記述言語：英語   出版者・発行元：Hypertension Research  

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.)

DOI： 10.1038/s41440-024-01733-4

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記述言語：英語   出版者・発行元：ESC Heart Failure  

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.

DOI： 10.1002/ehf2.14873

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記述言語：英語   出版者・発行元：International Heart Journal  

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.

DOI： 10.1536/ihj.24-067

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記述言語：英語   出版者・発行元：European Heart Journal - Quality of Care and Clinical Outcomes  

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.

DOI： 10.1093/ehjqcco/qcae005

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記述言語：英語   出版者・発行元：Circulation Journal  

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.

DOI： 10.1253/circj.CJ-24-0127

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記述言語：英語   出版者・発行元：European Journal of Preventive Cardiology  

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.

DOI： 10.1093/eurjpc/zwad375

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記述言語：英語   出版者・発行元：Journal of the American Heart Association  

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.

DOI： 10.1161/JAHA.123.031104

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記述言語：英語   出版者・発行元：Scientific Reports  

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.

DOI： 10.1038/s41598-023-51085-1

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記述言語：英語   出版者・発行元：Journal of the American Heart Association  

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.

DOI： 10.1161/JAHA.123.031219

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記述言語：英語   出版者・発行元：Circulation: Heart Failure  

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.

DOI： 10.1161/CIRCHEARTFAILURE.122.010347

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記述言語：英語   出版者・発行元：Circulation Journal  

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.

DOI： 10.1253/circj.CJ-22-0774

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記述言語：英語   出版者・発行元：JACC: Clinical Electrophysiology  

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.

DOI： 10.1016/j.jacep.2023.05.038

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記述言語：英語   出版者・発行元：JACC: Basic to Translational Science  

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.

DOI： 10.1016/j.jacbts.2023.02.014

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記述言語：英語   出版者・発行元：Helicobacter  

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.

DOI： 10.1111/hel.12988

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記述言語：英語   出版者・発行元：European Journal of Heart Failure  

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.

DOI： 10.1002/ejhf.2895

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：Hypertension Research  

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.].

DOI： 10.1038/s41440-023-01178-1

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記述言語：英語   出版者・発行元：Circulation Research  

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.

DOI： 10.1161/CIRCRESAHA.122.322227

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記述言語：英語   出版者・発行元：Nature Communications  

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.

DOI： 10.1038/s41467-023-37838-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：Circulation: Heart Failure  

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.

DOI： 10.1161/CIRCHEARTFAILURE.122.010320

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記述言語：英語   出版者・発行元：Circulation Journal  

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.

DOI： 10.1253/circj.CJ-22-0554

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PubMed

記述言語：英語   出版者・発行元：JACC: Asia  

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.

DOI： 10.1016/j.jacasi.2022.09.015

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記述言語：英語   出版者・発行元：CJC Open  

DOI： 10.1016/j.cjco.2022.11.009

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記述言語：日本語   出版者・発行元：一般社団法人 日本移植学会  

<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

CiNii Research

記述言語：英語   出版者・発行元：Circulation: Heart Failure  

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.

DOI： 10.1161/CIRCHEARTFAILURE.122.009366

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記述言語：英語   出版者・発行元：Science Signaling  

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.

DOI： 10.1126/scisignal.abn8017

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記述言語：英語   出版者・発行元：Journal of Cardiovascular Pharmacology  

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.

DOI： 10.1097/FJC.0000000000001328

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記述言語：英語   出版者・発行元：ESC Heart Failure  

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.

DOI： 10.1002/ehf2.13962

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記述言語：英語   出版者・発行元：JACC: Basic to Translational Science  

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.

DOI： 10.1016/j.jacbts.2022.03.012

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記述言語：英語   出版者・発行元：ESC Heart Failure  

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.

DOI： 10.1002/ehf2.13934

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記述言語：英語   出版者・発行元：International Journal of Cardiology  

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.

DOI： 10.1016/j.ijcard.2022.03.049

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記述言語：英語   出版者・発行元：Antioxidants  

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.

DOI： 10.3390/antiox11061069

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記述言語：英語   出版者・発行元：ESC Heart Failure  

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.

DOI： 10.1002/ehf2.13790

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出版者・発行元：Circulation Journal  

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.

DOI： 10.1253/circj.CJ-21-0376

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1253/circrep.CR-21-0001.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s42003-021-01675-4.

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cardiovascular Drugs and Therapy  

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.

DOI： 10.1007/s10557-020-07123-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-021-81736-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1172/jci.insight.132747

記述言語：英語   掲載種別：研究論文（学術雑誌）  

—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

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ehf2.12571

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.3489-19

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1253/circj.CJ-19-1039

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: An inverse relationship exists between hospital case volume and mortality in patients with heart failure (HF). However, hospital performance factors associated with mortality in HF patients have not been examined. We aimed to identify these using exploratory factor analysis and assess the relationship between these factors and 7-day, 30-day, and in-hospital mortality among HF patients in Japan. Methods and Results: We analyzed the records of 198,861 patients admitted to 683 certified hospitals of the Japanese Circulation Society between 2012 and 2014. Records were obtained from the nationwide database of the Japanese Registry Of All cardiac and vascular Diseases-Diagnostic Procedure Combination (JROAD-DPC). Using exploratory factor analysis, 90 hospital survey items were grouped into 5 factors, according to their collinearity: “Interventional cardiology”, “Cardiovascular surgery”, “Pediatric cardiology”, “Electrophysiology” and “Cardiac rehabilitation”. Multivariable logistic regression analysis was performed to determine the association between these factors and mortality. The 30-day mortality was 8.0%. Multivariable logistic regression analysis showed the “Pediatric cardiology” (odds ratio (OR) 0.677, 95% confidence interval [CI]: 0.628–0.729, P<0.0001), “Electrophysiology” (OR 0.876, 95% CI: 0.832–0.923, P<0.0001), and “Cardiac rehabilitation” (OR 0.832, 95% CI: 0.792–0.873, P<0.0001) factors were associated with lower mortality. In contrast, “Interventional cardiology” (OR 1.167, 95% CI: 1.070–1.272, P<0.0001) was associated with higher mortality. Conclusions: Hospital factors, including various cardiovascular therapeutic practices, may be associated with the early death of HF patients.

DOI： 10.1253/circj.CJ-19-0759

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1253/circj.CJ-18-1116

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jdi.12606

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.yjmcc.2016.09.013

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/cvr/cvw182

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1172/JCI85624

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12350-015-0258-5

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ijcha.2016.03.007

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ejphar.2016.03.022

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.yjmcc.2016.03.001

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1113/EP085251

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/CIRCRESAHA.115.306624

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ijcard.2015.08.022

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1536/ihj.15-108

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/ndt/gfv103

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.cardfail.2015.01.003

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1113/expphysiol.2014.084095

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1152/ajpheart.00053.2015

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/HJH.0000000000000281

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ijcard.2014.07.113

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ejphar.2014.06.008

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1152/ajpendo.00449.2013

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ijcard.2014.06.068

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.tcm.2014.03.003

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jjcc.2013.07.012

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/JAHA.113.000555

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ijcard.2013.08.073

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ijcard.2013.04.176

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12350-013-9722-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1089/ars.2012.4822

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/CIRCRESAHA.112.279760

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1152/ajpheart.00554.2011

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.yjmcc.2010.09.020

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1152/ajpheart.01185.2009

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jccase.2011.01.001

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.yjmcc.2010.12.018

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3164/jcbn.11-012FR

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.18632/aging.100261

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/CIRCULATIONAHA.110.958033

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jccase.2010.05.003

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1073/pnas.1002178107

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1152/ajpheart.00267.2009

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1152/ajpheart.01332.2008

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ijcard.2008.03.068

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/cvr/cvn280

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1365-2125.2008.03298.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1253/circj.CJ-08-0014

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1291/hypres.30.439

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/01.fjc.0000245405.41317.60

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.cardiores.2006.02.001

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/CIRCULATIONAHA.105.582239

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/01.HYP.0000208840.30778.00

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1152/ajpheart.00427.2006

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1152/ajpheart.00216.2005

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/CIRCULATIONAHA.104.524835

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

開催年月日： 2021年7月

記述言語：日本語   会議種別：口頭発表（一般）  

国名：日本国  

開催年月日： 2021年3月

記述言語：英語   会議種別：口頭発表（一般）  

国名：日本国  

開催年月日： 2020年11月

記述言語：英語   会議種別：口頭発表（一般）  

国名：日本国  

開催年月日： 2020年10月

記述言語：日本語   会議種別：口頭発表（一般）  

国名：日本国  

開催年月日： 2020年8月

記述言語：英語   会議種別：口頭発表（一般）  

国名：日本国  

開催年月日： 2019年10月 - 2020年10月

記述言語：日本語  

開催地：広島   国名：日本国  

開催年月日： 2019年7月 - 2020年7月

記述言語：日本語  

開催地：札幌   国名：日本国  

開催年月日： 2018年12月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

国名：日本国  

開催年月日： 2018年3月

記述言語：日本語  

国名：日本国  

開催年月日： 2018年3月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

国名：日本国  

開催年月日： 2017年12月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

国名：日本国  

開催年月日： 2017年10月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

国名：日本国  

開催年月日： 2017年10月 - 2017年9月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

国名：日本国  

開催年月日： 2017年4月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：長良川国際会議場, 岐阜   国名：日本国  

開催年月日： 2016年9月

記述言語：日本語   会議種別：口頭発表（一般）  

国名：日本国  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

種別：大会・シンポジウム等 

種別：査読等 

外国語雑誌　査読論文数：10

種別：大会・シンポジウム等 

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