A Phillip Owens1, Todd L Edwards2,3, Silvio Antoniak1, Julia E Geddings1, Eiman Jahangir4, Wei-Qi Wei5, Joshua C Denny5, Yacine Boulaftali1, Wolfgang Bergmeier6, Alan Daugherty7, Uchechukwu K A Sampson2,8,9, Nigel Mackman1. 1. Department of Medicine Division of Hematology and Oncology, UNC McAllister Heart Institute University of North Carolina at Chapel Hill Chapel Hill, NC 27599, USA. 2. Department of Medicine, Vanderbilt University Medical Center Nashville, TN 37203. 3. Division of Epidemiology, Vanderbilt University Medical Center Nashville, TN 37203. 4. Department of Cardiovascular Diseases John Ochsner Heart and Vascular Institute Ochsner Clinical School - The University of Queensland School of Medicine New Orleans, LA 70115. 5. Department of Biomedical Informatics, Vanderbilt University Medical Center Nashville, TN 37203. 6. Department of Biochemistry and Biophysics, UNC McAllister Heart Institute University of North Carolina at Chapel Hill Chapel Hill, NC 27599, USA. 7. Saha Cardiovascular Research Center University of Kentucky Lexington, KY 40536. 8. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center Nashville, TN 37203. 9. Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center Nashville, TN 37203.
Abstract
OBJECTIVE: Rupture of abdominal aortic aneurysms causes a high morbidity and mortality in the elderly population. Platelet-rich thrombi form on the surface of aneurysms and may contribute to disease progression. In this study, we used a pharmacological approach to examine a role of platelets in established aneurysms induced by angiotensin II infusion into hypercholesterolemic mice. APPROACH AND RESULTS: Administration of the platelet inhibitors aspirin or clopidogrel bisulfate to established abdominal aortic aneurysms dramatically reduced rupture. These platelet inhibitors reduced abdominal aortic platelet and macrophage recruitment resulting in decreased active matrix metalloproteinase-2 and matrix metalloproteinase-9. Platelet inhibitors also resulted in reduced plasma concentrations of platelet factor 4, cytokines, and components of the plasminogen activation system in mice. To determine the validity of these findings in human subjects, a cohort of aneurysm patients were retrospectively analyzed using developed and validated algorithms in the electronic medical record database at Vanderbilt University. Similar to mice, administration of aspirin or P2Y12 inhibitors was associated with reduced death among patients with abdominal aortic aneurysm. CONCLUSIONS: These results suggest that platelets contribute to abdominal aortic aneurysm progression and rupture.
OBJECTIVE:Rupture of abdominal aortic aneurysms causes a high morbidity and mortality in the elderly population. Platelet-rich thrombi form on the surface of aneurysms and may contribute to disease progression. In this study, we used a pharmacological approach to examine a role of platelets in established aneurysms induced by angiotensin II infusion into hypercholesterolemic mice. APPROACH AND RESULTS: Administration of the platelet inhibitors aspirin or clopidogrel bisulfate to established abdominal aortic aneurysms dramatically reduced rupture. These platelet inhibitors reduced abdominal aortic platelet and macrophage recruitment resulting in decreased active matrix metalloproteinase-2 and matrix metalloproteinase-9. Platelet inhibitors also resulted in reduced plasma concentrations of platelet factor 4, cytokines, and components of the plasminogen activation system in mice. To determine the validity of these findings in human subjects, a cohort of aneurysmpatients were retrospectively analyzed using developed and validated algorithms in the electronic medical record database at Vanderbilt University. Similar to mice, administration of aspirin or P2Y12 inhibitors was associated with reduced death among patients with abdominal aortic aneurysm. CONCLUSIONS: These results suggest that platelets contribute to abdominal aortic aneurysm progression and rupture.
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