Modulation of Inflammation in Heart Failure: The Role of Ziltivekimab and Canakinumab
DOI:
https://doi.org/10.12775/JEHS.2024.65.55579Keywords
ziltivekimab, canakinumab, heart failureAbstract
This article examines the role of inflammation in heart failure pathogenesis and explores novel therapeutic strategies targeting inflammatory pathways. The increasing prevalence of heart failure, particularly those with preserved ejection fraction (HFpEF), highlights the urgent demand for effective treatments. Canakinumab, a monoclonal antibody targeting interleukin-1β, has shown promise in reducing cardiovascular events by modulating inflammation, while Ziltivekimab, a newer monoclonal antibody targeting interleukin-6, demonstrates potential in heart failure patients with elevated inflammatory markers. The article reviews clinical trials, including CANTOS and RESCUE, providing evidence of the efficacy of patient outcomes. The findings underscore the importance of personalized treatment strategies on heart failure, with a focus on inflammation-driven pathways, positioning anti-inflammatory therapies as a significant advancement in cardiovascular disease management. Future research will determine the broader clinical applicability of these therapies in managing heart failure, its complications, and fostering more favorable outcomes.
References
Savarese, G. et al. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res 118, 3272–3287 (2023). https://doi.org/10.1093/cvr/cvac013
Murphy, S. P., Kakkar, R., McCarthy, C. P. & Januzzi, J. L. Inflammation in heart failure. J. Am. Coll. Cardiol. 75, 1324–1340 (2020). https://doi.org/10.1016/j.jacc.2020.01.014
Levine, B., Kalman, J., Mayer, L., Fillit, H. M. & Packer, M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N. Engl. J. Med. 323, 236–241 (1990). https://doi.org/10.1056/NEJM199007263230405
Testa, M. et al. Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J. Am. Coll. Cardiol. 28, 964–971 (1996). https://doi.org/10.1016/0735-1097(96)00258-2
Dibbs, Z. et al. Cytokines in heart failure: pathogenetic mechanisms and potential treatment. Proc. Assoc. Am. Physicians 111, 423–428 (1999).
Abbate, A. et al. Interleukin-1 and the inflammasome as therapeutic targets in cardiovascular disease. Circ. Res. 126, 1260–1280 (2020). https://doi.org/10.1161/CIRCRESAHA.120.315936
Li, Y. et al. Current targeting strategies and advanced nanoplatforms for atherosclerosis therapy. J. Drug Target 32, 128–147 (2024). https://doi.org/10.1080/1061186X.2023.2273001
Hafiane, A. & Daskalopoulou, S. S. Targeting the residual cardiovascular risk by specific anti-inflammatory interventions as a therapeutic strategy in atherosclerosis. Pharmacol. Res. 178, 106157 (2022). https://doi.org/10.1016/j.phrs.2022.106157
Anand, I. S. et al. C-reactive protein in heart failure. Circulation 112, 1428–1434 (2005). https://doi.org/10.1161/CIRCULATIONAHA.104.510768
Ridker, P. M. & Rane, M. Interleukin-6 signaling and anti-interleukin-6 therapeutics in cardiovascular disease. Circ. Res. 128, 1728–1746 (2021). https://doi.org/10.1161/CIRCRESAHA.121.319275
Alten, R. et al. The human anti-IL-1β monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis. Arthritis Res. Ther. 10, R67 (2008). https://doi.org/10.1186/ar2432
Lachmann, H. J. et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N. Engl. J. Med. 360, 2416–2425 (2009). https://doi.org/10.1056/NEJMoa0809575
Ruperto, N. et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367, 2396–2406 (2012). https://doi.org/10.1056/NEJMoa1205099
Schlesinger, N. et al. Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Ann. Rheum. Dis. 71, 1839–1848 (2012). https://doi.org/10.1136/annrheumdis-2011-200908
Ridker, P. M. et al. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 397, 2060–2069 (2021). https://doi.org/10.1016/S0140-6736(21)00721-7
Langsted, A., Kamstrup, P. R. & Nordestgaard, B. G. Lipoprotein(a): fasting and nonfasting levels, inflammation, and cardiovascular risk. Atherosclerosis 234, 95–101 (2014). https://doi.org/10.1016/j.atherosclerosis.2014.03.016
Puri, R. et al. Effect of C-reactive protein on lipoprotein(a)-associated cardiovascular risk in optimally treated patients with high-risk vascular disease. JAMA Cardiol. 5, 1136 (2020). https://doi.org/10.1001/jamacardio.2020.3427
Ridker, P. M. Anticytokine agents. Circ. Res. 124, 437–450 (2019). https://doi.org/10.1161/CIRCRESAHA.118.313129
Mooney, L. et al. Adverse outcomes associated with interleukin-6 in patients recently hospitalized for heart failure with preserved ejection fraction. Circ. Heart Fail. 16, (2023). https://doi.org/10.1161/CIRCHEARTFAILURE.122.010576
Dinarello, C. A. The IL-1 family of cytokines and receptors in rheumatic diseases. Nat. Rev. Rheumatol. 15, 612–632 (2019). https://doi.org/10.1038/s41584-019-0277-8
Hanna, A. & Frangogiannis, N. G. Inflammatory cytokines and chemokines as therapeutic targets in heart failure. Cardiovasc. Drugs Ther. 34, 849–863 (2020). https://doi.org/10.1007/s10557-020-06962-8
Van Tassell, B. W., Raleigh, J. M. V. & Abbate, A. Targeting interleukin-1 in heart failure and inflammatory heart disease. Curr. Heart Fail. Rep. 12, 33–41 (2015). https://doi.org/10.1007/s11897-014-0230-4
Frangogiannis, N. Interleukin-1 in cardiac injury, repair, and remodeling: pathophysiologic and translational concepts. Discoveries 3, e41 (2015). https://doi.org/10.15190/d.2015.31
Chai, R. et al. Cardiac remodeling in heart failure: role of pyroptosis and its therapeutic implications. Front. Cardiovasc. Med. 9, (2022). https://doi.org/10.3389/fcvm.2022.875517
Chia, Y. C. et al. Interleukin 6 and development of heart failure with preserved ejection fraction in the general population. J. Am. Heart Assoc. 10, (2021). https://doi.org/10.1161/JAHA.120.021032
Ridker, P. M. et al. Effects of interleukin-1β inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen. Circulation 126, 2739–2748 (2012). https://doi.org/10.1161/CIRCULATIONAHA.112.122556
Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017). https://doi.org/10.1056/NEJMoa1707914
Ridker, P. M. et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 391, 319–328 (2018). https://doi.org/10.1016/S0140-6736(17)32814-3
Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014). https://doi.org/10.1056/NEJMoa1408617
Sano, S. et al. Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome. J. Am. Coll. Cardiol. 71, 875–886 (2018). https://doi.org/10.1016/j.jacc.2017.12.037
Svensson, E. C. et al. TET2-driven clonal hematopoiesis and response to canakinumab. JAMA Cardiol. 7, 521 (2022). https://doi.org/10.1001/jamacardio.2021.5847
Durstenfeld, M. et al. Effect of interleukin 1b inhibition with canakinumab on inflammation and viral persistence in people with human immunodeficiency virus. ESC Congress, Aug 30 – Sept 02, London, UK (2024).
Wada, Y., Jensen, C., Meyer, A. S. P., Zonoozi, A. A. M. & Honda, H. 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. 82, 279–285 (2023). https://doi.org/10.1016/j.jjcc.2023.02.002
Andreotti, F. et al. Anti-inflammatory therapy in ischaemic heart disease: from canakinumab to colchicine. Eur. Heart J. Suppl. 23, E13–E18 (2021). https://doi.org/10.1093/eurheartj/suab014
Zubirán, R., Neufeld, E. B., Dasseux, A., Remaley, A. T. & Sorokin, A. V. Recent advances in targeted management of inflammation in atherosclerosis: a narrative review. Cardiol. Ther. 13, 465–491 (2024). https://doi.org/10.1007/s40119-023-00339-0
Gao, Y. et al. Factors associated with risk analysis for asymptomatic left ventricular diastolic dysfunction in nondialysis patients with chronic kidney disease. Ren. Fail. 46, (2024). https://doi.org/10.1080/0886022X.2023.2261007
Zoccali, C. & Mallamaci, F. Innate immunity system in patients with cardiovascular and kidney disease. Circ. Res. 132, 915–932 (2023). https://doi.org/10.1161/CIRCRESAHA.123.322067
Nowak, K. L. et al. A phase 1 randomized dose-escalation study of a human monoclonal antibody to IL-6 in CKD. Kidney360 2, 224–235 (2021). https://doi.org/10.34067/KID.0006152020
Adamstein, N. H. et al. Association of interleukin 6 inhibition with ziltivekimab and the neutrophil-lymphocyte ratio. JAMA Cardiol. 8, 177 (2023). https://doi.org/10.1001/jamacardio.2022.4743
Wada, Y., Jensen, C., Meyer, S., Yamamoto, Y. & Honda, H. Effects of interleukin-6 inhibition with ziltivekimab in patients at high risk of atherosclerotic events in Japan: results from the phase 2 RESCUE-2 trial. Eur. Heart J. 43, (2022). https://doi.org/10.1093/eurheartj/ehab892
Ridker, P. M. From RESCUE to ZEUS: will interleukin-6 inhibition with ziltivekimab prove effective for cardiovascular event reduction? Cardiovasc. Res. 117, e138–e140 (2021). https://doi.org/10.1093/cvr/cvab226
Bay, B., Arnold, N. & Waldeyer, C. C-reactive protein, pharmacological treatments and diet: how to target your inflammatory burden. Curr. Opin. Lipidol. 35, 141–148 (2024). https://doi.org/10.1097/MOL.0000000000000864
Matter, M. A., Tschaikowsky, T., Stähli, B. E. & Matter, C. M. Acute-on-chronic inflammation in acute myocardial infarction. Curr. Opin. Cardiol. 39, 535–542 (2024). https://doi.org/10.1097/HCO.0000000000001014
Petrie, M. et al. HERMES: Effects of ziltivekimab versus placebo on morbidity and mortality in patients with heart failure with mildly reduced or preserved ejection fraction and systemic inflammation. J. Card. Fail. 30, 126 (2024). https://doi.org/10.1016/j.cardfail.2024.06.018
Boczar, K. E., Beanlands, R., Wells, G. & Coyle, D. Cost-effectiveness of canakinumab from a Canadian perspective for recurrent cardiovascular events. CJC Open 4, 441–448 (2022). https://doi.org/10.1016/j.cjco.2022.01.001
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Copyright (c) 2024 Łukasz Wołowiec, Walery Zukow, Julia Pęcherz, Daria Czaplińska, Albert Jaśniak, Grzegorz Grześk
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