Stem Cell–Derived Cardiomyocytes and Beta-Adrenergic Receptor Blockade in Duchenne Muscular Dystrophy Cardiomyopathy

Forum Kamdar, Satyabrata Das, Wuming Gong, André Klaassen Kamdar, Tatyana A. Meyers, Pruthvi Shah, James M. Ervasti, De Wayne Townsend, Timothy J. Kamp, Joseph C. Wu, Mary G. Garry, Jianyi Zhang, Daniel J. Garry

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Background: Although cardiomyopathy has emerged as a leading cause of death in Duchenne muscular dystrophy (DMD), limited studies and therapies have emerged for dystrophic heart failure. Objectives: The purpose of this study was to model DMD cardiomyopathy using DMD patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and to identify physiological changes and future drug therapies. Methods: To explore and define therapies for DMD cardiomyopathy, the authors used DMD patient-specific hiPSC-derived cardiomyocytes to examine the physiological response to adrenergic agonists and β-blocker treatment. The authors further examined these agents in vivo using wild-type and mdx mouse models. Results: At baseline and following adrenergic stimulation, DMD hiPSC-derived cardiomyocytes had a significant increase in arrhythmic calcium traces compared to isogenic controls. Furthermore, these arrhythmias were significantly decreased with propranolol treatment. Using telemetry monitoring, the authors observed that mdx mice, which lack dystrophin, had an arrhythmic death when stimulated with isoproterenol; the lethal arrhythmias were rescued, in part, by propranolol pre-treatment. Using single-cell and bulk RNA sequencing (RNA-seq), the authors compared DMD and control hiPSC-derived cardiomyocytes, mdx mice, and control mice (in the presence or absence of propranolol and isoproterenol) and defined pathways that were perturbed under baseline conditions and pathways that were normalized after propranolol treatment in the mdx model. The authors also undertook transcriptome analysis of human DMD left ventricle samples and found that DMD hiPSC-derived cardiomyocytes have dysregulated pathways similar to the human DMD heart. The authors further determined that relatively few patients with DMD see a cardiovascular specialist or receive β-blocker therapy. Conclusions: The results highlight mechanisms and therapeutic interventions from human to animal and back to human in the dystrophic heart. These results may serve as a prelude for an adequately powered clinical study that examines the impact of β-blocker therapy in patients with dystrophinopathies.

Original languageEnglish (US)
Pages (from-to)1159-1174
Number of pages16
JournalJournal of the American College of Cardiology
Issue number10
StatePublished - Mar 17 2020

Bibliographical note

Funding Information:
The authors acknowledge the Duke Cardiac Repository for providing the human control LV samples and the University of Minnesota Muscular Dystrophy Center for providing the DMD LV samples. The authors acknowledge the Muscular Dystrophy Association for providing data from the Muscular Dystrophy Association U.S. Neuromuscular Patient Registry. The authors acknowledge the technical support of Debra Kulhanek, Daniel Mickelson, and Cynthia Faraday. The authors acknowledge the help of Grafika Labs in creating the graphic illustrations. Funding is acknowledged from the National Institutes of Health (R01HL122576 and U01HL100407). Dr. Kamp has been a consultant for Cellular Dynamics, Inc. Dr. Wu reports a relationship with Khloris. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Publisher Copyright:
© 2020 American College of Cardiology Foundation


  • Duchenne disease modeling
  • heart failure
  • human inducible pluripotent stem cells
  • muscular dystrophy cardiomyopathy
  • β-blockers


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