Background: Heart rate (HR) reduction by β-blocker might not benefit patients with heart failure and reduced ejection fraction (HFrEF) with atrial fibrillation (AF). Methods and Results: The J-CHF study was a prospective randomized multicenter trial that assigned 360 HFrEF patients to a 2.5 mg/5 mg/20 mg target dose of carvedilol. Carvedilol was uptitrated over 8 weeks and then the dose was fixed. Of 321 patients available for analysis, AF was identified in 65 (20%). Using the median absolute change in HR at 32 weeks (∆HR), the subjects were further divided into group A (∆HR >-6 beats/min) and B (∆HR ≤-6 beats/min). Both in sinus rhythm (SR) and AF, baseline characteristics and achieved carvedilol dose were similar between groups A and B. In SR, the time-dependent change in left ventricular EF (LVEF) and LV end-diastolic dimension (LVEDD) over 56 weeks was more favorable in B compared with A (∆LVEF, P=0.036; ∆LVEDD, P=0.047), and ∆HR was independently associated with ∆LVEF (P=0.040). Group B had a lower rate of the primary endpoint, defined as a composite of death and hospitalization due to cardiovascular causes including acute decompensated HF at 3 years (P=0.002). ∆HR was an independent predictor of the primary endpoint (P=0.01), but this was not observed in AF. Conclusions: Response to the carvedilol HR reduction might differ in HFrEF between SR and AF.

The primary step in the function of many different hormones and neurotransmitters involves receptor-mediated stimulation of the breakdown of plasma membrane inositol phospholipids. The phosphatidylinositol (PI)-turnover pathway generates two second messengers, inositol-(1, 4, S) trisphosphate (IP3) and sn1, 2-diacylglycerol (DAG). DAG stimulates membrane-bound phospholipid-dependent, Ca2+-dependent protein kinase C, while IP3 releases Ca2+ from endoplasmic reticulum stores. This PI-tumover pathway may have an important role in inducing cardiac myocyte hypertrophy, even in adult rat myocytes. This chapter discusses the polyphosphoinositide metabolism in pressure-overloaded hypertrophic adult rat heart subjected to a1-adrenergic stimulation. It determines PI-specific phospholipase C activity and IP3-kinase activity. PI-turnover pathway may have a quite important role in inducing cardiac myocyte hypertrophy. The properties of inositoltrisphosphate kinase, one of the enzyme consist of PI turn-over, are examined in hypertrophied rat heart.

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 m2at 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.

Introduction: Cardiac cachexia is a strong predictor of a poor clinical outcome in patients with heart failure (HF), whereas the prognosis of obese HF patients is more favorable compared with lean ...

Background: Autoantibody against beta(1)-adrenergic receptors (beta(1)-AAb) exerts agonist-like action inducing receptor uncoupling and myocardial damage. We attempted to determine the significance of beta(1)-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. beta(1)-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 (Delta LVEF) 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. beta(1)-AAb titer was significantly correlated with Delta LVEF 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 beta(1)-AAb is associated with favorable response to carvedilol in CHF.

Introduction: Autoimmune disorder is one of the features characterizing congestive heart failure (CHF) not only due to idiopathic dilated cardiomyopathy, but due to other etiologies. Autoantibody directed against β1-adrenergic receptors (β1-AAb) exerts agonist-like action inducing receptor uncoupling, and elicits persistent myocardial damage. We, therefore, attempted to determine the significance of β1-AAb in patients with CHF who received β-blocker carvedilol in the substudy of J-CHF study. Methods: In this prospective, randomized, multicenter trial, 117 patients (left ventricular ejection fraction [LVEF] ≤ 40%) with mild to moderate CHF were assigned to 2.5mg/5mg/20mg (n=38/36/43) carvedilol groups according to the target dose. Sera were collected at baseline and β1-AAb titer was determined using ELISA. Results: ELISA showed 66 patients as negative and 36/7/7/1 patients as 20-fold (x20) / x40 / x80 / x160 positive, respectively. When the study population was divided into β1-AAb high titer (≥ x40, H) and low titer (≤ x20, L) groups, there were no significant differences in vital signs or cardiac function at baseline between 2 groups. The % change of LVEF during 56 weeks after carvedilol introduction (ΔLVEF) was significantly larger in H than L (H, +85±78% vs. L, +43±65%, p=0.04). LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) decreased to a greater extent in H than L during 56 weeks (LVEDV, 182±50 to 119±43 ml vs. 202±52 to 167±58 ml, p<0.005 by ANOVA; LVESV, 136±47 to 62±36 ml vs. 141±47 to 97±53 ml, p=0.048 by ANOVA). β1-AAb titer was significantly correlated with ΔLVEF and the % change of LV volume (LVEF, r=0.24, p=0.02; LVEDV, r=-0.26, p=0.02; LVESV r=-0.27, p=0.01). Multiple regression analysis demonstrated that β1-AAb titer was an independent predictor of ΔLVEF and the % changes of LV volume after adjusting for age, gender, allocated dose of carvedilol, heart rate at baseline, plasma BNP at baseline, etiology of CHF and the presence of atrial fibrillation (ΔLVEF β=0.286, p=0.01; ΔLVEDV β=-0.227, p=0.04; ΔLVESV, β=-0.250, p=0.02). Conclusions: The findings in the present study suggested that β1-AAb has a crucial role as one of the determinants of reverse remodeling during carvedilol therapy for patients with CHF.

AIM:The Japan EPA Lipid Intervention Study (JELIS) reported a 19% reduction of the risk for coronary artery disease after long-term use of pure eicosapentaenoic acid (EPA) in Japanese patients with hypercholesterolemia. The variation in plasma fatty acid composition influenced the risk of coronary events. The aim of this study was to examine in JELIS participants the possible correlation of changes in plasma fatty acids with those of serum lipids.METHODS:The coefficient for the correlation between the absolute change in plasma fatty acid concentrations and the changes in serum lipids was calculated in 13,901 JELIS participants.RESULTS:Low-density lipoprotein (LDL) cholesterol exhibited a positive correlation with docosahexaenoic acid (DHA; r=0.117 in control group, r=0.155 in EPA group) and linoleic acid (r=0.139 in control group, r=0.177 in EPA group), but the correlation coefficients with EPA (r=0.097 in control group, r=-0.032 in EPA group) were less than 0.1. We distributed the patients into 9 groups according to tertiles of the change in EPA and DHA. The average absolute decrease of LDL cholesterol and L/H ratio in each group was significantly smaller (p<0.001) in the DHA-high tertile, but not in any EPA tertile.CONCLUSION:The changes in DHA, but not in EPA, showed a positive correlation with the changes in LDL-cholesterol.

AIM The present study examined the importance of reducing non-high-density lipoprotein cholesterol (non-HDL-C) for the primary prevention of the occurrence of coronary artery disease (CAD) in the JELIS, and the effects of EPA. METHODS The patients were distributed into 4 subgroups using the lipid management goal for LDL-C recommended by the Japan Atherosclerosis Society guideline (2007) and the goal for non-HDL-C defined as 30 mg/dL higher than LDL-C: A) achieved both goals; B) achieved the LDL-C but not non-HDL-C goal; C) achieved the non-HDL-C but not LDL-C goal; and D) did not attain either goal. The incidences of CAD in the 4 subgroups were compared, and the effects of eicosapentaenoic acid (EPA) on the risk of CAD in these subgroups were examined. RESULTS In the non-EPA group, the incidence of CAD in patients who did not achieve the goals for LDL-C or non-HDL-C was higher than in patients who achieved those goals. Patients in subgroups B, C, and D were at higher risk for CAD than those in subgroup A (B, HR 2.31; C, HR 1.90; D, HR 2.47). EPA reduced the risk of CAD by 38% in subgroups B, C, and D (p= 0.007). CONCLUSION We reconfirmed non-HDL-C as a predictor of the risk for CAD and a residual risk marker of CAD after LDL-C-lowering therapy. EPA was useful to reduce the occurrence of CAD in patients who did not achieve the goals for LDL-C and/or non-HDL-C.

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.

Autoantibody against β1-adrenergic receptors (β1-AAB) exerts agonist-like action and elicits myocardial damage. We attempted to determine the significance of β1-AAB in patients with congestive heart failure (CHF) who received β-blocker carvedilol in the substudy of J-CHF study.

AIM:The Japan EPA Lipid Intervention Study (JELIS) was the first prospective randomized clinical trial to demonstrate prevention of coronary events by pure eicosapentaenoic acid (EPA). The aim of this study was to examine the relationships between various plasma fatty acid concentrations and the risk of coronary events in JELIS participants.METHODS:In 15,534 participants, we calculated the hazard ratio for major coronary events (sudden cardiac death, fatal or nonfatal myocardial infarction, unstable angina pectoris, and angioplasty/stenting or coronary artery bypass grafting) relative to the on-treatment average level of plasma fatty acids with the Cox proportional hazard model.RESULTS:As a result of EPA intervention, the plasma EPA concentration increased, but the docosahexaenoic acid (DHA) concentration did not. The other fatty acids measured decreased slightly. The higher plasma level of EPA (hazard ratio=0.83, p=0.049, in all participants and hazard ratio=0.71, p=0.018, in the EPA intervention group), but not of DHA, was inversely associated with the risk of major coronary events. The associations between other fatty acids and the risk of major coronary events were not significant. In all JELIS participants, the risk of major coronary events was significantly decreased (20%) in the group with high (150 µg/mL or more) on-treatment plasma EPA concentration compared with that in the low (less than 87 µg/mL) group.CONCLUSION:The risk of coronary artery disease is influenced by variations in plasma fatty acid composition. Among n-3 polyunsaturated fatty acids, EPA and DHA exhibited differences in the correlation with the risk of major coronary events.

Echocardiography is one of the most important and clinically useful techniques in the assessment of dia-stolic function. Because of the prevalence of this technique, "diastology'' and even the concept of diastolic heart failure have become familiar to researchers and physicians. We believe the first description by Kitabatake and his colleagues in 1982 of the use of Doppler technique to assess the transmitral flow velocity pattern in various cardiac diseases was the beginning of this development. Since then, a number of excellent works regarding echocardio-graphic assessment of diastolic function have emerged from Japan. Here, we review the Japanese contributions to the development of the use of Doppler echocardiography in diastology.

In this paper, the extraction conditions yielding the highest steviol glycosides from the leaves of Stevia rebaudiana were determined using microwave (MAE) and ultrasonically assisted extraction (UAE) and biological activities of the extracts along with analyses of the residue from the extraction process were investigated. Under optimum conditions, 21.21 mg glycosides/g dried leaf in MAE and 14.90 mg glycosides/g dried leaf in UAE were quantified by HPLC analyses. After extraction, total chlorophyll, carotenoid contents and total dietary fibers were quantified as 15.14 mg/100 g, 2.93 mg/100 g and 6.5% in the raffinate phase. The total phenols were determined as 80.13 and 86.47 mg gallic acid/g extract, whereas the total flavonoids were 111.16 and 126.70 mg quercetin/g extract and DPPH radical scavenging activities were 91.39 and 92.40%, respectively. The extracts exhibited no cytotoxicity against healthy cell line and macrophage RAW 264.7 cells. The IC50 values were 68 μg/ml and >100 μg/ml for MAE and UAE. Overall, obtained results suggest that stevia extracts and its residue can be utilized holistically on industrial scale.

Background: The JELIS trial examined the preventive effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD) in hypercholesterolemia. Previous investigators have reported that patients with peripheral artery disease (PAD) have a poor prognosis due to the potential risk for CAD. We conducted a subanalysis to examine whether the incidence of CAD was high in patients with PAD and whether EPA prevented the occurrence of CAD.Methods and Results: Of 18,645 the Japan EPA lipid intervention study (JELIS) patients, 223 had PAD (control group; complicated (n=77), newly diagnosed (n=29), EPA group; complicated (n=96), newly diagnosed (n=21)). We analyzed the incidence of major coronary events (MCE) in the 2 groups. Cox proportional hazard ratio adjusted for baseline risk factor levels was used to test differences between the 2 groups. The incidence of MCE in the control group was significantly higher in patients complicated with PAD and in those newly diagnosed with PAD than in patients without PAD (complicated: hazard ratio 1.97, P=0.039; newly diagnosed: hazard ratio 2.88, P=0.030). As for patients with PAD, the EPA group had a significantly lower MCE hazard ratio than the control group (hazard ratio 0.44, 95% confidence interval 0.19-0.97, P=0.041).Conclusions: Subanalysis of the JELIS trial demonstrated that in patients with PAD the incidence of CAD was higher than in controls, and that EPA markedly reduced the occurrence of CAD in those patients. (Circ J 2010; 74: 1451-1457)

BACKGROUND:The JELIS trial examined the preventive effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD) in hypercholesterolemia. Previous investigators have reported that patients with peripheral artery disease (PAD) have a poor prognosis due to the potential risk for CAD. We conducted a subanalysis to examine whether the incidence of CAD was high in patients with PAD and whether EPA prevented the occurrence of CAD.METHODS AND RESULTS:Of 18,645 the Japan EPA lipid intervention study (JELIS) patients, 223 had PAD (control group; complicated (n=77), newly diagnosed (n=29), EPA group; complicated (n=96), newly diagnosed (n=21)). We analyzed the incidence of major coronary events (MCE) in the 2 groups. Cox proportional hazard ratio adjusted for baseline risk factor levels was used to test differences between the 2 groups. The incidence of MCE in the control group was significantly higher in patients complicated with PAD and in those newly diagnosed with PAD than in patients without PAD (complicated: hazard ratio 1.97, P=0.039; newly diagnosed: hazard ratio 2.88, P=0.030). As for patients with PAD, the EPA group had a significantly lower MCE hazard ratio than the control group (hazard ratio 0.44, 95% confidence interval 0.19-0.97, P=0.041).CONCLUSIONS:Subanalysis of the JELIS trial demonstrated that in patients with PAD the incidence of CAD was higher than in controls, and that EPA markedly reduced the occurrence of CAD in those patients.

Background: The mortality and morbidity rates of various cardiovascular diseases differ between Western countries and Japan. The age-and gender-specific prevalence rate of atrial fibrillation (AF) in the general population of Japan was determined using the data from periodic health examinations in 2003.Methods: Data of 630,138 subjects aged 40 years or more (47% were men and 34% were employees of companies and local governments) were collected from northern to southern Japan. The prevalence of diagnosed AF in each 10-year age group of both men and women was determined. Based on these prevalence rates and the Registry of Residents, the number of people having AF in Japan was estimated.Results: The prevalence rate of AF increased as both male and female subjects aged, and it was 4.4% for men but only 2.2% for women aged 80 years or more (p<0.0001). As a whole, the AF prevalence of men was three times that of women (1.35 versus 0.43%, p<0.0001). There may be approximately 716,000 people (95% confidence interval (CI), 711,000-720,000) with AF in Japan, an overall prevalence of 0.56%. The number of people having AF was projected to be 1.034 (95% CI, 1.029-1.039) million, an overall prevalence of 1.09%, in 2050.Conclusions: The prevalence of AF increased in Japan as the population aged, as in Western countries. The overall prevalence of AF in Japan is approximately two-thirds of that in the USA. The projected increase in the number of people having AF is modest in Japan in 2050. (C) 2008 Elsevier Ireland Ltd. All rights reserved.