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CARDIOVASCULAR

Cardioprotective and Survival Benefits of Long-Term Combined Therapy with β₂ Adrenoreceptor (AR) Agonist and β₁ AR Blocker in Dilated Cardiomyopathy Postmyocardial Infarction

Laboratory of Cardiovascular Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland

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 β₂ 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.

Address correspondence to: Dr. Mark I. Talan, National Institute on Aging, Intramural Research Program, Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224-6825. E-mail: talanm{at}grc.nia.nih.gov