Apolipoprotein B100 and white matter hyperintensity as distinct mediators of thrombolytic response in acute stroke:...

Intracranial atherosclerotic stenosis (ICAS) and cerebral small vessel disease (CSVD) frequently co-exist and contribute to poor stroke outcomes. Whether distinct pathophysiological mechanisms mediate large-vessel versus small-vessel disease effects on stroke outcomes, and whether these are modifiable by thrombolysis, remains unknown. In this prospective cohort study, acute ischemic stroke patients with ICAS and/or CSVD were enrolled. ICAS was defined as ≥ 50% cerebral arterial stenosis and CSVD by white matter hyperintensity (WMH), microbleeds or lacunes. Baseline data, 2-week early neurological improvement (ENI), and 3-month modified Rankin scale (mRS) were recorded. Plasma lipids, apolipoprotein B100 (apoB100), homocysteine (HCY), etc., were measured. Logistic regression and causal mediation analyses tested independent predictors and mediators of ENI and poor 3-month outcome (mRS ≥ 3). 262 patients were included. Two novel mediating mechanisms were identified: First, thrombolysis improves early neurological recovery partly via apoB100 reduction (33% mediation, β = 0.33, 95% CI 0.01-0.87), revealing a previously unrecognized fibrinolysis-lipoprotein metabolic interaction. Second, small-vessel disease independently predicts poor 3-month outcomes (deep WMH: OR 2.35, p = 0.03) and additionally mediates 20% of HCY's effect (β = 0.20, 95% CI 0.03-0.46), establishing WMH as a dual-mechanism therapeutic target. Notably, apoB100 exhibits context-dependent mediation: it suppresses the true neurological damage of intracranial stenosis (53% mediation, β = 0.17, 95% CI 0.04-0.34) while facilitating thrombolytic benefit-demonstrating conditional biomarker action in acute stroke. We identified that apoB100 is a modifiable factor linking ICAS and thrombolysis to early neurological recovery, while WMH partly mediates the effect of hyperhomocysteinemia on 3-month functional outcomes. Monitoring and targeting apoB100 may improve secondary prevention strategies in the post-statin era for patients with combined large- and small-artery cerebrovascular disease.Trial registrationChiCTR1800018315, 11/09/2018.