Zero Coronary Artery Calcium as a Marker of Vascular Resilience in High-Risk Adults

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) prevention relies on risk estimation. Yet among adults labeled high risk by the Pooled Cohort Equations (≥20%), coronary heart disease (CHD) event rates vary, with some experiencing few events, raising the possibility of a resilient phenotype. OBJECTIVES: This study aimed to investigate whether a coronary artery calcium (CAC) score of zero identifies a resilient lower-risk group among adults with high calculated ASCVD risk and compare their risk factor profiles with those with non-zero CAC. METHODS: We analyzed participants in the Multi-Ethnic Study of Atherosclerosis with Pooled Cohort Equations-estimated ASCVD risk ≥20% and CAC data. Baseline characteristics were compared using standardized mean differences. Ten-year CHD events were analyzed using Kaplan-Meier methods, with HRs for CAC = 0 vs CAC >0 estimated using Cox models adjusted for age, sex, and race/ethnicity. Effect modification by age and sex was assessed. RESULTS: Among 1,608 adults (mean age 73.2 years, 61.4% men) with ASCVD risk ≥20%, 359 (22.3%) had CAC = 0. Risk factors were similar between CAC groups, with standardized mean differences <0.20 for blood pressure, lipids, diabetes, and body mass index. Over 10 years, hard CHD incidence rates were 3.52 and 13.46 per 1,000 person-years for CAC = 0 and CAC >0, respectively. CAC = 0 was associated with lower CHD risk (HR: 0.27; 95% CI: 0.15-0.49). A significant CAC × age interaction (P = 0.023) indicated stronger protection at older ages. CONCLUSIONS: Nearly one-quarter of adults labeled high ASCVD risk had CAC = 0 and accrued few events despite similar risk factor burden. CAC = 0 may mark a resilient phenotype warranting targeted mechanistic investigation.