Abstract
Background To explore the pathophysiological features of ischemic stroke in patients with atrial fibrillation (AF), we evaluated the association between 268 plasma proteins and subsequent ischemic stroke in 2 large AF cohorts receiving oral anticoagulation. Methods and Results A case-cohort sample of patients with AF from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, including 282 cases with ischemic stroke or systemic embolism and a random sample of 4124 without these events, during 1.9 years of follow-up was used for identification. Validation was provided by a similar case-cohort sample of patients with AF from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, including 149 cases with ischemic stroke/systemic embolism and a random sample of 1062 without these events. In plasma obtained before randomization, 268 unique biomarkers were measured with OLINK proximity extension assay panels (CVD II, CVD III, and Inflammation) and conventional immunoassays. The association between biomarkers and outcomes was evaluated by random survival forest and adjusted Cox regression. According to random survival forest or Cox regression analyses, the biomarkers most strongly and consistently associated with ischemic stroke/systemic embolism were matrix metalloproteinase-9, NT-proBNP (N-terminal pro-B-type natriuretic peptide), osteopontin, sortilin, soluble suppression of tumorigenesis 2, and trefoil factor-3. The corresponding hazard ratios (95% CIs) for an interquartile difference were as follows: 1.18 (1.00-1.38), 1.55 (1.28-1.88), 1.28 (1.07-1.53), 1.19 (1.02-1.39), 1.23 (1.05-1.45), and 1.19 (0.97-1.45), respectively. Conclusions In patients with AF, of 268 unique biomarkers, the 6 biomarkers most strongly associated with subsequent ischemic stroke/systemic embolism represent fibrosis/remodeling (matrix metalloproteinase-9 and soluble suppression of tumorigenesis 2), cardiac dysfunction (NT-proBNP), vascular calcification (osteopontin), metabolism (sortilin), and mucosal integrity/ischemia (trefoil factor-3). Registration URL: https://www.clinicaltrials.gov. Unique Identifiers: NCT00412984 and NCT00262600.