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(Circulation. 2002;105:614.)
© 2002 American Heart Association, Inc.

Basic Science Reports

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

Stefan E. Hardt, MD; Yong-Jian Geng, MD, PhD; Olivier Montagne, MD; Kuniya Asai, MD, PhD; Chull Hong, MD; Gui Ping Yang, MD; Sanford P. Bishop, DVM, PhD; Song-Jung Kim, PhD; Dorothy E. Vatner, MD; Christine E. Seidman, MD; J.G. Seidman, PhD; Charles J. Homcy, MD; Stephen F. Vatner, MD

From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine and Department of Medicine, University of Medicine and Dentistry New Jersey, New Jersey Medical School, Newark (S.E.H., O.M., K.A., C.H., G.P.Y., S.-J.K., D.E.V., S.F.V.); University of Texas-Houston Medical School (Y.-J.G.); University of Alabama at Birmingham (S.P.B.); Harvard Medical School, Boston, Mass (C.E.S.); Howard Hughes Medical Institute, Boston, Mass (J.G.S.); and COR Therapeutics, South San Francisco, Calif (C.J.H.).

Correspondence to Stephen F. Vatner, MD, Cardiovascular Research Institute, New Jersey Medical School, University of Medicine and Dentistry New Jersey, 185 S Orange Ave, Medical Science Bldg I-576, Newark, NJ 07103-2714. E-mail vatnersf{at}umdnj.edu

Background— To understand further the pathogenesis of familial hypertrophic cardiomyopathy, we determined how the cardiomyopathy induced by an Arg403Gln missense mutation in the -myosin heavy chain (403) is affected by chronically enhancing sympathetic drive by mating the mice with those overexpressing G_s (G_sx403).

Methods and Results— Heart rate in 3-month-old conscious mice was elevated similarly (P<0.05) in mice overexpressing G_s (G_s mice; 746±14 bpm) and G_sx403 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_sx403 mice (88±1%, P<0.001) compared with WT (69±1%), 403 (75±1%), and G_s (69±2%) mice. Isolated cardiomyocytes from G_sx403 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 (7.8±0.3%) cardiomyocytes. Relaxation of myocytes was impaired in 403 mice compared with WT but enhanced in G_s and normalized in G_sx403 mice. This was also observed in vivo. In vivo isoproterenol (0.1 µg · kg^-1 · min^-1) increased LVEF to maximal levels in G_sx403 and G_s, whereas in 403, the response was attenuated compared with WT. At 10 months of age, G_sx403 had significantly depressed LVEF (57±4%). Histopathological examination demonstrated that myocyte hypertrophy and fibrosis were already present in young G_sx403 mice and that old animals had severe cardiomyopathy. By 15 months of age, the survival of G_sx403 was 0% compared with 100% for WT, 71% for G_s, and 100% for 403 mice (P<0.05).

Conclusions— These results show that the cardiomyopathy developed by G_sx403 mice is synergistic rather than additive, most likely owing to the elevated baseline function combined with enhanced responsiveness to sympathetic stimulation.

Key Words: hypertrophy • cardiomyopathy • heart failure

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