Novak Atara, Lorber Avraham, Itskovitz-Eldor Joseph, Binah Ofer
The Sohnis Family Stem Cells Center, Technion - Israel Institute of Technology, Haifa, Israel; ; The Rappaport Family Institute for Research in the Medical Sciences, Technion - Israel Institute of Technology, Haifa, Israel; ; Ruth & Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel;
Rambam Maimonides Med J. 2012 Jul 31;3(3):e0015. doi: 10.5041/RMMJ.10086. Print 2012 Jul.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic cardiac disorder characterized by life-threatening arrhythmias induced by physical or emotional stress, in the absence structural heart abnormalities. The arrhythmias may cause syncope or degenerate into cardiac arrest and sudden death which usually occurs during childhood. Recent studies have shown that CPVT is caused by mutations in the cardiac ryanodine receptor type 2 (RyR2) or calsequestrin 2 (CASQ2) genes. Both proteins are key contributors to the intracellular Ca(2+) handling process and play a pivotal role in Ca(2+) release from the sarcoplasmic reticulum to the cytosol during systole. Although the molecular pathogenesis of CPVT is not entirely clear, it was suggested that the CPVT mutations promote excessive sarcoplasmic reticulum Ca(2+) leak, which initiates delayed afterdepolarizations (DADs) and triggered arrhythmias in cardiac myocytes. The recent breakthrough discovery of induced pluripotent stem cells (iPSC) generated from somatic cells (e.g. fibroblasts, keratinocytes) now enables researches to investigate mutated cardiomyocytes generated from the patient's iPSC. To this end, in the present article we review recent studies on CPVT iPSC-derived cardiomyocytes, thus demonstrating in the mutated cells catecholamine-induced DADs and triggered arrhythmias.
儿茶酚胺能多形性室性心动过速（CPVT）是一种遗传性致心律失常性心脏病，其特征是在无结构性心脏异常的情况下，由身体或情绪应激诱发危及生命的心律失常。这些心律失常可能导致晕厥或恶化为心脏骤停和猝死，通常发生在儿童期。最近的研究表明，CPVT是由心脏2型兰尼碱受体（RyR2）或肌集钙蛋白2（CASQ2）基因突变引起的。这两种蛋白质都是细胞内钙（Ca2+）处理过程的关键因素，并且在收缩期从肌浆网向细胞质的钙（Ca2+）释放中起关键作用。虽然CPVT的分子发病机制尚不完全清楚，但有人认为CPVT突变会促进肌浆网钙（Ca2+）过度泄漏，从而引发延迟后去极化（DADs）并触发心肌细胞心律失常。最近从体细胞（如成纤维细胞、角质形成细胞）产生诱导多能干细胞（iPSC）的突破性发现，现在使研究人员能够研究由患者iPSC产生的突变心肌细胞。为此，在本文中我们综述了关于CPVT iPSC衍生心肌细胞的最新研究，从而在突变细胞中证明了儿茶酚胺诱导的DADs和触发的心律失常。
