Induced Pluripotent Stem Cell–Derived Cardiomyocytes from a Patient with MYL2-R58Q-Mediated Apical Hypertrophic Cardiomyopathy Show Hypertrophy, Myofibrillar Disarray, and Calcium Perturbations

Wei Zhou, J. Martijn Bos, Dan Ye, David J. Tester, Sybil Hrstka, Joseph Maleszewski, Steve R. Ommen, Rick A. Nishimura, Hartzell V Schaff, Chang Sung Kim, Michael John Ackerman

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Hypertrophic cardiomyopathy (HCM), characterized by unexplained left ventricular hypertrophy, is one of the most common heritable cardiovascular diseases. The myosin regulatory light chain (MYL2) mutation R58Q has been associated with severe cardiac hypertrophy and sudden cardiac death (SCD). Herein, we provide the first patient-specific, induced pluripotent stem cell–derived cardiomyocyte (iPSC-CM) model of MYL2-R58Q. The MYL2-R58Q iPSC-CMs were nearly 30% larger than control iPSC-CMs at day 60. The percentage of myofibrillar disarray and cells with irregular beating in MYL2-R58Q iPSC-CMs was significantly higher than that in control cells. MYL2-R58Q iPSC-CMs had significantly decreased peak ΔF/F0 of calcium transients and delayed decay time than controls. Additionally, the L-type Ca 2+ channel (LTCC) (I Ca,L ) density at 0 mV was reduced significantly by 45.3%. Overall, the MYL2-R58Q iPSC-CMs recapitulated the HCM phenotype by exhibiting hypertrophy, myofibrillar disarray, increased irregular beating, decreased [Ca 2+ ] i transients, and unexpectedly a nearly 50% reduction in LTCC peak current.

Original languageEnglish (US)
JournalJournal of cardiovascular translational research
DOIs
StatePublished - Jan 1 2019

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Hypertrophic Cardiomyopathy
Cardiac Myocytes
Hypertrophy
Calcium
Myosin Light Chains
Sudden Cardiac Death
Cardiomegaly
Left Ventricular Hypertrophy
Cardiovascular Diseases
Phenotype
Mutation

Keywords

  • Calcium transients
  • Disarray
  • Hypertrophic cardiomyopathy (HCM)
  • Induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs)
  • L-type Ca channel (LTCC)
  • Myosin regulatory light chain (MYL2)
  • R58Q

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmaceutical Science
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Cite this

@article{2106e256225742758f706da8f44850fd,
title = "Induced Pluripotent Stem Cell–Derived Cardiomyocytes from a Patient with MYL2-R58Q-Mediated Apical Hypertrophic Cardiomyopathy Show Hypertrophy, Myofibrillar Disarray, and Calcium Perturbations",
abstract = "Hypertrophic cardiomyopathy (HCM), characterized by unexplained left ventricular hypertrophy, is one of the most common heritable cardiovascular diseases. The myosin regulatory light chain (MYL2) mutation R58Q has been associated with severe cardiac hypertrophy and sudden cardiac death (SCD). Herein, we provide the first patient-specific, induced pluripotent stem cell–derived cardiomyocyte (iPSC-CM) model of MYL2-R58Q. The MYL2-R58Q iPSC-CMs were nearly 30{\%} larger than control iPSC-CMs at day 60. The percentage of myofibrillar disarray and cells with irregular beating in MYL2-R58Q iPSC-CMs was significantly higher than that in control cells. MYL2-R58Q iPSC-CMs had significantly decreased peak ΔF/F0 of calcium transients and delayed decay time than controls. Additionally, the L-type Ca 2+ channel (LTCC) (I Ca,L ) density at 0 mV was reduced significantly by 45.3{\%}. Overall, the MYL2-R58Q iPSC-CMs recapitulated the HCM phenotype by exhibiting hypertrophy, myofibrillar disarray, increased irregular beating, decreased [Ca 2+ ] i transients, and unexpectedly a nearly 50{\%} reduction in LTCC peak current.",
keywords = "Calcium transients, Disarray, Hypertrophic cardiomyopathy (HCM), Induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs), L-type Ca channel (LTCC), Myosin regulatory light chain (MYL2), R58Q",
author = "Wei Zhou and Bos, {J. Martijn} and Dan Ye and Tester, {David J.} and Sybil Hrstka and Joseph Maleszewski and Ommen, {Steve R.} and Nishimura, {Rick A.} and Schaff, {Hartzell V} and Kim, {Chang Sung} and Ackerman, {Michael John}",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s12265-019-09873-6",
language = "English (US)",
journal = "Journal of Cardiovascular Translational Research",
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T1 - Induced Pluripotent Stem Cell–Derived Cardiomyocytes from a Patient with MYL2-R58Q-Mediated Apical Hypertrophic Cardiomyopathy Show Hypertrophy, Myofibrillar Disarray, and Calcium Perturbations

AU - Zhou, Wei

AU - Bos, J. Martijn

AU - Ye, Dan

AU - Tester, David J.

AU - Hrstka, Sybil

AU - Maleszewski, Joseph

AU - Ommen, Steve R.

AU - Nishimura, Rick A.

AU - Schaff, Hartzell V

AU - Kim, Chang Sung

AU - Ackerman, Michael John

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Hypertrophic cardiomyopathy (HCM), characterized by unexplained left ventricular hypertrophy, is one of the most common heritable cardiovascular diseases. The myosin regulatory light chain (MYL2) mutation R58Q has been associated with severe cardiac hypertrophy and sudden cardiac death (SCD). Herein, we provide the first patient-specific, induced pluripotent stem cell–derived cardiomyocyte (iPSC-CM) model of MYL2-R58Q. The MYL2-R58Q iPSC-CMs were nearly 30% larger than control iPSC-CMs at day 60. The percentage of myofibrillar disarray and cells with irregular beating in MYL2-R58Q iPSC-CMs was significantly higher than that in control cells. MYL2-R58Q iPSC-CMs had significantly decreased peak ΔF/F0 of calcium transients and delayed decay time than controls. Additionally, the L-type Ca 2+ channel (LTCC) (I Ca,L ) density at 0 mV was reduced significantly by 45.3%. Overall, the MYL2-R58Q iPSC-CMs recapitulated the HCM phenotype by exhibiting hypertrophy, myofibrillar disarray, increased irregular beating, decreased [Ca 2+ ] i transients, and unexpectedly a nearly 50% reduction in LTCC peak current.

AB - Hypertrophic cardiomyopathy (HCM), characterized by unexplained left ventricular hypertrophy, is one of the most common heritable cardiovascular diseases. The myosin regulatory light chain (MYL2) mutation R58Q has been associated with severe cardiac hypertrophy and sudden cardiac death (SCD). Herein, we provide the first patient-specific, induced pluripotent stem cell–derived cardiomyocyte (iPSC-CM) model of MYL2-R58Q. The MYL2-R58Q iPSC-CMs were nearly 30% larger than control iPSC-CMs at day 60. The percentage of myofibrillar disarray and cells with irregular beating in MYL2-R58Q iPSC-CMs was significantly higher than that in control cells. MYL2-R58Q iPSC-CMs had significantly decreased peak ΔF/F0 of calcium transients and delayed decay time than controls. Additionally, the L-type Ca 2+ channel (LTCC) (I Ca,L ) density at 0 mV was reduced significantly by 45.3%. Overall, the MYL2-R58Q iPSC-CMs recapitulated the HCM phenotype by exhibiting hypertrophy, myofibrillar disarray, increased irregular beating, decreased [Ca 2+ ] i transients, and unexpectedly a nearly 50% reduction in LTCC peak current.

KW - Calcium transients

KW - Disarray

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KW - Myosin regulatory light chain (MYL2)

KW - R58Q

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SN - 1937-5387

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