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2018 - Hypertrophic cardiomyopathy-linked mutation in troponin T causes myofibrillar disarray and pro-arrhythmic action potential changes in human iPSC cardiomyocytes

Icon CE   CardioExcyte 96 publication in Journal of Molecular and Cellular Cardiology

Authors: 
Wang L., Kim K., Parikh S., Cadar A.G., Bersell K.R., He H., Pinto J.R., Kryshtal D.O., Knollmann B.C.

Journal: 
Journal of Molecular and Cellular Cardiology (2018) 114:320-327


Highlights: 

  • TnT-I79N hiPSC-CMs reproduce key cellular features of clinical HCM.
  • TnT-I79N mutation reduces Ca transients by increasing cytosolic Ca buffering.
  • TnT-I79N mutation causes pro-arrhythmic action potential changes.

Abstract:

Background
Mutations in cardiac troponin T (TnT) are linked to increased risk of ventricular arrhythmia and sudden death despite causing little to no cardiac hypertrophy. Studies in mice suggest that the hypertrophic cardiomyopathy (HCM)-associated TnT-I79N mutation increases myofilament Ca sensitivity and is arrhythmogenic, but whether findings from mice translate to human cardiomyocyte electrophysiology is not known.

Objectives
To study the effects of the TnT-I79N mutation in human cardiomyocytes.

Methods
Using CRISPR/Cas9, the TnT-I79N mutation was introduced into human induced pluripotent stem cells (hiPSCs). We then used the matrigel mattress method to generate single rod-shaped cardiomyocytes (CMs) and studied contractility, Ca handling and electrophysiology.

Results
Compared to isogenic control hiPSC-CMs, TnT-I79N hiPSC-CMs exhibited sarcomere disorganization, increased systolic function and impaired relaxation. The Ca-dependence of contractility was leftward shifted in mutation containing cardiomyocytes, demonstrating increased myofilament Ca sensitivity. In voltage-clamped hiPSC-CMs, TnT-I79N reduced intracellular Ca transients by enhancing cytosolic Ca buffering. These changes in Ca handling resulted in beat-to-beat instability and triangulation of the cardiac action potential, which are predictors of arrhythmia risk. The myofilament Ca sensitizer EMD57033 produced similar action potential triangulation in control hiPSC-CMs.

Conclusions
The TnT-I79N hiPSC-CM model not only reproduces key cellular features of TnT-linked HCM such as myofilament disarray, hypercontractility and diastolic dysfunction, but also suggests that this TnT mutation causes pro-arrhythmic changes of the human ventricular action potential.


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