Interleukin-6 predicts cardiovascular events beyond standard modifiable risk factors in individuals without atherosclerotic cardiovascular disease

Background Current risk stratification algorithms capture high-risk individuals with classical risk factors or established atherosclerotic cardiovascular disease (ASCVD). However, a clinically relevant proportion of individuals without threshold levels of standard modifiable risk factors (SMuRF) – namely hypertension, dyslipidemia, diabetes mellitus and smoking – experience cardiovascular (CV) events. Prompted by genetic data suggesting a causal role of interleukin-6 (IL-6) in the development of ASCVD, we investigated the role of IL-6 in the prediction of CV events in SMuRF-less individuals, to probe pathophysiologic links between low-grade inflammation and ASCVD development. Methods IL-6 was measured in 7,133 SMuRF-less UK Biobank participants with no known history of ASCVD. IL-6 measurements were performed as part of the proteomics substudy. The primary endpoint was a composite of non-fatal myocardial infarction, non-fatal stroke or CV death (MACE, major adverse cardiovascular events). Results During a median follow-up of 13.7 years, MACE occurred in 241 subjects. Those with MACE had higher IL-6 concentrations than event-free subjects (p<0.001). Kaplan-Meier analyses showed a stepwise increase in MACE across IL-6 tertiles (log-rank p<0.001). IL-6 was associated with MACE in univariable models (hazard ratio: 2.78; 95% confidence interval: 2.06, 3.73; p<0.001). After adjustment for age, sex, body mass index, and estimated glomerular filtration rate, SMuRF-less individuals with elevated IL-6 levels had an 81% increased risk of MACE (hazard ratio: 1.81; 95% confidence interval: 1.31, 2.49; p<0.001). In subgroup analyses, these associations were consistent after stratification by sex and lipoprotein(a) levels. Conclusion This analysis demonstrates a strong link between IL-6 concentrations and CV risk in SMuRF-less individuals. IL-6 predicts long-term risk even in individuals without traditional risk factors who are apparently healthy. These results highlight the importance of residual inflammatory risk in the development of ASCVD and support the rationale for ongoing investigations targeting the IL-6 axis for prevention of heart disease.