White Matter Hyperintensity Burden Modifies the Association Between Atrial Fibrillation and Cerebral Microbleeds
Ryu, W.-S.; Sunwoo, L.; Lee, M.; Kang, K.; Kim, J. G.; Lee, S. J.; Cha, J.-K.; Park, T. H.; Lee, J.-Y.; Lee, K.; Kwon, D. H.; Lee, J.; Park, H.-K.; Cho, Y.-J.; Hong, K.-S.; Lee, M.; Oh, M. S.; Yu, K.-H.; Gwak, D.-S.; Kim, D.-E.; Kim, H.; Kim, J.-T.; Kim, J.-G.; Choi, J. C.; Kim, W.-J.; Kwon, J.-H.; Yum, K. S.; Shin, D.-I.; Hong, J.-H.; Sohn, S.-I.; Lee, S.-H.; Kim, C.; Jeong, H.-B.; Park, K.-Y.; Lee, K.-J.; Kim, C. K.; Kang, J.; Kim, J. Y.; Bae, H.-J.; Kim, B. J.
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Background: In atrial fibrillation (AF), cerebral microbleed (CMB) burden guides anticoagulation decisions, yet AF is itself inconsistently associated with CMBs, a paradox unexplained by frameworks that treat CMBs as a unitary marker of small vessel disease. We hypothesized that the white matter hyperintensity (WMH) context in which CMBs arise modifies their vascular meaning, and that this context-dependence underlies the inconsistent AF-CMB association. Methods: From a multicenter Korean stroke registry, we analyzed 5,735 first-ever ischemic stroke patients imaged at nine centers using susceptibility-weighted MRI. WMH volume and CMB count were extracted by validated deep learning pipelines. Patients were cross-classified by age-adjusted WMH residual (median split) and CMB count (2) into four groups. The AF-CMB association was estimated by multivariable logistic regression within each WMH stratum with formal interaction testing. Spatial CMB distribution was analyzed against the Automated Anatomical Labeling atlas. Results: In the full cohort (mean age 69.5 years; 57.7% male), AF was not associated with CMBs (OR 1.04; 95% CI 0.87-1.25). Stratification yielded divergent estimates: the adjusted AF OR was 1.46 (1.11-1.93; P = 0.007) in the WMH-low stratum and 0.95 (0.73-1.22; P = 0.665) in the WMH-high stratum, with significant interaction (OR 0.56; P < 0.001). The discordant phenotype (low WMH, high CMB; 8.9%) was enriched for AF (28.0%) and showed fronto-temporal cortical predominance with deep structure sparing. AF independently reduced the proportion of deep CMBs (IRR 0.80; P = 0.040). The interaction was preserved across prespecified sensitivity analyses. Conclusions: The AF-CMB association is confined to patients with low WMH burden relative to age and is accompanied by a topographically distinct CMB distribution. Clinical assessment of small vessel disease based on WMH alone may overlook a CMB phenotype linked to AF.
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