Ischaemic stroke remains one of the leading causes of death and long-term disability worldwide. A significant proportion of these strokes are linked to the rupture of carotid atherosclerotic plaques. Traditionally, the severity of carotid stenosis has guided clinical decision-making, yet increasing evidence points to the importance of plaque composition over luminal narrowing in predicting stroke risk. Particularly in individuals without symptoms or with only mild stenosis, the internal components of a plaque—such as calcification, lipid-rich necrotic core (LRNC) and intraplaque haemorrhage (IPH)—may offer greater insight into future cerebrovascular events. The Rotterdam Study, a large-scale population-based research initiative, aimed to characterise how these subclinical plaques evolve over time using serial MRI, and to assess whether certain plaque features at baseline could predict the onset of more vulnerable compositions.
Calcification as a Precursor to Haemorrhage
One of the most striking findings from the study was the association between pre-existing calcification and the subsequent development of IPH. Over a follow-up period of nearly six years, individuals whose carotid plaques exhibited calcification at baseline were significantly more likely to develop IPH compared to those without calcification. This association persisted even after adjusting for a wide range of cardiovascular risk factors, including cholesterol levels, blood pressure, medication use and body mass index. The strength of this link suggests that calcification, typically viewed as a stabilising feature in advanced atherosclerosis, may play a more complex role in the early stages of plaque development.
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Further post hoc analyses supported a temporal sequence in which calcification tends to appear before IPH. This may be explained by mechanical stress at the junctions of calcified and softer plaque tissue. These stress concentrations could damage immature blood vessels within the plaque, triggering haemorrhage. While the Rotterdam Study did not assess the specific morphology of calcifications—such as whether they were superficial or deep—previous research has shown that calcifications closer to the vessel lumen are more likely to be involved in such stress-related processes. These insights call for a reassessment of the assumption that calcification always signals plaque stability, especially in subclinical populations.
Gradual Evolution Towards Complexity
The study also demonstrated that carotid plaques become progressively more complex over time, often without causing significant narrowing of the artery. Simulated over a 30-year period, the data showed that plaques with no detectable components or only a single feature at age 55 frequently developed into multicomponent plaques by age 70. This transformation occurred even in individuals with minimal or no luminal stenosis, suggesting that plaque complexity is a better indicator of future risk than traditional measurements of arterial narrowing.
By employing a modelling approach based on the Chapman-Kolmogorov equation, the researchers were able to predict how different combinations of plaque components would evolve with age. This approach took into account sex-specific patterns and used age segments of six years, corresponding to the interval between baseline and follow-up MRIs. The findings revealed a steady increase in the proportion of plaques with two or more components, rising from around 10% at age 55 to more than 50% after age 70. These results reinforce the importance of longitudinal imaging studies in tracking atherosclerotic progression and highlight the limitations of one-time assessments in evaluating stroke risk.
Sex Differences in Plaque Progression
Sex emerged as a significant factor in the evolution of carotid plaque composition. While men and women had similar age distributions within the study population, men were more likely to present with multicomponent plaques at baseline and were also more prone to progress to complex plaques that included IPH. Specifically, 21% of men with plaques initially classified as free of components or having only one feature went on to develop multicomponent plaques with IPH, compared to just 13% of women.
These sex-specific differences persisted even after accounting for variables such as blood pressure, cholesterol, medication and plaque size. The pattern remained consistent across different age groups, including those aged 70 and above. This suggests an intrinsic biological difference in how plaques evolve between men and women, which may help explain the observed disparities in stroke incidence and outcomes. Understanding these differences could pave the way for sex-specific screening and prevention strategies, particularly in identifying those at highest risk before symptoms appear.
The Rotterdam Study offers compelling evidence that subclinical carotid plaques undergo a predictable transformation over time, driven not only by traditional risk factors but also by interactions between internal plaque components. The finding that calcification can precede and potentially facilitate the development of IPH challenges conventional wisdom and underscores the need for more nuanced interpretations of imaging results. Moreover, the gradual but consistent shift toward multicomponent plaques with age—especially among men—highlights the progressive nature of atherosclerosis even in individuals without significant stenosis.
These findings support a move towards composition-based assessment of carotid plaques using non-invasive imaging tools like MRI. They also suggest that early identification of high-risk plaque profiles could enable timely intervention, potentially preventing stroke before it occurs. Future research should explore the morphological features of calcification and incorporate additional plaque characteristics to further refine risk stratification. Importantly, ongoing longitudinal studies will be essential to confirm these patterns and extend their relevance to broader populations with varying cardiovascular risk.
Source: Radiology
Image Credit: iStock
