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Following recognition of innate immune pathways leading from the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome to IL-1 to IL-6 and on to the hepatically derived clinical biomarker CRP (C-reactive protein), an expanding literature has led to understanding of the proatherogenic role for IL-6 in cardiovascular disease and thus the potential for IL-6 inhibition as a novel method for vascular protection. In this review, we provide an overview of the mechanisms by which IL-6 signaling occurs and how that impacts upon pharmacological inhibition; describe murine models of IL-6 and atherogenesis; summarize human epidemiological data outlining the utility of IL-6 as a biomarker of vascular risk; outline genetic data suggesting a causal role for IL-6 in systemic atherothrombosis and aneurysm formation; and then detail the potential role of IL-6 inhibition in stable coronary disease, acute coronary syndromes, heart failure, and the atherothrombotic complications associated with chronic kidney disease and end-stage renal failure. Finally, we review anti-inflammatory and antithrombotic findings for ziltivekimab, a novel IL-6 ligand inhibitor being developed specifically for use in atherosclerotic disease and poised to be tested formally in a large-scale cardiovascular outcomes trial focused on individuals with chronic kidney disease and elevated levels of CRP, a population at high residual atherothrombotic risk, high residual inflammatory risk, and considerable unmet clinical need.<\/jats:p>","DOI":"10.1161\/circresaha.121.319077","type":"journal-article","created":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T05:01:48Z","timestamp":1621227708000},"page":"1728-1746","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":682,"title":["Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease"],"prefix":"10.1161","volume":"128","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1249-4522","authenticated-orcid":true,"given":"Paul M.","family":"Ridker","sequence":"first","affiliation":[{"name":"Department of Medicine, Center for Cardiovascular Disease Prevention, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manas","family":"Rane","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Cardiovascular Disease Prevention, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.313129"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0b013e32834ad504"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11883-017-0660-3"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306656"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz283"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707914"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehy310"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1809798"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1912388"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2021372"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/CRD.0000000000000021"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2018.02.062"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2021.02.060"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0008-8749(89)90095-6"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI114498"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2018.45"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2011.01.034"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3632"},{"key":"e_1_3_3_20_2","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1385\/1-59259-405-0:213","volume-title":"In: Cytokine Knockouts. 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