Abnormal Calcium Handling Properties Underlie Familial Hypertrophic Cardiomyopathy Pathology in Patient-Specific Induced Pluripotent Stem Cells

Abstract

Summary Familial hypertrophic cardiomyopathy (HCM) is a prevalent hereditary cardiac disorder linked to arrhythmia and sudden cardiac death. While the causes of HCM have been identified as genetic mutations in the cardiac sarcomere, the pathways by which sarcomeric mutations engender myocyte hypertrophy and electrophysiological abnormalities are not understood. To elucidate the mechanisms underlying HCM development, we generated patient-specific induced pluripotent stem cell cardiomyocytes (iPSC-CMs) from a ten-member family cohort carrying a hereditary HCM missense mutation (Arg663His) in the MYH7 gene. Diseased iPSC-CMs recapitulated numerous aspects of the HCM phenotype including cellular enlargement and contractile arrhythmia at the single-cell level. Calcium (Ca2+) imaging indicated dysregulation of Ca2+ cycling and elevation in intracellular Ca2+ ([Ca2+]i) are central mechanisms for disease pathogenesis. Pharmacological restoration of Ca2+ homeostasis prevented development of hypertrophy and electrophysiological irregularities. We anticipate that these findings will help elucidate the mechanisms underlying HCM development and identify novel therapies for the disease.

Automated Video-Based Analysis of Contractility and Calcium Flux in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Cultured over Different Spatial Scales

“…For example, abnormal calcium flux has been reported in iPS-CM derived from patients with hypertrophic cardiomyopathy who harbor mutations in MYH7, a component of the cell contraction apparatus. 27 This aberration may be explained by stress-induced decoupling between calcium flux and mechanical contractility, and this cardiomyopathy could be tracked noninvasively with genetic calcium sensors combined with computational motion tracking. The same features could be used to test drugs that desensitize sarcomeres to calcium.…”

Accurate nanoelectrode recording of human pluripotent stem cell-derived cardiomyocytes for assaying drugs and modeling disease

“…From repairing damaged tissue in vivo to predicting drug efficacy, human pluripotent stem cells (hPSCs) have become a promising solution to many bottlenecks in human biological research [1][2][3][4][5][6] . There have been many efforts to generate cardiomyocytes (CMs) derived from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) due to the difficulty in obtaining human cardiac tissue by other methods 7 .…”

Relevance of the plasma membrane calcium-ATPase in the homeostasis of calcium in the fetal liver

“…48 Employing iPSCs derived from patients suffering from hypertrophic cardiomyopathy or Parkinson disease, alterations in calcium handling and an increase in the levels of intracellular Ca 2C have been found in close relationship to the genesis of these pathologies. 49,50 Therefore, the role of PMCAs in regulating calcium perturbations in excitable and nonexcitable tissues represents an active area of ongoing research.…”