Masanori Konishi

Adiponectin protects against doxorubicin-induced cardiomyopathy by anti-apoptotic effects through AMPK up-regulation

AIMS Adiponectin (APN) has been reported to protect against ischaemia-reperfusion injury and hypertrophy. However, few reports have investigated the cardioprotective effects of APN in doxorubicin (DOX)-induced cardiomyopathy; therefore, we studied the cardioprotective mechanisms of APN in this model. METHODS AND RESULTS In an in vivo study, we quantified the cardiac pathohistology of C57BL/6 mice [wild-type (WT) mice], APN transgenic mice with high APN concentrations [APN transgenic sense (SE) mice], and those with reduced APN concentrations [APN transgenic antisense (AS) mice] after intraperitoneal injections of DOX (4 mg/kg) weekly for 6 weeks. The survival rate after 14 days was significantly increased in APN-SE mice (WT vs. APN-AS vs. APN-SE: 40 vs. 17 vs. 73%, P < 0.05). We assessed myocardial pathohistological changes and observed that fibrosis and apoptosis were significantly decreased in APN-SE mice compared with those of the other groups. We also assessed DOX-induced apoptotic mechanisms in vitro using cultured cardiomyocytes isolated from neonatal WT mice. The expression of adenosine monophosphate-activated protein kinase (AMPK) and anti-apoptotic factor Bcl-2 increased, but that of pro-apoptotic factor Bax decreased in cardiomyocytes treated with highly concentrated APN. The protective effects of APN were reversed by the addition of an AMPK inhibitor (dorsomorphin) to the culture medium. CONCLUSION These data suggest that APN improved cardiac function through anti-apoptotic effects by up-regulation of AMPK in DOX-induced cardiomyopathy in mice.

Clinical Characteristics of Acute Decompensated Heart Failure With Rapid Onset of Symptoms

BACKGROUND Few reports regarding the definition, epidemiology, and pathophysiology of acute decompensated heart failure (ADHF) are available. The clinical characteristics of 194 consecutive ADHF patients with abrupt onset of symptoms were investigated. METHODS AND RESULTS Patients with acute coronary syndromes including acute myocardial infarction, acute pneumonia, severe valvular disease, and end-stage renal disease that required dialysis therapy were excluded. Patients were divided into 2 groups: rapid-progression group, onset within 24 hours before admission (n = 78); and gradual-progression group, onset more than 24 hours before admission (n = 52). No significant differences were observed in the age, gender, prescriptions, and hematological data between the 2 groups. The proportion of patients who drank excessive water was higher in the rapid-progression group. Systolic blood pressure, diastolic blood pressure, heart rate, left ventricular ejection fraction, and left ventricular wall thickness were greater in patients in the rapid-progression group. Indexes indicating left ventricular diastolic function were significantly deteriorated in the rapid-progression group. CONCLUSION Excessive water intake, acute hypertension, and diastolic dysfunction are associated with the pathophysiology of abrupt-onset ADHF. Hypertensive patients with diastolic dysfunction should be treated cautiously to prevent the occurrence of ADHF.

Synergistic effects of HMG‐CoA reductase inhibitor and angiotensin II receptor blocker on load‐induced heart failure

5‐Hydroxy‐3‐methylglutaryl‐CoA reductase inhibitors (statins) have beneficial effects in patients with heart failure (HF), regardless of serum cholesterol levels. However, their synergic effects with angiotensin II receptor blocker (ARB) remain to be established. We assessed the existence and potential underlying mechanisms of the effects of combined ARB [losartan (LOS)] and statin [simvastatin (SIM)] on cardiac function in rats and mice with load‐induced HF. Salt‐loaded Dahl salt‐sensitive (DS) rats were treated with vehicle, LOS, SIM, or LOS + SIM for 8 weeks. To mimic load‐induced HF in vitro, cultured neonatal rat cardiomyocytes (NRCM) were cyclically stretched. We also investigated the effect of LOS + SIM on pressure overload‐induced HF using mice with transverse aortic constriction (TAC). LOS + SIM improved left ventricular (LV) function and reduced LV hypertrophy more than the monotherapies in both salt‐loaded DS rats and TAC‐operated mice. LV‐tissue increases in Rho kinase and matrix metalloproteinase‐9 activity were decreased to a greater extent by LOS + SIM than by LOS and SIM monotherapies. Plasma levels of Exp‐3174, a LOS metabolite, were higher in LOS + SIM‐treated DS rats than in LOS‐treated rats. Stretch‐induced hypertrophy of NRCM pretreated with SIM + Exp‐3174 was significantly attenuated from that with LOS, Exp‐3174, SIM, or LOS + SIM. SIM administration significantly enhanced mitophagy in mouse hearts after TAC. However, LOS + SIM reduced mitophagy, and the salutary effect of SIM in mouse hearts after TAC was abolished in AT1R−/− mice. In conclusion, LOS and SIM have beneficial myocardial effects on load‐induced HF via differential pleiotropic effects. Thus, combination therapy of these drugs thus has potential as a therapeutic strategy for HF.