Accelerated cardiomyopathy in mice with overexpression of cardiac Gsα and a missense mutation in the α-myosin heavy chain

Abstract

Background - To understand further the pathogenesis of familial hypertrophic cardiomyopathy, we determined how the cardiomyopathy induced by an Arg403→Gln missense mutation in the α-myosin heavy chain (403) is affected by chronically enhancing sympathetic drive by mating the mice with those overexpressing Gsα (Gsα×403). Methods and Results - Heart rate in 3-month-old conscious mice was elevated similarly (P<0.05) in mice overexpressing Gsα (Gsα mice; 746±14 bpm) and Gsα×403 mice (718±19 bpm) compared with littermate wild-type mice (WT; 623±18 bpm) and 403 mice (594±16 bpm). Left ventricular ejection fraction (LVEF), as determined by echocardiography, was enhanced in Gsα×403 mice (88±1%, P<0.001) compared with WT (69±1%), 403 (75±1%), and Gsα (69<2%) mice. Isolated cardiomyocytes from Gsα×403 mice also exhibited higher (P<0.001) baseline percent contraction (11.9±0.5%) than WT (7.0±0.5%), 403 (5.5±0.5%), and Gsα (7.8±0.3%) cardiomyocytes. Relaxation of myocytes was impaired in 403 mice compared with WT but enhanced in Gsα and normalized in Gsα×403 mice. This was also observed in vivo. In vivo isoproterenol (0.1 μg · kg-1 · min-1) increased LVEF to maximal levels in Gsα×403 and Gsα, whereas in 403, the response was attenuated compared with WT. At 10 months of age, Gsα×403 had significantly depressed LVEF (57×4%). Histopathological examination demonstrated that myocyte hypertrophy and fibrosis were already present in young Gsα×403 mice and that old animals had severe cardiomyopathy. By 15 months of age, the survival of Gsα×403 was 0% compared with 100% for WT, 71% for Gsα, and 100% for 403 mice (P<0.05). Conclusions - These results show that the cardiomyopathy developed by Gsα×403 mice is synergistic rather than additive, most likely owing to the elevated baseline function combined with enhanced responsiveness to sympathetic stimulation.