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Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic

Haodi Wu1,2,3, Huaxiao Yang1,2,3, June-Wha Rhee1,2,3

  • 1Stanford Cardiovascular Institute, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA, USA.

European Heart Journal
|June 21, 2019
PubMed

Insights

Diastolic dysfunction in hypertrophic cardiomyopathy is recapitulated in patient-specific stem cell-derived heart cells. This study reveals cellular mechanisms and identifies potential therapeutic targets for this condition.

Area of Science:

  • Cardiology
  • Stem Cell Biology
  • Molecular Biology

Background:

  • Diastolic dysfunction (DD) is a significant clinical issue in hypertrophic cardiomyopathy (HCM), contributing to patient morbidity and mortality.
  • The precise cellular mechanisms driving DD in HCM remain incompletely understood, and effective treatments are lacking.
  • Patient-derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer a powerful model for studying HCM and discovering new therapies.

Purpose of the Study:

  • To investigate the cellular mechanisms of diastolic dysfunction in hypertrophic cardiomyopathy using patient-specific iPSC-CMs.
  • To identify potential therapeutic targets for treating diastolic dysfunction in HCM.
  • To establish a disease model for drug screening and development.

Main Methods:

  • Generation of iPSC-CMs from healthy controls and HCM patients with DD.
  • Micropatterning of iPSC-CMs to assess diastolic function, Ca2+ handling, and myofilament Ca2+ sensitivity.
  • Utilizing ratiometric Ca2+ imaging and traction force microscopy.
  • Confirmation with genome-edited isogenic iPSC lines carrying HCM mutations.
  • Investigating the expression of ion channels (LTCC, TRPC) in HCM iPSC-CMs.

Main Results:

  • HCM iPSC-CMs exhibited impaired diastolic function, characterized by prolonged relaxation, reduced relaxation rate, and shortened sarcomere length.
  • Elevated diastolic intracellular calcium ([Ca2+]i) and abnormal Ca2+ handling were observed in HCM iPSC-CMs, worsening with beta-adrenergic stimulation.
  • Increased myofilament Ca2+ sensitivity was detected in HCM iPSC-CMs.
  • Cytosolic diastolic Ca2+ overload, slowed Ca2+ recycling, and increased myofilament Ca2+ sensitivity collectively impaired relaxation.
  • Treatment targeting Ca2+ or late Na+ current restored diastolic homeostasis and improved cell survival.
  • Increased expression of LTCC and TRPC channels in HCM iPSC-CMs correlated with diastolic Ca2+ overload.

Conclusions:

  • This study successfully recapitulated diastolic dysfunction in HCM at the single-cell level using iPSC-CMs.
  • Novel cellular mechanisms, including disturbed Ca2+ signaling, were identified as key contributors to DD in HCM.
  • Partial blockade of Ca2+ or late Na+ current demonstrated therapeutic potential by restoring diastolic function and improving cell survival.
  • iPSC-CMs serve as a valuable platform for elucidating disease mechanisms and discovering therapeutic targets for HCM-related DD.
Abstract

Keywords:
Calcium homeostasisCardiomyocytesDiastolic dysfunctionHypertrophic cardiomyopathyInduced pluripotent stem cellsMYBPC3MYH7TNNT2

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