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Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations

Vasco Sequeira1, Paul J M Wijnker, Louise L A M Nijenkamp

  • 1Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands. v.sequeiraoliveira@vumc.nl

Circulation Research
|March 20, 2013
PubMed

Insights

High myofilament Ca(2+) sensitivity is common in human hypertrophic cardiomyopathy (HCM) and linked to altered protein phosphorylation. Length-dependent activation is also perturbed in HCM, indicating a shared disease mechanism.

Area of Science:

  • Cardiovascular Research
  • Molecular Cardiology
  • Genetics of Heart Disease

Background:

  • Familial hypertrophic cardiomyopathy (HCM) pathogenesis is linked to high myofilament Ca(2+) sensitivity.
  • Human data on myofilament Ca(2+) sensitivity, protein phosphorylation, and muscle length effects in HCM are limited.

Purpose of the Study:

  • To determine if high myofilament Ca(2+) sensitivity and altered length-dependent activation characterize human HCM.
  • To investigate these characteristics in HCM patients with mutations in thick and thin filament proteins.

Main Methods:

  • Cardiac samples from HCM patients (thick/thin filament mutations) and controls were analyzed.
  • Cardiomyocyte force measurements assessed myofilament Ca(2+) sensitivity and length-dependent activation.
  • Protein kinase A (PKA) phosphorylation levels were examined, and exogenous PKA treatment was applied.

Main Results:

  • All HCM samples exhibited higher myofilament Ca(2+) sensitivity and lower PKA target phosphorylation than controls.
  • Length-dependent activation was reduced in all HCM samples.
  • PKA treatment normalized length-dependent activation in some HCM subtypes but not others, suggesting complex mechanisms.

Conclusions:

  • High myofilament Ca(2+) sensitivity is a hallmark of human HCM, partly due to PKA target hypophosphorylation.
  • Altered length-dependent activation, particularly with missense mutations, points to a common HCM pathomechanism possibly involving non-PKA modifications or altered protein interactions.
Abstract

Keywords:
calciumcardiomyopathycontractilityhypertrophymyocardium

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