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Hypertrophic cardiomyopathy-linked mutation in troponin T causes myofibrillar disarray and pro-arrhythmic action

Lili Wang1, Kyungsoo Kim1, Shan Parikh1

  • 1Division of Clinical Pharmacology, Vanderbilt Univ Medical Ctr, Nashville, TN, Medical Research Building IV, Rm.1275, 2215B Garland Ave, Nashville, TN 37232, USA.

Journal of Molecular and Cellular Cardiology
|December 9, 2017
PubMed

Insights

The cardiac troponin T (TnT) I79N mutation increases myofilament calcium sensitivity in human cardiomyocytes, leading to cellular changes that predict arrhythmia risk. This study models TnT-linked hypertrophic cardiomyopathy (HCM) in human cells, revealing pro-arrhythmic effects.

Area of Science:

  • Cardiovascular Research
  • Molecular Cardiology
  • Stem Cell Biology

Background:

  • Cardiac troponin T (TnT) mutations are linked to ventricular arrhythmia and sudden death.
  • The TnT-I79N mutation, associated with hypertrophic cardiomyopathy (HCM), increases myofilament calcium sensitivity in mice.
  • The arrhythmogenic effects of TnT-I79N in human cardiomyocytes remain uncharacterized.

Purpose of the Study:

  • To investigate the electrophysiological and contractile effects of the TnT-I79N mutation in human cardiomyocytes.
  • To establish a human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model for studying TnT-linked HCM.

Main Methods:

  • CRISPR/Cas9 gene editing was used to introduce the TnT-I79N mutation into hiPSCs.
  • Single rod-shaped cardiomyocytes (CMs) were generated using the matrigel mattress method.
  • Contractility, calcium handling, and electrophysiology of mutant and control hiPSC-CMs were analyzed.

Main Results:

  • TnT-I79N hiPSC-CMs displayed sarcomere disorganization, enhanced systolic function, and impaired relaxation.
  • Increased myofilament calcium sensitivity was observed, indicated by a leftward shift in the calcium-dependence of contractility.
  • Altered calcium handling, including reduced intracellular calcium transients and enhanced cytosolic calcium buffering, led to action potential triangulation and beat-to-beat instability, predicting arrhythmia risk.

Conclusions:

  • The TnT-I79N hiPSC-CM model recapitulates key cellular features of TnT-linked HCM.
  • The TnT-I79N mutation induces pro-arrhythmic changes in human ventricular action potential electrophysiology.
  • This model provides insights into the mechanisms underlying arrhythmia in TnT-associated cardiomyopathies.
Abstract

Keywords:
ArrhythmiaCalciumHuman induced pluripotent stem cellsHypertrophic cardiomyopathyTroponin TVentricular AP

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