New insights into the molecular basis of atrial fibrillation: mechanistic and therapeutic implications.

This editorial refers to a collection of nine reviews and nine original articles that are part of this special issue on atrial fibrillation, guest edited by Dobromir Dobrev and Stanley Nattel. Atrial fibrillation (AF), the most common sustained arrhythmia, is associated with substantial cardiovascular morbidity and mortality, with stroke being the most critical complication.1 Present drugs used for AF therapy have major limitations, including incomplete efficacy and risks of life-threatening proarrhythmic events and bleeding complications.1,2 Non-pharmacological ablation procedures are efficient and relatively safe, but the very large size of the patient population allows ablation treatment of only a small number of patients. Therefore, drug therapy remains the mainstay of AF treatment. Maintenance of sinus rhythm (rhythm control) appears preferable, but studies to date have failed to demonstrate tangible advantages of rhythm control. The failure to show benefits in mortality and stroke incidence motivates attempts to identify new therapeutic targets relating to basic mechanisms underlying arrhythmia susceptibility. A better mechanistic understanding of the molecular basis of AF may allow for the development of safer and more effective treatment approaches. The mechanisms underlying AF susceptibility are multiple and incompletely understood. The two major determinants of AF maintenance are reentry and ectopic impulse formation (ectopic activity).3 Reentry induction requires an appropriate arrhythmogenic substrate and a trigger that initiates reentry within the substrate. The likelihood of reentry is determined by the tissue properties of conduction and refractoriness, with slow conduction and short refractoriness making persistence of reentry more likely. Ectopic activity is governed by factors controlling the occurrence of afterdepolarizations, primarily Ca2+ handling abnormalities that can cause early and delayed afterdepolarizations. The changes in atrial structure and function that result from heart disease, and indeed AF itself, constitute atrial remodelling and are key elements of the …

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