Lillehei Heart Institute, Cardiovascular Division, University of Minnesota, Minneapolis, Minnesota; Paul and Sheila Muscular Dystrophy Center, University of Minnesota, Minneapolis, Minnesota.
Lillehei Heart Institute, Cardiovascular Division, University of Minnesota, Minneapolis, Minnesota.
J Am Coll Cardiol. 2020 Mar 17;75(10):1159-1174. doi: 10.1016/j.jacc.2019.12.066.
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.
尽管心肌病已成为杜兴氏肌营养不良症（DMD）患者死亡的主要原因，但针对营养不良性心力衰竭的研究和治疗方法有限。
本研究旨在使用 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，并确定生理变化和未来的药物治疗方法。
为了探索和定义 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。作者进一步在野生型和 mdx 小鼠模型中检查了这些药物。
在基线水平和肾上腺素刺激后，与同基因对照相比，DMD hiPSC 衍生的心肌细胞的心律失常钙迹有明显增加。此外，用普萘洛尔治疗可显著减少这些心律失常。通过遥测监测，作者观察到缺乏肌营养不良蛋白的 mdx 小鼠在异丙肾上腺素刺激下发生心律失常性死亡；普萘洛尔预处理部分挽救了致命性心律失常。通过单细胞和批量 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（在存在或不存在普萘洛尔和异丙肾上腺素的情况下），并确定了在基线条件下受到干扰的途径以及在 mdx 模型中用普萘洛尔治疗后恢复正常的途径。作者还对人类 DMD 左心室样本进行了转录组分析，发现 DMD hiPSC 衍生的心肌细胞具有与人类 DMD 心脏相似的失调途径。作者还进一步确定，只有少数 DMD 患者会看心血管专家或接受β受体阻滞剂治疗。
这些结果突出了从人类到动物再到人类的营养不良心脏中的机制和治疗干预措施。这些结果可能为一项充分 powered 的临床研究奠定基础，该研究将检查β受体阻滞剂治疗对肌营养不良蛋白病患者的影响。
