Ischemic stroke is defined as an episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction. It is a polyetiological disease with profound differences among subtypes. Most of the previous studies attributed stroke to age, gender, hypertension, diabetes, hypercholesterolemia, smoking, coronary artery disease, arterial fibrillation, physical inactivity, and obesity.[20, 21] The present study explored the incidence of risk factors for LAA ischemic stroke based on carotid CEUS. It was concluded that the atherosclerotic ischemic stroke is associated with hypertension, plaque echogenicity, plaque thickness, and degree of intraplaque neovascularization in Chinese adults. Furthermore, the ROC curve for separating ischemic stroke patients from controls had a sensitivity of 70.91% (95% CI, 61.5–79.2%) and specificity of 82.35% (95% CI, 65.5–93.2%), with a cutoff value of IPNV > grade 2.
According to the TOAST classification system, large-artery atherosclerosis, cardioembolism, small artery occlusion (lacunar), stroke of other determined etiology, and stroke of undetermined etiology are primarily based on clinical features in addition to information obtained during brain imaging, echocardiography, neurosonography, and cerebral angiography. The risk factors, clinical characteristics, and prognosis of ischemic stroke may vary greatly among subtypes. Previous studies have shown that the proportion of strokes due to LAA is greater than that due to small artery occlusion or cardioembolism. Data from randomized controlled trials indicate that a 10-mm Hg reduction in systolic blood pressure was associated with a decrease in risk of stroke of approximately one third. In a meta-analysis of individual participant data from 61 prospective observational studies on blood pressure and mortality, every 20-mm Hg decrease in systolic blood pressure or 10-mm Hg decrease in diastolic blood pressure was associated with a more than two-fold decrease in stroke mortality for blood pressure ≥ 115/75 mm Hg. Consistent with previous research[24, 25], the present study found that hypertension is associated with an increased risk of atherosclerotic ischemic stroke. Elevated blood pressure led to premature aging and increased endothelial cell turnover, which progressed to endothelial dysfunction. A recent report showed that hypertension driven by the sympathetic nervous system can influence mechanisms that regulate the hematopoietic system, contributing to atherosclerosis and cardiovascular events. Li et al. demonstrated that very high blood pressure during the acute phase of ischemic stroke increased the risk of adverse clinical outcomes.
Carotid plaques reflect the degree of atherosclerosis in the vascular system. Unstable atherosclerotic carotid plaques are particularly vulnerable to rupture, which is induced by the loss of thin fibrous cap integrity, strong intraplaque inflammatory reaction, and luminal blood communication with the thrombogenic core of the plaque.[29, 30] Thrombogenic material is diffused into circulation after plaque rupture, thereby occluding the intracranial cerebral arteries and resulting in ischemia of cortical and subcortical brain tissue. However, identification of vulnerable atherosclerotic plaques in patients poses a significant clinical challenge.
A Northern Manhattan Study demonstrated that plaque subjects with maximum carotid plaque thickness > 1.9 mm had a 2.8-fold increase in risk of combined vascular events and were associated with a 1.8-fold increase in risk of ischemic stroke. Consistent with this notion, carotid plaque thickness for the LAA stroke group was significantly greater than that for the non-cerebral infarction group (2.42 ± 0.92 vs. 1.92 ± 0.60 mm; P = 0.000). The specificity to predict the incidence of LAA stroke was 88.24% (95% CI, 72.5–96.7%), with a cut-off value of > 2.4 mm.
In a meta-analysis of individual patient data from seven studies with a total of 7557 subjects, Gupta et al. demonstrated a significant positive relationship between predominantly echolucent plaques (compared to predominantly echogenic) and the risk of future stroke across all degrees of stenosis. Another study showed that juxtaluminal hypoechoic plaque area had a linear association with future stroke rate, stratified by a juxtaluminal black hypoechoic area size of 8 mm2. Consistently with previous research, echogenicity of plaques in the present study group was mainly class I (uniformly anechoic) or class II (predominantly hypoechogenic or anechoic with < 50% echogenic areas). Furthermore, with a cut-off value of ≤ class II, the sensitivity predicting the onset of LAA stroke was 84.55% (95% CI, 76.4–90.7%). A number of histopathologic studies suggest that the presence of hypoechoic or echolucent areas in any one component of the plaque was associated with a lipid-rich necrotic core and intraplaque hemorrhage, which are markers for plaque vulnerability[34, 35]. This explains why echolucent plaques have a higher relative risk of stroke compared to patients with echogenic plaques.
Ultrasound contrast agents can serve as blood pool-enhancing agents to allow better visualization of vascular structures and flow as well as perfusion in the context of imaging vasa vasorum and atherosclerotic plaque neovascularization. CEUS results indicated that hypoechoic plaques and IPNV among atherosclerotic ischemic stroke patients were more common than in control patients. In addition, IPNV was a very strong predictor of LAA ischemic stroke, with the area under the ROC curve of 0.807 at the cutoff point of IPNV > grade 2. Consistent with these findings, hypoechoic plaques tend to have more vulnerable pathologic features, abundant lipids, and hemorrhage and are associated with an increased risk of cerebrovascular events. Varetto et al. reported a statistically significant correlation between increased vascularization of carotid atherosclerotic plaques evaluated by CEUS and cerebrovascular neurological events. Similarly, Wu et al. concluded that strong contrast enhancement can reveal culprit lesions, likely suggesting greater neovascularization and/or inflammatory activity in atherosclerotic lesions.
Information on the degree of carotid stenosis was not included in this study. Recent atherosclerosis research has suggested that lumen narrowing may not be a reliable indicator of plaque severity because positive artery remodeling of the vessel wall is associated with the culprit lesions[36, 37]. Notably, vulnerable atherosclerotic plaque may suggest an increased risk of cerebrovascular events, even with low-grade carotid narrowing. Plaque thickness was incorporated in the study, which can represent the degree of stenosis to some extent. Indeed, by combining standard carotid ultrasonography and CEUS, carotid atherosclerotic plaques with a high risk of rupture can be detected.
Several limitations should be considered in the present study. First, the data were based on one hospital-based cohort. The number of enrolled cases was low, with different numbers of cases between study and control groups, which may imply some bias. Second, this study utilized a visual approach to semi-quantify IPNV using CEUS, rather than an objective quantitative method. Finally, the findings were not validated within the scope of this study and several years may be needed for other prospective studies to estimate the risk factor performance.