Women's Heart Attack Risk Starts Rising at Lower Plaque Levels Than Men's

The standard approach to cardiovascular risk in women has long borrowed from data generated predominantly in men. Clinical thresholds for worrying plaque levels, guidelines for when to recommend aggressive treatment, and the definitions of "high risk" that drive decisions about statin therapy and cardiac intervention were all developed from populations in which women were underrepresented. A large imaging study from Mass General Brigham is now providing direct evidence that those thresholds may systematically underestimate cardiac danger in women.

The analysis, published in Circulation on February 23, 2026, used detailed cardiac imaging from 4,267 adults enrolled in the PROMISE trial - a prospective multicenter study conducted across 193 North American sites. Researchers measured both total plaque volume and total plaque burden (the amount of plaque relative to vessel size) using coronary computed tomography angiography, then tracked outcomes over a median of 26 months. The central finding: women's risk of major adverse cardiovascular events rises at a substantially lower plaque threshold than men's, and that risk increases more steeply once it starts climbing.

The Numbers Behind the Gap

Women in the study carried considerably less coronary artery plaque than men. Median total plaque volume was 78 cubic millimeters in women versus 156 cubic millimeters in men - roughly half. Fewer women had plaque in their coronary arteries at all: 55 percent of women showed detectable plaque, compared with 75 percent of men.

Despite this, over the follow-up period, women were approximately as likely as men to experience a major adverse cardiovascular event - defined as cardiovascular death, nonfatal heart attack, or hospitalization for unstable chest pain. The absolute event rate was 2.3 percent in women versus 3.4 percent in men, a modest numerical difference that was not statistically significant after accounting for differences in age and other risk factors.

The key finding emerges when plaque burden is plotted against event risk for the two groups separately. Women's risk begins to rise meaningfully at a total plaque burden of approximately 20 percent. Men's risk remains relatively flat until about 28 percent, then increases more gradually. In women, risk rises more sharply with each additional percentage point of plaque burden. The two curves cross and then diverge, meaning that at moderate plaque levels, women face substantially higher risk than men carrying the same relative plaque load.

Smaller Arteries, Disproportionate Impact

"Because women have smaller coronary arteries, a small amount of plaque can have a bigger impact," said senior author Borek Foldyna of 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."

This is a plausible mechanical explanation. Coronary artery diameter is smaller on average in women, so a given volume of plaque occupies a larger proportion of the vessel lumen. Even without high-risk plaque features like thin fibrous caps or lipid-rich cores - which were less common in women in this study - the geometric relationship between plaque volume and obstruction creates inherently greater hemodynamic impact per unit of plaque in a narrower tube.

The sex difference in risk trajectory persisted after the researchers adjusted for traditional cardiovascular risk factors, for the presence of high-risk plaque subtypes, and for other imaging findings. It also remained significant after adjusting for menopausal status, although the risk differential was particularly pronounced after menopause - consistent with the known role of estrogen in cardiovascular protection during the premenopausal years.

Toward Sex-Specific Risk Assessment

"Our findings suggest that applying uniform thresholds across sexes to determine whether patients' plaque measures put them at high risk for MACE may underestimate risk in women," said lead author Jan Brendel of the Mass General Brigham Cardiovascular Imaging Research Center. "Based on the apparent differences in risk trajectories between men and women, incorporating sex, and even age, into the interpretation of plaque metrics is an important next step toward more individualized risk assessment."

The study draws on an existing trial dataset and is therefore observational; it characterizes associations rather than establishing causes. The PROMISE trial enrolled adults with stable chest pain and no prior coronary artery disease, so the findings apply most directly to that population and may not extend to patients with known disease or different clinical presentations. Longer follow-up might reveal whether the risk curves converge, diverge further, or shift over time.

The finding builds on a growing body of evidence that cardiovascular disease manifests differently in women - in its risk factors, in its symptoms, in its response to treatment, and now in the relationship between imaging-measured disease burden and outcomes. Stacey Rosen of the American Heart Association described the work as "another important example of why it is imperative to recognize that cardiovascular disease can impact men and women so differently," noting the need for clinical practice to reflect "fundamental, biological differences in the way health conditions manifest in women vs. men."