Contemporary Concepts in the Onset and Maintenance of Atrial Fibrillation: Mechanisms, Substrates, and Clinical Implications

Atrial Fibrillation (AF) is a disease of increasing electrical and structural heterogeneity, where triggers dominate early, and substrate-anchored drivers tend to predominate subsequently. Low-voltage substrate regions are a common feature, and typically correlate with underlying fibrotic scar. As the atrial milieu remodels and AF progresses from paroxysmal to persistent, longstanding persistent, and permanent forms, the electrical conduction patterns and structural topology become more disorganized, more likely to fibrillate due to unidirectional conduction block and obstructed pathways, and less likely to terminate spontaneously even with drug, ablative, or surgical intervention. Ablative targeting of the disorganized areas in addition to standard pulmonary vein isolation can improve the success rate for treatment of the more advanced forms of AF. Yet, if AF is perpetuated without satisfactory intervention, it becomes increasingly reflective of a more complex, spatially heterogeneous, and recalcitrant milieu arising from electrical uncoupling, fibrosis, adipose deposits, calcification, and wall thickness gradients. For more efficacious treatment, better understanding of the mechanisms by which AF is initiated and perpetuated must be prioritized. Development of techniques to enhance the analysis of atrial substrate properties, and to determine best areas for ablative therapy to improve outcome during electrophysiologic study and treatment, are needed. Additionally, attention to lifestyle-based factors such as patient diet and exercise are important for prevention and control of arrhythmia. Anti-inflammatory interventions may halt or even partially reverse electrical and structural remodeling and reduce arrhythmia severity. Possible new modalities include novel drug intervention and advanced pacing methods.