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Background: Anemia portends a poor clinical outcome in patients with chronic heart failure (CHF). However, its mechanism remains unknown. We sought to elucidate the effect of anemia on patients with HF with reduced ejection fraction (HFrEF) who receive carvedilol therapy., Methods and results: J-CHF study was a prospective, randomized, multicenter trial that assigned 360 HFrEF patients to 2.5 mg/5 mg/20 mg carvedilol groups according to the target dose. At baseline 70 patients (19%) had anemia ([A]) defined as hemoglobin level (Hb) <13 g/dL (male) or <12 g/dL (female) and the remaining 290 did not ([N]). Allocated and achieved doses of carvedilol were similar. Left ventricular ejection fraction (LVEF) and plasma B-type natriuretic peptide (BNP) level significantly improved in both groups over 56 weeks, but they were smaller in [A] than in [N] (LVEF, P=0.046; BNP, P<0.0001 by ANOVA). Baseline Hb was an independent predictor of absolute change in LVEF (β=0.13, P=0.047) and BNP (β=-0.10, P=0.01). Presence of chronic kidney disease defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 at baseline was not associated with differential response to carvedilol therapy. During 3.8±1.4 years follow-up, group [A] had a higher incidence of the composite endpoint of death, hospitalization for cardiovascular causes including HF compared with [N] (P=0.006). Baseline Hb was an independent predictor of the composite endpoint (hazard ratio 0.86, P=0.04), whereas baseline eGFR was not., Conclusions: Our data suggested that anemia was associated with a blunted response to carvedilol in HFrEF patients.

Background: Autoantibody against β1-adrenergic receptors (β1-AAb) exerts agonist-like action inducing receptor uncoupling and myocardial damage. We attempted to determine the significance of β1-AAb in chronic heart failure (CHF) patients who received carvedilol in a substudy of the Japanese Chronic Heart Failure study., Methods and Results: In this prospective, randomized, multicenter trial, 117 patients were assigned to 2.5 mg, 5 mg, and 20 mg (n = 38, 36, and 43) carvedilol groups according to the target dose. β1-AAb was positive in 51 patients (44%, P) and negative in 66 (56%, N). The percentage increase of left ventricular ejection fraction over 56 weeks (ΔLVEF) was larger in P than in N (P = .050) and in the high-titer group (H) than in the low-titer group (L; P = .04). Left ventricular (LV) volume decreased to a greater extent in H than in L over 56 weeks. β1-AAb titer was significantly correlated with ΔLVEF and the percentage change of LV volume and was an independent predictor of them. No difference was seen in the composite end point (all-cause mortality and hospitalization for cardiovascular diseases or heart failure). However, in patients with dilated cardiomyopathy, it was more common in the 2.5 mg group than in the other groups in N, and it was similar among the 3 groups in P., Conclusions: Our data suggest that the presence of β1-AAb is associated with favorable response to carvedilol in CHF., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: In chronic heart failure (CHF), it remains unclear whether the minimal dose of beta-blockade is related to survival benefits and which parameter predicts morbidity and mortality. We sought to determine the minimal dose related to survival benefits by comparing the efficacy and safety of three doses of carvedilol and the best predictive parameter for effective outcomes in Japanese patients with CHF., Methods: In this prospective, randomized, stratified trial, 364 patients with mild to moderate CHF were assigned to a daily carvedilol dose of 2.5, 5, or 20mg, plus optimal standard therapy., Findings: During the mean 3-year follow-up, resting heart rate (HR) and BNP were significantly reduced with dose-response relations in the early period but without dose-response relations in the late period. The LVEF and the LVDd were increased and decreased, respectively, without a dose-response relation. No significant difference was seen in the composite primary endpoint of all-cause mortality and hospitalization for cardiovascular diseases and heart failure. Multivariate analysis indicated early decreases in HR and BNP predicted long-term outcomes. However, adverse events increased dose-dependently. Among 237 polymorphisms in 87 heart failure-related genes, the osteopontin G-156 del genotype was associated with an event-free survival rate (Wilcoxon test, P=0.030)., Conclusions: A low carvedilol dose is effective if the HR and/or plasma BNP has been reduced. Carvedilol therapy should be guided by reductions in HR and/or BNP, especially by initial HR reduction, but not only by its dose. OPN might be a surrogate genetic marker for long-term event-free survival., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

In our previous study it was observed that the frequencies of UGT1A1*6, UGT2B7*3 and CYP2D6*10 in patients who have a low level ability of glucuronidation were significantly higher than those in patients with a high level of ability of glucuronidation. The same tendency was found in the frequency of CYP2D6*5, though there was no significant difference. The purpose of this study was to evaluate the effects of the polymorphism on pharmacokinetics of carvedilol by population pharmacokinetic analysis. Population pharmacokinetic analysis was performed using 373 plasma concentrations from 41 patients with chronic heart failure or angina pectoris. A one compartment pharmacokinetic model with first-order absorption (for oral dosing) was used to describe the concentration-versus-time data for carvedilol. We examined the effects of various clinical and genetic covariables in the regression models for clearance and volume of distribution. The results suggested that the factors of interindividual variation for carvedilol clearance were creatinine clearance and polymorphisms of UGT2B7 and CYP2D6 in the Japanese population with heart disease. It was estimated that UGT2B7*3 decreased the clearance of carvedilol by 37%, but UGT2B7*2 did not show any effect. Clearance in the patients who have intermediate activity of CYP2D6 was decreased by 39%.

Background: Tenascin-C (TN-C), an extracellular matrix glycoprotein, is specifically expressed at high levels during embryonic development, but not in the adult heart. TN-C reappears at sites of inflammatory tissue remodeling or wound healing under various pathologic conditions, such as acute myocardial infarction, acute myocarditis, and some cases of cardiomyopathy. Therefore, the expression of TN-C might be useful for detecting the clinical characteristics of, and ventricular remodeling in, dilated cardiomyopathy (DCM)., Methods and Results: Circulating serum TN-C levels in 107 patients with DCM were measured using an ELISA kit. Clinical data were also assessed by Pearson's or Spearman's correlation analysis to estimate correlations between variables. Serum TN-C levels in DCM patients were higher than those in normal controls (p<0.001). TNC levels showed a significantly positive correlation with New York Heart Association functional class (p<0.001), B-type natriuretic peptide level (p<0.001), cardiothoracic ratio on chest X-ray (p<0.01), left ventricular end-diastolic diameter (p<0.05) and left ventricular end-systolic diameter (p<0.01), and a significantly negative correlation with left ventricular ejection fraction (p<0.01)., Conclusions: The findings suggest that increased serum TN-C levels indicate the severity of heart failure, left ventricular dysfunction and remodeling in patients with DCM.

The efficacy of beta-blockers for improving the survival rate of patients with chronic heart failure has been confirmed by results deriving from a series of randomized controlled trials (RCTs) such as MERIT-HF, CIBIS-II, and COPERNICUS. Thus, treatment guidelines recommend that beta-blockers should be used in all patients with heart failure resulting from left ventricular systolic dysfunction who can tolerate with beta-blockers. Despite these guidelines, actual rates of beta-blocker prescription has been lower than expected, and when used, beta-blockers are generally prescribed in doses lower than what has been shown to reduce morbidity and mortality in RCTs. In the MUCHA trial conducted in Japan, the beta-blocker carvedilol decreased the cardiovascular risk for hospitalization in a dose-dependent manner. The 5 mg/day dose achieved a remarkable reduction that was nearly as great as the 20 mg/day dose. Whether this low-dose therapy was sufficient was not fully investigated by the MUCHA trial. Moreover, there is an ethnic difference in the effective dose between patients in Japan and Western countries, which may depend on a difference in beta1-receptor sensitivity. J-CHF trial may suggest that low doses of carvedilol under 2.5 mg/day have a beneficial effect. This trial is a randomized multi-center parallel group dose-comparison study, and with sub-studies such as an analysis of genetic polymorphisms on voluntary participation. This trial may serve as a tailored approach for Japanese physicians in the clinical management of heart failure.

Background: There are few biological markers, which strictly show the severity of congestive heart failure (CHF)., Methods and Results: Lymphocyte G-protein coupled receptor kinase (GRK) mRNA expression was measured by quantitative reverse transcription-polymerase chain reaction in 15 CHF patients: 5 patients classified as New York Heart Association class-II treated with angiotensin converting enzyme inhibitor (ACEI) (IIA), 5 patients in class-II without ACEI (IIC), and 5 patients in class-III treated with ACEI (IIIA). GRK mRNA level in IIIA was significantly higher than those in IIA (p<0.05). GRK mRNA level in IIA were significantly lower than those in IIC (p<0.05)., Conclusions: The expression level of lymphocyte GRK might show the severity of CHF, and ACEI treatment could reduce the level of GRK in CHF patients.

Aims: We investigated the correlation of adrenergic receptor polymorphisms, alpha(2c)Del322-325, beta(1)Ser49Gly and beta(1)Arg389Gly, with the risk of heart failure in the Japanese population., Methods: These polymorphisms were analysed by polymerase chain reaction-restriction fragment length polymorphism in patients with chronic heart failure due to idiopathic dilated cardiomyopathy (DCM) and compared with the control group., Results: There were no differences or any trends in the allele and genotype frequencies of the beta(1)Ser49Gly and beta(1)Arg389Gly polymorphisms. The allele frequency of the alpha(2c)Del322-325 variant was lower in patients than in controls (0.11 vs. 0.04, P = 0.011 < 0.017, by Bonferroni correction), while the genotype frequency just failed to reach significance (P = 0.022 > 0.017, by Bonferroni correction)., Conclusions: In this population, the variants beta(1)Ser49, beta(1)Arg389, and alpha(2c)Del322-325 do not appear to be risk factors for chronic heart failure due to DCM. The alpha(2c)Del322-325 variant may in fact confer some protection.

Background: Heart failure consists of two phenotypes: systolic heart failure and diastolic heart failure (DHF). A growing body of evidence demonstrated benefits of beta-blocker, angiotensin-converting enzyme inhibitor, and angiotensin II receptor blocker in systolic heart failure; however, evidence leading to therapeutic strategy of DHF is lacking., Methods and Results: The Japanese Diastolic Heart Failure Study (J-DHF) is a multicenter, prospective, randomized trial designed to assess effects of beta-blocker in patients with DHF. A total of 800 patients (400 patients in each group) will be enrolled. The primary outcome is a composite of cardiovascular death and unplanned admission to hospital for congestive heart failure. Other outcomes include all-cause mortality, worsening of the symptoms of heart failure, or a need for modification of the treatment for heart failure. Serial assessment of echocardiographic and neurohumoral parameters and cost analysis of the treatment regimen will be conducted. The follow-up period is a minimum of 2 years., Conclusion: This study will provide important evidences for the treatment of DHF.

Background: It has been suspected for some time that patients with chronic heart failure (CHF) have abnormal muscle metabolism, so in the present study the muscle metabolism of the arm and leg were compared by (31)P magnetic resonance spectroscopy ((31)P-MRS) to examine the relationship to exercise tolerance., Methods and Results: The study group comprised 13 patients and 11 normal controls. Calf-plantar and forearm-wrist flexion were performed to evaluate the metabolic capacity assessed as the phosphocreatine breakdown rate (PCr-slope) and muscle pH at a submaximal (70% peak) work rate (submax-pH). Exercise of both the arm and leg resulted in an earlier decrease in PCr and muscle pH in patients with CHF compared with controls. There were significant correlations between peak oxygen uptake (peak V(O2)) and the PCr-slope in both limbs in patients with CHF (forearm: r=0.63, p<0.05; calf: r=0.60, p<0.05), but no correlations in normal controls. There was a close correlation between the ventilatory anaerobic threshold (AT) and the PCr-slope in the calf (r=0.85, p<0.01), but not in the forearm in patients with CHF. Submax-pH in both upper and lower limbs was not significantly correlated to peak V(O2) or AT in either patients with CHF or controls., Conclusions: Although metabolic abnormalities during exercise are seen in both arms and legs, leg muscle abnormalities, in particular, are closely related to systemic exercise intolerance in patients with CHF.

Background: The efficacy and optimum dose of beta-blockers have not been established in Japanese patients with chronic heart failure (CHF). The efficacy and safety of two doses of carvedilol, a beta-blocker with vasodilator and antioxidant actions, were investigated in Japanese patients with CHF., Methods: After screening and a carvedilol challenge phase, 174 patients with mild to moderate CHF were randomly assigned (double-blinded) to placebo, 2.5 mg of carvedilol twice daily, or 10 mg of carvedilol twice daily. After a 2- to 4-week uptitration phase, maintenance treatment was continued for 24 to 48 weeks. The primary end point was improvement of the global assessment of CHF by the attending physician. Secondary end points were death or hospitalization for cardiovascular disease, cardiovascular hospitalization, hospitalization for heart failure, change of left ventricular ejection fraction, and change in New York Heart Association class., Results: Carvedilol therapy achieved dose-dependent improvement of all end points (P for linear trend, range.002 to <.001). Both carvedilol groups showed marked risk reduction (71% to 91%) for cardiovascular and CHF hospitalization and for death or cardiovascular hospitalization (P range,.024 to <.001 for pairwise comparisons with placebo). No significant differences were observed for noncardiovascular hospitalization or adverse events., Conclusions: In Japanese patients with mild or moderate CHF, carvedilol achieved dose-related improvement of CHF and left ventricular ejection fraction; cardiovascular hospitalization was markedly reduced. At 5 mg/d, carvedilol conferred an important patient benefit, less than at 20 mg/d.

Very limited epidemiological data are available regarding the prognosis of heart failure and temporal changes in survival in a population-based setting in Japan. It is estimated from the total sales of digitalis, its prescription rate and usage ratio for arrhythmias that at least one million of patients suffer from heart failure in Japan. Dilated cardiomyopathy (DCM) is a major cause of severe heart failure. Over the past 27 years, three cohorts corresponding to three different periods of 9 years were investigated. Ten-year survivals were progressively improved. Patients were older and less severely affected, partly explaining the improvement in survival. In the subgroups treated with ACE inhibitors and beta blockers, calculated ten-year survival rate reached over 90%.

Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor blockers have been demonstrated to improve symptoms and prognosis in heart failure (HF). We compared the effects of ACE inhibition and AT1 receptor blockade on myocardial beta-adrenoceptor desensitization in rabbits with HF established 3 weeks after myocardial infarction (MI) with left circumflex coronary artery ligation. Rabbits with MI were randomized to no treatment, the ACE inhibitor temocapril (0.5 mg/kg/day) or AT1 receptor blocker valsartan (3 mg/kg/day). Echocardiographic examinations showed that, relative to rabbits with untreated MI, rabbits receiving temocapril or valsartan had a limitation of cardiac remodeling and prevention of the development of systolic dysfunction. Circulating plasma norepinephrine levels that were markedly elevated in MI animals were strongly inhibited by temocapril or valsartan therapy. beta-Adrenoceptor density, beta-adrenoceptor proportion showing high-affinity agonist binding, and basal and isoproterenol-stimulated adenylate cyclase activities were significantly reduced in MI rabbits. These defects were similarly reversed by temocapril or valsartan. Importantly, as found in human HF, myocardial protein levels of beta-adrenoceptor kinase 1 and G(i alpha) were significantly elevated in MI rabbits, suggesting that these molecules are contributing to the defects in myocardial beta-adrenoceptor signaling. The expression levels of these molecules were normalized equally by both treatments. The results suggest that pharmacologically different interventions in the renin-angiotensin system can equivalently improve the derangements in the beta-adrenoceptor signaling system in the failing heart. This may be important for the beneficial effects of these agents in HF.

Aims We investigated the correlation of adrenergic receptor polymorphisms, α2cDel322–325, β1Ser49Gly and β1Arg389Gly, with the risk of heart failure in the Japanese population. Methods These polymorphisms were analysed by polymerase chain reaction-restriction fragment length polymorphism in patients with chronic heart failure due to idiopathic dilated cardiomyopathy (DCM) and compared with the control group. Results There were no differences or any trends in the allele and genotype frequencies of the β1Ser49Gly and β1Arg389Gly polymorphisms. The allele frequency of the α2cDel322–325 variant was lower in patients than in controls (0.11 vs. 0.04, P = 0.011 < 0.017, by Bonferroni correction), while the genotype frequency just failed to reach significance ( P = 0.022 > 0.017, by Bonferroni correction). Conclusions In this population, the variants β1Ser49, β1Arg389, and α2cDel322–325 do not appear to be risk factors for chronic heart failure due to DCM. The α2cDel322–325 variant may in fact confer some protection. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether localised skeletal muscle training, which does not have a great influence on the heart, improves abnormalities of calf muscle metabolism in patients with chronic heart failure.Methods: Seven cardiac patients in New York Heart Association class II and III undertook a random order crossover trial. Training consisted of unilateral calf plantar flexion exercise. Before and after training, the patients' metabolic responses were examined during the calf exercise test with phosphorus-31 nuclear magnetic resonance spectroscopy (31P-MRS) and calf blood flow with plethysmography. The new Borg scale was employed as a subjective fatigue scale.Results: In a constant load exercise test (70% of maximum load achieved during the incremental exercise), standardised phosphocreatine and intracellular pH decreased less after training (p < 0.05, repeated measures analysis of variance). The new Borg scale improved significantly after training (p < 0.05). Blood flow did not change significantly in either test.Conclusions: In patients with chronic heart failure, localised calf skeletal muscle training improved oxidative capacity without changes in calf blood flow. This training also improved the subjective fatigue scale. This training method may therefore alleviate leg fatigue experienced in daily activities. [ABSTRACT FROM AUTHOR]