beta-Adrenergic receptor blockade arrests myocyte damage and preserves cardiac function in the transgenic G(s alpha) mouse

Transgenic (TG) mice with cardiac G(s alpha) overexpression exhibit enhance d inotropic and chronotropic responses to sympathetic stimulation, but deve lop cardiomyopathy with age. We tested the hypothesis that cardiomyopathy i n TG mice with Gs alpha overexpression could be averted with chronic beta-a drenergic receptor (beta-AR) blockade. TG mice and age-matched wild-type li ttermates were treated with the beta-AR blocker propranolol for 6-7 months, starting at a time when the cardiomyopathy was developing but was not yet severe enough to induce significant cardiac depression (9.5 months of age), and ending at a time when cardiac depression and cardiomyopathy would have been clearly manifest (16 months of age). Propranolol treatment, which can induce cardiac depression in the normal heart, actually prevented cardiac dilation and the depressed left ventricular function characteristic of olde r TG mice, and abolished premature mortality. Propranolol also prevented th e increase in myocyte cross-sectional area and myocardial fibrosis. Myocyte apoptosis, already apparent in 3-month-old TG mice, was actually eliminate d by chronic propranolol. This study indicates that chronic sympathetic sti mulation over an extended period is deleterious and results in cardiomyopat hy. Conversely, PAR blockade is salutary in this situation and can prevent the development of cardiomyopathy.