Atrial Fibrillation and Mechanisms of Stroke

Thirty-three million people have atrial fibrillation (AF), a disorder of heart rhythm.1 Over the past several decades, we have learned that this dysrhythmia originates in the interplay between genetic predisposition, ectopic electrical activity, and abnormal atrial tissue substrate and then feeds back to remodel and worsen tissue substrate and, thereby, propagates itself.2 Although the importance of AF partly derives from its strong association with ischemic stroke, there have not been as many advances in our understanding of the mechanisms of stroke in AF. Current views rest on a century old hypothesis that fibrillation of the atrium produces stasis of blood, which causes thrombus formation and embolism to the brain. When other abnormalities are acknowledged to play a role, the dysrhythmia is still considered the primary cause of thromboembolism.3 Although this formulation is intuitively appealing, recent work suggests that the pathogenesis of stroke in AF is more complicated and involves factors in addition to the dysrhythmia.AF and stroke have been associated in rigorous studies,4 indicating a true association rather than a spurious finding. Epidemiological logic suggests 3 explanations: (1) AF causes stroke, (2) stroke causes AF, and (3) AF is associated with other factors that cause stroke.To help judge whether one factor causes another or whether the 2 are simply correlated, the epidemiologist Bradford Hill proposed the following widely accepted criteria: (1) strength of association, (2) consistency, (3) specificity, (4) temporality, (5) biological gradient, (6) plausibility, (7) coherence, (8) accordance with experimental results, and (9) analogy.5 The relationship between AF and stroke fulfills several of these criteria. Patients with AF face a strongly elevated risk of stroke—about 3- to 5-fold higher after adjustment for risk factors.4 AF has been consistently associated with stroke in different cohorts.6 And a causal association is biologically …