{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T03:10:00Z","timestamp":1783134600209,"version":"3.54.6"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>The American Heart Association\u2019s Life\u2019s Simple 7 (LS7) is a health metric that captures important factors associated with cardiovascular and cerebrovascular health. Previous studies highlight the potential of plasma metabolites to serve as a marker for lifestyle and health behavior that could be a target for stroke prevention. The objectives of this study were to identify metabolites that were associated with LS7 and incident ischemic stroke and mediate the relationship between the two.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>Targeted metabolomic profiling of 162 metabolites by liquid chromatography\u2013tandem mass spectrometry was used to identify candidate metabolites in a stroke case\u2013cohort nested within the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Weighted linear regression and weighted Cox proportional hazard models were used to identify metabolites that were associated with LS7 and incident ischemic stroke, respectively. Effect measures were based on a 1-SD change in metabolite level. Metabolite mediators were examined using inverse odds ratio weighting mediation analysis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              The study comprised 1075 ischemic stroke cases and 968 participants in the random cohort sample. Three out of 162 metabolites were associated with the overall LS7 score including guanosine (\u03b2, \u22120.46 [95% CI, \u22120.65 to \u22120.27];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =2.87\u00d710\n              <jats:sup>\u22126<\/jats:sup>\n              ), cotinine (\u03b2, \u22120.49 [95% CI, \u22120.70 to \u22120.28];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =7.74\u00d710\n              <jats:sup>\u22126<\/jats:sup>\n              ), and acetylneuraminic acid (\u03b2, \u22120.59 [95% CI, \u22120.77 to \u22120.42];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =4.29\u00d710\n              <jats:sup>\u221211<\/jats:sup>\n              ). Guanosine (hazard ratio, 1.47 [95% CI, 1.31\u20131.65];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =6.97\u00d710\n              <jats:sup>\u221211<\/jats:sup>\n              ), cotinine (hazard ratio, 1.30 [95% CI, 1.16\u20131.44];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =2.09\u00d710\n              <jats:sup>\u22126<\/jats:sup>\n              ), and acetylneuraminic acid (hazard ratio, 1.29 [95% CI, 1.15\u20131.45];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =9.24\u00d710\n              <jats:sup>\u22126<\/jats:sup>\n              ) were associated with incident ischemic stroke. The mediation analysis identified guanosine (27% mediation, indirect effect;\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.002), cotinine (30% mediation, indirect effect;\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.004), and acetylneurminic acid (22% mediation, indirect effect;\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.041) partially mediated the relationship between LS7 and ischemic stroke.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>We identified guanosine, cotinine, and acetylneuraminic acid that were associated with LS7, incident ischemic stroke, and mediated the relationship between LS7 and ischemic stroke.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.123.044714","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T09:01:00Z","timestamp":1710406860000},"page":"1191-1199","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Plasma Metabolites and Life\u2019s Simple 7 in REGARDS"],"prefix":"10.1161","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3260-491X","authenticated-orcid":true,"given":"Naruchorn","family":"Kijpaisalratana","sequence":"first","affiliation":[{"name":"Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (N.K., Z.A., W.T.K.)."},{"name":"Division of Neurology, Department of Medicine (N.K.), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand."},{"name":"Division of Academic Affairs (N.K.), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0316-4348","authenticated-orcid":true,"given":"Zsuzsanna","family":"Ament","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (N.K., Z.A., W.T.K.)."},{"name":"Department of Neurology, Massachusetts General Hospital, Boston (Z.A., A.-L.G.G., W.T.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2140-3856","authenticated-orcid":true,"given":"Amit","family":"Patki","sequence":"additional","affiliation":[{"name":"Department of Epidemiology (A.P., A.C.J., C.A.C., M.R.I.), School of Public Health, University of Alabama at Birmingham."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4442-3454","authenticated-orcid":true,"given":"Varun M.","family":"Bhave","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA (V.M.B., W.T.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3827-2426","authenticated-orcid":true,"given":"Alana C.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Epidemiology (A.P., A.C.J., C.A.C., M.R.I.), School of Public Health, University of Alabama at Birmingham."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4568-8609","authenticated-orcid":true,"given":"Catharine A.","family":"Couch","sequence":"additional","affiliation":[{"name":"Department of Epidemiology (A.P., A.C.J., C.A.C., M.R.I.), School of Public Health, University of Alabama at Birmingham."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7036-5203","authenticated-orcid":true,"given":"Ana-Lucia","family":"Garcia Guarniz","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Boston (Z.A., A.-L.G.G., W.T.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7871-6143","authenticated-orcid":true,"given":"Mary","family":"Cushman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington (M.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8614-7190","authenticated-orcid":true,"given":"D. Leann","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Biostatistics (D.L.L., S.E.J.), School of Public Health, University of Alabama at Birmingham."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7594-6587","authenticated-orcid":true,"given":"Suzanne E.","family":"Judd","sequence":"additional","affiliation":[{"name":"Department of Biostatistics (D.L.L., S.E.J.), School of Public Health, University of Alabama at Birmingham."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Ryan","family":"Irvin","sequence":"additional","affiliation":[{"name":"Department of Epidemiology (A.P., A.C.J., C.A.C., M.R.I.), School of Public Health, University of Alabama at Birmingham."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2519-8530","authenticated-orcid":true,"given":"W. Taylor","family":"Kimberly","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (N.K., Z.A., W.T.K.)."},{"name":"Department of Neurology, Massachusetts General Hospital, Boston (Z.A., A.-L.G.G., W.T.K.)."},{"name":"Harvard Medical School, Boston, MA (V.M.B., W.T.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000950"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2021-068208"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001052"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.192703"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.120.016482"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.111.000352"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.122.025703"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.120.030836"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1157"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.5853\/jos.2018.03454"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000200262"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26552"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X231162648"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000207264"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a115471"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.2307\/2336266"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2007.11.008"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.str.20.10.1407"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.13467"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.070722"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000006957"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2022.100654"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12975-020-00862-5"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.92989"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.13698"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12507"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwu278"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0954422410000326"},{"key":"e_1_3_3_30_2","first-page":"423","article-title":"Guanosine induces necrosis of cultured aortic endothelial cells.","volume":"145","author":"Han Z","year":"1994","unstructured":"Han, Z, Wyche, JH. Guanosine induces necrosis of cultured aortic endothelial cells. Am J Pathol. 1994;145:423\u2013427.","journal-title":"Am J Pathol"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1982.235"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2012.00173"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1586\/erc.10.56"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.93.3.552"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.279.2.119"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2020.1869502"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.102989"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12872-020-01690-z"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.121.008459"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2018.03.017"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.004589"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0049-3848(02)00087-7"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.031139"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12975-023-01181-1"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001078"}],"container-title":["Stroke"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/STROKEAHA.123.044714","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T12:05:14Z","timestamp":1751285114000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/STROKEAHA.123.044714"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5]]},"references-count":44,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2024,5]]}},"alternative-id":["10.1161\/STROKEAHA.123.044714"],"URL":"https:\/\/doi.org\/10.1161\/strokeaha.123.044714","relation":{},"ISSN":["0039-2499","1524-4628"],"issn-type":[{"value":"0039-2499","type":"print"},{"value":"1524-4628","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5]]},"assertion":[{"value":"2023-08-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-20","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}