Background— Studies in isolated cardiac myocytes have demonstrated that signaling via specific β₁-adrenergic receptor subtypes (β₁ARs) promotes but that signaling via β₂ARs protects from cell death. We hypothesized that prolonged β₂AR stimulation or β₁AR 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 β₂AR agonists fenoterol or zinterol, starting at 2 weeks after MI, reduced the extent of LV dilation, infarct expansion, and EF decline. The β₁AR blocker metoprolol did not affect the former and preserved EF to a lesser extent than did the β₂AR agonists. At 8 weeks after ligation, apoptosis was reduced by all drugs but to a greater extent by β₂AR agonists than by the β₁AR blocker. Both β₂AR agonists and the β₁AR blocker improved AV coupling, the former mainly by reducing Ea and the latter mainly by increasing Ees. Only the β₂AR agonists reduced the Eed and the MI size by reducing infarct expansion.

Conclusions— These results provide proof of concept for the efficacy of chronic β₂AR stimulation in this DCM model.