Department of Pharmacology, University of California, Davis, CA, USA.
Faculties of Kinesiology and Medicine, University of Calgary, Calgary, Alberta, Canada.
Br J Pharmacol. 2020 Oct;177(19):4497-4515. doi: 10.1111/bph.15198. Epub 2020 Aug 9.
Pharmacotherapy of atrial fibrillation (AF), the most common cardiac arrhythmia, remains unsatisfactory due to low efficacy and safety concerns. New therapeutic strategies target atrial-predominant ion-channels and involve multichannel block (poly)therapy. As AF is characterized by rapid and irregular atrial activations, compounds displaying potent antiarrhythmic effects at fast and minimal effects at slow rates are desirable. We present a novel systems pharmacology framework to quantitatively evaluate synergistic anti-AF effects of combined block of multiple atrial-predominant K currents (ultra-rapid delayed rectifier K current, I , small conductance Ca -activated K current, I , K 3.1 2-pore-domain K current, I ) in AF.
We constructed experimentally calibrated populations of virtual atrial myocyte models in normal sinus rhythm and AF-remodelled conditions using two distinct, well-established atrial models. Sensitivity analyses on our atrial populations was used to investigate the rate dependence of action potential duration (APD) changes due to blocking I , I or I and interactions caused by blocking of these currents in modulating APD. Block was simulated in both single myocytes and one-dimensional tissue strands to confirm insights from the sensitivity analyses and examine anti-arrhythmic effects of multi-atrial-predominant K current block in single cells and coupled tissue.
In both virtual atrial myocytes and tissues, multiple atrial-predominant K -current block promoted favourable positive rate-dependent APD prolongation and displayed positive rate-dependent synergy, that is, increasing synergistic antiarrhythmic effects at fast pacing versus slow rates.
Simultaneous block of multiple atrial-predominant K currents may be a valuable antiarrhythmic pharmacotherapeutic strategy for AF.
心房颤动（AF）是最常见的心律失常，由于疗效低和安全性问题，其药物治疗仍不尽如人意。新的治疗策略针对以心房为主的离子通道，涉及多通道阻断（多）治疗。由于 AF 的特征是快速而不规则的心房激活，因此需要显示出在快速和最小作用时对缓慢作用具有强大抗心律失常作用的化合物。我们提出了一种新的系统药理学框架，用于定量评估联合阻断多种以心房为主的 K 电流（超快延迟整流 K 电流，I ，小电导 Ca 激活 K 电流，I ，K 3.1 2 孔域 K 电流，I ）对 AF 的协同抗 AF 作用。
我们使用两种不同的、成熟的心房模型，在正常窦性节律和 AF 重塑条件下构建经过实验校准的虚拟心房肌细胞模型群体。我们对心房群体进行了敏感性分析，以研究由于阻断 I ，I 或 I 引起的动作电位持续时间（APD）变化的速率依赖性，以及阻断这些电流对 APD 的调制引起的相互作用。在单个心肌细胞和一维组织链中模拟阻断，以确认敏感性分析的结果，并检查多以心房为主的 K 电流阻断在单个细胞和偶联组织中的抗心律失常作用。
在虚拟心房肌细胞和组织中，多种以心房为主的 K 电流阻断促进了有利的正性速率依赖性 APD 延长，并显示出正性速率依赖性协同作用，即在快速起搏与缓慢起搏时，协同抗心律失常作用增加。
同时阻断多种以心房为主的 K 电流可能是治疗 AF 的一种有价值的抗心律失常药物治疗策略。
