Mechanisms of atrial fibrillation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. The prevalence of AF is increasing as the median age of the population is on rise. Incidence of AF increases with age, as one in five individuals over age 85 has AF. Several clinical conditions are associated with AF, most importantly ischemic heart disease, diabetes, hypertension, cardiomyopathy, valvular heart disease, and heart failure. AF is a complex disease and its pathogenesis is multifactorial. The relatively recent discovery of the importance of the pulmonary veins (PV) in the origin of triggers and generation of AF has helped us better understand the pathophysiology of AF. The region of the PVs and the adjoining posterior left atrium (PLA) possesses a unique, heterogeneous pattern of myocyte orientation; the abrupt changes in electrical conduction patterns that result in these regions make the atria more susceptible to AF (by setting up substrate for reentry). Another important factor that contributes to atrial arrhythmogenesis is the unique expression of key ion channels in the atrium. Compared to the ventricles, some ion channels, e.g., I _KAch and I _Kur, are predominantly expressed in atrial myocytes; these channels, by contributing to shortening of refractoriness, make the atria more vulnerable to fibrillation. In addition, the PVs and PLA have a unique pattern of ion channel and gap junction expression that makes the atria susceptible to AF. Ca²⁺ dysregulation has also been noted to play an important role in generation and maintenance of AF, with excitation-contraction coupling being significantly altered in fibrillating myocytes (as compared to normal atrial myocytes). In addition to ion channel, gap junction, and Ca²⁺ remodeling, structural remodeling - specifically fibrosis - has been implicated in AF initiation and maintenance, especially in the setting of structural heart disease, e.g., heart failure. Key signaling pathways that are thought to create fibrosis in the atrium including TGF-β signaling, oxidative stress, and angiotensin II signaling. The autonomic nervous system is also thought to play an important role in generation of AF, with both the sympathetic and parasympathetic thought to play an important role in AF initiation and maintenance. Recently, Genome-wide association studies have also provided us with new insights into genetic predisposition in AF generation. In this chapter, we have reviewed in detail the role of these pathophysiological mechanisms in the generation and maintenance of AF.