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

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:75

Article

Kamdar, Forum^1,2  Das, Satyabrata¹  Gong, Wuming¹  Kamdar, Andre Klaassen¹  Meyers, Tatyana A.³  Shah, Pruthvi¹  Ervasti, James M.^2,4  Townsend, DeWayne^1,2,3  Kamp, Timothy J.⁵  Wu, Joseph C.⁶  Garry, Mary G.^1,2  Zhang, Jianyi⁷  Garry, Daniel J.^1,2,3,8 

[1] Univ Minnesota, Lillehei Heart Inst, Cardiovasc Div, Minneapolis, MN USA

[2] Univ Minnesota, Paul & Sheila Muscular Dystrophy Ctr, Minneapolis, MN USA

[3] Univ Minnesota, Dept Integrat Biol & Physiol, Minneapolis, MN USA

[4] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN USA

[5] Univ Wisconsin, Cardiovasc Med, Madison, WI USA

[6] Stanford Univ, Stanford Cardiovasc Inst, Palo Alto, CA 94304 USA

[7] Univ Alabama Birmingham, Dept Biomed Engn, Birmingham, AL 35294 USA

[8] Univ Minnesota, Stem Cell Inst, Minneapolis, MN USA

关键词: beta-blockers;    Duchenne disease modeling;    muscular dystrophy cardiomyopathy;    heart failure;    human inducible pluripotent stem cells;   

DOI  :  10.1016/j.jacc.2019.12.066

来源: Elsevier

【 摘 要 】

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 beta-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 beta-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 beta-blocker therapy in patients with dystrophinopathies. (C) 2020 by the American College of Cardiology Foundation.

【 授权许可】

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