Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University PO Box 616, 6200 MD, Maastricht, the Netherlands.
Computational Biology, Department of Computer Science, University of Oxford, Oxford, OX1 3QD, United Kingdom.
Pharmacol Res. 2019 Oct;148:104444. doi: 10.1016/j.phrs.2019.104444. Epub 2019 Sep 4.
Cardiac arrhythmias are a global health burden, contributing significantly to morbidity and mortality worldwide. Despite technological advances in catheter ablation therapy, antiarrhythmic drugs (AADs) remain a cornerstone for the management of cardiac arrhythmias. Experimental and translational studies have shown that commonly used AADs exert multiple effects in the heart, the manifestation of which strongly depends on the exact experimental or clinical conditions. This diversity makes the optimal clinical application of AADs challenging. Here, we present a novel computational tool designed to facilitate a better understanding of the complex mechanisms of action of AADs (the Maastricht Antiarrhythmic Drug Evaluator, MANTA). In this tool, we integrated published computational cardiomyocyte models from different species (mouse, guinea pig, rabbit, dog, and human), regions (atrial, ventricular, and Purkinje cells) and disease conditions (atrial fibrillation- and heart failure-related remodeling). Subsequently, we investigated the effects of clinically available AADs (Vaughan-Williams Classes I, III, IV and multi-channel blockers) on action potential (AP) properties and the occurrence of proarrhythmic effects such as early afterdepolarizations. Steady-state drug effects were simulated based on a newly compiled overview of published IC values for each cardiac ion channel and by integrating state-dependent block of the cardiac Na-current by Class I AADs using a Markov-model approach. Using MANTA, we demonstrated and characterized important species-, rate-, cell-type-, and disease-state-specific AAD effects, including 1) a stronger effect of Class III AADs in large mammals than in rodents; 2) a rate-dependent decrease in upstroke velocity with Class I AADs and reverse rate-dependent effects of Class III AADs on action potential duration; 3) ventricular-predominant effects of pure I blockers; 4) preferential reduction in atrial AP upstroke velocity with vernakalant; and 5) excessive AP prolongation with Class III AADs other than amiodarone under heart failure conditions. In conclusion, the effects of AADs are highly complex and strongly dependent on the experimental or clinical conditions. MANTA is a powerful and freely available tool reproducing a wide range of AAD characteristics that enables analyses of the underlying ionic mechanisms. Use of MANTA is expected to improve our understanding of AAD effects on cellular electrophysiology under a wide range of conditions, which may provide clinically-relevant information on the safety and efficacy of AAD treatment.
心律失常是全球范围内的健康负担，对全球的发病率和死亡率有重要影响。尽管导管消融治疗技术取得了进步，但抗心律失常药物（AADs）仍然是心律失常治疗的基石。实验和转化研究表明，常用的 AAD 在心脏中具有多种作用，其表现强烈依赖于确切的实验或临床条件。这种多样性使得 AAD 的最佳临床应用具有挑战性。在这里，我们提出了一种新的计算工具，旨在帮助更好地理解 AAD 的复杂作用机制（马斯特里赫特抗心律失常药物评估器，MANTA）。在该工具中，我们整合了来自不同物种（小鼠、豚鼠、兔、狗和人）、区域（心房、心室和浦肯野细胞）和疾病状态（心房颤动和心力衰竭相关重构）的已发表计算心肌细胞模型。随后，我们研究了临床上可用的 AAD（Vaughan-Williams 类 I、III、IV 和多通道阻滞剂）对动作电位（AP）特性和致心律失常作用（如早期后除极）的影响。基于每个心脏离子通道的已发表 IC 值的新综述，以及使用 Markov 模型方法整合 I 类 AAD 对心脏 Na 电流的状态依赖性阻滞，模拟了稳态药物效应。使用 MANTA，我们展示并描述了重要的物种特异性、速率特异性、细胞类型特异性和疾病状态特异性的 AAD 作用，包括 1）I 类 AAD 在大型哺乳动物中的作用比在啮齿动物中更强；2）I 类 AAD 引起的上升速度随速率依赖性降低，III 类 AAD 对动作电位持续时间的反向速率依赖性影响；3）纯 I 阻滞剂的心室优势作用；4）维纳卡兰对心房 AP 上升速度的优先降低；5）心力衰竭条件下除胺碘酮外，III 类 AAD 引起的 AP 过度延长。总之，AAD 的作用非常复杂，强烈依赖于实验或临床条件。MANTA 是一种强大且免费的工具，可再现广泛的 AAD 特性，能够分析潜在的离子机制。使用 MANTA 有望提高我们对广泛条件下 AAD 对细胞电生理学影响的理解，从而为 AAD 治疗的安全性和有效性提供临床相关信息。
