{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T03:22:05Z","timestamp":1783480925419,"version":"3.55.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"24","license":[{"start":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T00:00:00Z","timestamp":1765843200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2025,12,16]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Atrial fibrillation and other cardiac arrhythmias pose a major public health burden, but prevention remains difficult. We investigated a genetic variant that we found to act like a natural lifelong cardiac sodium channel blockade.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We studied the impact of the Finnish-enriched\n                      <jats:italic toggle=\"yes\">SCN5A<\/jats:italic>\n                      missense variant (rs45620037 [T220I]) on cardiac arrhythmias, associated mortality, and ECG phenotypes in a multicohort observational study with &gt;1 million individuals across 3 cohorts (FinnGen, UK Biobank, and Health 2000).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We identified protective effects of T220I on multiple common cardiac arrhythmias, most notably atrial fibrillation (cause-specific hazard ratio [HR], 0.56 [95% CI, 0.50\u20130.63];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.0001), but also ventricular premature depolarization or ventricular tachycardia, as well as increasing susceptibility to conduction-slowing conditions, such as sick sinus syndrome (mostly in older age groups). Overall, T220I conveyed protection from death resulting from cardiac arrhythmia (HR, 0.65 [95% CI, 0.46\u20130.92];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.015) without a significant effect on overall mortality risk (HR, 0.92;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.27). T220I heterozygosity had similar electrophysiological effects as some pharmacological sodium channel blockers, such as significantly shortening QT intervals (\u22127.49 ms [95% CI, \u221210.07 to \u22124.91] ms;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.0037; n=3188) in the Health 2000 cohort, which we replicated in the UK Biobank (n=66\u2009616). In addition, T220I protected from (left) heart failure and dilated cardiomyopathy. After myocardial infarction, we found that T220I increased mortality risk, consistent with known sodium channel blocker effects, which, however, normalized to baseline 10 to 15 years after myocardial infarction. We found that T220I could lower a high genetic burden (ie, a high polygenic score) for atrial fibrillation to population average.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic toggle=\"yes\">SCN5A<\/jats:italic>\n                      T220I variant, consistent with a previously described weak loss-of-function effect, acted like a genetic proxy for cardiac sodium channel blockade. This enabled us to gain new potentially clinically relevant insights for pharmacological sodium channel blockade, such as after myocardial infarction, which would be too risky to investigate with clinical trials. Our findings may also inspire redesign of cardiac sodium channel blockers.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.075057","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T10:00:11Z","timestamp":1763978411000},"page":"1679-1690","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Leveraging a Genetic Proxy to Investigate the Effects of Lifelong Cardiac Sodium Channel Blockade"],"prefix":"10.1161","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1487-7909","authenticated-orcid":true,"given":"Julian S.","family":"Wanner","sequence":"first","affiliation":[{"name":"Hasso Plattner Institute, Digital Engineering Faculty, University of Potsdam, Germany (J.S.W., M.K., H.O.H.)."},{"name":"Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Finland (J.S.W., J.R., H.O.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maren","family":"Krafft","sequence":"additional","affiliation":[{"name":"Hasso Plattner Institute, Digital Engineering Faculty, University of Potsdam, Germany (J.S.W., M.K., H.O.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teemu","family":"Niiranen","sequence":"additional","affiliation":[{"name":"Population Health Unit, Finnish Institute for Health and Welfare, Helsinki, Finland (T.N.)."},{"name":"Department of Internal Medicine, Turku University Hospital and University of Turku, Finland (T.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic S.","family":"Zimmerman","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure &amp; Arrhythmias, Amsterdam UMC, University of Amsterdam, the Netherlands (D.S.Z., S.J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"FinnGen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2067-0533","authenticated-orcid":true,"given":"Patrick T.","family":"Ellinor","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (P.T.E., S.J.J., J.R.)."},{"name":"Division of Cardiology, Heart and Vascular Institute, Mass General Brigham, Boston, MA (P.T.E., S.J.J., J.R)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6319-4314","authenticated-orcid":true,"given":"Girish","family":"Nadkarni","sequence":"additional","affiliation":[{"name":"Hasso Plattner Institute for Digital Health at Mount Sinai, Mount Sinai School of Medicine, New York, NY (G.N., H.O.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1605-9782","authenticated-orcid":true,"given":"Sean J.","family":"Jurgens","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (P.T.E., S.J.J., J.R.)."},{"name":"Division of Cardiology, Heart and Vascular Institute, Mass General Brigham, Boston, MA (P.T.E., S.J.J., J.R)."},{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure &amp; Arrhythmias, Amsterdam UMC, University of Amsterdam, the Netherlands (D.S.Z., S.J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6429-5149","authenticated-orcid":true,"given":"Joel","family":"R\u00e4m\u00f6","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Finland (J.S.W., J.R., H.O.H.)."},{"name":"Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (P.T.E., S.J.J., J.R.)."},{"name":"Division of Cardiology, Heart and Vascular Institute, Mass General Brigham, Boston, MA (P.T.E., S.J.J., J.R)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9893-3850","authenticated-orcid":true,"given":"Henrike O.","family":"Heyne","sequence":"additional","affiliation":[{"name":"Hasso Plattner Institute, Digital Engineering Faculty, University of Potsdam, Germany (J.S.W., M.K., H.O.H.)."},{"name":"Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Finland (J.S.W., J.R., H.O.H.)."},{"name":"Hasso Plattner Institute for Digital Health at Mount Sinai, Mount Sinai School of Medicine, New York, NY (G.N., H.O.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/euae195"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2024.1528"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacep.2018.03.006"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-01007-6"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-0188-7"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12551-018-0442-3"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c140069"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90359-3"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2020.05.015"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2013.10.034"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.293.4.447"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.757955"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05420-7"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0579-z"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06045-0"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2010.09.084"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.115.001157"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2014.07.036"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI18062"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010985"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2005.08.043"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1222"},{"key":"e_1_3_3_24_2","unstructured":"National Center for Biotechnology Information National Library of Medicine. ClinVar VCV000009396 (SCN5A:c.659C>T p.Thr220Ile). Accessed November 14 2024. https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/variation\/VCV000009396"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.111.962597"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.101.5.510"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-024-02930-3"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2018.00139"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05473-8"},{"key":"e_1_3_3_30_2","unstructured":"Aromaa A Koskinen S eds. Health and functional capacity in Finland: baseline results of the Health 2000 health examination survey. Helsinki National Public Health Institute. Accessed November 15 2024. https:\/\/www.julkari.fi\/handle\/10024\/78534"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)61602-X"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1542-474x.1997.tb00325.x"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09718-5"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0133-9"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199103213241201"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0800-0"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9149(92)90562-d"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2023.101036"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.035455"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-34893-9_2"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/joa3.12097"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0708789"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa021328"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2019422"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.125.075057","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T18:00:25Z","timestamp":1773079225000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.125.075057"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,16]]},"references-count":43,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2025,12,16]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.125.075057"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.125.075057","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,16]]},"assertion":[{"value":"2025-04-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}