The Prognostic Value of Serum Interleukin-6 Concentrations for 9 Cardiovascular and Mortality Outcomes: The Cross
Zhiqi Yao1, Zeina A Dardari1, Michael J LaMonte2
1Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, Baltimore, Maryland, USA.
Insights
Higher interleukin-6 (IL-6) levels are linked to increased cardiovascular disease (CVD) risk and mortality. This finding highlights IL-6
Area of Science:
- Cardiovascular Medicine
- Inflammation Biology
- Epidemiology
Background:
- Interleukin-6 (IL-6) is a key inflammatory cytokine with a potential role in cardiovascular disease (CVD) pathogenesis.
- Understanding IL-6's association with CVD events in diverse populations is crucial for evaluating IL-6 inhibition strategies.
- Previous studies indicate a link between IL-6 and CVD, but comprehensive analysis across multiple cohorts is needed.
Purpose of the Study:
- To investigate the association between circulating Interleukin-6 (IL-6) concentrations and the risk of incident cardiovascular events and mortality.
- To analyze pooled data from large, multiethnic prospective cohorts to provide robust evidence on IL-6's role in CVD.
- To examine IL-6 associations across various subgroups and in secondary prevention settings.
Main Methods:
- Harmonized individual-level data from 14 prospective cohorts, including IL-6 measurements and follow-up on 9 cardiovascular outcomes.
- Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) for IL-6 quartiles and continuous variable.
- Subgroup analyses were conducted based on chronic kidney disease, diabetes, hsCRP, BMI, and secondary prevention status; discrimination was assessed using AUC.
Main Results:
- Higher IL-6 concentrations were significantly associated with an increased risk for all 9 evaluated cardiovascular and mortality outcomes.
- The strongest association was observed for coronary heart disease (CHD)-specific mortality (HR: 2.12), and the weakest for myocardial infarction (HR: 1.45).
- Findings were consistent across key subgroups, including those with chronic kidney disease and diabetes, and in secondary prevention populations.
Conclusions:
- Elevated IL-6 levels are strongly associated with a higher risk of cardiovascular events and mortality in a large, diverse population.
- The consistent associations across various subgroups underscore the significant role of IL-6-mediated inflammation in overall cardiovascular risk.
- These findings support IL-6 as a potential therapeutic target for cardiovascular disease prevention.
Background:
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.
Objectives:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
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