Stem Cell-Derived Cardiomyocytes and Beta-Adrenergic Receptor Blockade in Duchenne Muscular Dystrophy Cardiomyopathy.
Stem Cell-Derived Cardiomyocytes and Beta-Adrenergic Receptor Blockade in Duchenne Muscular Dystrophy Cardiomyopathy.
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DOI：
10.1016/j.jacc.2019.12.066
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发表时间：
2020-03-17
影响因子：
24
通讯作者：
Garry, Daniel J.
中科院分区：
文献类型：
--
作者：
Kamdar, Forum;Das, Satyabrata;Gong, Wuming;Kamdar, Andre Klaassen;Meyers, Tatyana A.;Shah, Pruthvi;Ervasti, James M.;Townsend, DeWayne;Kamp, Timothy J.;Wu, Joseph C.;Garry, Mary G.;Zhang, Jianyi;Garry, Daniel J.
关键词：
虽然心肌病已成为杜氏肌营养不良症（DMD）的主要死因，但对营养不良性心力衰竭的研究和治疗有限。本研究的目的是使用DMD患者特异性人诱导多能干细胞（hiPSC）衍生的心肌细胞来模拟DMD心肌病，并鉴定生理变化和未来的药物治疗。为了探索和确定DMD心肌病的治疗方法，作者使用DMD患者特异性hiPSC衍生的心肌细胞来检查对肾上腺素能激动剂和β受体阻滞剂治疗的生理反应。作者使用野生型和mdx小鼠模型进一步检查了这些药物。在基线和肾上腺素能刺激后，与同基因对照相比，DMD hiPSC衍生的心肌细胞具有显著增加的钙离子痕量。此外，这些心律失常与普萘洛尔治疗显着减少。通过遥测监测，作者观察到缺乏抗肌萎缩蛋白的mdx小鼠，在异丙肾上腺素刺激下会出现心律失常性死亡;致死性心律失常部分被普萘洛尔预处理所挽救。使用单细胞和批量RNA测序（RNA-seq），作者比较了DMD和对照hiPSC衍生的心肌细胞、mdx小鼠和对照小鼠（存在或不存在普萘洛尔和异丙肾上腺素），并定义了在基线条件下受到干扰的途径和mdx模型中普萘洛尔治疗后正常化的途径。作者还对人DMD左心室样品进行了转录组分析，发现DMD hiPSC衍生的心肌细胞具有与人DMD心脏相似的失调途径。作者进一步确定，相对较少的DMD患者会去看心血管专家或接受β受体阻滞剂治疗。结果突出了营养不良心脏中从人到动物再到人的机制和治疗干预。这些结果可作为充分把握度的临床研究的前奏，该研究检查了β受体阻滞剂治疗对肌营养不良蛋白病患者的影响。
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. 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. 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. 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. 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.
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