Deciphering the fundamental mechanisms of atrial fibrillation: a quest for over a century.

Abstract

Atrial fibrillation (AF), the most frequent clinical arrhythmia, is associated with increased cardiovascular morbidity and mortality, with stroke, myocardial infarction, and heart failure being the most critical complications.1 Presently available drugs for AF therapy have moderate efficacy and important limitations, particularly increasing the risk of life-threatening proarrhythmic events and bleeding complications.1,2 Ablation procedures are moderately effective and relatively safe, but the increasing size of the patient population limits applicability to only a small proportion of patients.1 Therefore, drug therapy is still the mainstay of AF treatment. Although maintenance of sinus rhythm (rhythm control) appears preferable, clinical studies failed to demonstrate clear advantages to rate over rhythm control, likely because current pharmacological approaches do not target the critical determinants of the fundamental mechanisms of AF.3,4 A better mechanistic understanding of the molecular basis of AF is expected to foster the development of safer and more effective treatment approaches. Although the basic mechanisms of AF have been described in the medical literature for over a century, the underlying cellular and molecular mechanisms are incompletely understood.5 It is assumed that independent of the underlying cause, which may be very diverse, ectopic impulse formation (ectopic activity) and re-entry are the two major determinants of AF pathophysiology.2 Re-entry requires a vulnerable substrate and an initiating trigger. The likelihood of re-entry formation is determined by the tissue properties of conduction and refractoriness, with conduction disturbances and short refractoriness making formation …