The Past, Present, and Potential Future of Sodium Channel Block as an Atrial Fibrillation Suppressing Strategy.
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.
*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.
Martin
M
Aguilar
Stanley
S
Nattel
D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004059:Diffusion of Innovation; D055808:Drug Discovery / Q000266:history / Q000639:trends; D015507:Drugs, Investigational / Q000009:adverse effects / Q000627:therapeutic use*; D005544:Forecasting; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects; D026941:Sodium Channel Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D015507:Drugs, Investigational; D026941:Sodium Channel Blockers; D015222:Sodium Channels