Consequences of pressure overload on sarcomere protein mutation-induced hypertrophic cardiomyopathy

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 αAMHC^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.