{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T13:13:17Z","timestamp":1788441197570,"version":"build-2803163510"},"reference-count":109,"publisher":"IMR Press","issue":"8","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Rev. Cardiovasc. Med."],"abstract":"<jats:p>Atherosclerosis remains the leading cause of global mortality, most commonly manifesting as ischemic heart disease, stroke, and peripheral arterial disease. Although age-adjusted cardiovascular mortality has declined in many developed nations, the global burden of atherosclerotic disease continues to rise due to population aging and growth. This narrative review examines the evolving understanding of atherosclerosis, which has shifted from a predominantly lipid-centric model to a chronic inflammatory disease. Atherosclerosis is initiated by the retention and modification of apolipoprotein B-containing lipoproteins within the arterial wall and propagated by innate and adaptive immune responses, alongside the development of new treatment strategies. Central to this process is activation of the NLRP3 inflammasome and downstream IL-1\u03b2\u2013IL-6 signaling and pyroptotic cell death, which amplify vascular inflammation and promote plaque progression and instability. Clinical evidence demonstrates that targeting inflammation, independent of lipid lowering, reduces cardiovascular events, as exemplified by agents such as canakinumab and colchicine. Consequently, the therapeutic landscape is rapidly evolving, with ongoing efforts to refine cytokine-targeted approaches (e.g., IL-6 inhibition), develop selective NLRP3 inhibitors, and advance innovative modalities including cell-based interventions. These strategies aim to provide more durable, precise, and potentially disease-modifying or even curative approaches. However, challenges related to safety, the high cost of biologic agents, and optimal patient selection have limited widespread implementation. A major barrier remains the lack of sensitive and specific biomarkers to identify patients with active vascular inflammation, complicating trial design and therapeutic targeting. In addition to circulating markers such as high-sensitivity C-reactive protein (hsCRP) and IL-6, emerging insights highlight the liver as a central hub linking inflammation and thrombosis through complement and coagulation pathways, offering potential avenues for developing novel biomarkers. Despite promising advances, clinical translation faces persistent challenges, including increased infection risk, inadequate biomarkers for patient selection, cost constraints, and regulatory and payer requirements for hard clinical endpoints. Precision medicine approaches, drug repurposing, and innovative delivery systems may help accelerate development. Ultimately, the management of atherosclerosis is shifting toward a multifaceted approach that integrates lipid-lowering, inflammation resolution, and genetic correction to achieve durable cardiovascular protection.<\/jats:p>","DOI":"10.31083\/rcm52626","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:17:46Z","timestamp":1788437866000},"source":"Crossref","is-referenced-by-count":0,"title":["Targeting Inflammation in Atherosclerosis: Mechanistic Rationale, Clinical Trials, and Regulatory Considerations"],"prefix":"10.31083","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6011-6959","authenticated-orcid":true,"given":"Lazar","family":"Mandinov","sequence":"first","affiliation":[{"name":"Cardiovascular Therapeutic Area, Parexel, Newton, MA 02466, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6574-7559","authenticated-orcid":true,"given":"Chris A.","family":"Learn","sequence":"additional","affiliation":[{"name":"Cell and Gene & Early Phase Therapeutic Area, Parexel, Raleigh, NC 27609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Nedkoff L, Briffa T, Zemedikun D, Herrington S, Wright FL. Global Trends in Atherosclerotic Cardiovascular Disease. Clinical Therapeutics. 2023; 45: 1087\u20131091.","DOI":"10.1016\/j.clinthera.2023.09.020"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Chong B, Jayabaskaran J, Jauhari SM, Chan SP, Goh R, Kueh MTW, et al. Global burden of cardiovascular diseases: projections from 2025 to 2050. European Journal of Preventive Cardiology. 2025; 32: 1001\u20131015.","DOI":"10.1093\/eurjpc\/zwae281"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Wang W, Hu M, Liu H, Zhang X, Li H, Zhou F, et al. Global Burden of Disease Study 2019 suggests that metabolic risk factors are the leading drivers of the burden of ischemic heart disease. Cell Metabolism. 2021; 33: 1943\u20131956.e2.","DOI":"10.1016\/j.cmet.2021.08.005"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Barquera S, Pedroza-Tob\u00edas A, Medina C, Hern\u00e1ndez-Barrera L, Bibbins-Domingo K, Lozano R, et al. Global Overview of the Epidemiology of Atherosclerotic Cardiovascular Disease. Archives of Medical Research. 2015; 46: 328\u2013338.","DOI":"10.1016\/j.arcmed.2015.06.006"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Imakita M, Yutani C, Strong JP, Sakurai I, Sumiyoshi A, Watanabe T, et al. Second nation-wide study of atherosclerosis in infants, children and young adults in Japan. Atherosclerosis. 2001; 155: 487\u2013497.","DOI":"10.1016\/s0021-9150(00)00595-5"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Nakashima Y, Chen YX, Kinukawa N, Sueishi K. Distributions of diffuse intimal thickening in human arteries: preferential expression in atherosclerosis-prone arteries from an early age. Virchows Archiv: an International Journal of Pathology. 2002; 441: 279\u2013288.","DOI":"10.1007\/s00428-002-0605-1"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Takei H, Strong JP, Yutani C, Malcom GT. Comparison of coronary and aortic atherosclerosis in youth from Japan and the USA. Atherosclerosis. 2005; 180: 171\u2013179.","DOI":"10.1016\/j.atherosclerosis.2004.11.014"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Tanaka K, Masuda J, Imamura T, Sueishi K, Nakashima T, Sakurai I, et al. A nation-wide study of atherosclerosis in infants, children and young adults in Japan. Atherosclerosis. 1988; 72: 143\u2013156.","DOI":"10.1016\/0021-9150(88)90075-5"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Fan J, Watanabe T. Atherosclerosis: Known and unknown. Pathology International. 2022; 72: 151\u2013160.","DOI":"10.1111\/pin.13202"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Steinberg D. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part I. Journal of Lipid Research. 2004; 45: 1583\u20131593.","DOI":"10.1194\/jlr.R400003-JLR200"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Endo A. A gift from nature: the birth of the statins. Nature Medicine. 2008; 14: 1050\u20131052.","DOI":"10.1038\/nm1008-1050"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Carmena R, Duriez P, Fruchart JC. Atherogenic lipoprotein particles in atherosclerosis. Circulation. 2004; 109: III2\u20137.","DOI":"10.1161\/01.CIR.0000131511.50734.44"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Rader DJ, Hovingh GK. HDL and cardiovascular disease. Lancet (London, England). 2014; 384: 618\u2013625.","DOI":"10.1016\/S0140-6736(14)61217-4"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993; 362: 801\u2013809.","DOI":"10.1038\/362801a0"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Fan J, Watanabe T. Inflammatory reactions in the pathogenesis of atherosclerosis. Journal of Atherosclerosis and Thrombosis. 2003; 10: 63\u201371.","DOI":"10.5551\/jat.10.63"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Ross R. Atherosclerosis--an inflammatory disease. The New England Journal of Medicine. 1999; 340: 115\u2013126.","DOI":"10.1056\/NEJM199901143400207"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Hoogeveen RC, Ballantyne CM. Residual Cardiovascular Risk at Low LDL: Remnants, Lipoprotein(a), and Inflammation. Clinical Chemistry. 2021; 67: 143\u2013153.","DOI":"10.1093\/clinchem\/hvaa252"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Di Muro FM, Vogel B, Sartori S, Bay B, Oliva A, Feng Y, et al. Prognostic impact of residual inflammatory and triglyceride risk in statin-treated patients with well-controlled LDL cholesterol and atherosclerotic cardiovascular disease. European Journal of Preventive Cardiology. 2026; 33: 742\u2013751.","DOI":"10.1093\/eurjpc\/zwaf112"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Ridker PM, Bhatt DL, Pradhan AD, Glynn RJ, MacFadyen JG, Nissen SE, et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet (London, England). 2023; 401: 1293\u20131301.","DOI":"10.1016\/S0140-6736(23)00215-5"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Ridker PM. Targeting residual inflammatory risk: The next frontier for atherosclerosis treatment and prevention. Vascular Pharmacology. 2023; 153: 107238.","DOI":"10.1016\/j.vph.2023.107238"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. European Heart Journal. 2017; 38: 2459\u20132472.","DOI":"10.1093\/eurheartj\/ehx144"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"De Oliveira-Gomes D, Joshi PH, Peterson ED, Rohatgi A, Khera A, Navar AM. Apolipoprotein B: Bridging the Gap Between Evidence and Clinical Practice. Circulation. 2024; 150: 62\u201379.","DOI":"10.1161\/CIRCULATIONAHA.124.068885"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Libby P. The changing landscape of atherosclerosis. Nature. 2021; 592: 524\u2013533.","DOI":"10.1038\/s41586-021-03392-8"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Bor\u00e9n J, Chapman MJ, Krauss RM, Packard CJ, Bentzon JF, Binder CJ, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. European Heart Journal. 2020; 41: 2313\u20132330.","DOI":"10.1093\/eurheartj\/ehz962"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Tabas I, Williams KJ, Bor\u00e9n J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007; 116: 1832\u20131844.","DOI":"10.1161\/CIRCULATIONAHA.106.676890"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Pandit R, Yurdagul A. The Atherosclerotic Plaque Microenvironment as a Therapeutic Target. Current Atherosclerosis Reports. 2025; 27: 47.","DOI":"10.1007\/s11883-025-01294-y"},{"key":"ref27","doi-asserted-by":"crossref","unstructured":"O\u00f6rni K, Pentik\u00e4inen MO, Ala-Korpela M, Kovanen PT. Aggregation, fusion, and vesicle formation of modified low density lipoprotein particles: molecular mechanisms and effects on matrix interactions. Journal of Lipid Research. 2000; 41: 1703\u20131714.","DOI":"10.1016\/S0022-2275(20)31964-7"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"O\u00f6rni K, Posio P, Ala-Korpela M, Jauhiainen M, Kovanen PT. Sphingomyelinase induces aggregation and fusion of small very low-density lipoprotein and intermediate-density lipoprotein particles and increases their retention to human arterial proteoglycans. Arteriosclerosis, Thrombosis, and Vascular Biology. 2005; 25: 1678\u20131683.","DOI":"10.1161\/01.ATV.0000168912.42941.60"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Roy CR, Salcedo SP, Gorvel JPE. Pathogen-endoplasmic-reticulum interactions: in through the out door. Nature Reviews. Immunology. 2006; 6: 136\u2013147.","DOI":"10.1038\/nri1775"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proceedings of the National Academy of Sciences of the United States of America. 1995; 92: 3893\u20133897.","DOI":"10.1073\/pnas.92.9.3893"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nature Immunology. 2010; 11: 155\u2013161.","DOI":"10.1038\/ni.1836"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Binder CJ, Papac-Milicevic N, Witztum JL. Innate sensing of oxidation-specific epitopes in health and disease. Nature Reviews. Immunology. 2016; 16: 485\u2013497.","DOI":"10.1038\/nri.2016.63"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"B\u00e4ck M, Yurdagul A Jr, Tabas I, \u00d6\u00f6rni K, Kovanen PT. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nature Reviews. Cardiology. 2019; 16: 389\u2013406.","DOI":"10.1038\/s41569-019-0169-2"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Paulson KE, Zhu SN, Chen M, Nurmohamed S, Jongstra-Bilen J, Cybulsky MI. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circulation Research. 2010; 106: 383\u2013390.","DOI":"10.1161\/CIRCRESAHA.109.210781"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Guarino AJ, Tulenko TN, Wrenn SP. Cholesterol crystal nucleation from enzymatically modified low-density lipoproteins: combined effect of sphingomyelinase and cholesterol esterase. Biochemistry. 2004; 43: 1685\u20131693.","DOI":"10.1021\/bi035747r"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Khan BV, Harrison DG, Olbrych MT, Alexander RW, Medford RM. Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proceedings of the National Academy of Sciences of the United States of America. 1996; 93: 9114\u20139119.","DOI":"10.1073\/pnas.93.17.9114"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Habas K, Shang L. Alterations in intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in human endothelial cells. Tissue & Cell. 2018; 54: 139\u2013143.","DOI":"10.1016\/j.tice.2018.09.002"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Lehti S, Nguyen SD, Belevich I, Vihinen H, Heikkil\u00e4 HM, Soliymani R, et al. Extracellular Lipids Accumulate in Human Carotid Arteries as Distinct Three-Dimensional Structures and Have Proinflammatory Properties. The American Journal of Pathology. 2018; 188: 525\u2013538.","DOI":"10.1016\/j.ajpath.2017.09.019"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Westerterp M, Gautier EL, Ganda A, Molusky MM, Wang W, Fotakis P, et al. Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity. Cell Metabolism. 2017; 25: 1294\u20131304.e6.","DOI":"10.1016\/j.cmet.2017.04.005"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010; 464: 1357\u20131361.","DOI":"10.1038\/nature08938"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"Estruch M, Rajam\u00e4ki K, Sanchez-Quesada JL, Kovanen PT, \u00d6\u00f6rni K, Benitez S, et al. Electronegative LDL induces priming and inflammasome activation leading to IL-1\u03b2 release in human monocytes and macrophages. Biochimica et Biophysica Acta. 2015; 1851: 1442\u20131449.","DOI":"10.1016\/j.bbalip.2015.08.009"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, Carpenter SB, et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nature Immunology. 2013; 14: 812\u2013820.","DOI":"10.1038\/ni.2639"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"Duewell P, Latz E. Assessment and quantification of crystal-induced lysosomal damage. Methods in Molecular Biology (Clifton, N.J.). 2013; 1040: 19\u201327.","DOI":"10.1007\/978-1-62703-523-1_3"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nature Reviews. 2016; 16: 407\u2013420.","DOI":"10.1038\/nri.2016.58"},{"key":"ref45","doi-asserted-by":"publisher","unstructured":"Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014; 510: 92\u2013101.","DOI":"10.1038\/nature13479"},{"key":"ref46","doi-asserted-by":"publisher","unstructured":"de Jong RJ, Paulin N, Lemnitzer P, Viola JR, Winter C, Ferraro B, et al. Protective Aptitude of Annexin A1 in Arterial Neointima Formation in Atherosclerosis-Prone Mice-Brief Report. Arteriosclerosis, Thrombosis, and Vascular Biology. 2017; 37: 312\u2013315.","DOI":"10.1161\/ATVBAHA.116.308744"},{"key":"ref47","doi-asserted-by":"publisher","unstructured":"Falk E, Nakano M, Bentzon JF, Finn AV, Virmani R. Update on acute coronary syndromes: the pathologists' view. European Heart Journal. 2013; 34: 719\u2013728.","DOI":"10.1093\/eurheartj\/ehs411"},{"key":"ref48","doi-asserted-by":"publisher","unstructured":"Foks AC, Lichtman AH, Kuiper J. Treating atherosclerosis with regulatory T cells. Arteriosclerosis, Thrombosis, and Vascular Biology. 2015; 35: 280\u2013287.","DOI":"10.1161\/ATVBAHA.114.303568"},{"key":"ref49","doi-asserted-by":"publisher","unstructured":"Lopategi A, Flores-Costa R, Rius B, L\u00f3pez-Vicario C, Alcaraz-Quiles J, Titos E, et al. Frontline Science: Specialized proresolving lipid mediators inhibit the priming and activation of the macrophage NLRP3 inflammasome. Journal of Leukocyte Biology. 2019; 105: 25\u201336.","DOI":"10.1002\/JLB.3HI0517-206RR"},{"key":"ref50","doi-asserted-by":"publisher","unstructured":"Nathan C, Ding A. Nonresolving inflammation. Cell. 2010; 140: 871\u2013882.","DOI":"10.1016\/j.cell.2010.02.029"},{"key":"ref51","doi-asserted-by":"publisher","unstructured":"Fredman G, Tabas I. Boosting Inflammation Resolution in Atherosclerosis: The Next Frontier for Therapy. The American Journal of Pathology. 2017; 187: 1211\u20131221.","DOI":"10.1016\/j.ajpath.2017.01.018"},{"key":"ref52","doi-asserted-by":"publisher","unstructured":"Czepluch FS, Kuschicke H, Dellas C, Riggert J, Hasenfuss G, Sch\u00e4fer K. Increased proatherogenic monocyte-platelet cross-talk in monocyte subpopulations of patients with stable coronary artery disease. Journal of Internal Medicine. 2014; 275: 144\u2013154.","DOI":"10.1111\/joim.12145"},{"key":"ref53","doi-asserted-by":"publisher","unstructured":"Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013; 38: 792\u2013804.","DOI":"10.1016\/j.immuni.2013.04.004"},{"key":"ref54","doi-asserted-by":"publisher","unstructured":"Allahverdian S, Chehroudi AC, McManus BM, Abraham T, Francis GA. Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. Circulation. 2014; 129: 1551\u20131559.","DOI":"10.1161\/CIRCULATIONAHA.113.005015"},{"key":"ref55","doi-asserted-by":"publisher","unstructured":"Bennett MR, Sinha S, Owens GK. Vascular Smooth Muscle Cells in Atherosclerosis. Circulation Research. 2016; 118: 692\u2013702.","DOI":"10.1161\/CIRCRESAHA.115.306361"},{"key":"ref56","doi-asserted-by":"publisher","unstructured":"B\u00e4ck M, Weber C, Lutgens E. Regulation of atherosclerotic plaque inflammation. Journal of Internal Medicine. 2015; 278: 462\u2013482.","DOI":"10.1111\/joim.12367"},{"key":"ref57","doi-asserted-by":"publisher","unstructured":"Di Gregoli K, Johnson JL. Role of colony-stimulating factors in atherosclerosis. Current Opinion in Lipidology. 2012; 23: 412\u2013421.","DOI":"10.1097\/MOL.0b013e328357ca6e"},{"key":"ref58","doi-asserted-by":"publisher","unstructured":"Ushach I, Zlotnik A. Biological role of granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on cells of the myeloid lineage. Journal of Leukocyte Biology. 2016; 100: 481\u2013489.","DOI":"10.1189\/jlb.3RU0316-144R"},{"key":"ref59","doi-asserted-by":"publisher","unstructured":"St\u00f6ger JL, Gijbels MJJ, van der Velden S, Manca M, van der Loos CM, Biessen EAL, et al. Distribution of macrophage polarization markers in human atherosclerosis. Atherosclerosis. 2012; 225: 461\u2013468.","DOI":"10.1016\/j.atherosclerosis.2012.09.013"},{"key":"ref60","doi-asserted-by":"publisher","unstructured":"Williams JW, Huang LH, Randolph GJ. Cytokine Circuits in Cardiovascular Disease. Immunity. 2019; 50: 941\u2013954.","DOI":"10.1016\/j.immuni.2019.03.007"},{"key":"ref61","doi-asserted-by":"publisher","unstructured":"Ridker PM. From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection. Circulation Research. 2016; 118: 145\u2013156.","DOI":"10.1161\/CIRCRESAHA.115.306656"},{"key":"ref62","doi-asserted-by":"publisher","unstructured":"Henein MY, Vancheri S, Longo G, Vancheri F. The Role of Inflammation in Cardiovascular Disease. International Journal of Molecular Sciences. 2022; 23: 12906.","DOI":"10.3390\/ijms232112906"},{"key":"ref63","doi-asserted-by":"publisher","unstructured":"da Silva RF, Lappalainen J, Lee-Rueckert M, Kovanen PT. Conversion of human M-CSF macrophages into foam cells reduces their proinflammatory responses to classical M1-polarizing activation. Atherosclerosis. 2016; 248: 170\u2013178.","DOI":"10.1016\/j.atherosclerosis.2016.03.012"},{"key":"ref64","doi-asserted-by":"publisher","unstructured":"Kavurma MM, Rayner KJ, Karunakaran D. The walking dead: macrophage inflammation and death in atherosclerosis. Current Opinion in Lipidology. 2017; 28: 91\u201398.","DOI":"10.1097\/MOL.0000000000000394"},{"key":"ref65","doi-asserted-by":"publisher","unstructured":"Sakakura K, Nakano M, Otsuka F, Ladich E, Kolodgie FD, Virmani R. Pathophysiology of atherosclerosis plaque progression. Heart, Lung & Circulation. 2013; 22: 399\u2013411.","DOI":"10.1016\/j.hlc.2013.03.001"},{"key":"ref66","doi-asserted-by":"publisher","unstructured":"Libby P, Tabas I, Fredman G, Fisher EA. Inflammation and its resolution as determinants of acute coronary syndromes. Circulation Research. 2014; 114: 1867\u20131879.","DOI":"10.1161\/CIRCRESAHA.114.302699"},{"key":"ref67","doi-asserted-by":"publisher","unstructured":"Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R. Concept of vulnerable\/unstable plaque. Arteriosclerosis, Thrombosis, and Vascular Biology. 2010; 30: 1282\u20131292.","DOI":"10.1161\/ATVBAHA.108.179739"},{"key":"ref68","doi-asserted-by":"publisher","unstructured":"Sun L, Ma W, Gao W, Xing Y, Chen L, Xia Z, et al. Propofol directly induces caspase-1-dependent macrophage pyroptosis through the NLRP3-ASC inflammasome. Cell Death & Disease. 2019; 10: 542.","DOI":"10.1038\/s41419-019-1761-4"},{"key":"ref69","doi-asserted-by":"publisher","unstructured":"Huang X, Xie M, Wang Y, Lu X, Mei F, Zhang K, et al. Porphyromonas gingivalis aggravates atherosclerotic plaque instability by promoting lipid-laden macrophage necroptosis. Signal Transduction and Targeted Therapy. 2025; 10: 171.","DOI":"10.1038\/s41392-025-02251-6"},{"key":"ref70","doi-asserted-by":"publisher","unstructured":"Ouimet M, Franklin V, Mak E, Liao X, Tabas I, Marcel YL. Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metabolism. 2011; 13: 655\u2013667.","DOI":"10.1016\/j.cmet.2011.03.023"},{"key":"ref71","doi-asserted-by":"publisher","unstructured":"Zeng W, Wu D, Sun Y, Suo Y, Yu Q, Zeng M, et al. The selective NLRP3 inhibitor MCC950 hinders atherosclerosis development by attenuating inflammation and pyroptosis in macrophages. Scientific Reports. 2021; 11: 19305.","DOI":"10.1038\/s41598-021-98437-3"},{"key":"ref72","doi-asserted-by":"publisher","unstructured":"Campana L, Starkey Lewis PJ, Pellicoro A, Aucott RL, Man J, O'Duibhir E, et al. The STAT3-IL-10-IL-6 Pathway Is a Novel Regulator of Macrophage Efferocytosis and Phenotypic Conversion in Sterile Liver Injury. Journal of Immunology (Baltimore, Md.: 1950). 2018; 200: 1169\u20131187.","DOI":"10.4049\/jimmunol.1701247"},{"key":"ref73","doi-asserted-by":"publisher","unstructured":"Fredman G, Hellmann J, Proto JD, Kuriakose G, Colas RA, Dorweiler B, et al. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nature Communications. 2016; 7: 12859.","DOI":"10.1038\/ncomms12859"},{"key":"ref74","doi-asserted-by":"publisher","unstructured":"Cardilo-Reis L, Gruber S, Schreier SM, Drechsler M, Papac-Milicevic N, Weber C, et al. Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype. EMBO Molecular Medicine. 2012; 4: 1072\u20131086.","DOI":"10.1002\/emmm.201201374"},{"key":"ref75","doi-asserted-by":"publisher","unstructured":"Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, et al. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. The New England Journal of Medicine. 2019; 380: 752\u2013762.","DOI":"10.1056\/NEJMoa1809798"},{"key":"ref76","doi-asserted-by":"publisher","unstructured":"O'Donoghue ML, Glaser R, Cavender MA, Aylward PE, Bonaca MP, Budaj A, et al. Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial. JAMA. 2016; 315: 1591\u20131599.","DOI":"10.1001\/jama.2016.3609"},{"key":"ref77","doi-asserted-by":"publisher","unstructured":"Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. The New England Journal of Medicine. 2017; 377: 1119\u20131131.","DOI":"10.1056\/NEJMoa1707914"},{"key":"ref78","doi-asserted-by":"publisher","unstructured":"Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. Journal of the American College of Cardiology. 2013; 61: 404\u2013410.","DOI":"10.1016\/j.jacc.2012.10.027"},{"key":"ref79","doi-asserted-by":"publisher","unstructured":"Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. The New England Journal of Medicine. 2019; 381: 2497\u20132505.","DOI":"10.1056\/NEJMoa1912388"},{"key":"ref80","doi-asserted-by":"publisher","unstructured":"Ruperto N, Brunner HI, Quartier P, Constantin T, Wulffraat N, Horneff G, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. The New England Journal of Medicine. 2012; 367: 2396\u20132406.","DOI":"10.1056\/NEJMoa1205099"},{"key":"ref81","doi-asserted-by":"publisher","unstructured":"Abbate A, Wohlford GF, Del Buono MG, Chiabrando JG, Markley R, Turlington J, et al. Interleukin-1 blockade with anakinra and heart failure following ST-segment elevation myocardial infarction: results from a pooled analysis of the VCUART clinical trials. European Heart Journal. Cardiovascular Pharmacotherapy. 2022; 8: 503\u2013510.","DOI":"10.1093\/ehjcvp\/pvab075"},{"key":"ref82","doi-asserted-by":"publisher","unstructured":"Nelson K, Fuster V, Ridker PM. Low-Dose Colchicine for Secondary Prevention of Coronary Artery Disease: JACC Review Topic of the Week. Journal of the American College of Cardiology. 2023; 82: 648\u2013660.","DOI":"10.1016\/j.jacc.2023.05.055"},{"key":"ref83","doi-asserted-by":"publisher","unstructured":"Ridker PM, Rane M. Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease. Circulation Research. 2021; 128: 1728\u20131746.","DOI":"10.1161\/CIRCRESAHA.121.319077"},{"key":"ref84","doi-asserted-by":"publisher","unstructured":"Cronstein BN, Molad Y, Reibman J, Balakhane E, Levin RI, Weissmann G. Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. The Journal of Clinical Investigation. 1995; 96: 994\u20131002.","DOI":"10.1172\/JCI118147"},{"key":"ref85","doi-asserted-by":"publisher","unstructured":"Martinon F, P\u00e9trilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006; 440: 237\u2013241.","DOI":"10.1038\/nature04516"},{"key":"ref86","doi-asserted-by":"publisher","unstructured":"Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, et al. Colchicine in Patients with Chronic Coronary Disease. The New England Journal of Medicine. 2020; 383: 1838\u20131847.","DOI":"10.1056\/NEJMoa2021372"},{"key":"ref87","doi-asserted-by":"publisher","unstructured":"Samuel M, Tardif JC, Bouabdallaoui N, Khairy P, Dub\u00e9 MP, Blondeau L, et al. Colchicine for Secondary Prevention of Cardiovascular Disease: A Systematic Review and Meta-analysis of Randomized Controlled Trials. The Canadian Journal of Cardiology. 2021; 37: 776\u2013785.","DOI":"10.1016\/j.cjca.2020.10.006"},{"key":"ref88","doi-asserted-by":"publisher","unstructured":"Finocchiaro S, Mazzone PM, Ammirabile N, Bordonaro C, Cusmano C, Cutore L, et al. Anti-inflammatory pharmacotherapy in patients with cardiovascular disease. European Heart Journal. Cardiovascular Pharmacotherapy. 2025; 11: 712\u2013728.","DOI":"10.1093\/ehjcvp\/pvaf058"},{"key":"ref89","doi-asserted-by":"publisher","unstructured":"Ridker PM, Baeres FMM, Hveplund A, Engelmann MMD, Hovingh GK, Lincoff AM, et al. Rationale, Design, and Baseline Clinical Characteristics of the Ziltivekimab Cardiovascular Outcomes Trial: Interleukin-6 Inhibition and Atherosclerotic Event Rate Reduction. JAMA Cardiology. 2026; 11: 89\u201397.","DOI":"10.1001\/jamacardio.2025.4491"},{"key":"ref90","doi-asserted-by":"publisher","unstructured":"Ridker PM, Devalaraja M, Baeres FMM, Engelmann MDM, Hovingh GK, Ivkovic 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 (London, England). 2021; 397: 2060\u20132069.","DOI":"10.1016\/S0140-6736(21)00520-1"},{"key":"ref91","doi-asserted-by":"publisher","unstructured":"Garbers C, Heink S, Korn T, Rose-John S. Interleukin-6: designing specific therapeutics for a complex cytokine. Nature Reviews. Drug Discovery. 2018; 17: 395\u2013412.","DOI":"10.1038\/nrd.2018.45"},{"key":"ref92","doi-asserted-by":"publisher","unstructured":"Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting Interleukin-6 Signaling in Clinic. Immunity. 2019; 50: 1007\u20131023.","DOI":"10.1016\/j.immuni.2019.03.026"},{"key":"ref93","doi-asserted-by":"publisher","unstructured":"Kleveland O, Kunszt G, Bratlie M, Ueland T, Broch K, Holte E, 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. European Heart Journal. 2016; 37: 2406\u20132413.","DOI":"10.1093\/eurheartj\/ehw171"},{"key":"ref94","doi-asserted-by":"publisher","unstructured":"Broch K, Anstensrud AK, Woxholt S, Sharma K, T\u00f8llefsen IM, Bendz B, et al. Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction. Journal of the American College of Cardiology. 2021; 77: 1845\u20131855.","DOI":"10.1016\/j.jacc.2021.02.049"},{"key":"ref95","doi-asserted-by":"publisher","unstructured":"Mandinov L, Mandinova A, Soldi R, Graziani I, Bagala C, Prudovsky I, et al. Interleukin 1: the choreographer for the restenotic ballet. Thrombosis and Haemostasis. 2003; 90: 369\u2013371.","DOI":"10.1160\/TH03-06-0340"},{"key":"ref96","doi-asserted-by":"publisher","unstructured":"Mandinov L, Mandinova A, Kyurkchiev S, Kyurkchiev D, Kehayov I, Kolev V, et al. Copper chelation represses the vascular response to injury. Proceedings of the National Academy of Sciences of the United States of America. 2003; 100: 6700\u20136705.","DOI":"10.1073\/pnas.1231994100"},{"key":"ref97","doi-asserted-by":"publisher","unstructured":"Musolino PL, Rosser SJ, Brittan M, Newby DE, Berry C, Riley PR, et al. Gene therapy in cardiac and vascular diseases: a review of approaches to treat genetic and common cardiovascular diseases with novel gene-based therapeutics. Cardiovascular Research. 2025; 121: 1843\u20131855.","DOI":"10.1093\/cvr\/cvaf109"},{"key":"ref98","doi-asserted-by":"publisher","unstructured":"Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nature Reviews. Drug Discovery. 2018; 17: 688.","DOI":"10.1038\/nrd.2018.149"},{"key":"ref99","doi-asserted-by":"publisher","unstructured":"Brydges SD, Broderick L, McGeough MD, Pena CA, Mueller JL, Hoffman HM. Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies. The Journal of Clinical Investigation. 2013; 123: 4695\u20134705.","DOI":"10.1172\/JCI71543"},{"key":"ref100","doi-asserted-by":"publisher","unstructured":"Kl\u00fcck V, Jansen TLTA, Janssen M, Comarniceanu A, Efd\u00e9 M, Tengesdal IW, et al. Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial. The Lancet. Rheumatology. 2020; 2: e270\u2013e280.","DOI":"10.1016\/s2665-9913(20)30065-5"},{"key":"ref101","doi-asserted-by":"publisher","unstructured":"Kiran S, Rakib A, Singh UP. The NLRP3 Inflammasome Inhibitor Dapansutrile Attenuates Cyclophosphamide-Induced Interstitial Cystitis. Frontiers in Immunology. 2022; 13: 903834.","DOI":"10.3389\/fimmu.2022.903834"},{"key":"ref102","doi-asserted-by":"publisher","unstructured":"Shen DM, Byth KF, Bertheloot D, Braams S, Bradley S, Dean D, et al. Discovery of DFV890, a Potent Sulfonimidamide-Containing NLRP3 Inflammasome Inhibitor. Journal of Medicinal Chemistry. 2025; 68: 5529\u20135550.","DOI":"10.1021\/acs.jmedchem.4c02759"},{"key":"ref103","doi-asserted-by":"publisher","unstructured":"Gatlik E, Mehes B, Voltz E, Sommer U, Tritto E, Lestini G, et al. First-in-human safety, tolerability, and pharmacokinetic results of DFV890, an oral low-molecular-weight NLRP3 inhibitor. Clinical and Translational Science. 2024; 17: e13789.","DOI":"10.1111\/cts.13789"},{"key":"ref104","doi-asserted-by":"publisher","unstructured":"Dhindsa DS, Desai SR, Jin Q, Sandesara PB, Mehta A, Liu C, et al. Circulating progenitor cells and outcomes in patients with coronary artery disease. International Journal of Cardiology. 2023; 373: 7\u201316.","DOI":"10.1016\/j.ijcard.2022.11.047"},{"key":"ref105","doi-asserted-by":"publisher","unstructured":"Pelliccia F, Zimarino M, De Luca G, Viceconte N, Tanzilli G, De Caterina R. Endothelial Progenitor Cells in Coronary Artery Disease: From Bench to Bedside. Stem Cells Translational Medicine. 2022; 11: 451\u2013460.","DOI":"10.1093\/stcltm\/szac010"},{"key":"ref106","doi-asserted-by":"publisher","unstructured":"Vasa M, Fichtlscherer S, Adler K, Aicher A, Martin H, Zeiher AM, et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation. 2001; 103: 2885\u20132890.","DOI":"10.1161\/hc2401.092816"},{"key":"ref107","doi-asserted-by":"publisher","unstructured":"Zheng Y, Zhang X, Wang Z, Zhang R, Wei H, Yan X, et al. MCC950 as a promising candidate for blocking NLRP3 inflammasome activation: A review of preclinical research and future directions. Archiv Der Pharmazie. 2024; 357: e2400459.","DOI":"10.1002\/ardp.202400459"},{"key":"ref108","doi-asserted-by":"publisher","unstructured":"Tibaut M, Caprnda M, Kubatka P, Sinkovi\u010d A, Valentova V, Filipova S, et al. Markers of Atherosclerosis: Part 1 - Serological Markers. Heart, Lung & Circulation. 2019; 28: 667\u2013677.","DOI":"10.1016\/j.hlc.2018.06.1057"},{"key":"ref109","doi-asserted-by":"publisher","unstructured":"Peerschke EI, Yin W, Ghebrehiwet B. Complement activation on platelets: implications for vascular inflammation and thrombosis. Molecular Immunology. 2010; 47: 2170\u20132175.","DOI":"10.1016\/j.molimm.2010.05.009"}],"container-title":["Reviews in Cardiovascular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/RCM\/27\/8\/10.31083\/RCM52626","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:19:03Z","timestamp":1788437943000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/RCM\/27\/8\/10.31083\/RCM52626"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":109,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026]]}},"alternative-id":["S1530-6550(26)03465-0"],"URL":"https:\/\/doi.org\/10.31083\/rcm52626","relation":{},"ISSN":["1530-6550","2153-8174"],"issn-type":[{"value":"1530-6550","type":"print"},{"value":"2153-8174","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]},"article-number":"52626"}}