Abstract 4367541: Mortality Implications of Cardiovascular-Kidney-Metabolic Syndrome Stage 3 Classification Based on Coronary Artery Calcium Score Cut-Offs: Insights from Pooled Multi-Ethnic Population Cohorts

Introduction: Cardiovascular-Kidney-Metabolic (CKM) Syndrome Stage 3 is associated with higher mortality than earlier stages. Current criteria upgrades Stage 1 and 2 to Stage 3 solely based on the presence of any coronary artery calcium (CAC >0). This may overestimate risk in CKM Stage 3 individuals with low CAC burden and no additional high-risk features. Although CAC ≥100 is a well-established threshold associated with increased mortality, its utility in refining risk within the CKM classification framework has not been established. Methods: Participants from the Multi-Ethnic Study of Atherosclerosis and Coronary Artery Risk Development in Young Adults cohorts were stratified by CKM stage. CKM Stage 3 individuals classified solely due to CAC >0 were further categorized into two groups: CAC <100 and CAC ≥100. 10-year all-cause mortality rates were calculated both unadjusted and adjusted for age, sex, race, and cohort. Survival analyses included Kaplan-Meier curves and pairwise log-rank tests with Bonferroni correction. Cox proportional hazards models were used to estimate adjusted hazard ratios and generate adjusted survival curves. Models were adjusted for age, sex, race, and cohort with CKM Stage 0 as the reference group. Results: Among 9,019 individuals (mean age 56 ±10 years, 46.1% male, 55.3% non-white), mortality rates increased with advancing CKM stage. 1,871 (49.3%) CKM Stage 3 participants met criteria solely due to CAC >0, including 1,219 (32.1%) with CAC <100. Within this subgroup, those with CAC ≥100 and CAC <100 had adjusted mortality rates of 6.1 (95% CI, 3.7–10.3) and 4.0 (95% CI, 2.5-6.4) per 1,000 person-years, respectively. In multivariable adjusted analysis, only CKM Stage 3 due to CAC ≥100 was independently associated with increased mortality risk (HR 2.20; 95% CI, 1.25-3.85; p=0.006) compared to CKM Stage 0. CKM Stage 3 due to CAC <100 had similar mortality risk (HR 1.56; 95% CI, 0.90-2.68; p=0.11) as CKM Stage 0. Conclusions: Classification to CKM Stage 3 based solely on CAC <100 is not associated with significantly increased mortality. Mortality risk in this population appears to be driven by CAC burden, suggesting that incorporating CAC thresholds into CKM Stage 3 criteria may improve CKM risk stratification.