Ischemic stroke (IS) stands as a prominent worldwide contributor to both mortality and disability, presenting a substantial risk to public health and welfare (1). Atherosclerosis, a persistent inflammatory, metabolic, and multifaceted condition impacting the inner lining of medium and large arteries, emerges as a primary causative factor of IS, with carotid artery atherosclerotic plaque playing a significant role in its development (2). Traditionally, the assessment of stroke risk has focused on the degree of carotid stenosis. While severe carotid artery narrowing remains an important risk factor, emerging evidence suggests that patients with non-severe stenosis may also experience ischemic events (3, 4). Recent studies indicate that the stability of carotid artery atherosclerotic plaque, rather than just the degree of stenosis, is closely linked to the occurrence of ischemic stroke (IS). In fact, 25–50% of IS events are associated with the rupture of vulnerable plaques (5–7).

The distinctive features of unstable carotid artery plaques can be detected and measured using a range of non-invasive imaging techniques, including ultrasonography (US), computed tomography (CT), high-resolution magnetic resonance imaging (MRI), and nuclear imaging methods (8, 9). These advanced imaging modalities provide valuable information beyond just the degree of arterial narrowing, allowing for improved risk stratification and targeted management of patients at risk of ischemic stroke. Ultrasonography is an excellent screening tool for carotid artery atherosclerosis, as it is cost-effective, rapid, and widely accessible, enabling frequent follow-up examinations (10, 11). Contrast-enhanced ultrasound (CEUS) is a novel non-invasive technique that employs contrast agents containing gas microbubbles, which generate strong echo signals under ultrasound, enhancing image contrast and allowing for clearer visualization of tissue perfusion and structural features (12). As a “tracer” of the vascular system, CEUS can clearly delineate the contours of the vascular intima and carotid artery atherosclerotic plaques, including ulcerated plaques, enabling the assessment of plaque stability based on morphological characteristics (13, 14).

To date, however, there has been a paucity of multi-center, large-scale studies investigating the CEUS features of carotid artery plaques in the ischemic stroke population. To address this gap, we evaluate the CEUS characteristics of carotid artery plaques in patients with ischemic stroke.

CEUS has gained popularity in its application for quantifying the structural characteristics of carotid atherosclerotic plaques, evaluating plaque stability, and assessing neovascularization. This analysis revealed that patients with a history of stroke exhibited significantly greater intensity of plaque enhancement versus the control group. This finding highlights the potential of CEUS as a valuable tool in distinguishing carotid plaques between stroke patients and non-stroke individuals. CEUS has the capability to detect neo-angiogenesis or enhanced inflammatory activity within the plaque of patients with IS. These processes are typically associated with increased plaque instability and rupture risk. Therefore, an increase in contrast enhancement intensity may serve as a potential biomarker of plaque vulnerability and tendency of stroke. Moreover, the rate of positive plaque enhancement was higher in IS patients versus non-stroke patients. The presence of enhanced contrast within the plaque, as detected by CEUS, further emphasizes the value of this modality in identifying high-risk atherosclerotic plaques. The existence of intra-plaque enhancement may indicate an active, unstable plaque state, which is associated with a higher risk of plaque rupture and consequently, an increased likelihood of stroke occurrence (Figure 5).

The sensitivity of CEUS in the diagnosis of IS indicates that it can correctly identify approximately 68% of patients who have experienced an IS event. While this value is not exceptionally high, it still maintains clinical utility, given the complex and multifactorial nature of stroke diagnosis. In non-IS patients, CEUS can correctly exclude approximately 61% of individuals. The relatively low specificity may reflect the limitations of CEUS in distinguishing plaque characteristics not associated with stroke, or the presence of similar plaque enhancement features in some non-stroke patients. The AUC was 0.697, indicating a moderate overall diagnostic performance of CEUS in differentiating IS patients from non-IS individuals. Although the AUC value did not reach a very high level, it still suggests the diagnostic potential of CEUS, particularly when combined with other clinical information and imaging modalities (Figure 6).

Vulnerable carotid plaques are a significant contributor to ischemic stroke, and the formation of new blood vessels (neovascularization) within the plaque plays a crucial role in increasing plaque vulnerability (15). The neomicrovasculature that develops within the plaque lacks the normal connective tissue support, making it prone to rupture and bleeding. This can lead to plaque instability and intraplaque hemorrhage (16). The presence of this neomicrovasculature within the carotid plaque serves as an independent risk factor for plaque rupture, hemorrhage, and a strong predictor of future cardiovascular and cerebrovascular events (17). The development of these delicate new blood vessels disrupts the structural integrity of the plaque, rendering it more unstable and prone to potentially devastating consequences, such as ischemic stroke.

CEUS, as a technique that reflects the microvascular system of the plaque, employs contrast agent microbubbles with similar characteristics to red blood cells, remaining within the vascular lumen (18). A number of studies have established a connection between the enhancement observed in CEUS and the histological vascular density of carotid plaques (19, 20). In patients undergoing carotid endarterectomy, pre-operative CEUS and CT examinations were conducted, followed by quantitative analysis of plaque enhancement and subsequent histopathological analysis. The results indicated a significantly higher CEUS plaque enhancement intensity in patients with CT-diagnosed IS compared to asymptomatic patients. Moreover, higher CEUS enhancement intensity correlated with a thinner fibrous cap and increased inflammatory infiltration on histopathology (21).

Quantitative analysis is an emerging trend in radiology, aiming to minimize subjectivity and enhance inter-observer consistency (22). The evaluation of neovascularization in atherosclerotic plaques using CEUS involves both semi-quantitative visual assessment and software-based quantitative assessment (23). The semi-quantitative assessment employs a scoring system proposed by Meng et al. (39), which categorizes plaque neovascularization into three levels: mild, with detectable microbubble flow only in the plaque’s adventitia; moderate, with detectable microbubble flow in the plaque shoulders and within the plaque; and severe, with detectable microbubble flow throughout the entire plaque, including the plaque tip. Quantitative assessment utilizes dedicated analysis software to quantify the plaque enhancement intensity and neovascularization within the plaque on CEUS. The contrast quantification software adjusts the ROI frame-by-frame based on plaque size and shape, and establishes another ROI in the center of the carotid lumen near the plaque’s proximal end as a reference (24). The software then automatically generates time-intensity curves for the plaque and lumen, calculating the enhancement intensity values and enhancement density (25). Schmidt et al. (26) confirmed a significant correlation between CEUS-detected neovascular quantity and histologically determined plaque vascular density, indicating good consistency between CEUS and histopathology in assessing plaque neovascularization. In patients scheduled for carotid endarterectomy, it is feasible to perform quantitative and volumetric imaging of the carotid artery and neovascularization within the plaque using CEUS (27). In this meta-analysis, both quantitative and semi-quantitative assessments supported the value of CEUS in ischemic stroke. The results of this meta-analysis underscore the potential role of CEUS in the assessment of carotid plaque stability and stroke risk. However, to establish CEUS as a routine clinical examination tool, further research is needed to optimize its diagnostic performance, determine the optimal examination protocol, and delineate its applicability across different patient populations. Additionally, exploring the combined use of CEUS with other imaging modalities, such as CT and MRI, may improve the accuracy and reliability of stroke risk assessment. While this meta-analysis provides new insights and evidence to support the application of CEUS in stroke prevention and management, future studies will need to address the current challenges and drive the further development of this technology.

However, this study has certain limitations. The included studies were primarily observational or cross-sectional in design, resulting in lower methodological quality. Additionally, the criteria for semi-quantitative plaque enhancement grading were not completely consistent, leading to unavoidable heterogeneity. Furthermore, the dichotomization of semi-quantitative plaque enhancement data may have reduced the interpretability of the results.

The CEUS characteristics of carotid plaques in IS significantly differ from those in patients without stroke, demonstrating higher plaque enhancement intensity and positive enhancement rate. These findings emphasize the prominent role of CEUS in the diagnosis and risk stratification of IS.