{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:52:32Z","timestamp":1792014752142,"version":"4.4.0"},"reference-count":0,"publisher":"Canadian Science Publishing","license":[{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.nrcresearchpress.com\/page\/about\/CorporateTextAndDataMining"}],"content-domain":{"domain":["cdnsciencepub.com"],"crossmark-restriction":false},"short-container-title":["Can. J. Physiol. Pharmacol."],"abstract":"<jats:p>Heart failure with preserved ejection fraction (HFpEF) commonly coexists with atrial fibrillation (AF), but shared mechanisms remain unclear. In this study, we hypothesized that Pitx2, a transcription factor located near the strongest genetic locus associated with AF in humans, increases susceptibility to HFpEF-like remodeling. We also sought to understand pathways that might be central to this increased risk. Male and female Pitx2+\/\u2212 mice and wild-type littermates received 3-week subcutaneous osmotic pump infusion of saline or angiotensin II (Ang II; 500 ng\/kg\/min). Cardiac structure and function were assessed by echocardiography and catheterization, and functional capacity by exercise treadmill. RNA transcriptomic profiling was performed to identify candidate pathways. In a separate cohort, Ang II\u2013treated mice were randomized to oral GKT136901 (30 mg\/kg\/day) or vehicle during infusion. After Ang II infusion, Pitx2+\/\u2212 mice developed exaggerated HFpEF-like changes, including greater left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, elevated left ventricular end-diastolic pressure, and reduced treadmill performance. RNA-seq showed enrichment of metabolic and stress-response pathways with selective upregulation of Nox4, confirmed by RT-qPCR. GKT136901 attenuated structural remodeling, diastolic dysfunction indices, elevated filling pressures, and cardiomyocyte hypertrophy, but did not improve endurance. These findings implicate redox signaling, including Nox4, in AF genetic susceptibility\u2013HFpEF interactions.<\/jats:p>","DOI":"10.1139\/cjpp-2026-0223","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:36:30Z","timestamp":1792013790000},"update-policy":"https:\/\/doi.org\/10.1139\/csp-crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Nox4 Mediates Diastolic Function in a Genetic Model of Pitx2 Haploinsufficiency."],"prefix":"10.1139","author":[{"given":"Sumner L","family":"Gardner","sequence":"first","affiliation":[{"name":"Vanderbilt University, Nashville, Tennessee, United States;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anam","family":"Fatima","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Medicine, Cardiology, Nashville, Tennessee, United States;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faris","family":"Abusharkh","sequence":"additional","affiliation":[{"name":"Vanderbilt University, Nashville, Tennessee, United States;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Kobeck","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Medicine, Cardiology, Nashville, Tennessee, United States;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chitra","family":"Basu","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Medicine, Cardiology, Nashville, Tennessee, United States;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis J","family":"Miller","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Medicine, Cardiology, Nashville, Tennessee, United States"},{"name":"US Department of Veterans Affairs,  Medicine, Cardiology, Nashville, Tennessee, United States;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vineet","family":"Agrawal","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Medicine, Cardiology, Nashville, Tennessee, United States"},{"name":"US Department of Veterans Affairs,  Medicine, Cardiology, Nashville, Tennessee, United States;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"155","published-online":{"date-parts":[[2026,10,14]]},"container-title":["Canadian Journal of Physiology and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdnsciencepub.com\/doi\/pdf\/10.1139\/cjpp-2026-0223","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:36:31Z","timestamp":1792013791000},"score":1,"resource":{"primary":{"URL":"https:\/\/cdnsciencepub.com\/doi\/10.1139\/cjpp-2026-0223"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,14]]},"references-count":0,"alternative-id":["10.1139\/cjpp-2026-0223"],"URL":"https:\/\/doi.org\/10.1139\/cjpp-2026-0223","relation":{},"ISSN":["0008-4212","1205-7541"],"issn-type":[{"value":"0008-4212","type":"print"},{"value":"1205-7541","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,14]]},"assertion":[{"value":"2026-07-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cjpp-2026-0223"}}