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NMDAR expression was detected using immunofluorescence (IF) and Western blotting (WB). Spontaneous ventricular arrhythmias (VAs) in mice were detected using electrocardiogram backpacks. Electrical remodeling post\u2010MI was detected using patch clamp recordings, quantitative real\u2010time polymerase chain reactions, IF, and WB. Mechanistic studies were performed using bioinformatic analysis, plasmid and small interfering RNA transfection, lentiviral packaging, and site\u2010directed mutagenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>NMDAR is highly expressed in patients with ischemic heart disease and mice with MI. NMDAR inhibition reduces the occurrence of VAs. Mechanistically, NMDAR activation promotes electrophysiological remodeling, as characterized by decreased Nav1.5, Kv11.1, Kv4.2, Kv7.1, Kir2.1, and Cav1.2 expression in patients with ischemic heart disease and mice with MI and rescues these ion channels dysregulation in mice with MI to varying degrees by NMDAR inhibition. Decreased Nav1.5 expression and inward sodium current density were attenuated by NMDAR inhibition in primary rat cardiomyocytes. Moreover, NMDAR activation upregulates T\u2010Box Transcription Factor 3 (TBX3) post\u2010translationally, further downregulating Nav1.5 transcriptionally. Furthermore, AKT1 is the predominant isoform in the ventricular myocardium upstream of TBX3 and mediates NMDAR\u2010induced TBX3 upregulation in cardiomyocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>NMDAR activation contributes to MI\u2010induced VAs by regulating the AKT1\u2013TBX3\u2013Nav1.5 axis, providing novel therapeutic strategies for treating ischemic arrhythmias.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.70085","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T11:34:51Z","timestamp":1755862491000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["NMDA\u2010Type Glutamate Receptor Activation Promotes Ischemic Arrhythmias by Targeting the AKT1\u2013TBX3\u2013Nav1.5 Axis"],"prefix":"10.1111","volume":"241","author":[{"given":"Yuxian","family":"He","sequence":"first","affiliation":[{"name":"Heart Center, Department of Cardiovascular Medicine Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Atrial Fibrillation Center, School of Medicine, The First Affiliated Hospital Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinggang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Heart Center, Department of Cardiovascular Medicine Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zewei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Atrial Fibrillation Center, School of Medicine, The First Affiliated Hospital Zhejiang University  Hangzhou 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