{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T04:48:40Z","timestamp":1767761320172,"version":"3.48.0"},"reference-count":113,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cathet Cardio Intervent"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Cholesterol crystal embolism (CCE) is a systemic thromboinflammatory disorder (the intertwined activation of inflammatory pathways and coagulation cascades) characterized by the embolization of cholesterol crystals (CCs) from atherosclerotic plaques into microvasculature, leading to multiorgan dysfunction. Despite its clinical significance, CCE remains underdiagnosed due to nonspecific presentations and diagnostic challenges. This review synthesizes current evidence on the central role of CC\u2010induced neutrophil extracellular trap (NET) formation in driving endothelial injury, thrombosis, and gastrointestinal cancer progression with a specific focus on gastrointestinal malignancies. Mechanistically, CCs activate the TLR4\/9\u2010NLRP3 inflammasome cascade, triggering IL\u20101\u03b2 release and PAD4\u2010mediated histone citrullination, which culminate in NETosis. These NETs exacerbate vascular damage by promoting endothelial dysfunction, platelet adhesion, and immune evasion. In gastrointestinal cancer (e.g., colorectal, hepatocellular, pancreatic), CCs remodel the tumor microenvironment (TME) by inducing NET\u2010driven immunosuppression, extracellular matrix degradation, and metastatic niche formation. The interplay between CCs, NETs, and inflammation creates a self\u2010perpetuating cycle that worsens atherosclerosis, CCE, and tumor metastasis. Emerging therapeutic strategies targeting this cholesterol\u2010NET\u2010inflammation axis show promise. DNase I and heparin disrupt NET scaffolds, while PAD4 inhibitors (e.g., GSK484) block NET generation. Colchicine demonstrates dual anti\u2010inflammatory and NETosis\u2010inhibitory effects, and lipid\u2010lowering agents (statins, PCSK9 inhibitors) mitigate CC burden. Nanotherapies, such as HDL\u2010mimetic nanoparticles, offer targeted delivery to restore immune surveillance. This review highlights the need for personalized, biomarker\u2010guided therapies to disrupt the pathogenic CC\u2010NET axis proposing an integrated approach to mitigate CC\u2010mediated damage in cardiovascular and gastrointestinal oncologic disease.<\/jats:p>","DOI":"10.1002\/ccd.70325","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T19:18:42Z","timestamp":1763666322000},"page":"326-341","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cholesterol Crystals and Neutrophil Extracellular Traps: Drivers of Thromboinflammation in Atherosclerosis and Gastrointestinal Cancers"],"prefix":"10.1002","volume":"107","author":[{"given":"Yashvi","family":"Pethani","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Oak Hill Hospital Brookville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neha","family":"Pethani","sequence":"additional","affiliation":[{"name":"Department of Dermatology Karmdeep Hospital Ahmedabad Gujarat India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rima","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Pharmacology All India Institute of Medical Sciences (AIIMS) Rajkot Gujarat India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jignesh","family":"Shah","sequence":"additional","affiliation":[{"name":"L J Institute of Pharmacy L J University Ahmedabad Gujarat India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2687-2240","authenticated-orcid":false,"given":"Darshil","family":"Shah","sequence":"additional","affiliation":[{"name":"L J Institute of Pharmacy L J University Ahmedabad Gujarat India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_9_2_1","DOI":"10.1097\/MD.0000000000030769"},{"doi-asserted-by":"publisher","key":"e_1_2_9_3_1","DOI":"10.1016\/j.amjcard.2021.11.039"},{"doi-asserted-by":"publisher","key":"e_1_2_9_4_1","DOI":"10.1007\/978-981-19-0394-6_9"},{"doi-asserted-by":"publisher","key":"e_1_2_9_5_1","DOI":"10.1016\/j.ijcard.2024.131974"},{"issue":"3","key":"e_1_2_9_6_1","first-page":"549","article-title":"Arterial Occlusions Produced by Emboli From Eroded Aortic Atheromatous Plaques","volume":"21","author":"Flory C. M.","year":"1945","journal-title":"American Journal of Pathology"},{"doi-asserted-by":"publisher","key":"e_1_2_9_7_1","DOI":"10.1007\/s12024-024-00917-1"},{"doi-asserted-by":"publisher","key":"e_1_2_9_8_1","DOI":"10.1097\/TXD.0000000000001158"},{"doi-asserted-by":"publisher","key":"e_1_2_9_9_1","DOI":"10.1038\/s41569-021-00542-3"},{"doi-asserted-by":"publisher","key":"e_1_2_9_10_1","DOI":"10.1096\/fj.202301316R"},{"issue":"10","key":"e_1_2_9_11_1","article-title":"Cutaneous Dermatologic Manifestations of Cardiovascular Diseases: A Narrative Review","volume":"16","author":"Kaye A. D.","year":"2024","journal-title":"Cureus"},{"doi-asserted-by":"publisher","key":"e_1_2_9_12_1","DOI":"10.1016\/j.ensci.2021.100388"},{"doi-asserted-by":"publisher","key":"e_1_2_9_13_1","DOI":"10.1093\/rheumatology\/keaa495"},{"doi-asserted-by":"publisher","key":"e_1_2_9_14_1","DOI":"10.1111\/joic.12483"},{"doi-asserted-by":"publisher","key":"e_1_2_9_15_1","DOI":"10.1093\/eurheartj\/ehad655.1277"},{"doi-asserted-by":"publisher","key":"e_1_2_9_16_1","DOI":"10.1371\/journal.pone.0289743"},{"issue":"2","key":"e_1_2_9_17_1","article-title":"Progressive Cutaneous Cholesterol Emboli Syndrome","volume":"17","author":"Szumel E. S.","year":"2025","journal-title":"Cureus"},{"doi-asserted-by":"publisher","key":"e_1_2_9_18_1","DOI":"10.3389\/fcvm.2022.905363"},{"doi-asserted-by":"publisher","key":"e_1_2_9_19_1","DOI":"10.3390\/biomedicines10081850"},{"doi-asserted-by":"publisher","key":"e_1_2_9_20_1","DOI":"10.2478\/rrlm-2025-0008"},{"doi-asserted-by":"publisher","key":"e_1_2_9_21_1","DOI":"10.1097\/HC9.0000000000000513"},{"doi-asserted-by":"publisher","key":"e_1_2_9_22_1","DOI":"10.1177\/00033197211040375"},{"issue":"2","key":"e_1_2_9_23_1","first-page":"205","article-title":"Rare Cause of Acute Kidney Injury Following Coronary Angiography: Cholesterol Crystal Embolus","volume":"10","author":"Memi\u015f S.","year":"2025","journal-title":"Bagcilar Medical Bulletin"},{"doi-asserted-by":"publisher","key":"e_1_2_9_24_1","DOI":"10.1177\/15347346211058590"},{"doi-asserted-by":"publisher","key":"e_1_2_9_25_1","DOI":"10.2169\/internalmedicine.3469-24"},{"doi-asserted-by":"publisher","key":"e_1_2_9_26_1","DOI":"10.1007\/s10072-024-07973-z"},{"doi-asserted-by":"publisher","key":"e_1_2_9_27_1","DOI":"10.1111\/1744-9987.13706"},{"doi-asserted-by":"publisher","key":"e_1_2_9_28_1","DOI":"10.1177\/23969873241274213"},{"doi-asserted-by":"publisher","key":"e_1_2_9_29_1","DOI":"10.1038\/s41467-017-01186-z"},{"doi-asserted-by":"publisher","key":"e_1_2_9_30_1","DOI":"10.1080\/10520295.2022.2036813"},{"doi-asserted-by":"publisher","key":"e_1_2_9_31_1","DOI":"10.1080\/1744666X.2021.1937129"},{"doi-asserted-by":"publisher","key":"e_1_2_9_32_1","DOI":"10.1146\/annurev-pharmtox-031023-125300"},{"doi-asserted-by":"publisher","key":"e_1_2_9_33_1","DOI":"10.5551\/jat.RV22033"},{"doi-asserted-by":"publisher","key":"e_1_2_9_34_1","DOI":"10.1161\/CIRCRESAHA.119.315625"},{"doi-asserted-by":"publisher","key":"e_1_2_9_35_1","DOI":"10.1016\/j.jlr.2024.100534"},{"doi-asserted-by":"publisher","key":"e_1_2_9_36_1","DOI":"10.3389\/fimmu.2022.1028953"},{"doi-asserted-by":"publisher","key":"e_1_2_9_37_1","DOI":"10.1007\/978-3-031-41192-2_14"},{"doi-asserted-by":"publisher","key":"e_1_2_9_38_1","DOI":"10.1016\/j.lfs.2023.121867"},{"doi-asserted-by":"publisher","key":"e_1_2_9_39_1","DOI":"10.1177\/15353702231184217"},{"doi-asserted-by":"publisher","key":"e_1_2_9_40_1","DOI":"10.1007\/s11010-024-04931-3"},{"doi-asserted-by":"publisher","key":"e_1_2_9_41_1","DOI":"10.2147\/JIR.S507330"},{"doi-asserted-by":"publisher","key":"e_1_2_9_42_1","DOI":"10.1093\/cvr\/cvac189"},{"doi-asserted-by":"publisher","key":"e_1_2_9_43_1","DOI":"10.1097\/SLA.0000000000006196"},{"doi-asserted-by":"publisher","key":"e_1_2_9_44_1","DOI":"10.1186\/s12950-024-00423-9"},{"doi-asserted-by":"publisher","key":"e_1_2_9_45_1","DOI":"10.2147\/JIR.S460333"},{"doi-asserted-by":"publisher","key":"e_1_2_9_46_1","DOI":"10.1186\/s10020-024-00809-8"},{"doi-asserted-by":"publisher","key":"e_1_2_9_47_1","DOI":"10.3390\/jcdd11030072"},{"doi-asserted-by":"publisher","key":"e_1_2_9_48_1","DOI":"10.3390\/gucdd3020007"},{"doi-asserted-by":"publisher","key":"e_1_2_9_49_1","DOI":"10.1016\/j.ahjo.2025.100507"},{"doi-asserted-by":"publisher","key":"e_1_2_9_50_1","DOI":"10.1016\/j.heliyon.2024.e39425"},{"doi-asserted-by":"publisher","key":"e_1_2_9_51_1","DOI":"10.1038\/s42255-020-0174-0"},{"doi-asserted-by":"publisher","key":"e_1_2_9_52_1","DOI":"10.1016\/j.biopha.2024.117714"},{"doi-asserted-by":"publisher","key":"e_1_2_9_53_1","DOI":"10.7150\/ijbs.92274"},{"doi-asserted-by":"publisher","key":"e_1_2_9_54_1","DOI":"10.1038\/s44321-023-00015-9"},{"doi-asserted-by":"publisher","key":"e_1_2_9_55_1","DOI":"10.1007\/s12272-023-01473-y"},{"doi-asserted-by":"publisher","key":"e_1_2_9_56_1","DOI":"10.3389\/fonc.2025.1579054"},{"doi-asserted-by":"publisher","key":"e_1_2_9_57_1","DOI":"10.1002\/adma.202310318"},{"doi-asserted-by":"publisher","key":"e_1_2_9_58_1","DOI":"10.3390\/cells8070716"},{"doi-asserted-by":"publisher","key":"e_1_2_9_59_1","DOI":"10.3390\/cells13040337"},{"doi-asserted-by":"publisher","key":"e_1_2_9_60_1","DOI":"10.3390\/ijms21176319"},{"doi-asserted-by":"publisher","key":"e_1_2_9_61_1","DOI":"10.1186\/s12929-023-00964-w"},{"doi-asserted-by":"publisher","key":"e_1_2_9_62_1","DOI":"10.1016\/j.thromres.2021.12.018"},{"doi-asserted-by":"publisher","key":"e_1_2_9_63_1","DOI":"10.1016\/j.atherosclerosis.2019.06.919"},{"doi-asserted-by":"publisher","key":"e_1_2_9_64_1","DOI":"10.1038\/s41598-022-22410-x"},{"doi-asserted-by":"publisher","key":"e_1_2_9_65_1","DOI":"10.1186\/s12951-025-03522-8"},{"doi-asserted-by":"publisher","key":"e_1_2_9_66_1","DOI":"10.3389\/fimmu.2024.1439231"},{"doi-asserted-by":"publisher","key":"e_1_2_9_67_1","DOI":"10.2147\/OTT.S504637"},{"doi-asserted-by":"publisher","key":"e_1_2_9_68_1","DOI":"10.1002\/anie.202412844"},{"doi-asserted-by":"publisher","key":"e_1_2_9_69_1","DOI":"10.1016\/j.biomaterials.2025.123147"},{"doi-asserted-by":"publisher","key":"e_1_2_9_70_1","DOI":"10.3390\/vaccines11020261"},{"doi-asserted-by":"publisher","key":"e_1_2_9_71_1","DOI":"10.2147\/JIR.S526936"},{"doi-asserted-by":"publisher","key":"e_1_2_9_72_1","DOI":"10.1002\/art.43062"},{"doi-asserted-by":"publisher","key":"e_1_2_9_73_1","DOI":"10.1186\/s12951-025-03195-3"},{"doi-asserted-by":"publisher","key":"e_1_2_9_74_1","DOI":"10.1016\/j.biopha.2024.117289"},{"doi-asserted-by":"publisher","key":"e_1_2_9_75_1","DOI":"10.1038\/s41392-024-02027-4"},{"doi-asserted-by":"publisher","key":"e_1_2_9_76_1","DOI":"10.1186\/s12964-024-01563-4"},{"doi-asserted-by":"publisher","key":"e_1_2_9_77_1","DOI":"10.1038\/s41392-024-01933-x"},{"doi-asserted-by":"publisher","key":"e_1_2_9_78_1","DOI":"10.1038\/s41598-024-64710-4"},{"doi-asserted-by":"publisher","key":"e_1_2_9_79_1","DOI":"10.2147\/ITT.S495095"},{"doi-asserted-by":"publisher","key":"e_1_2_9_80_1","DOI":"10.1007\/s13105-024-01058-3"},{"doi-asserted-by":"publisher","key":"e_1_2_9_81_1","DOI":"10.1172\/jci.insight.134796"},{"doi-asserted-by":"publisher","key":"e_1_2_9_82_1","DOI":"10.34133\/bmef.0102"},{"doi-asserted-by":"publisher","key":"e_1_2_9_83_1","DOI":"10.1016\/j.jconrel.2024.01.068"},{"doi-asserted-by":"publisher","key":"e_1_2_9_84_1","DOI":"10.1038\/s41423-025-01286-7"},{"doi-asserted-by":"publisher","key":"e_1_2_9_85_1","DOI":"10.1111\/jth.15313"},{"issue":"10","key":"e_1_2_9_86_1","first-page":"16852","article-title":"High\u2010Dose Atorvastatin and Rosuvastatin Reduce Neutrophil Extracellular Traps\u2010Related Proteins in Coronary Artery Disease: Association With Prothrombotic State","volume":"134","author":"St\u0119pie\u0144 K.","year":"2024","journal-title":"Polish Archives of Internal Medicine"},{"issue":"12","key":"e_1_2_9_87_1","first-page":"1205","article-title":"Neutrophil Extracellular Traps (NETs) in Cardiovascular Diseases: From Molecular Mechanisms to Therapeutic Interventions","volume":"81","author":"Natorska J.","year":"2023","journal-title":"Kardiologia Polska"},{"doi-asserted-by":"publisher","key":"e_1_2_9_88_1","DOI":"10.1055\/s-0043-1777304"},{"doi-asserted-by":"publisher","key":"e_1_2_9_89_1","DOI":"10.1016\/j.actbio.2025.03.032"},{"doi-asserted-by":"publisher","key":"e_1_2_9_90_1","DOI":"10.1038\/s44161-023-00278-y"},{"doi-asserted-by":"publisher","key":"e_1_2_9_91_1","DOI":"10.4103\/1673-5374.380904"},{"doi-asserted-by":"publisher","key":"e_1_2_9_92_1","DOI":"10.1111\/imr.13277"},{"doi-asserted-by":"publisher","key":"e_1_2_9_93_1","DOI":"10.7150\/jca.94669"},{"doi-asserted-by":"publisher","key":"e_1_2_9_94_1","DOI":"10.3390\/ijms25073983"},{"doi-asserted-by":"publisher","key":"e_1_2_9_95_1","DOI":"10.1055\/a-2609-3457"},{"doi-asserted-by":"publisher","key":"e_1_2_9_96_1","DOI":"10.1016\/j.biopha.2024.117310"},{"doi-asserted-by":"publisher","key":"e_1_2_9_97_1","DOI":"10.1161\/ATVBAHA.124.320150"},{"doi-asserted-by":"publisher","key":"e_1_2_9_98_1","DOI":"10.3892\/br.2025.1991"},{"doi-asserted-by":"publisher","key":"e_1_2_9_99_1","DOI":"10.1158\/1535-7163.MCT-19-1020"},{"doi-asserted-by":"publisher","key":"e_1_2_9_100_1","DOI":"10.1038\/s41467-024-53554-1"},{"doi-asserted-by":"publisher","key":"e_1_2_9_101_1","DOI":"10.2147\/IJN.S255546"},{"doi-asserted-by":"publisher","key":"e_1_2_9_102_1","DOI":"10.1016\/j.biopha.2023.115826"},{"doi-asserted-by":"publisher","key":"e_1_2_9_103_1","DOI":"10.1021\/acsnano.3c03390"},{"doi-asserted-by":"publisher","key":"e_1_2_9_104_1","DOI":"10.3390\/ijms26115272"},{"doi-asserted-by":"publisher","key":"e_1_2_9_105_1","DOI":"10.1186\/s40164-025-00670-3"},{"doi-asserted-by":"publisher","key":"e_1_2_9_106_1","DOI":"10.1007\/s10557-022-07326-y"},{"doi-asserted-by":"publisher","key":"e_1_2_9_107_1","DOI":"10.1111\/eci.14326"},{"doi-asserted-by":"publisher","key":"e_1_2_9_108_1","DOI":"10.3389\/fcvm.2024.1345521"},{"doi-asserted-by":"publisher","key":"e_1_2_9_109_1","DOI":"10.1016\/j.jlr.2024.100554"},{"doi-asserted-by":"publisher","key":"e_1_2_9_110_1","DOI":"10.1093\/eurheartj\/ehae554"},{"doi-asserted-by":"publisher","key":"e_1_2_9_111_1","DOI":"10.1016\/j.tips.2024.12.003"},{"doi-asserted-by":"publisher","key":"e_1_2_9_112_1","DOI":"10.3389\/fcvm.2024.1356023"},{"doi-asserted-by":"publisher","key":"e_1_2_9_113_1","DOI":"10.1186\/s12959-023-00559-3"},{"doi-asserted-by":"publisher","key":"e_1_2_9_114_1","DOI":"10.1111\/j.1538-7836.2010.04144.x"}],"container-title":["Catheterization and Cardiovascular Interventions"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ccd.70325","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T04:39:41Z","timestamp":1767760781000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ccd.70325"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,20]]},"references-count":113,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/ccd.70325"],"URL":"https:\/\/doi.org\/10.1002\/ccd.70325","archive":["Portico"],"relation":{},"ISSN":["1522-1946","1522-726X"],"issn-type":[{"type":"print","value":"1522-1946"},{"type":"electronic","value":"1522-726X"}],"subject":[],"published":{"date-parts":[[2025,11,20]]},"assertion":[{"value":"2025-09-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}