Congestive heart failure induces endothelial cell apoptosis: Protective role of carvedilol

OBJECTIVES The purposes of this study were to determine whether the serum o f patients with congestive heart failure (CHF) can induce apoptosis of endo thelial cells and to elucidate the underlying mechanisms. Moreover, the eff ect of the beta-blocker carvedilol was investigated. BACKGROUND Congestive heart failure is associated with impaired endothelial function in the peripheral systemic vasculature and with systemic release of inflammatory cytokines. Pro-inflammatory cytokines have been shown to in duce endothelial cell apoptosis in vitro. Therefore, we hypothesized that C HF is associated with enhanced apoptosis of endothelial cells. METHODS Human umbilical vein endothelial cells were exposed to the serum of patients with CHF (n = 15) or healthy volunteers (n = 11), and apoptosis w as determined by fluorescence staining of the nuclei and demonstration of d eoxyribonucleic acid laddering. Moreover, apoptotic membrane particles were detected in plasma samples of patients with CHF. RESULTS The serum of patients with CHF revealed a significantly enhanced pr o-apoptotic activity as compared with age- and gender-matched healthy volun teers (p < 0.001). Furthermore, patients with CHF revealed significantly el evated plasma concentrations of apoptotic membrane particles. Apoptosis of endothelial cells correlated with elevated tumor necrosis factor-alpha (TNF -alpha) (r = 0.585, p = 0.002) and soluble TNF receptor serum levels (r = 0 .517, p = 0.007). Carvedilol completely suppressed the increase in apoptosi s induced by the serum of patients with CHF. Moreover, carvedilol dose-depe ndently inhibited TNF-alpha-induced apoptosis. The antiapoptotic activity o f carvedilol was mediated by reduced activation of the caspase cascade thro ugh inhibition of mitochondrial cytochrome c release. The suppression of ap optosis by carvedilol was due to its antioxidative rather than beta-blockin g effects, as the analogue BM91.0228, which has no beta-blocking activity, exerted similar effects. CONCLUSIONS These findings indicate that endothelial cell apoptosis may pla y a role in the pathophysiology of heart failure. Inhibition of endothelial cell apoptosis by carvedilol may contribute to the beneficial effects of c arvedilol in patients with heart failure. (C) 2000 by the American College of Cardiology.