Genetic Destruction of Transcription Factor in His-Purkinje System Mimicked J Wave Syndrome in Mouse

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Background: It is controversial whether J wave syndrome (JWS) is caused by early repolarization or delayed depolarization. We characterized mice genetically deleted in a transcription factor, which is expressed specifically in His-Purkinje system (HPS) and regulates ion channel gene expression. Methods: We performed surface electrocardiography and intracardiac electrophysiological study (EPS) in knock-out mice (KO) and wild-type littermates (WT). Subgroup of mice underwent isoproterenol administration, swimming exercise, or myocardial infarction (MI) procedure. Heart was excised for immunohistochemistry and RT-PCR. Results: Electrocardiogram showed significantly longer QT interval (KO/WT 21.3/18.0 ms) and higher J wave amplitude (KO/WT 0.22/0.09 mV) in KO. Hypothermia to 30 degreeC increased J wave amplitude only in KO. Isoproterenol and swimming evoked advanced atrioventricular block (AVB) and/or non-sustained ventricular tachycardia (VT) in KO, but not in WT. The interval between His potential to the end of QRS complex was significantly prolonged in KO (KO/WT 27.1/23.9 ms). After MI procedure, KO showed sustained VT and recurrent non-sustained VT, whereas WT showed fewer non-sustained VT. Immunohistochemistry and RT-PCR exhibited reduced expression of connexin40 and scn5a in KO compared to WT. Conclusions: Impaired conduction of HPS induced by genetic deletion of a HPS-specific transcription factor mimicked JWS in mice.