Evaluation of Carotid Plaque Rupture and Neovascularization by Contrast-Enhanced Ultrasound Imaging: an Exploratory Study Based on Histopathology

A significant portion of ischemic stroke is on account of emboli caused by fibrous cap rupture of vulnerable plaque with intraplaque neovascularization as a significant triggering factor to plaque vulnerability. Contrast-enhanced ultrasound (CEUS) could offer detailed information on plaque surface and intraplaque microvascular. This study aims to comprehensively assess the value of CEUS for the detection of plaque rupture and neovascularization in histologically verified plaques that had been removed from the patients who had undergone carotid endarterectomy (CEA). Fifty-one consecutive subjects (mean age, 67.0 ± 6.5 years; 43 [84.3%] men) scheduled for CEA were recruited. Standard ultrasound and CEUS were performed prior to surgery. Based on the direction of the contrast agents that diffuse within the plaques, plaques were divided as "inside-out" direction (contrast agents diffuse from the artery lumen towards the inside of the plaque) and non-inside-out direction. Plaque enhancement was assessed by using a semi-quantitative grading scale (grade 1: no enhancement; grade 2: moderate enhancement; grade 3: extensive enhancement). Plaques were evaluated for histopathologic characteristics according to Oxford Plaque Study (OPS) standard postoperative. Intraplaque neovascularization as manifested by the appearance of CD34-positive microvessels was characterized in terms of microvessel density (MVD), microvessel area (MVA), and microvessel shape (MVS). In 51 plaques, the sensitivity, specificity, positive, and negative predictive values of contrast agent inside-out direction diffusion for the detection of plaque fibrous cap rupture were 87.5%, 92.6%, 91.3%, and 89.3%, respectively. The incidence of cap rupture was significantly higher in contrast agent inside-out direction diffusion than non-inside-out direction diffusion (73.9% vs 25.0%, p < 0.001), and inside-out direction diffusion did exhibit higher frequency of vulnerable plaques (OPS grades 3-4) (95.7% vs 53.6%, p = 0.001). Multivariate logistic regression analysis revealed the contrast agent inside-out direction diffusion as an independent correlate to plaque rupture (OR 8.5, 95% CI 2.4-30.1, p = 0.001). With increasing plaque enhancement, plaque MVD (p < 0.001), plaque MVA (p = 0.012), and percentage of highly irregular-shaped microvessels increased (p < 0.001). Contrast agent inside-out direction diffusion could indicate plaque rupture. The increase in plaque enhancement paralleled increased, larger, and more irregular-shaped microvessels, which may suggest an increased risk of plaque vulnerability.