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An abnormal Ca(2+) response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy

D Fatkin1, B K McConnell, J O Mudd

  • 1Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts, USA.

The Journal of Clinical Investigation
|December 6, 2000
PubMed

Insights

Familial hypertrophic cardiomyopathy (FHC) is caused by sarcomere protein gene mutations. Abnormal calcium responses initiate hypertrophic responses in FHC, suggesting new therapeutic targets.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Genetics

Background:

  • Familial hypertrophic cardiomyopathy (FHC) results from dominant-negative sarcomere protein gene mutations.
  • FHC is characterized by left-ventricular hypertrophy, angina, dyspnea, and risk of sudden death.

Purpose of the Study:

  • To investigate the role of calcium (Ca2+) dysregulation in FHC pathogenesis.
  • To explore the impact of pharmacologic agents on FHC progression in a murine model.

Main Methods:

  • Utilized a murine model of FHC with a cardiac myosin heavy-chain gene missense mutation (alphaMHC(403/+)).
  • Administered calcineurin inhibitors or a K(+)-channel agonist to FHC mice and wild-type controls.
  • Assessed cardiac myocyte Ca2+ concentrations and hypertrophic responses.
  • Investigated the effect of Ca2+-channel antagonists.

Main Results:

  • Pharmacologic treatment exacerbated hypertrophy and worsened histopathology in FHC mice.
  • Both agents increased diastolic Ca2+ in wild-type myocytes but not in FHC myocytes.
  • Ca2+-channel antagonist pretreatment normalized Ca2+ levels and prevented exaggerated hypertrophy in FHC mice.

Conclusions:

  • Sarcomere protein gene mutations in FHC lead to abnormal Ca2+ handling, initiating hypertrophic responses.
  • Environmental factors influence FHC progression, highlighting a Ca2+-dependent pathway.
  • These findings suggest potential therapeutic strategies targeting Ca2+ regulation in FHC.

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