Interleukin-6 provides added value on top of the SMART risk score for prediction of cardiovascular mortality in patients with established ASCVD

Clin Res Cardiol (2025). DOI 10.1007/s00392-025-02625-4
B. Kurt (Aachen)¹, M. Reugels (Aachen)¹, K. M. Schneider (Aachen)², M. Kleber (Mannheim)³, 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, K. Just (Aachen)⁴, J. Stingl (Aachen)⁴, A. Gombert (Aachen)⁵, M. Lehrke (Traunstein)⁶, W. März (Mannheim)⁷, 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; ³Universitätsklinikum Mannheim Med V. - Nephrologie, Endokrinologie und Rheumatologie Mannheim, Deutschland; ⁴Uniklinik RWTH Aachen Institut für Klinische Pharmakologie Aachen, Deutschland; ⁵Uniklinik RWTH Aachen Klinik für Gefäßchirurgie Aachen, Deutschland; ⁶Klinikum Traunstein Kardiologie Traunstein, Deutschland; ⁷SYNLAB Holding Deutschland GmbH SYNLAB Akademie Mannheim, Deutschland

Background: Interleukin-6 (IL-6) is causally involved in the development of atherosclerotic cardiovascular disease (ASCVD). Large cardiovascular outcome trials targeting the IL-6 pathway are ongoing. IL-6 has been found to identify patients with residual inflammatory risk. To get more information on clinical relevance we here analyzed whether adjustment of the SMART (Second Manifestations of Arterial Disease) risk score by IL-6 provides significant added value in the prediction of CV death in patients with established ASCVD.

 

Methods: We included 1,814 UK Biobank participants with established ASCVD and available circulating IL-6 levels (proteomics subset). The UK Biobank is a population-based cohort study that was conducted in the UK from 2006 to 2010. Furthermore, IL-6 was measured in 2,999 patients with ASCVD (coronary artery disease) who underwent coronary angiography at baseline (1997-2000) and are part of the Ludwigshafen Risk and Cardiovascular Health Study (LURIC). The primary end point was CV death.

 

Results: Mean age of the UK Biobank participants at baseline was 56.6 years and 46% were male. 214 CV death events occurred during the median follow-up period of 13.4 years. Increasing baseline levels of IL-6 predicted CV death. Adjustment of the SMART risk score by IL-6 significantly improved prediction of 10-year risk of CV death (SMART risk score: Chi²: 70.54, SMART risk score + IL-6: Chi²: 75.87; delta Chi²: 5.34; fraction of new information: 7.03%). We validated our findings in the LURIC study (559 CV death events; SMART risk score: Chi²: 383.11; SMART risk score + IL-6: Chi²: 394.08; delta Chi²: 10.97; fraction of new information: 2.78%).

 

Conclusion: The addition of IL-6 on top of the SMART score improves risk prediction of CV death in patients with established ASCVD in two independent cohorts. IL-6 might serve as a useful biomarker to identify patients with residual inflammatory risk for CV risk stratification, and guiding of anti-inflammatory therapies in cardiovascular disease.