{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:40:18Z","timestamp":1789778418429,"version":"4.0.1"},"reference-count":19,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Coagulation factor XI (FXI) is a promising therapeutic target for preventing thromboembolic disease while preserving hemostasis. However, recent translational and epidemiological findings have raised concerns that lowering FXI levels may increase heart failure risk. To clarify these potential risks, we investigated whether lifelong genetically reduced FXI levels were associated with risk of heart failure and imaging correlates of cardiovascular function.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              We used a genome-wide association study of circulating FXI levels in the deCODE cohort (N=35\u2005559) to identify a genetic proxy in the\n              <jats:italic toggle=\"yes\">F11<\/jats:italic>\n              gene for circulating FXI levels. To validate this genetic proxy, we examined its associations with positive control thromboembolic diseases and its mechanistic specificity using cardiovascular risk factors unrelated to coagulation. We then obtained genetic associations for the primary outcome of all-cause heart failure (139\u2005533 cases and 1\u2005568\u2005809 controls) and secondary outcomes of heart failure subtypes (up to 42\u2005081 cases), atrial fibrillation (181\u2005446 cases), and magnetic resonance imaging correlates of cardiovascular function (up to 38\u2005251 participants). We performed Mendelian randomization analyses using the Wald ratio method to estimate the association of a lifelong 1-SD reduction in genetically proxied FXI levels on each outcome.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              We identified an\n              <jats:italic toggle=\"yes\">F11<\/jats:italic>\n              variant that reduced circulating FXI levels by 0.33 SD units (\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;1\u00d710\n              <jats:sup>\u2212200<\/jats:sup>\n              ), conferred protection against venous thromboembolism (odds ratio per 1-SD reduction in FXI levels, 0.61 [95% CI, 0.60\u20130.63];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =1.85\u00d710\n              <jats:sup>\u2212198<\/jats:sup>\n              ), and showed no association with cardiovascular risk factors (\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &gt;0.05). Genetically proxied lower FXI levels were not associated with all-cause heart failure (odds ratio, 0.99 [95% CI, 0.96\u20131.01];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.34), nor with any secondary clinical or radiographic outcomes (all\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &gt;0.05).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Current human genetic evidence does not support an adverse effect of lower FXI levels on heart failure risk or cardiovascular function. Further studies examining the effect of FXI levels on cardiac events and function are warranted.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.125.322971","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T05:00:16Z","timestamp":1750914016000},"page":"1664-1669","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Human Genetic Evidence Does Not Support a Causal Role for Reduced FXI Levels in Heart Failure Pathogenesis\u2014Brief Report"],"prefix":"10.1161","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6924-0641","authenticated-orcid":true,"given":"Iyas","family":"Daghlas","sequence":"first","affiliation":[{"name":"Department of Neurology, University of California San Francisco Weill Institute for Neurosciences, University of California San Francisco (I.D.)."}],"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 (D.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.124.070278"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/strokeaha.124.049808"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-025-01144-z"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn0910"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1017\/pcm.2023.5"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adj1182"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001779"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00978-w"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3190"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01286-7"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05165-3"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.str.24.1.35"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-02064-3"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-02072-3"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15823-7"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01090-3"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.20517\/jca.2022.10"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2018.05.018"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000209431"}],"container-title":["Arteriosclerosis, Thrombosis, and Vascular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/ATVBAHA.125.322971","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T18:00:46Z","timestamp":1756317646000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/ATVBAHA.125.322971"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9]]},"references-count":19,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1161\/ATVBAHA.125.322971"],"URL":"https:\/\/doi.org\/10.1161\/atvbaha.125.322971","relation":{},"ISSN":["1079-5642","1524-4636"],"issn-type":[{"value":"1079-5642","type":"print"},{"value":"1524-4636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9]]},"assertion":[{"value":"2025-04-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}