Background: Activation of the Interleukin-6 (IL-6) pathway drives development of atherosclerotic cardiovascular disease (ASCVD). IL-6 levels are associated with cardiovascular events in patients without history of ASCVD. To evaluate IL-6 as a clinical useful biomarker in primary prevention more information about its ability to add on top of established risk scores is needed.
Methods: IL-6 was measured at baseline in 49,462 UK Biobank participants with no history of previous ASCVD (proteomics subset). The UK Biobank is a population-based cohort study that was conducted in the UK from 2006 to 2010, which recruited 502,505 volunteers aged 37 - 73 years at baseline. The primary end point was CV death.
Results: Mean age of the participants at baseline was 56.6 years and 46% were male. 864 CV death events occurred during the median follow-up period of 13.4 years. Quartiles of increasing baseline levels of IL-6 predicted CV death. This association remained significant after adjustment for age, sex, BMI, type 2 diabetes, total cholesterol, HDL-C, systolic blood pressure and eGFR (Chi2: 823.51, p<0.0001). Addition of IL-6 to a model containing age, sex, BMI, type 2 diabetes, smoking and eGFR led to a higher incremental added value in risk prediction than addition of total cholesterol or blood pressure (model + IL-6: delta Chi2: 89.11; fraction of new information: 10.21%; model + total cholesterol: delta Chi2: 13.76; fraction of new information: 1.73%; model + systolic blood pressure: delta Chi2: 14.11; fraction of new information: 1.83%). Adjustment of the Framingham risk score or SCORE2 by IL-6 enables a more accurate prediction of 10-year risk of CV death (Framingham + IL-6: delta Chi2: 82.81; fraction of new information: 26.13%; delta C-index: 0.025; SCORE2 + IL-6: delta Chi2: 73.54; fraction of new information: 32.71%, delta C-index: 0.033).
Conclusion: Circulating IL-6 is a strong and independent predictor of CV death in individuals with no history of ASCVD. Model performance of the Framingham risk score and SCORE2 was significantly improved after addition of IL-6. These data suggest that IL-6 is a clinical useful biomarker to early identify patients at inflammatory cardiovascular risk.
