Impact of Genetic Discoveries on the Classification of Lone Atrial Fibrillation

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, represents a major burden to patients and health care systems through its sequelae of heart failure and stroke. Its age-dependent increase in prevalence has led to worrisome predictions of an expanding burden secondary to our aging population. This growing epidemic is further exacerbated by a current lack of highly effective therapies for the arrhythmia stemming from our incomplete understanding of its complex pathophysiology. Recent genetic studies, triggered in part by evidence of a hereditary component of AF, have begun to identify predisposing genes and offer further insights into the mechanisms of lone AF. A variety of ion channels and most recently a circulating hormone have been implicated. The apparent genetic diversity underlying the arrhythmia has served to emphasize the heterogeneity of factors that govern its initiation and maintenance. The different causative genes seem to predispose to AF through distinct putative mechanisms, including enhanced and delayed atrial action potential repolarization, cellular hyperexcitability, and conduction velocity heterogeneity. Classification of lone AF into mechanistic subgroups serves to emphasize its heterogeneity and has the potential to guide developmental and clinical treatment strategies. The frequent recalcitrant nature of the arrhythmia to contemporary pharmacological and invasive therapies may be overcome through an ability to identify, through genetics, the mechanistic subclass of AF for an individual patient. Proper identification of the culprit pathophysiology may permit administration of a targeted form of therapy that carries maximal efficacy and minimal risk in a manner consistent with the vision of pharmacogenomics.