Accelerated Cardiomyopathy in Mice With Overexpression of Cardiac G s α and a Missense Mutation in the α-Myosin Heavy Chain

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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 G s α (G s αx403). Methods and Results — Heart rate in 3-month-old conscious mice was elevated similarly ( P s α (G s α mice; 746±14 bpm) and G s αx403 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 G s αx403 mice (88±1%, P s α (69±2%) mice. Isolated cardiomyocytes from G s αx403 mice also exhibited higher ( P s α (7.8±0.3%) cardiomyocytes. Relaxation of myocytes was impaired in 403 mice compared with WT but enhanced in G s α and normalized in G s αx403 mice. This was also observed in vivo. In vivo isoproterenol (0.1 μg · kg −1 · min −1 ) increased LVEF to maximal levels in G s αx403 and G s α, whereas in 403, the response was attenuated compared with WT. At 10 months of age, G s αx403 had significantly depressed LVEF (57±4%). Histopathological examination demonstrated that myocyte hypertrophy and fibrosis were already present in young G s αx403 mice and that old animals had severe cardiomyopathy. By 15 months of age, the survival of G s αx403 was 0% compared with 100% for WT, 71% for G s α, and 100% for 403 mice ( P Conclusions — These results show that the cardiomyopathy developed by G s αx403 mice is synergistic rather than additive, most likely owing to the elevated baseline function combined with enhanced responsiveness to sympathetic stimulation.