Federico Carbone1, Fabio Rigamonti2, Fabienne Burger3, Aline Roth3, Maria Bertolotto4, Giovanni Spinella5, Bianca Pane5, Domenico Palombo5, Aldo Pende4, Aldo Bonaventura4, Luca Liberale6, Alessandra Vecchié4, Franco Dallegri7, François Mach8, Fabrizio Montecucco9. 1. First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, 6 viale Benedetto XV, 13132 Genoa, Italy. Electronic address: federico.carbone@edu.unige.it. 2. Division of Cardiology, Department of Medical Specialties, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1211 Geneva, Switzerland. 3. Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, 64 Avenue de la Roseraie, 1211 Geneva, Switzerland. 4. First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, 6 viale Benedetto XV, 13132 Genoa, Italy. 5. Vascular and Endovascular Surgery Unit, Department of Surgery, Ospedale Policlinico San Martino, 10 Largo Benzi, 16132 Genoa, Italy. 6. First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, 6 viale Benedetto XV, 13132 Genoa, Italy; Center for Molecular Cardiology, University of Zürich, 12 Wagistrasse, 8952 Schlieren, Switzerland. 7. First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, 6 viale Benedetto XV, 13132 Genoa, Italy; Ospedale Policlinico San Martino, 10 Largo Benzi, 16132 Genoa, Italy. 8. Division of Cardiology, Department of Medical Specialties, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1211 Geneva, Switzerland; Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, 64 Avenue de la Roseraie, 1211 Geneva, Switzerland. 9. First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, 6 viale Benedetto XV, 13132 Genoa, Italy; Ospedale Policlinico San Martino, 10 Largo Benzi, 16132 Genoa, Italy; Centre of Excellence for Biomedical Research (CEBR), University of Genoa, 9 viale Benedetto XV, 16132 Genoa, Italy.
Abstract
BACKGROUND: Inflammatory mediators in the blood stream and within plaques are key determinants in atherogenesis. Here, we investigated serum osteopontin (OPN) as a potential predictor of poor outcome in patients with severe carotid atherosclerosis. METHODS: Carotid plaques and serum were collected from patients asymptomatic (n=185) or symptomatic (n=40) for ischemic stroke. Plaques were stained for lipids, smooth muscle cells, neutrophils, M1 and M2 macrophage subsets and matrix metallopropteinase-9 (MMP-9). Serum levels of OPN and interleukin-6 (IL-6) were determined by colorimetric enzyme-linked immunosorbent assays. RESULTS: Symptomatic patients showed a two-fold increase in serum OPN levels. In both symptomatic and asymptomatic patients, OPN levels positively correlated with intraplaque count of neutrophils, total macrophages, and MMP-9 content. In asymptomatic patients, OPN levels also positively correlated with lipids and M1 macrophage subsets. Receiver operating characteristic curve analysis identified serum OPN concentration of 70ng/ml as the best cut-off value to predict major adverse cardiovascular events (MACEs). Patients with high OPN levels had more vulnerable plaque phenotype and reduced levels of HDL-cholesterol and IL-6 as compared to low OPN levels. Kaplan-Meier curve confirmed that patients with OPN levels >70ng/ml had more MACEs at a 24-month follow-up. In the multivariate survival analysis, OPN levels >70ng/ml predicted MACEs, independently of age, gender, and symptomatic status. CONCLUSION: High circulating OPN levels were strongly correlated with vulnerability parameters within plaques and predict MACEs in patients with severe carotid artery stenosis. Although confirmation is needed from larger trials, OPN could be a promising clinical tool to assess atherosclerotic outcomes.
BACKGROUND: Inflammatory mediators in the blood stream and within plaques are key determinants in atherogenesis. Here, we investigated serum osteopontin (OPN) as a potential predictor of poor outcome in patients with severe carotid atherosclerosis. METHODS: Carotid plaques and serum were collected from patients asymptomatic (n=185) or symptomatic (n=40) for ischemic stroke. Plaques were stained for lipids, smooth muscle cells, neutrophils, M1 and M2 macrophage subsets and matrix metallopropteinase-9 (MMP-9). Serum levels of OPN and interleukin-6 (IL-6) were determined by colorimetric enzyme-linked immunosorbent assays. RESULTS: Symptomatic patients showed a two-fold increase in serum OPN levels. In both symptomatic and asymptomatic patients, OPN levels positively correlated with intraplaque count of neutrophils, total macrophages, and MMP-9 content. In asymptomatic patients, OPN levels also positively correlated with lipids and M1 macrophage subsets. Receiver operating characteristic curve analysis identified serum OPN concentration of 70ng/ml as the best cut-off value to predict major adverse cardiovascular events (MACEs). Patients with high OPN levels had more vulnerable plaque phenotype and reduced levels of HDL-cholesterol and IL-6 as compared to low OPN levels. Kaplan-Meier curve confirmed that patients with OPN levels >70ng/ml had more MACEs at a 24-month follow-up. In the multivariate survival analysis, OPN levels >70ng/ml predicted MACEs, independently of age, gender, and symptomatic status. CONCLUSION: High circulating OPN levels were strongly correlated with vulnerability parameters within plaques and predict MACEs in patients with severe carotid artery stenosis. Although confirmation is needed from larger trials, OPN could be a promising clinical tool to assess atherosclerotic outcomes.
Authors: Saud Alhusaini; Sherif Karama; Tuong-Vi Nguyen; Alexander Thiel; Boris C Bernhardt; Simon R Cox; Janie Corley; Adele Taylor; Alan C Evans; John M Star; Mark E Bastin; Joanna M Wardlaw; Ian J Deary; Simon Ducharme Journal: Ann Neurol Date: 2018-10-05 Impact factor: 10.422