Atrial Cardiomyopathy Drives Stroke Risk Independent of Atrial Fibrillation: A Multi-Cohort Analysis

Abstract 2313896, presented at Western Atrial Fibrillation Symposium 2026

Atrial fibrillation (AF) is associated with stroke, yet outcomes often occur without detected arrhythmia. Atrial cardiomyopathy (AtCM) may represent the substrate conferring thromboembolic risk independent of AF. We aimed to identify distinct atrial phenotypes, derive a clinically applicable AtCM definition, and determine stroke pathways.Unsupervised clustering of 3,328 CHS participants free of AF, CHF, or CVA at baseline was performed using 10 atrial-specific variables including left atrial size, function, and electrocardiographic markers. The highest-risk cluster was defined as AtCM. We derived a diagnostic rule using recursive partitioning and validated it in FHS (Offspring/Gen 3) and ARIC. Cox models adjusted for CHA₂DS₂-VASc, LVEF, NT-proBNP, and CRP estimated associations with composite stroke/AF. Among AtCM patients with incident stroke, we classified pathways as "direct" (no prior AF) or "via AF".Clustering identified 4 phenogroups with progressively worse outcomes. Cluster 4 (5.4%, n=180) demonstrated highest risk (aHR 2.27 [1.74-2.95]). Our 3-variable AtCM definition (moderate/severe LA enlargement plus P-wave duration >120 ms or |PTFV1| >600 μV·ms) identified 174 CHS participants (5.3%) with accuracy 94.5%, sensitivity 47.8%, specificity 97.2%, PPV 49.4%. AtCM improved stroke discrimination beyond CHA₂DS₂-VASc (AUROC 0.66 vs 0.60, p< 0.001). Among 38 AtCM patients with stroke, 26 (68.4%) occurred via direct pathway versus 12 (31.6%) via AF (p=0.03). In validation (n=11,587, age 59±17 years), 467 participants (4.0%) met AtCM criteria with increased composite risk (aHR 2.13 [1.58-2.87]) and improved discrimination (AUROC 0.80 vs 0.71, p< 0.001). After adjusting for AF as time-varying covariate, AtCM remained associated with stroke (aHR 1.35 [1.10-1.65], p=0.003). Among 30 AtCM patients with stroke, 27 (90.0%) occurred via direct pathway.We developed and validated a phenomapping strategy identifying AtCM that substantially improved stroke prediction beyond traditional risk scores. The majority (64-92%) of strokes in AtCM patients occurred independent of AF, and AtCM remained predictive after adjusting for incident AF, demonstrating that atrial substrate (not arrhythmia) drives thromboembolic risk. These findings support targeting atrial myopathy rather than AF detection for stroke prevention.