Stroke remains a leading cause of morbidity, mortality, and long-term disability worldwide, with ischemic stroke accounting for the majority of cases (1). A substantial proportion of ischemic strokes are caused by extracranial carotid artery atherosclerosis, underscoring the importance of carotid artery pathology in cerebrovascular events (2). Early identification of patients at heightened stroke risk due to carotid atherosclerosis is therefore critical for implementing effective prevention strategies (3).

Traditional risk stratification for carotid atherosclerosis has primarily relied on assessing luminal stenosis severity using ultrasonography or angiographic methods, as established by landmark trials such as the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST) (4). However, emerging evidence highlights that plaque vulnerability, rather than stenosis alone, plays a pivotal role in ischemic stroke pathogenesis (5). Vulnerable plaques are characterized by specific histopathological features, including large lipid cores, a thin fibrous cap, intraplaque hemorrhage, neovascularization, and inflammation, all of which increase the risk of rupture and thromboembolism (6). Nevertheless, different studies highlight that plaque pathology, in addition to stenosis, is essential to understand in the pathogenesis of ischemic stroke. Up to 30% of ischemic strokes occur in patients with high-risk non-stenotic plaques characterized by thin soft caps, ruptured or ulcerated inflamed fibrous caps, hemorrhagic intraplaque hemorrhage (IPH), active inflammatory processes, and large lipid-rich necrotic cores. IPH is plaque strongest predictor of ischemic event and poor prognosis, regardless of the degree of stenosis (7–9).

Carotid ultrasonography has emerged as a sophisticated diagnostic modality, enabling in vivo assessment of plaque composition and stability (10). Advanced techniques, including contrast-enhanced ultrasound (CEUS) and elastography, facilitate detailed evaluations of plaque echogenicity, neovascularization, and mechanical properties, thereby enhancing risk prediction capabilities (11). Nonetheless, the prognostic significance of these imaging features is still under investigation. Historically, luminal stenosis was regarded as the primary predictor of stroke risk; however, accumulating evidence suggests that ultrasound-derived plaque characteristics (such as echolucency, surface ulceration, intraplaque hemorrhage, and neovascularization) offer prognostic insights independent of stenosis severity.

In a prospective study, Huang et al. (2024) identified a distinctive CEUS perfusion pattern where microbubbles penetrated from the superficial plaque surface into the plaque interior, correlating with a stroke risk of 2.32 (95% CI: 1.175, 4.594) (12). A meta-analysis of CEUS studies further indicated that plaque enhancement was significantly greater in stroke patients compared to controls (13). Different studies have demonstrated concordance between ultrasound features and histologically verified intraplaque hemorrhage, characterized by hypoechoic plaque cores, irregular plaque surfaces, and heightened neovascularization (14–16). In addition, retrospective cohort data suggest that plaques exhibiting intraplaque hemorrhage and ulceration are associated with markedly increased risk, even in cases of moderate stenosis (17). These findings indicate the value of ultrasound-based plaque characterization in enhancing risk stratification beyond mere reliance on stenosis severity.

Despite these advancements, a substantial gap persists in the clinical application of comprehensive plaque characterization for risk assessment in asymptomatic carotid artery disease (18). Alternative imaging modalities, such as carotid MRI and computed tomography angiography (CTA), may provide additional structural and compositional insights; however, their routine clinical application remains limited (19, 20). Recent studies indicate that while MRI provide detailed compositional analysis and CTA facilitates luminal assessment, factors such as cost, restricted availability, and the necessity for contrast agents hinder their integration into standard screening protocols, particularly in primary care settings (21, 22). In contrast, ultrasound is a non-invasive and widely accessible method capable of evaluating various plaque characteristics, including echogenicity, intraplaque hemorrhage, and mechanical attributes pertinent to plaque stability and rupture vulnerability. Emerging ultrasound-derived biomarkers, such as intraplaque neovascularization, gray-scale median (GSM), and plaque stiffness, have been established as independent predictors of cerebrovascular outcomes. Multimodal ultrasound approaches, which combine superb microvascular imaging with shear-wave elastography, have revealed that extensive intraplaque neovascularization and reduced plaque stiffness are associated with an increased risk of poor functional outcomes 90 days post-ischemic stroke or transient ischemic attack (TIA). CEUS provides a precise evaluation of intraplaque neovascularization, correlating well with microvessel density, and is augmented by GSM quantification, which characterizes plaque tissue and enhances reproducibility in cerebrovascular risk stratification (23–25).

This study aims to address this gap by analyzing the prognostic value of ultrasound-detected plaque phenotypes in relation to stroke risk. The integration of these imaging biomarkers into clinical practice holds the potential to improve plaque and stroke risk management through enhanced risk stratification, earlier identification of at-risk individuals, and the implementation of targeted preventive interventions. In doing so, this study advances risk prediction models by emphasizing plaque phenotype rather than stenosis severity, a shift that may substantially improve precision care in the management of cerebrovascular disease.

This retrospective study explored the relation between the ultrasound features of carotid plaques and stroke risk and showed that different ultrasound features are predictors of stroke risk within the upcoming year. This ground-breaking work enhances clinical knowledge of the cerebrovascular risk for the first time looking at the specific features of the plaques, rather than their general classification as unstable or other plaques, and this way elucidates even more the biology and the mechanisms and the physiopathology cerebrovascular disease. This is because, while plaque echogenicity is a marker of tissue microarchitecture within a plaque, the association demonstrated with stroke risk is that plaque echogenicity is inversely associated with stroke risk. When echogenicity is low, the plaque is a hemorrhagic one; when it is medium or high, it is a fibrous one. Moreover, there is a notable risk of intracranial hemorrhage associated with soft plaques, and the plaque microarchitecture is one that is rich in hemorrhagic tissue (31, 32).

The findings of the study confirm that plaques containing medium to high levels of echogenicity correspond to lower risk of stroke, substantiating that ultrasounds can differentiate between stable and unstable plaques. In contrast, plaques with low levels of echogenicity correspond to a higher risk due to the possibility of the plaques being soft and lipid-dense, associated with inflammatory cellular infiltration, rupture, and immature neovascularization, regions that are prone to rupture (33). These high echogenicity plaques contain a lower risk of rupture due to their structural integrity and because they contain collagen-rich or calcified matrices that reduce embolic potential (34). These findings also confirm that ultrasounds have the clinical potential to detect the presence of atheroclastic plaques within the carotids and to assess a risk potential of certain plaques and tissue via the tissue composition of the plaques (35).

Risk of stroke can be assessed based only on the presence of plaques, particularly on the carotid bifurcation. The bifurcation’s complex hemodynamics consisting of disrupted laminar flow and low shear stress accelerates the atherosclerotic process and the development of hazardous atherosclerotic plaques (36). The abnormal flow dynamics are also the primary cause of the bifurcation’s tendency of forming plaques of such significant risk (37). The disrupted laminar flow, low shear stress, and flow reversal present in the carotid bifurcation create mechanical strain on the endothelium which is associated with the activation of atherosclerosis-promoting biochemical cascades. The hemodynamics dictate plaques that are perilous in every respect from progressive enlargement, to surface erosion, to complete rupture. Plaques at arterial bifurcations also contribute to stroke risk by acting as embolic reservoirs and hemodynamically significant stenoses. The diseased plaques that form at the arterial bifurcations heighten the risk of stroke by hemodynamically significant stenoses of the arterial lumen (38). The plaques discovered at the bifurcations of the arteries are known to elevate stroke risk by narrowing the artery’s lumen (39).

Stroke incidence had significant associations with intraplaque hemorrhage. The rupture of plaque’s weak neovessels releases blood, causing oxidative stress and inflammation that weakens the cap fibroplasia (40). The fragile neovessels that are usually formed by hypoxia-driven angiogenesis, are present in the atherosclerotic core. The ruptured immature neovessels located within the plaque are able to release blood (41). The oxidative stress, inflammation, and the neutrophils that are present within the plaque, are a result of de-oxygenated blood and its byproducts (28). Fibrous cap weakening due to these processes, rupturations, and ensuing cerebral events (42). These findings highlight the importance of detecting intraplaque hemorrhage, as documented in the studies that utilized ultrasound, MRI, and histopathology, for plaque instability (43, 44).

Patients who had a stroke later had higher levels of neovascularization within their plaque, measured with contrast-enhanced ultrasound. The presence of microvessels in a plaque has become regarded as a key sign of ruptured plaque (45). The vascularization of a plaque is caused by the presence of hypoxic tissues within the thickened intima of the artery in combination with excess production of proangiogenic factors such as vascular endothelial growth factor (VEGF) (46). While the growth of additional blood vessels may be expected, newly formed vessels, on their own, tend to be poorly constructed. Lacking one of the pivotal structural elements, pericytes, and their outer matrix, the vessels become particularly prone to structural failure. Thus, they tend to become increasingly permeable, allowing intra-plaque hemorrhage and the entry of inflammatory factors and cells into the plaque (47). Therefore, because they are more prone to hemorrhage and tend to rupture, plaques with a higher vascularization are at a greater risk of forming a thrombosis (48).

Plaque that measures longer than 10 mm with an Atherogenic burden and vulnerable tissues such as bleeding tissues and neovessels, together, increases the odds for increased plaque burden (49). Furthermore, large plaques comprise neovascular tissues and hemorrhagic volumes, both of which underpin and add to the underlying risk (50). These examples underscore the importance of the shape of atherosclerosis instead of just the presence of such an ailment. It was noted that, as evidenced by a smaller proportion of fibrous regions and the computed Young’s moduli (which of the elastography soft tissues), decreased plaque consistency was linked with increased cerebrovascular accident risk, especially since the mean Young’s moduli between groups was statistically uniform. While mean plaque stiffness was similar among groups, this strongly suggests that the texture of plaque (the presence of softer, thus more mobile regions within a plaque), as opposed to generalized plaque stiffness, was more reflective of its susceptibility to that plaque. Regions that are lipid-laden, and comprise soft necrotic tissues that are subject to Shear planes, are at a higher risk of fracture. Plaques that are rigid exhibit a pattern of fibrous and calcified tissues, which results in uniform stiffness and detracts from plaques that are symptomatic (51). Although increased IMT was recorded in stroke patients, it did not remain independently significant after adjustments for treatment multivariate, implying that features related to plaques are more predictive than generalized artery thickening.

The implications of the results here are important, especially in relation to clinical management of patients with asymptomatic carotid artery diseases. This research illustrates the additional prognostic value that can be derived from the evaluation of individual plaque characteristics, as revealed by ultrasound. These findings are undoubtedly clinically actionable. Currently, guidelines place primary importance on the percentage of stenosis as the sole basis upon which clinical decisions are made for intervention. This, however, should not be the case, as our study findings point out the other plaques, as well as their microstructural features, which possess substantial prognostic value and should be analyzed in addition to the significant stenosis. Enhanced ultrasound, such as the contrast enhanced ultrasound and elastography, can provide the means to identify high-risk patients. This, in turn, may reduce the number of patients who are at low risk and prevent unnecessary interventions in the low-risk patients.

In addition, the implications of our study have the potential to refine artificial intelligence (AI) and deep learning techniques for the automated recognition and assessment of carotid plaques, significantly enhancing reproducibility and scalability in clinical processes, particularly in risk assessment and stratification. Recent studies have demonstrated that deep learning models can markedly enhance the clinical potential of carotid plaque detection, improving diagnostic accuracy, sensitivity, and reducing clinician workload and diagnostic time (52). By integrating the findings that underscore the prognostic value of individual plaque characteristics beyond the degree of stenosis, AI algorithms can be trained to recognize and evaluate a broader range of ultrasound features and microstructural attributes (53). This approach allows for the development of sophisticated models that can analyze complex imaging data, leading to more accurate identification of high-risk patients. As these AI systems learn from diverse datasets that include various plaque features they can improve their predictive capabilities, ensuring that clinicians receive reliable assessments that inform treatment decisions.

Nevertheless, it is important to acknowledge the limitations of this study. First, as a retrospective cohort study conducted at a single tertiary hospital, the findings may be subject to selection bias and may not be generalizable to broader populations or other healthcare settings. Second, the reliance on operator-dependent ultrasound imaging introduces potential variability in plaque characterization, even though standardized protocols were followed. Multicenter studies with consistent imaging protocols are needed to validate these findings. Third, the one-year follow-up period may not capture the long-term stroke risk associated with carotid plaque features. Extending follow-up durations could provide deeper insights into the temporal relationships between plaque instability and cerebrovascular events. In addition, although multivariate regression was employed to control for confounding factors, residual confounding cannot be entirely excluded. The study also did not incorporate advanced imaging modalities such as magnetic resonance imaging or computed tomography angiography, which could complement ultrasound findings by providing additional structural and compositional details. Future research should focus on prospective, multicenter studies with larger and more diverse cohorts to confirm the predictive value of ultrasound-derived plaque features. Integration of multimodal imaging approaches and machine learning models may enhance the precision of risk stratification. Furthermore, exploring the impact of targeted interventions based on plaque phenotype could provide actionable insights for personalized stroke prevention strategies.”

This study demonstrates that specific ultrasound imaging features of carotid plaques (echogenicity, anatomical location, plaque length, intraplaque hemorrhage, neovascularization grade, and plaque hardness) are independently associated with stroke risk. These findings highlight the importance of evaluating plaque composition and stability alongside luminal stenosis for ischemic stroke risk stratification. Advanced ultrasound modalities, including contrast-enhanced imaging and elastography, provide effective tools for identifying high-risk patients who may benefit from targeted preventive interventions. Despite its limitations, this study provides a basis for integrating imaging biomarkers into clinical practice and underscores the need for further research to validate and extend these observations. By shifting the emphasis from stenosis severity to plaque vulnerability, this approach has the potential to improve stroke prevention and patient outcomes.