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REVIEW

Insights into the Role of Inflammation in the Management of Atherosclerosis

, &
Pages 2223-2239 | Received 24 Apr 2022, Accepted 28 Mar 2023, Published online: 24 May 2023

References

  • World Health Organization. Cardiovascular diseases (CVDs). Fact Sheet. World Health Organ. 2021;42:207–216.
  • Libby P, Buring JE, Badimon L, et al. Atherosclerosis. Nat Rev Dis Primers. 2019;5(1):56. doi:10.1038/s41572-019-0106-z
  • Kaptoge S, Di Angelantonio E, Lowe G, et al.; Emerging Risk Factors C. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375(9709):132–140.
  • Bohula EA, Giugliano RP, Cannon CP, et al. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation. 2015;132(13):1224–1233. doi:10.1161/CIRCULATIONAHA.115.018381
  • Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352(1):20–28. doi:10.1056/NEJMoa042378
  • Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–1131. doi:10.1056/NEJMoa1707914
  • Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020;383(19):1838–1847. doi:10.1056/NEJMoa2021372
  • Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381(26):2497–2505. doi:10.1056/NEJMoa1912388
  • Gistera A, Hansson GK. The immunology of atherosclerosis. Nat Rev Nephrol. 2017;13(6):368–380. doi:10.1038/nrneph.2017.51
  • Haley NJ, Shio H, Fowler S. Characterization of lipid-laden aortic cells from cholesterol-fed rabbits. I. Resolution of aortic cell populations by metrizamide density gradient centrifugation. Lab Invest. 1977;37(3):287–296.
  • Robbins CS, Hilgendorf I, Weber GF, et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med. 2013;19(9):1166–1172. doi:10.1038/nm.3258
  • Goldstein JL, Ho YK, Basu SK, Brown MS. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci U S A. 1979;76(1):333–337. doi:10.1073/pnas.76.1.333
  • Bennett MR, Sinha S, Owens GK. Vascular smooth muscle cells in atherosclerosis. Circ Res. 2016;118(4):692–702. doi:10.1161/CIRCRESAHA.115.306361
  • Barrett TJ. Macrophages in atherosclerosis regression. Arterioscler Thromb Vasc Biol. 2020;40(1):20–33. doi:10.1161/ATVBAHA.119.312802
  • Back M, Yurdagul A Jr, Tabas I, Oorni K, Kovanen PT. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol. 2019;16(7):389–406. doi:10.1038/s41569-019-0169-2
  • Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787–795. doi:10.1172/JCI59643
  • Murray PJ, Allen JE, Biswas SK, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14–20. doi:10.1016/j.immuni.2014.06.008
  • Chistiakov DA, Bobryshev YV, Nikiforov NG, Elizova NV, Sobenin IA, Orekhov AN. Macrophage phenotypic plasticity in atherosclerosis: the associated features and the peculiarities of the expression of inflammatory genes. Int J Cardiol. 2015;184:436–445. doi:10.1016/j.ijcard.2015.03.055
  • de Gaetano M, Crean D, Barry M, Belton O. M1- and M2-type macrophage responses are predictive of adverse outcomes in human atherosclerosis. Front Immunol. 2016;7:275. doi:10.3389/fimmu.2016.00275
  • Stoger JL, Gijbels MJ, van der Velden S, et al. Distribution of macrophage polarization markers in human atherosclerosis. Atherosclerosis. 2012;225(2):461–468. doi:10.1016/j.atherosclerosis.2012.09.013
  • Williams JW, Giannarelli C, Rahman A, Randolph GJ, Kovacic JC. Macrophage biology, classification, and phenotype in cardiovascular disease: JACC macrophage in CVD series (part 1). J Am Coll Cardiol. 2018;72(18):2166–2180. doi:10.1016/j.jacc.2018.08.2148
  • Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464(7293):1357–1361. doi:10.1038/nature08938
  • Rajamaki K, Lappalainen J, Oorni K, et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One. 2010;5(7):e11765. doi:10.1371/journal.pone.0011765
  • Loppnow H, Libby P. Proliferating or interleukin 1-activated human vascular smooth muscle cells secrete copious interleukin 6. J Clin Invest. 1990;85(3):731–738. doi:10.1172/JCI114498
  • Ridker PM. From CANTOS to CIRT to COLCOT to clinic: will all atherosclerosis patients soon be treated with combination lipid-lowering and inflammation-inhibiting agents? Circulation. 2020;141(10):787–789. doi:10.1161/CIRCULATIONAHA.119.045256
  • Saigusa R, Winkels H, Ley K. T cell subsets and functions in atherosclerosis. Nat Rev Cardiol. 2020;17(7):387–401. doi:10.1038/s41569-020-0352-5
  • Libby P. The changing landscape of atherosclerosis. Nature. 2021;592(7855):524–533. doi:10.1038/s41586-021-03392-8
  • Partida RA, Libby P, Crea F, Jang IK. Plaque erosion: a new in vivo diagnosis and a potential major shift in the management of patients with acute coronary syndromes. Eur Heart J. 2018;39(22):2070–2076. doi:10.1093/eurheartj/ehx786
  • Kolte D, Libby P, Jang IK. New insights into plaque erosion as a mechanism of acute coronary syndromes. JAMA. 2021;325(11):1043–1044. doi:10.1001/jama.2021.0069
  • Fulcher J, O’Connell R, Voysey M, et al.; Cholesterol Treatment Trialists C. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet. 2015;385(9976):1397–1405.
  • Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the Jupiter trial. Lancet. 2009;373(9670):1175–1182. doi:10.1016/S0140-6736(09)60447-5
  • Soehnlein O, Libby P. Targeting inflammation in atherosclerosis - from experimental insights to the clinic. Nat Rev Drug Discov. 2021;20(8):589–610. doi:10.1038/s41573-021-00198-1
  • Scheffer DDL, Latini A. Exercise-induced immune system response: anti-inflammatory status on peripheral and central organs. Biochim Biophys Acta Mol Basis Dis. 2020;1866(10):165823. doi:10.1016/j.bbadis.2020.165823
  • Noz MP, Hartman YAW, Hopman MTE, et al. Sixteen-week physical activity intervention in subjects with increased cardiometabolic risk shifts innate immune function towards a less proinflammatory state. J Am Heart Assoc. 2019;8(21):e013764. doi:10.1161/JAHA.119.013764
  • Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest. 2017;127(1):1–4. doi:10.1172/JCI92035
  • Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract. 2014;105(2):141–150. doi:10.1016/j.diabres.2014.04.006
  • Kojta I, Chacinska M, Blachnio-Zabielska A. Obesity, bioactive lipids, and adipose tissue inflammation in insulin resistance. Nutrients. 2020;12(5):1305. doi:10.3390/nu12051305
  • Kraus WE, Bhapkar M, Huffman KM, et al. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinol. 2019;7(9):673–683. doi:10.1016/S2213-8587(19)30151-2
  • Esposito K, Pontillo A, Di Palo C, et al. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA. 2003;289(14):1799–1804. doi:10.1001/jama.289.14.1799
  • Jha P, Peto R. Global effects of smoking, of quitting, and of taxing tobacco. N Engl J Med. 2014;370(1):60–68. doi:10.1056/NEJMra1308383
  • Darabseh MZ, Maden-Wilkinson TM, Welbourne G, et al. Fourteen days of smoking cessation improves muscle fatigue resistance and reverses markers of systemic inflammation. Sci Rep. 2021;11(1):12286. doi:10.1038/s41598-021-91510-x
  • Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA. 2004;292(12):1440–1446. doi:10.1001/jama.292.12.1440
  • Rallidis LS, Lekakis J, Kolomvotsou A, et al. Close adherence to a Mediterranean diet improves endothelial function in subjects with abdominal obesity. Am J Clin Nutr. 2009;90(2):263–268. doi:10.3945/ajcn.2008.27290
  • Galland L. Diet and inflammation. Nutr Clin Pract. 2010;25(6):634–640. doi:10.1177/0884533610385703
  • Ortega-Paz L, Capodanno D, Angiolillo DJ. Canakinumab for secondary prevention of coronary artery disease. Future Cardiol. 2021;17(3):427–442. doi:10.2217/fca-2020-0211
  • Ridker PM, Howard CP, Walter V, et al. Effects of interleukin-1beta inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation. 2012;126(23):2739–2748. doi:10.1161/CIRCULATIONAHA.112.122556
  • Nguyen MT, Fernando S, Schwarz N, Tan JT, Bursill CA, Psaltis PJ. Inflammation as a Therapeutic Target in Atherosclerosis. J Clin Med. 2019;8(8):1109. doi:10.3390/jcm8081109
  • Ridker PM, MacFadyen JG, Thuren T, et al. Effect of interleukin-1 beta inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10105):1833–1842. doi:10.1016/S0140-6736(17)32247-X
  • Libby P. Targeting inflammatory pathways in cardiovascular disease: the inflammasome, interleukin-1, interleukin-6 and beyond. Cells. 2021;10(4):951. doi:10.3390/cells10040951
  • Hemenway G, Frishman WH. Therapeutic implications of NLRP3-mediated inflammation in coronary artery disease. Cardiol Rev. 2022;30(2):90–99. doi:10.1097/CRD.0000000000000391
  • Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013;61(4):404–410. doi:10.1016/j.jacc.2012.10.027
  • Tong DC, Quinn S, Nasis A, et al. Colchicine in patients with acute coronary syndrome: the Australian COPS randomized clinical trial. Circulation. 2020;142(20):1890–1900. doi:10.1161/CIRCULATIONAHA.120.050771
  • Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis. 2001;60(8):729–735. doi:10.1136/ard.60.8.729
  • Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2019;380(8):752–762. doi:10.1056/NEJMoa1809798
  • Yamamoto-Furusho JK. Inflammatory bowel disease therapy: blockade of cytokines and cytokine signaling pathways. Curr Opin Gastroenterol. 2018;34(4):187–193. doi:10.1097/MOG.0000000000000444
  • Reich K, Papp KA, Blauvelt A, et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. Lancet. 2017;390(10091):276–288. doi:10.1016/S0140-6736(17)31279-5
  • Aaltonen KJ, Virkki LM, Malmivaara A, Konttinen YT, Nordstrom DC, Blom M. Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS One. 2012;7(1):e30275. doi:10.1371/journal.pone.0030275
  • Grebe A, Hoss F, Latz E. NLRP3 inflammasome and the IL-1 pathway in atherosclerosis. Circ Res. 2018;122(12):1722–1740. doi:10.1161/CIRCRESAHA.118.311362
  • Burzynski LC, Humphry M, Pyrillou K, et al. The coagulation and immune systems are directly linked through the activation of interleukin-1 alpha by thrombin. Immunity. 2019;50(4):1033–42 e6. doi:10.1016/j.immuni.2019.03.003
  • Vromman A, Ruvkun V, Shvartz E, et al. Stage-dependent differential effects of interleukin-1 isoforms on experimental atherosclerosis. Eur Heart J. 2019;40(30):2482–2491. doi:10.1093/eurheartj/ehz008
  • Galea J, Armstrong J, Gadsdon P, Holden H, Francis SE, Holt CM. Interleukin-1 beta in coronary arteries of patients with ischemic heart disease. Arterioscler Thromb Vasc Biol. 1996;16(8):1000–1006. doi:10.1161/01.ATV.16.8.1000
  • Abbate A, Trankle CR, Buckley LF, et al. Interleukin-1 blockade inhibits the acute inflammatory response in patients with ST-segment-elevation myocardial infarction. J Am Heart Assoc. 2020;9(5):e014941. doi:10.1161/JAHA.119.014941
  • Morton AC, Rothman AM, Greenwood JP, et al. The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study. Eur Heart J. 2015;36(6):377–384. doi:10.1093/eurheartj/ehu272
  • Interleukin 1 Genetics C. Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis. Lancet Diabetes Endocrinol. 2015;3(4):243–253. doi:10.1016/S2213-8587(15)00034-0
  • El Sayed H, Kerensky R, Stecher M, Mohanty P, Davies M. A randomized phase II study of Xilonix, a targeted therapy against interleukin 1 alpha, for the prevention of superficial femoral artery restenosis after percutaneous revascularization. J Vasc Surg. 2016;63(1):133–41 e1. doi:10.1016/j.jvs.2015.08.069
  • Yasukawa H, Ohishi M, Mori H, et al. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol. 2003;4(6):551–556. doi:10.1038/ni938
  • Huber SA, Sakkinen P, Conze D, Hardin N, Tracy R. Interleukin-6 exacerbates early atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 1999;19(10):2364–2367. doi:10.1161/01.ATV.19.10.2364
  • Schieffer B, Selle T, Hilfiker A, et al. Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis. Circulation. 2004;110(22):3493–3500. doi:10.1161/01.CIR.0000148135.08582.97
  • Schuett H, Oestreich R, Waetzig GH, et al. Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2012;32(2):281–290. doi:10.1161/ATVBAHA.111.229435
  • Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000;101(15):1767–1772. doi:10.1161/01.CIR.101.15.1767
  • Swerdlow DI, Holmes MV, Kuchenbaecker KB, et al.; Interleukin-6 Receptor Mendelian Randomisation Analysis C. The interleukin-6 receptor as a target for prevention of coronary heart disease: a Mendelian randomisation analysis. Lancet. 2012;379(9822):1214–1224.
  • Kleveland O, Kunszt G, Bratlie M, et al. Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: a double-blind, randomized, placebo-controlled phase 2 trial. Eur Heart J. 2016;37(30):2406–2413. doi:10.1093/eurheartj/ehw171
  • Broch K, Anstensrud AK, Woxholt S, et al. Randomized trial of interleukin-6 receptor inhibition in patients with acute ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2021;77(15):1845–1855. doi:10.1016/j.jacc.2021.02.049
  • Ridker PM, Devalaraja M, Baeres FMM, et al. 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
  • Ridker PM. From RESCUE to ZEUS: will interleukin-6 inhibition with ziltivekimab prove effective for cardiovascular event reduction? Cardiovasc Res. 2021;117(11):e138–e40. doi:10.1093/cvr/cvab231
  • Tousoulis D, Oikonomou E, Economou EK, Crea F, Kaski JC. Inflammatory cytokines in atherosclerosis: current therapeutic approaches. Eur Heart J. 2016;37(22):1723–1732. doi:10.1093/eurheartj/ehv759
  • Barath P, Fishbein MC, Cao J, Berenson J, Helfant RH, Forrester JS. Detection and localization of tumor necrosis factor in human atheroma. Am J Cardiol. 1990;65(5):297–302. doi:10.1016/0002-9149(90)90291-8
  • Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E. Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation. 2000;101(18):2149–2153. doi:10.1161/01.CIR.101.18.2149
  • Full LE, Monaco C. Targeting inflammation as a therapeutic strategy in accelerated atherosclerosis in rheumatoid arthritis. Cardiovasc Ther. 2011;29(4):231–242. doi:10.1111/j.1755-5922.2010.00159.x
  • Barnabe C, Martin BJ, Ghali WA. Systematic review and meta-analysis: anti-tumor necrosis factor alpha therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care Res. 2011;63(4):522–529. doi:10.1002/acr.20371
  • Roubille C, Richer V, Starnino T, et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74(3):480–489. doi:10.1136/annrheumdis-2014-206624
  • Gonzalez-Juanatey C, Llorca J, Sanchez-Andrade A, Garcia-Porrua C, Martin J, Gonzalez-Gay MA. Short-term Adalimumab therapy improves endo-thelial function in patients with rheumatoid arthritis refractory to infliximab. Clin Exp Rheumatol. 2006;24(3):309–312.
  • Gonzalez-Juanatey C, Vazquez-Rodriguez TR, Miranda-Filloy JA, et al. Anti-TNF-alpha-Adalimumab therapy is associated with persistent improvement of endothelial function without progression of carotid intima-media wall thickness in patients with rheumatoid arthritis refractory to conventional therapy. Mediators Inflamm. 2012;2012:674265. doi:10.1155/2012/674265
  • Bissonnette R, Harel F, Krueger JG, et al. TNF-alpha antagonist and vascular inflammation in patients with psoriasis vulgaris: a randomized placebo-controlled study. J Invest Dermatol. 2017;137(8):1638–1645. doi:10.1016/j.jid.2017.02.977
  • Tam LS, Shang Q, Kun EW, et al. The effects of golimumab on subclinical atherosclerosis and arterial stiffness in ankylosing spondylitis-a randomized, placebo-controlled pilot trial. Rheumatology. 2014;53(6):1065–1074. doi:10.1093/rheumatology/ket469
  • Huang R, Zhao SR, Li Y, et al. Association of tumor necrosis factor-alpha gene polymorphisms and coronary artery disease susceptibility: a systematic review and meta-analysis. BMC Med Genet. 2020;21(1):29. doi:10.1186/s12881-020-0952-2
  • Hassan S, Milman U, Feld J, et al. Effects of anti-TNF-alpha treatment on lipid profile in rheumatic diseases: an analytical cohort study. Arthritis Res Ther. 2016;18(1):261. doi:10.1186/s13075-016-1148-1
  • Schrezenmeier E, Dorner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;16(3):155–166. doi:10.1038/s41584-020-0372-x
  • Sharma TS, Wasko MC, Tang X, et al. Hydroxychloroquine use is associated with decreased incident cardiovascular events in rheumatoid arthritis patients. J Am Heart Assoc. 2016;5(1). doi:10.1161/JAHA.115.002867
  • Hartman O, Kovanen PT, Lehtonen J, Eklund KK, Sinisalo J. Hydroxychloroquine for the prevention of recurrent cardiovascular events in myocardial infarction patients: rationale and design of the OXI trial. Eur Heart J Cardiovasc Pharmacother. 2017;3(2):92–97. doi:10.1093/ehjcvp/pvw035
  • Coll RC, Robertson AA, Chae JJ, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21(3):248–255. doi:10.1038/nm.3806
  • van der Heijden T, Kritikou E, Venema W, et al. NLRP3 inflammasome inhibition by MCC950 reduces atherosclerotic lesion development in apolipoprotein E-deficient mice-brief report. Arterioscler Thromb Vasc Biol. 2017;37(8):1457–1461. doi:10.1161/ATVBAHA.117.309575
  • Zhuang T, Li S, Yi X, et al. Tranilast directly targets NLRP3 to protect melanocytes from keratinocyte-derived IL-1beta under oxidative stress. Front Cell Dev Biol. 2020;8:588. doi:10.3389/fcell.2020.00588
  • Chen S, Wang Y, Pan Y, et al. Novel role for tranilast in regulating NLRP3 ubiquitination, vascular inflammation, and atherosclerosis. J Am Heart Assoc. 2020;9(12):e015513. doi:10.1161/JAHA.119.015513
  • Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 2012;12(3):180–190. doi:10.1038/nri3156
  • Lu LF, Rudensky A. Molecular orchestration of differentiation and function of regulatory T cells. Genes Dev. 2009;23(11):1270–1282. doi:10.1101/gad.1791009
  • Klatzmann D, Abbas AK. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol. 2015;15(5):283–294. doi:10.1038/nri3823
  • Proto JD, Doran AC, Gusarova G, et al. Regulatory T cells promote macrophage efferocytosis during inflammation resolution. Immunity. 2018;49(4):666–77 e6. doi:10.1016/j.immuni.2018.07.015
  • Zhao RSS TX, Lu Y, Hubsch A, et al. Low dose interleukin-2 in patients with stable ischaemic heart disease and acute coronary syndrome (LILACS). Eur Heart J. 2020;41(Issue Supplement_2):e022452.
  • Wolf D, Gerhardt T, Winkels H, et al. Pathogenic autoimmunity in atherosclerosis evolves from initially protective apolipoprotein B100-reactive CD4(+) T-regulatory cells. Circulation. 2020;142(13):1279–1293. doi:10.1161/CIRCULATIONAHA.119.042863
  • Netea MG, Joosten LA, Latz E, et al. Trained immunity: a program of innate immune memory in health and disease. Science. 2016;352(6284):aaf1098. doi:10.1126/science.aaf1098
  • Seijkens TTP, van Tiel CM, Kusters PJH, et al. Targeting CD40-induced TRAF6 signaling in macrophages reduces atherosclerosis. J Am Coll Cardiol. 2018;71(5):527–542. doi:10.1016/j.jacc.2017.11.055
  • Kojima Y, Volkmer JP, McKenna K, et al. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature. 2016;536(7614):86–90. doi:10.1038/nature18935
  • Wirka RC, Wagh D, Paik DT, et al. Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis. Nat Med. 2019;25(8):1280–1289. doi:10.1038/s41591-019-0512-5
  • Chen PY, Qin L, Li G, et al. Endothelial TGF-beta signalling drives vascular inflammation and atherosclerosis. Nat Metab. 2019;1(9):912–926. doi:10.1038/s42255-019-0102-3
  • Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42(34):3227–3337. doi:10.1093/eurheartj/ehab484
  • Deftereos SG, Beerkens FJ, Shah B, et al. Colchicine in cardiovascular disease: in-depth review. Circulation. 2022;145(1):61–78. doi:10.1161/CIRCULATIONAHA.121.056171