BACKGROUND: To understand further the pathogenesis of familial hypertrophic 
cardiomyopathy, we determined how the cardiomyopathy induced by an Arg403-->Gln 
missense mutation in the alpha-myosin heavy chain (403) is affected by 
chronically enhancing sympathetic drive by mating the mice with those 
overexpressing G(s)alpha (G(s)alpha x403).
METHODS AND RESULTS: Heart rate in 3-month-old conscious mice was elevated 
similarly (P<0.05) in mice overexpressing G(s)alpha (G(s)alpha mice; 746 +/- 14 
bpm) and G(s)alpha x403 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)alpha 
x403 mice (88+/- 1%, P<0.001) compared with WT (69+/- 1%), 403 (75+/- 1%), and 
G(s)alpha (69 +/- 2%) mice. Isolated cardiomyocytes from G(s)alpha x403 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 G(s)alpha (7.8+/- 0.3%) cardiomyocytes. 
Relaxation of myocytes was impaired in 403 mice compared with WT but enhanced in 
G(s)alpha and normalized in G(s)alpha x403 mice. This was also observed in vivo. 
In vivo isoproterenol (0.1 microgram . kg(-1) . min(-1)) increased LVEF to 
maximal levels in G(s)alpha x403 and G(s)alpha, whereas in 403, the response was 
attenuated compared with WT. At 10 months of age, G(s)alpha x403 had 
significantly depressed LVEF (57 +/- 4%). Histopathological examination 
demonstrated that myocyte hypertrophy and fibrosis were already present in young 
G(s)alpha x403 mice and that old animals had severe cardiomyopathy. By 15 months 
of age, the survival of G(s)alpha x403 was 0% compared with 100% for WT, 71% for 
G(s)alpha, and 100% for 403 mice (P<0.05).
CONCLUSIONS: These results show that the cardiomyopathy developed by G(s)alpha 
x403 mice is synergistic rather than additive, most likely owing to the elevated 
baseline function combined with enhanced responsiveness to sympathetic 
stimulation.