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

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 (Gsαx403). 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 Gsαx403 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 Gsαx403 mice (88±1%, P<0.001) compared with WT (69±1%), 403 (75±1%), and Gsα (69±2%) mice. Isolated cardiomyocytes from Gsαx403 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 e...