Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
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DOI：
10.1113/jp276757
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发表时间：
2020-07
期刊：
影响因子：
--
通讯作者：
Knollmann BC
中科院分区：
文献类型：
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作者：
Wleklinski MJ;Kannankeril PJ;Knollmann BC
儿茶酚胺能多形性室性心动过速（CPVT）是一种应激性心脏通道病变，未经治疗的患者死亡率很高。自1995年首次将CPVT描述为临床综合征以来，我们的理解已经大大增加。现在已经确定，致命的心律失常是由横纹肌中主要的钙储存细胞器——肌浆网（SR）不受调节的“病理性”钙释放引起的。关于病理性钙释放的分子机制，关于引发室性心动过速的心律失常的组织起源，以及关于最佳治疗方法的重要问题仍然存在。目前已确定6个参与SR钙释放的基因突变为CPVT的遗传原因：RYR2（编码ryanodine受体钙释放通道）、CASQ2（编码cardiac calsequestrin）、TRDN（编码triadin）、CALM1、CALM2和CALM3（编码相同的钙调蛋白）。在这里，我们回顾了每种CPVT亚型以及CPVT突变如何改变蛋白质功能，RyR2钙释放通道调节和细胞钙处理。然后，我们讨论了围绕CPVT的组织机制的研究和假设，例如窦房结功能障碍在CPVT中的病理生理作用，以及致心律失常的搏动是来自传导系统还是心室工作心肌。最后，我们回顾了可用于CPVT患者的治疗方法，它们的疗效，以及如何在未来改进治疗。儿茶酚胺能多形性室性心动过速（CPVT）是一种心律失常，以β-肾上腺素能受体刺激引起室性心动过速为特征。在这里，我们描述了从β-肾上腺素能刺激到单/多态室性心动过速形成的机制进展。这篇综述的目的是强调目前导致CPVT的分子机制，然后讨论围绕心律失常的细胞/组织起源的当前假设和研究。
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced cardiac channelopathy that has a high mortality in untreated patients. Our understanding has grown tremendously since CPVT was first described as a clinical syndrome in 1995. It is now established that the deadly arrhythmias are caused by unregulated ‘pathological’ calcium release from the sarcoplasmic reticulum (SR), the major calcium storage organelle in striated muscle. Important questions remain regarding the molecular mechanisms that are responsible for the pathological calcium release, regarding the tissue origin of the arrhythmic beats that initiate ventricular tachycardia, and regarding optimal therapeutic approaches. At present, mutations in six genes involved in SR calcium release have been identified as the genetic cause of CPVT: RYR2 (encoding ryanodine receptor calcium release channel), CASQ2 (encoding cardiac calsequestrin), TRDN (encoding triadin), CALM1, CALM2 and CALM3 (encoding identical calmodulin protein). Here, we review each CPVT subtype and how CPVT mutations alter protein function, RyR2 calcium release channel regulation, and cellular calcium handling. We then discuss research and hypotheses surrounding the tissue mechanisms underlying CPVT, such as the pathophysiological role of sinus node dysfunction in CPVT, and whether the arrhythmogenic beats originate from the conduction system or the ventricular working myocardium. Finally, we review the treatments that are available for patients with CPVT, their efficacy, and how therapy could be improved in the future. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a cardiac arrhythmia characterized by the presence of ventricular tachycardia in response to β-adrenergic receptor stimulation. Here, we describe the mechanistic progression from β-adrenergic stimulation to the formation of mono/polymorphic ventricular tachycardia. The goal of this review is to highlight the current molecular mechanisms that lead to CPVT followed by a discussion of the current hypotheses and research around the cellular/tissue origin of the arrhythmias.