Abstract:
Cardiac arrhythmias cause significant morbidity and mortality and pose a major public health problem. They arise from disruptions in the normally orderly propagation of cardiac electrophysiological activation and recovery through successive cardiomyocytes in the heart. They reflect abnormalities in automaticity, initiation, conduction, or recovery in cardiomyocyte excitation. The latter properties are dependent on surface membrane electrophysiological mechanisms underlying the cardiac action potential. Their disruption results from spatial or temporal instabilities and heterogeneities in the generation and propagation of cellular excitation. These arise from abnormal function in their underlying surface membrane, ion channels, and transporters, as well as the interactions between them. The latter, in turn, form common regulatory targets for the hierarchical network of diverse signaling mechanisms reviewed here. In addition to direct molecular-level pharmacological or physiological actions on these surface membrane biomolecules, accessory, adhesion, signal transduction, and cytoskeletal anchoring proteins modify both their properties and localization. At the cellular level of excitation-contraction coupling processes, Ca2+ homeostatic and phosphorylation processes affect channel activity and membrane excitability directly or through intermediate signaling. Systems-level autonomic cellular signaling exerts both acute channel and longer-term actions on channel expression. Further upstream intermediaries from metabolic changes modulate the channels both themselves and through modifying Ca2+ homeostasis. Finally, longer-term organ-level inflammatory and structural changes, such as fibrotic and hypertrophic remodeling, similarly can influence all these physiological processes with potential pro-arrhythmic consequences. These normal physiological processes may target either individual or groups of ionic channel species and alter with particular pathological conditions. They are also potentially alterable by direct pharmacological action, or effects on longer-term targets modifying protein or cofactor structure, expression, or localization. Their participating specific biomolecules, often clarified in experimental genetically modified models, thus constitute potential therapeutic targets. The insights clarified by the physiological and pharmacological framework outlined here provide a basis for a recent modernized drug classification. Together, they offer a translational framework for current drug understanding. This would facilitate future mechanistically directed therapeutic advances, for which a number of examples are considered here. The latter are potentially useful for treating cardiac, in particular arrhythmic, disease.
摘要:
心律失常会导致大量的发病率和死亡率,并构成主要的公共卫生问题。它们起因于心脏电生理激活和通过心脏中的连续心肌细胞恢复的正常有序传播的破坏。它们反映了自动化的异常,initiation,传导,或心肌细胞兴奋恢复。后者的特性取决于心脏动作电位的表面膜电生理机制。它们的破坏是由于细胞激发的产生和传播中的空间或时间不稳定性和异质性所致。这些是由于其下面的表面膜的功能异常而引起的,离子通道,和运输商,以及它们之间的相互作用。后者,反过来,为此处审查的各种信令机制的分层网络形成共同的监管目标。除了对这些表面膜生物分子的直接分子水平的药理学或生理学作用外,附件,附着力,信号转导,和细胞骨架锚定蛋白修饰它们的性质和定位。在细胞水平的激发-收缩耦合过程,Ca2+稳态和磷酸化过程直接或通过中间信号传导影响通道活性和膜兴奋性。系统水平的自主细胞信号传导对通道表达既有急性通道又有长期作用。来自代谢变化的其他上游中间体调节通道本身和通过改变Ca2稳态。最后,长期的器官水平炎症和结构变化,如纤维化和肥厚性重塑,类似地,可以影响所有这些生理过程,并产生潜在的致心律失常的后果.这些正常的生理过程可以靶向单个或成组的离子通道物质,并随特定的病理状况而改变。它们也可能通过直接的药理作用而改变,或对长期靶标修饰蛋白质或辅因子结构的影响,表达式,或本地化。他们参与的特定生物分子,经常在实验转基因模型中阐明,从而构成潜在的治疗靶点。本文概述的生理学和药理学框架阐明的见解为最近的现代化药物分类提供了基础。一起,它们为当前的药物理解提供了一个转化框架。这将促进未来机械指导的治疗进展,这里考虑了一些例子。后者可能用于治疗心脏,特别是心律失常,疾病。