Extracellular vesicle-derived CD14 is independently associated with the extent of cardiovascular disease burden in patients with manifest vascular disease

Background: In patients with established cardiovascular disease, high levels of the extracellular vesicle (EV)-derived proteins cystatin C, CD14, and alpha 2-antiplasmin predict recurrent cardiovascular events. We examined whether these proteins are associated with the extent of vascular disease. Methods: In 1062 patients from the SMART (Secondary Manifestations in ARTerial disease) study, EVs were isolated from plasma at baseline. Cystatin C, CD14, and alpha 2-antiplasmin were measured in these vesicles using a multiplex assay. The extent of vascular disease burden was determined by a sum score that incorporates history and current presence of clinically manifest coronary, cerebrovascular, peripheral arterial, and abdominal aneurysm disease, and parameters of atherosclerosis that were assessed during the SMART screening protocol (ankle-brachial index, common carotid intimamedia thickness, carotid stenosis, and aorta diameter). The relation between EV protein levels and extent of vascular disease was evaluated using ordinal multivariable regression models. Results: EV-derived CD14 was significantly associated with the number of affected vascular territories (OR 2.4, 95% CI 1.4-4.1) as represented by the sum score, independently of cardiovascular risk factors. Cystatin C and a2-antiplasmin EV levels did not show an independent association with vascular disease extent. When investigating parameters of the sum score separately, we did not observe a strong association between any of the EV-derived proteins and the markers of atherosclerosis. Conclusions: EV-derived CD14 levels are strongly correlated to the extent of vascular disease, but not specifically to markers that reflect atherosclerosis burden, in patients with manifest cardiovascular disease.