The role of inflammation in coronary artery disease’s pathophysiology dates back to more than 100 years ago. By the end of the 18th century, Virchow described atherosclerosis as “endarteritis deformans” for the first time. Since then, many studies at the cellular level have shown that lipid accumulation in blood vessels cannot justify the development and progression of the atherosclerosis process. Today, it is established that metabolic factors in conjunction with the inflammatory process lead to the initiation and progression of atherosclerosis. Still, the interaction of innate and adaptive immune systems for the development of atherosclerosis is not fully understood.
Despite significant progress in cardiovascular disease therapies, patients with cardiovascular disease are at high risk of adverse clinical outcomes. Current treatments have focused on lowering low-density lipoprotein-cholesterol concentration, inhibiting platelet activation and coagulation cascades, controlling blood pressure and glucose levels. None of these FDA-approved therapies have targeted the inflammatory pathways involved in atherosclerosis.
Clinical studies have emerged in the cardiovascular field to target inflammation in the past five years. Canakinumab, a monoclonal antibody targeting interleukin-1β, was one of the first anti-inflammatory medications shown to lower the risk of adverse cardiovascular events. In 2017, Ridker and colleagues1 showed that canakinumab led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering among patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. Two years later, in 2019, Ridker and colleagues2 published the efficacy of low-dose methotrexate to prevent atherosclerotic events. Unlike the Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS), methotrexate-an antimetabolite medication indicated for the treatment of autoimmune diseases and a variety of cancers- not only failed to show any efficacy in lowering adverse cardiovascular events among patients with previous myocardial infarction or multivessel coronary disease but also resulted in elevations in liver enzyme levels, reductions in leukocyte counts, hematocrit levels, and a higher incidence of non–basal-cell skin cancers than placebo. The negative result implies the need for explicitly targeting the inflammatory pathways directly involved in atherosclerosis. In 2020, 2 studies evaluated the efficacy of colchicine in reducing atherosclerotic events. Both studies3, 4 showed that patients with chronic coronary artery disease who received colchicine 0.5mg daily had a lower risk of cardiovascular events compared who received placebo. Lastly, a double-blind, randomized, placebo-controlled phase 2 trial5 evaluated the efficacy of ziltivekimab-a human monoclonal IL-6 inhibitor- among chronic kidney disease patients with elevated high-sensitivity CRP. The study showed that ziltivekimab significantly reduced biomarkers of inflammation relevant to atherosclerosis. The study paves the way for conducting a large-scale cardiovascular outcomes trial to investigate the effect of ziltivekimab at high risk of cardiovascular events.
In today’s practice, monoclonal antibodies targeting interleukins are standard therapies in many medicine subspeciality like oncology (many cancers: lymphoma, leukemia), rheumatology (autoimmune disease: rheumatoid arthritis, gout), gastroenterology (Crohn’s disease), and infectious disease (COVID-19 treatment). In the cardiovascular field, although randomized trials are emerging about the efficacy of monoclonal antibodies targeting inflammatory pathways to reduce the cardiovascular risk in patients with atherosclerotic disease, still further evidence is needed. The role of inflammation in atherosclerosis is well-established, and cardiologists may need to better familiarize themselves with inflammatory pathways involved in atherosclerosis since many anti-inflammatory medications will probably be routinely prescribed in the near future to lower the elevated cardiovascular risk.
- Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ and Group CT. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377:1119-1131.
- Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, Mam V, Hasan A, Rosenberg Y, Iturriaga E, Gupta M, Tsigoulis M, Verma S, Clearfield M, Libby P, Goldhaber SZ, Seagle R, Ofori C, Saklayen M, Butman S, Singh N, Le May M, Bertrand O, Johnston J, Paynter NP, Glynn RJ and Investigators C. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. N Engl J Med. 2019;380:752-762.
- Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, Berry C, Lopez-Sendon J, Ostadal P, Koenig W, Angoulvant D, Gregoire JC, Lavoie MA, Dube MP, Rhainds D, Provencher M, Blondeau L, Orfanos A, L’Allier PL, Guertin MC and Roubille F. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381:2497-2505.
- Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, The SHK, Xu XF, Ireland MA, Lenderink T, Latchem D, Hoogslag P, Jerzewski A, Nierop P, Whelan A, Hendriks R, Swart H, Schaap J, Kuijper AFM, van Hessen MWJ, Saklani P, Tan I, Thompson AG, Morton A, Judkins C, Bax WA, Dirksen M, Alings M, Hankey GJ, Budgeon CA, Tijssen JGP, Cornel JH, Thompson PL and LoDoCo2 Trial I. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020;383:1838-1847.
- Ridker PM, Devalaraja M, Baeres FMM, Engelmann MDM, Hovingh GK, Ivkovic M, Lo L, Kling D, Pergola P, Raj D, Libby P, Davidson M and Investigators R. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomized, placebo-controlled, phase 2 trial. Lancet. 2021;397:2060-2069.
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