Cardioprotective and survival benefits of long-term combined therapy with β₂ adrenoreceptor (AR) agonist and β₁ AR blocker in dilated cardiomyopathy postmyocardial infarction

We have reported therapeutic effectiveness of pharmacological stimulation of β₂ adrenoreceptors (ARs) to attenuate the cardiac remodeling and myocardial infarction (MI) expansion in a rat model of dilated cardiomyopathy (DCM) post-MI. Furthermore, the combination of β₂ AR stimulation with β₁ AR blockade exceeded the therapeutic effectiveness of β₁ AR blockade. However, these studies were relatively short (6 weeks). In this study, in the same experimental model, we compared different effects, including survival benefit, of combined therapy with the β₁ AR blocker, metoprolol, plus the β₁ AR agonist, fenoterol (β₁^-β₂ ⁺), and either therapy alone (β₁^- or β₂⁺) during the 1-year study. Therapy was started 2 weeks after permanent ligation of the left coronary artery. Cardiac remodeling, MI expansion, and left ventricular function were assessed by serial echocardiography and compared with untreated animals (nT). Sixty-seven percent mortality in nT was reduced to 33% in the β₁ ^-β₂⁺ (p < 0.01). Progressive cardiac remodeling observed in nT and β₁^- was significantly attenuated in β₁^-β₂⁺, during the first 6 months of treatment. In β₁ ^-β₂⁺, MI expansion was completely prevented, and functional decline was significantly attenuated during the entire year. Myocardial apoptosis was significantly reduced in both β₁^-β₂⁺ and β₁^-. A reduction of cardiac β₁ AR density and decreases in chronotropic and contractile responses to β₂ AR-specific stimulation in the absence of a reduction of β₂ AR density in nT were precluded in rats receiving combined therapy. The results demonstrate the cardioprotective and survival benefit of long-term combination therapy of β₂ AR agonists and β₁ AR blockers in a model of DCM.