Priebe L, Beuckelmann D J
Department of Medicine III, University of Cologne, Germany.
Circ Res. 1998 Jun 15;82(11):1206-23. doi: 10.1161/01.res.82.11.1206.
Patients with severe heart failure are at high risk of sudden cardiac death. In the majority of these patients, sudden cardiac death is thought to be due to ventricular tachyarrhythmias. Alterations of the electric properties of single myocytes in heart failure may favor the occurrence of ventricular arrhythmias in these patients by inducing early or delayed afterdepolarizations. Mathematical models of the cellular action potential and its underlying ionic currents could help to elucidate possible arrhythmogenic mechanisms on a cellular level. In the present study, selected ionic currents based on human data are incorporated into a model of the ventricular action potential for the purpose of studying the cellular electrophysiological consequences of heart failure. Ionic currents that are not yet sufficiently characterized in human ventricular myocytes are adopted from the action potential model developed by Luo and Rudy (LR model). The main results obtained from this model are as follows: The action potential in ventricular myocytes from failing hearts is longer than in nonfailing control hearts. The major underlying mechanisms for this prolongation are the enhanced activity of the Na+-Ca2+ exchanger, the slowed diastolic decay of the [Ca2+]i transient, and the reduction of the inwardly rectifying K+ current and the Na+-K+ pump current in myocytes of failing hearts. Furthermore, the fast and slow components of the delayed rectifier K+ current (I(Kr) and I(Ks), respectively) are of utmost importance in determining repolarization of the human ventricular action potential. In contrast, the influence of the transient outward K+ current on APD is only small in both cell groups. Inhibition of I(Kr) promotes the development of early afterdepolarizations in failing, but not nonfailing, myocytes. Furthermore, spontaneous Ca2+ release from the sarcoplasmic reticulum triggers a premature action potential only in failing myocytes. This model of the ventricular action potential and its alterations in heart failure is intended to serve as a tool for investigating the effects of therapeutic interventions on the electric excitability of the human ventricular myocardium.
重度心力衰竭患者发生心源性猝死的风险很高。在这些患者中，大多数心源性猝死被认为是由室性快速性心律失常所致。心力衰竭时单个心肌细胞电特性的改变可能通过诱发早期或延迟后去极化，促使这些患者发生室性心律失常。细胞动作电位及其潜在离子电流的数学模型有助于在细胞水平阐明可能的致心律失常机制。在本研究中，基于人类数据选择的离子电流被纳入心室动作电位模型，以研究心力衰竭的细胞电生理后果。在人类心室肌细胞中尚未得到充分表征的离子电流取自Luo和Rudy开发的动作电位模型（LR模型）。该模型得到的主要结果如下：衰竭心脏的心室肌细胞动作电位比非衰竭对照心脏的长。这种延长的主要潜在机制是钠钙交换体活性增强、胞内钙瞬变的舒张期衰减减慢以及衰竭心脏肌细胞内向整流钾电流和钠钾泵电流降低。此外，延迟整流钾电流的快速和慢速成分（分别为I(Kr)和I(Ks)）在决定人类心室动作电位复极化方面至关重要。相比之下，瞬时外向钾电流对动作电位时程的影响在两组细胞中都很小。抑制I(Kr)会促进衰竭但非非衰竭心肌细胞早期后去极化的发生。此外，肌浆网自发释放钙仅在衰竭心肌细胞中触发过早动作电位。这个心室动作电位及其在心力衰竭中改变的模型旨在作为一种工具，用于研究治疗干预对人类心室心肌电兴奋性的影响。
