Publications by authors named "Tomomi Ide"

118 Publications

Beta-Blocker Use Is Associated With Prevention of Left Ventricular Remodeling in Recovered Dilated Cardiomyopathy.

J Am Heart Assoc 2021 Jun 31;10(12):e019240. Epub 2021 May 31.

Department of Cardiovascular Medicine Faculty of Medical Sciences Kyushu University Fukuoka Japan.

Background Withdrawal of optimal medical therapy has been reported to relapse cardiac dysfunction in patients with dilated cardiomyopathy (DCM) whose cardiac function had improved. However, it is unknown whether beta-blockers can prevent deterioration of cardiac function in those patients. We examined the effect of beta-blockers on left ventricular ejection fraction (LVEF) in recovered DCM. Methods and Results We analyzed the clinical personal record of DCM, a national database of the Japanese Ministry of Health, Labor and Welfare, between 2003 and 2014. Recovered DCM was defined as a previously documented LVEF <40% and a current LVEF ≥40%. Patients with recovered DCM were divided into 2 groups according to the use of beta-blockers. A one-to-one propensity case-matched analysis was used. The primary outcome was defined as a decrease in LVEF >10% at 2 years of follow-up. Of 5370 eligible patients, 4104 received beta-blockers. Propensity score matching yielded 1087 pairs. Mean age was 61.9 years, and 1619 (74.5%) were men. Mean LVEF was 49.3±8.2%, and median B-type natriuretic peptide was 46.6 (interquartile range, 18.0-118.1) pg/mL. The primary outcome was observed less frequently in the beta-blocker group than in the no-beta-blocker group (19.6% versus 24.0%; odds ratio [OR], 0.77; 95% CI, 0.63-0.95; =0.013). Subgroup analysis demonstrated that female patients (women: OR, 0.54; 95% CI, 0.36-0.81; men: OR, 0.88; 95% CI, 0.69-1.12; for interaction=0.040) were benefited by beta-blockers. Conclusions Beta-blocker use could prevent deterioration of left ventricular systolic function in patients with recovered DCM.
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http://dx.doi.org/10.1161/JAHA.120.019240DOI Listing
June 2021

HFA/HFSA/JHFS Position Statement on Endomyocardial Biopsy.

J Card Fail 2021 Apr 27. Epub 2021 Apr 27.

Cleveland Clinic, Cleveland OH, USA.

Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant (HTx) rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumours. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples has significantly improved diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: 1) an overview of the practical approach to EMB, 2) an update on indications for EMB, 3) a revised plan for HTx rejection surveillance, 4) the impact of multimodality imaging on EMB, and 5) the current clinical practice in the worldwide use of EMB.
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http://dx.doi.org/10.1016/j.cardfail.2021.04.010DOI Listing
April 2021

Heart Failure Association of the ESC, Heart Failure Society of America and Japanese Heart Failure Society Position statement on endomyocardial biopsy.

Eur J Heart Fail 2021 May 19. Epub 2021 May 19.

Cleveland Clinic, Cleveland, OH, USA.

Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant (HTx) rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumours. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples have significantly improved diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (i) an overview of the practical approach to EMB, (ii) an update on indications for EMB, (iii) a revised plan for HTx rejection surveillance, (iv) the impact of multimodality imaging on EMB, and (v) the current clinical practice in the worldwide use of EMB.
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http://dx.doi.org/10.1002/ejhf.2190DOI Listing
May 2021

Alteration of circadian machinery in monocytes underlies chronic kidney disease-associated cardiac inflammation and fibrosis.

Nat Commun 2021 05 13;12(1):2783. Epub 2021 May 13.

Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

Dysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. The CLOCK protein is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene (Clk/Clk) exhibit abnormal rhythms in numerous physiological processes. However, here we report that chronic kidney disease (CKD)-induced cardiac inflammation and fibrosis are attenuated in Clk/Clk mice even though they have high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder in Clk/Clk mice with 5/6 nephrectomy (5/6Nx) led to identification of the monocytic expression of G protein-coupled receptor 68 (GPR68) as a risk factor of CKD-induced inflammation and fibrosis of heart. 5/6Nx induces the expression of GPR68 in circulating monocytes via altered CLOCK activation by increasing serum levels of retinol and its binding protein (RBP4). The high-GPR68-expressing monocytes have increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbates inflammation and fibrosis of heart. Serum retinol and RBP4 levels in CKD patients are also sufficient to induce the expression of GPR68 in human monocytes. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure.
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http://dx.doi.org/10.1038/s41467-021-23050-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119956PMC
May 2021

Clinical Characteristics and Outcomes of Hospitalized Patients With Heart Failure From the Large-Scale Japanese Registry Of Acute Decompensated Heart Failure (JROADHF).

Circ J 2021 Apr 15. Epub 2021 Apr 15.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University.

Background: With aging population, the prevalence and incidence of heart failure (HF) have been increasing worldwide. However, the characteristics and outcomes of patients with HF in an era of aging are not well established in Japan.Methods and Results:The Japanese Registry Of Acute Decompensated Heart Failure (JROADHF), a retrospective, multicenter, nationwide registry, was designed to study the clinical characteristics and outcomes of patients hospitalized with HF throughout Japan in 2013. One-hundred and twenty-eight hospitals were selected by cluster random sampling and 13,238 hospitalized patients with HF were identified by medical record review. Demographics, medical history, severity, treatment, and in-hospital and long-term outcome data were collected from the Diagnostic Procedure Combination and medical charts. Data were analyzed using univariate and multivariate logistic regression analysis. The mean age of registered patients was 78.0±12.5 years and 52.8% were male. Elderly patients (age >75 years) accounted for 68.9%, and HF with preserved ejection fraction (HFpEF) accounted for 45.1%. Median length of hospital stay was 18 days and in-hospital mortality was 7.7%. The median follow-up period was 4.3 years, and the incidence rates for cardiovascular death and rehospitalization for HF were 7.1 and 21.1 per 100 person-years, respectively.

Conclusions: A contemporary nationwide registry demonstrated that hospitalized HF patients were very elderly, HFpEF was common, and their prognosis was still poor in Japan.
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http://dx.doi.org/10.1253/circj.CJ-20-0947DOI Listing
April 2021

Urinary N-terminal pro-B-type natriuretic peptide as a biomarker for cardiovascular events in a general Japanese population: the Hisayama Study.

Environ Health Prev Med 2021 Apr 12;26(1):47. Epub 2021 Apr 12.

Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Epidemiological evidence has shown that serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations, a diagnostic biomarker for heart failure, are positively associated with cardiovascular risk. Since NT-proBNP in serum is excreted in urine, it is hypothesized that urinary NT-proBNP concentrations are correlated with serum concentrations and linked with cardiovascular risk in the general population.

Methods: A total of 3060 community-dwelling residents aged ≥ 40 years without history of cardiovascular disease (CVD) were followed up for a median of 8.3 years (2007-2015). Serum and urinary concentrations of NT-proBNP at baseline were compared. The hazard ratios (HRs) and their 95% confidence intervals (CIs) for the association between NT-proBNP concentrations and the risk of developing CVD were computed using the Cox proportional hazards model.

Results: The median values (interquartile ranges) of serum and urinary NT-proBNP concentrations at baseline were 56 (32-104) pg/mL and 20 (18-25) pg/mL, respectively. There was a strong quadratic correlation between the serum and urinary concentrations of NT-proBNP (coefficient of determination [R] = 0.72): urinary concentrations of 20, 27, and 43 pg/mL were equivalent to serum concentrations of 55, 125, and 300 pg/mL, respectively. During the follow-up period, 170 subjects developed CVD. The age- and sex-adjusted risk of CVD increased significantly with higher urinary NT-proBNP levels (P for trend < 0.001). This association remained significant after adjustment for traditional cardiovascular risk factors (P for trend = 0.009). The multivariable-adjusted risk of developing CVD almost doubled in subjects with urinary NT-proBNP of ≥ 43 pg/mL as compared to those with urinary NT-proBNP of ≤ 19 pg/mL (HR 2.07, 95% CI 1.20-3.56).

Conclusions: The present study demonstrated that urinary NT-proBNP concentrations were well-correlated with serum concentrations and were positively associated with cardiovascular risk. Given that urine sampling is noninvasive and does not require specially trained personnel, urinary NT-proBNP concentrations have the potential to be an easy and useful biomarker for detecting people at higher cardiovascular risk.
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http://dx.doi.org/10.1186/s12199-021-00970-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042718PMC
April 2021

Clinical Characteristics and Contemporary Management of Patients With Cardiomyopathies in Japan - Report From a National Registry of Clinical Personal Records.

Circ Rep 2021 Feb 11;3(3):142-152. Epub 2021 Feb 11.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University Fukuoka Japan.

The clinical features of patients with cardiomyopathy, including dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), or restrictive cardiomyopathy (RCM), have not been recently elucidated in Japan. We collected individual patient data regarding demographics, echocardiogram, and treatment in DCM from 2003 to 2014 and in HCM and RCM from 2009 to 2014 from the national registry of clinical personal records organized by the Japanese Ministry of Health, Labour and Welfare. In all, 44,136 patients were included in this registry: 40,537 with DCM, 3,553 with HCM, and 46 with RCM. The median age at diagnosis was older for DCM and HCM than RCM (54 and 55 vs. 42 years, respectively). Male patients accounted for 74.6%, 58.7%, and 60.9% of the DCM, HCM, and RCM groups, respectively. NYHA functional Class III-IV was found in 26.9%, 11.3%, and 58.1% of patients in the DCM, HCM, and RCM groups, respectively. In the DCM group, the rates of β-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker prescription were 69% and 76%, respectively. In regional subgroup analysis, the median age at diagnosis of DCM and HCM was younger in the Kanto region. A family history of HCM was less frequent in the Hokkaido/Tohoku region. The national registry of clinical personal records of cardiomyopathy could provide important information regarding the demographics, clinical characteristics, and management of cardiomyopathy throughout Japan.
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http://dx.doi.org/10.1253/circrep.CR-21-0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956877PMC
February 2021

Development of a selective three-dimensional HPLC system for enantiomer discriminated analysis of lactate and 3-hydroxybutyrate in human plasma and urine.

J Pharm Biomed Anal 2021 Feb 26;195:113871. Epub 2020 Dec 26.

Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan; School of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. Electronic address:

For the enantiomer discriminated determination of lactate (LA) and 3-hydroxybutyrate (3HB) in various complicated samples, a three-dimensional HPLC (3D-HPLC) system has been designed and developed by investigating the separation of the target analytes from unknown substances observed in the real target matrices. LA and 3HB were pre-column derivatized with 4-nitro-7-piperazino-2,1,3-benzoxadiazole for the sensitive fluorescence detection and introduced into the 3D-HPLC system composed of reversed-phase, mixed-mode and enantioselective separations. The present method was validated by calibration curves, precision and accuracy using standard solutions and human samples, and sufficient values were obtained. Using the method, the levels of d-LA, l-LA, d-3Hb and l-3HB were determined, and their concentrations were 9.9, 1004.2, 79.7 and 2.1 μM in the human plasma and 16.0, 86.6, 8.7 and 4.8 μM in the human urine, respectively. The present 3D-HPLC system could selectively determine trace amounts of the target hydroxy acid enantiomers without disturbance of the intrinsic interfering substances in complicated matrices and the applications to various disease samples are expected.
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http://dx.doi.org/10.1016/j.jpba.2020.113871DOI Listing
February 2021

Heart Rate Reduction with Ivabradine Prevents Cardiac Rupture after Myocardial Infarction in Mice.

Cardiovasc Drugs Ther 2021 Jan 7. Epub 2021 Jan 7.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

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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http://dx.doi.org/10.1007/s10557-020-07123-5DOI Listing
January 2021

Determination of phenylalanine enantiomers in the plasma and urine of mammals and ᴅ-amino acid oxidase deficient rodents using two-dimensional high-performance liquid chromatography.

Biochim Biophys Acta Proteins Proteom 2021 01 22;1869(1):140540. Epub 2020 Sep 22.

Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; College of Pharmacy, Taipei Medical University, 250 WuXing Street, Taipei 11031, Taiwan. Electronic address:

A two-dimensional (2D) HPLC system focusing on the determination of phenylalanine (Phe) enantiomers in mammalian physiological fluids has been developed. ᴅ-Phe is indicated to have potential values as a disease biomarker and therapeutic molecule in several neuronal and metabolic disorders, thus the regulation of ᴅ-Phe in mammals is a matter of interest. However, the precise determination of amino acid enantiomers is difficult in complex biological samples, and the development of an analytical method with practically acceptable sensitivity, selectivity and throughput is expected. In the present study, a 2D-HPLC system equipped with a reversed-phase column in the 1st dimension and an enantioselective column in the 2nd dimension has been designed, following the fluorescence derivatization of the target amino acid enantiomers with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F). The analytical method was validated using both plasma and urine samples, and successfully applied to human, rat and mouse fluids. Trace levels of ᴅ-Phe were determined in the plasma, and the %ᴅ values were around 0.1% for all species. In the urine, relatively large amounts of ᴅ-Phe were observed, and the %ᴅ values for humans, rats and mice were 3.99, 1.76 and 5.25%, respectively. The relationships between the enzymatic activity of ᴅ-amino acid oxidase (DAO) and the amounts of intrinsic ᴅ-Phe have also been clarified, and high ᴅ-Phe amounts were observed (around 0.3% in the plasma and around 50% in the urine) in the DAO deficient rats and mice.
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http://dx.doi.org/10.1016/j.bbapap.2020.140540DOI Listing
January 2021

Systemic-to-Pulmonary Collateral Flow Correlates with Clinical Condition Late After the Fontan Procedure.

Pediatr Cardiol 2020 Dec 11;41(8):1800-1806. Epub 2020 Sep 11.

Department of Pediatric Cardiology, Fukuoka Children's Hospital, 5-1-1 Kashiiteriha, Fukuoka, Japan.

In the Fontan circulation, there is a substantial degree of systemic-to-pulmonary collateral flow (SPCF), which can be measured by cardiac magnetic resonance (CMR). However, the correlation between the degree of SPCF and long-term outcomes is not fully understood. We retrospectively studied 321 patients who underwent the Fontan procedure and CMR at a single center. Using CMR, we calculated SPCF as pulmonary blood flow - systemic blood flow. %SPCF was defined as SPCF ÷ pulmonary blood flow. The mean age of patients at CMR was 14.3 ± 7.5 years. The average %SPCF was 13.0% ± 11.0%. With a multivariate analysis, %SPCF was significantly correlated with time (i.e., the longer the time period since the Fontan procedure, the lower the %SPCF) (p = 0.006), previous total anomalous pulmonary vein drainage (p = 0.007), a low pulmonary artery index (Nakata index) before the Fontan procedure (p = 0.04), and older age at the time of the Fontan procedure (p = 0.002). Regarding the findings after the Fontan procedure, %SPCF was significantly correlated with ventricular end-diastolic volume (p < 0.001), ventricular end-systolic volume (p < 0.001), central venous pressure (p < 0.001), plasma brain natriuretic peptide concentration (p < 0.001), hemoptysis (p = 0.009), and poor New York Heart Association functional class (p = 0.007). SPCF was correlated with clinical condition after the Fontan procedure. The importance of sufficient growth of the pulmonary vascular bed should be emphasized because the development of SPCF is believed to result from the poor condition of the pulmonary circulation.
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http://dx.doi.org/10.1007/s00246-020-02450-8DOI Listing
December 2020

Is High Heart Rate Always Harmful to Heart Failure Patients? - Reply.

Circ J 2020 08 31;84(9):1674-1675. Epub 2020 Jul 31.

Department of Clinical Development, Ono Pharmaceutical Co., Ltd.

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http://dx.doi.org/10.1253/circj.CJ-20-0590DOI Listing
August 2020

Serum N-terminal pro-B-type natriuretic peptide as a predictor for future development of atrial fibrillation in a general population: the Hisayama Study.

Int J Cardiol 2020 Dec 24;320:90-96. Epub 2020 Jun 24.

Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

Background: Biomarkers for predicting future development of atrial fibrillation (AF) have not been fully established in general populations. The aim of this study was to assess the predictive ability of serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) for the development of AF.

Methods And Results: A total of 3126 community-dwelling Japanese subjects aged ≥ 40 years without a history of AF in 2002 were followed up for a median of 10.2 years. Serum NT-proBNP levels at baseline were divided into four categories (≤ 54, 55-124, 125-299, and ≥ 300 pg/mL) according to the current guidelines and prior reports. The hazard ratios for the development of AF were estimated using a Cox proportional hazards model. During the follow-up period, 153 subjects developed new-onset AF. The age- and sex-adjusted cumulative incidence of AF increased significantly with higher serum NT-proBNP levels (p < 0.001 for trend). The association remained significant after adjustment for known risk factors for AF and cardiovascular disease (hazard ratio [95% confidence interval]: ≤ 54 pg/mL: 1.00 [reference]; 55-124 pg/mL: 1.72 [1.00-2.97]; 125-299 pg/mL: 3.95 [2.23-6.98]; ≥ 300 pg/mL: 8.51 [4.48-16.17]; p < 0.001 for trend). Furthermore, incorporation of serum NT-proBNP levels into the model consisting of known risk factors for AF and cardiovascular disease significantly improved the predictive ability for developing AF (Harrell's c-statistics: 0.828 to 0.844, p = 0.01; continuous net reclassification improvement: 0.41, p < 0.001; integrated discrimination improvement: 0.031, p < 0.001).

Conclusions: Serum NT-proBNP levels can be a risk biomarker for predicting future development of AF in a general Japanese population.
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http://dx.doi.org/10.1016/j.ijcard.2020.06.018DOI Listing
December 2020

Preoperative Threshold for Normalizing Right Ventricular Volume After Transcatheter Closure of Adult Atrial Septal Defect.

Circ J 2020 07 16;84(8):1312-1319. Epub 2020 Jun 16.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University.

Background: The latest guidelines recommend early intervention in adult atrial septal defect (ASD) patients with signs of right ventricular (RV) enlargement. However, the criteria of RV enlargement for optimal intervention remain unclear. We investigated the preoperative determinants for normalizing the RV volume after transcatheter closure of ASD in adults.Methods and Results:We retrospectively analyzed 52 ASD patients who underwent transcatheter closure. Cardiac magnetic resonance imaging (CMR) measured RV volume before and 1 year after the closure. The patients were divided into normalized (postoperative RV end-systolic volume index [RVESVI] <47 mL/mand end-diastolic volume index [RVEDVI] <108 mL/m) and non-normalized (postoperative RVESVI ≥47 mL/mor RVEDVI ≥108 mL/m) groups. Preoperative RVESVI was significantly smaller (72 mL/mvs. 80 mL/m) and RVEF was higher (56% vs. 51%) in the normalized group compared with the non-normalized group. Receiver-operating characteristic analysis for the normalization of postoperative RV volume showed that the preoperative threshold value of RVESVI was 75 mL/m. In addition, multivariate analysis showed that preoperative RVESVI was an independent predictor for normalization of RV volume.

Conclusions: Preoperative RVESVI is an independent predictor for normalization of RV volume at 1 year after transcatheter closure of ASD in adults. Early intervention before RVESVI reaches 75 mL/mmay confer optimal timing for normalizing RV volume.
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http://dx.doi.org/10.1253/circj.CJ-20-0136DOI Listing
July 2020

Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity.

JCI Insight 2020 05 7;5(9). Epub 2020 May 7.

Department of Cardiovascular Medicine and.

Doxorubicin (DOX), a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicin-induced 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.
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http://dx.doi.org/10.1172/jci.insight.132747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253028PMC
May 2020

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.

Circ J 2020 04 2;84(5):742-753. Epub 2020 Apr 2.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University.

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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http://dx.doi.org/10.1253/circj.CJ-19-0759DOI Listing
April 2020

Roxadustat Markedly Reduces Myocardial Ischemia Reperfusion Injury in Mice.

Circ J 2020 05 24;84(6):1028-1033. Epub 2020 Mar 24.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University.

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.
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http://dx.doi.org/10.1253/circj.CJ-19-1039DOI Listing
May 2020

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.

Hypertension 2020 04 11;75(4):991-1001. Epub 2020 Mar 11.

From the Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan (K.O., S.I., M.I., A.I., T.T., N.E., T.Y., M.S., H.D., H.T.).

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.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14400DOI Listing
April 2020

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

ESC Heart Fail 2020 02 17;7(1):339-347. Epub 2020 Jan 17.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.

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.
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http://dx.doi.org/10.1002/ehf2.12571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083406PMC
February 2020

Left Ventricular Noncompaction with Multiple Thrombi in Apical Aneurysm.

Intern Med 2020 Feb 24;59(3):377-381. Epub 2019 Oct 24.

Department of Cardiovascular Medicine, Kyushu University Faculty of Medicine Graduate School of Medical Sciences School of Medicine, Japan.

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.
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http://dx.doi.org/10.2169/internalmedicine.3489-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028405PMC
February 2020

NT-proBNP and Risk of Dementia in a General Japanese Elderly Population: The Hisayama Study.

J Am Heart Assoc 2019 09 24;8(17):e011652. Epub 2019 Aug 24.

Department of Epidemiology and Public Health Graduate School of Medical Sciences Kyushu University Fukuoka Japan.

Background Epidemiological evidence implies a link between heart disease and dementia. However, few prospective studies have assessed the association between serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels and dementia. Methods and Results A total of 1635 community-dwelling Japanese elderly aged ≥60 years without dementia (57% women, mean age±SD 70.8±7.7 years) were followed up for 10 years. Serum NT-proBNP levels were divided into 4 categories (≤54, 55-124, 125-299, and ≥300 pg/mL). The hazard ratios were estimated using a Cox proportional hazards model. During the follow-up period, 377 subjects developed all-cause dementia, 247 Alzheimer disease, and 102 vascular dementia. The age- and sex-adjusted incidence of all-cause dementia was 31.5 per 1000 person-years and increased significantly with higher serum NT-proBNP levels, being 16.4, 32.0, 35.7, and 45.5, respectively (P for trend <0.01). Subjects with serum NT-proBNP levels of ≥300 pg/mL had a significantly higher risk of all-cause dementia (hazard ratio=2.46, 95% CI 1.63-3.71) than those with serum NT-proBNP levels of ≤54 pg/mL after adjusting for confounders. Similar risks were observed for Alzheimer disease and vascular dementia. Incorporation of the serum NT-proBNP level into a model with known risk factors for dementia significantly improved the predictive ability for incident dementia (c-statistics 0.780-0.787, P=0.02; net reclassification improvement 0.189, P=0.001; integrated discrimination improvement 0.011, P=0.003). Conclusions Higher serum NT-proBNP levels were significantly associated with an increased risk of dementia. Serum NT-proBNP could be a novel biomarker for predicting future risk of dementia in the general elderly population.
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http://dx.doi.org/10.1161/JAHA.118.011652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755853PMC
September 2019

Blockade of L-type Ca channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-κB pathway.

Sci Rep 2019 07 8;9(1):9850. Epub 2019 Jul 8.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.

Ca/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 Ca. We hypothesized that blockade of L-type Ca 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 Ca 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 Ca elevation and activation of CaMKII-NF-κB pathway. LTCC blockers might be potential therapeutic agents against DOX-induced cardiomyopathy.
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http://dx.doi.org/10.1038/s41598-019-46367-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614470PMC
July 2019

Outcome of patients with functional single ventricular heart after pacemaker implantation: What makes it poor, and what can we do?

Heart Rhythm 2019 12 25;16(12):1870-1874. Epub 2019 Jun 25.

Department of Pediatric Cardiology, Fukuoka Children's Hospital, Fukuoka, Japan.

Background: Pacemaker implantation in patients with single ventricle is associated with poor outcomes.

Objective: The purpose of this study was to determine the reasons for the poor outcomes of pacemaker implantation.

Methods: We performed a retrospective chart review of patients with single ventricle who had undergone permanent pacemaker implantation. Patients were categorized into 3 groups based on the site of pacing and the proportion of ventricular pacing (VP) as follows: (1) atrial pacing group with atrial pacing only (n = 11); (2) low VP group with low daily VP proportion (<50%; n = 12); and (3) high VP group with high daily VP proportion (≥50%; n = 15). Pacing leads were placed at the epicardium in all patients.

Results: No patients in the atrial pacing or low VP groups died, whereas the survival rate in the high VP group was 58.9% and 39.3% at 10 and 20 years, respectively, after pacemaker implantation. Among the post-Fontan patients, plasma brain natriuretic peptide (BNP) levels significantly increased with the proportion of VP: 11.7, 20.3, and 28.4 pg/mL in the atrial pacing, low VP, and high VP groups, respectively (P = 0.04). In the high VP group, the plasma BNP level was significantly lower in patients with an apical pacing lead than in those with a nonapical pacing lead (27.0 pg/mL vs 82.8 pg/mL, respectively; P = .03).

Conclusion: A higher proportion of VP was associated with poor outcome and higher plasma BNP levels, probably due to ventricular dyssynchrony. In epicardial ventricular pacing, apical pacing is better to avoid the increase in ventricular stress and plasma BNP level.
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http://dx.doi.org/10.1016/j.hrthm.2019.06.019DOI Listing
December 2019

Triglyceride deposit cardiomyovasculopathy: a rare cardiovascular disorder.

Orphanet J Rare Dis 2019 06 11;14(1):134. Epub 2019 Jun 11.

Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Triglyceride deposit cardiomyovasculopathy (TGCV) is a phenotype primarily reported in patients carrying genetic mutations in PNPLA2 encoding adipose triglyceride lipase (ATGL) which releases long chain fatty acid (LCFA) as a major energy source by the intracellular TG hydrolysis. These patients suffered from intractable heart failure requiring cardiac transplantation. Moreover, we identified TGCV patients without PNPLA2 mutations based on pathological and clinical studies. We provided the diagnostic criteria, in which TGCV with and without PNPLA2 mutations were designated as primary TGCV (P-TGCV) and idiopathic TGCV (I-TGCV), respectively. We hereby report clinical profiles of TGCV patients. Between 2014 and 2018, 7 P-TGCV and 18 I-TGCV Japanese patients have been registered in the International Registry. Patients with I-TGCV, of which etiologies and causes are not known yet, suffered from adult-onset severe heart disease, including heart failure and coronary artery disease, associated with a marked reduction in ATGL activity and myocardial washout rate of LCFA tracer, as similar to those with P-TGCV. The present first registry-based study showed that TGCV is an intractable, at least at the moment, and heterogeneous cardiovascular disorder.
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http://dx.doi.org/10.1186/s13023-019-1087-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560904PMC
June 2019

Electrocardiographic Left Ventricular Hypertrophy Is Independently Associated With Better Long-Term Outcomes in Dilated Cardiomyopathy Patients.

Circ Rep 2019 May 30;1(6):248-254. Epub 2019 May 30.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University Fukuoka Japan.

Electrocardiogram (ECG) findings of left ventricular hypertrophy (LVH; ECG-LVH) are observed in patients with dilated cardiomyopathy (DCM), but the prognostic importance is unclear. The present study assessed the impact of QRS voltage on long-term outcomes, including mortality and rehospitalization, in patients with DCM using a database of patients hospitalized for worsening heart failure (HF). We analyzed a total of 261 patients with DCM in the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), a prospective cohort studying the characteristics and treatments in a broad sample of HF patients. ECG-LVH were diagnosed according to the Sokolow-Lyon voltage criteria. A total of 81 patients (31.0%) had ECG-LVH. During a mean follow-up period of 1.8 years, patients with ECG-LVH had a lower rate of all-cause death (9.0% vs. 20.3%, P=0.029) and composite of all-cause death and rehospitalization due to worsening HF (26.9% vs. 45.9%, P=0.007) than those without it. After multivariable adjustment, ECG-LVH was an independent negative predictor for the risk of composite all-cause death and rehospitalization (hazard ratio, 0.358; 95% CI: 0.157-0.857, P=0.049). ECG-LVH were independently associated with better long-term outcome in patients with DCM.
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http://dx.doi.org/10.1253/circrep.CR-19-0025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889487PMC
May 2019

Cardioprotective effect of renin-angiotensin inhibitors and β-blockers in trastuzumab-related cardiotoxicity.

Clin Res Cardiol 2019 Oct 11;108(10):1128-1139. Epub 2019 Mar 11.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: Trastuzumab-related cardiotoxicity (TRC) has been considered as reversible. However, recent studies have raised concern against reversibility of left ventricular (LV) systolic dysfunction in breast cancer patients treated with trastuzumab. In addition, the efficacy of medical treatment for heart failure (HF) including renin-angiotensin inhibitors and β-blockers has not been defined in TRC.

Methods And Results: We retrospectively studied 160 patients with breast cancer receiving trastuzumab in the adjuvant (n = 129) as well as metastatic (n = 31) settings in our institution from 2006 to 2015. During the median follow-up of 3.5 years, 20 patients (15.5%) receiving adjuvant trastuzumab and 7 patients (22.6%) with metastatic breast cancer developed TRC with a mean decrease in LV ejection fraction (EF) of 19.8%. By the multivariate analysis, lower LVEF before trastuzumab (OR 1.30; 95% CI 1.16-1.48; P = 0.0001) independently predicted subsequent development of TRC. LV systolic dysfunction was reversible in 20 patients (74.1%) with a median time to recovery of 7 months, which was independently associated with lower dose of anthracyclines (OR 1.03; 95% CI 1.01-1.07, P = 0.020) and an introduction of renin-angiotensin inhibitors and β-blockers (OR 19.0; 95% CI 1.00-592.2, P = 0.034).

Conclusions: Irreversible decline in LVEF occurred in patients who underwent trastuzumab in combination with anthracyclines with a relatively high frequency. The lower cumulative dose of anthracyclines and HF treatment including renin-angiotensin inhibitors and β-blockers were both independent predictors to enhance LV functional reversibility in patients with TRC.
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http://dx.doi.org/10.1007/s00392-019-01448-4DOI Listing
October 2019

Simple Risk Score to Predict Survival in Acute Decompensated Heart Failure - AB Score.

Circ J 2019 04 7;83(5):1019-1024. Epub 2019 Mar 7.

Department of Cardiovascular Medicine, Nara Medical University.

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 AB 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 AB 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 AB score is useful for estimating survival rate in ADHF patients at discharge.
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http://dx.doi.org/10.1253/circj.CJ-18-1116DOI Listing
April 2019

Ivabradine for the Treatment of Cardiovascular Diseases.

Circ J 2019 01 29;83(2):252-260. Epub 2018 Dec 29.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University.

Higher heart rate (HR) is independently related to worse outcomes in various cardiac diseases, including hypertension, coronary artery disease, and heart failure (HF). HR is determined by the pacemaker activity of cells within the sinoatrial node. The hyperpolarization-activated cyclic nucleotide-gated (HCN) 4 channel, one of 4 HCN isoforms, generates the I current and plays an important role in the regulation of pacemaker activity in the sinoatrial node. Ivabradine is a novel and only available HCN inhibitor, which can reduce HR and has been approved for stable angina and chronic HF in many countries other than Japan. In this review, we summarize the current knowledge of the HCN4 channel and ivabradine, including the function of HCN4 in cardiac pacemaking, the mechanism of action of I inhibition by ivabradine, and the pharmacological and clinical effects of ivabradine in cardiac diseases as HF, coronary artery disease, and atrial fibrillation.
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http://dx.doi.org/10.1253/circj.CJ-18-1184DOI Listing
January 2019

Comparative proteomic analysis identifies exosomal Eps8 protein as a potential metastatic biomarker for pancreatic cancer.

Oncol Rep 2019 Feb 15;41(2):1019-1034. Epub 2018 Nov 15.

Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka 411‑8777, Japan.

Exosomes are small vesicles found in extracellular environments including blood, urine, and cell culture medium. Their contents are cell‑type specific, and molecules embedded in exosomes can be useful fluid‑based clinical biomarkers. To identify proteins with metastatic marker potential, we conducted a comparative exosomal proteome analysis using human pancreatic cancer cell lines derived from metastasis, ascites, and primary tumors. Metastatic potential of cell lines was assessed by migratory and invasive activities. A pancreatic cancer cell line from metastasis (SU.86.86) revealed 23‑fold and 20‑fold increases in cell migratory and invasive activities, respectively, compared to the MIA PaCa‑2 cell line derived from primary tumor cells. Liquid chromatography‑mass spectrometry‑based proteome analysis and subsequent validation by immunoblot analysis revealed that epidermal growth factor receptor pathway substrate 8 (Eps8) was highly abundant in exosomes from metastasis‑derived SU.86.86 cells. Comparison of 12 pancreatic cancer cell lines derived from different stages of malignancy revealed a strong relationship between exosomal Eps8 protein levels and cell motile activities (migration: r=0.85, P=4.2x10‑4; invasion: r=0.60, P=3.2x10‑2). Conversely, relationships between intracellular Eps8 protein levels and cell motile activities were moderate (migration: r=0.65, P=2.0x10‑2; invasion: r=0.51, P=9.2x10‑2). It was therefore concluded that exosomal Eps8 protein levels were correlated with the migratory cell potential of human pancreatic cancer cells, indicating that exosomal Eps8 has the potential to be a metastatic biomarker for human pancreatic cancer.
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http://dx.doi.org/10.3892/or.2018.6869DOI Listing
February 2019