.6

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  • IFN-γ-STAT1-ERK Pathway Mediates Protective Effects of Invariant Natural Killer T Cells Against Doxorubicin-Induced Cardiomyocyte Death Reviewed International journal

    Sada M, Matsushima S, Ikeda M, Ikeda S, Okabe K, Ishikita A, Tadokoro T, Enzan N, Yamamoto T, Miyamoto HD, Tsutsui Y, Miyake R, Setoyama D, Kang D, Ide T, Tsutsui H.

    JACC Basic Transl Sci.   2023.6

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  • A higher resting heart rate is associated with cardiovascular event risk in patients with type 2 diabetes mellitus without known cardiovascular disease

    Ikeda, S; Shinohara, K; Enzan, N; Matsushima, S; Tohyama, T; Funakoshi, K; Kishimoto, J; Itoh, H; Komuro, I; Tsutsui, H

    HYPERTENSION RESEARCH   46 ( 5 )   1090 - 1099   2023.5   ISSN:0916-9636 eISSN:1348-4214

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    A higher resting heart rate (RHR) is associated with an increased risk of cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and cardiovascular diseases. The aim of this study was to investigate the association between RHR and cardiovascular events in T2DM patients with diabetic retinopathy and without known cardiovascular disease. We analyzed the association between RHR and cardiovascular events, including coronary, cerebral, renal and vascular events or cardiovascular death in T2DM patients with retinopathy and hyperlipidemia without prior cardiovascular events who were enrolled in the EMPATHY study. Data from 4746 patients were analyzed. The median RHR was 76 bpm. Patients were divided into four groups based on their baseline RHR (< 60, 60–69, 70–79, and ≥80 bpm). Patients with a higher RHR were more likely to be younger and had a higher body mass index, blood pressure value, HbA1c value, and estimated glomerular filtration rate and a lower B-type natriuretic peptide value; they also had a higher proportion of current smoking status, neuropathy, and nephropathy. After adjusting for confounders, including the aforementioned risk factors, a RHR of 70–79 bpm and a RHR ≥ 80 bpm were significantly associated with cardiovascular events (hazard ratio 1.50, 95% CI 1.03–2.20; and hazard ratio 1.62, 95% CI 1.11–2.36; respectively) compared to a RHR of 60–69 bpm. The analysis using restricted cubic splines indicated that the cardiovascular risk seemed to be similarly high when the RHR range was ≥70 bpm. In conclusion, in T2DM patients with diabetic retinopathy and without known cardiovascular disease, a high RHR, particularly ≥70 bpm, was associated with the risk of cardiovascular events compared to a RHR of 60–69 bpm. [Figure not available: see fulltext.].

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  • ZBP1 Protects Against mtDNA-Induced Myocardial Inflammation in Failing Hearts

    Enzan, N; Matsushima, S; Ikeda, S; Okabe, K; Ishikita, A; Yamamoto, T; Sada, M; Miyake, R; Tsutsui, Y; Nishimura, R; Toyohara, T; Ikeda, Y; Shojima, Y; Miyamoto, HD; Tadokoro, T; Ikeda, M; Abe, K; Ide, T; Kinugawa, S; Tsutsui, H

    CIRCULATION RESEARCH   132 ( 9 )   1110 - 1126   2023.4   ISSN:0009-7330 eISSN:1524-4571

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    Background: Mitochondrial DNA (mtDNA)-induced myocardial inflammation is intimately involved in cardiac remodeling. ZBP1 (Z-DNA binding protein 1) is a pattern recognition receptor positively regulating inflammation in response to mtDNA in inflammatory cells, fibroblasts, and endothelial cells. However, the role of ZBP1 in myocardial inflammation and cardiac remodeling remains unclear. The aim of this study was to elucidate the role of ZBP1 in mtDNA-induced inflammation in cardiomyocytes and failing hearts. Methods: mtDNA was administrated into isolated cardiomyocytes. Myocardial infarctionwas conducted in wild type and ZBP1 knockout mice. Results: We here found that, unlike in macrophages, ZBP1 knockdown unexpectedly exacerbated mtDNA-induced inflammation such as increases in IL (interleukin)-1β and IL-6, accompanied by increases in RIPK3 (receptor interacting protein kinase 3), phosphorylated NF-κB (nuclear factor-κB), and NLRP3 (nucleotide-binding domain and leucine-rich-repeat family pyrin domain containing 3) in cardiomyocytes. RIPK3 knockdown canceled further increases in phosphorylated NF-κB, NLRP3, IL-1β, and IL-6 by ZBP1 knockdown in cardiomyocytes in response to mtDNA. Furthermore, NF-κB knockdown suppressed such increases in NLRP3, IL-1β, and IL-6 by ZBP1 knockdown in response to mtDNA. CpG-oligodeoxynucleotide, a Toll-like receptor 9 stimulator, increased RIPK3, IL-1β, and IL-6 and ZBP1 knockdown exacerbated them. Dloop, a component of mtDNA, but not Tert and B2m, components of nuclear DNA, was increased in cytosolic fraction from noninfarcted region of mouse hearts after myocardial infarction compared with control hearts. Consistent with this change, ZBP1, RIPK3, phosphorylated NF-κB, NLRP3, IL-1β, and IL-6 were increased in failing hearts. ZBP1 knockout mice exacerbated left ventricular dilatation and dysfunction after myocardial infarction, accompanied by further increases in RIPK3, phosphorylated NF-κB, NLRP3, IL-1β, and IL-6. In histological analysis, ZBP1 knockout increased interstitial fibrosis and myocardial apoptosis in failing hearts. Conclusions: Our study reveals unexpected protective roles of ZBP1 against cardiac remodeling as an endogenous suppressor of mtDNA-induced myocardial inflammation.

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  • RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function

    Shiraishi, C; Matsumoto, A; Ichihara, K; Yamamoto, T; Yokoyama, T; Mizoo, T; Hatano, A; Matsumoto, M; Tanaka, Y; Matsuura-Suzuki, E; Iwasaki, S; Matsushima, S; Tsutsui, H; Nakayama, KI

    NATURE COMMUNICATIONS   14 ( 1 )   2131   2023.4   eISSN:2041-1723

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    Although several ribosomal protein paralogs are expressed in a tissue-specific manner, how these proteins affect translation and why they are required only in certain tissues have remained unclear. Here we show that RPL3L, a paralog of RPL3 specifically expressed in heart and skeletal muscle, influences translation elongation dynamics. Deficiency of RPL3L-containing ribosomes in RPL3L knockout male mice resulted in impaired cardiac contractility. Ribosome occupancy at mRNA codons was found to be altered in the RPL3L-deficient heart, and the changes were negatively correlated with those observed in myoblasts overexpressing RPL3L. RPL3L-containing ribosomes were less prone to collisions compared with RPL3-containing canonical ribosomes. Although the loss of RPL3L-containing ribosomes altered translation elongation dynamics for the entire transcriptome, its effects were most pronounced for transcripts related to cardiac muscle contraction and dilated cardiomyopathy, with the abundance of the encoded proteins being correspondingly decreased. Our results provide further insight into the mechanisms and physiological relevance of tissue-specific translational regulation.

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  • ZBP1 protects against mtDNA-induced myocardial inflammation in failing hearts. Invited Reviewed International journal

    Enzan N, Matsushima S, Ikeda S, Okabe K, Ishikita A, Yamamto T, Sada M, Miyake R, Tsutsui Y, Nishimura R, Toyohara T, Ikeda Y, Shojima Y, Miyamoto DH, Tadokoro T, Ikeda M, Abe K, Ide T, Kinugawa S, Tsutsui H

    Circ Res   2023.4

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  • Propensity-Matched Study of Early Cardiac Rehabilitation in Patients With Acute Decompensated Heart Failure

    Enzan, N; Matsushima, S; Kaku, H; Tohyama, T; Nezu, T; Higuchi, T; Nagatomi, Y; Fujino, T; Hashimoto, T; Ide, T; Tsutsui, H

    CIRCULATION-HEART FAILURE   16 ( 4 )   e010320   2023.4   ISSN:1941-3289 eISSN:1941-3297

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    Background: The impact of early implementation of cardiac rehabilitation (CR) in heart failure (HF) patients remains to be elucidated. This study sought to determine whether CR during HF hospitalization could improve prognostic outcomes in patients with acute decompensated HF. Methods: We analyzed patients with HF enrolled in the JROADHF (Japanese Registry of Acute Decompensated Heart Failure) registry, a retrospective, multicenter, nationwide registry of patients hospitalized for acute decompensated HF. Eligible patients were divided into 2 groups according to CR during hospitalization. The primary outcome was a composite of cardiovascular death or rehospitalization due to cardiovascular event after discharge. The secondary outcomes were cardiovascular death and cardiovascular event rehospitalization. Results: Out of 10 473 eligible patients, 3210 patients underwent CR. Propensity score matching yielded 2804 pairs. Mean age was 77±12 years and 3127 (55.8%) were male. During a mean follow-up of 2.8 years, the CR group had lower incidence rates of the composite outcome (291 versus 327 events per 1000 patient-years; rate ratio, 0.890 [95% CI, 0.830-0.954]; P=0.001) and rehospitalization due to cardiovascular event (262 versus 295 events per 1000 patient-years; rate ratio, 0.888 [95% CI, 0.825-0.956]; P=0.002) than the no CR group. In-hospital CR was associated with an improvement in Barthel index for activities of daily living (P=0.002). Patients with very low Barthel index at admission were benefited by CR in comparison with patients with independent Barthel index (very low; hazard ratio, 0.834 [95% CI, 0.742-0.938]: independent; hazard ratio, 0.985 [95% CI, 0.891-1.088]; P for interaction=0.035). Conclusions: CR implementation during hospitalization was associated with better long-term outcomes in patients with acute decompensated HF. These data support the need for a randomized, controlled, adequately powered trial to definitively test the role of early physical rehabilitation in hospitalized patients with HF.

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  • Nationwide Temporal Trends in Clinical Characteristics and Treatment of Dilated Cardiomyopathy From 2003 to 2013 in Japan-A Report From Clinical Personal Records

    Tsutsui, Y; Matsushima, S; Enzan, N; Noda, E; Shinohara, K; Hashimoto, T; Ide, T; Kinugawa, S; Tsutsui, H

    CIRCULATION JOURNAL   87 ( 4 )   500 - 507   2023.4   ISSN:1346-9843 eISSN:1347-4820

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    Background: Little is known about nationwide temporal trends in the clinical characteristics and treatment of dilated cardiomyopathy (DCM) in Japan. Methods and Results: We collected data regarding demographics, echocardiography, and treatment of DCM between 2003 to 2013 from Clinical Personal Records, a national registry organized by the Japanese Ministry of Health, Labour, and Welfare. Among the 40,794 DCM patients screened, 27,702 with left ventricular ejection fraction (LVEF) <50% and age ≥18 years were enrolled in this study and divided into 3 groups according to registration year: Group 1, 2003-2005 (10,006 patients); Group 2, 2006-2010 (11,252 patients); and Group 3, 2011-2013 (6,444 patients). Over time, there were decreases in age at registration (mean [±SD] 58.6±13.0 vs. 56.8±13.8 vs. 56.2±13.8 years; P<0.001) and LVEF (33.5±10.0% vs. 31.1±9.9% vs. 29.2± 9.7%; P<0.001), and an increase in patients with New York Heart Association Class III-IV (28.2% vs. 35.2% vs. 41.0%; P<0.001). The use of β-blockers (59.1% vs. 79.3% vs. 87.8%; P<0.001) and mineralocorticoid receptor antagonists (30.6% vs. 35.8% vs. 39.7%; P<0.001) increased over time. In multivariate analysis, male sex, systolic blood pressure, chronic kidney disease, hemoglobin, and registration year were positively associated, whereas age and LVEF were negatively associated, with β-blocker prescription. Conclusions: Although the clinical characteristics of DCM changed, the implementation of optimal medical therapy for DCM increased from 2003 to 2013 in Japan.

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  • Long-Term Outcomes of Heart Failure Patients With Preserved, Mildly Reduced, and Reduced Ejection Fraction

    Nagata, T; Ide, T; Tohyama, T; Kaku, H; Enzan, N; Matsushima, S; Ikeda, M; Todaka, K; Tsutsui, H

    JACC-ASIA   3 ( 2 )   315 - 316   2023.4   ISSN:2772-3747

  • Beneficial Effects of Dipeptidyl Peptidase-4 Inhibitors on Heart Failure With Preserved Ejection Fraction and Diabetes

    Enzan N., Matsushima S., Kaku H., Tohyama T., Nagata T., Ide T., Tsutsui H.

    JACC: Asia   3 ( 1 )   93 - 104   2023.2   ISSN:2772-3747

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    Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to exert pleiotropic effects on heart failure (HF) in animal experiments. Objectives: This study sought to investigate the impact of DPP-4 inhibitors on HF patients with diabetes mellitus (DM). Methods: We analyzed hospitalized patients with HF and DM enrolled in the JROADHF (Japanese Registry Of Acute Decompensated Heart Failure) registry, a nationwide registry of acute decompensated HF. Primary exposure was the use of a DPP-4 inhibitor. The primary outcome was a composite of cardiovascular death or HF hospitalization during the median follow-up of 3.6 years according to left ventricular ejection fraction. Results: Out of 2,999 eligible patients, 1,130 had heart failure with preserved ejection fraction (HFpEF), 572 had heart failure with midrange ejection fraction (HFmrEF), and 1,297 had heart failure with reduced ejection fraction (HFrEF). In each cohort, 444, 232, and 574 patients received a DPP-4 inhibitor, respectively. A multivariable Cox regression model showed that DPP-4 inhibitor use was associated with a lower composite of cardiovascular death or HF hospitalization in HFpEF (HR: 0.69; 95% CI: 0.55-0.87; P = 0.002) but not in HFmrEF and HFrEF. Restricted cubic spline analysis demonstrated that DPP-4 inhibitors were beneficial in patients with higher left ventricular ejection fraction. In HFpEF cohort, propensity score matching yielded 263 pairs. DPP-4 inhibitor use was associated with a lower incidence rate of the composite of cardiovascular death or HF hospitalization (19.2 vs 25.9 events per 100 patient-years; rate ratio: 0.74; 95% CI: 0.57-0.97; P = 0.027) in matched patients. Conclusions: DPP-4 inhibitor use was associated with better long-term outcomes in HFpEF patients with DM.

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  • EFFECTIVENESS OF STATIN INTENSIVE THERAPY IN TYPE 2 DIABETES WITH HIGH VISIT-TO-VISIT BLOOD PRESSURE VARIABILITY

    Ikeda, S; Shinohara, K; Enzan, N; Matsushima, S; Tohyama, T; Funakoshi, K; Kishimoto, J; Itoh, H; Komuro, I; Tsutsui, H

    JOURNAL OF HYPERTENSION   41   E44 - E45   2023.1   ISSN:0263-6352 eISSN:1473-5598

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  • Histologic Diagnosis of Coronary Amyloidosis Using Percutaneous Transluminal Directional Atherectomy

    Yoshida, D; Hashimoto, T; Katsuki, M; Ishikita, A; Ishikawa, Y; Fujino, T; Shinohara, K; Matsushima, S; Kinugawa, S; Nakano, Y; Katsuki, S; Matoba, T; Hayashidani, S; Tsutsui, H

    CJC OPEN   5 ( 1 )   99 - 102   2023.1   ISSN:2589-790X

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  • 抗HLA抗体陽性患者に対する心臓移植周術期脱感作療法の経験

    藤野 剛雄, 山元 昇栄, 橋本 亨, 篠原 啓介, 松島 将士, 松永 章吾, 牛島 智基, 園田 拓道, 金萬 仁志, 豊沢 真代, 塩瀬 明, 絹川 真太郎

    Japanese Journal of Transplantation   58 ( Supplement )   s197_1 - s197_1   2023   ISSN:05787947 eISSN:21880034

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    <p>心臓移植レシピエント候補の中でもpanel reactive antibody (PRA)高値の症例は、ドナー特異的抗HLA抗体(DSA)を生じやすく、移植後の拒絶反応リスクが高いことが想定される。</p><p>当院では、心臓移植を施行した61例のうち、4例(男性1例、女性3例)に周術期の脱感作療法を施行した。いずれもhigh PRAかつpreformed DSA陽性の症例であった。プロトコールとして、全例で移植術直前に血漿交換と免疫グロブリン投与を併用した。移植後の経過として、1例で急性期にgrade 1R/2の細胞性拒絶反応を認めたが、抗体関連拒絶反応を発症した症例はなく、心機能低下を来した症例もなかった。</p><p>当院でのhigh PRA症例に対する周術期脱感作療法は安全に施行でき、術後に問題となる拒絶反応も見られなかった。注意して長期経過を観察する必要がある。また、本邦では血漿交換や免疫グロブリン療法、さらにはリツキシマブといった治療は心臓移植における脱感作療法に対しては保険適応外であり、治療の有効性・必要性について今後も検証が必要である。</p>

    DOI: 10.11386/jst.58.supplement_s197_1

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  • Immunomodulatory Cell Therapy Using αGalCer-Pulsed Dendritic Cells Ameliorates Heart Failure in a Murine Dilated Cardiomyopathy Model

    Ikeda, M; Ide, T; Matsushima, S; Ikeda, S; Okabe, K; Ishikita, A; Tadokoro, T; Sada, M; Abe, K; Sato, M; Hanada, A; Arai, S; Ohtani, K; Nonami, A; Mizuno, S; Morimoto, S; Motohashi, S; Akashi, K; Taniguchi, M; Tsutsui, H

    CIRCULATION-HEART FAILURE   15 ( 12 )   1125 - 1139   2022.12   ISSN:1941-3289 eISSN:1941-3297

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    Background: Dilated cardiomyopathy (DCM) is a life-threatening disease, resulting in refractory heart failure. An immune disorder underlies the pathophysiology associated with heart failure progression. Invariant natural killer T (iNKT) cell activation is a prospective therapeutic strategy for ischemic heart disease. However, its efficacy in nonischemic cardiomyopathy, such as DCM, remains to be elucidated, and the feasible modality for iNKT cell activation in humans is yet to be validated. Methods: Dendritic cells isolated from human volunteers were pulsed with α-galactosylceramide ex vivo, which were used as α-galactosylceramide-pulsed dendritic cells (αGCDCs). We treated DCM mice harboring mutated troponin TΔK210/ΔK210with αGCDCs and evaluated the efficacy of iNKT cell activation on heart failure in DCM mice. Furthermore, we investigated the molecular basis underlying its therapeutic effects in these mice and analyzed primary cardiac cells under iNKT cell-secreted cytokines. Results: The number of iNKT cells in the spleens of DCM mice was reduced compared with that in wild-type mice, whereas αGCDC treatment activated iNKT cells, prolonged survival of DCM mice, and prevented decline in the left ventricular ejection fraction for 4 weeks, accompanied by suppressed interstitial fibrosis. Mechanistically, αGCDC treatment suppressed TGF (transforming growth factor)-β signaling and expression of fibrotic genes and restored vasculature that was impaired in DCM hearts by upregulating angiopoietin 1 (Angpt1) expression. Consistently, IFNγ (interferon gamma) suppressed TGF-β-induced Smad2/3 signaling and the expression of fibrotic genes in cardiac fibroblasts and upregulated Angpt1 expression in cardiomyocytes via Stat1. Conclusions: Immunomodulatory cell therapy with αGCDCs is a novel therapeutic strategy for heart failure in DCM.

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  • Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis

    Abe, K; Ikeda, M; Ide, T; Tadokoro, T; Miyamoto, HD; Furusawa, S; Tsutsui, Y; Miyake, R; Ishimaru, K; Watanabe, M; Matsushima, S; Koumura, T; Yamada, KI; Imai, H; Tsutsui, H

    SCIENCE SIGNALING   15 ( 758 )   eabn8017   2022.11   ISSN:1945-0877 eISSN:1937-9145

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    Clinical use of doxorubicin (DOX) is limited because of its cardiotoxicity, referred to as DOX-induced cardiomyopathy (DIC). Mitochondria-dependent ferroptosis, which is triggered by iron overload and excessive lipid peroxidation, plays a pivotal role in the progression of DIC. Here, we showed that DOX accumulated in mitochondria by intercalating into mitochondrial DNA (mtDNA), inducing ferroptosis in an mtDNA content-dependent manner. In addition, DOX disrupted heme synthesis by decreasing the abundance of 5'-aminolevulinate synthase 1 (Alas1), the rate-limiting enzyme in this process, thereby impairing iron utilization, resulting in iron overload and ferroptosis in mitochondria in cultured cardiomyocytes. Alas1 overexpression prevented this outcome. Administration of 5-aminolevulinic acid (5-ALA), the product of Alas1, to cultured cardiomyocytes and mice suppressed iron overload and lipid peroxidation, thereby preventing DOX-induced ferroptosis and DIC. Our findings reveal that the accumulation of DOX and iron in mitochondria cooperatively induces ferroptosis in cardiomyocytes and suggest that 5-ALA can be used as a potential therapeutic agent for DIC.

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  • Ethoxyquin is a Competent Radical-Trapping Antioxidant for Preventing Ferroptosis in Doxorubicin Cardiotoxicity

    Tadokoro, T; Ikeda, M; Abe, K; Ide, T; Miyamoto, HD; Furusawa, S; Ishimaru, K; Watanabe, M; Ishikita, A; Matsushima, S; Koumura, T; Yamada, K; Imai, H; Tsutsui, H

    JOURNAL OF CARDIOVASCULAR PHARMACOLOGY   80 ( 5 )   690 - 699   2022.11   ISSN:0160-2446 eISSN:1533-4023

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    Doxorubicin (DOX) is an effective anti-cancer agent for various malignancies. Nevertheless, it has a side effect of cardiotoxicity, referred to as doxorubicin-induced cardiomyopathy (DIC), that is associated with a poorer prognosis. This cardiotoxicity limits the clinical use of DOX as a therapeutic agent for malignancies. Recently, ferroptosis, a form of regulated cell death induced by the accumulation of lipid peroxides, has been recognized as a major pathophysiology of DIC. Ethoxyquin is a lipophilic antioxidant widely used for food preservation and thus may be a potential therapeutic drug for preventing DIC. However, the efficacy of ethoxyquin against ferroptosis and DIC remains to be fully elucidated. Here, we investigated the inhibitory action of ethoxyquin against GPx4-deficient ferroptosis and its therapeutic efficacy against DOX-induced cell death in cultured cardiomyocytes and cardiotoxicity in a murine model of DIC. In cultured cardiomyocytes, ethoxyquin treatment effectively prevented GPx4-deficient ferroptosis. Ethoxyquin also prevented DOX-induced cell death, accompanied by the suppression of malondialdehyde (MDA) and mitochondrial lipid peroxides, which were induced by DOX. Furthermore, ethoxyquin significantly prevented DOX-induced cell death without any suppression of caspase cleavages representing apoptosis. In DIC mice, ethoxyquin treatment ameliorated cardiac impairments, such as contractile dysfunction and myocardial atrophy, and lung congestion. Ethoxyquin also suppressed serum lactate dehydrogenase and creatine kinase activities, decreased the levels of lipid peroxides such as MDA and acrolein, inhibited cardiac fibrosis, and reduced TUNEL-positive cells in the hearts of DIC mice. Collectively, ethoxyquin is a competent antioxidant for preventing ferroptosis in DIC and can be its prospective therapeutic drug.

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  • Iron Overload via Heme Degradation in the Endoplasmic Reticulum Triggers Ferroptosis in Myocardial Ischemia-Reperfusion Injury

    Miyamoto, HD; Ikeda, M; Ide, T; Tadokoro, T; Furusawa, S; Abe, K; Ishimaru, K; Enzan, N; Sada, M; Yamamoto, T; Matsushima, S; Koumura, T; Yamada, K; Imai, H; Tsutsui, H

    JACC-BASIC TO TRANSLATIONAL SCIENCE   7 ( 8 )   801 - 820   2022.8   ISSN:2452-302X

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    Ischemia-reperfusion (I/R) injury is a promising therapeutic target to improve clinical outcomes after acute myocardial infarction. Ferroptosis, triggered by iron overload and excessive lipid peroxides, is reportedly involved in I/R injury. However, its significance and mechanistic basis remain unclear. Here, we show that glutathione peroxidase 4 (GPx4), a key endogenous suppressor of ferroptosis, determines the susceptibility to myocardial I/R injury. Importantly, ferroptosis is a major mode of cell death in I/R injury, distinct from mitochondrial permeability transition (MPT)–driven necrosis. This suggests that the use of therapeutics targeting both modes is an effective strategy to further reduce the infarct size and thereby ameliorate cardiac remodeling after I/R injury. Furthermore, we demonstrate that heme oxygenase 1 up-regulation in response to hypoxia and hypoxia/reoxygenation degrades heme and thereby induces iron overload and ferroptosis in the endoplasmic reticulum (ER) of cardiomyocytes. Collectively, ferroptosis triggered by GPx4 reduction and iron overload in the ER is distinct from MPT-driven necrosis in both in vivo phenotype and in vitro mechanism for I/R injury. The use of therapeutics targeting ferroptosis in conjunction with cyclosporine A can be a promising strategy for I/R injury.

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  • Home-based cardiac rehabilitation using information and communication technology for heart failure patients with frailty

    Nagatomi, Y; Ide, T; Higuchi, T; Nezu, T; Fujino, T; Tohyama, T; Nagata, T; Higo, T; Hashimoto, T; Matsushima, S; Shinohara, K; Yokoyama, T; Eguchi, A; Ogusu, A; Ikeda, M; Ishikawa, Y; Yamashita, F; Kinugawa, S; Tsutsui, H

    ESC HEART FAILURE   9 ( 4 )   2407 - 2418   2022.8   ISSN:2055-5822

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    Aims: Cardiac rehabilitation (CR) is an evidence-based, secondary preventive strategy that improves mortality and morbidity rates in patients with heart failure (HF). However, the implementation and continuation of CR remains unsatisfactory, particularly for outpatients with physical frailty. This study investigated the efficacy and safety of a comprehensive home-based cardiac rehabilitation (HBCR) programme that combines patient education, exercise guidance, and nutritional guidance using information and communication technology (ICT). Methods and results: This study was a single-centre, open-label, randomized, controlled trial. Between April 2020 and November 2020, 30 outpatients with chronic HF (New York Heart Association II–III) and physical frailty were enrolled. The control group (n = 15) continued with standard care, while the HBCR group (n = 15) also received comprehensive, individualized CR, including ICT-based exercise and nutrition guidance using ICT via a Fitbit® device for 3 months. The CR team communicated with each patient in HBCR group once a week via the application messaging tool and planned the training frequency and intensity of training individually for the next week according to each patient's symptoms and recorded pulse data during exercise. Dietitians conducted a nutritional assessment and then provided individual nutritional advice using the picture-posting function of the application. The primary outcome was the change in the 6 min walking distance (6MWD). The participants' mean age was 63.7 ± 10.1 years, 53% were male, and 87% had non-ischaemic heart disease. The observed change in the 6MWD was significantly greater in the HBCR group (52.1 ± 43.9 m vs. −4.3 ± 38.8 m; P < 0.001) at a 73% of adherence rate. There was no significant change in adverse events in either group. Conclusions: Our comprehensive HBCR programme using ICT for HF patients with physical frailty improved exercise tolerance and improved lower extremity muscle strength in our sample, suggesting management with individualized ICT-based programmes as a safe and effective approach. Considering the increasing number of HF patients with frailty worldwide, our approach provides an efficient method to keep patients engaged in physical activity in their daily life.

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  • Fulminant necrotizing eosinophilic myocarditis after COVID-19 vaccination survived with mechanical circulatory support

    Kimura, M; Hashimoto, T; Noda, E; Ishikawa, Y; Ishikita, A; Fujino, T; Matsushima, S; Ide, T; Kinugawa, S; Nagaoka, K; Ushijima, T; Shiose, A; Tsutsui, H

    ESC HEART FAILURE   9 ( 4 )   2732 - 2737   2022.8   ISSN:2055-5822

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    A 69-year-old man was hospitalized for heart failure 7 days after coronavirus disease 2019 (COVID-19) mRNA vaccination. Electrocardiography showed ST-segment elevation and echocardiography demonstrated severe left ventricular dysfunction. Venoarterial extracorporeal membrane oxygenation and Impella 5.0 were instituted because of cardiogenic shock and ventricular fibrillation. Endomyocardial biopsy demonstrated necrotizing eosinophilic myocarditis (NEM). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) PCR test was negative. He had no infection or history of new drug exposure. NEM was likely related to COVID-19 vaccination. He was administered 10 mg/kg of prednisolone following methylprednisolone pulse treatment (1000 mg/day for 3 days). Left ventricular function recovered and he was weaned from mechanical circulatory support (MCS). Follow-up endomyocardial biopsy showed no inflammatory cell infiltration. This is the first report of biopsy-proven NEM after COVID-19 vaccination survived with MCS and immunosuppression therapy. It is a rare condition but early, accurate diagnosis and early aggressive intervention can rescue patients.

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  • Serial measurement of B-type natriuretic peptide and future cardiovascular events in patients with type 2 diabetes mellitus without known cardiovascular disease

    Ikeda, S; Shinohara, K; Enzan, N; Matsushima, S; Tohyama, T; Funakoshi, K; Kishimoto, J; Itoh, H; Komuro, I; Tsutsui, H

    INTERNATIONAL JOURNAL OF CARDIOLOGY   356   98 - 104   2022.6   ISSN:0167-5273 eISSN:1874-1754

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    Background: In patients with type 2 diabetes mellitus (T2DM) without known cardiovascular disease, the association between B-type natriuretic peptide (BNP) and cardiovascular events except for heart failure has not been elucidated. We aimed to investigate this association in high-risk T2DM patients. Methods: We analyzed the association between BNP and cardiovascular events, including coronary, cerebral, renal, and vascular events or cardiovascular death based on the single and serial measurement of BNP in T2DM patients with retinopathy and hyperlipidemia without known cardiovascular disease enrolled in the EMPATHY study. Results: Data from 4966 patients were analyzed for baseline BNP analysis. The median BNP value was 15.0 pg/mL. When analyzed in quartiles of baseline BNP (interquartile range 7.5–29.2 pg/mL), Q2, Q3, and Q4 were associated with cardiovascular events compared with Q1 (hazard ratio [HR]: Q2, 1.91 [P = 0.003]; Q3, 1.63 [P = 0.031]; Q4, 3.20 [P < 0.001]). The analysis of 12-month BNP showed similar associations. In serial BNP measurement, compared with low–low BNP group (baseline ≤35 pg/mL and 12-month ≤35 pg/mL), low–high BNP group as well as high–high BNP group was associated with cardiovascular events (HR: low–high, 2.05 [P = 0.004]; high–high, 2.07 [P = 0.001]) and non-renal cardiovascular events. High–low BNP group tended to be associated with non-renal cardiovascular events (HR vs low–low: 2.05 [P = 0.056]). Conclusions: BNP levels were associated with first cardiovascular events except for heart failure in T2DM patients with retinopathy and hyperlipidemia. Serial BNP measurement may be useful in further stratifying high-risk patients among this T2DM population.

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  • Yin and Yang of NADPH Oxidases in Myocardial Ischemia-Reperfusion

    Matsushima, S; Sadoshima, J

    ANTIOXIDANTS   11 ( 6 )   2022.6   ISSN:2076-3921 eISSN:2076-3921

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    Oxidative stress is critically involved in the pathophysiology of myocardial ischemicreperfusion (I/R) injury. NADPH oxidase (Nox) 2 and 4, major sources of reactive oxygen species (ROS) in cardiomyocytes, are upregulated in response to I/R. Suppression of Nox‐derived ROS prevents mitochondrial dysfunction and endoplasmic reticulum (ER) stress, leading to attenuation of myocardial I/R injury. However, minimal levels of ROS by either Nox2 or Nox4 are required for energy metabolism during I/R in the heart, preserving hypoxia‐inducible factor‐1α (HIF‐1α) and peroxisome proliferator‐activated receptor‐α (PPARα) levels. Furthermore, extreme suppression of Nox activity induces reductive stress, leading to paradoxical increases in ROS levels. Nox4 has distinct roles in organelles such as mitochondria, ER, and ER‐mitochondria contact sites (MAMs). Mitochondrial Nox4 exerts a detrimental effect, causing ROS‐induced mitochondrial dysfunction during I/R, whereas Nox4 in the ER and MAMs is potentially protective against I/R injury through regulation of autophagy and MAM function, respectively. Although Nox isoforms are potential therapeutic targets for I/R injury, to maximize the effect of intervention, it is likely important to optimize the ROS level and selectively inhibit Nox4 in mitochondria. Here, we discuss the ‘Yin and Yang’ functions of Nox isoforms during myocardial I/R.

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  • The use of angiotensin II receptor blocker is associated with greater recovery of cardiac function than angiotensin-converting enzyme inhibitor in dilated cardiomyopathy

    Enzan, N; Matsushima, S; Ide, T; Tohyama, T; Funakoshi, K; Higo, T; Tsutsui, H

    ESC HEART FAILURE   9 ( 2 )   1175 - 1185   2022.4   ISSN:2055-5822

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    Aims: Angiotensin-converting enzyme inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) have been shown to be associated with recovery of cardiac function in patients with dilated cardiomyopathy (DCM). The aim of this study was to assess comparative effectiveness of ACEis vs. ARBs on recovery of left ventricular ejection fraction (LVEF) among patients with DCM. Methods and results: We analysed the clinical personal records of DCM, a national database of the Japanese Ministry of Health, Labour and Welfare, from 2003 to 2014. Patients with LVEF < 40% and on either ACEis or ARBs were included. Eligible patients were divided into two groups according to the use of ACEis or ARBs. A one-to-one propensity case-matched analysis was used. The primary outcome was defined as LVEF ≥ 40% at 3 years of follow-up. Out of 4618 eligible patients, 2238 patients received ACEis and 2380 patients received ARBs. Propensity score matching yielded 1341 pairs. Mean age was 56.0 years, 2041 (76.1%) were male, median duration of heart failure was 1 year, and mean LVEF was 27.6%. The primary outcome was observed more frequently in ARB group than in ACEi group (59.8% vs. 54.1%; odds ratio 1.26; 95% confidence interval 1.08–1.47; P = 0.003). The per-protocol analysis showed similar results (62.0% vs. 54.0%; odds ratio 1.39; 95% confidence interval 1.17–1.66; P < 0.001). The change in LVEF from baseline to 3 years of follow-up was greater in ARB group than in ACEi group (15.8 ± 0.4% vs. 14.0 ± 0.4%, P = 0.003). The subgroup analysis showed that this effect was observed independently of systolic blood pressure, heart rate, LVEF, chronic kidney disease, and concomitant use of beta-blockers and mineralocorticoid receptor antagonists. Conclusions: The use of ARBs was associated with LVEF recovery more frequently than ACEis among patients with DCM and reduced LVEF.

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  • Electrocardiographic Diagnosis of Hypertrophic Cardiomyopathy in the Pre- and Post-Diagnostic Phases in Children and Adolescents

    Yoshinaga, M; Horigome, H; Ayusawa, M; Yasuda, K; Kogaki, S; Doi, S; Tateno, S; Ohta, K; Hokosaki, T; Nishihara, E; Iwamoto, M; Sumitomo, N; Ushinohama, H; Izumida, N; Tauchi, N; Kato, Y; Kato, T; Chisaka, T; Higaki, T; Yoneyama, T; Abe, K; Nozaki, Y; Komori, A; Kawai, S; Ninomiya, Y; Tanaka, Y; Nuruki, N; Sonoda, M; Ueno, K; Hazeki, D; Nomura, Y; Sato, S; Hirono, K; Hosokawa, S; Takechi, F; Ishikawa, Y; Hata, T; Ichida, F; Ohno, S; Makita, N; Horie, M; Matsushima, S; Tsutsui, H; Ogata, H; Takahashi, H; Nagashima, M

    CIRCULATION JOURNAL   86 ( 1 )   118 - +   2022.1   ISSN:1346-9843 eISSN:1347-4820

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    Background: The usefulness of electrocardiographic (ECG) voltage criteria for diagnosing hypertrophic cardiomyopathy (HCM) in pediatric patients is poorly defined. Methods and Results: ECGs at the 1st grade (mean [±SD] age 6.6±0.3 years) were available for 11 patients diagnosed with HCM at around the 7th grade (13.2±0.3 years). ECGs were available for another 64 patients diagnosed with HCM in the 1st (n=15), 7th (n=32), and 10th (n=17) grades. Fifty-one voltage criteria were developed by grade and sex using 62,841 ECGs from the general population. Voltage criteria were set at the 99.95th percentile (1/2,000) point based on the estimated prevalence of childhood HCM (2.9 per 100,000 [1/34,483]) to decrease false negatives. Conventional criteria were from guidelines for school-aged children in Japan. Of 11 patients before diagnosis, 2 satisfied conventional criteria in 1st grade; 5 (56%) of the remaining 9 patients fulfilled 2 voltage criteria (R wave in limb-lead I [RI]+S wave in lead V3 [SV3] and R wave in lead V3 [RV3]+SV3). Robustness analysis for sensitivity showed RV3+SV3 was superior to RI+SV3. For all patients after diagnosis, RI+SV4 was the main candidate. However, conventional criteria were more useful than voltage criteria. Conclusions: Early HCM prediction was possible using RV3+SV3 in >50% of patients in 1st grade. Voltage criteria may help diagnose prediagnostic or early HCM, and prevent tragic accidents, although further prospective studies are required.

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  • GFAT2 Mediates Cardiac Hypertrophy through HBP-O-GlcNAcylation-Akt Pathway. Reviewed International journal

    Ishikita A, Matsushima S, Ikeda S, Okabe K, Nishimura R, Tadokoro T, Enzan N, Yamamoto T, Sada M, Tsutsui Y, Miyake R, Ikeda M, Ide T, Kinugawa S, Tsutsui H

    iScience. 24(12):103517, 2021   2021.6

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  • Clinical Characteristics and Contemporary Management of Patients With Cardiomyopathies in Japan - Report From a National Registry of Clinical Personal Records Invited Reviewed International journal

    Enzan N, Matsushima S, Ide T, Kaku H, Tohyama T, Funakoshi K, Higo T, Tsutsui H; Research Group of Idiopathic Cardiomyopathy

    Circ Rep   3 ( 3 )   142   2021.2

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    DOI: 10.1253/circrep.CR-21-0001.

  • Cardiac-specific loss of mitoNEET expression is linked with age-related heart failure Invited Reviewed International journal

    Furihata T, Takada S, Kakutani N, Maekawa S, Tsuda M, Matsumoto J, Mizushima W, Fukushima A, Yokota T, Enzan N, Matsushima S, Handa H, Fumoto Y, Nio-Kobayashi J, Iwanaga T, Tanaka S, Tsutsui H, Sabe H, Kinugawa S.

    Commun Biol.   4 ( 1 )   138   2021.1

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    DOI: 10.1038/s42003-021-01675-4.

  • Heart Rate Reduction with Ivabradine Prevents Cardiac Rupture after Myocardial Infarction in Mice. Reviewed International journal

    Ikeda M, Ide T, Furusawa S, Ishimaru K, Tadokoro T, Miyamoto HD, Ikeda S, Okabe K, Ishikita A, Abe K, Matsushima S, Tsutsui H.

    Cardiovasc Drugs Ther.   36 ( 2 )   257 - 262   2021.1   ISSN:0920-3206 eISSN:1573-7241

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    Purpose: Cardiac rupture is a fatal complication following myocardial infarction (MI). An increase in heart rate (HR) is reportedly an independent risk factor for cardiac rupture during acute MI. However, the role of HR reduction in cardiac rupture after MI remains to be fully elucidated. We aimed to evaluate the therapeutic efficacy of HR reduction with ivabradine (IVA) on post-MI cardiac rupture in mice. Methods: We induced MI in mice by ligating the left anterior descending coronary artery. Subsequently, we subcutaneously implanted osmotic pumps filled with IVA solution or vehicle (Veh) in the surviving MI mice at 24 h postoperatively. We biochemically analyzed the myocardium on day 5, additionally observed the mice for 10 days, and analyzed the rates of cardiac rupture and non-cardiac rupture death, and survival after MI. Results: HR was significantly lower in the IVA-treated mice, whereas blood pressure was comparable between the two groups. Compared to the Veh-treated mice, apoptosis was significantly reduced in the MI border zone in the IVA-treated mice. Although there were no differences in the infarct size of the surviving MI mice between the two groups, HR reduction with IVA significantly reduced cardiac rupture (rupture rate 26 and 8% in the Veh-treated and IVA-treated groups, respectively) and improved survival after MI. Conclusion: Our findings suggest that HR reduction with IVA prevents cardiac rupture after MI. This may be particularly effective in MI patients with a high HR who are either unable to adequately tolerate β-blockers or whose HR remains high despite receiving β-blockers.

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  • Systemic oxidative stress is associated with lower aerobic capacity and impaired skeletal muscle energy metabolism in heart failure patients Invited Reviewed International journal

    Yokota T, Kinugawa S, Hirabayashi K, Yamato M, Takada S, Suga T, Nakano I, Fukushima A, Matsushima S, Okita K, Tsutsui H.

    Sci Rep   11 ( 1 )   2272   2021.1

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    DOI: 10.1038/s41598-021-81736-0

  • Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity Reviewed

    Tomonori Tadokoro, Masataka Ikeda, Tomomi Ide, Hiroko Deguchi, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Shouji Matsushima, Tomoko Koumura, Ken Ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui

    JCI Insight   5 ( 9 )   2020.5

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    Doxorubicin (DOX), a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicininduced cardiomyopathy (DIC). This cardiotoxicity often limits chemotherapy for malignancies and is associated with poor prognosis. However, the molecular mechanism underlying this cardiotoxicity is yet to be fully elucidated. Here, we show that DOX downregulated glutathione peroxidase 4 (GPx4) and induced excessive lipid peroxidation through DOX-Fe2+ complex in mitochondria, leading to mitochondria-dependent ferroptosis; we also show that mitochondria-dependent ferroptosis is a major cause of DOX cardiotoxicity. In DIC mice, the left ventricular ejection fraction was significantly impaired, and fibrosis and TUNEL+ cells were induced at day 14. Additionally, GPx4, an endogenous regulator of ferroptosis, was downregulated, accompanied by the accumulation of lipid peroxides, especially in mitochondria. These cardiac impairments were ameliorated in GPx4 Tg mice and exacerbated in GPx4 heterodeletion mice. In cultured cardiomyocytes, GPx4 overexpression or iron chelation targeting Fe2+ in mitochondria prevented DOX-induced ferroptosis, demonstrating that DOX triggered ferroptosis in mitochondria. Furthermore, concomitant inhibition of ferroptosis and apoptosis with ferrostatin-1 and zVAD-FMK fully prevented DOX-induced cardiomyocyte death. Our findings suggest that mitochondria-dependent ferroptosis plays a key role in progression of DIC and that ferroptosis is the major form of regulated cell death in DOX cardiotoxicity.

    DOI: 10.1172/jci.insight.132747

  • DPP (dipeptidyl peptidase)-4 inhibitor attenuates ANG II (angiotensin II)–induced cardiac hypertrophy via GLP (glucagon-like peptide)-1–dependent suppression of NOx (nicotinamide adenine dinucleotide phosphate oxidase) 4-HDAC (histone deacetylase) 4 pathway Reviewed

    Kosuke Okabe, Shouji Matsushima, Soichiro Ikeda, Masataka Ikeda, Akihito Ishikita, Tomonori Tadokoro, Nobuyuki Enzan, Taishi Yamamoto, Masashi Sada, Hiroko Deguchi, Keisuke Shinohara, Tomomi Ide, Hiroyuki Tsutsui

    Hypertension   991 - 1001   2020.4

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    —Nox4 (NADPH [Nicotinamide adenine dinucleotide phosphate] oxidase 4) is a major source of oxidative stress and is intimately involved in cardiac hypertrophy. DPP (Dipeptidyl peptidase)-4 inhibitor has been reported to regulate Nox4 expression in adipose tissues. However, its effects on Nox4 in cardiac hypertrophy are still unclear. We investigated whether DPP-4 inhibitor could ameliorate cardiac hypertrophy by regulating Nox4 and its downstream targets. Ang II (Angiotensin II; 1.44 mg/kg per day) or saline was continuously infused into C57BL/6J mice with or without teneligliptin (a DPP-4 inhibitor, 30 mg/kg per day) in the drinking water for 1 week. Teneligliptin significantly suppressed plasma DPP-4 activity without any significant changing aortic blood pressure or metabolic parameters such as blood glucose and insulin levels. It attenuated Ang II–induced increases in left ventricular wall thickness and the ratio of heart weight to body weight. It also significantly suppressed Ang II–induced increases in Nox4 mRNA, 4-hydroxy-2-nonenal, and phosphorylation of HDAC4 (histone deacetylase 4), a downstream target of Nox4 and a crucial suppressor of cardiac hypertrophy, in the heart. Exendin-3 (150 pmol/kg per minute), a GLP-1 (glucagon-like peptide 1) receptor antagonist, abrogated these inhibitory effects of teneligliptin on Nox4, 4-hydroxy-2-nonenal, phosphorylation of HDAC4, and cardiac hypertrophy. In cultured neonatal cardiomyocytes, exendin-4 (100 nmol/L, 24 hours), a GLP-1 receptor agonist, ameliorated Ang II–induced cardiomyocyte hypertrophy and decreased in Nox4, 4-hydroxy-2-nonenal, and phosphorylation of HDAC4. Furthermore, exendin-4 prevented Ang II–induced decrease in nuclear HDAC4 in cardiomyocytes. In conclusion, GLP-1 receptor stimulation by DPP-4 inhibitor can attenuate Ang II–induced cardiac hypertrophy by suppressing of the Nox4-HDAC4 axis in cardiomyocytes.

    DOI: 10.1161/HYPERTENSIONAHA.119.14400

  • Left ventricular noncompaction with multiple thrombi in apical aneurysm Reviewed

    Daisuke Yakabe, Shouji Matsushima, Saori Uchino, Kisho Ohtani, Tomomi Ide, Taiki Higo, Hiroyuki Tsutsui

    Internal Medicine   59 ( 3 )   377 - 381   2020.2

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    A 44-year-old man was admitted to our hospital due to heart failure. Transthoracic echocardiography demonstrated global hypokinesis with an ejection fraction of 25%, prominent trabeculation and deep intertrabecular recesses, and apical aneurysm with multiple thrombi (10×13 mm in the inferior wall, 15×8 mm in the anterior wall). Cardiac magnetic resonance imaging showed an increased ratio of noncompacted (NC) to compacted (C) myocardium (NC/C ratio >2.3) and apical aneurysm. Coronary angiography revealed no significant stenosis. He was therefore diagnosed with left ventricular noncompaction complicated by apical aneurysm. Four weeks after starting anticoagulation, the multiple apical thrombi disappeared without clinical signs of embolism.

    DOI: 10.2169/internalmedicine.3489-19

  • Spironolactone use is associated with improved outcomes in heart failure with mid-range ejection fraction Reviewed

    Nobuyuki Enzan, Shouji Matsushima, Tomomi Ide, Hidetaka Kaku, Taiki Higo, Miyuki Tsuchihashi-Makaya, Hiroyuki Tsutsui

    ESC Heart Failure   7 ( 1 )   339 - 347   2020.2

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    Aims: Spironolactone has been shown to improve outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). We investigated whether the discharge use of spironolactone could be associated with better long-term outcomes among patients with HF with mid-range EF (HFmrEF). Methods and results: We analysed HFmrEF (left ventricular EF 40–49%) patients enrolled in the Japanese Cardiac Registry of Heart Failure in Cardiology, which prospectively studied the clinical characteristics, treatments, and long-term outcomes of patients hospitalized due to HF. Patients were divided into two groups according to the use of spironolactone at discharge. The primary outcome was a composite of all-cause death or HF rehospitalization. A total of 457 patients had HFmrEF. The mean age was 69.3 years and 286 (62.6%) were male. Among them, spironolactone was prescribed at discharge in 158 patients (34.6%). Chronic kidney disease (7.6% vs. 16.8%, P = 0.007) was less prevalent and loop diuretics (89.2% vs. 70.2%, P < 0.001) were more often prescribed in patients with spironolactone. During a mean follow-up of 2.2 years, patients with spironolactone had a lower incidence rate of the primary outcome than those without it (171.5 vs. 278.8 primary outcome per 1000 patient-years, incidence rate ratio 0.61, 95% confidence interval 0.44–0.86; P = 0.004). After multivariable adjustment, spironolactone use at discharge was associated with a significant reduction in the composite of all-cause death or HF rehospitalization (adjusted hazard ratio 0.63, 95% confidence interval 0.44–0.90, P = 0.010). Conclusions: Among patients with HF hospitalized for HFmrEF, spironolactone use at discharge was associated with better long-term outcomes.

    DOI: 10.1002/ehf2.12571

  • Roxadustat markedly reduces myocardial ischemia reperfusion injury in mice Reviewed

    Hiroko Deguchi, Masataka Ikeda, Tomomi Ide, Tomonori Tadokoro, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Keita Saku, Shouji Matsushima, Hiroyuki Tsutsui

    Circulation Journal   84 ( 6 )   1028 - 1033   2020

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    Background: Ischemic preconditioning (IPC) is an effective procedure to protect against ischemia/reperfusion (I/R) injury. Hypoxia-inducible factor-1α (Hif-1α) is a key molecule in IPC, and roxadustat (RXD), a first-in-class prolyl hydroxylase domain-containing protein inhibitor, has been recently developed to treat anemia in patients with chronic kidney disease. Thus, we investigated whether RXD pretreatment protects against I/R injury. Methods and Results: RXD pretreatment markedly reduced the infarct size and suppressed plasma creatinine kinase activity in a murine I/R model. Analysis of oxygen metabolism showed that RXD could produce ischemic tolerance by shifting metabolism from aerobic to anaerobic respiration. Conclusions: RXD pretreatment may be a novel strategy against I/R injury.

    DOI: 10.1253/circj.CJ-19-1039

  • 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 ― Reviewed

    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   84 ( 5 )   742 - 753   2020

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    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.

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  • Blockade of L-type Ca2+ channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-κB pathway Reviewed

    Soichiro Ikeda, Shouji Matsushima, Kosuke Okabe, Masataka Ikeda, Akihito Ishikita, Tomonori Tadokoro, Nobuyuki Enzan, Taishi Yamamoto, Masashi Sada, Hiroko Deguchi, Sachio Morimoto, Tomomi Ide, Hiroyuki Tsutsui

    Scientific reports   9 ( 1 )   2019.12

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    Ca2+/calmodulin-dependent protein kinase II (CaMKII) and nuclear factor-kappa B (NF-κB) play crucial roles in pathogenesis of doxorubicin (DOX)-induced cardiomyopathy. Their activities are regulated by intracellular Ca2+. We hypothesized that blockade of L-type Ca2+ channel (LTCC) could attenuate DOX-induced cardiomyopathy by regulating CaMKII and NF-κB. DOX activated CaMKII and NF-κB through their phosphorylation and increased cleaved caspase 3 in cardiomyocytes. Pharmacological blockade or gene knockdown of LTCC by nifedipine or small interfering RNA, respectively, suppressed DOX-induced phosphorylation of CaMKII and NF-κB and apoptosis in cardiomyocytes, accompanied by decreasing intracellular Ca2+ concentration. Autocamtide 2-related inhibitory peptide (AIP), a selective CaMKII inhibitor, inhibited DOX-induced phosphorylation of NF-κB and cardiomyocyte apoptosis. Inhibition of NF-κB activity by ammonium pyrrolidinedithiocarbamate (PDTC) suppressed DOX-induced cardiomyocyte apoptosis. DOX-treatment (18 mg/kg via intravenous 3 injections over 1 week) increased phosphorylation of CaMKII and NF-κB in mouse hearts. Nifedipine (10 mg/kg/day) significantly suppressed DOX-induced phosphorylation of CaMKII and NF-κB and cardiomyocyte injury and apoptosis in mouse hearts. Moreover, it attenuated DOX-induced left ventricular dysfunction and dilatation. Our findings suggest that blockade of LTCC attenuates DOX-induced cardiomyocyte apoptosis via suppressing intracellular Ca2+ elevation and activation of CaMKII-NF-κB pathway. LTCC blockers might be potential therapeutic agents against DOX-induced cardiomyopathy.

    DOI: 10.1038/s41598-019-46367-6

  • Left Ventricular Noncompaction with Multiple Thrombi in Apical Aneurysm. Reviewed International journal

    Yakabe D, Matsushima S, Uchino S, Ohtani K, Ide T, Higo T, Tsutsui H

    2019.8

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  • Predicting Survival in Acute Decompensated Heart Failure with the Simple Risk Score: A2B Score. Reviewed International journal

    Nakada Y, Kawakami R, Matsushima S, Ide T, Kanaoka K, Ueda T, Ishihara S, Nishida T, Onoue K, Soeda T, Okayama S, Watanabe M, Okura H, Tsuchihashi-Makaya M, Tsutsui H, Saito Y.

    Circ J   2019.6

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  • Electrocardiographic Left Ventricular Hypertrophy is Independently Associated with Better Long-Term Outcomes in Dilated Cardiomyopathy Patients. Reviewed International journal

    Matsushima S, Kaku H, Enzan N, Ide T, Higo T, Tsuchihashi-Makaya M, Tsutsui H

    Circ Rep   2019.6

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  • Blockade of L-type Ca2+ channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-κB pathway. Reviewed International journal

    Ikeda S, Matsushima S, Okabe K, Ikeda M, Ishikita A, Tadokoro T, Enzan N, Yamamoto T, Sada M, Deguchi H, Morimoto S, Ide T, Tsutsui H.

    Sci Rep   2019.6

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  • Simple risk score to predict survival in acute decompensated heart failure A2B score Reviewed

    Yasuki Nakada, Rika Kawakami, Shouji Matsushima, Tomomi Ide, Koshiro Kanaoka, Tomoya Ueda, Satomi Ishihara, Taku Nishida, Kenji Onoue, Tsunenari Soeda, Satoshi Okayama, Makoto Watanabe, Hiroyuki Okura, Miyuki Tsuchihashi-Makaya, Hiroyuki Tsutsui, Yoshihiko Saito

    Circulation Journal   83 ( 5 )   1019 - 1024   2019

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    Background: Prognosis after acute decompensated heart failure (ADHF) is poor. An appropriate risk score that would allow for improved care and treatment of ADHF patients after discharge, however, is lacking. Methods and Results: We used 2 HF cohorts, the NARA-HF study and JCARE-CARD, as derivation and validation cohorts, respectively. The primary endpoint was all-cause death during the 2-year follow-up, excluding in-hospital death. Age, hemoglobin (Hb), and brain natriuretic peptide (BNP) at discharge were identified as independent risk factors. We determined 3 categorizations on the basis of these parameters, termed A2B score: age (<65 years, 0; 65-74 years, 1; ≥75 years, 2), anemia (Hb <10 g/dL, 2; 10-11.9 g/dL, 1; ≥12 g/dL, 0) and BNP (<200 pg/mL, 0; 200-499 pg/mL, 1; ≥500 pg/mL, 2). We divided patients into 4 groups according to A2B score (extremely low, 0; low, 1-2; medium, 3-4; high, 5-6). For the extremely low-risk group, the 2-year survival rate was 97.8%, compared with 84.5%, 66.1%, and 45.2% for the low-, medium-, and high-risk groups, respectively. Using the JCARE-CARD as a validation model, for the extremely low-risk group, the 2-year survival was 95.4%, compared with 90.2%, 75.0%, and 55.6% for the low-, medium-, and high-risk groups, respectively. Conclusions: The user-friendly A2B score is useful for estimating survival rate in ADHF patients at discharge.

    DOI: 10.1253/circj.CJ-18-1116

  • Pioglitazone improves whole-body aerobic capacity and skeletal muscle energy metabolism in patients with metabolic syndrome Reviewed

    Takashi Yokota, Shintaro Kinugawa, Kagami Hirabayashi, Tadashi Suga, Shingo Takada, Masashi Omokawa, Tomoyasu Kadoguchi, Masashige Takahashi, Arata Fukushima, Shouji Matsushima, Mayumi Yamato, Koichi Okita, Hiroyuki Tsutsui

    Journal of Diabetes Investigation   8 ( 4 )   535 - 541   2017.7

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    Aims/Introduction: Low aerobic capacity is a strong and independent predictor of all-cause mortality in patients with metabolic syndrome (MetS). Here, we investigated the effects of pioglitazone treatment on whole-body aerobic capacity and skeletal muscle energy metabolism in MetS patients. Materials and Methods: A total of 14 male patients with MetS received oral pioglitazone 15 mg/day for 4 months. To assess whole-body aerobic capacity, exercise testing with a bicycle ergometer was carried out before and after pioglitazone treatment. To assess skeletal muscle energy metabolism, intramyocellular lipid in the resting leg and high-energy phosphates in the calf muscle during plantar-flexion exercise were measured using 1proton- and 31phosphorus magnetic resonance spectroscopy, respectively. Results: Pioglitazone significantly increased peak oxygen uptake (25.1 ± 4.9 mL/kg/min pretreatment vs 27.2 ± 3.9 mL/kg/min post- treatment, P < 0.05) and anaerobic threshold (12.7 ± 1.9 mL/kg/min pretreatment vs 13.6 ± 1.6 mL/kg/min post-treatment, P < 0.05), although daily physical activity was comparable before and after the treatment. Intramyocellular lipid content was significantly reduced after pioglitazone treatment by 26%, indicating improved skeletal muscle fatty acid metabolism. Pioglitazone also significantly decreased the muscle phosphocreatine loss during exercise by 13%, indicating improved skeletal muscle high-energy phosphate metabolism. Notably, the increase in anaerobic threshold; that is, submaximal aerobic capacity, closely correlated with the decrease in intramyocellular lipid content after pioglitazone treatment. Conclusions: Pioglitazone significantly improved the MetS patients’ whole-body aerobic capacity and skeletal muscle energy metabolism. The beneficial effect of pioglitazone on whole-body aerobic capacity might be at least in part through improved fatty acid metabolism in the skeletal muscle.

    DOI: 10.1111/jdi.12606

  • Pioglitazone improves whole-body aerobic capacity and skeletal muscle energy metabolism in patients with metabolic syndrome. Reviewed International journal

    Yokota T, Kinugawa S, Hirabayashi K, Suga T, Takada S, Omokawa M, Kadoguchi T, Takahashi M, Fukushima A, Matsushima S, Yamato M, Okita K, Tsutsui H.

    J Diabetes Investig   2017.6

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  • The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes Reviewed

    Wataru Mizushima, Hidehisa Takahashi, Masashi Watanabe, Shintaro Kinugawa, Shouji Matsushima, Shingo Takada, Takashi Yokota, Takaaki Furihata, Junichi Matsumoto, Masaya Tsuda, Ikuru Chiba, Shun Nagashima, Shigeru Yanagi, Masaki Matsumoto, Keiichi I. Nakayama, Hiroyuki Tsutsui, Shigetsugu Hatakeyama

    Journal of Molecular and Cellular Cardiology   100   43 - 53   2016.11

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    A failing heart shows severe energy insufficiency, and it is presumed that this energy shortage plays a critical role in the development of cardiac dysfunction. However, little is known about the mechanisms that cause energy metabolic alterations in the failing heart. Here, we show that the novel RING-finger protein 207 (RNF207), which is specifically expressed in the heart, plays a role in cardiac energy metabolism. Depletion of RNF207 in neonatal rat cardiomyocytes (NRCs) leads to a reduced cellular concentration of adenosine triphosphate (ATP) and mitochondrial dysfunction. Consistent with this result, we observed here that the expression of RNF207 was significantly reduced in mice with common cardiac diseases including heart failure. Intriguingly, proteomic approaches revealed that RNF207 interacts with the voltage-dependent anion channel (VDAC), which is considered to be a key regulator of mitochondria function, as an RNF207-interacting protein. Our findings indicate that RNF207 is involved in ATP production by cardiomyocytes, suggesting that RNF207 plays an important role in the development of heart failure.

    DOI: 10.1016/j.yjmcc.2016.09.013

  • The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes. Reviewed International journal

    松島 将士

    J Mol Cell Cardiol   100:   43 - 53   2016.10

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  • Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling Reviewed

    Shouji Matsushima, Junya Kuroda, Peiyong Zhai, Tong Liu, Shohei Ikeda, Narayani Nagarajan, Shin Ichi Oka, Takashi Yokota, Shintaro Kinugawa, Chiao Po Hsu, Hong Li, Hiroyuki Tsutsui, Junichi Sadoshima

    Journal of Clinical Investigation   126 ( 9 )   3403 - 3416   2016.9

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    NADPH oxidases (Noxes) produce ROS that regulate cell growth and death. NOX4 expression in cardiomyocytes (CMs) plays an important role in cardiac remodeling and injury, but the posttranslational mechanisms that modulate this enzyme are poorly understood. Here, we determined that FYN, a Src family tyrosine kinase, interacts with the C-terminal domain of NOX4. FYN and NOX4 colocalized in perinuclear mitochondria, ER, and nuclear fractions in CMs, and FYN expression negatively regulated NOX4-induced O2 - production and apoptosis in CMs. Mechanistically, we found that direct phosphorylation of tyrosine 566 on NOX4 was critical for this FYN-mediated negative regulation. Transverse aortic constriction activated FYN in the left ventricle (LV), and FYN-deficient mice displayed exacerbated cardiac hypertrophy and dysfunction and increased ROS production and apoptosis. Deletion of Nox4 rescued the exaggerated LV remodeling in FYN-deficient mice. Furthermore, FYN expression was markedly decreased in failing human hearts, corroborating its role as a regulator of cardiac cell death and ROS production. In conclusion, FYN is activated by oxidative stress and serves as a negative feedback regulator of NOX4 in CMs during cardiac remodeling.

    DOI: 10.1172/JCI85624

  • Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling. Reviewed International journal

    松島 将士

    Journal of Clinical Investigation   126 ( 9 )   3403 - 34-16   2016.9

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  • Dipeptidyl peptidase-4 inhibitor improved exercise capacity and mitochondrial biogenesis in mice with heart failure via activation of glucagon-like peptide-1 receptor signalling Reviewed

    Shingo Takada, Yoshihiro Masaki, Shintaro Kinugawa, Junichi Matsumoto, Takaaki Furihata, Wataru Mizushima, Tomoyasu Kadoguchi, Arata Fukushima, Tsuneaki Homma, Masashige Takahashi, Shinichi Harashima, Shouji Matsushima, Takashi Yokota, Shinya Tanaka, Koichi Okita, Hiroyuki Tsutsui

    Cardiovascular research   111 ( 4 )   338 - 347   2016.9

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    Aims Exercise capacity is reduced in heart failure (HF) patients, due mostly to skeletal muscle abnormalities including impaired energy metabolism, mitochondrial dysfunction, fibre type transition, and atrophy. Glucagon-like peptide-1 (GLP-1) has been shown to improve exercise capacity in HF patients. We investigated the effects of the administration of a dipeptidyl peptidase (DPP)-4 inhibitor on the exercise capacity and skeletal muscle abnormalities in an HF mouse model after myocardial infarction (MI). Methods and results MI was created in male C57BL/6J mice by ligating the left coronary artery, and a sham operation was performed in other mice. The mice were then divided into two groups according to the treatment with or without a DPP-4 inhibitor, MK-0626 [1 mg/kg body weight (BW)/day] provided in the diet. Four weeks later, the exercise capacity evaluated by treadmill test was revealed to be limited in the MI mice, and it was ameliorated in the MI + MK-0626 group without affecting the infarct size or cardiac function. The citrate synthase activity, mitochondrial oxidative phosphorylation capacity, supercomplex formation, and their quantity were reduced in the skeletal muscle from the MI mice, and these decreases were normalized in the MI + MK-0626 group, in association with the improvement of mitochondrial biogenesis. Immunohistochemical staining also revealed that a shift toward the fast-twitch fibre type in the MI mice was also reversed by MK-0626. Favourable effects of MK-0626 were significantly inhibited by treatment of GLP-1 antagonist, Exendin-(9-39) (150 pmol/kg BW/min, subcutaneous osmotic pumps) in MI + MK-0626 mice. Similarly, exercise capacity and mitochondrial function were significantly improved by treatment of GLP-1 agonist, Exendin-4 (1 nmol/kg/BW/h, subcutaneous osmotic pumps). Conclusions A DPP-4 inhibitor may be a novel therapeutic agent against the exercise intolerance seen in HF patients by improving the mitochondrial biogenesis in their skeletal muscle.

    DOI: 10.1093/cvr/cvw182

  • The experimental model of transition from compensated cardiac hypertrophy to failure created by transverse aortic constriction in mice Reviewed

    Takaaki Furihata, Shintaro Kinugawa, Shingo Takada, Arata Fukushima, Masashige Takahashi, Tsuneaki Homma, Yoshihiro Masaki, Masaya Tsuda, Junichi Matsumoto, Wataru Mizushima, Shouji Matsushima, Takashi Yokota, Hiroyuki Tsutsui

    IJC Heart and Vasculature   11   24 - 28   2016.6

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    Background: Transverse aortic constriction (TAC) operation is used as an experimental model of left ventricular (LV) hypertrophy and LV failure in mice. The severity of LV remodeling or failure may depend on the degree of TAC, but is variable among operated animals. Therefore, we tried to identify the optimal diameter of TAC to create this model with ease and high reproducibility. Methods and results: To produce TAC in C57BL/6J mice (7-9 weeks, body weight 19-26 g, n = 109), a 7-0 nylon suture ligature was tightly tied around the transverse aorta against needles with 3 different diameters (mm); 0.40, 0.385 and 0.375. LV wall thickness, end-diastolic dimension, fractional shortening were measured by echocardiography. At 4 weeks after TAC, no mouse with the 0.400 mm gauge progressed in LV failure. The 0.385 mm pin gauge mouse kept a more survival rate compared with the 0.375 mm (59% vs 48%), representing same efficient in LV failure. With the 0.385 mm pin gauge, hearts of mice remained LV hypertrophy at 1 week after TAC, followed by LV failure at 4 weeks. Conclusion: TAC with the diameter of 0.385 mm can effectively induce the transition from LV hypertrophy to failure in mice with relatively preserved survival.

    DOI: 10.1016/j.ijcha.2016.03.007

  • Incidental focal myocardial 18F-FDG uptake indicating asymptomatic coronary artery disease Reviewed

    Tadao Aikawa, Masanao Naya, Osamu Manabe, Masahiko Obara, Shouji Matsushima, Nagara Tamaki, Hiroyuki Tsutsui

    Journal of Nuclear Cardiology   23 ( 3 )   596 - 598   2016.6

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    DOI: 10.1007/s12350-015-0258-5

  • Poldip2 negatively regulates matrix synthesis at focal adhesions Reviewed

    Shouji Matsushima, Daniela Zablocki, Hiroyuki Tsutsui, Junichi Sadoshima

    Journal of Molecular and Cellular Cardiology   94   10 - 12   2016.5

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    DOI: 10.1016/j.yjmcc.2016.03.001

  • Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice Reviewed

    Arata Fukushima, Shintaro Kinugawa, Shingo Takada, Junichi Matsumoto, Takaaki Furihata, Wataru Mizushima, Masaya Tsuda, Takashi Yokota, Shouji Matsushima, Koichi Okita, Hiroyuki Tsutsui

    European Journal of Pharmacology   779   147 - 156   2016.5

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    Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6 J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10 mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress.

    DOI: 10.1016/j.ejphar.2016.03.022

  • Sesamin prevents decline in exercise capacity and impairment of skeletal muscle mitochondrial function in mice with high-fat diet-induced diabetes Reviewed

    Shingo Takada, Shintaro Kinugawa, Shouji Matsushima, Daisuke Takemoto, Takaaki Furihata, Wataru Mizushima, Arata Fukushima, Takashi Yokota, Yoshiko Ono, Hiroshi Shibata, Koichi Okita, Hiroyuki Tsutsui

    Experimental Physiology   100 ( 11 )   1319 - 1330   2015.11

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    We previously reported that exercise capacity and skeletal muscle mitochondrial function in diabetic mice were impaired, in association with the activation of NAD(P)H oxidase. It has been reported that sesamin inhibits NAD(P)H oxidase-induced superoxide production. Therefore, we examined whether the antioxidant sesamin could prevent a decline in exercise capacity in mice with high-fat diet (HFD)-induced diabetes. C57BL/6J mice were fed a normal diet (ND) or HFD, then treated or not with sesamin (0.2%) to yield the following four groups: ND, ND+Sesamin, HFD and HFD+Sesamin (n = 10 each). After 8 weeks, body weight, fat weight, blood glucose, insulin, triglyceride, total cholesterol and fatty acid were significantly increased in HFD compared with ND mice. Sesamin prevented the increases in blood insulin and lipid levels in HFD-fed mice, but did not affect the plasma glucose. Exercise capacity determined by treadmill tests was significantly reduced in HFD mice, but almost completely recovered in HFD+Sesamin mice. Citrate synthase activity was significantly decreased in the skeletal muscle of HFD mice, and these decreases were also inhibited by sesamin. Superoxide anion and NAD(P)H oxidase activity were significantly increased in HFD mice compared with the ND mice and were ameliorated by sesamin. Sesamin prevented the decline in exercise capacity in HFD-induced diabetic mice via maintenance of mitochondrial function, fat oxidation and attenuation of oxidative stress in the skeletal muscle. Our data suggest that sesamin may be useful as a novel agent for the treatment of diabetes mellitus.

    DOI: 10.1113/EP085251

  • MIR-206 Mediates YAP-Induced Cardiac Hypertrophy and Survival Reviewed

    Yanfei Yang, Dominic P. Del Re, Noritsugu Nakano, Sebastiano Sciarretta, Peiyong Zhai, Jiyeon Park, Danish Sayed, Akihiro Shirakabe, Shoji Matsushima, Yongkyu Park, Bin Tian, Maha Abdellatif, Junichi Sadoshima

    Circulation research   117 ( 10 )   891 - 904   2015.10

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    Rationale: In Drosophila, the Hippo signaling pathway negatively regulates organ size by suppressing cell proliferation and survival through the inhibition of Yorkie, a transcriptional cofactor. Yes-associated protein (YAP), the mammalian homolog of Yorkie, promotes cardiomyocyte growth and survival in postnatal hearts. However, the underlying mechanism responsible for the beneficial effect of YAP in cardiomyocytes remains unclear. Objectives: We investigated whether miR-206, a microRNA known to promote hypertrophy in skeletal muscle, mediates the effect of YAP on promotion of survival and hypertrophy in cardiomyocytes. Methods and Results: Microarray analysis indicated that YAP increased miR-206 expression in cardiomyocytes. Increased miR-206 expression induced cardiac hypertrophy and inhibited cell death in cultured cardiomyocytes, similar to that of YAP. Downregulation of endogenous miR-206 in cardiomyocytes attenuated YAP-induced cardiac hypertrophy and survival, suggesting that miR-206 plays a critical role in mediating YAP function. Cardiac-specific overexpression of miR-206 in mice induced hypertrophy and protected the heart from ischemia/reperfusion injury, whereas suppression of miR-206 exacerbated ischemia/reperfusion injury and prevented pressure overload-induced cardiac hypertrophy. miR-206 negatively regulates Forkhead box protein P1 expression in cardiomyocytes and overexpression of Forkhead box protein P1 attenuated miR-206-induced cardiac hypertrophy and survival, suggesting that Forkhead box protein P1 is a functional target of miR-206. Conclusions: YAP increases the abundance of miR-206, which in turn plays an essential role in mediating hypertrophy and survival by silencing Forkhead box protein P1 in cardiomyocytes.

    DOI: 10.1161/CIRCRESAHA.115.306624

  • Low-intensity exercise under ischemic conditions enhances metabolic stress in patients with heart failure Reviewed

    Masashige Takahashi, Shintaro Kinugawa, Shingo Takada, Kagami Hirabayashi, Takashi Yokota, Shouji Matsushima, Akimichi Saito, Koichi Okita, Hiroyuki Tsutsui

    International Journal of Cardiology   201   142 - 144   2015.10

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    DOI: 10.1016/j.ijcard.2015.08.022

  • Skeletal muscle abnormalities in heart failure Reviewed

    Shintaro Kinugawa, Shingo Takada, Shouji Matsushima, Koichi Okita, Hiroyuki Tsutsui

    International heart journal   56 ( 5 )   475 - 484   2015.9

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    Exercise capacity is lowered in patients with heart failure, which limits their daily activities and also reduces their quality of life. Furthermore, lowered exercise capacity has been well demonstrated to be closely related to the severity and prognosis of heart failure. Skeletal muscle abnormalities including abnormal energy metabolism, transition of myofibers from type I to type II, mitochondrial dysfunction, reduction in muscular strength, and muscle atrophy have been shown to play a central role in lowered exercise capacity. The skeletal muscle abnormalities can be classified into the following main types: 1) low endurance due to mitochondrial dysfunction; and 2) low muscle mass and muscle strength due to imbalance of protein synthesis and degradation. The molecular mechanisms of these skeletal muscle abnormalities have been studied mainly using animal models. The current review including our recent study will focus upon the skeletal muscle abnormalities in heart failure.

    DOI: 10.1536/ihj.15-108

  • AST-120 ameliorates lowered exercise capacity and mitochondrial biogenesis in the skeletal muscle from mice with chronic kidney disease via reducing oxidative stress Reviewed

    Mikito Nishikawa, Naoki Ishimori, Shingo Takada, Akimichi Saito, Tomoyasu Kadoguchi, Takaaki Furihata, Arata Fukushima, Shouji Matsushima, Takashi Yokota, Shintaro Kinugawa, Hiroyuki Tsutsui

    Nephrology Dialysis Transplantation   30 ( 6 )   934 - 942   2015.6

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    Background. Exercise capacity and quality of life are markedly impaired in chronic kidney disease (CKD). Increased plasma uremic toxins such as indoxyl sulfate (IS), which induce oxidative stress, may be involved in this process. An oral adsorbent, AST-120, can reduce circulating IS, however, its effects on skeletal muscle and exercise capacity have not been investigated in CKD. Methods. Subtotal-nephrectomy or sham operation was performed in 8-week-old C57BL/6J mice. They were divided into two groups with or without 8% (w/w) of AST-120 in standard diet for 20 weeks. Sham, Sham + AST-120, CKD and CKD + AST-120 (n = 12, each group) were studied. We also conducted a C2C12 cell culture study to determine the direct effects of IS on oxidative stress. Results. Plasma IS levels were significantly increased in CKD compared with Sham (1.05 ± 0.11 versus 0.21 ± 0.03 mg/dL, P <0.05), which was significantly ameliorated in CKD + AST-120 (0.41 ± 0.06 mg/dL). The running distance to exhaustion determined by treadmill tests was significantly reduced in CKD compared with Sham (267 ± 17 versus 427 ± 36 m, P <0.05), and this reduction was also significantly ameliorated in CKD + AST-120 (407 ± 38 m) without altering skeletal muscle weight. Citrate synthase activity and mitochondrial biogenesis gene were downregulated, and superoxide production was significantly increased in the skeletal muscle from CKD, and these changes were normalized in CKD + AST-120. Incubation of C2C12 cells with IS significantly increased NAD(P)H oxidase activity. Conclusions. The administration of AST-120 improved exercise capacity and mitochondrial biogenesis of skeletal muscle via reducing oxidative stress. AST-120 may be a novel therapeutic agent against exercise intolerance in CKD.

    DOI: 10.1093/ndt/gfv103

  • Serum brain-derived neurotropic factor level predicts adverse clinical outcomes in patients with heart failure Reviewed

    Arata Fukushima, Shintaro Kinugawa, Tsuneaki Homma, Yoshihiro Masaki, Takaaki Furihata, Takashi Yokota, Shouji Matsushima, Shingo Takada, Tomoyasu Kadoguchi, Koji Oba, Koichi Okita, Hiroyuki Tsutsui

    Journal of Cardiac Failure   21 ( 4 )   300 - 306   2015.4

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    Background Brain-derived neurotropic factor (BDNF) is involved in cardiovascular diseases as well as skeletal muscle energy metabolism and depression. We investigated whether serum BDNF level was associated with prognosis in patients with heart failure (HF). Methods and Results We measured the serum BDNF level in 58 patients with HF (59.2 ± 13.7 years old, New York Heart Association functional class I-III) at baseline, and adverse events, including all cardiac deaths and HF rehospitalizations, were recorded during the median follow-up of 20.3 months. In a univariate analysis, serum BDNF levels were significantly associated with peak oxygen capacity (β = 0.547; P =.003), anaerobic threshold (β = 0.929; P =.004), and log minute ventilation/carbon dioxide production slope (β = -10.15; P =.005), but not Patient Health Questionnaire scores (β = -0.099; P =.586). A multivariate analysis demonstrated that serum BDNF level was an independent prognostic factor of adverse events (hazard ratio 0.41, 95% confidence interval 0.20-0.84; P =.003). The receiver operating characteristic curve demonstrated that low levels of BDNF (<17.4 ng/mL) were associated with higher rates of adverse events compared with high levels of BDNF (≥17.4 ng/mL; log rank test: P <.001). Conclusions Decreased serum BDNF levels were significantly associated with adverse outcomes in HF patients, suggesting that these levels can be a useful prognostic biomarker.

    DOI: 10.1016/j.cardfail.2015.01.003

  • Angiotensin II can directly induce mitochondrial dysfunction, decrease oxidative fibre number and induce atrophy in mouse hindlimb skeletal muscle Reviewed

    Tomoyasu Kadoguchi, Shintaro Kinugawa, Shingo Takada, Arata Fukushima, Takaaki Furihata, Tsuneaki Homma, Yoshihiro Masaki, Wataru Mizushima, Mikito Nishikawa, Masashige Takahashi, Takashi Yokota, Shouji Matsushima, Koichi Okita, Hiroyuki Tsutsui

    Experimental Physiology   100 ( 3 )   312 - 322   2015.3

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    New findings: What is the central question of this study? Does angiotensin II directly induce skeletal muscle abnormalities? What is the main finding and its importance? Angiotensin II induces skeletal muscle abnormalities and reduced exercise capacity. Mitochondrial dysfunction and a decreased number of oxidative fibres are manifest early, while muscle atrophy is seen later. Thus, angiotensin II may play an important role in the skeletal muscle abnormalities observed in a wide variety of diseases. Skeletal muscle abnormalities, such as mitochondrial dysfunction, a decreased percentage of oxidative fibres and atrophy, are the main cause of reduced exercise capacity observed in ageing and various diseases, including heart failure. The renin-angiotensin system, particularly angiotensin II (Ang II), is activated in the skeletal muscle in these conditions. Here, we examined whether Ang II could directly induce these skeletal muscle abnormalities and investigated their time course. Angiotensin II (1000 ng kg-1 min-1) or vehicle was administered to male C57BL/6J mice (10-12 weeks of age) via subcutaneously implanted osmotic minipumps for 1 or 4 weeks. Angiotensin II significantly decreased body and hindlimb skeletal muscle weights compared with vehicle at 4 weeks. In parallel, muscle cross-sectional area was also decreased in the skeletal muscle at 4 weeks. Muscle RING finger-1 and atrogin-1 were significantly increased in the skeletal muscle from mice treated with Ang II. In addition, cleaved caspase-3 and terminal deoxynucleotidyl trasferase-mediated dUTP nick-positive nuclei were significantly increased in mice treated with Ang II at 1 and 4 weeks, respectively. Mitochondrial oxidative enzymes, such as citrate synthase, complex I and complex III activities were significantly decreased in the skeletal muscle from mice treated Ang II at 1 and 4 weeks. NAD(P)H oxidase-derived superoxide production was increased. NADH staining revealed that type I fibres were decreased and type IIb fibres increased in mice treated with Ang II at 1 week. The work and running distance evaluated by a treadmill test were significantly decreased in mice treated with Ang II at 4 weeks. Thus, Ang II could directly induce the abnormalities in skeletal muscle function and structure.

    DOI: 10.1113/expphysiol.2014.084095

  • The role of sirtuins in cardiac disease Reviewed

    Shouji Matsushima, Junichi Sadoshima

    American Journal of Physiology - Heart and Circulatory Physiology   309 ( 9 )   H1375 - H1389   2015

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    Modification of histones is one of the important mechanisms of epigenetics, in which genetic control is determined by factors other than an individual’s DNA sequence. Sirtuin family proteins, which are class III histone deacetylases, were originally identified as gene silencers that affect the mating type of yeast, leading to the name “silent mating-type information regulation 2” (SIR2). They are characterized by their requirement of nicotinamide adenine dinucleotide for their enzyme activity, unlike other classes of histone deacetylases. Sirtuins have been traditionally linked to longevity and the beneficial effects of calorie restriction and DNA damage repair. Recently, sirtuins have been shown to be involved in a wide range of physiological and pathological processes, including aging, energy responses to low calorie availability, and stress resistance, as well as apoptosis and inflammation. Sirtuins can also regulate mitochondrial biogenesis and circadian clocks. Seven sirtuin family proteins (Sirt1-7) have been identified as mammalian SIR2 orthologs, localized in different subcellular compartments, namely, the cytoplasm (Sirt1, 2), the mitochondria (Sirt3, 4, 5), and the nucleus (Sirt1, 2, 6, 7). Sirt1 is evolutionarily close to yeast SIR2 and has been the most intensively investigated in the cardiovascular system. Endogenous Sirt1 plays a pivotal role in mediating the cell death/survival process and has been implicated in the pathogenesis of cardiovascular disease. Downregulation of Sirt2 is protective against ischemic-reperfusion injury. Increased Sirt3 expression has been shown to correlate with longevity in humans. In addition, Sirt3 protects cardiomyocytes from aging and oxidative stress and suppresses cardiac hypertrophy. Sirt6 has also recently been demonstrated to attenuate cardiac hypertrophy, and Sirt7 is known to regulate apoptosis and stress responses in the heart. On the other hand, the roles of Sirt4 and Sirt5 in the heart remain largely uncharacterized.

    DOI: 10.1152/ajpheart.00053.2015

  • Pioglitazone ameliorates the lowered exercise capacity and impaired mitochondrial function of the skeletal muscle in type 2 diabetic mice Reviewed

    Shingo Takada, Kagami Hirabayashi, Shintaro Kinugawa, Takashi Yokota, Shouji Matsushima, Tadashi Suga, Tomoyasu Kadoguchi, Arata Fukushima, Tsuneaki Homma, Wataru Mizushima, Yoshihiro Masaki, Takaaki Furihata, Ryoichi Katsuyama, Koichi Okita, Hiroyuki Tsutsui

    European Journal of Pharmacology   740   690 - 696   2014.10

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    We have reported that exercise capacity is reduced in high fat diet (HFD)-induced diabetic mice, and that this reduction is associated with impaired mitochondrial function in skeletal muscle (SKM). However, it remains to be clarified whether the treatment of diabetes ameliorates the reduced exercise capacity. Therefore, we examined whether an insulin-sensitizing drug, pioglitazone, could improve exercise capacity in HFD mice. C57BL/6J mice were fed a normal diet (ND) or HFD, then treated with or without pioglitazone (3 mg/kg/day) to yield the following 4 groups: ND+vehicle, ND+pioglitazone, HFD+vehicle, and HFD+pioglitazone (n=10 each). After 8 weeks, body weight, plasma glucose, and insulin in the HFD+vehicle were significantly increased compared to the ND+vehicle group. Pioglitazone normalized the insulin levels in HFD-fed mice, but did not affect the body weight or plasma glucose. Exercise capacity determined by treadmill tests was significantly reduced in the HFD+vehicle, and this reduction was almost completely ameliorated in HFD+pioglitazone mice. ADP-dependent mitochondrial respiration, complex I and III activities, and citrate synthase activity were significantly decreased in the SKM of the HFD+vehicle animals, and these decreases were also attenuated by pioglitazone. NAD(P)H oxidase activity was significantly increased in the HFD+vehicle compared with the ND+vehicle, and this increase was ameliorated in HFD+pioglitazone mice. Pioglitazone improved the exercise capacity in diabetic mice, which was due to the improvement in mitochondrial function and attenuation of oxidative stress in the SKM. Our data suggest that pioglitazone may be useful as an agent for the treatment of diabetes mellitus.

    DOI: 10.1016/j.ejphar.2014.06.008

  • Combinations of olmesartan and a calciumchannel blocker or a diuretic inelderly hypertensive patients A randomized, controlled trial Reviewed

    Toshio Ogihara, Takao Saruta, Hiromi Rakugi, Ikuo Saito, Kazuaki Shimamoto, Hiroaki Matsuoka, Kazuyuki Shimada, Sadayoshi Ito, Masatsugu Horiuchi, Tsutomu Imaizumi, Shuichi Takishita, Jitsuo Higaki, Shigehiro Katayama, Genjiroh Kimura, Satoshi Umemura, Nobuyuki Ura, Koichi Hayashi, Masato Odawara, Norio Tanahashi, Toshihiko Ishimitsu, Naoki Kashihara, Satoshi Morita, Satoshi Teramukai, T. Anno, S. Aoyama, N. Arima, Y. Bando, Y. Dohi, H. Fujioka, M. Fukuda, S. Fukuda, M. Fukuta, Y. Futamura, Y. Hirakawa, K. Imaeda, H. Imai, A. Imamura, M. Ito, O. Ito, T. Ito, T. Iwa, J. Izumi, Y. Kaga, K. Kanematsu, Y. Kato, Y. Kawata, T. Kitamura, K. Kobayashi, M. Koyasu, S. Kuwabara, M. Kuzuya, M. Maekawa, H. Mihara, F. Mitsuguchi, T. Murohara, T. Narita, K. Negi, Y. Numaguchi, T. Ohya, N. Okayama, K. Okuma, N. Ozaki, N. Ozeki, K. Sato, T. Sawada, Y. Seino, M. Suezawa, T. Suzuki, Y. Suzuki, N. Takahashi, R. Takahashi, N. Tanaka, Y. Wakida, H. Watanuki, M. Watarai, K. Yamada, S. Yamashita, M. Yoshikane, M. Goto, Y. Ishida, H. Kimura, K. Takahashi, N. Yashima, Y. Abe, S. Fujiwara, H. Higashino, M. Kaizuka, O. Minami, Y. Ogiu, T. Osanai, T. Sasaki, A. Sato, K. Sugimoto, H. Takahashi, K. Tanabe, D. Azuma, C. Ibuki, H. Inoya, T. Iyo, M. Kusaka, M. Ogawa, Y. Okubo, H. Rinno, M. Sano, T. Shishikura, H. Takahara, M. Takano, T. Takemura, S. Yamamoto, Y. Yonemitsu, M. Hasui, T. Honda, M. Igase, S. Kimoto, K. Kohno, S. Kondo, T. Oonishi, H. Saeki, T. Sunayama, H. Takahashi, C. Wakisaka, H. Watanabe, K. Watanabe, Y. Iwahori, Alan H.C. Lau, S. Ando, H. Eguchi, M. Fujino, J. Fukui, T. Gondo, S. Hatakeyama, K. Hirano, Y. Hirooka, H. Ikeda, T. Inou, T. Jinnouchi, T. Kadokami, H. Kai, H. Kameo, M. Kaneyuki, A. Katoh, H. Kishikawa, H. Koiwaya, K. Kusaba, S. Maeda, S. Maki, M. Matsumoto, T. Matsumoto, J. Matsumura, S. Matsuo, H. Meno, S. Miki, J. Miyagi, T. Miyauchi, S. Mori, M. Nagashima, S. Nagata, R. Nakamura, T. Nakamura, H. Niiyama, K. Noda, M. Nohara, Y. Ohta, I. Onitsuka, T. Otonari, S. Ouma, T. Sakisaka, K. Saku, K. Sasaki, S. Sasaki, Y. Sawayama, M. Shihara, K. Shiota, K. Shirakawa, Y. Tachikawa, S. Takemura, T. Takeuchi, M. Tanabe, M. Tanaka, H. Tashiro, M. Tatsukawa, T. Tsuchihashi, T. Tsuiki, T. Tsutsui, Y. Uehara, H. Umei, T. Yamada, J. Yamagata, T. Ajihara, K. Hagiwara, S. Imamura, M. Inoue, I. Konno, K. Konta, Y. Kubota, H. Kumakawa, T. Kuwana, H. Mitsuhashi, Y. Miyazaki, J. Nagashima, M. Nambu, T. Nishimaki, M. Sato, Y. Taneda, T. Tezuka, T. Yabuki, F. Ando, Y. Fuwa, S. Umeda, O. Araki, Y. Furushima, Y. Hattori, H. Hirabayashi, M. Horigome, J. Hoshino, C. Iguchi, H. Inamura, H. Kawauchi, S. Kogure, H. Kubo, F. Naganuma, T. Nagao, T. Nagao, T. Nagata, H. Nakashima, Y. Shimizu, H. Shoda, M. Tachibana, K. Yabe, R. Kuwashima, R. Mouri, T. Murakami, H. Muraoka, S. Nomura, F. Okuno, N. Sasaki, R. Sasaki, T. Satoh, M. Shirataki, H. Sugino, H. Takahashi, H. Takemoto, J. Ashihara, T. Betsuyaku, T. Fujita, T. Haga, M. Hayashi, Y. Hayashi, K. Hirasawa, Y. Ishii, R. Ishimoto, T. Komakine, M. Kyuma, I. Maeda, H. Matsuda, T. Matsuki, T. Matsumoto, T. Mito, M. Mizutani, H. Morimoto, S. Natori, T. Nishimiya, M. Nishimura, H. Oimatsu, H. Ooiwa, S. Saitoh, Y. Sasagawa, T. Segawa, H. Shuke, K. Sotozono, S. Takagi, S. Tanaka, M. Tashi, T. Tsubokura, Y. Ueno, K. Urabe, K. Yamauchi, H. Yoshida, M. Amano, Y. Hiroumi, K. Iiyama, H. Kido, A. Kosaka, A. Nogami, M. Okada, M. Shigenobu, R. Shigeta, S. Takagi, T. Takamiya, T. Takemura, S. Tomimoto, T. Tsuboi, N. Abe, E. Akaogi, S. Iida, K. Ito, H. Jonouchi, T. Matsushima, H. Miura, M. Miyazaki, S. Okubo, T. Araki, O. Iritani, K. Masuya, S. Morimoto, T. Nakahashi, Y. Wakasa, M. Yanagi, Y. Abe, H. Ito, T. Kawakami, Y. Kawamorita, H. Okamoto, H. Omori, T. Suzuki, T. Yoshida, K. Akiyama, S. Fujita, T. Hamamoto, K. Hasegawa, M. Hattori, H. Imachi, T. Ishida, H. Ishihama, K. Kaifu, H. Kishikawa, M. Kono, M. Kunishige, T. Maeta, H. Masugata, I. Matsumoto, N. Matsuoka, H. Miki, S. Mori, T. Morita, Y. Nishijima, E. Ohashi, Y. Okauchi, T. Okura, Y. Onishi, K. Ono, S. Senda, I. Seo, Y. Sugimoto, M. Tada, K. Yokoi, K. Yoshinare, K. Arikawa, Y. Hayashi, K. Iida, S. Miyata, H. Mizoguchi, A. Osako, S. Saishoji, I. Shimozono, S. Takenouchi, S. Tanaka, T. Furuki, N. Hatori, T. Iwaki, E. Kametsu, T. Kawafune, I. Kobayashi, T. Kubo, I. Michishita, F. Nonaka, H. Numata, A. Ogata, K. Okubo, T. Sano, R. Sawada, T. Sekino, N. Shimizu, H. Shionoiri, H. Tsuchiya, Y. Watanabe, H. Yamamoto, G. Yasuda, M. Aoki, Y. Iwasaki, H. Kawamoto, S. Kitagawa, M. Matsumoto, M. Nishinaga, M. Nishiyama, K. Tsuboi, I. Ueda, T. Yabe, H. Yamada, T. Yoshida, K. Azuma, O. Doi, R. Fukami, Y. Horio, Y. Ichikawa, S. Ikeda, T. Inaba, S. Mimori, K. Ohmori, K. Sasaki, A. Sato, H. Toyama, Y. Toyama, T. Hamasaki, H. Hayashi, T. Isono, S. Kageyama, K. Komaki, S. Matoba, H. Matsubara, T. Matubara, C. Nakagawa, D. Nishi, M. Nishi, K. Oiwa, H. Takamatsu, H. Takashima, T. Takegami, K. Takenaka, H. Yamada, Y. Yasuda, M. Horiguchi, J. Iemura, N. Isaka, T. Ishiga, T. Kato, T. Kitamura, M. Kobayashi, M. Setsuda, K. Shimono, M. Abe, T. Abe, Y. Abe, Y. Akino, H. Ebina, G. Hirasawa, K. Hirasawa, H. Kamada, M. Kishi, K. Kohama, S. Kyogoku, K. Matsuo, Y. Meguro, S. Miyasato, K. Morita, H. Nakagawa, Y. Otake, H. Saito, A. Sasaki, I. Sasaki, S. Sato, N. Uchida, Y. Utsumi, S. Yamaguchi, K. Hosokawa, Y. Ishiyama, S. Kariya, H. Komidori, M. Kuwabara, H. Ohta, S. Sonoda, M. Takii, N. Wake, N. Yokota, A. Iijima, T. Shinozaki, T. Takeda, A. Ito, H. Kawano, Y. Koide, H. Matsuoka, K. Nakao, K. Yamaguchi, A. Yamanaka, Y. Furiya, T. Kimu, Y. Kuga, Y. Nishida, Y. Saito, K. Sugie, T. Takami, M. Yamasaki, Y. Kaneko, H. Kawabata, S. Nakayama, Y. Abe, H. Ando, T. Fujino, K. Gotoh, T. Kakuma, I. Katsuragi, A. Kuroda, T. Masaki, K. Ninomiya, K. Okita, H. Ono, T. Watanabe, A. Yoshiiwa, K. Abe, S. Deguchi, F. Ikeda, H. Kataoka, N. Komai, K. Koten, K. Kusano, N. Maeda, H. Makino, S. Matano, T. Ohe, K. Shikata, M. Gushiken, R. Hamada, K. Matsushima, T. Shimabukuro, S. Tohma, T. Akagi, F. Akai, T. Amatsu, N. Babaya, S. Ban, K. Fujii, M. Fujimoto, Y. Fujimura, S. Fukumoto, M. Funauchi, H. Hanada, K. Hasegawa, N. Hayashi, T. Hibuse, M. Higashida, H. Honde, A. Imagawa, Y. Imamura, S. Inoue, R. Ishii, K. Ishikawa, K. Ishitani, H. Ito, S. Kaito, A. Kamitani, K. Kamiya, N. Kasayuki, R. Kawanami, T. Kawasaki, Y. Kijima, K. Kinoshita, M. Kishibuchi, Y. Kitamura, M. Kobayashi, T. Kono, Y. Maeda, K. Masaki, H. Matsumoto, S. Matsuoka, R. Matsuwaka, K. Minamikata, M. Miyagawa, H. Miyamoto, M. Miyamoto, E. Miyazaki, K. Miyoshi, M. Mune, N. Nakagawa, Y. Nakagawa, F. Nakamura, T. Nakamura, K. Nakanishi, Y. Nakatani, J. Nariyama, H. Nishida, M. Nishino, M. Nishiyama, K. Nishizawa, R. Nohara, A. Nose, H. Ogasawara, R. Ogawa, Y. Ohno, M. Ojima, Y. Okuyama, H. Otani, S. Otani, H. Park, H. Saito, A. Sakai, H. Sakamoto, H. Sata, Y. Sekine, T. Shinozuka, T. Suga, K. Sugimoto, M. Sugiyama, K. Suyama, K. Suyama, J. Tachi, T. Takagi, C. Takaori, M. Takenaka, T. Tamai, K. Tanaka, Y. Tanaka, K. Tane, M. Taniura, N. Tatsuda, Y. Teramoto, K. Teranaka, S. Teranishi, J. Terasaki, K. Toki, K. Tsuji, Y. Tsuji, T. Tsunetoshi, K. Ujino, S. Umeki, N. Wakagi, N. Wakaki, K. Yamaguchi, Y. Yamamoto, S. Yanagitani, M. Yoshida, H. Yoshimoto, H. Yoshioka, H. Ikeda, M. Matsumoto, K. Nagae, M. Nishiyama, K. Noda, M. Ohga, M. Akui, H. Aoki, J. Arafune, M. Arai, T. Arai, I. Asami, K. Eguchi, T. Fujino, H. Fujinuma, H. Fukata, J. Fukuda, T. Hamasaki, M. Haneda, I. Hisauchi, T. Hogi, M. Ichikawa, T. Iijima, H. Inoue, Y. Inoue, T. Kakinuma, H. Kanai, U. Kaneko, T. Kano, T. Katsumi, T. Kawashima, K. Kogure, O. Komuro, Y. Kubouchi, N. Kujirai, K. Kurokawa, T. Lee, K. Maeda, T. Majima, Y. Maruyama, S. Mashiba, K. Mashiko, K. Matsumoto, M. Matsuzawa, Y. Mitsugi, J. Morita, C. Nakajima, Y. Nakazato, Y. Nashida, H. Nasuhara, Y. Numajiri, T. Ogasawara, T. Okudaira, I. Osawa, N. Otani, A. Otsuka, Y. Ozawa, T. Sakai, Y. Sakai, K. Shimizu, T. Shinozaki, M. Shirai, K. Shiroma, H. Shuto, H. Suzuki, A. Tada, M. Takagi, K. Takahashi, N. Takahashi, A. Taniguchi, Y. Tonegawa, M. Toyoda, T. Tsuchiya, M. Uchida, H. Uchino, H. Wada, O. Wada, H. Yoshioka, H. Horie, M. Ichikawa, K. Ikenoue, T. Kawashima, H. Mizuhara, S. Ono, S. Ishikawa, K. Kawakami, S. Yano, N. Kubota, A. Nakagawa, T. Shigemasa, S. Suwa, T. Akabane, M. Amagai, Y. Asanobu, S. Horinaka, T. Iijima, K. Kasai, T. Kataoka, M. Kobayashi, T. Masuda, I. Nakano, M. Namekawa, A. Numabe, A. Ono, K. Sakata, I. Taguchi, T. Tomotsune, S. Toyoda, M. Arizumi, Y. Morimoto, A. Ota, S. Sawada, K. Yata, H. Akita, T. Akitsu, K. Amemiya, M. Ando, N. Aoki, J. Aoyagi, T. Baba, T. Degawa, S. Eto, K. Fujimoto, H. Fukuda, T. Furukawa, I. Goto, A. Hachiya, Y. Hanatani, K. Hara, T. Haruta, K. Hasegawa, T. Hatano, M. Hayashi, T. Hirano, M. Hiratsuka, Y. Horikawa, T. Horiuchi, M. Hosoya, K. Ichikawa, K. Iguchi, H. Imai, K. Ishibashi, K. Ishida, Y. Ishii, S. Ishiwata, T. Iwama, H. Kadota, S. Kaku, Y. Kamisaka, R. Kanbara, T. Kanematsu, A. Kashiwagi, I. Kawa, B. Kawai, M. Kawai, S. Kiuchi, T. Kiyozuka, S. Koba, H. Kobayashi, K. Koike, H. Kojima, E. Koshibu, Y. Koshibu, I. Kubo, K. Kuga, T. Kushiro, S. Miyakata, M. Miyakawa, F. Miyoshi, Y. Mochida, N. Moriyama, T. Myojo, M. Nagashima, H. Nakada, T. Nakai, T. Nakamura, Y. Nakaya, M. Nishizawa, S. Nishizawa, K. Oba, Y. Obu, N. Ohara, M. Okazaki, Y. Okazaki, K. Okumura, T. Ono, Y. Osamura, M. Otsuka, M. Ouchi, N. Sakamoto, Y. Sakata, S. Saneshige, M. Sasajima, T. Satoi, Y. Sengoku, K. Shibuya, H. Shimizu, K. Shimokado, M. Shoji, H. Tabata, A. Takahashi, H. Takakura, T. Takao, M. Taya, H. Tomonari, T. Tsunematsu, A. Uehata, T. Umezawa, H. Usui, T. Watanabe, Y. Yajima, F. Yamada, K. Yamada, A. Yamaguchi, T. Yamaguchi, K. Yamamoto, M. Yamamoto, T. Hamada, I. Hisatome, K. Arita, M. Arita, E. Doi, H. Furuta, T. Hano, T. Hashizume, A. Hibino, N. Kodama, A. Saika, J. Ueda, T. Fujita, T. Ito, M. Sakano, T. Sugawara, H. Tachibana, H. Toda, S. Fujimoto, T. Furui, Y. Hadano, T. Kaneko, A. Kawabata, S. Kawamoto, M. Mezuki, M. Mochizuki, M. Nakatsuka, S. Ono, N. Tahara, M. Kuroda, H. Manabe

    Journal of hypertension   32 ( 10 )   2054 - 2063   2014.10

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    Objective: The aim of the present study was to compare the cardiovascular effects of olmesartan, an angiotensin II receptor blocker, combined with a calcium channel blocker (CCB) or a diuretic, in a prospective, randomized, openlabel, blinded endpoint trial. Methods: Japanese hypertensive patients aged at least 65 to less than 85 years with SBP at least 140mmHg and/or DBP at least 90mmHg with antihypertensive treatment, or SBP at least 160mmHg and/or DBP at least 100mmHg without antihypertensive treatment were randomized to receive olmesartan with either a dihydropyridine CCB or a low-dose diuretic. If SBP and/or DBP remained at least 140 and/or at least 90mmHg, the other antihypertensive drug was added. The primary endpoint was a composite of fatal and nonfatal cardiovascular events. The median follow-up time was 3.3 years. Results: Blood pressure decreased similarly in both groups. The primary endpoint occurred in 116/2568 patients (4.5%) in the olmesartan plus CCB group and in 135/2573 patients (5.3%) in the olmesartan plus diuretic group [hazard ratio 0.83, 95% confidence interval (CI) 0.65- 1.07, P=0.16]. Rates of all-cause death and cardiovascular deaths were similar. Among patients aged at least 75 years, the incidence of stroke tended to be lower in the olmesartan plus CCB group than in the olmesartan plus diuretic group (hazard ratio 0.63, 95% CI 0.38-1.02, P=0.059, interaction P=0.019). Fewer patients in the olmesartan plus CCB group (8.2%, 211/2568) than in the olmesartan plus diuretic group (9.8%, 253/2573; P=0.046) experienced serious adverse events. Conclusion: Despite no significant difference in cardiovascular events, the different safety profiles suggest that the combination of olmesartan and CCB may be preferable to that of olmesartan and diuretic.

    DOI: 10.1097/HJH.0000000000000281

  • Intramyocellular lipid is increased in the skeletal muscle of patients with dilated cardiomyopathy with lowered exercise capacity Reviewed

    Kagami Hirabayashi, Shintaro Kinugawa, Takashi Yokota, Shingo Takada, Arata Fukushima, Tadashi Suga, Masashige Takahashi, Taisuke Ono, Noriteru Morita, Masashi Omokawa, Kuniaki Harada, Noriko Oyama-Manabe, Hiroaki Shirato, Shouji Matsushima, Koichi Okita, Hiroyuki Tsutsui

    International Journal of Cardiology   176 ( 3 )   1110 - 1112   2014.10

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    DOI: 10.1016/j.ijcard.2014.07.113

  • Clinical characteristics and CHADS2 score in patients with heart failure and atrial fibrillation Insights from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) Reviewed

    Sanae Hamaguchi, Shintaro Kinugawa, Shouji Matsushima, Arata Fukushima, Takashi Yokota, Mamoru Sakakibara, Hisashi Yokoshiki, Miyuki Tsuchihashi-Makaya, Hiroyuki Tsutsui

    International Journal of Cardiology   176 ( 1 )   239 - 242   2014.9

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    DOI: 10.1016/j.ijcard.2014.06.068

  • (Pro)renin receptor in skeletal muscle is involved in the development of insulin resistance associated with postinfarct heart failure in mice Reviewed

    Arata Fukushima, Shintaro Kinugawa, Shingo Takada, Shouji Matsushima, Mochamad Ali Sobirin, Taisuke Ono, Masashige Takahashi, Tadashi Suga, Tsuneaki Homma, Yoshihiro Masaki, Takaaki Furihata, Tomoyasu Kadoguchi, Takashi Yokota, Koichi Okita, Hiroyuki Tsutsui

    American Journal of Physiology - Endocrinology and Metabolism   307 ( 6 )   E503 - E514   2014.9

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    We previously reported that insulin resistance was induced by the impairment of insulin signaling in the skeletal muscle from heart failure (HF) via NAD(P)H oxidase-dependent oxidative stress. (Pro)renin receptor [(P)RR] is involved in the activation of local renin-angiotensin system and subsequent oxidative stress. We thus examined whether (P)RR inhibitor, handle region peptide (HRP), could ameliorate insulin resistance in HF after myocardial infarction (MI) by improving oxidative stress and insulin signaling in the skeletal muscle. C57BL6J mice were divided into four groups: sham operated (Sham, n = 10), Sham treated with HRP (Sham+HRP, 0.1 mg·kg-1·day-1, n = 10), MI operated (MI, n = 10), and MI treated with HRP (MI+HRP, 0.1 mg/kg/day, n = 10). After 4 wk, MI mice showed left ventricular dysfunction, which was not affected by HRP. (P)RR was upregulated in the skeletal muscle after MI (149% of sham, P < 0.05). The decrease in plasma glucose after insulin load was smaller in MI than in Sham (21 ± 2 vs. 44 ± 3%, P < 0.05), and was greater in MI+HRP (38 ± 2%, P < 0.05) than in MI. Insulin-stimulated serine phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle from MI by 48 and 49% of Sham, both of which were ameliorated in MI+HRP. Superoxide production and NAD(P)H oxidase activities were increased in MI, which was inhibited in MI+HRP. HRP ameliorated insulin resistance associated with HF by improving insulin signaling via the inhibition of NAD(P)H oxidase-induced superoxide production in the skeletal muscle. The (P)RR pathway is involved in the development of insulin resistance, at least in part, via the impairment of insulin signaling in the skeletal muscle from HF.

    DOI: 10.1152/ajpendo.00449.2013

  • Physiological and pathological functions of NADPH oxidases during myocardial ischemia-reperfusion Reviewed

    Shouji Matsushima, Hiroyuki Tsutsui, Junichi Sadoshima

    Trends in Cardiovascular Medicine   24 ( 5 )   202 - 205   2014.7

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    Oxidative stress, the presence of reactive oxygen species (ROS) in excess of the antioxidant capacity in the heart induces myocardial damage, accumulation of which leads to ischemic heart disease and heart failure. NADPH oxidase (Nox) 2 and 4 are the major sources of O2- and H2O2 in the heart and play a crucial role in the regulation of growth and death in cardiomyocytes. Both Nox2 and Nox4 are upregulated in response to ischemia-reperfusion (I/R), thereby contributing to ROS production and consequent myocardial injury. Suppression of either one of them can reduce ROS and I/R injury in the heart. Importantly, however, a minimum level of ROS production by either Nox2 or Nox4 is essential for the activation of HIF-1α and inhibition of PPARα during I/R, such that combined suppression of both Nox2 and Nox4 exacerbates myocardial I/R injury. Thus, either excessive activation or suppression of Noxs below physiological levels can induce cardiac injury. Here we discuss both detrimental and salutary functions of Nox isoforms during myocardial I/R.

    DOI: 10.1016/j.tcm.2014.03.003

  • Hyponatremia is an independent predictor of adverse clinical outcomes in hospitalized patients due to worsening heart failure Reviewed

    Sanae Hamaguchi, Shintaro Kinugawa, Miyuki Tsuchihashi-Makaya, Shouji Matsushima, Mamoru Sakakibara, Naoki Ishimori, Daisuke Goto, Hiroyuki Tsutsui

    Journal of Cardiology   63 ( 3 )   182 - 188   2014.3

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    Background and purpose: Hyponatremia is common and is associated with poor in-hospital outcomes in patients hospitalized with heart failure (HF). However, it is unknown whether hyponatremia is associated with long-term adverse outcomes. The purpose of this study was to clarify the characteristics, clinical status on admission, and management during hospitalization according to the serum sodium concentration on admission, and determine whether hyponatremia was associated with in-hospital as well as long-term outcomes in 1677 patients hospitalized with worsening HF on index hospitalization registered in the database of the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). Methods and subjects: We studied the characteristics and in-hospital treatment in 1659 patients hospitalized with worsening HF by using the JCARE-CARD database. Patients were divided into 2 groups according to serum sodium concentration on admission <135. mEq/mL (n= 176; 10.6%) or ≥135. mEq/mL (n= 1483; 89.4%). Results: The mean age was 70.7 years and 59.2% were male. Etiology was ischemic in 33.9% and mean left ventricular ejection fraction was 42.4%. After adjustment for covariates, hyponatremia was independently associated with in-hospital death [adjusted odds ratio (OR) 2.453, 95% confidence interval (CI) 1.265-4.755, p= 0.008]. It was significantly associated also with adverse long-term (mean 2.1. ±. 0.8 years) outcomes including all-cause death (OR 1.952, 95% CI 1.433-2.657), cardiac death (OR 2.053, 95% CI 1.413-2.983), and rehospitalization due to worsening HF (OR 1.488, 95% CI 1.134-1.953). Conclusions: Hyponatremia was independently associated with not only in-hospital but also long-term adverse outcomes in patients hospitalized with worsening HF.

    DOI: 10.1016/j.jjcc.2013.07.012

  • Elimination of NADPH oxidase activity promotes reductive stress and sensitizes the heart to ischemic injury. Reviewed

    Qiujun Yu, Chi Fung Lee, Wang Wang, Georgios Karamanlidis, Junya Kuroda, Shouji Matsushima, Junichi Sadoshima, Rong Tian

    Journal of the American Heart Association   3 ( 1 )   e000555   2014

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    The NADPH oxidase family (Nox) produces reactive oxygen species by adding the electron donated by NADPH to oxygen. Excessive reactive oxygen species production under a variety of pathological conditions has been attributed to increased Nox activity. Here, we aimed at investigating the role of Nox in cardiac ischemic injury through gain- and loss-of-function approaches. We modulated Nox activity in the heart by cardiac-specific expression of Nox4 and dominant negative Nox4. Modulation of Nox activity drastically changes the cellular redox status. Increasing Nox activity by cardiac-specific overexpression of Nox4 imposed oxidative stress on the myocardium [increased NAD(P)(+)/NAD(P)H and decreased glutathione/glutathione disulfide ratio] and worsened cardiac energetics and contractile function after ischemia-reperfusion. Overexpression of the dominant negative Nox4 (DN), which abolished the Nox function, led to a markedly reduced state [decreased NAD(P)(+)/NAD(P)H and increased glutathione/glutathione disulfide ratio] at baseline and paradoxically promoted mitochondrial reactive oxygen species production during ischemia resulting in no recovery of heart function after reperfusion. Limiting the generation of reducing equivalent through modulating carbon substrates availability partially restored the NAD(+)/NADH ratio and protected dominant negative Nox4 hearts from ischemic injury. This study reveals an important role of Nox in cardiac redox regulation and highlights the complexity of developing therapies that affect the intricately connected redox states.

    DOI: 10.1161/JAHA.113.000555

  • Increased plasma soluble (pro)renin receptor levels are correlated with renal dysfunction in patients with heart failure Reviewed

    Arata Fukushima, Shintaro Kinugawa, Tsuneaki Homma, Yoshihiro Masaki, Takaaki Furihata, Takahiro Abe, Tadashi Suga, Shingo Takada, Tomoyasu Kadoguchi, Koichi Okita, Shouji Matsushima, Hiroyuki Tsutsui

    International Journal of Cardiology   168 ( 4 )   4313 - 4314   2013.10

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    DOI: 10.1016/j.ijcard.2013.04.176

  • Decreased serum brain-derived neurotrophic factor levels are correlated with exercise intolerance in patients with heart failure Reviewed

    Arata Fukushima, Shintaro Kinugawa, Tsuneaki Homma, Yoshihiro Masaki, Takaaki Furihata, Takashi Yokota, Shouji Matsushima, Takahiro Abe, Tadashi Suga, Shingo Takada, Tomoyasu Kadoguchi, Ryoichi Katsuyama, Koji Oba, Koichi Okita, Hiroyuki Tsutsui

    International Journal of Cardiology   168 ( 5 )   e142 - e144   2013.10

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    DOI: 10.1016/j.ijcard.2013.08.073

  • Whole body assessment by 18 F-FDG PET in a patient with infective endocarditis Reviewed

    Atsuro Masuda, Osamu Manabe, Masanao Naya, Noriko Oyama-Manabe, Shiro Yamada, Shouji Matsushima, Florian Gaertner, Satoshi Yamada, Hiroyuki Tsutsui, Nagara Tamaki

    Journal of Nuclear Cardiology   20 ( 4 )   641 - 643   2013.8

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    DOI: 10.1007/s12350-013-9722-2

  • Broad suppression of NADPH oxidase activity exacerbates ischemia/reperfusion injury through inadvertent downregulation of hypoxia-inducible factor-1α and upregulation of peroxisome proliferator-activated receptor-α Reviewed

    Shouji Matsushima, Junya Kuroda, Tetsuro Ago, Peiyong Zhai, Yoshiyuki Ikeda, Shinichi Oka, Guo Hua Fong, Rong Tian, Junichi Sadoshima

    Circulation research   112 ( 8 )   1135 - 1149   2013.4

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    RATIONALE: NADPH oxidase (Nox) 2 and Nox4 are major components of the Nox family which purposefully produce reactive oxidative species, namely O 2- and H2O2, in the heart. The isoform-specific contribution of Nox2 and Nox4 to ischemia/reperfusion (I/R) injury is poorly understood. OBJECTIVE: We investigated the role of Nox2 and Nox4 in mediating oxidative stress and myocardial injury during I/R using loss-of-function mouse models. METHODS AND RESULTS: Systemic (s) Nox2 knockout (KO), sNox4 KO, and cardiac-specific (c) Nox4 KO mice were subjected to I/R (30 minutes/24 hours, respectively). Both myocardial infarct size/area at risk and O2- production were lower in sNox2 KO, sNox4 KO, and cNox4 KO than in wild-type mice. Unexpectedly, however, the myocardial infarct size/area at risk was greater, despite less O2- production, in sNox2 KO+cNox4 KO (double-KO) mice and transgenic mice (Tg) with cardiac-specific expression of dominant-negative Nox, which suppresses both Nox2 and Nox4, than in wild-type or single KO mice. Hypoxia-inducible factor-1α was downregulated whereas peroxisome proliferator-activated receptor-α was upregulated in Tg-dominant-negative Nox mice. A cross with mice deficient in prolyl hydroxylase 2, which hydroxylates hypoxia-inducible factor-1α, rescued the I/R injury and prevented upregulation of peroxisome proliferator-activated receptor-α in Tg-dominant-negative Nox mice. A cross with peroxisome proliferator-activated receptor-α KO mice also attenuated the injury in Tg- dominant-negative Nox mice. CONCLUSIONS: Both Nox2 and Nox4 contribute to the increase in reactive oxidative species and injury by I/R. However, low levels of reactive oxidative species produced by either Nox2 or Nox4 regulate hypoxia-inducible factor-1α and peroxisome proliferator-activated receptor-α, thereby protecting the heart against I/R, suggesting that Noxs also act as a physiological sensor for myocardial adaptation.

    DOI: 10.1161/CIRCRESAHA.111.300171

  • Interacting with thioredoxin-1-disease or no disease? Reviewed

    Tim Christian Zschauer, Shouji Matsushima, Joachim Altschmied, Dan Shao, Junichi Sadoshima, Judith Haendeler

    Antioxidants and Redox Signaling   18 ( 9 )   1053 - 1062   2013.3

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    Significance: Many cardiovascular disorders are accompanied by a deregulated cellular redox balance resulting in elevated levels of intracellular reactive oxygen species (ROS). One major antioxidative cellular molecule is thioredoxin-1 (Trx-1). Its indispensability is demonstrated by the embryonic lethality of Trx-1 deficient mice. Trx-1 is ubiquitously expressed in cells and has numerous, diverse functions. It not only reduces oxidized proteins or, together with peroxiredoxins, detoxifies H2O2, but also binds to several proteins and thereby regulates their functions. The interaction partners of Trx-1 differ depending on its localization in the cytosol or in the nucleus. Recent Advances/Critical Issues: Over the past decade it has become clear that Trx-1 is not only critical for tumor functions, which has resulted in therapeutic approaches targeting this protein, but also essential for proper functions of the vasculature and the heart. Changes in post-translational modifications of Trx-1 or in its interactions with other proteins can lead to a switch from a physiologic state of cells and organs to diverse pathologies. This review provides insights into the role of Trx-1 in different physiological situations and cardiac hypertrophy, ischemia reperfusion injury, heart failure, atherosclerosis, and diabetes mellitus type 2, underscoring the central role of Trx-1 in cardiovascular health and disease. Future Directions: Thus, the manipulation of Trx-1 activity in the heart and/or vasculature, for example, by small molecules, seems to be a promising therapeutic option in cardiovascular diseases, as general anti-oxidant treatments would not take into account interactions of Trx-1 with other proteins and also eliminate vital ROS.

    DOI: 10.1089/ars.2012.4822

  • Increased oxidative stress in the nucleus caused by Nox4 mediates oxidation of HDAC4 and cardiac hypertrophy Reviewed

    Shouji Matsushima, Junya Kuroda, Tetsuro Ago, Peiyong Zhai, Ji Yeon Park, Lai Hua Xie, Bin Tian, Junichi Sadoshima

    Circulation research   112 ( 4 )   651 - 663   2013.2

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    Rationale: Oxidation of cysteine residues in class II histone deacetylases (HDACs), including HDAC4, causes nuclear exit, thereby inducing cardiac hypertrophy. The cellular source of reactive oxygen species responsible for oxidation of HDAC4 remains unknown. Objective: We investigated whether nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4), a major nicotinamide adenine dinucleotide phosphate oxidase, mediates cysteine oxidation of HDAC4. Methods and Results: Phenylephrine (100 μmol/L), an α1 adrenergic agonist, induced upregulation of Nox4 (1.5-fold; P<0.05) within 5 minutes, accompanied by increases in O2 (3.5-fold; P<0.01) from the nuclear membrane and nuclear exit of HDAC4 in cardiomyocytes. Knockdown of Nox4, but not Nox2, attenuated O2 production in the nucleus and prevented phenylephrine-induced oxidation and nuclear exit of HDAC4. After continuous infusion of phenylephrine (20 mg/kg per day) for 14 days, wild-type and cardiac-specific Nox4 knockout mice exhibited similar aortic pressures. Left ventricular weight/tibial length (5.7±0.2 versus 6.4±0.2 mg/mm; P<0.05) and cardiomyocytes cross-sectional area (223±13 versus 258±12 μm; P<0.05) were significantly smaller in cardiac-specific Nox4 knockout than in wild-type mice. Nuclear O2production in the heart was significantly lower in cardiac-specific Nox4 knockout than in wild-type mice (4116±314 versus 7057±1710 relative light unit; P<0.05), and cysteine oxidation of HDAC4 was decreased. HDAC4 oxidation and cardiac hypertrophy were also attenuated in cardiac-specific Nox4 knockout mice 2 weeks after transverse aortic constriction. Conclusions: Nox4 plays an essential role in mediating cysteine oxidation and nuclear exit of HDAC4, thereby mediating cardiac hypertrophy in response to phenylephrine and pressure overload.

    DOI: 10.1161/CIRCRESAHA.112.279760

  • Oxidative stress and heart failure Reviewed

    Hiroyuki Tsutsui, Shintaro Kinugawa, Shouji Matsushima

    American Journal of Physiology - Heart and Circulatory Physiology   301 ( 6 )   2181 - 2190   2011.12

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    Oxidative stress, defined as an excess production of reactive oxygen species (ROS) relative to antioxidant defense, has been shown to play an important role in the pathophysiology of cardiac remodeling and heart failure (HF). It induces subtle changes in intracellular pathways, redox signaling, at lower levels, but causes cellular dysfunction and damage at higher levels. ROS are derived from several intracellular sources, including mitochondria, NAD(P)H oxidase, xanthine oxidase, and uncoupled nitric oxide synthase. The production of ROS is increased within the mitochondria from failing hearts, whereas normal antioxidant enzyme activities are preserved. Chronic increases in ROS production in the mitochondria lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage as well as functional decline, further ROS generation, and cellular injury. ROS directly impair contractile function by modifying proteins central to excitation-contraction coupling. Moreover, ROS activate a broad variety of hypertrophy signaling kinases and transcription factors and mediate apoptosis. They also stimulate cardiac fibroblast proliferation and activate the matrix metalloproteinases, leading to the extracellular matrix remodeling. These cellular events are involved in the development and progression of maladaptive myocardial remodeling and failure. Oxidative stress is also involved in the skeletal muscle dysfunction, which may be associated with exercise intolerance and insulin resistance in HF. Therefore, oxidative stress is involved in the pathophysiology of HF in the heart as well as in the skeletal muscle. A better understanding of these mechanisms may enable the development of novel and effective therapeutic strategies against HF.

    DOI: 10.1152/ajpheart.00554.2011

  • Application of recombinant thioredoxin1 for treatment of heart disease Reviewed

    Shouji Matsushima, Daniela Zablocki, Junichi Sadoshima

    Journal of Molecular and Cellular Cardiology   51 ( 4 )   570 - 573   2011.10

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    Thioredoxin 1 (Trx1) is a small molecule with reactive cysteines that reduces proteins with disulfide bonds through a thiol disulfide exchange reaction. Accumulating lines of evidence suggest that Trx1 protects the heart from ischemia/reperfusion injury, pathological hypertrophy, and inflammation; induces preconditioning effects and angiogenesis; and upregulates mitochondrial genes. Exogenously given recombinant Trx1 (r-Trx1) may protect the heart through its actions in both extracellular and intracellular spaces. In this brief review, the potential of Trx1 therapy for heart disease is discussed. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure.".

    DOI: 10.1016/j.yjmcc.2010.09.020

  • Oxidative stress impairs insulin signal in skeletal muscle and causes insulin resistance in postinfarct heart failure Reviewed

    Yukihiro Ohta, Shintaro Kinugawa, Shouji Matsushima, Taisuke Ono, Mochamad A. Sobirin, Naoki Inoue, Takashi Yokota, Kagami Hirabayashi, Hiroyuki Tsutsui

    American Journal of Physiology - Heart and Circulatory Physiology   300 ( 5 )   H1637 - H1644   2011.5

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    Insulin resistance has been shown to occur as a consequence of heart failure. However, its exact mechanisms in this setting remain unknown. We have previously reported that oxidative stress is enhanced in the skeletal muscle from mice with heart failure after myocardial infarction (MI) (30). This study is aimed to investigate whether insulin resistance in postinfarct heart failure is due to the impairment of insulin signaling in the skeletal muscle caused by oxidative stress. Mice were divided into four groups: sham operated (sham); sham treated with apocynin, an inhibitor of NAD(P)H oxidase activation (10 mmol/l in drinking water); MI; and MI treated with apocynin. After 4 wk, intraperitoneal insulin tolerance tests were performed, and skeletal muscle samples were obtained for insulin signaling measurements. MI mice showed left ventricular dilation and dysfunction by echocardiography and increased left ventricular end-diastolic pressure and lung weight. The decrease in glucose level after insulin load significantly attenuated in MI compared with sham. Insulin-stimulated serine phosphorylation of Akt and glucose transporter-4 translocation were decreased in MI mice by 61 and 23%, respectively. Apocynin ameliorated the increase in oxidative stress and NAD(P)H oxidase activities measured by the lucigenin assay in the skeletal muscle after MI. It also improved insulin resistance and inhibited the decrease of Akt phosphorylation and glucose transporter-4 translocation. Insulin resistance was induced by the direct impairment of insulin signaling in the skeletal muscle from postinfarct heart failure, which was associated with the enhanced oxidative stress via NAD(P)H oxidase.

    DOI: 10.1152/ajpheart.01185.2009

  • Successful termination of recurrent ventricular arrhythmias by adaptive servo-ventilation in a patient with heart failure Reviewed

    Shiro Yamada, Mamoru Sakakibara, Shouji Matsushima, Akimichi Saito, Tsuneaki Homma, Arata Fukushima, Yoshihiro Masaki, Masaya Watanabe, Hirofumi Mitsuyama, Hisashi Yokoshiki, Hiroyuki Tsutsui

    Journal of Cardiology Cases   3 ( 2 )   e57 - e61   2011.4

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    A 60-year-old woman who underwent operation due to severe aortic stenosis with left ventricular dysfunction had frequent nonsustained ventricular tachycardia (NSVT) at night. She had an increased apnea-hypopnea index and a reduction in minimum O2 saturation during sleep, which was closely associated with the frequency of NSVT. Adaptive servo-ventilation (ASV) therapy improved sleep disorder breathing (SDB) and also reduced ventricular arrhythmias. These effects were associated with the attenuation of the sympathetic nerve activities by the analysis of heart rate variability. ASV is expected to be effective in the treatment of ventricular tachyarrhythmias in patients with heart failure and SDB.

    DOI: 10.1016/j.jccase.2011.01.001

  • Regulation of myocardial growth and death by NADPH oxidase Reviewed

    Yasuhiro Maejima, Junya Kuroda, Shouji Matsushima, Tetsuro Ago, Junichi Sadoshima

    Journal of Molecular and Cellular Cardiology   50 ( 3 )   408 - 416   2011.3

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    The NADPH oxidases (Nox) are transmembrane proteins dedicated to producing reactive oxygen species (ROS), including superoxide and hydrogen peroxide, by transferring electrons from NAD(P)H to molecular oxygen. Nox2 and Nox4 are expressed in the heart and play an important role in mediating oxidative stress at baseline and under stress. Nox2 is primarily localized on the plasma membrane, whereas Nox4 is found primarily on intracellular membranes, on mitochondria, the endoplasmic reticulum or the nucleus. Although Nox2 plays an important role in mediating angiotensin II-induced cardiac hypertrophy, Nox4 mediates cardiac hypertrophy and heart failure in response to pressure overload. Expression of Nox4 is upregulated by hypertrophic stimuli, and Nox4 in mitochondria plays an essential role in mediating oxidative stress during pressure overload-induced cardiac hypertrophy. Upregulation of Nox4 induces oxidation of mitochondrial proteins, including aconitase, thereby causing mitochondrial dysfunction and myocardial cell death. On the other hand, Noxs also appear to mediate physiological functions, such as erythropoiesis and angiogenesis. In this review, we discuss the role of Noxs in mediating oxidative stress and both pathological and physiological functions of Noxs in the heart.

    DOI: 10.1016/j.yjmcc.2010.12.018

  • Oxidative stress in cardiac and skeletal muscle dysfunction associated with diabetes mellitus Reviewed

    Hiroyuki Tsutsui, Shintaro Kinugawa, Shouji Matsushima, Takashi Yokota

    Journal of Clinical Biochemistry and Nutrition   48 ( 1 )   68 - 71   2011.1

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    Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease. It also causes skeletal muscle dysfunction, which is responsible for reduced exercise capacity commonly seen in heart failure. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac and skeletal muscle dysfunction in heart failure and diabetes mellitus. Based on the findings in animal models, this review discusses the role of oxidative stress that may be involved in the development and progression of cardiac and skeletal dysfunction associated with diabetes.

    DOI: 10.3164/jcbn.11-012FR

  • The NADPH oxidase Nox4 and aging in the heart Reviewed

    Tetsuro Ago, Shouji Matsushima, Junya Kuroda, Daniela Zablocki, Takanari Kitazono, Junichi Sadoshima

    Aging   2 ( 12 )   1012 - 1016   2010.12

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    Oxidative stress in mitochondria is believed to promote aging. Although passive leakage of electron from the m itochondrial electron transport chain has been considered as a major source of oxidative stress in the heart and the cardiomyocytes therein, enzymes actively producing reactive oxygen species may also exist in mitochondria. We have shown recently that Nox4, a member of the NADPH oxidase family, is localized on intracellular membranes, primarily at mitochondria, in cardiomyocytes. Mitochondrial expression of Nox4 is upregulated by cardiac stress and aging in the heart, where Nox4 could become a major source of oxidative stress. This raises an intriguing possibility that Nox4 may play an important role in mediating aging of the heart. Here we discuss the potential involvement of Nox4 in mitochondrial oxidative stress and aging in the heart.

    DOI: 10.18632/aging.100261

  • Silent information regulator 1 protects the heart from ischemia/reperfusion Reviewed

    Chiao Po Hsu, Peiyong Zhai, Takanobu Yamamoto, Yasuhiro Maejima, Shouji Matsushima, Nirmala Hariharan, Dan Shao, Hiromitsu Takagi, Shinichi Oka, Junichi Sadoshima

    Circulation   122 ( 21 )   2170 - 2182   2010.11

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    Background-: Silent information regulator 1 (Sirt1), a class III histone deacetylase, retards aging and protects the heart from oxidative stress. We here examined whether Sirt1 is protective against myocardial ischemia/reperfusion (I/R). Methods and results-: Protein and mRNA expression of Sirt1 is significantly reduced by I/R. Cardiac-specific Sirt1 mice exhibited a significant increase (44±5% versus 15±5%; P=0.01) in the size of myocardial infarction/area at risk. In transgenic mice with cardiac-specific overexpression of Sirt1, both myocardial infarction/area at risk (15±4% versus 36±8%; P=0.004) and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive nuclei (4±3% versus 10±1%; P<0.003) were significantly reduced compared with nontransgenic mice. In Langendorff-perfused hearts, the functional recovery during reperfusion was significantly greater in transgenic mice with cardiac-specific overexpression of Sirt1 than in nontransgenic mice. Sirt1 positively regulates expression of prosurvival molecules, including manganese superoxide dismutase, thioredoxin-1, and Bcl-xL, whereas it negatively regulates the proapoptotic molecules Bax and cleaved caspase-3. The level of oxidative stress after I/R, as evaluated by anti-8-hydroxydeoxyguanosine staining, was negatively regulated by Sirt1. Sirt1 stimulates the transcriptional activity of FoxO1, which in turn plays an essential role in mediating Sirt1-induced upregulation of manganese superoxide dismutase and suppression of oxidative stress in cardiac myocytes. Sirt1 plays an important role in mediating I/R-induced increases in the nuclear localization of FoxO1 in vivo. Conclusions-: These results suggest that Sirt1 protects the heart from I/R injury through upregulation of antioxidants and downregulation of proapoptotic molecules through activation of FoxO and decreases in oxidative stress.

    DOI: 10.1161/CIRCULATIONAHA.110.958033

  • Successful adaptive servo-ventilation for patients with acute cardiogenic pulmonary edema due to severe aortic stenosis Reviewed

    Mamoru Sakakibara, Shiro Yamada, Shouji Matsushima, Akimichi Saito, Yoshihiro Masaki, Tsuneaki Honma, Suguru Kubota, Yoshiro Matsui, Hiroyuki Tsutsui

    Journal of Cardiology Cases   2 ( 2 )   e115 - e118   2010.10

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    A 60-year-old woman with severe aortic stenosis (AS) and congenital bicuspid aortic valve was admitted to our hospital due to cardiogenic pulmonary edema. Noninvasive adaptive servo-ventilation (ASV) improved her symptoms and respiratory status. It was associated with favorable hemodynamic effects including an increase in cardiac output and a decrease in pulmonary vascular resistance without alternating systemic blood pressure. An improvement in oxygenation and the favorable hemodynamic effects might lead to the stabilization of clinical status. Noninvasive ventilation with ASV can avert tracheal intubation by improving oxygenation and is expected to be convenient and useful in the treatment of acute pulmonary edema.

    DOI: 10.1016/j.jccase.2010.05.003

  • NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart Reviewed

    Junya Kuroda, Tetsuro Ago, Shouji Matsushima, Peiyong Zhai, Michael D. Schneider, Junichi Sadoshima

    Proceedings of the National Academy of Sciences of the United States of America   107 ( 35 )   15565 - 15570   2010.8

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    NAD(P)H oxidases (Noxs) produce O2- and play an important role in cardiovascular pathophysiology. The Nox4 isoform is expressed primarily in the mitochondria in cardiac myocytes. To elucidate the function of endogenous Nox4 in the heart, we generated cardiac-specific Nox4-/- (c-Nox4-/-) mice. Nox4 expression was inhibited in c-Nox4 -/- mice in a heart-specific manner, and there was no compensatory up-regulationin other Nox enzymes. These mice exhibited reducedlevels of O 2- in the heart, indicating that Nox4 is a significant source of O2- in cardiac myocytes. The baseline cardiac phenotype was normal in young c-Nox4-/- mice. In response to pressure overload (PO), however, increases in Nox4 expression and O2 - production in mitochondria were abolished in c-Nox4-/- mice, and c-Nox4-/- mice exhibited significantly attenuated cardiac hypertrophy, interstitial fibrosis and apoptosis, and better cardiac function compared with WT mice. Mitochondrial swelling, cytochrome c release, and decreases in both mitochondrial DNA and aconitase activity in response to PO were attenuated in c-Nox4-/- mice. On the other hand, overexpression of Nox4 in mouse hearts exacerbated cardiac dysfunction, fibrosis, and apoptosis in response to PO. These results suggest that Nox4 in cardiac myocytes is a major source of mitochondrial oxidative stress, thereby mediating mitochondrial and cardiac dysfunction during PO.

    DOI: 10.1073/pnas.1002178107

  • Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice Reviewed

    Takashi Yokota, Shintaro Kinugawa, Kagami Hirabayashi, Shouji Matsushima, Naoki Inoue, Yukihiro Ohta, Sanae Hamaguchi, Mochamad A. Sobirin, Taisuke Ono, Tadashi Suga, Satoshi Kuroda, Shinya Tanaka, Fumio Terasaki, Koichi Okita, Hiroyuki Tsutsui

    American Journal of Physiology - Heart and Circulatory Physiology   297 ( 3 )   H1069 - H1077   2009.9

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    Insulin resistance or diabetes is associated with limited exercise capacity, which can be caused by the abnormal energy metabolism in skeletal muscle. Oxidative stress is involved in mitochondrial dysfunction in diabetes. We hypothesized that increased oxidative stress could cause mitochondrial dysfunction in skeletal muscle and make contribution to exercise intolerance in diabetes. C57/BL6J mice were fed on normal diet or high fat diet (HFD) for 8 wk to induce obesity with insulin resistance and diabetes. Treadmill tests with expired gas analysis were performed to determine the exercise capacity and whole body oxygen uptake (V̇O 2). The work (vertical distance X body weight) to exhaustion was reduced in the HFD mice by 36%, accompanied by a 16% decrease of peak V̇O 2. Mitochondrial ADP-stimulated respiration, electron transport chain complex I and III activities, and mitochondrial content in skeletal muscle were decreased in the HFD mice. Furthermore, superoxide production and NAD(P)H oxidase activity in skeletal muscle were significantly increased in the HFD mice. Intriguingly, the treatment of HFD-fed mice with apocynin [10 mmol/l; an inhibitor of NAD(P)H oxidase activation] improved exercise intolerance and mitochondrial dysfunction in skeletal muscle without affecting glucose metabolism itself. The exercise capacity and mitochondrial function in skeletal muscle were impaired in type 2 diabetes, which might be due to enhanced oxidative stress. Therapies designed to regulate oxidative stress and maintain mitochondrial function could be beneficial to improve the exercise capacity in type 2 diabetes.

    DOI: 10.1152/ajpheart.00267.2009

  • Increased myocardial NAD(P)H oxidase-derived superoxide causes the exacerbation of postinfarct heart failure in type 2 diabetes Reviewed

    Shouji Matsushima, Shintaro Kinugawa, Takashi Yokota, Naoki Inoue, Yukihiro Ohta, Sanae Hamaguchi, Hiroyuki Tsutsui

    American Journal of Physiology - Heart and Circulatory Physiology   297 ( 1 )   H409 - H416   2009.7

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    Type 2 diabetes adversely affects the outcomes in patients with myocardial infarction (MI), which is associated with the development of left ventricular (LV) failure. NAD(P)H oxidase-derived superoxide (O2-) production is increased in type 2 diabetes. However, its pathophysiological significance in advanced post-MI LV failure associated with type 2 diabetes remains unestablished. We thus hypothesized that an inhibitor of NAD(P)H oxidase activation, apocynin, could attenuate the exacerbated LV failure after MI in high-fat diet (HFD)-induced obese mice with type 2 diabetes. Male C57BL/6J mice were fed on either HFD or normal diet (ND) for 8 wk. At 4 wk of feeding, MI was created in mice by ligating the left coronary artery. HFD-fed MI mice were treated with either 10 mmol/l apocynin or vehicle. HFD + MI had significantly greater LV end-diastolic diameter (LVEDD; 5.7 ± 0.1 vs. 5.3 ± 0.2 mm), end-diastolic pressure (12 ± 2 vs. 8 ± 1 mmHg), and lung weight/tibial length (10.1 ± 0.3 vs. 8.7 ± 0.7 mg/mm) than ND + MI, which was accompanied by an increased interstitial fibrosis of non-infarcted LV. Treatment of HFD + MI with apocynin significantly decreased LVEDD (5.4 ± 0.1 mm), LV end-diastolic pressure (9.7 ± 0.8 mmHg), lung weight/tibial length (9.0 ± 0.3 mg/mm), and concomitantly interstitial fibrosis of noninfarcted LV to the ND + MI level without affecting body weight, glucose metabolism, and infarct size. NAD(P)H oxidase activity and O 2- production were increased in noninfarcted LV tissues from HFD + MI, both of which were attenuated by apocynin to the ND + MI level. Type 2 diabetes was associated with the exacerbation of LV failure after MI via increasing NAD(P)H oxidase-derived O2-, which may be a novel important therapeutic target in advanced heart failure with diabetes.

    DOI: 10.1152/ajpheart.01332.2008

  • Left main coronary artery atresia diagnosed by multidetector computed tomography Reviewed

    Takahiko Saito, Masatoshi Motohashi, Shouji Matsushima, Naotaka Saito, Takehiro Kubota, Kimitaka Tasai, Hiroshi Asajima

    International Journal of Cardiology   135 ( 1 )   e27 - e29   2009.6

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    Left main coronary artery atresia is an extremely rare disease. Differential diagnosis of left main coronary artery atresia from atherosclerotic occlusion of left main coronary artery is difficult even if performing invasive coronary angiography. We present a case of a 48-year-old male with left main coronary artery atresia. Echocardiography showed left ventricular dysfunction. Invasive coronary angiography showed absence of left main coronary artery. A multidetector computed tomography showed a string-like structure at the site of left main coronary artery. A diagnosis of left main coronary artery atresia was made, and he underwent coronary artery bypass grafting. At the operation, a thin and not-sclerotic left main coronary artery was observed. Echocardiography, performed after the surgery, showed normalization of the left ventricular systolic function. Multidetector computed tomography might be a useful method to diagnose left main coronary artery atresia.

    DOI: 10.1016/j.ijcard.2008.03.068

  • Mitochondrial oxidative stress and dysfunction in myocardial remodelling Reviewed

    Hiroyuki Tsutsui, Shintaro Kinugawa, Shouji Matsushima

    Cardiovascular research   81 ( 3 )   449 - 456   2009.2

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    Recent experimental and clinical studies have suggested that oxidative stress is enhanced in myocardial remodelling and failure. The production of oxygen radicals is increased in the failing heart, whereas normal antioxidant enzyme activities are preserved. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and can be a therapeutic target against oxidant-induced damage in the failing myocardium. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage as well as functional decline, further oxygen radical generation, and cellular injury. Reactive oxygen species induce myocyte hypertrophy, apoptosis, and interstitial fibrosis by activating matrix metalloproteinases. These cellular events play an important role in the development and progression of maladaptive myocardial remodelling and failure. Therefore, oxidative stress and mtDNA damage are good therapeutic targets. Overexpression of the genes for peroxiredoxin-3 (Prx-3), a mitochondrial antioxidant, or mitochondrial transcription factor A (TFAM), could ameliorate the decline in mtDNA copy number in failing hearts. Consistent with alterations in mtDNA, the decrease in mitochondrial function was also prevented. Therefore, the activation of Prx-3 or TFAM gene expression could ameliorate the pathophysiological processes seen in mitochondrial dysfunction and myocardial remodelling. Inhibition of oxidative stress and mtDNA damage could be novel and effective treatment strategies for heart failure.

    DOI: 10.1093/cvr/cvn280

  • QT prolongation and torsade de pointes associated with solifenacin in an 81-year-old woman Reviewed

    Hiroshi Asajima, Yohei Sekiguchi, Shoji Matsushima, Naotaka Saito, Takahiko Saito

    British journal of clinical pharmacology   66 ( 6 )   896 - 897   2008.12

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    DOI: 10.1111/j.1365-2125.2008.03298.x

  • Oxidative stress and mitochondrial DNA damage in heart failure Reviewed

    Hiroyuki Tsutsui, Shintaro Kinugawa, Shouji Matsushima

    Circulation Journal   72 ( SUPPL. A )   A31 - A37   2008

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    Recent experimental and clinical studies have suggested that oxidative stress is enhanced in heart failure. The production of oxygen radicals is increased in the failing heart while antioxidant enzyme activities are preserved. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and also a target against oxidant-induced damage in the failing myocardium. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage, as well as functional decline, further oxygen radical generation, and cellular injury. Reactive oxygen species induce myocyte hypertrophy, apoptosis, and interstitial fibrosis by activating matrix metalloproteinases. These cellular events play an important role in the development and progression of maladaptive cardiac remodeling and failure. Therefore, oxidative stress and mtDNA damage are good therapeutic targets. Overexpression of peroxiredoxin-3 (Prx-3), mitochon-drial antioxidant, or mitochondrial transcription factor A (TFAM) could ameliorate the decline in mtDNA copy number in failing hearts. Consistent with alterations in mtDNA, the decrease in oxidative capacities is also prevented. Therefore, the activation of Prx-3 or TFAM expression could ameliorate the pathophysiological processes seen in myocardial failure. Inhibition of oxidative stress and mtDNA damage could be novel and potentially effective treatment strategies for heart failure.

    DOI: 10.1253/circj.CJ-08-0014

  • Angiotensin II type 1 receptor blocker attenuates myocardial remodelling and preserves diastolic function in diabetic heart Reviewed

    Hiroyuki Tsutsui, Shouji Matsushima, Shintaro Kinugawa, Tomomi Ide, Naoki Inoue, Yukihiro Ohta, Takashi Yokota, Sanae Hamaguchi, Kenji Sunagawa

    Hypertension Research   30 ( 5 )   439 - 449   2007.5

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    Blockade of the renin-angiotensin system reduces cardiovascular morbidity and mortality in diabetic patients. Angiotensin II (Ang II) plays an important role in the structural and functional abnormalities of the diabetic heart. We investigated whether or not Ang II type 1 receptor blocker (ARB) could attenuate left ventricular (LV) remodeling in male mice with diabetes mellitus (DM) induced by the injection of streptozotocin (200 mg/kg, i.p.). Diabetic mice were treated with candesartan (1 mg/kg/day; DM+Candesartan, n=7) or vehicle (DM+Vehicle, n=7) for 8 weeks. Heart rate and aortic blood pressure were comparable between the groups. Normal systolic function was preserved in diabetic mice. In contrast diastolic function was impaired in DM+Vehicle and was improved in DM+Candesartan, as assessed by the deceleration time of the peak velocity of transmitral diastolic flow (40.3±0.3 vs. 37.3±0.5 ms, p<0.01) and the time needed for relaxation of 50% maximal LV pressure to baseline value (τ; 10.6±0.7 vs. 8.7±0.6 ms, p<0.05) without significant changes in heart rate and aortic blood pressure. Improvement of LV diastolic function was accompanied by the attenuation of myocyte hypertrophy, interstitial fibrosis and apoptosis in association with the expression of connective tissue growth factor (CTGF) and myocardial oxidative stress. Moreover, candesartan directly inhibited Ang II-mediated Induction of CTGF in cultured cardiac fibroblasts. ARB might be beneficial to prevent cardiac abnormalities in DM.

    DOI: 10.1291/hypres.30.439

  • Angiotensin II type 1 receptor blocker attenuates exacerbated left ventricular remodeling and failure in diabetes-associated myocardial infarction Reviewed

    Hidenori Matsusaka, Shintaro Kinugawa, Tomomi Ide, Shouji Matsushima, Tetsuya Shiomi, Toru Kubota, Kenji Sunagawa, Hiroyuki Tsutsui

    Journal of Cardiovascular Pharmacology   48 ( 3 )   95 - 102   2006.9

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    Diabetes mellitus adversely affects the outcomes in patients with myocardial infarction (MI), due in part to the exacerbation of left ventricular (LV) remodeling. Although angiotensin II type 1 receptor blocker (ARB) has been demonstrated to be effective in the treatment of heart failure, information about the potential benefits of ARB on advanced LV failure associated with diabetes is lacking. To induce diabetes, male mice were injected intraperitoneally with streptozotocin (200 mg/kg). At 2 weeks, anterior MI was created by ligating the left coronary artery. These animals received treatment with olmesartan (0.1 mg/kg/day; n = 50) or vehicle (n = 51) for 4 weeks. Diabetes worsened the survival and exaggerated echocardiographic LV dilatation and dysfunction in MI. Treatment of diabetic MI mice with olmesartan significantly improved the survival rate (42% versus 27%, P < 0.05) without affecting blood glucose, arterial blood pressure, or infarct size. It also attenuated LV dysfunction in diabetic MI. Likewise, olmesartan attenuated myocyte hypertrophy, interstitial fibrosis, and the number of apoptotic cells in the noninfarcted LV from diabetic MI. Post-MI LV remodeling and failure in diabetes were ameliorated by ARB, providing further evidence that angiotensin II plays a pivotal role in the exacerbated heart failure after diabetic MI.

    DOI: 10.1097/01.fjc.0000245405.41317.60

  • Targeted deletion of p53 prevents cardiac rupture after myocardial infarction in mice Reviewed

    Hidenori Matsusaka, Tomomi Ide, Shouji Matsushima, Masaki Ikeuchi, Toru Kubota, Kenji Sunagawa, Shintaro Kinugawa, Hiroyuki Tsutsui

    Cardiovascular research   70 ( 3 )   457 - 465   2006.6

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    Objective: Apoptosis may play an important role in cardiac remodeling after myocardial infarction (MI). p53 is a well-known proapoptotic factor. However, its pathophysiological significance in these conditions remains unclear. We thus examined the effects of target deletion of the p53 gene on post-MI hearts. Methods: Anterior MI was created in male heterozygous p53-deficient (p53+/-; n = 28) mice and sibling wild-type (p53+/+; n = 29) mice by ligating the left coronary artery. Results: By day 7, p53+/- mice had significantly better survival rate than p53+/+ mice (89% vs. 69%, P < 0.05). Notably, p53+/- mice had a significantly lower incidence of left ventricular (LV) rupture (7% vs. 28%, P < 0.05) despite comparable infarct size (60 ± 2% vs. 59 ± 2%, P = NS), heart rate (488 ± 15 vs. 489 ± 17 bpm, P = NS), or mean arterial blood pressure (80 ± 2 vs. 78 ± 3 mm Hg, P = NS). The extent of infiltrating interstitial cells including macrophages into the post-MI hearts was not altered by the deletion of p53. Further, collagen deposition as well as the zymographic MMP-2 and -9 activities were comparable between p53+/- and p53+/+ mice with MI. However, the p53+/- mice had a significantly thicker infarct wall. The number of TUNEL-positive cells in the infarct area was significantly lower in p53+/- mice than in p53+/+ mice (423 ± 86 vs. 1330 ± 275/105 cells, P < 0.01). Conclusions: p53 is involved in cardiac rupture after MI, probably via the induction of a proapoptotic pathway. The inhibition of p53 may be a potentially useful therapeutic strategy to manage post-MI patients.

    DOI: 10.1016/j.cardiores.2006.02.001

  • Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload Reviewed

    Hidenori Matsusaka, Tomomi Ide, Shouji Matsushima, Masaki Ikeuchi, Toru Kubota, Kenji Sunagawa, Shintaro Kinugawa, Hiroyuki Tsutsui

    Hypertension   47 ( 4 )   711 - 717   2006.4

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    Matrix metalloproteinases (MMPs) play an important role in the extracellular matrix remodeling. Experimental and clinical studies have demonstrated that MMP 2 and 9 are upregulated in the dilated failing hearts and involved in the development and progression of myocardial remodeling. However, little is known about the role of MMPs in mediating adverse myocardial remodeling in response to chronic pressure overload (PO). We, thus, hypothesized that selective disruption of the MMP 2 gene could ameliorate PO-induced cardiac hypertrophy and dysfunction in mice. PO hypertrophy was induced by transverse aortic constriction (TAC) in male MMP 2 knockout (KO) mice (n=10) and sibling wild-type (WT) mice (n=9). At 6 weeks, myocardial MMP 2 zymographic activity was 2.4-fold increased in WT+TAC, and this increase was not observed in KO+TAC, with no significant alterations in other MMPs (MMP 1, 3, 8, and 9) or tissue inhibitors of MMPs (1, 2, 3, and 4). TAC resulted in a significant increase in left ventricular (LV) weight and LV end-diastolic pressure (EDP) with preserved systolic function. KO+TAC mice exerted significantly lower LV weight/body weight (4.2±0.2 versus 5.0±0.2 mg/g; P<0.01), lung weight/body weight (4.9±0.2 versus 6.2±0.4 mg/g; P<0.01), and LV end-diastolic pressure (4±1 versus 10±2 mm Hg; P<0.05) than WT+TAC mice despite comparable aortic pressure. KO+TAC mice had less myocyte hypertrophy (cross-sectional area; 322±14 versus 392±14 μm2; P<0.01) and interstitial fibrosis (collagen volume fraction; 3.3±0.5 versus 8.2±1.0%; P<0.01) than WT+TAC mice. MMP 2 plays an important role in PO-induced LV hypertrophy and dysfunction. The inhibition of MMP 2 activation may, therefore, be a useful therapeutic strategy to manage hypertensive heart disease.

    DOI: 10.1161/01.HYP.0000208840.30778.00

  • Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice Reviewed

    Shouji Matsushima, Tomomi Ide, Mayumi Yamato, Hidenori Matsusaka, Fumiyuki Hattori, Masaki Ikeuchi, Toru Kubota, Kenji Sunagawa, Yasuhiro Hasegawa, Tatsuya Kurihara, Shinzo Oikawa, Shintaro Kinugawa, Hiroyuki Tsutsui

    Circulation   113 ( 14 )   1779 - 1786   2006.4

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    BACKGROUND - Mitochondrial oxidative stress and damage play major roles in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). We hypothesized that overexpression of the mitochondrial antioxidant, peroxiredoxin-3 (Prx-3), could attenuate this deleterious process. METHODS AND RESULTS - We created MI in 12- to 16-week-old, male Prx-3-transgenic mice (TG+MI, n=37) and nontransgenic wild-type mice (WT+MI, n=39) by ligating the left coronary artery. Prx-3 protein levels were 1.8 times higher in the hearts from TG than WT mice, with no significant changes in other antioxidant enzymes. At 4 weeks after MI, LV thiobarbituric acid-reactive substances in the mitochondria were significantly lower in TG+MI than in WT+MI mice (mean±SEM, 1.5±0.2 vs 2.2±0.2 nmol/mg protein; n=8 each, P<0.05). LV cavity dilatation and dysfunction were attenuated in TG+MI compared with WT+MI mice, with no significant differences in infarct size (56±1% vs 55±1%; n=6 each, P=NS) and aortic pressure between groups. Mean LV end-diastolic pressures and lung weights in TG+MI mice were also larger than those in WT+sham-operated mice but smaller than those in WT+MI mice. Improvement in LV function in TG+MI mice was accompanied by a decrease in myocyte hypertrophy, interstitial fibrosis, and apoptosis in the noninfarcted LV. Mitochondrial DNA copy number and complex enzyme activities were significantly decreased in WT+MI mice, and this decrease was also ameliorated in TG+MI mice. CONCLUSIONS - Overexpression of Prx-3 inhibited LV remodeling and failure after MI. Therapies designed to interfere with mitochondrial oxidative stress including the antioxidant Prx-3 might be beneficial in preventing cardiac failure.

    DOI: 10.1161/CIRCULATIONAHA.105.582239

  • Overexpression of glutathione peroxidase attenuates myocardial remodeling and preserves diastolic function in diabetic heart Reviewed

    Shouji Matsushima, Shintaro Kinugawa, Tomomi Ide, Hidenori Matsusaka, Naoki Inoue, Yukihiro Ohta, Takashi Yokota, Kenji Sunagawa, Hiroyuki Tsutsui

    American Journal of Physiology - Heart and Circulatory Physiology   291 ( 5 )   H2237 - H2245   2006

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    Oxidative stress plays an important role in the structural and functional abnormalities of diabetic heart. Glutathione peroxidase (GSHPx) is a critical antioxidant enzyme that removes H2O2 in both the cytosol and mitochondia. We hypothesized that the overexpression of GSHPx gene could attenuate left ventricular (LV) remodeling in diabetes mellitus (DM). We induced DM by injection of streptozotocin (160 mg/kg ip) in male GSHPx transgenic mice (TG+DM) and nontransgenic wildtype littermates (WT+DM). GSHPx activity was higher in the hearts of TG mice compared with WT mice, with no significant changes in other antioxidant enzymes. LV thiobarbituric acid-reactive substances measured in TG+DM at 8 wk were significantly lower than those in WT+DM (58 ± 3 vs. 71 ± 5 nmol/g, P < 0.05). Heart rate and aortic blood pressure were comparable between groups. Systolic function was preserved normal in WT+DM and TG+DM mice. In contrast, diastolic function was impaired in WT+DM and was improved in TG+DM as assessed by the deceleration time of peak velocity of transmitral diastolic flow and the time needed for relaxation of 50% maximal LV pressure to baseline value (tau; 13.5 ± 1.2 vs. 8.9 ± 0.7 ms, P < 0.01). The TG+DM values were comparable with those of WT+Control (tau; 7.8 ± 0.2 ms). Improvement of LV diastolic function was accompanied by the attenuation of myocyte hypertrophy, interstitial fibrosis, and apoptosis. Overexpression of GSHPx gene ameliorated LV remodeling and diastolic dysfunction in DM. Therapies designed to interfere with oxidative stress might be beneficial to prevent cardiac abnormalities in DM.

    DOI: 10.1152/ajpheart.00427.2006

  • Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy Reviewed

    Hidenori Matsusaka, Masaki Ikeuchi, Shouji Matsushima, Tomomi Ide, Toru Kubota, Arthur M. Feldman, Akira Takeshita, Kenji Sunagawa, Hiroyuki Tsutsui

    American Journal of Physiology - Heart and Circulatory Physiology   289 ( 5 58-5 )   H1858 - H1864   2005.11

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    Tumor necrosis factor-α (TNF-α) plays a pathophysiological role in the development and progression of heart failure. Matrix metalloproteinase (MMP)-2 is involved in extracellular matrix remodeling. Recent evidence suggests a protective role for this protease against tissue inflammation. Although MMP-2 is upregulated in the failing heart, little is known about its pathophysiological role. We thus hypothesized that ablation of the MMP-2 gene could affect cardiac remodeling and failure in TNF-α-induced cardiomyopathy. We crossed transgenic mice with cardiac-specific overexpression of TNF-α (TG) with MMP-2 knockout (KO) mice. Four groups of male and female mice were studied: wild-type (WT) with wild MMP-2 (WT/MMP+/+), WT with MMP-2 KO (WT/MMP-/-), TNF-α TG with wild MMP-2 (TG/MMP+/+), and TG with MMP-2 KO (TG/MMP-/-). The upregulation of MMP-2 zymographic activity in TG/MMP+/+ mice was completely abolished in TG/MMP-/- mice, and other MMPs and tissue inhibitors of metalloproteinase were comparable between groups. Survival was shorter for male TG/ MMP-/- than TG/MMP+/+ mice. Female TG/MMP-/- mice were more severely affected than TG/MMP+/+ mice with diminished cardiac function. Myocardial TNF-α and other proinflammatory cytokines were increased in TG/MMP+/+ mice, and this increase was similarly observed in TG/MMP-/- mice. The extent of myocardial infiltrating cells including macrophages was greater in TG/MMP -/- than in TG/MMP+/+ mice. Selective ablation of the MMP-2 gene reduces survival and exacerbates cardiac failure in association with the increased level of myocardial inflammation. MMP-2 may play a cardioprotective role in the pathogenesis of cytokine-induced cardiomyopathy.

    DOI: 10.1152/ajpheart.00216.2005

  • Overexpression of mitochondrial transcription factor A ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction Reviewed

    Masaki Ikeuchi, Hidenori Matsusaka, Dongchon Kang, Shouji Matsushima, Tomomi Ide, Toru Kubota, Toshiyuki Fujiwara, Naotaka Hamasaki, Akira Takeshita, Kenji Sunagawa, Hiroyuki Tsutsui

    Circulation   112 ( 5 )   683 - 690   2005.8

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    Background - Mitochondrial DNA (mtDNA) copy number is decreased not only in mtDNA-mutation diseases but also in a wide variety of acquired degenerative and ischemic diseases. Mitochondrial transcription factor A (TFAM) is essential for mtDNA transcription and replication. Myocardial mtDNA copy number and TFAM expression both decreased in cardiac failure. However, the functional significance of TFAM has not been established in this disease state. Methods and Results - We have now addressed this question by creating transgenic (Tg) mice that overexpress human TFAM gene and examined whether TFAM could protect the heart from mtDNA deficiencies and attenuate left ventricular (LV) remodeling and failure after myocardial infarction (MI) created by ligating the left coronary artery. TFAM overexpression could ameliorate the decrease in mtDNA copy number and mitochondrial complex enzyme activities in post-MI hearts. Survival rate during 4 weeks of MI was significantly higher in Tg-MI than in wild-type (WT) littermates (WT-MI), although infarct size was comparable. LV cavity dilatation and dysfunction were significantly attenuated in Tg-MI. LV end-diastolic pressure was increased in WT-MI, and it was also reduced in Tg-MI. Improvement of LV function in Tg-MI was accompanied by a decrease in myocyte hypertrophy, apoptosis, and interstitial fibrosis as well as oxidative stress in the noninfarcted LV. Conclusions - Overexpression of TFAM inhibited LV remodeling after MI. TFAM may provide a novel therapeutic strategy of cardiac failure.

    DOI: 10.1161/CIRCULATIONAHA.104.524835

  • Inhibition of TGF-β signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction Reviewed

    Masaki Ikeuchi, Hiroyuki Tsutsui, Tetsuya Shiomi, Hidenori Matsusaka, Shouji Matsushima, Jing Wen, Toru Kubota, Akira Takeshita

    Cardiovascular research   64 ( 3 )   526 - 535   2004.12

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    Transforming growth factor (TGF)-β promotes the deposition of extracellular matrix protein and also acts as an anti-inflammatory cytokine. These biological effects might be involved in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). However, its pathophysiological significance remains obscure in post-MI hearts. Anterior MI was produced in mice by ligating the left coronary artery. TGF-β mRNA levels increased in both infarcted and noninfarcted LV after MI. To block TGF-β signaling during the early phase of MI, an extracellular domain of TGF-β type II receptor (TβIIR) plasmid was transfected into the limb skeletal muscles 7 days before ligation. TβIIR increased the mortality during 24 h of MI, as well as exacerbated LV dilatation and contractile dysfunction, the infiltration of neutrophils, and gene expression of tumor necrosis factor-α, interleukin-1β, and monocyte chemoattractant protein-1 compared with nontreated MI mice despite the comparable infarct size. Next, to block TGF-β signaling during the later phase, TβIIR was transfected into mice at days 0 and 7 after ligation. At 4 weeks, LV dilatation and contractile dysfunction in association with myocyte hypertrophy and interstitial fibrosis of noninfarcted LV seen in MI mice were prevented by TβIIR. The activation of TGF-β is protective against ischemic myocardial damage during the early phase. However, the beneficial effects might be lost, when its expression is sustained, thereby leading to LV remodeling and failure after MI.

    DOI: 10.1016/j.cardiores.2004.07.017

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Books

  • 「心不全の概念を理解しよう」:実践!心不全療養指導士

    松島将士(Role:Joint author)

    MEDICAL VIEW  2023.3 

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  • 心不全の疫学と病型

    松島 将士、筒井裕之

    臨床循環器学 (文光堂)  2021.6 

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    Responsible for pages:35号(Vol.11 No.1) 50-54ページ, 2021年   Language:Japanese   Book type:General book, introductory book for general audience

  • 実験医学別冊 もっとよくわかる!循環器学と精密医療

    松島将士(Role:Joint author)

    羊土社  2020.7 

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    Language:English   Book type:Scholarly book

  • 糖尿病における心筋障害のメカニズム

    松島 将士(Role:Sole author)

    医歯薬出版  2020.7 

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    Language:Japanese   Book type:General book, introductory book for general audience

  • 実験医学別冊 もっとよくわかる!循環器学と精密医療

    松島将士(Role:Joint author)

    羊土社  2020.7 

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Presentations

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MISC

  • 「β遮断薬・α遮断薬」

    松島 将士

    Heart View   2016.6

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  • 【慢性炎症と心血管疾患】慢性炎症と心不全

    松島 将士, 絹川 真太郎

    別冊Bio Clinica: 慢性炎症と疾患   13 ( 2 )   16 - 19   2024.11

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    Language:Japanese   Publisher:(株)北隆館  

    慢性炎症が心不全の病態に関連することは多くの基礎研究,臨床研究により知られていたが,炎症ネットワークの複雑さや炎症が寄与する心不全病態の不均一さなどから抗炎症治療は確立していなかった。しかし,近年になって心不全の病態形成における自然免疫系の役割が明らかとなり,また,CANTOS試験ではIL-1βに対するモノクローナル抗体による標的抗サイトカイン療法が心筋梗塞患者の心不全発症を抑制することが報告された。本稿では心不全における慢性炎症の役割と炎症を標的とした治療の可能性について概説する。(著者抄録)

  • 治療法の再整理とアップデートのために 専門家による私の治療 慢性心不全

    松島 将士, 筒井 裕之

    日本医事新報   ( 5117 )   46 - 47   2022.5   ISSN:0385-9215

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  • ミトコンドリア機能障害・ERストレス Reviewed

    松島 将士

    2021.6

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  • 難治性疾患(難病)を学ぶ 肥大型心筋症 Reviewed

    松島将士、筒井裕之

    遺伝子医学 (メディカルドウ)   2020.7

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  • 診断基準と疫学を識る-拡張型心筋症のすべて

    松島 将士、筒井裕之

    2019.8

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  • MRAの多施設共同研究を解説する-EMPHASIS-HFとJ-EMPHASIS-HF

    松島 将士

    2019.6

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  • 拡張相肥大型心筋症

    松島 将士

    2019.6

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  • 酸化ストレス

    松島 将士

    2019.6

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  • ミトコンドリア機能異常による心不全

    松島 将士

    2019.6

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  • NADPH oxidase

    松島 将士

    心不全-最新の基礎・臨床研究の進歩-日本臨床   2018.6

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  • Helicobacter pyloriと非胃・十二指腸疾患とのかかわりはここまで明らかになった

    松島 将士、松島 瑠美子

    Helicobacter Research   2017.12

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  • 心筋リモデリングにおけるFynによるNox4制御機構

    松島 将士、 佐渡島純一、筒井裕之

    循環器専門医   2017.9

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  • 心筋リモデリングと酸化ストレス

    松島 将士

    月刊心臓   2017.8

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  • 高血圧患者のECG

    松島 将士、筒井裕之

    血圧   2017.6

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  • 心不全の疫学的特徴と臨床像

    松島 将士、筒井裕之

    Medical Practice   2017.4

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Professional Memberships

  • 日本循環器学会、日本心不全学会、日本心臓病学会、日本心臓リハビリテーション学会

  • 日本循環器学会、日本心不全学会、日本心臓病学会、日本心臓リハビリテーション学会

  • 日本循環器学会、日本心不全学会、日本心臓病学会、日本心臓リハビリテーション学会、日本内科学会

  • 日本循環器学会、日本心不全学会、日本心臓病学会、日本心臓リハビリテーション学会、日本内科学会、アメリカ心臓協会

  • 日本循環器学会、日本心不全学会、日本心臓病学会、日本心臓リハビリテーション学会、日本内科学会、アメリカ心臓協会

Committee Memberships

  • 日本循環器学会   Councilor   Domestic

    2024.4 - 2026.3   

  • 日本循環器学会   九州支部評議員   Domestic

    2024.4 - 2026.3   

  • ISHR日本部会U-45   Organizer   Foreign country

    2022.6 - 2022.1   

  • ISHR日本部会   Councilor   Foreign country

    2020.4 - 2024.3   

  • 日本心不全学会   学術委員   Domestic

    2016.11 - 2023.10   

Academic Activities

  • Screening of academic papers

    Role(s): Peer review

    2023

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:16

  • Screening of academic papers

    Role(s): Peer review

    2022

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:5

  • Screening of academic papers

    Role(s): Peer review

    2021

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:10

  • Screening of academic papers

    Role(s): Peer review

    2020

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:15

  • Screening of academic papers

    Role(s): Peer review

    2019

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:12

  • 事務局 International contribution

    ISHR日本部会  ( Japan ) 2018.12

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  • Screening of academic papers

    Role(s): Peer review

    2018

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:10

  • 座長(Chairmanship)

    第20回日本心不全学会  ( Japan ) 2016.10

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Research Projects

  • 心不全における細胞質内ミトコンドリアDNA蓄積と炎症惹起の新規分子機序の解明

    Grant number:24K11218  2024.4 - 2027.3

    科学研究費助成事業  

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    Authorship:Principal investigator 

  • Novel Mechanisms of Inflammation in Pulmonary Hypertension

    Grant number:23K07579  2023.4 - 2026.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    阿部 弘太郎, 松島 将士

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    Grant type:Scientific research funding

    肺高血圧症疾患モデルの病態進展における血漿および組織中のmtDNA増加と、mtDNAをリガンドとする非TLR9経路であるZBP1を介した無菌性炎症の分子機序について検証する。また、ZBP1ノックアウトマウスやヒト肺高血圧症培養平滑筋細胞を用いて、ZBP1阻害による難治性肺高血圧症の治療効果とその下流の分子機序を明らかにする。

    CiNii Research

  • 心不全患者における腎性貧血の臨床的意義の解明に関する研究

    2023 - 2027

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    Grant type:Contract research

  • O結合グリコシル化制御に基づくサルコペニアの新規治療法開発

    Grant number:22K19754  2022.6 - 2024.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

    絹川 真太郎, 松島 将士

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    Grant type:Scientific research funding

    本研究は、『加齢における骨格筋萎縮の進展にタンパク合成や分解に関わる種々のタンパクのO-GLcNAc化修飾が重要な役割を果たしている』という仮説を立て、O-GlcNAc化の制御による骨格筋萎縮の予防・治療法を開発することを目的とする。骨格筋が生体の代謝の中心であることに注目し、その代謝産物による翻訳後修飾であり、リン酸化と競合的に働くO-GlcNAc化修飾に着目した点が、本研究の新規性である。本研究では、これまで注目されていなかったO-GlcNAc化修飾に注目して、加齢における骨格筋萎縮にO-GlcNAc化修飾が重要な役割を果たしているのではないか、という学術的に根本的な疑問の解決に挑戦する。

    CiNii Research

  • 心不全におけるミトコンドリア-小胞体接触の役割の解明と新規治療の開発

    2022.4 - 2025.3

  • Pathophysiology and Clinical Impact of Anemia in Patients with Advanced Heart Failure

    Grant number:22K08103  2022.4 - 2025.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    藤野 剛雄, 筒井 裕之, 絹川 真太郎, 遠山 岳詩, 松島 将士

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    Grant type:Scientific research funding

    本研究では、全国の重症心不全センターと協力し、心臓移植待機中の重症心不全患者を後ろ向きおよび前向きに登録して全国規模の多施設レジストリを構築する。構築したレジストリを用いて、わが国の心臓移植待機中の予後予測因子を解明する。さらに、心不全の重要な併存症である貧血に注目する。前向き登録の患者検体を用いて鉄代謝や慢性炎症、酸化ストレスのバイオマーカーを測定し、心臓移植待機中の重症心不全における貧血の原因と病態を解明する。また、心臓移植待機中の貧血の合併頻度や臨床経過に及ぼす影響を解析する。

    CiNii Research

  • Golgi apparatus-centered organelle network in cardiac remodeling

    Grant number:23K24331  2022.4 - 2025.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    筒井 裕之, 瀬戸山 大樹, 絹川 真太郎, 松島 将士

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    Grant type:Scientific research funding

    継続課題のため、記入しない。

    CiNii Research

  • Pathobiological role of Ca2+/calmodulin-dependent PDE1 in HFpEF

    Grant number:22K08126  2022.4 - 2025.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    橋本 亨, 絹川 真太郎, 松島 将士

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    Grant type:Scientific research funding

    左室駆出率の保たれた心不全(heart failure with preserved ejection fraction, HFpEF)は心不全患者の半数を占めるが、予後を改善する治療法が確立していない。HFpEFの病態解明と新規治療法の開発は喫緊の課題である。本研究においては、HFpEFにおけるPDE1の機能を解明し、PDE1標的治療が有効であることを証明する。 本研究の成果はPDE1を標的とするHFpEFの新規治療法の基盤となり、患者の予後改善に役立つ。

    CiNii Research

  • Establishment of novel therapy for heart failure via mitochondria quality control by Mieap in cardiomyocytes

    Grant number:21K19485  2021.7 - 2023.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

    Tsutsui Hiroyuki

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    Grant type:Scientific research funding

    Impairment of cardiac function was accompanied by an increase in the protein level of Mieap in post-infarct failing myocardium. Mieap was co-stained with mitochondria in cultured cardiomyocytes by immunostaining, suggesting that Mieap is localized in mitochondria. Furthermore, knockout of Mieap increased hydrogen peroxide-induced cell death in cultured cardiomyocytes. Mieap knockout mice had increased mortality after myocardial infarction compared to wild-type mice. In addition, cardiomegaly progressed, cardiac hypertrophy progressed, cardiac function deterioration was accelerated, and lung weight and heart weight increased. These findings indicated that Mieap, as a mitochondrial protein, has cardioprotective action against oxidative stress, which promotes the progress of myocardial remodeling.

    CiNii Research

  • Elucidation of the mechanism by which myokines regulate aging progress

    Grant number:21H03360  2021.4 - 2024.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Kinugawa Shintaro

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    Grant type:Scientific research funding

    A myokine library was created by analyzing proteins secreted from skeletal muscle using mass spectrometry. In addition, by comparing the results of mass spectrometry analysis of blood from aging mice, we identified myokines that change with age (aging myokine profiling). We revealed that the secretion of brain-derived neurotrophic factor, a myokine, was decreased with age and was closely related to mitochondrial function and exercise capacity. We succeeded in observing the secretion dynamics of brain-derived neurotrophic factor in real time using a confocal microscope. As a result of comprehensive analysis of Rab proteins, it became clear that two types of Rab proteins may be involved in the secretion of myokines from C2C12 cells.

    CiNii Research

  • 心不全の発症・重症化の高精度予測とそれに基づく最適な治療戦略の開発

    2021.4 - 2022.3

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    Authorship:Coinvestigator(s) 

  • a

    Grant number:21K08082  2021 - 2023

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Matsushima Shoji

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    Authorship:Principal investigator  Grant type:Scientific research funding

    Cardiac hypertrophy was suppressed in a pressure-load-induced remodeling model in myocardial-specific Mitol knockout mice. This antihypertrophic effect was accompanied by suppression of cardiac hypertrophic signaling factors and reduction of markers of oxidative stress. In addition, siRNA knockdown of Mitol in cardiomyocytes suppressed hypertrophy induced by hypertrophic stimuli. Similar anti-cardiac hypertrophic effects and mechanisms were observed with GRP75 inhibitor treatment.
    Inhibition of Mitol and GRP75 function reduced mitochondria-endoplasmic reticulum contact, resulting in an antihypertrophic effect.

    CiNii Research

  • 心不全の発症・重症化の高精度予測とそれに基づく最適な治療戦略の開発

    2019.4 - 2019.3

    九州大学 

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    Authorship:Coinvestigator(s) 

  • 心筋リモデリングにおけるスルフィレドキシンによるミトコンドリアレドックス制御機構

    Grant number:19H03655  2019 - 2021

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    筒井 裕之, 康 東天, 松島 将士, 井手 友美, 西村 明幸

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    Authorship:Coinvestigator(s)  Grant type:Scientific research funding

    心不全の病態基盤である心筋リモデリングの形成・進展には心筋細胞のミトコンドリアの酸化ストレスが密接に関与している。スルフィレドキシン(SRX)は、不活性型ペルオキシレドキシン(Prx)を還元し蛋白グルタチオン化を制御する酵素であり、心筋細胞のミトコンドリアレドックス制御の基盤分子と考えられる。本研究は心筋リモデリングにおけるSRXのミトコンドリアレッドクス制御の意義を解明し、SRX機能安定化によるレドックス適正化を介したミトコンドリア機能の保持という独自のパラダイムに基づく新たな心不全の予防・治療法の開発を目指すものである。

    CiNii Research

  • 拡張型心筋症におけるSPARMAの役割

    2019 - 2020

    第6回日本心臓財団・拡張型心筋症治療開発研究助成

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    Authorship:Principal investigator  Grant type:Contract research

  • 心不全の発症・重症化の高精度予測とそれに基づく最適な治療戦略の開発

    2018.4 - 2019.3

    九州大学 

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    Authorship:Coinvestigator(s) 

  • 心不全におけるMAM形成の意義

    2018

    持田記念研究助成

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    Authorship:Principal investigator  Grant type:Contract research

  • 心不全の発症・重症化の高精度予測とそれに基づく最適な治療戦略の開発

    2017.4 - 2019.3

    九州大学 

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    Authorship:Coinvestigator(s) 

    わが国における心不全の発症・重症化の高精度予測とそれに基づく最適な治療戦略の開発を目指す

  • ミトコンドリア蛋白輸送機構の心筋リモデリングにおける意義の解明と治療への応用

    Grant number:17K09581  2017 - 2019

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • ミトコンドリア蛋白輸送機構の心筋リモデリングにおける意義の解明と治療への応用

    Grant number:17K09581  2017 - 2019

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • 心筋細胞におけるオルガネラネットワーク制御を介した新たな心不全治療

    2017

    平成29年度持田記念研究助成

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    Authorship:Principal investigator  Grant type:Contract research

  • 心筋リモデリングにおけるミトコンドリア・小胞体間輸送機構の解明と新たな心不全治療

    2017

    平成29年度臨床研究助成奨励賞

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    Authorship:Principal investigator  Grant type:Contract research

  • FynによるNox4の新たな制御機構の解明に関する研究

    2016

    第11回Vascular Biology Innovation Conference研究助成

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    Authorship:Principal investigator  Grant type:Contract research

  • わが国における拡張相肥大型心筋症を対象とした登録観察研究

    2015.4 - 2018.3

    九州大学大学院医学研究院循環器内科学 

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    Authorship:Coinvestigator(s) 

  • 心筋リモデリングにおけるmitoNEETによるミトコンドリア機能制御機構の解明

    Grant number:15H04815  2015 - 2017

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Coinvestigator(s)  Grant type:Scientific research funding

  • 心血管病における心臓周囲脂肪ミトコンドリアの役割

    Grant number:15K09115  2015 - 2017

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Authorship:Coinvestigator(s)  Grant type:Scientific research funding

  • Nox4を介したミトコンドリア形態制御の分子基盤解明による新たな心不全治療の開発

    Grant number:15K19358  2015 - 2016

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)

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    Authorship:Principal investigator  Grant type:Scientific research funding

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Educational Activities

  • 大学院医学研究学府の大学院生の教育:心不全の基礎研究および臨床研究
    医学部生の教育:臨床の指導および基礎研究の指導

Class subject

  • 3学年系統医学Ⅱ(循環器)「病歴・身体診察の基本と胸部X線」

    2024.10 - 2025.3   Second semester

  • 学年系統医学Ⅱ(循環器)「病歴・身体診察の基本と胸部X線」

    2023.10 - 2024.3   Second semester

  • 3学年系統医学Ⅱ(循環器)「病歴・身体診察の基本と胸部X線」

    2022.10 - 2023.3   Second semester

  • 臨床医学基本実習「⑧胸部診察(循環器)」

    2022.4 - 2022.9   First semester

  • 臨床医学基本実習「胸部診察②(循環器)」

    2021.10 - 2022.3   Second semester

  • 検査実習 心電図演習

    2020.10 - 2021.3   Second semester

  • 臨床医学基本実習「胸部診察②(循環器)」

    2020.10 - 2021.3   Second semester

  • 臨床医学基本実習(患者実習)

    2020.10 - 2021.3   Second semester

  • 検査実習 心電図演習

    2019.10 - 2020.3   Second semester

  • 臨床医学基本実習(患者実習)

    2019.10 - 2020.3   Second semester

  • 臨床医学基本実習「胸部診察②(循環器)」

    2019.10 - 2020.3   Second semester

  • 検査実習 心電図演習

    2018.10 - 2019.3   Second semester

  • 臨床医学基本実習(患者実習)

    2018.10 - 2019.3   Second semester

  • 臨床医学基本実習「胸部診察②(循環器)」

    2018.10 - 2019.3   Second semester

  • 検査実習 心電図演習

    2017.10 - 2018.3   Second semester

  • 臨床医学基本実習「胸部診察②(循環器)」

    2017.10 - 2018.3   Second semester

  • 臨床医学基本実習(患者実習)

    2017.10 - 2018.3   Second semester

  • 検査実習 心電図演習

    2016.10 - 2017.3   Second semester

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Teaching Student Awards

  • 第8回日本循環器学会基礎研究フォーラム(BCVR) YIA Award 優秀賞

    Year and month of award:2024.12

    Classification of award-winning students:Doctoral student   Name of award-winning student:諌山(庄島)耀子

  • 第136回日循九州地方会女性研究者奨励賞 優秀賞

    Year and month of award:2024.6

    Classification of award-winning students:Doctoral student   Name of award-winning student:野田英里

Other educational activity and Special note

  • 2024  Lecture at Education Method and Practice  循環器内科の大学院生7名に心不全の病態解明に関する基礎研究の指導医を行った

  • 2023  Special Affairs  循環器内科の大学院生7名に心不全の病態解明に関する基礎研究の指導医を行った

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    循環器内科の大学院生7名に心不全の病態解明に関する基礎研究の指導医を行った

  • 2022  Special Affairs  循環器内科の大学院生9名に心不全の病態解明に関する基礎研究の指導医を行った

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    循環器内科の大学院生9名に心不全の病態解明に関する基礎研究の指導医を行った

  • 2021  Special Affairs  循環器内科の大学院生10名に心不全の病態解明に関する基礎研究の指導医を行った

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    循環器内科の大学院生10名に心不全の病態解明に関する基礎研究の指導医を行った

  • 2019  Special Affairs  循環器内科の大学院生8名に心不全の病態解明に関する基礎研究の指導医を行った

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    循環器内科の大学院生8名に心不全の病態解明に関する基礎研究の指導医を行った

  • 2018  Special Affairs  循環器内科の大学院生6名に心不全の病態解明に関する基礎研究の指導医を行った

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    循環器内科の大学院生6名に心不全の病態解明に関する基礎研究の指導医を行った

  • 2016  Special Affairs  循環器内科の大学院生2名に心不全の病態解明に関する基礎研究の指導医を行った

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    循環器内科の大学院生2名に心不全の病態解明に関する基礎研究の指導医を行った

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Outline of Social Contribution and International Cooperation activities

  • 米国ニュージャージ医科大学の佐渡島純一教授と共同で心不全の病態解明に関する基礎研究を推進している。

Travel Abroad

  • 2010.3 - 2012.12

    Staying countory name 1:United States   Staying institution name 1:ニュージャージー医科歯科大学

Specialized clinical area

  • Biology / Medicine, Dentistry and Pharmacy / Internal Medicine / Cardiology

Clinician qualification

  • Specialist

    The Japanese Circulation Society(JCS)

Year of medical license acquisition

  • 2001

Notable Clinical Activities

  • 心不全臨床グループの指導医として、重症心不全患者の診療に従事し、人工心臓、心臓移植医療を推進している。