Interleukin-6 and CV risk beyond standard modifiable risk factors (SMuRF) in individuals without atherosclerotic cardiovascular disease

M. Reugels (Aachen)¹, B. Kurt (Aachen)¹, K. M. Schneider (Dresden)², F. Wenzl (Zürich)³, C. B. Fordyce (Vancouver)⁴, N. J. Pagidipati (Durham)⁵, V. Rocha (Sao Paulo)⁶, M. Fudim (Durham)⁷, A. Sharma (Montreal)⁸, J. Spießhöfer (Aachen)⁹, A. Milzi (Lugano)¹⁰, M. Lehrke (Traunstein)¹¹, H. Shimokawa (Sendai)¹², G. Liuzzo (Rome)¹³, L. Tokgozoglu (Ankara)¹⁴, F. Crea (Rome)¹⁵, T. F. Lüscher (Zürich)¹⁶, P. Libby (Boston)¹⁷, P. M. Ridker (Boston)¹⁸, N. Marx (Aachen)¹, C. V. Schneider (Aachen)¹⁹, F. Kahles (Aachen)^1
1Uniklinik RWTH Aachen Med. Klinik I - Kardiologie, Angiologie und Internistische Intensivmedizin Aachen, Deutschland; ²Technische Universität Dresden Medizinische Klinik und Poliklinik I Dresden, Deutschland; ³University of Zurich Center for Molecular Cardiology Zürich, Schweiz; ⁴Vancouver General Hospital, University of British Columbia Division of Cardiology, Department of Medicine and the Centre for Cardiovascular Innovation Vancouver, Kanada; ⁵Duke University School of Medicine Duke University Medical Center; Division of Cardiology, Department of Medicine Durham, USA; ⁶University of Sao Paulo Medical School Hospital Heart Institute (Instituto do Coracao (InCor)) Sao Paulo, Deutschland; ⁷Duke Cardiology Clinic - Clinic 2F/2G Durham, USA; ⁸McGill University Division of Cardiology, Research Institute of the McGill University Health Centre Montreal, Kanada; ⁹Uniklinik RWTH Aachen Med. Klinik V - Klinik für Pneumologie und Internistische Intensivmedizin Aachen, Deutschland; ¹⁰Istituto Cardiocentro Ticino - EOC Lugano, Schweiz; ¹¹Klinikum Traunstein Kardiologie Traunstein, Deutschland; ¹²Tohoku University Graduate School of Medicine Department of Cardiovascular Medicine Sendai, Japan; ¹³Fondazione Policlinico Universitario A. Gemelli – IRCCS and Catholic University of the Sacred Heart
 Department of Cardiovascular Sciences - CUORE Rome, Italien; ¹⁴Hacettepe University Medical Faculty Department of Cardiology Ankara, Türkei; ¹⁵Catholic University of the Sacred Heart Agostino Gemelli Hospital Rome, Italien; ¹⁶Stiftung für Herz- und Kreislaufforschung Zürich, Schweiz; ¹⁷MassGeneralBrigham Hospital, and Harvard Medical School Heart and Vascular Institute Boston, USA; ¹⁸Brigham and Women’s Hospital Center for Cardiovascular Disease Prevention, Division of Preventive Medicine Boston, USA; ¹⁹Uniklinik RWTH Aachen Med. Klinik III - Gastroenterologie, Stoffwechselerkrankungen und Internistische Intensivmedizin Aachen, Deutschland

Background: Chronic low-grade inflammation promotes the development of atherosclerotic cardiovascular disease (ASCVD). Genetic data suggest a causal role of interleukin-6 (IL-6) in the development of coronary heart disease and heart failure. Current risk stratification algorithms capture high-risk individuals with classical risk factors or established ASCVD. However, a clinically relevant proportion of subjects without threshold levels of standard modifiable risk factors (SMuRF) – namely hypertension, dyslipidemia, diabetes mellitus and smoking – experience cardiovascular (CV) events. To probe pathophysiologic links between low-grade inflammation and ASCVD development beyond traditional risk factors, we investigated the role of IL-6 in prediction of long-term CV risk in SMuRF-less individuals.

Methods: IL-6 was measured in 7133 SMuRF-less UK Biobank participants with no known history of ASCVD. The UK Biobank is a population-based cohort study conducted in the UK between 2006 and 2010. IL-6 measurements were performed as part of the proteomics sub-study. The primary endpoint was a composite of non-fatal myocardial infarction, non-fatal stroke or CV death (major adverse cardiovascular death, MACE). To investigate the associations of IL-6 levels with MACE, Kaplan-Meier and Cox proportional hazards models with restricted cubic splines were used.

Results: The cohort had a median age of 52 years and 60% of the participants were female. During a median follow-up time of 13.7 years, MACE occured 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 strongly associated with MACE in univariable Cox proportional hazard regression models (Hazard ratio (HR): 2.78; 95% confidence interval (CI): 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 increased risk of MACE by 81% (HR: 1.81; 95% CI: 1.31, 2.49; p<0.001). In subgroup analyses, these associations were consistent after stratification by sex and lipoprotein (a) levels (log-rank p<0.001).

Conclusion: This analysis demonstrates a strong link between IL-6 concentrations and CV risk in SMuRF-less individuals. IL-6 predicts MACE over 13.7 years even in individuals who are apparently healthy and have no prevalent traditional risk factors. 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.