Standard methods for calculating heart attack risk based on arterial plaque may be underestimating risks for women, according to a new study.

In the study, published Monday in Circulation: Cardiovascular Imaging, women had a similar risk for nonfatal heart attack, hospitalization for chest pain, or death from any cause as men, despite having less plaque in their arteries.

Women also faced elevated risk at lower levels of plaque than men, with risk beginning to rise at a 20% vs 28% plaque burden in women vs men. As plaque levels increased, women’s risk rose more sharply than men’s.

“Cardiovascular disease remains the leading cause of death in women, yet much of our risk prediction framework has historically been derived from predominantly male populations,” said Jan Brendel, MD, postdoctoral research fellow at Massachusetts General Hospital in Boston and lead author of the study. “Women have less coronary plaque overall, which can lead to the perception that they are lower risk.”

A Quantitative Approach

Following prior studies suggesting women may experience cardiovascular risk events even without large obstructive lesions, Brendel’s team became interested in whether quantitative imaging biomarkers, specifically plaque burden measured by coronary CT angiography, might reveal subtle, sex-related differences in how atherosclerosis translates into clinical risk.

The researchers analyzed data from 4267 patients enrolled in the PROMISE trial, a study comparing diagnostic strategies in stable outpatients with chest pain and no prior history of coronary artery disease. The patients were randomly assigned to coronary CT angiography.

Rather than simply assessing the degree of artery blockage, Brendel’s group measured each patient’s plaque volume and plaque burden. They then followed patients for a mean of 26 months to assess major adverse cardiovascular events (MACE).

“Quantitative plaque assessment is shifting the field toward imaging-based phenotyping and more individualized cardiovascular risk stratification, rather than binary obstructive versus nonobstructive classification of coronary plaque,” Brendel said.

While MACE incidence did not differ markedly between men and women, there was a difference in the pattern of the risk. In women, MACE risk rose steeply at low plaque levels and then leveled off, whereas men had a more delayed, gradual increase in risk with increasing plaque.

Interpreting Plaque Burden

One challenge Brendel and his collaborators faced was ensuring appropriate interpretation of subtle sex differences without overstating findings.

“We observed substantial overlap between women and men, particularly at higher levels of plaque burden, where statistical precision is more limited,” Brendel said. “Rather than indicating a dramatic divergence, the results point to nuanced differences in how coronary plaque relates to risk — with risk in women appearing to emerge at lower plaque levels.”

The findings suggest plaque measurements in women should be interpreted with nuance, and that those with low-to-moderate plaque burden should not automatically be assumed to be at low risk,” Brendel said.

“Integrating quantitative plaque assessment into cardiovascular risk stratification, with attention to sex, may help refine prevention strategies,” he added.

Outdated Practice Guidelines

Armin Arbab-Zadeh, MD, MPH, director of cardiac computed tomography in the Division of Cardiology at Johns Hopkins Hospital in Baltimore, published an editorial Monday in Circulation: Cardiovascular Imaging discussing the results of the study.

“I disagree with the authors’ interpretation of the study results because of the many potential confounding factors,” Arbab-Zadeh, who was not involved with the study, told Medscape Medical News. “I am not saying their conclusions are false but rather that the information is insufficient to draw these conclusions.”

Arbab-Zadeh emphasized it’s important that women with suspected coronary artery disease receive adequate testing and treatment.

“This is a much bigger concern than the minor differences outlined in the study,” he said. “Practice guidelines still focus on detecting obstructive rather than nonobstructive coronary artery disease, while the latter actually accounts for more myocardial infarctions, as shown in the PROMISE trial. Since women tend to have more nonobstructive [disease] compared to age- and risk-matched men, women are disproportionately affected by this outdated practice, which should be changed.”

“This study should raise awareness for evaluation and diagnosis for all women who present with symptoms of chest pain or symptoms concerning for angina,” said Sadiya Khan, MD, director of the Center for Population Science and Aging at Northwestern University Feinberg School of Medicine in Chicago. “The critical piece is that symptoms should not be dismissed.”

Khan, who also was not involved in the PROMISE trial analysis, added that in the future, use of the American Heart Association’s PREVENT risk score would be helpful because it is a more contemporary model for how plaque correlates with risk.

The study was funded by the National Institutes of Health and the National Heart, Lung, and Blood Institute. Some authors reported receiving funding from other research institutes and receiving consulting fees from pharmaceutical and device manufacturers. Borek Foldyna reported receiving institutional research support from AstraZeneca, MedImmune, Cleerly Health, and MedTrace.

Catherine Shaffer is a freelance science and medical writer with a background in molecular biology and pharmaceutical research. Her work has appeared extensively in scientific trade and mainstream publications and on public radio.