Intraplaque Neovascularization, CD68+ and iNOS2+ Macrophage Infiltrate Intensity Are Associated with Atherothrombosis and Intraplaque Hemorrhage in Severe Carotid Atherosclerosis

Abstract

Background: Atherosclerosis is a progressive disease that results from endothelial dysfunction, inflammatory arterial wall disorder and the formation of the atheromatous plaque. This results in carotid artery stenosis and is responsible for atherothrombotic stroke and ischemic injury. Low-grade plaque inflammation determines biological stability and lesion progression. Methods: Sixty-seven cases with active perilesional inflammatory cell infiltrate were selected from a larger cohort of patients undergoing carotid endarterectomy. CD68+, iNOS2+ and Arg1+ macrophages and CD31+ endothelial cells were quantified around the atheroma lipid core using digital morphometry, and expression levels were correlated with determinants of instability: ulceration, thrombosis, plaque hemorrhage, calcification patterns and neovessel formation. Results: Patients with intraplaque hemorrhage had greater CD68+ macrophage infiltration (p = 0.003). In 12 cases where iNOS2 predominated over Arg1 positivity, the occurrence of atherothrombotic events was significantly more frequent (p = 0.046). CD31 expression, representing neovessel formation, correlated positively with atherothrombosis (p = 0.020). Conclusions: Intraplaque hemorrhage is often described against the background of an intense inflammatory cell infiltrate. Atherothrombosis is associated with the presence of neovessels and pro-inflammatory macrophages expressing iNOS2. Modulating macrophage polarization may be a successful therapeutic approach to prevent plaque destabilization.