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Sarcomere Shortening of Pluripotent Stem Cell-Derived Cardiomyocytes using Fluorescent-Tagged Sarcomere Proteins.
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Advances in the Genetic Basis and Pathogenesis of Sarcomere Cardiomyopathies

Raquel Yotti1,2, Christine E Seidman3,4,5, Jonathan G Seidman3

  • 1Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, 28007 Madrid, Spain;

Annual Review of Genomics and Human Genetics
|April 13, 2019
PubMed

Insights

Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) stem from genetic variants affecting heart muscle proteins. New research reveals molecular mechanisms in HCM related to relaxation and energy conservation, and in DCM, titin variants impairing muscle development, paving the way for new treatments.

Area of Science:

  • Cardiovascular Medicine
  • Genetics
  • Molecular Biology

Background:

  • Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are prevalent heart muscle diseases.
  • These conditions result from pathogenic variants in genes encoding sarcomere proteins.
  • HCM involves unexplained cardiac hypertrophy with altered contractility and relaxation; DCM features enlarged ventricles and impaired function.

Purpose of the Study:

  • To review recent analyses offering new insights into the molecular mechanisms underlying HCM and DCM.
  • To highlight novel pathophysiologic mechanisms discovered for these cardiomyopathies.
  • To identify potential new pharmacological targets and cardioprotective strategies.

Main Methods:

  • Review of recent scientific analyses and studies on hypertrophic cardiomyopathy and dilated cardiomyopathy.
  • Focus on molecular mechanisms, genetic variants, and their functional consequences.
  • Analysis of findings related to sarcomere protein gene mutations.

Main Results:

  • HCM studies emphasize the role of disturbed conformational changes during relaxation and energy conservation due to mutations.
  • DCM studies reveal a high prevalence of truncating variants in titin.
  • These titin variants impair contractile function by disrupting sarcomerogenesis.

Conclusions:

  • Understanding these new pathophysiologic mechanisms is crucial for advancing cardiovascular medicine.
  • Identified mechanisms provide opportunities for developing novel pharmacological therapies.
  • Future cardioprotective strategies can be informed by these molecular insights into HCM and DCM.

Keywords:
dilated cardiomyopathygene-based diagnosishypertrophic cardiomyopathyinteracting-heads motifsarcomere physiologytitin

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