Sub-Agatston coronary calcification on non-contrast cardiac CT and cardiovascular risk

AIMS: To develop assessments of low-density ("sub-Agatston") coronary artery calcification (CAC) on non-contrast CT calcium score (CTCS) examinations to evaluate its association with the risk of atherosclerotic major adverse cardiac events (MACE) and with high-risk plaque (HRP) features from coronary CT angiography (CCTA). METHODS: We analyzed 1837 asymptomatic individuals from the CLARIFY CTCS registry (NCT04075162) and 1075 patients presenting at chest-pain clinics from the SCOT-HEART trial (NCT01149590). MACE comprised death, myocardial infarction, stroke, or revascularization. We developed the vulnerable calcium index (VCI), which quantifies the proportional CAC mass increase after region-growing from 130 HU (Agatston) to 110 HU. Cox models were adjusted for age, sex, diabetes, hypertension, smoking, baseline statin use, and Agatston score. The association between VCI and CCTA-defined HRP (low-attenuation plaque, positive remodeling, spotty calcifications, mixed plaque, punctate calcification, napkin-ring sign) was assessed in patients with paired CTCS and CCTA in SCOT-HEART. RESULTS: Median follow-up was 4.8 y (CLARIFY) and 4.9 y (SCOT-HEART). VCI was independently associated with MACE in both cohorts: CLARIFY (adjusted hazard ratio [HR] 1.12, 95% CI 1.02-1.22, p=0.02) per unit increase in VCI and SCOT-HEART (adjusted HR 1.16, 1.03-1.31, p=0.02). Patients in the top quartile of adjusted model risk had markedly higher event rates compared with the lowest quartile (CLARIFY HR 25.0; SCOT-HEART HR 33.7 vs Q1, p<0.005 for both). Addition of VCI to Agatston significantly improved C-index (CLARIFY: 0.62 to 0.66, p<0.001; SCOT-HEART: 0.72 to 0.75, p<0.001) and net reclassification index (CLARIFY: 0.52 [0.40, 0.64], p<0.005; SCOT-HEART: 0.72 [0.48, 0.94], p<0.005). In SCOT-HEART, VCI was associated with all HRP features (OR: 1.45 to 1.85, p<0.001), adjusted for Agatston score. CONCLUSION: VCI captures sub-Agatston CAC linked to HRP and independently improves MACE prediction in both a primary-prevention and a mixed-risk symptomatic chest pain population. Incorporating VCI into CAC reporting may refine preventive risk stratification beyond the conventional Agatston score.