Deficit of CD38/cyclic ADP-ribose is differentially compensated in hearts by gender.

To elucidate whether myocardial CD38/cyclic ADP-ribose (cADPR) signaling plays a physiological role, we investigated the heart of CD38 knockout mice (CD38KO). In CD38KO, the myocardial cADPR content was reduced by 85% compared with wild-type mice (WT). Cardiac hypertrophy developed only in males. At 36 degrees C, none of the parameters for Ca(2+) transients and forces of the papillary muscles differed between WT and CD38KO. In contrast, at 27 degrees C, at which cADPR does not work, the peak [Ca(2+)](i) was increased and the decline in [Ca(2+)](i) was accelerated in CD38KO compared with WT. In CD38KO, the protein expression of SR Ca(2+) ATPase type2 (SERCA2) and the SERCA2-to-phospholamban ratio were increased compared with WT. The ryanodine receptor protein was increased only in female CD38KO compared with WT. These data suggest that the CD38/cADPR signaling plays an important role in intracellular Ca(2+) homeostasis in cardiac myocytes in vivo. Its deficiency was compensated differentially according to gender.

Should increasing the dose or adding an AT1 receptor blocker follow a relatively low dose of ACE inhibitor initiated in acute myocardial infarction?

OBJECTIVE: Based on currently available clinical evidence, we should use high-dose angiotensin converting enzyme inhibitor (ACE-I) for patients with acute myocardial infarction (MI), initiating it at incremental doses to avoid excessive hypotension. Recent animal studies with acute MI models failed to demonstrate the superiority of the combination therapy of ACE-I and angiotensin receptor blocker (ARB) to high-dose ACE-I treatment with comparable blood pressure reductions, which however might be attributed to the initiation of the targeted doses from the beginning. The aim of this study was to compare the effect of increasing the dose of ACE-I with that of adding ARB following a relatively low dose of ACE-I on the survival and left ventricular (LV) remodeling after MI. METHODS: Rats underwent left coronary artery ligation and were treated with either ACE-I temocapril (5 mg/kg/day) or vehicle for 2 weeks, which was initiated 3 days after the surgery. The rats treated with temocapril were further randomly assigned to receive either high-dose temocapril (10 mg/kg/day) or combination therapy (temocapril 5 mg/kg/day+olmesartan 2.5 mg/kg/day), which was continued for another 6 weeks. RESULTS: Both treatments similarly reduced the blood pressure, improved survival and ameliorated LV enlargement. In contrast, several parameters of LV function were significantly ameliorated only by the high-dose ACE-I but not by the combination therapy. CONCLUSIONS: After the initiation of a relatively low dose of ACE-I in acute MI, increasing the dose of ACE-I or adding ARB may equally improve survival and LV remodeling in the setting of an equal hypotensive effect. Further study with a longer treatment protocol is required to determine whether the several favorable effects on LV function elicited only by the high-dose ACE-I treatment provide further beneficial effects on survival and LV remodeling compared with the combination therapy.

Characteristics and 1-year prognosis of medically treated patients with chronic heart failure in Japan.

The study was designed to characterize patients with chronic heart failure (CHF) in Japan in terms of the etiologies and prognosis. CHF was defined by ejection fraction (EF >or=50%), left ventricular diastolic dimension (LVDD >or=55 mm) or a past history of congestive heart failure. Among the 721 recruited patients, the most frequent etiology for CHF was dilated cardiomyopathy (DCM) in patients aged less than 59 years, and valvular heart disease (VHD) in those aged 70 years or more. The 1-year crude mortality was 8% overall and 12% in patients with myocardial infarction (MI). Sudden death accounted for 40% of the total deaths among all patients, and 60% in patients with MI. Multivariate logistic regression analysis showed that brain natriuretic peptide (BNP) was a consistent prognostic marker in CHF patients with a variety of etiologies. Total death and hospitalization because of heart failure were significantly less frequent in patients with BNP less than 100 pg/ml. In conclusion, the etiologies of Japanese CHF appear to be more diverse than those of other Western countries, but BNP is an excellent prognostic marker despite the etiological diversity. Sudden, unexpected death in CHF patients is also a serious problem in Japan. A nation-wide epidemiologic study should be done to characterize Japanese CHF.

Evaluation of heart-rate turbulence as a new prognostic marker in patients with chronic heart failure.

The significance of heart-rate turbulence (HRT) in patients with chronic heart failure (CHF) was evaluated to examine whether it is sensitive to the risk of ventricular tachycardia (VT). HRT is reported to predict the prognosis after myocardial infarction (MI), but its prognostic value in patients with CHF remains unknown. HRT was measured in 50 CHF patients (left ventricular ejection fraction <50% and/or left ventricular end-diastolic diameter >55 mm, 34 cardiomyopathy, 16 post-MI) and 21 patients without obvious heart diseases (control). HRT slope and HRT onset were measured by the original definitions using digitized Holter ECG recordings. Cardiac pump function was assessed by echocardiography. The value of the HRT slope was significantly lower in CHF than in control (3.7 +/- 1.7 vs 16.4 +/- 5.3, mean +/- SD, p < 0.01). The value of the HRT onset in patients with CHF was significantly higher than that in control patients (-1.1 +/- 1.9 vs -3.6 +/- 1.7, mean +/- SD, p < 0.05). The HRT slope and onset in CHF patients with VT were nearly identical to those without VT. The HRT slope appears to be a powerful prognostic marker that shows significant differences between CHF subgroups when divided by clinical events; that is, CHF death and CHF hospitalization. However, it has limited value for predicting fatal ventricular arrhythmias.