Oxford University Computing Laboratory, Parks Road, Oxford, UK.
Am J Physiol Heart Circ Physiol. 2010 May;298(5):H1577-87. doi: 10.1152/ajpheart.00936.2009. Epub 2010 Mar 5.
Protracted QT interval (QTI) adaptation to abrupt heart rate (HR) changes has been identified as a clinical arrhythmic risk marker. This study investigates the ionic mechanisms of QTI rate adaptation and its relationship to arrhythmic risk. Computer simulations and experimental recordings in human and canine ventricular tissue were used to investigate the ionic basis of QTI and action potential duration (APD) to abrupt changes in HR with a protocol commonly used in clinical studies. The time for 90% QTI adaptation is 3.5 min in simulations, in agreement with experimental and clinical data in humans. APD adaptation follows similar dynamics, being faster in mid-myocardial cells (2.5 min) than in endocardial and epicardial cells (3.5 min). Both QTI and APD adapt in two phases following an abrupt HR change: a fast initial phase with time constant < 30 s, mainly related to L-type calcium and slow-delayed rectifier potassium current, and a second slow phase of >2 min driven by intracellular sodium concentration (Na(+)) dynamics. Alterations in Na(+) dynamics due to Na(+)/K(+) pump current inhibition result in protracted rate adaptation and are associated with increased proarrhythmic risk, as indicated by action potential triangulation and faster L-type calcium current recovery from inactivation, leading to the formation of early afterdepolarizations. In conclusion, this study suggests that protracted QTI adaptation could be an indicator of altered Na(+) dynamics following Na(+)/K(+) pump inhibition as it occurs in patients with ischemia or heart failure. An increased risk of cardiac arrhythmias in patients with protracted rate adaptation may be due to an increased risk of early after-depolarization formation.
延长的 QT 间期（QTI）适应突发心率（HR）变化已被确定为临床心律失常风险标志物。本研究调查了 QTI 率适应的离子机制及其与心律失常风险的关系。使用计算机模拟和人心和犬心组织的实验记录，研究了 HR 突然变化时 QTI 和动作电位时程（APD）的离子基础，使用了临床研究中常用的方案。模拟中，90%QTI 适应的时间为 3.5 分钟，与人类的实验和临床数据一致。APD 适应遵循类似的动力学，在中层心肌细胞（2.5 分钟）比心内膜和心外膜细胞（3.5 分钟）更快。在 HR 突然变化后，QTI 和 APD 都以两个阶段适应：快速初始阶段，时间常数 < 30 秒，主要与 L 型钙和缓慢延迟整流钾电流有关，以及第二缓慢阶段 >2 分钟，由细胞内钠浓度（Na(+)）动力学驱动。由于钠/钾泵电流抑制导致 Na(+)动力学改变，导致 QTI 延长，与心律失常风险增加有关，如动作电位三角化和 L 型钙电流从失活中更快恢复，导致早期后除极形成。总之，本研究表明，延长的 QTI 适应可能是由于缺血或心力衰竭患者中钠/钾泵抑制导致的 Na(+)动力学改变的指标。由于早期后除极形成的风险增加，延长率适应的患者发生心律失常的风险可能增加。
