Screening of Multiple Biomarkers Associated With Ischemic Stroke in Atrial Fibrillation

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.

Multiplex protein screening of biomarkers associated with major bleeding in patients with atrial fibrillation treated with oral anticoagulation

“…However, very recently, OPN was found to induce atrial fibrosis 32 and to be significantly associated with incident AF 33 . It is also strongly associated with future ischemic stroke in patients with AF during anticoagulant treatment 34 . Recently, it was shown that humans express multiple OPN isoforms that have different functional effects 35 .…”

Urinary Proteome Changes in Global Cerebral Ischemia-Reperfusion Injury Rat Model Using Proteomics

“…FGG was also highly expressed in the ischemic penumbra of focal cerebral ischemia rats [14]. Trefoil factor 2 was upregulated in the plasma of atrial brillation patients with ischemic stroke [15].…”

“…The mRNA expression of T-kininogen 1 was upregulated in the blood of idiopathic thrombophilia [19]. Cathepsin Z was upregulated in the plasma of atrial brillation patients with ischemic stroke [15]. Parvalbumin alpha protein and mRNA were reduced in the hippocampal tissue of C57BL6 mice with unilateral right carotid ligation.…”

A Review of Biomarkers for Ischemic Stroke Evaluation in Patients With Non-valvular Atrial Fibrillation

“…First, most studies are observational studies with small samples size, which limits the clinical value of the identified markers. At the same time, limited by the study design, most studies investigate the correlation between only one biomarker and IS in AF patients, and a single biomarker might be disturbed by other confounding factors, and only a few studies evaluate the role of multiple biomarkers ( 203 ). Second, the majority of the study population was treated patients with anticoagulation therapy, and studies focusing on un-anticoagulated patients and other populations are lacking.…”