Beneficial effects of chronic pharmacological manipulation of β-adrenoreceptor subtype signaling in rodent dilated ischemic cardiomyopathy

Background-Studies in isolated cardiac myocytes have demonstrated that signaling via specific beta(1)-adrenergic receptor subtypes (beta(1)ARs) promotes but that signaling via beta(2)ARs protects from cell death. We hypothesized that prolonged beta(2)AR stimulation or beta(1)AR blockade would each protect myocytes from death and thereby ameliorate cardiac remodeling in chronic heart failure. Methods and Results-A large myocardial infarction (MI) induced in rats by coronary artery ligation resulted in a dilated cardiomyopathy (DCM) characterized by infarct expansion and a progressive increase in left ventricular (LV) end-diastolic volume, accompanied by a reduction in ejection fraction (EF), as assessed by repeated echocardiography. Pressure-volume analysis at 8 weeks after ligation showed that diastolic stiffness (Eed) and arterial elastance (Ea) were increased, end-systolic elastance (Ees) was decreased, and arterioventricular (AV) coupling (Ea/Ees) had deteriorated. Apoptosis was present in both peri-infarct and remote myocardium. Chronic (6-week) administration of the beta(2)AR agonists fenoterol or zinterol, starting at 2 weeks after MI, reduced the extent of LV dilation, infarct expansion, and EF decline. The beta(1)AR blocker metoprolol did not affect the former and preserved EF to a lesser extent than did the beta(2)AR agonists. At 8 weeks after ligation, apoptosis was reduced by all drugs but to a greater extent by beta(2)AR agonists than by the beta(1)AR blocker. Both beta(2)AR agonists and the beta(1)AR blocker improved AV coupling, the former mainly by reducing Ea and the latter mainly by increasing Ees. Only the beta(2)AR agonists reduced the Eed and the MI size by reducing infarct expansion. Conclusions-These results provide proof of concept for the efficacy of chronic beta(2)AR stimulation in this DCM model.