The Prognostic Value of Serum Interleukin-6 Concentrations for 9 Cardiovascular and Mortality Outcomes: The Cross Cohort Collaboration (CCC).

Abstract

Interleukin (IL)-6 has emerged as a promising target for cardiovascular disease (CVD) prevention. Better understanding IL-6's contribution to CVD events in community-based, diverse cohorts and in clinically relevant subgroups will provide critical context about IL-6 inhibition for CVD prevention. The aim of this study was to evaluate the association of circulating IL-6 concentrations with incident cardiovascular events and mortality using pooled data from large multiethnic prospective cohorts. The authors harmonized individual-level participant data from 14 cohorts with blood IL-6 measurements and follow-up data on any of 9 prespecified outcomes: myocardial infarction, stroke, atrial fibrillation, heart failure, total coronary heart disease (CHD), total CVD, all-cause mortality, CVD-specific mortality, and CHD-specific mortality. Multivariable-adjusted Cox proportional hazards models were used to estimate HRs and corresponding 95% CIs. IL-6 was analyzed by quartiles and as a log-transformed continuous variable. Associations were further examined by chronic kidney disease status, diabetes status, high-sensitivity C-reactive protein (hsCRP) concentrations, body mass index categories, as well as in secondary prevention. Discrimination was evaluated using the area under the curve across 4 models: base, base plus IL-6, base plus hsCRP, and base plus both markers. Among 59,396 participants, the median IL-6 concentration was 1.91 pg/mL. The mean age was 63.6 ± 12.4 years. 67.6% were women, and 20.6% were Black. The longest median follow-up time was 15.8 years (for CVD-specific mortality). Higher IL-6 concentrations were associated with increased risk for all 9 outcomes. The strongest association was observed for CHD-specific mortality, with an adjusted HR of 2.12 (95% CI: 1.88-2.39) in the highest compared with the lowest IL-6 quartile. The weakest association was for myocardial infarction (HR: 1.45; 95% CI: 1.28-1.64). Findings were robust and consistent in all key subgroups as well as in secondary prevention. IL-6 alone demonstrated modest additive discrimination beyond hsCRP for stroke, heart failure, CVD, CHD, and mortality. In this large, harmonized, individual-level participant data analysis of prospective cohorts, higher IL-6 concentrations were strongly associated with 9 cardiovascular and mortality outcomes after controlling for clinical covariates. These associations were consistent across cardiometabolic subgroups, chronic kidney disease status, and secondary prevention populations, highlighting the broad and consistent role of IL-6-mediated inflammation in cardiovascular risk.