Department of Computer Systems, New York City College of Technology, Doctoral Program in Computer Science, Graduate Center, City University of New York, New York, New York, USA.
Physiol Rep. 2022 Jun;10(12):e15356. doi: 10.14814/phy2.15356.
Pharmacological agents that prolong action potential duration (APD) to a larger extent at slow rates than at the fast excitation rates typical of ventricular tachycardia exhibit reverse rate dependence. Reverse rate dependence has been linked to the lack of efficacy of class III agents at preventing arrhythmias because the doses required to have an antiarrhythmic effect at fast rates may have pro-arrhythmic effects at slow rates due to an excessive APD prolongation. In this report, we show that, in computer models of the ventricular action potential, APD prolongation by accelerating phase 2 repolarization (by increasing I ) and decelerating phase 3 repolarization (by blocking I and I ) results in a robust positive rate dependence (i.e., larger APD prolongation at fast rates than at slow rates). In contrast, APD prolongation by blocking a specific potassium channel type results in reverse rate dependence or a moderate positive rate dependence. Interventions that result in a strong positive rate dependence tend to decrease the repolarization reserve because they require substantial I block. However, limiting I block to ~50% results in a strong positive rate dependence with moderate decrease in repolarization reserve. In conclusion, the use of a combination of I activators and I and I blockers could result in APD prolongation that potentially maximizes antiarrhythmic effects (by maximizing APD prolongation at fast excitation rates) and minimizes pro-arrhythmic effects (by minimizing APD prolongation at slow excitation rates).
药理制剂在缓慢激发速率下比在室性心动过速的典型快速激发速率下更能延长动作电位持续时间（APD），表现出反向速率依赖性。反向速率依赖性与 III 类药物在预防心律失常方面的疗效不足有关，因为在快速激发速率下达到抗心律失常效果所需的剂量可能会因 APD 过度延长而在缓慢激发速率下产生致心律失常作用。在本报告中，我们表明，在心室动作电位的计算机模型中，通过加速 2 相复极化（通过增加 I ）和减速 3 相复极化（通过阻断 I 和 I ）来延长 APD，会导致强大的正向速率依赖性（即，在快速激发速率下比在缓慢激发速率下更长的 APD 延长）。相比之下，通过阻断特定的钾通道类型来延长 APD 会导致反向速率依赖性或适度的正速率依赖性。导致强正向速率依赖性的干预措施往往会降低复极储备，因为它们需要大量的 I 阻断。然而，将 I 阻断限制在约 50%会导致强烈的正速率依赖性和适度的复极储备减少。总之，使用 I 激活剂和 I 和 I 阻断剂的组合可能会导致 APD 延长，从而最大限度地提高抗心律失常效果（通过最大限度地延长快速激发速率下的 APD 延长）并最小化致心律失常作用（通过最小化缓慢激发速率下的 APD 延长）。
