A new study published in the journal Radiology has shown that carotid artery plaques—fatty, cholesterol-laden buildups in the arteries—can become progressively more dangerous over time even in patients who exhibit no symptoms. Researchers from Erasmus MC University Medical Center Rotterdam, in collaboration with the Radiological Society of North America, analyzed nearly a decade’s worth of data from more than 800 participants in the long-running Rotterdam Study to uncover critical insights into how plaque composition evolves and how these changes can elevate stroke risk.
Background: Why Carotid Plaques Matter
Carotid artery plaques are key markers of atherosclerosis, a condition in which arteries become clogged with deposits of fat, cholesterol, and other substances. Over time, these plaques can harden—a process known as calcification—which until recently was thought to confer greater stability and lower the risk of rupture. But plaque rupture is a leading cause of ischemic stroke: when a plaque breaks open, it can trigger the formation of a blood clot that may travel to the brain and block its blood supply.
“For decades, we have believed that calcified plaques are relatively harmless, but our new findings challenge that assumption,” said study lead author Dr. Daniel Bos, associate professor of Clinical Epidemiology and Neurovascular Imaging at Erasmus MC. “We now know that even heavily calcified plaques can undergo dangerous changes, such as intraplaque hemorrhage, which dramatically increases the risk of rupture and stroke.”
About the Rotterdam Study
The Rotterdam Study is a prospective, population-based cohort study initiated in 1990 to investigate a wide range of chronic diseases among elderly individuals. To date, it has tracked health outcomes—including cardiovascular disease, dementia, and cancer—in thousands of participants aged 45 and older. For this specific research, investigators focused on 802 participants who had subclinical carotid artery atherosclerosis detected by imaging but had not experienced any related symptoms or events, such as transient ischemic attacks (TIAs) or strokes.
The investigators used high-resolution magnetic resonance imaging (MRI) to examine the composition of carotid plaques at baseline and then again six years later. MRI is uniquely suited to characterize plaque components—such as lipid-rich necrotic cores, calcifications, and hemorrhage—without any invasive procedures. By analyzing two sets of images per participant, the team could monitor how each individual’s plaque changed over time.
Study Design and Methodology
At the outset of the study, each of the 802 participants underwent a baseline carotid MRI scan between 45 and 75 years of age. Those with visible atherosclerotic plaques but no history of stroke or TIA were invited back for a follow-up scan approximately six years later. Researchers then compared the baseline and follow-up images to identify what new components had developed, which existing features had grown, and which plaques had remained stable.
Key MRI markers assessed included:
• Calcification: regions of hardened calcium deposits within the plaque.
• Lipid-rich necrotic core (LRNC): areas containing dead and dying cells, cholesterol crystals, and other debris.
• Intraplaque hemorrhage (IPH): bleeding inside a plaque, which can destabilize its structure.
• Fibrous cap thickness: the layer of fibrous tissue that covers the lipid core; thinning of this cap is a warning sign of imminent rupture.
Using sophisticated image-processing algorithms, the researchers quantified the volume and distribution of these components in each plaque. They also recorded participants’ demographic and clinical data—such as age, sex, blood pressure, cholesterol levels, smoking status, and medication use—to control for potential confounding factors. Finally, the team performed statistical modeling to determine which baseline features predicted dangerous changes and to project how plaques would evolve over the participants’ lifetimes.
Key Findings: Calcification Does Not Guarantee Stability
Contrary to prior belief, the researchers found that calcified plaques were not inherently benign. In fact, plaques that already contained calcifications at the beginning of the study were twice as likely to develop intraplaque hemorrhage over the next six years compared to plaques without calcification. Intraplaque hemorrhage is widely recognized as the single strongest indicator of plaque vulnerability and an imminent risk of rupture.
Specifically:
• Among plaques that were non-calcified at baseline, only 12 percent developed new IPH by the six-year follow-up.
• Among plaques that were already heavily calcified at baseline, 25 percent developed IPH during the same interval.
• Plaques composed of a single component (such as predominantly calcified or predominantly lipidic) at baseline tended to evolve into more complex, multicomponent structures, with approximately 55 percent of single-component plaques progressing to multi-feature plaques by six years.
“These data reveal that calcification may actually be a marker for more aggressive plaque biology,” said Dr. Bos. “It appears that once calcium is present, other destabilizing processes—particularly bleeding within the plaque—can occur more rapidly. We must rethink how we assess calcified plaques; they are not automatically ‘safe.’”
Gender Differences and Plaque Complexity
The study also uncovered distinct gender-related patterns in plaque evolution. Although both men and women experienced progression to complex plaques over six years, men demonstrated more rapid accumulation of multicomponent features. Among male participants, 62 percent of single-component plaques advanced to multicomponent status by the six-year mark, compared with 48 percent among female participants. Furthermore, men had a higher incidence of intraplaque hemorrhage overall.
While the reasons for these sex-based differences remain under investigation, researchers note that men typically have higher rates of smoking and more adverse lipid profiles, which may accelerate plaque progression. Hormonal influences and differences in arterial wall biology could also contribute.
Projected Posterity: Simulating Thirty Years of Plaque Evolution
To estimate how carotid plaques might behave over an even longer time span, the investigators used mathematical modeling to simulate plaque changes over 30 years in a hypothetical cohort resembling the study participants. The models incorporated real-world transition probabilities derived from the six-year scan data—essentially extrapolating how often specific plaque changes occurred in the initial cohort.
The simulations predicted that by age 70, over half of those who started with a single-component plaque at age 45 would have developed complex multicomponent plaques, including features such as calcification, lipid cores, and intraplaque hemorrhage. Among those whose plaques were non-calcified at age 45, 45 percent were projected to have acquired both calcification and IPH by age 70.
“These simulations underscore the silent but inexorable nature of atherosclerosis,” said co-author Dr. Hessam AzariJafari, deputy director of the CSHub at MIT. “Our data suggest that routine monitoring of plaque composition—even in asymptomatic individuals—is essential because plaques can transform in unpredictable ways that heighten stroke risk.”
Implications for Clinical Care and Stroke Prevention
Until now, most clinical guidelines have prioritized the degree of luminal narrowing (stenosis) as seen on ultrasound or angiography when deciding whether to intervene—either by intensifying medical therapy or recommending surgical procedures. However, the Rotterdam investigators argue that focusing solely on stenosis may miss patients whose plaques have worrisome compositional features despite only moderate narrowing.
“Carotid endarterectomy and stenting have traditionally targeted patients with significant stenosis—often 70 percent or more,” explained co-author Dr. Xi Kathy Zhou, a professor of population health sciences at Weill Cornell Medicine. “But these new findings indicate that plaques with low-grade stenosis (40–50 percent) may still harbor high-risk features, such as IPH, that put patients at substantial risk for stroke. We need to integrate plaque composition—especially intraplaque hemorrhage—into risk models and decide who needs more aggressive therapy.”
The study supports the growing consensus that MRI-based plaque imaging should become more widespread, particularly in patients with known risk factors—such as uncontrolled hypertension, diabetes, or familial history of premature cardiovascular disease—even if they remain asymptomatic. Some academic centers in Europe and Asia have already incorporated advanced carotid MRI into routine screening for certain high-risk patients, enabling clinicians to identify plaque vulnerability markers and tailor preventative strategies accordingly.
Future Research Directions: Understanding Plaque Interaction
While the study documented how individual plaque components emerge and coalesce, lingering questions remain about the interplay among these features. For instance, does the presence of extensive calcification accelerate intraplaque microbleeds by creating stress points along the plaque surface? Or do lipid-rich cores make plaques more prone to hemorrhage, which in turn triggers calcium deposition as a reparative response? These mechanistic questions will require laboratory studies using advanced imaging, histology, and possibly molecular biomarkers to elucidate the pathways linking calcification, lipid accumulation, and bleeding.
“Our next step is to conduct longitudinal molecular imaging studies—potentially using PET-MRI hybrid scanners—to visualize inflammatory activity within plaques,” said Dr. Zhou. “We believe that chronic inflammation drives many of these dangerous plaque transitions, and by targeting inflammation pharmacologically, we might slow or reverse plaque progression.”
Strengths and Limitations of the Study
This study’s most notable strength lies in its large, population-based design and the availability of high-quality MRI data at two time points for more than eight hundred participants. The cohort’s breadth—encompassing a wide age range and balanced gender distribution—adds credibility to the findings and enhances their generalizability to other elderly and middle-aged populations.
However, several important limitations were acknowledged:
• Interval duration: Six years between scans provides valuable insight, but more frequent imaging—annually or biennially—could capture rapid plaque changes that six-year intervals might miss.
• MRI accessibility: Advanced plaque MRI is not universally available, especially in resource-limited settings, which can hinder widespread clinical adoption of compositional screening.
• Lack of outcomes data: Although the study documented compositional changes, it did not directly correlate these changes with actual stroke or TIA events. Future research must link plaque progression patterns to clinical outcomes.
• Unmeasured confounders: Although the investigators adjusted for traditional risk factors, residual confounding from lifestyle behaviors, medication adherence, or genetic predispositions may influence plaque evolution.
Expert Commentary: A Paradigm Shift in Atherosclerosis Management
Dr. Andrew Scott, a neurologist at Johns Hopkins University who was not involved in the study, hailed the findings as “a game-changer for stroke prevention.” “We have known for years that some patients with moderate carotid stenosis still suffer strokes, while others with severe stenosis remain asymptomatic,” he said. “This new data on plaque composition explains part of that paradox. Combining luminal measurements with plaque imaging will give us a more complete risk profile and allow us to intervene earlier.”
Echoing this view, Dr. Priya Ramanathan, a vascular surgeon at Stanford Medicine, noted, “In my practice, I have begun ordering carotid MRI for certain patients with 50–69 percent stenosis if they also have additional risk factors. When I find intraplaque hemorrhage, I counsel them strongly toward surgical options, even if their stenosis would not have otherwise met traditional thresholds. This study offers solid evidence that we are on the right track.”
Policy Implications and Calls for Guidelines Update
Given the accumulating evidence, medical societies such as the American Heart Association and the European Society of Cardiology are likely to reevaluate their guidelines for carotid atherosclerosis screening and management. The Rotterdam team suggests that after further validation, clinical practice should include:
• Routine plaque composition assessment by MRI for high-risk, asymptomatic individuals.
• Reassessment of intervention thresholds to account for vulnerable plaque features even in cases of moderate stenosis.
• Expansion of research funding for molecular and multimodal imaging studies to fully characterize the atherosclerotic process.
Until formal guidelines are updated, clinicians face the challenge of balancing the benefits of advanced imaging against additional costs and potential patient anxiety. Nevertheless, Dr. Bos emphasized that “the cost of advanced MRI pales in comparison to the lifetime expenses and human suffering associated with a preventable stroke.” He urged hospitals and insurers to adopt a forward-looking approach to reimbursement and resource allocation.
Conclusion: Shaping the Future of Stroke Prevention
This groundbreaking research from the Rotterdam Study reveals that carotid plaques—long assumed harmless once calcified—can transform into dangerous, multicomponent lesions that raise the risk of stroke. By showing that calcified plaques are twice as likely to develop intraplaque hemorrhage over six years, and that most single-component plaques become complex by age 70, the study calls for a fundamental shift in how clinicians screen for and manage atherosclerosis.
As the medical community moves toward integrating advanced plaque imaging into routine care, patients and healthcare systems may benefit from earlier detection of high-risk lesions, more personalized treatment strategies—ranging from intensified medical therapy to timely surgical intervention—and, ultimately, a reduction in the burden of stroke. The study’s authors and external experts alike emphasize that ongoing research into the molecular drivers of plaque instability will further refine risk prediction and prevention efforts.
In an era where precision medicine is rapidly expanding, the lessons gleaned from MRI-based plaque characterization will ensure that asymptomatic patients receive the care they need before a sudden stroke robs them of health and independence. As Dr. Bos concluded, “Our goal is to move from a reactive model—treating stroke after it happens—to a proactive one where we identify and neutralize the most dangerous plaques before they ever present clinically.”
The official publication, “Longitudinal Evolution of Carotid Plaque Composition in Asymptomatic Adults: Insights from the Rotterdam Study,” appears in the June 2025 issue of Radiology. The full text is available open access at radiology.rsna.org.
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