Same Plaque, Higher Risk: How Heart Disease Hits Women Differently

Heart disease kills more women than any other cause of illness, yet its presentation, progression, and risk factors in women differ in ways that clinical medicine has been slow to fully incorporate. For decades, cardiovascular risk calculators and treatment thresholds derived largely from studies of middle-aged men have been applied uniformly to women - often without adjustment for the documented biological differences between the sexes. A new imaging study directly quantifies one of those differences and finds it is substantial.

The research, published February 23, 2026, in Circulation: Cardiovascular Imaging, analyzed coronary CT angiography scans from 4,267 adults in the PROMISE trial - a prospective study of people presenting with stable chest pain and no prior history of coronary artery disease, treated at 193 clinical sites across the United States and Canada. The key finding is stark: women face their first significant rise in cardiovascular event risk at a total plaque burden of about 20 percent, while men don't hit comparable risk until around 28 percent - and risk climbs more steeply for women as plaque accumulates.

Half the Plaque, the Same Outcomes

The disparity starts with what's in the arteries. Among the 4,267 participants - average age 60, 51 percent women - women were less likely to have detectable coronary artery plaque (55 percent vs. 75 percent in men). When plaque was present, women had roughly half the total volume: a median of 78 cubic millimeters compared with 156 cubic millimeters in men. Women also had fewer plaques classified as high-risk based on their composition.

None of that translated into protection. Over approximately two years of follow-up, 2.3 percent of women experienced a major adverse cardiovascular event - defined as cardiovascular death, nonfatal heart attack, or hospitalization for unstable chest pain - compared with 3.4 percent of men. The difference was not statistically significant after accounting for age and other baseline characteristics. Women and men were, in effect, at equivalent clinical risk despite women carrying far less plaque by volume.

The Threshold Gap and What It Means Clinically

The mechanism behind this apparent paradox becomes clearer when plaque burden - not raw volume but plaque relative to vessel size - is examined against outcomes separately for each sex. In women, risk of a cardiac event begins to rise at a total plaque burden of approximately 20 percent. In men, the equivalent inflection point sits at approximately 28 percent. Beyond those thresholds, risk increases more sharply in women than in men for each additional percentage point of plaque accumulation.

"Because women have smaller coronary arteries, a small amount of plaque can have a bigger impact," said senior author Borek Foldyna, an assistant professor in radiology at Harvard Medical School. "Moderate increases in plaque burden appear to have disproportionate risk in women, suggesting that standard definitions of high risk may underestimate risk in women."

The geometric reasoning is straightforward. A blood vessel's flow capacity depends on its cross-sectional area, which scales with the square of the radius. In a narrower artery, the same absolute amount of plaque narrows the lumen proportionally more, reducing flow capacity to a greater degree. Women's coronary arteries average smaller diameters than men's - a consistent anatomical finding - which means a given plaque volume fills a larger fraction of the available space.

Menopause as a Modifier

The divergence in risk trajectories was particularly pronounced after menopause. Estrogen is known to influence cardiovascular health through multiple pathways - affecting lipid profiles, blood pressure, vascular inflammation, and the biology of plaque formation and stability. The loss of estrogen at menopause accelerates several cardiovascular risk factors, and the PROMISE data suggest it also shifts the relationship between plaque burden and event risk in ways that are not captured by currently used assessment tools.

The sex difference in risk trajectory held after adjusting for menopausal status, but its amplification in post-menopausal women points to hormonal biology as one contributor to the gap. Whether hormone-related factors affect the physical properties of plaque, the susceptibility of smaller arteries to plaque-related obstruction, or both, remains an active area of investigation.

Limitations and Next Steps

The study is observational and draws on a subset of the PROMISE trial population. Follow-up was approximately two years - a period sufficient to capture near-term events but potentially too short to observe risk trajectories in younger patients or in people with lower overall plaque burden. The trial enrolled adults with stable chest pain at U.S. and Canadian academic and community sites, a population that may not reflect the full spectrum of people at cardiac risk.

Lead author Jan Brendel of the Mass General Brigham Cardiovascular Imaging Research Center called for the next step to be direct: "incorporating sex, and even age, into the interpretation of plaque metrics is an important next step toward more individualized risk assessment." What that looks like in practice - whether as lower intervention thresholds for women in clinical guidelines, as sex-specific scoring algorithms in imaging reports, or as modified definitions of high-risk plaque in women - are questions that this study frames but does not resolve.