Aguilar Martin, Nattel Stanley
*Research Center, Montreal Heart Institute, Montreal, Québec, Canada; †Department of Physiology, Université de Montréal, Montreal, Québec, Canada; ‡Department of Medicine, McGill University, Montreal, Québec, Canada; §Department of Medicine, Université de Montréal, Montreal, Québec, Canada; and ¶Department of Pharmacology and Therapeutics, McGill University, Montreal, Québec, Canada.
J Cardiovasc Pharmacol. 2015 Nov;66(5):432-40. doi: 10.1097/FJC.0000000000000271.
Despite major advances in arrhythmia therapy, atrial fibrillation (AF) remains a challenge. A significant limitation in AF management is the lack of safe and effective drugs to restore and/or maintain sinus rhythm. The rational design of a new generation of AF-selective Na(+) channel blockers (NCBs) is emerging as a promising AF-suppressing strategy. Recent theoretical and experimental advances have generated insights into the mechanisms underlying AF maintenance and termination by antiarrhythmic drugs. Our understanding of antiarrhythmic drug-induced proarrhythmia has also grown in sophistication. These discoveries have created new possibilities in therapeutic targeting and renewed interest in improved NCB antiarrhythmic drugs. Recently described differences in atrial versus ventricular electrophysiology can be exploited in the prospective design of atrial-selective NCBs. Furthermore, state-dependent block has been shown to be an important modulator of NCB rate selectivity. Together, differential atrial-ventricular electrophysiological actions and state-dependent block form the backbone for the rational design of an AF-selective NCB. Synergistic combinations incorporating both NCB and block of K(+) currents may allow for further enhancement of AF selectivity. Future work on translating these basic research advances into the development of an optimized AF-selective NCB has the potential to provide safer and more effective pharmacotherapeutic options for AF, thereby fulfilling a major unmet clinical need.
尽管心律失常治疗取得了重大进展，但心房颤动（AF）仍然是一个挑战。房颤管理中的一个重大限制是缺乏安全有效的药物来恢复和/或维持窦性心律。新一代房颤选择性钠（Na+）通道阻滞剂（NCBs）的合理设计正在成为一种有前景的房颤抑制策略。最近的理论和实验进展使人们对抗心律失常药物维持和终止房颤的潜在机制有了更深入的了解。我们对抗心律失常药物诱发的心律失常的理解也更加成熟。这些发现为治疗靶点创造了新的可能性，并重新激发了人们对改进NCB抗心律失常药物的兴趣。最近描述的心房与心室电生理学差异可用于心房选择性NCBs的前瞻性设计。此外，电压依赖性阻滞已被证明是NCB速率选择性的重要调节因素。心房-心室电生理作用差异和电压依赖性阻滞共同构成了合理设计房颤选择性NCB的基础。将NCB与钾（K+）电流阻滞相结合的协同组合可能会进一步提高房颤选择性。未来将这些基础研究进展转化为优化的房颤选择性NCB开发的工作，有可能为房颤提供更安全、更有效的药物治疗选择，从而满足一项尚未得到满足的重大临床需求。
