{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:26:30Z","timestamp":1788870390707,"version":"build-2803163510"},"reference-count":9,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>The effects of lipid-lowering drug targets on different ischemic stroke subtypes are not fully understood. We aimed to explore the mechanisms by which lipid-lowering drug targets differentially affect the risk of ischemic stroke subtypes and their underlying pathophysiology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>Using a 2-sample Mendelian randomization approach, we assessed the effects of genetically proxied low-density lipoprotein cholesterol (LDL-c) and 3 clinically approved LDL-lowering drugs (HMGCR [3-hydroxy-3-methylglutaryl-CoA reductase], PCSK9 [proprotein convertase subtilisin\/kexin type 9], and NPC1L1 [Niemann-Pick C1-Like 1]) on stroke subtypes and brain imaging biomarkers associated with small vessel stroke (SVS), including white matter hyperintensity volume and perivascular spaces.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>In genome-wide Mendelian randomization analyses, lower genetically predicted LDL-c was significantly associated with a reduced risk of any stroke, ischemic stroke, and large artery stroke, supporting previous findings. Significant associations between genetically predicted LDL-c and cardioembolic stroke, SVS, and biomarkers, perivascular space and white matter hyperintensity volume, were not identified in this study. In drug-target Mendelian randomization analysis, genetically proxied reduced LDL-c through NPC1L1 inhibition was associated with lower odds of perivascular space (odds ratio per 1-mg\/dL decrease, 0.79 [95% CI, 0.67\u20130.93]) and with lower odds of SVS (odds ratio, 0.29 [95% CI, 0.10\u20130.85]).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>This study provides supporting evidence of a potentially protective effect of LDL-c lowering through NPC1L1 inhibition on perivascular space and SVS risk, highlighting novel therapeutic targets for SVS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.123.045297","type":"journal-article","created":{"date-parts":[[2024,4,4]],"date-time":"2024-04-04T05:00:56Z","timestamp":1712206856000},"page":"1676-1679","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["LDL-c Lowering, Ischemic Stroke, and Small Vessel Disease Brain Imaging Biomarkers: A Mendelian Randomization Study"],"prefix":"10.1161","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7591-5684","authenticated-orcid":true,"given":"Marie-Joe","family":"Dib","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia (M.-J.D., J.A.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7700-8102","authenticated-orcid":true,"given":"Loukas","family":"Zagkos","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, United Kingdom (L.Z., D.M., D.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devendra","family":"Meena","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, United Kingdom (L.Z., D.M., D.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Burgess","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit, Department of Population Health Sciences, University of Bristol, United Kingdom (S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9035-5670","authenticated-orcid":true,"given":"Julio A.","family":"Chirinos","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia (M.-J.D., J.A.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7312-7078","authenticated-orcid":true,"given":"Dipender","family":"Gill","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, United Kingdom (L.Z., D.M., 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