Sex-Specific Risk Thresholds in Coronary Artery Disease: Why Plaque Burden Metrics Demand Re-evaluation in Women

Highlights

• Major adverse cardiovascular events (MACE) emerge at a significantly lower total plaque burden (PB) in women (20%) compared to men (28%).
• The risk trajectory for women rises more sharply; a hazard ratio (HR) of 1.5 is reached at 32% PB in women versus 42% in men.
• Noncalcified plaque burden is a particularly potent risk marker in women, with risk elevation beginning at just 7% burden.
• These findings from the PROMISE trial suggest that traditional ‘one-size-fits-all’ quantitative plaque interpretations may systematically underestimate cardiovascular risk in female patients.

Background

For decades, the clinical management of coronary artery disease (CAD) has been guided by a ‘stenosis-centric’ model, largely derived from cohorts where men were overrepresented. However, it is increasingly recognized that coronary computed tomography angiography (CCTA) provides insights far beyond luminal narrowing, allowing for the quantification of total plaque volume and composition. Despite this technological leap, the interpretation of these quantitative plaque metrics has remained largely gender-blind.

Clinical outcomes in women with stable chest pain often differ from men. Women typically present with a lower overall prevalence of obstructive CAD but experience comparable or even worse cardiovascular outcomes in certain risk strata. This phenomenon, often referred to as the ‘female paradox’ in cardiology, suggests that the biological impact of atherosclerosis may differ between sexes. There is an urgent unmet need to determine whether the prognostic ‘tipping point’—the level of plaque burden at which risk significantly escalates—is the same for both women and men.

Key Content

The Evolution of Coronary Imaging: From Stenosis to Plaque Burden

The transition from invasive coronary angiography to CCTA marked a shift toward identifying the ‘vulnerable patient’ rather than just the ‘vulnerable lesion.’ Pivotal trials such as SCOT-HEART and the original PROMISE trial established CCTA as a frontline diagnostic tool for stable chest pain. While SCOT-HEART demonstrated that CCTA-guided management reduced myocardial infarction (MI) rates, the original PROMISE trial (NCT01174550) showed that CCTA was a viable alternative to functional testing.

However, early analyses focused primarily on the degree of stenosis (e.g., >50% or >70%). Recent methodological advances in semi-automated and AI-driven quantitative CT (QCT) have enabled researchers to measure Plaque Burden (PB)—the percentage of vessel volume occupied by plaque. PB is a more comprehensive metric than stenosis as it accounts for positive remodeling, where plaque expands outward without initially narrowing the lumen.

Evidence Synthesis: The PROMISE Trial Quantitative Sub-analysis

The recent analysis by Brendel et al. (2026) utilized the PROMISE trial’s CCTA arm to investigate sex-specific risk trajectories. Analyzing 4,267 patients (2,199 women) over a median of 26 months, the study highlights several critical disparities:

1. Plaque Prevalence and Volume

Women were found to have a lower prevalence of any coronary plaque (55% vs. 75% in men, P<0.001) and lower total plaque volume. This aligns with long-standing observations that women often present with ‘clean’ or less diseased coronaries by traditional standards. However, the burden (normalized to vessel size) and the subsequent event rates were surprisingly similar between the sexes.

2. Sex-Specific Risk Trajectories

The most striking finding was the divergence in MACE risk (death, MI, or unstable angina) relative to PB. Using sex-stratified spline Cox models, the researchers identified the following thresholds:

• Total Plaque Burden: Hazard ratios crossed 1.0 (indicating increased risk relative to the baseline) at 20% PB in women, compared to 28% in men.
• Escalated Risk: An HR of 1.5 was reached at 32% PB in women, whereas men did not reach this level of risk until they hit 42% PB.
• Noncalcified Plaque (NCP): NCP is often associated with lipid-rich, unstable lesions. In women, risk elevation for NCP began at 7% burden, compared to 9% in men. The gap widened at higher burdens, with women reaching HR 1.5 at 13% NCP vs. 20% in men.

3. Comparative Analysis with Existing Literature

These findings complement data from the ICONIC study, which suggested that low-attenuation plaque (a subset of NCP) is a strong predictor of acute coronary syndromes. The PROMISE sub-analysis extends this by demonstrating that even modest amounts of NCP are more ‘toxic’ in the female vasculature. This suggests that the female coronary environment may be more sensitive to inflammatory or metabolic triggers associated with noncalcified plaque.

Expert Commentary

The findings by Brendel et al. provide a robust statistical basis for what many clinicians have long suspected: women’s hearts are more vulnerable to less ‘visible’ disease. Several biological and physiological mechanisms may explain this sensitivity.

The Role of Microvascular Dysfunction and Inflammation

Women are more likely to exhibit coronary microvascular dysfunction (CMD) and endothelial impairment. It is hypothesized that even a lower burden of epicardial plaque can synergize with underlying microvascular issues to precipitate MACE. Furthermore, the inflammatory profile of plaque in women—often influenced by hormonal shifts and distinct autoimmune factors—may lead to higher plaque activity despite lower total volume.

Challenging the ‘Yentl Syndrome’

Historically, women have been undertreated because their diagnostic results do not reach the ‘male’ threshold for severity. If a radiologist or cardiologist uses a 30% PB threshold to define ‘high risk,’ they would capture many men but miss a significant cohort of women who are already at a 1.5-fold increased risk. This study argues for ‘sex-aware’ reporting in CCTA. Guidelines should be updated to suggest that a 20-25% PB in a woman carries the same clinical weight as a 30-35% PB in a man.

Limitations and Methodological Considerations

While the study is powered by the rigorous PROMISE cohort, limitations include the relatively short median follow-up of 26 months. Longer-term data are needed to see if these trajectories diverge further over decades. Additionally, while quantitative CT is becoming more accessible, the widespread implementation of sex-specific thresholds requires standardized software across different hospital systems to ensure reproducibility.

Conclusion

The PROMISE trial sub-analysis represents a landmark shift in cardiovascular prevention. By demonstrating that MACE risk in women emerges at lower plaque burdens and rises more precipitously, it provides a clear mandate for sex-specific clinical thresholds. For the practicing clinician, these results suggest that stable chest pain in women should be managed aggressively even when plaque appears ‘modest’ by traditional standards. Future research must now focus on whether interventions—such as intensive statin therapy or anti-inflammatory agents—targeted at these lower female-specific thresholds can bridge the mortality gap in cardiovascular health.

References

• Brendel JM, Mayrhofer T, Karády J, et al. Risk in Women Emerges at Lower Coronary Plaque Burden Than in Men: PROMISE Trial. Circ Cardiovasc Imaging. 2026;19(2):e019011. PMID: 41725544.
• Douglas PS, Hoffmann U, Patel MR, et al. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med. 2015;372(14):1291-1300. PMID: 25773919.
• Newby DE, Adamson PD, Berry C, et al. Coronary CT Angiography and 5-Year Outcomes in Patients with Stable Chest Pain. N Engl J Med. 2018;379(10):924-933. PMID: 30145934.
• Ferencik M, Mayrhofer T, Bittner DO, et al. Use of High-Risk Plaque Predicts Incident Cardiovascular Events in Patients With Low-Gradient Stenosis and Low ASCVD Risk: The PROMISE Trial. JACC Cardiovasc Imaging. 2018;11(10):1402-1411. PMID: 30282077.