An abnormal Ca2+ response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy

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

Research output: Contribution to journalArticle

157 Citations (Scopus)

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
StatePublished - 2000
Externally publishedYes

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Familial Hypertrophic Cardiomyopathy
Sarcomeres
Mutant Proteins
Muscle Cells
Cardiac Myosins
Mutation
Myosin Heavy Chains
Left Ventricular Hypertrophy
Missense Mutation
Sudden Death
Cardiac Myocytes
Dyspnea
Hypertrophy
Proteins
Growth
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Fatkin, D., McConnell, B. K., Mudd, J., Semsarian, C., Moskowitz, I. G. P., Schoen, F. J., ... Seidman, J. G. (2000). An abnormal Ca2+ response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy. Journal of Clinical Investigation, 106(11), 1351-1359.

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

In: Journal of Clinical Investigation, Vol. 106, No. 11, 2000, p. 1351-1359.

Research output: Contribution to journalArticle

Fatkin, D, McConnell, BK, Mudd, J, Semsarian, C, Moskowitz, IGP, Schoen, FJ, Giewat, M, Seidman, CE & Seidman, JG 2000, 'An abnormal Ca2+ response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy', Journal of Clinical Investigation, vol. 106, no. 11, pp. 1351-1359.
Fatkin D, McConnell BK, Mudd J, Semsarian C, Moskowitz IGP, Schoen FJ et al. An abnormal Ca2+ response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy. Journal of Clinical Investigation. 2000;106(11):1351-1359.
Fatkin, Diane ; McConnell, Bradley K. ; Mudd, James ; Semsarian, Christopher ; Moskowitz, Ivan G P ; Schoen, Frederick J. ; Giewat, Michael ; Seidman, Christine E. ; Seidman, J. G. / An abnormal Ca2+ response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy. In: Journal of Clinical Investigation. 2000 ; Vol. 106, No. 11. pp. 1351-1359.
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