{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T18:58:10Z","timestamp":1791140290615,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              The strongest genetic risk factors for atrial fibrillation (AF) are DNA variants on chromosome 4q25 near the transcription factor gene\n              <jats:italic>PITX2<\/jats:italic>\n              (Pitx2:Paired-like homeodomain transcription factor 2). Mice deficient in\n              <jats:italic>Pitx2<\/jats:italic>\n              (\n              <jats:italic>Pitx2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>+\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              ) have increased AF susceptibility, although the molecular mechanism(s) remains controversial.\n              <jats:italic>Pitx2<\/jats:italic>\n              encodes a transcription factor that activates an antioxidant response to promote cardiac repair. Increased reactive oxygen species causing oxidation of polyunsaturated fatty acids generates reactive lipid dicarbonyl moieties that adduct to proteins and other macromolecules to promote cellular injury. We tested the hypothesis that oxidative stress, and specifically isolevuglandins, the most reactive lipid dicarbonyls identified, are increased in the setting of\n              <jats:italic>Pitx2<\/jats:italic>\n              deficiency to promote proarrhythmic remodeling and AF.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              <jats:italic>Pitx2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>+\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              and\n              <jats:italic>Pitx2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>+\/+<\/jats:italic>\n              <\/jats:sup>\n              wild-type littermate control mice were treated orally with vehicle, the lipid dicarbonyl scavenger 2-hydroxybenzylamine, or an inactive control compound at weaning, until study at age 16 to 18 weeks.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              <jats:italic>Pitx2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>+\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              mice demonstrated increased P wave duration indicative of slowed atrial conduction, as well as increased inducible AF burden and sustained AF, compared with wild type, and these abnormalities were prevented by 2-hydroxybenzylamine. Both reactive oxygen species and isolevuglandin protein adducts were elevated in\n              <jats:italic>Pitx2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>+\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              atria with reduced expression of reactive oxygen species\u2013protective genes. High-resolution respirometry demonstrated impaired mitochondrial function in\n              <jats:italic>Pitx2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>+\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              atria, with disruption of mitochondrial integrity and cell-cell junctions with connexin lateralization, as well as decreased mitochondrial biogenesis gene expression. Proarrhythmic ionic current remodeling in\n              <jats:italic>Pitx2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>+\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              atrial myocytes included elevated resting membrane potential, abbreviated action potential duration, and reduced maximum phase 0 upstroke velocity compared with wild type. Most of these abnormalities were ameliorated or prevented by 2-hydroxybenzylamine.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              These results demonstrate a critical role for lipid dicarbonyl mediators of oxidative stress in the proarrhythmic remodeling and AF susceptibility that occurs with\n              <jats:italic>Pitx2<\/jats:italic>\n              deficiency, implying the possibility of genotype-specific therapy to prevent AF.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.124.013199","type":"journal-article","created":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T10:00:18Z","timestamp":1740391218000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Oxidative Stress Causes Mitochondrial and Electrophysiologic Dysfunction to Promote Atrial Fibrillation in\n            <i>\n              Pitx2\n              <sup>+\/\u2212<\/sup>\n            <\/i>\n            Mice"],"prefix":"10.1161","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7779-9277","authenticated-orcid":true,"given":"Tuerdi","family":"Subati","sequence":"first","affiliation":[{"name":"Department of Medicine (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."},{"name":"Department of Pharmacology (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2869-0659","authenticated-orcid":true,"given":"Kyungsoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicine (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."},{"name":"Department of Pharmacology (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9315-154X","authenticated-orcid":true,"given":"Zhenjiang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medicine (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."},{"name":"Department of Pharmacology (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew B.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Medicine (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."},{"name":"Department of Pharmacology (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1410-6995","authenticated-orcid":true,"given":"Joseph C.","family":"Van Amburg","sequence":"additional","affiliation":[{"name":"Department of Medicine (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."},{"name":"Department of Pharmacology (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0075-094X","authenticated-orcid":true,"given":"Isis L.","family":"Christopher","sequence":"additional","affiliation":[{"name":"Department of Medicine (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."},{"name":"Department of Pharmacology (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9404-0235","authenticated-orcid":true,"given":"Owen P.","family":"Dougherty","sequence":"additional","affiliation":[{"name":"Department of Medicine (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."},{"name":"Department of Pharmacology (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7347-9663","authenticated-orcid":true,"given":"Kaylen K.","family":"Woodall","sequence":"additional","affiliation":[{"name":"Department of Medicine (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."},{"name":"Department of Pharmacology (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0391-3916","authenticated-orcid":true,"given":"Charles D.","family":"Smart","sequence":"additional","affiliation":[{"name":"Department of Medicine (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."},{"name":"Department of Pharmacology (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. 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Amarnath, V. Agrawal, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."},{"name":"Department of Pharmacology (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.), Vanderbilt Univ School of Medicine, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8568-9457","authenticated-orcid":true,"given":"Jeffrey E.","family":"Saffitz","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA (J.E.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1342-4457","authenticated-orcid":true,"given":"Katherine T.","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Medicine (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. 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