Age-dependent cardiomyopathy and heart failure phenotype in mice overexpressing beta(2)-adrenergic receptors in the heart

Objective: To explore long-term cardiac phenotype in transgenic (TG) mice w ith 300-fold overexpression of beta (2)-adrenergic receptors (AR). Methods: Echocardiography was performed serially on a cohort of wild-type and TG mi ce (n=26 each) between 4 and 15 months of age. Survival was monitored and a utopsy and histological examinations were performed. Results: Heart rate wa s higher in TG than in wild-type mice throughout the study period. The left ventricular dimensions and fractional shortening were similar between TG a nd wild-type groups during 4-6 months. Starting at 9 months, however, TG mi ce showed progressive reduction in fractional shortening and systolic wall thickening, and increase in left ventricular dimensions and left ventricula r mass, indicating onset of heart failure, left ventricular hypertrophy and remodeling. Abnormal waveforms in the electrocardigram and episodes of ven tricular ectopic beats were also observed in TG mice. Death of TG mice star ted at 8.5 months, and the cumulative mortality was 81% by 15 months (P<0.0 001 vs. 4% in wild-type mice). The majority of deaths were due to severe he art failure, indicated by cardiac dilatation, lung congestion, pleural effu sion and atrial thrombus. Left ventricular sections showed widespread inter stitial fibrosis, loss of myocytes and myocyte hypertrophy in TG mice. Conc lusions: A high level of <beta>(2)AR overexpression results in cardiomyopat hy and heart failure. The onset was slower and the expression levels of rec eptors required are much higher than previously described for the beta (1)A R overexpression. (C) 2000 Elsevier Science BN. All rights reserved.