Cohn R D, Durbeej M, Moore S A, Coral-Vazquez R, Prouty S, Campbell K P
Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
J Clin Invest. 2001 Jan;107(2):R1-7. doi: 10.1172/JCI11642.
Cardiomyopathy is a multifactorial disease, and the dystrophin-glycoprotein complex has been implicated in the pathogenesis of both hereditary and acquired forms of the disease. Using mouse models of cardiomyopathy made by ablating genes for components of the sarcoglycan complex, we show that long-term treatment with verapamil, a calcium channel blocker with vasodilator properties, can alleviate the severe cardiomyopathic phenotype, restoring normal serum levels for cardiac troponin I and normal cardiac muscle morphology. Interruption of verapamil treatment leads again to vascular dysfunction and acute myocardial necrosis, indicating that predilection for cardiomyopathy is a continuing process. In contrast, verapamil did not prevent cardiac muscle pathology in dystrophin-deficient mdx mice, which neither show a disruption of the sarcoglycan complex in vascular smooth muscle nor vascular dysfunction. Hence, our data strongly suggest that pharmacological intervention with verapamil merits investigation as a potential therapeutic option not only for patients with sarcoglycan mutations, but also for patients with idiopathic cardiomyopathy associated with myocardial ischemia not related to atherosclerotic coronary artery disease.
心肌病是一种多因素疾病，抗肌萎缩蛋白-糖蛋白复合物与该疾病的遗传性和获得性形式的发病机制均有关联。利用通过剔除肌聚糖复合物成分基因构建的心肌病小鼠模型，我们发现，维拉帕米（一种具有血管舒张特性的钙通道阻滞剂）长期治疗可缓解严重的心肌病表型，使心肌肌钙蛋白I的血清水平恢复正常，并使心肌形态恢复正常。维拉帕米治疗中断会再次导致血管功能障碍和急性心肌坏死，这表明对心肌病的易感性是一个持续的过程。相比之下，维拉帕米并不能预防抗肌萎缩蛋白缺乏的mdx小鼠的心肌病变，这些小鼠既未表现出血管平滑肌中肌聚糖复合物的破坏，也没有血管功能障碍。因此，我们的数据强烈表明，维拉帕米的药物干预不仅值得作为肌聚糖突变患者的潜在治疗选择进行研究，也值得作为与非动脉粥样硬化性冠状动脉疾病无关的心肌缺血相关特发性心肌病患者的潜在治疗选择进行研究。
