An abnormal Ca2+ response in mutant sarcomere protein–mediated familial hypertrophic cardiomyopathy
Diane Fatkin, Bradley K. McConnell, James O. Mudd, Christopher Semsarian, Ivan G.P. Moskowitz, Frederick J. Schoen, Michael Giewat, Christine E. Seidman, J.G. Seidman
Diane Fatkin, Bradley K. McConnell, James O. Mudd, Christopher Semsarian, Ivan G.P. Moskowitz, Frederick J. Schoen, Michael Giewat, Christine E. Seidman, J.G. Seidman
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An abnormal Ca2+ response in mutant sarcomere protein–mediated familial hypertrophic cardiomyopathy

Abstract

Dominant-negative sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy, angina, and dyspnea that can result in sudden death. We report here that a murine model of FHC bearing a cardiac myosin heavy-chain gene missense mutation (αMHC403/+), when treated with calcineurin inhibitors or a K+-channel agonist, developed accentuated hypertrophy, worsened histopathology, and was at risk for early death. Despite distinct pharmacologic targets, each agent augmented diastolic Ca2+ concentrations in wild-type cardiac myocytes; αMHC403/+ myocytes failed to respond. Pretreatment with a Ca2+-channel antagonist abrogated diastolic Ca2+ changes in wild-type myocytes and prevented the exaggerated hypertrophic response of treated αMHC403/+ mice. We conclude that FHC-causing sarcomere protein gene mutations cause abnormal Ca2+ responses that initiate a hypertrophic response. These data define an important Ca2+-dependent step in the pathway by which mutant sarcomere proteins trigger myocyte growth and remodel the heart, provide definitive evidence that environment influences progression of FHC, and suggest a rational therapeutic approach to this prevalent human disease.

Authors

Diane Fatkin, Bradley K. McConnell, James O. Mudd, Christopher Semsarian, Ivan G.P. Moskowitz, Frederick J. Schoen, Michael Giewat, Christine E. Seidman, J.G. Seidman

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The pathway leading from sarcomere protein gene mutation to hypertrophic...
The pathway leading from sarcomere protein gene mutation to hypertrophic cardiomyopathy and the role of an abnormal Ca2+ response. CsA and FK506 may increase cytoplasmic Ca2+ through interaction with calcineurin or by activation of the L-type Ca2+ channel. Cytoplasmic Ca2+ enters the sarcoplasmic reticulum by way of an ATPase-dependent calcium pump (SERCA) and exits by way of the inositol triphosphate receptor (InsP3R) and the ryanodine receptor (RyR). Small increases in Ca2+ trigger Ca2+-induced Ca2+ release (CICR) primarily through the RyR. Considerable Ca2+ is stored in the sarcomere. We hypothesize that sarcomeres containing mutant myosins (denoted by asterisks) store more Ca2+ than normal sarcomeres, causing a reduction in sarcoplasmic reticulum Ca2+ that signals a hypertrophic response. Most Ca2+ in the sarcomere and sarcoplasmic reticulum is bound to carrier proteins, whereas most Ca2+ in the cytoplasm is free. Diltiazem is an inhibitor of the L-type Ca2+ channel, whereas minoxidil is an activator of the K+ channel.