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Dystrophic heart failure blocked by membrane sealant poloxamer

机译：营养不良性心力衰竭被膜密封剂泊洛沙姆阻止

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摘要

Dystrophin deficiency causes Duchenne muscular dystrophy (DMD) in humans, an inherited and progressive disease of striated muscle deterioration that frequently involves pronounced cardiomyopathy(1). Heart failure is the second leading cause of fatalities in DMD1,2. Progress towards defining the molecular basis of disease in DMD has mostly come from studies on skeletal muscle, with comparatively little attention directed to cardiac muscle. The pathophysiological mechanisms involved in cardiac myocytes may differ significantly from skeletal myofibres; this is underscored by the presence of significant cardiac disease in patients with truncated or reduced levels of dystrophin but without skeletal muscle disease(3). Here we show that intact, isolated dystrophin-deficient cardiac myocytes have reduced compliance and increased susceptibility to stretch-mediated calcium overload, leading to cell contracture and death, and that application of the membrane sealant poloxamer 188 corrects these defects in vitro. In vivo administration of poloxamer 188 to dystrophic mice instantly improved ventricular geometry and blocked the development of acute cardiac failure during a dobutamine-mediated stress protocol. Once issues relating to optimal dosing and long-term effects of poloxamer 188 in humans have been resolved, chemical-based membrane sealants could represent a new therapeutic approach for preventing or reversing the progression of cardiomyopathy and heart failure in muscular dystrophy.
机译：肌营养不良蛋白缺乏症会导致人的Duchenne肌营养不良（DMD），这是一种横纹肌恶化的遗传性和进行性疾病，通常涉及明显的心肌病（1）。心力衰竭是DMD1,2中死亡的第二大主要原因。定义DMD中疾病的分子基础的进展主要来自骨骼肌的研究，而对心肌的关注相对较少。心肌细胞所涉及的病理生理机制可能与骨骼肌纤维明显不同。肌营养不良蛋白水平下降或下降但没有骨骼肌疾病的患者存在严重的心脏病（3）。在这里，我们显示完整的，分离的肌营养不良蛋白缺陷型心肌细胞降低了依从性，并且对拉伸介导的钙超载增加了敏感性，导致细胞挛缩和死亡，膜密封剂泊洛沙姆188的应用在体外纠正了这些缺陷。向营养不良的小鼠体内施用泊洛沙姆188可立即改善心室的几何形状，并在多巴酚丁胺介导的应激方案期间阻止急性心力衰竭的发展。一旦解决了与泊洛沙姆188在人体内的最佳剂量和长期作用有关的问题，基于化学的膜密封剂就可以代表一种预防或逆转心肌营养不良和心力衰竭在肌营养不良中进展的新治疗方法。

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