The role of interleukin 6 in the development of cardiovascular pathology

According the current concepts, chronic subclinical (low-grade) inflammation, the development of which is associated with uncontrolled activation of innate and adaptive immunity plays a fundamental role at all stages of atherosclerotic progression related to cardiovascular diseases (CVD). The significant contribution of inflammation to the development of atherosclerotic vascular lesions has drawn attention to the similarity between the immunopathogenesis mechanisms of atherosclerosis in CVD and rheumatoid arthritis, and subsequently other systemic immune-mediated rheumatic diseases (IMRDs). Among the numerous inflammatory mediators and “immune” cells involved in the immunopathogenesis of atherosclerosis in both CVD and IMIRDs, central roles are occupied by “pro-inflammatory” cytokines such as interleukin (IL)-1, IL-6, TNFα, as well as IL-17 and interferon type I, which closely interact within the “cytokine network”. As a promising therapeutic target, particular attention is drawn to IL-6, which occupies a central place in the development of many IMIDs and CVDs associated with atherosclerotic vascular lesions: coronary heart disease, acute coronary syndrome, peripheral arterial disease, ischemic stroke, heart failure, and others. Of particular importance is the fact that IL-6 hyperproduction plays a significant role in the development of a wide range of cardiometabolic diseases, including type 2 diabetes mellitus, obesity, chronic kidney disease, and metabolic dysfunction-associated fatty liver disease, associated with the development of atherosclerotic vascular lesions. Data were obtained indicating the important clinical significance of IL-6 determination for predicting the risk of premature mortality and other cardiovascular complications both in the general population of conditionally “healthy” people and in patients with various manifestations and forms of CVD. Currently, several genetically engineered biological agents - monoclonal antibodies specific for both IL-6R and IL-6 itself - have been developed. Several RCTs have recently been initiated to study the efficacy and safety of new anti-IL-6 mAbs: ziltivekimab, clazakizumab, and Pacibekitug (TOUR006) in patients with coronary artery disease, heart failure, and CKD. The article will review new data regarding the pathogenetic and clinical significance of IL-6 and the prospects for IL-6 inhibition as a component of anti-inflammatory therapy for CVD.

1. Mallat Z., Tedgui A. Century of Milestones and Breakthroughs Related to the Immune Mechanisms of Atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2024;44(5):1002–1006. DOI: 10.1161/atvbaha.124.319397

2. Libby P., Soehnlein O. Inflammation in atherosclerosis: Lessons and therapeutic implications. Immunity. 2025;58(10):2383–2401. DOI: 10.1016/j.immuni.2025.09.012

3. Duewell P., Kono H., Rayner K.J., et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464(7293):1357–1361. Erratum in: Nature. 2010;466(7306):652. DOI: 10.1038/nature08938

4. Ridker P.M., Everett B.M., Thuren T., et al.; CANTOS Trial Group. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N. Engl. J. Med. 2017;377(12):1119–1131. DOI: 10.1056/NEJMoa1707914

5. Nasonov E.L., Popkova T.V. Anti-inflammatory therapy for atherosclerosis: contribution to and lessons of rheumatology. Rheumatology Science and Practice. 2017;55(5):465–473. (In Russ.). DOI: 10.14412/1995-4484-2017-465-473

6. Buckley L.F., Libby P. Colchicine's Role in Cardiovascular Disease Management. Arterioscler. Thromb. Vasc. Biol. 2024;44(5):1031–1041. Erratum in: Arterioscler Thromb. Vasc. Biol. 2024;44(7):e208. DOI: 10.1161/ATV.0000000000000172. DOI: 10.1161/atvbaha.124.319851

7. Nasonov E.L., Drapkina O.M. Colchicine: Repositioning an “ancient” medicine in the 21st century. Rheumatology Science and Practice. 2024;62(5):445–464. (In Russ.). DOI: 10.47360/1995-4484-2024-445-464 EDN: WGVYSO

8. Mensah G.A., Arnold N., Prabhu S.D., et al. Inflammation and Cardiovascular Disease: 2025 ACC Scientific Statement: A Report of the American College of Cardiology. J. Am. Coll. Cardiol. 2025:S0735-1097(25)07555-2. Epub ahead of print. DOI: 10.1016/j.jacc.2025.08.047

9. Pasceri V., Yeh E.T. A tale of two diseases: atherosclerosis and rheumatoid arthritis. Circulation. 1999;100:2124–2126. DOI: 10.1161/01.CIR.100.21.2124

10. Nasonov E.L. The problem of atherothrombosis in rheumatology. Vestnik RAMN. 2003;(7):6–10 (In Russ.). EDN: OITTKT

11. Porsch F., Binder C.J. Autoimmune diseases and atherosclerotic cardiovascular disease. Nat. Rev. Cardiol. 2024;21(11):780–807. DOI: 10.1038/s41569-024-01045-7

12. Nasonov E.L., Eliseev M.S. Role of interleukin 1 in the development of human diseases. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2016;54(1):60–77. (In Russ.). DOI: 10.14412/1995-4484-2016-60-77 EDN: WYEHHP

13. Zhang H., Dhalla N.S. The Role of Pro-Inflammatory Cytokines in the Pathogenesis of Cardiovascular Disease. Int. J. Mol. Sci. 2024;25(2):1082. DOI: 10.3390/ijms25021082

14. Nasonov E.L., Lila A.M. Inhibition of interleukin 6 in immune inflammatory rheumatic diseases: achievements, prospects, and hopes. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2017;55(6):590–599. (In Russ.)]. DOI: 10.14412/1995-4484-2017-590-599 EDN: YPXRAO

15. Kishimoto T., Kang S. IL-6 Revisited: From Rheumatoid Arthritis to CAR T Cell Therapy and COVID-19. Annu. Rev. Immunol. 2022;40:323–348. DOI: 10.1146/annurev-immunol-101220-023458

16. Mehta N.N., deGoma E., Shapiro M.D. IL-6 and Cardiovascular Risk: A Narrative Review. Curr. Atheroscler. Rep. 2024;27(1):12. DOI: 10.1007/s11883-024-01259-7

17. Preda A., Tirandi A., Leo G., et al. IL-6 in the spotlight: From cardiovascular pathophysiology to therapy. Eur. J. Clin. Invest. 2026;56(1):e70161. DOI: 10.1111/eci.7016

18. Kurt B., Rex K., Reugels M., et al. Inflammatory Biomarkers in Heart Failure: Clinical Perspectives on hsCRP, IL-6 and Emerging Candidates. Curr. Heart Fail. Rep. 2025;22(1):35. DOI: 10.1007/s11897-025-00710-3

19. Kreiner F.F., Kraaijenhof J.M., von Herrath M., et al. Interleukin 6 in diabetes, chronic kidney disease, and cardiovascular disease: mechanisms and therapeutic perspectives. Expert Rev. Clin. Immunol. 2022;18(4):377–389. DOI: 10.1080/1744666X.2022.2045952

20. Rose-John S., Jenkins B.J., Garbers C., et al. Targeting IL-6 trans-signalling: past, present and future prospects. Nat. Rev. Immunol. 2023;23(10):666–681. DOI: 10.1038/s41577-023-00856-y

21. Nasonov E.L., Feist E. The prospects of interleukin-6 inhibition in rheumatoid arthritis: Olokizumab (novel monoclonal antibodies to IL-6). Nauchno-Prakticheskaya Revmatologia=Rheumatology Science and Practice. 2022;60(5):505–518 (In Russ.). DOI: 10.47360/1995-4484-2022-505-518

22. Feist E., Nasonov E. Interleukin 6 inhibition in rheumatoid arthritis: Highlight on olokizumab. touchREVIEWS in RMD. 2023;2(1):17–27. DOI: 10.17925/RMD.2023.2.1.17

23. Nasonov E.L., Lila A.M. Janus kinase inhibitors in immuno-inflammatory rheumatic diseases: new opportunities and prospects. Rheumatology Science and Practice. 2019;57(1):8–16. (In Russ.). DOI: 10.14412/1995-4484-2019-8-16 EDN: MMBSNH

24. Ridker P.M., Devalaraja M., Baeres F.M.M., et al.; RESCUE Investigators. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2021;397(10289):2060–2069. DOI: 10.1016/S0140-6736(21)00520-1

25. Ridker P.M., Baeres F.M.M., Hveplund A., et al. Rationale, Design, and Baseline Clinical Characteristics of the Ziltivekimab Cardiovascular Outcomes Trial: Interleukin-6 Inhibition and Atherosclerotic Event Rate Reduction. JAMA Cardiol. 2026;11(1):89–97. DOI: 10.1001/jamacardio.2025.4491

26. Wada Y., Jensen C., Meyer A.S.P., et al. Efficacy and safety of interleukin-6 inhibition with ziltivekimab in patients at high risk of atherosclerotic events in Japan (RESCUE-2): A randomized, double-blind, placebo-controlled, phase 2 trial. J. Cardiol. 2023;82(4):279–285. DOI: 10.1016/j.jjcc.2023.05.006

27. Huse C., Gregersen I., Holme F.A., et al. Role of Interleukin-6 in Atherothrombosis and Myocardial Infarction. Curr. Atheroscler. Rep. 2026;28(1):13. DOI: 10.1007/s11883-025-01387-8

28. Oren O., Small A.M., Libby P. Clonal hematopoiesis and atherosclerosis. J. Clin. Invest. 2024;134(19):e180066. DOI: 10.1172/JCI180066

29. Sikking M.A., Stroeks S.L.V.M., Waring O.J., et al. Clonal Hematopoiesis of Indeterminate Potential From a Heart Failure Specialist's Point of View. J. Am. Heart Assoc. 2023;12(15):e030603. DOI: 10.1161/JAHA.123.030603

30. Knopp T., Jung R., Wild J., et al. Myeloid cell-derived interleukin-6 induces vascular dysfunction and vascular and systemic inflammation. Eur. Heart J. Open. 2024;4(4):oeae046. DOI: 10.1093/ehjopen/oeae046

31. Lin W., Song H., Shen J., et al. Functional role of skeletal muscle-derived interleukin-6 and its effects on lipid metabolism. Front. Physiol. 2023;14:1110926. DOI: 10.3389/fphys.2023.1110926

32. Makris A., Barkas F., Sfikakis P.P., et al. Lipoprotein(a), Interleukin-6 inhibitors, and atherosclerotic cardiovascular disease: Is there an association? Atheroscler. Plus. 2023;54:1–6. DOI: 10.1016/j.athplu.2023.09.001

33. Razavi A.C., Blaha M.J., Sperling L.S., Whelton S.P. Lp(a) and Inflammation in Cardiovascular Disease: On the Horizon for Risk Assessment and Future Therapies. J. Am. Coll. Cardiol. 2025;86(21):2014–2016. DOI: 10.1016/j.jacc.2025.10.013

34. Ferreira J.P., Vasques-Nóvoa F., Neves J.S., et al. Comparison of interleukin-6 and high-sensitivity C-reactive protein for cardiovascular risk assessment: Findings from the MESA study. Atherosclerosis. 2024;390:117461. DOI: 10.1016/j.atherosclerosis.2024.117461

35. Khan M.S., Talha K.M., Maqsood M.H., et al. Interleukin-6 and Cardiovascular Events in Healthy Adults: MESA. JACC Adv. 2024;3(8):101063. DOI: 10.1016/j.jacadv.2024.101063

36. King E.A., Davis J.W., Degner J.F. Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval. PLoS Genet. 2019;15(12):e1008489. DOI: 10.1371/journal.pgen.1008489

37. Minikel E.V., Painter J.L., Dong C.C., Nelson M.R. Refining the impact of genetic evidence on clinical success. Nature. 2024;629(8012):624–629. DOI: 10.1038/s41586-024-07316-0

38. Walsh R., Jurgens S.J., Erdmann J., Bezzina C.R. Genome-wide association studies of cardiovascular disease. Physiol. Rev. 2023;103(3):2039–2055. DOI: 10.1152/physrev.00024.2022

39. deGoma E., Walsh J., Georgakis M.K. Human Genetics Informing Drug Development in Cardiovascular Disease: Interleukin-6 Signaling as a Case Study. Circ. Genom. Precis Med. 2025;18(4):e005103. DOI: 10.1161/CIRCGEN.125.005103

40. Zhang L., Omarov M., Xu L., et al. IL6 genetic perturbation mimicking IL-6 inhibition is associated with lower cardiometabolic risk. Nat. Cardiovasc. Res. 2025;4(9):1172–1186. DOI: 10.1038/s44161-025-00700-7

41. deGoma E., Walsh J., Georgakis M.K. Human Genetics Informing Drug Development in Cardiovascular Disease: Interleukin-6 Signaling as a Case Study. Circ. Genom. Precis. Med. 2025;18(4):e005103. DOI: 10.1161/CIRCGEN.125.005103

42. Zhang L., Omarov M., Xu L., et al. IL6 genetic perturbation mimicking IL-6 inhibition is associated with lower cardiometabolic risk. Nat. Cardiovasc. Res. 2025;4(9):1172–1186. DOI: 10.1038/s44161-025-00700-7

43. Ou G., Cai H., Yao K., et al. Exploring the therapeutic potential of interleukin-6 receptor blockade in cardiovascular disease treatment through Mendelian randomization. Sci. Rep. 2024;14(1):21452. DOI: 10.1038/s41598-024-72195-4

44. Cupido A.J., Asselbergs F.W., Natarajan P.; CHARGE Inflammation Working Group; Ridker P.M., Hovingh G.K., Schmidt A.F. Dissecting the IL-6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R. Br. J. Clin. Pharmacol. 2022;88(6):2875– 2884. DOI: 10.1111/bcp.15191

45. Georgakis M.K., Malik R., Gill D., et al.; INVENT Consortium, CHARGE Inflammation Working Group. Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study. Circ. Genom. Precis. Med. 2020;13(3):e002872. DOI: 10.1161/CIRCGEN.119.002872

46. Pan Z., Cheng J., Yang W., et al. Effect of colchicine on inflammatory markers in patients with coronary artery disease: A meta-analysis of clinical trials. Eur. J. Pharmacol. 2022;927:175068. DOI: 10.1016/j.ejphar.2022.175068

47. Gotzmann M., Henk P., Stervbo U., et al. Empagliflozin Reduces Interleukin-6 Levels in Patients with Heart Failure. J. Clin. Med. 2023;12(13):4458. DOI: 10.3390/jcm12134458

48. Reis A.S.L.D.S., Furtado G.E., Menuchi M.R.T.P., Borges G.F. The Impact of Exercise on Interleukin-6 to Counteract Immunosenescence: Methodological Quality and Overview of Systematic Reviews. Healthcare (Basel). 2024;12(10):954. DOI: 10.3390/healthcare12100954

49. Mendieta G., Ridker P.M., Borlaug B.A., et al. Ziltivekimab in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the ATHENA and HERMES trials. Eur. J. Heart Fail. 2026:xuag153. DOI: 10.1093/ejhf/xuag153

50. Choudhury R.P., Hargreaves R., Chai J., Fisher E.A. Inflammation reprogramming and immunomodulation: Next-generation treatments for atherosclerosis. Cell. Rep. Med. 2025;6(9):102288. DOI: 10.1016/j.xcrm.2025.102288

51. Monaco C., McNamara C.A., Slütter B., et al. International Network of Excellence on Immune Checkpoints in Atherosclerosis: “CHECKPOINT ATHERO”. Immunotherapy for atherosclerosis. Physiol. Rev. 2025;105(4):2141–2230. DOI: 10.1152/physrev.00016.2024

52. Engelen S.E., Robinson A.J.B., Zurke Y.X., Monaco C. Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed? Nat. Rev. Cardiol. 2022;19(8):522–542. DOI: 10.1038/s41569-021-00668-4