ADVERSE-EFFECTS OF CHRONIC ENDOGENOUS SYMPATHETIC DRIVE INDUCED BY CARDIAC G(S-ALPHA) OVEREXPRESSION

To study the physiological effect of the overexpression of myocardial G(s alpha) (protein levels increased by approximately threefold in tra nsgenic mice), we examined the responsiveness to sympathomimetic amine s by echocardiography (9 MHz) in five transgenic mice and five control mice (both 10.3+/-0.2 months old). Myocardial contractility in transg enic mice, as assessed by left ventricular (LV) fractional shortening (LVFS) and LV ejection fraction (LVEF), was not different from that of control mice at baseline (LVFS, 40+/-3% versus 36+/-2%; LVEF, 78+/-3% versus 74+/-3%). LVFS and LVEF values in transgenic mice during isopr oterenol (ISO, 0.02 mu g/kg per minute) infusion were higher than the values in control mice (LVFS, 68+/-4% versus 48+/-3%; LVEF, 96+/-1% ve rsus 86+/-3%; P<.05). Norepinephrine (NE, 0.2 mu g/kg per minute) infu sion also increased LVFS and LVEF in transgenic mice more than in cont rol mice (LVFS, 59+/-4% versus 47+/-3%; LVEF, 93+/-2% versus 85+/-3%; P<.05). Heart rates of transgenic mice were higher than those of contr ol mice during ISO and NE infusion. In three transgenic mice with hear t rates held constant, LV dP/dt rose by 33+/-2% with ISO (0.02 mu g/kg per minute) and by only 13+/-2% in three wild-type control mice (P<.0 1). NE (0.1 mu g/kg per minute) also induced a greater effect on LV dP /dt in the three transgenic mice with heart rates held constant compar ed with three wild-type control mice (65+/-8% versus 28+/-4%, P<.05). Pathological and histological analyses of older transgenic mouse heart s (16.0+/-0.8 months old) revealed hypertrophy, degeneration, atrophy of cells, and replacement fibrosis reflected by significant increases in collagen volume in the subendocardium (5.2+/-1.4% versus 1.2+/-0.3% , P<.05) and in the cross-sectional area of myocytes (298+/-29 versus 187+/-12 mu m(2), P<.05) compared with control mouse hearts. These res ults suggest that G(s alpha) overexpression enhances the efficacy of t he beta-adrenergic receptor-G(s)-adenylpl cyclase signaling pathway. T his in turn leads to augmented inotropic and chronotropic responses to endogenous sympathetic stimulation. This action over the life of the animal results in myocardial damage characterized by cellular degenera tion, necrosis, and replacement fibrosis, with the remaining cells und ergoing compensatory hypertrophy. As a model, this transgenic mouse of fers new insights into the mechanisms of cardiomyopathy and heart fail ure and provides a new tool for their study.