Contrast –Enhanced Ultrasound (CEUS) neovascularisation diagnostic limitation in unstable atherosclerotic plaque with extensive calcified component

Purpose: Incidence of stroke every year increases worldwide, according to the World Health Organization ischemic stroke remains the second leading cause of disability in Europe after ischaemic heart disease and is the sixth leading cause worldwide [1]. There are several causes for cerebral ischemia and if risk factors are diagnosed timely, the risk of stroke can be reduced significantly. The unstable plaque abruption and embolization to intracerebral artery is one of main ischemic stroke cause [2-3]. This demonstrates the need for a more accurate diagnostic tool for evaluation of plaque structural changes with multiparametric imaging. CEUS is one of the most perspective method for unstable atherosclerotic plaque diagnostic and is timely accessible, but it has limitations [4-9]. The purpose of this prospective study was to analyze multi-parametric US techniques ability to confirm the plaque instability more precisely than the baseline investigation of Duplex US and find out correlation between the CEUS results and histological findings. To analyze CEUS limitations in confirming plaque’s instability, evaluate specificity, sensitivity and find out correlation between contrast US techniques results and histological findings. Methods and materials: During the study, conducted from 2018 to 2020, 73 patients with duplex ultrasound detected unstable plaque were enrolled. All patients examined with Duplex US, CEUS, CTA and in 50 cases the histology of the atherosclerotic plaque was acquired after endarterectomy.
Project study selection criteria: The criteria for inclusion in the study are as follows:
Carotid artery moderate and severe stenosis detected by ultrasound (by NASCET).
In CTA or ultrasound B mode there are following plaque features:
B mode ultrasound structural marked hypoechogenicity/heterogeneity
CTA Hypodense/heterogenic plaque;
Irregularity of the surface of the plaque, but no indication of ulceration;
Plaque with ulceration;
Neovascularization in the plaque in vasa vasorum level suspected by other imaging methods (US microvascular imaging (SMI), magnetic resonance angiography).
The site of plaque is accessible and visible by B mode, Duplex Doppler and CEUS
Available peripheral vein access for intravenous contrast media injection
The exclusion criteria are as follows:
Mild plaque-related stenosis <50%;
Carotid artery stent
Atrial fibrillation or any other arrhythmia;
Hypotension (TA<120 mmHg);
Heart failure III, IV NYHA stage;
Person has disability (mental disorders, physical disability by modified Rankin Scale >3)
Impossible to provide peripheral venous access for the contrast agent administration;
Allergy to iodine-containing contrast agent and/or absence of CTA data;
Allergy to ultrasound contrast agent SonoVue (Bracco, Milan);
CEUS examination:
CEUS examination was performed after B mode and Color doppler and Spectral doppler multiparametric ultrasound evaluation by the ultrasound equipment with specific contrast software using contrast agent SonoVue (Bracco, Milan) 1,0-2,0 ml with intravenous administration of contrast bolus followed by saline flush (10 ml).
CEUS scanning is performed continuously for first 90 seconds and continued intermittently for up to 3-5 minutes. The dynamic process of scanning is stored as cine loops and still images with information about timing. Stored clips are used for later review or specified postprocessing as the examination is dynamic and subtle uptake requires additional analysis [4, 7.].
One group consisted of patients with extensive calcified plaque component, second group - soft plaques. For every group CEUS sensitivity, specificity was calculated in comparison with histology results. Neovascularization in CEUS examination was defined in 3 grades – no neovascularization (Grade 0), poorly (Grade1), well visible (Grade2) [10]. Contrast uptake onset time was analyzed below and above 30 seconds (early and late).
Results: Unstable plaque was diagnosed in 73 patients using Duplex US method and in 74 patients using CT method. Comparing both methods statistically significant correlation was found (rs = 0.781; p = 0.0001). Comparing 2 groups: soft plaques neovascularisation by CEUS was diagnosed in 33 cases (16 cases with Grade1 and 17 - Grade 2). Comparing results with histology - sensitivity was 77.78%, specificity 60%, positive predictive value 77.78%, negative predictive value 71.52%, accuracy 76.3%; In a group with extensive calcified plaques - neovascularisation was detected in 9 patients (52.9%), methods sensitivity 53.4%, specificity 36.5%, positive predictive value 64.54%, negative predictive value 31.4%, accuracy 47.83%, respectively. Comparing CEUS method and results of histology statistically significant correlation was found (rs = 0.61; p = 0.002). Comparing results with CEUS grading and contrast arrival time, was found statistically significant difference between groups (p=0.035) with earlier vasa vasorum enhancement in Grade 2 subgroup. Conclusion: CEUS as an advanced ultrasound method provides additional information to the atherosclerotic plaque instability and vasa vasorum detection, with positive correlation to the grade of stenosis and histological results. Extensive calcinosis is important limitation factor in carotid atherosclerotic plaque neovascularization diagnostics by CEUS, reducing methods sensitivity by 24.38%, specificity 35.02%, negative predictive value up to 2 times, positive predictive value by 13.24%. Soft plaque neovascularization Grade 2 have tendency to uptake contrast earlier than Grade 1. CEUS method is advised to be included in a high cardiovascular risk population when Duplex US suggests soft and/or heterogenic plaque >50%.