Department of Chemistry, Life Sciences and Environmental Sustainability - University of Parma Parco Area delle Scienze, Parma, Italy.
Center of Excellence for Toxicological Research (CERT) - University of Parma, Parma, Italy.
PLoS One. 2018 Mar 1;13(3):e0193416. doi: 10.1371/journal.pone.0193416. eCollection 2018.
Electrical restitution (ER) is a major determinant of repolarization stability and, under fast pacing rate, it reveals memory properties of the cardiac action potential (AP), whose dynamics have never been fully elucidated, nor their ionic mechanisms. Previous studies have looked at ER mainly in terms of changes in AP duration (APD) when the preceding diastolic interval (DI) changes and described dynamic conditions where this relationship shows hysteresis which, in turn, has been proposed as a marker of short-term AP memory and repolarization stability. By means of numerical simulations of a non-propagated human ventricular AP, we show here that measuring ER as APD versus the preceding cycle length (CL) provides additional information on repolarization dynamics which is not contained in the companion formulation. We focus particularly on fast pacing rate conditions with a beat-to-beat variable CL, where memory properties emerge from APD vs CL and not from APD vs DI and should thus be stored in APD and not in DI. We provide an ion-currents characterization of such conditions under periodic and random CL variability, and show that the memory stored in APD plays a stabilizing role on AP repolarization under pacing rate perturbations. The gating kinetics of L-type calcium current seems to be the main determinant of this safety mechanism. We also show that, at fast pacing rate and under otherwise identical pacing conditions, a periodically beat-to-beat changing CL is more effective than a random one in stabilizing repolarization. In summary, we propose a novel view of short-term AP memory, differentially stored between systole and diastole, which opens a number of methodological and theoretical implications for the understanding of arrhythmia development.
电折返（ER）是复极稳定性的主要决定因素，在快速起搏率下，它揭示了心脏动作电位（AP）的记忆特性，其动力学尚未得到充分阐明，离子机制也没有。先前的研究主要从 AP 持续时间（APD）随前一个舒张间隔（DI）变化的角度来看待 ER，并描述了这种关系表现出滞后的动态条件，滞后性反过来又被提出作为短期 AP 记忆和复极稳定性的标志物。通过对未传播的人心室 AP 的数值模拟，我们在这里表明，将 ER 作为 APD 与前一个周期长度（CL）进行测量，可以提供有关复极动力学的附加信息，而这些信息在伴随的公式中并不包含。我们特别关注具有逐拍变化 CL 的快速起搏率条件，其中记忆特性源自 APD 与 CL 的关系，而不是源自 APD 与 DI 的关系，因此应该存储在 APD 中，而不是 DI 中。我们对周期性和随机 CL 变化下的这些条件进行了离子电流特性分析，并表明存储在 APD 中的记忆在起搏率扰动下对 AP 复极起到稳定作用。L 型钙电流的门控动力学似乎是这种安全机制的主要决定因素。我们还表明，在快速起搏率下，在其他起搏条件相同的情况下，周期性的逐拍变化的 CL 比随机的 CL 更有效地稳定复极。总之，我们提出了一种新的短期 AP 记忆观点，分别存储在收缩期和舒张期，这为理解心律失常的发展开辟了许多方法学和理论上的可能性。
