Cardiovascular Institute, Stanford University School of Medicine, 1651 Page Mill Road, Palo Alto, CA, 94305, USA.
Curr Cardiol Rep. 2018 May 25;20(7):57. doi: 10.1007/s11886-018-1000-0.
Cardiovascular disease is the leading contributor to mortality and morbidity. Many deaths of heart failure patients can be attributed to sudden cardiac death due primarily to ventricular arrhythmia. Currently, most anti-arrhythmics modulate ion channel conductivity or β-adrenergic signaling, but these drugs have limited efficacy for some indications, and can potentially be proarrhythmic.
Recent studies have shown that mutations in proteins other than cardiac ion channels may confer susceptibility to congenital as well as acquired arrhythmias. Additionally, ion channels themselves are subject to regulation at the levels of channel expression, trafficking and post-translational modification; thus, research into the regulation of ion channels may elucidate disease mechanisms and potential therapeutic targets for future drug development. This review summarizes the current knowledge of the molecular mechanisms of arrhythmia susceptibility and discusses technological advances such as induced pluripotent stem cell-derived cardiomyocytes, gene editing, functional genomics, and physiological screening platforms that provide a new paradigm for discovery of new therapeutic targets to treat congenital and acquired diseases of the heart rhythm.
心血管疾病是导致死亡率和发病率的主要原因。心力衰竭患者的许多死亡可归因于主要由室性心律失常引起的心脏性猝死。目前，大多数抗心律失常药物调节离子通道导电性或β-肾上腺素能信号，但这些药物对某些适应症的疗效有限，并且可能有致心律失常作用。
最近的研究表明，除心脏离子通道以外的蛋白质突变可能导致先天性和获得性心律失常易感性。此外，离子通道本身在通道表达、运输和翻译后修饰水平上受到调节；因此，对离子通道的调节的研究可能阐明疾病机制和潜在的治疗靶点，为未来的药物开发提供新的范例。本综述总结了心律失常易感性的分子机制的现有知识，并讨论了诱导多能干细胞衍生的心肌细胞、基因编辑、功能基因组学和生理筛选平台等技术进步，为发现治疗先天性和获得性心脏节律疾病的新治疗靶点提供了新的范例。
