Chronic Treatment with Carvedilol Improves Ventricular Function and Reduces Myocyte Apoptosis in an Animal Model of Heart Failure

Abstract

Background: \(\beta\)-blocker treatment has emerged as an effective treatment modality for heart failure. Interestingly, \(\beta\)-blockers can activate both pro-apoptotic and anti-apoptotic pathways. Nevertheless, the mechanism for improved cardiac function seen with \(\beta\)-blocker treatment remains largely unknown. Carvedilol is a non-selective \(\beta\)-blocker with \(\alpha\)-receptor blockade and antioxidant properties. We therefore studied the impact of the effects of carvedilol in an animal model of end-stage heart failure. Results: To test whether chronic treatment with \(\beta\)-blockade decreases apoptosis, we treated myopathic turkeys with two dosages of carvedilol, 1 mg/kg (\(DCM_1\)) and 20 mg/kg (\(DCM_{20}\)), for four weeks and compared them to non-treated DCM animals (\(DCM_0\)) and to control turkeys (CON). Echocardiographic measurements showed that non-treated DCM animals had a significantly lower fractional shortening (FS) when compared to CON (68.73 \(\pm\) 1.37 vs. 18.76 \(\pm\) 0.59%, p < 0.001). Both doses of carvedilol significantly improved FS (33.83 \(\pm\) 10.11 and 27.73 \(\pm\) 6.18% vs. 18.76 \(\pm\) 0.59 % for untreated DCM, p < 0.001). DCM left ventricles were characterized by a higher percentage of apoptotic nuclei when compared to CON (5.64 \(\pm\) 0.49 vs. 1.72 \(\pm\) 0.12%, respectively p < 0.001). Both doses of carvedilol significantly reduced the number of apoptotic nuclei (2.32 \(\pm\) 0.23% and 2.36 \(\pm\) 0.26% 1 mg and 20 mg/kg respectively). Conclusions: Carvedilol improves ventricular function. Furthermore, treatment with carvedilol decreased the incidence of apoptosis in cardiac myocytes from failing hearts at both doses. These data suggest that the inhibition of apoptosis with carvedilol may lead to improvement in ventricular function and may underlie a beneficial effect of \(\beta\)-blockade independent of heart rate lowering effects.