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Interleukin-6 provides added value on top of established risk scores for prediction of cardiovascular death in 49,462 individuals without ASCVD

https://doi.org/10.1007/s00392-025-02625-4

Berkan Kurt (Aachen)1, M. Reugels (Aachen)1, K. M. Schneider (Aachen)2, A. Milzi (Aachen)1, A. G. Antwerpen (Aachen)1, K. Rex (Aachen)1, K. L. Aygar (Aachen)1, J. Bornemann (Aachen)1, N. Ganesh (Aachen)1, A. Giacin (Aachen)1, S. Just (Aachen)1, A. Kapoor (Aachen)1, A. M. Mertens (Aachen)1, K. Müser (Aachen)1, M. Neuhaus (Aachen)1, L. B. Quintana Selek (Aachen)1, R. Salagundi (Aachen)1, M. Sausen (Aachen)1, N. Tabaza (Aachen)1, A. Gombert (Aachen)3, M. Lehrke (Traunstein)4, N. Marx (Aachen)1, C. V. Schneider (Aachen)2, F. Kahles (Aachen)1

1Uniklinik RWTH Aachen Med. Klinik I - Kardiologie, Angiologie und Internistische Intensivmedizin Aachen, Deutschland; 2Uniklinik RWTH Aachen Med. Klinik III - Gastroenterologie und Stoffwechselkrankheiten Aachen, Deutschland; 3Uniklinik RWTH Aachen Klinik für Gefäßchirurgie Aachen, Deutschland; 4Klinikum Traunstein Kardiologie Traunstein, Deutschland

 

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. 

 

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