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

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    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.

    Original languageEnglish (US)
    Pages (from-to)1351-1359
    Number of pages9
    JournalJournal of Clinical Investigation
    Volume106
    Issue number11
    DOIs
    StatePublished - Jan 1 2000

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    ASJC Scopus subject areas

    • Medicine(all)

    Cite this

    Fatkin, D., McConnell, B. K., Mudd, J. O., Semsarian, C., Moskowitz, I. G. P., Schoen, F. J., Giewat, M., Seidman, C. E., & Seidman, J. G. (2000). An abnormal Ca2+ response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy. Journal of Clinical Investigation, 106(11), 1351-1359. https://doi.org/10.1172/JCI11093