Wickenden A D, Kaprielian R, Kassiri Z, Tsoporis J N, Tsushima R, Fishman G I, Backx P H
Toronto Hospital, Department of Medicine, Ontario, Canada.
Cardiovasc Res. 1998 Feb;37(2):312-23. doi: 10.1016/s0008-6363(97)00256-3.
Action potential prolongation is a common finding in human heart failure and in animal models of cardiac hypertrophy. The mechanism of action potential prolongation involves altered expression of a variety of depolarising and hyperpolarising currents in the myocardium. In particular, decreased density of the transient outward potassium current seems to play a prominent role, regardless of species, precipitating factors or the severity of hypertrophy. The decreased density of the transient outward current appears to be caused by reduced transcription of Kv4.2 and Kv4.3 and may be caused in part by an inhibitory effect of alpha-adrenoceptor stimulation. During the early stage of the disease process, action potential prolongation may increase the amplitude of the intracellular calcium transient, causing positive inotropy. We argue therefore, that action prolongation may be a compensatory response which may acutely support the compromised cardiac output. In severe hypertrophy and end-stage heart failure however, despite continued action potential prolongation, the amplitude of the calcium transient becomes severely reduced. The mechanism underlying this event appears to involve reduced expression of calcium handling proteins, and these late events may herald the onset of failure. At present the events leading to the late changes in calcium handling are poorly understood. However, chronic activation of compensatory mechanisms including action potential prolongation may trigger these late events. In the present article we outline a hypothesis which describes a potential role for action potential prolongation, and the associated elevation in the levels of intracellular calcium, in maladaptive gene expression and the progression toward cardiac failure.
动作电位延长在人类心力衰竭以及心脏肥大的动物模型中很常见。动作电位延长的机制涉及心肌中多种去极化和超极化电流的表达改变。特别是，无论物种、促发因素或肥大的严重程度如何，瞬时外向钾电流密度降低似乎都起着重要作用。瞬时外向电流密度降低似乎是由Kv4.2和Kv4.3转录减少引起的，部分可能是由α-肾上腺素能受体刺激的抑制作用导致的。在疾病过程的早期，动作电位延长可能会增加细胞内钙瞬变的幅度，导致正性肌力作用。因此，我们认为动作电位延长可能是一种代偿反应，可能会急性支持受损的心输出量。然而，在严重肥大和终末期心力衰竭中，尽管动作电位持续延长，但钙瞬变的幅度会严重降低。这一事件的潜在机制似乎涉及钙处理蛋白表达的减少，这些晚期事件可能预示着心力衰竭的开始。目前，导致钙处理后期变化的事件尚不清楚。然而，包括动作电位延长在内的代偿机制的慢性激活可能会引发这些晚期事件。在本文中，我们概述了一个假说，该假说描述了动作电位延长以及细胞内钙水平的相关升高在适应性不良基因表达和心力衰竭进展中的潜在作用。
