Sex differences beyond stenosis in quantitative plaque phenotype, coronary anatomy, FFR-CT, and cardiovascular outcomes: the BEYOND-PLAQUE study

Background Sex differences in coronary artery disease extend beyond luminal stenosis and include differences in plaque burden and composition. However, women often experience comparable cardiovascular outcomes despite lower quantified plaque. Purpose To evaluate sex differences in quantitative plaque phenotype, coronary anatomy, FFR-CT, and cardiovascular outcomes. Methods 3,771 consecutive patients (1813 women, y men) undergoing clinically indicated coronary CT angiography with quantitative plaque analysis and fractional flow reserve–derived from CT (FFR-CT) had evaluation for total plaque volume (TPV), calcified plaque volume (CPV), non-calcified plaque volume (NCPV), low-attenuation plaque volume (LAPV), and total plaque atheroma volume (TPAV). Total coronary volume was measured as a marker of lumen size. Baseline demographics and clinical cardiovascular (CV) risk factors were recorded and compared between sexes. The primary endpoint was a composite of CV death or myocardial infarction (MI). The secondary endpoint was CV death, MI, or ischemic stroke. Results Women were older (57.8 ± 8.8 vs 55.7 ± 9.5 years, p < 0.0001) and had higher prevalence of diabetes (25.4% vs 19.2%, p < 0.0001) and hypertension (50.1% vs 44.3%, p = 0.0004). Although women had a higher risk[RR1] burden, they exhibited substantially lower plaque burden across subtypes: median TPV 43 mm³ (IQR 8–127) vs 111.5 mm³ (28–340), CPV 2 mm³ (0–15) vs 8 mm³ (0–56), and NCPV 41 mm³ (7–105) vs 99 mm³ (27–277). Total plaque atheroma volume was also lower in women (2.2% [0.4–6.6] vs 4.2% [1.1–13]).Women demonstrated less ischemia by lowest FFR-CT ≤0.80 (31.0% vs 45.9%). Despite lower plaque burden and less frequent ischemia, women experienced similar rates of CV death or MI compared with men (3.4% vs 4.0%, p = 0.32). Similarly, rates of the secondary endpoint (CV death, MI, or ischemic stroke) were comparable between women and men (7.8% vs 8.2%, p = 0.66). Notably, women demonstrated significantly smaller total vessel and lumen volumes (both p < 0.0001), which, in combination with physiologic coronary tapering, may limit effective myocardial perfusion. In multivariable analysis, non-calcified plaque atheroma volume independently predicted CV death or MI (HR 1.053, 95% CI 1.036–1.069, p < 0.0001), whereas sex was not independently associated with outcomes. Conclusions Women exhibit substantially lower plaque burden and less frequent ischemia by FFR-CT compared with men, yet experience comparable CV event rates. Smaller coronary vessel and lumen volumes may represent an alternative anatomical pathway contributing to risk beyond plaque burden alone, suggesting that plaque burden alone does not fully explain sex-specific CV risk.