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Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential

James G W Smith1, Thomas Owen2, Jamie R Bhagwan3

  • 1Wolfson Centre for Stem Cells, Tissue Engineering and Modelling, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK; Faculty of Medicine and Health Sciences, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK.

Stem Cell Reports
|November 6, 2018
PubMed

Insights

This study modeled hypertrophic cardiomyopathy (HCM) using human stem cells with a specific mutation. Dual drug treatment effectively rescued abnormal heart cell function, highlighting a potential therapy for HCM.

Area of Science:

  • Cardiology
  • Genetics
  • Stem Cell Biology

Background:

  • Hypertrophic cardiomyopathy (HCM) is a primary heart muscle contractility disorder.
  • Understanding the genetic basis and molecular mechanisms of HCM is crucial for developing effective treatments.
  • Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer a valuable model for studying cardiac diseases.

Purpose of the Study:

  • To investigate the mechanistic basis of HCM using isogenic hiPSC-CMs with the E99K-ACTC1 cardiac actin mutation.
  • To explore genotype-phenotype correlations in HCM.
  • To identify potential pharmacological rescue strategies for HCM.

Main Methods:

  • Generation of isogenic pairs of hiPSC-CMs carrying the E99K-ACTC1 mutation.
  • Assessment of arrhythmogenesis and aberrant phenotypes in 3D engineered heart tissues and 2D monolayers.
  • Analysis of Ca2+ handling and gene expression.
  • Pharmacological rescue experiments using dantroline and ranolazine.

Main Results:

  • Arrhythmogenesis was observed in all E99K-ACTC1 hiPSC-CMs.
  • Phenotypic severity varied, with the heterozygote father's hiPSC-CMs showing the most aberrant phenotypes.
  • E99K-expressing hiPSC-CMs from the sons exhibited less pronounced pathological phenotypes.
  • Dual dantroline/ranolazine treatment demonstrated the most effective pharmacological rescue.

Conclusions:

  • The E99K mutant protein is a central cause of HCM.
  • Interactions between genetic lesions, epigenetics, and patient age influence HCM phenotype.
  • Isogenic hiPSC-CMs are valuable tools for genotype-phenotype correlations in HCM.
  • Combined dantroline and ranolazine show promise for HCM treatment.

Keywords:
arrhythmiacardiomyopathycontractile functionhypertrophy

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