Plaque Burden Outlasts Ischemia as Long-Term Predictor of Heart Risk

For decades, cardiologists have wrestled with a deceptively simple question: when a patient with chest pain undergoes heart imaging, which finding matters more for predicting future trouble — the sheer volume of cholesterol-laden plaque clogging the coronary arteries, or the degree to which the heart muscle is starved of blood? A large new study published in the European Journal of Nuclear Medicine and Molecular Imaging offers one of the most detailed answers yet, and the answer changes depending on how far into the future you look. Analyzing 1,385 patients followed for a median of 7.1 years, researchers found that the total burden of atherosclerotic plaque, measured with artificial intelligence-enhanced CT scans, remained a consistent and independent predictor of death, heart attack, and unstable angina across three, six, and nine years of follow-up. Ischemia, measured with ultra-precise PET scans, told a different story: it was a powerful predictor of early and mid-term events, but its prognostic grip loosened over the long haul.

The study, led by Jorge Dahdal of Amsterdam University Medical Center together with colleagues from Turku University Hospital in Finland and several European institutions, is notable for its technical rigor. Every patient underwent both coronary computed tomography angiography (CCTA) and positron emission tomography (PET) myocardial perfusion imaging using oxygen-15 labeled water, a tracer considered the gold standard for quantifying absolute blood flow to the heart muscle. Rather than relying on the subjective, visual assessments that have long dominated clinical practice, the team deployed an FDA-cleared AI software platform to measure plaque volume in every coronary segment larger than 1.5 millimeters in diameter. The software distinguishes atherosclerotic tissue from epicardial fat and the vessel lumen, sums the volume of every lesion, and normalizes that total to the overall volume of the vessel tree. The resulting metric, percent atheroma volume or PAV, expresses the proportion of the coronary artery wall occupied by plaque — a continuous, quantitative measure of how much atherosclerosis a patient carries.

On the functional side, the researchers quantified hyperemic myocardial blood flow, or hMBF, the rate at which blood reaches the heart muscle when it is pushed to its maximum demand. Patients abstained from caffeine for at least 24 hours before their scans, and pharmacologic hyperemia was induced with intravenous adenosine at 140 micrograms per kilogram per minute. Dedicated software packages at the two centers, CardiacVUer in Amsterdam and Carimas in Turku, generated parametric flow maps across the standard 17-segment model of the left ventricle. The team defined regional hMBF as the lowest mean flow across two contiguous myocardial segments, a deliberately conservative measure that captures focal flow reductions without diluting them in a whole-heart average. Perfusion was classified as normal above 2.3 milliliters per minute per gram and graded as mildly, moderately, or severely reduced below that threshold. The two measures were, unsurprisingly, related: patients with more plaque tended to have lower hyperemic flow, with a moderate inverse correlation (Spearman’s rho of -0.47).

The cohort itself reflected the messy reality of real-world cardiology. Between 2007 and 2016, symptomatic patients with suspected coronary artery disease and no prior cardiac history were enrolled at two centers with different imaging philosophies. In Amsterdam, combined CCTA and PET perfusion imaging was performed routinely in all referred patients, while in Turku, PET was performed selectively when CCTA suggested obstructive disease. The patients had a mean age of 62 years, 54 percent were male, 58 percent had hypertension, and 18 percent had diabetes. Median percent atheroma volume was 7.9 percent, with nearly 28 percent of patients showing extensive plaque burden, and impaired regional perfusion was detected in roughly half the cohort. Twenty percent of patients underwent early revascularization — stenting or bypass surgery within six months of imaging — a fact that would prove central to interpreting the results.

Over a median follow-up of 7.1 years, extending as far as 13.3 years, 185 patients — 13.4 percent of the cohort — experienced the composite outcome of all-cause death, non-fatal myocardial infarction, or unstable angina. Deaths accounted for just over half of these events, followed by heart attacks and unstable angina. The cumulative event rate climbed from 5.2 percent at three years to 9.5 percent at six years and 12.1 percent at nine years. Patients who suffered events had dramatically higher plaque burden than those who did not — a median PAV of 15.4 percent versus 7.0 percent — and significantly lower regional blood flow, 1.85 versus 2.38 milliliters per minute per gram. Kaplan-Meier survival curves showed a stepwise deterioration in event-free survival with each increasing stage of plaque burden and each grade of perfusion impairment, a visual gradient that foreshadowed the statistical findings to come.

The heart of the analysis lay in a series of multivariable Cox regression models that pitted the two imaging metrics against each other while adjusting for age, sex, hypertension, diabetes, and early revascularization. When each measure was considered alone, both predicted events at every timepoint. But when both were entered into the same model — a head-to-head test of independent prognostic value — a clear division of labor emerged. Each 1 percent increase in percent atheroma volume raised the hazard of an event by roughly 3.5 to 4.7 percent at all three timepoints, with adjusted hazard ratios of 1.047, 1.035, and 1.036 at three, six, and nine years respectively, all highly statistically significant. Regional hMBF, by contrast, remained independently predictive at three years (a hazard ratio of 1.050 per 0.1 milliliter per minute per gram decrease, p = 0.004) and six years (1.028, p = 0.024), but the association weakened to statistical insignificance by nine years (1.020, p = 0.063).

Why would ischemia’s predictive power fade while plaque burden’s endured? The answer, the researchers argue, lies largely in what happened after the scans were taken. Interaction analysis revealed that early revascularization significantly modified the prognostic associations of both metrics, suggesting that opening blocked arteries changes the natural history that the imaging had captured. When the team repeated the analysis after excluding the 281 patients who underwent early revascularization, the picture transformed: both plaque burden and regional blood flow were significantly associated with outcomes at all three timepoints, including nine years. In other words, untreated ischemia retains its full prognostic force over the long term, but once clinicians relieve it with stents or bypass grafts, the flow measurement no longer reflects the risk it once did — the risk has been, at least partly, defused. Plaque burden, by contrast, is not so easily erased; it represents the cumulative atherosclerotic substrate that continues to generate risk regardless of any single intervention.

These findings land in the middle of an ongoing and often heated debate about the value of ischemia detection. Landmark randomized trials such as COURAGE and ISCHEMIA showed that revascularization guided by ischemia, while effective at relieving symptoms, does not reliably improve hard clinical outcomes compared with guideline-directed medical therapy in stable coronary disease. Skeptics have used those results to question whether ischemia imaging is worth the cost and radiation. But the authors of the new study point out that those trials relied on earlier-generation perfusion techniques or even non-imaging exercise testing, which may have failed to fully characterize the burden and complexity of ischemia. Quantitative PET perfusion imaging offers a continuous, precise measurement rather than a binary yes-or-no answer, and observational studies have consistently shown it adds prognostic information beyond anatomy. This study is among the first to demonstrate that PET-derived ischemia remains independently predictive even when integrated with AI-based quantitative plaque analysis, a technique rapidly entering clinical practice.

The clinical implications are correspondingly two-pronged. Recent scientific statements from the American College of Cardiology and the American Heart Association now endorse AI-based quantitative plaque analysis to enhance risk assessment and guide preventive therapy in patients with plaque visible on CCTA. The new data suggest that percent atheroma volume may be particularly valuable for long-term risk stratification, especially in patients with non-obstructive disease whose anatomic risk is otherwise underestimated, potentially justifying more intensive lipid-lowering and preventive strategies. Regional hyperemic blood flow, meanwhile, identifies patients at elevated near-term risk and may inform symptom-directed management and closer short-term follow-up. The two measurements, in effect, answer different questions: plaque burden describes the size of the reservoir of future risk, while ischemia signals how much of that risk is about to be expressed. Staging frameworks linking plaque volume to preventive treatment targets have been proposed, though optimal thresholds remain under active investigation.

The authors are careful to acknowledge the study’s limitations. As a retrospective observational analysis, it lacked comprehensive data on post-imaging medical therapy, used all-cause rather than cardiovascular-specific mortality, and involved different scanner hardware across the two centers. The findings pertain specifically to absolute flow measurements from oxygen-15 water PET and may not extend directly to flow reserve indices or other tracers. Residual confounding is an inherent risk, particularly around the selection of patients for early revascularization. Yet the consistency of the results across alternative plaque and perfusion metrics, different revascularization definitions, and both imaging protocols strengthens the central conclusion: anatomy and function are not rivals but complementary windows onto coronary disease, each with its own temporal signature. For a field still deciding how best to deploy its increasingly powerful imaging arsenal, that temporal map — plaque for the long game, ischemia for the near term — may prove one of the most actionable findings yet.

Subject of Research: Time-dependent prognostic value of coronary plaque burden and hyperemic myocardial blood flow in suspected coronary artery disease

Article Title: Time-dependent prognostic value of coronary plaque burden and hyperemic myocardial blood flow

Article References: Time-dependent prognostic value of coronary plaque burden and hyperemic myocardial blood flow. (n.d.). https://doi.org/10.1007/s00259-026-08135-3

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08135-3

Keywords: coronary artery disease, CCTA, PET imaging, plaque burden, myocardial ischemia, percent atheroma volume, hyperemic myocardial blood flow, risk stratification, artificial intelligence, revascularization, cardiovascular outcomes, nuclear medicine