Consequences of Pressure Overload on Sarcomere Protein Mutation-Induced Hypertrophic Cardiomyopathy

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Abstract
Background— Whether ventricular remodeling from hypertrophic cardiomyopathy (HCM), systemic hypertension, or other pathologies arises through a common signaling pathway or through independent molecular mechanisms is unknown. To study this, we assessed cardiac hypertrophy in a mouse model of HCM subjected to increased left ventricular (LV) load. Methods and Results— Transverse aortic banding of mice with or without an Arg403Gln cardiac myosin heavy chain mutation (αMHC 403/+ ) produced similarly elevated LV pressures (120±30 versus 112±14 mm Hg; P =NS). No mice developed heart failure, and mortality (26% αMHC 403/+ , 35% wild-type) was comparable. Load-induced hypertrophy was identical in banded 129SvEv αMHC 403/+ mice (LV anterior wall [LVAW]=1.28±0.11) and 129SvEv wild-type mice (LVAW=1.29±0.11 mm; P =NS). Genetically outbred Black Swiss (BS) αMHC 403/+ mice showed only mildly exaggerated hypertrophy in response to aortic banding (BS αMHC 403/+ LVAW=1.30±0.13 mm; BS wild-type LVAW=1.17±0.15 mm; P =0.03), suggesting some effect from a BS genetic locus that modifies hypertrophy induced by the cardiac MHC Arg403Gln mutation. Histopathology and molecular markers of hypertrophy were comparable in all banded 129SvEv or BS mice. Banded αMHC 403/+ mice had potential for greater hypertrophy, because cyclosporin A treatment markedly augmented hypertrophy. Conclusions— The uniform hypertrophic response to increased ventricular load in wild-type and αMHC 403/+ mice indicates independent cardiac remodeling pathways and predicts that coexistent hypertension and HCM should not profoundly exacerbate cardiac hypertrophy. In contrast, sarcomere mutation and cyclosporin A-mediated calcineurin inhibition stimulate a shared hypertrophic signaling pathway. Defining distinct signaling pathways that trigger myocyte growth should help to tailor therapies for cardiac hypertrophy.