Ellinwood Nicholas, Dobrev Dobromir, Morotti Stefano, Grandi Eleonora
Department of Pharmacology, University of California Davis, Davis, California 95616, USA.
Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany.
Chaos. 2017 Sep;27(9):093918. doi: 10.1063/1.5000226.
The K1.5 potassium channel, which underlies the ultra-rapid delayed-rectifier current (I) and is predominantly expressed in atria vs. ventricles, has emerged as a promising target to treat atrial fibrillation (AF). However, while numerous K1.5-selective compounds have been screened, characterized, and tested in various animal models of AF, evidence of antiarrhythmic efficacy in humans is still lacking. Moreover, current guidelines for pre-clinical assessment of candidate drugs heavily rely on steady-state concentration-response curves or IC values, which can overlook adverse cardiotoxic effects. We sought to investigate the effects of kinetics and state-dependent binding of I-targeting drugs on atrial electrophysiology in silico and reveal the ideal properties of I blockers that maximize anti-AF efficacy and minimize pro-arrhythmic risk. To this aim, we developed a new Markov model of I that describes K1.5 gating based on experimental voltage-clamp data in atrial myocytes from patient right-atrial samples in normal sinus rhythm. We extended the I formulation to account for state-specificity and kinetics of K1.5-drug interactions and incorporated it into our human atrial cell model. We simulated 1- and 3-Hz pacing protocols in drug-free conditions and with a [drug] equal to the IC value. The effects of binding and unbinding kinetics were determined by examining permutations of the forward (k) and reverse (k) binding rates to the closed, open, and inactivated states of the K1.5 channel. We identified a subset of ideal drugs exhibiting anti-AF electrophysiological parameter changes at fast pacing rates (effective refractory period prolongation), while having little effect on normal sinus rhythm (limited action potential prolongation). Our results highlight that accurately accounting for channel interactions with drugs, including kinetics and state-dependent binding, is critical for developing safer and more effective pharmacological anti-AF options.
K1.5钾通道是超快速延迟整流电流（I）的基础，主要在心房而非心室中表达，已成为治疗心房颤动（AF）的一个有前景的靶点。然而，尽管已经筛选、表征并在各种AF动物模型中测试了许多K1.5选择性化合物，但仍缺乏在人体中的抗心律失常疗效证据。此外，目前候选药物临床前评估指南严重依赖稳态浓度-反应曲线或IC值，这可能会忽略不良心脏毒性作用。我们试图在计算机模拟中研究靶向I的药物的动力学和状态依赖性结合对心房电生理的影响，并揭示能使抗AF疗效最大化和促心律失常风险最小化的I阻滞剂的理想特性。为此，我们基于正常窦性心律患者右心房样本中心房肌细胞的实验电压钳数据，开发了一种新的I马尔可夫模型，该模型描述了K1.5门控。我们扩展了I的公式，以考虑K1.5与药物相互作用的状态特异性和动力学，并将其纳入我们的人体心房细胞模型。我们在无药物条件下以及药物浓度等于IC值的情况下模拟了1赫兹和3赫兹起搏方案。通过检查K1.5通道关闭、开放和失活状态的正向（k）和反向（k）结合速率的排列来确定结合和解离动力学的影响。我们确定了一组理想药物，它们在快速起搏速率下表现出抗AF电生理参数变化（有效不应期延长），而对正常窦性心律影响很小（动作电位延长有限）。我们的结果强调，准确考虑通道与药物的相互作用，包括动力学和状态依赖性结合，对于开发更安全、更有效的抗AF药物选择至关重要。
