Screening of Multiple Biomarkers Associated With Ischemic Stroke in Atrial Fibrillation
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 o...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-12-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.120.018984 |
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| author | Ziad Hijazi Lars Wallentin Johan Lindbäck John H. Alexander Stuart J. Connolly John W. Eikelboom Michael D. Ezekowitz Christopher B. Granger Renato D. Lopes Tymon Pol Salim Yusuf Jonas Oldgren Agneta Siegbahn |
| author_facet | Ziad Hijazi Lars Wallentin Johan Lindbäck John H. Alexander Stuart J. Connolly John W. Eikelboom Michael D. Ezekowitz Christopher B. Granger Renato D. Lopes Tymon Pol Salim Yusuf Jonas Oldgren Agneta Siegbahn |
| author_sort | Ziad Hijazi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T10:51:32Z |
| format | Article |
| id | doaj.art-09faa38f34544078bc872e48e57b7a7c |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-18T10:51:32Z |
| publishDate | 2020-12-01 |
| publisher | Wiley |
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| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-09faa38f34544078bc872e48e57b7a7c2022-12-21T21:10:26ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802020-12-0192410.1161/JAHA.120.018984Screening of Multiple Biomarkers Associated With Ischemic Stroke in Atrial FibrillationZiad Hijazi0Lars Wallentin1Johan Lindbäck2John H. Alexander3Stuart J. Connolly4John W. Eikelboom5Michael D. Ezekowitz6Christopher B. Granger7Renato D. Lopes8Tymon Pol9Salim Yusuf10Jonas Oldgren11Agneta Siegbahn12Department of Medical Sciences Cardiology Uppsala University Uppsala SwedenDepartment of Medical Sciences Cardiology Uppsala University Uppsala SwedenUppsala Clinical Research Center Uppsala University Uppsala SwedenDuke Clinical Research InstituteDuke Health Durham NCPopulation Health Research Institute Hamilton ON CanadaPopulation Health Research Institute Hamilton ON CanadaThomas Jefferson University Philadelphia PADuke Clinical Research InstituteDuke Health Durham NCDuke Clinical Research InstituteDuke Health Durham NCDepartment of Medical Sciences Cardiology Uppsala University Uppsala SwedenPopulation Health Research Institute Hamilton ON CanadaDepartment of Medical Sciences Cardiology Uppsala University Uppsala SwedenUppsala Clinical Research Center Uppsala University Uppsala SwedenBackground 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.https://www.ahajournals.org/doi/10.1161/JAHA.120.018984atrial fibrillationbiomarkersischemic strokepathophysiological featuresscreening |
| spellingShingle | Ziad Hijazi Lars Wallentin Johan Lindbäck John H. Alexander Stuart J. Connolly John W. Eikelboom Michael D. Ezekowitz Christopher B. Granger Renato D. Lopes Tymon Pol Salim Yusuf Jonas Oldgren Agneta Siegbahn Screening of Multiple Biomarkers Associated With Ischemic Stroke in Atrial Fibrillation Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease atrial fibrillation biomarkers ischemic stroke pathophysiological features screening |
| title | Screening of Multiple Biomarkers Associated With Ischemic Stroke in Atrial Fibrillation |
| title_full | Screening of Multiple Biomarkers Associated With Ischemic Stroke in Atrial Fibrillation |
| title_fullStr | Screening of Multiple Biomarkers Associated With Ischemic Stroke in Atrial Fibrillation |
| title_full_unstemmed | Screening of Multiple Biomarkers Associated With Ischemic Stroke in Atrial Fibrillation |
| title_short | Screening of Multiple Biomarkers Associated With Ischemic Stroke in Atrial Fibrillation |
| title_sort | screening of multiple biomarkers associated with ischemic stroke in atrial fibrillation |
| topic | atrial fibrillation biomarkers ischemic stroke pathophysiological features screening |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.120.018984 |
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