Abstract Body: Myocardial ischemia induces re-expression of fetal genes, including Notch1, raising the possibility that the Notch1 receptor contributes to the remodeling occurring in the injured heart. To test this hypothesis, the consequences of loss of Notch1 gene on the electrophysiological properties of the heart after myocardial infarction (MI) were evaluated using experimental animals. Specifically, male and female mice with cardiac-restricted, inducible deletion of Notch1 gene (conditional knock-out, cKO) and corresponding wild-type (WT) mice were studied in the naïve state and after MI. By electrocardiograms, WT and cKO naïve mice had no arrhythmias. In contrast, at one day after MI, premature ventricular complexes occurred in 69% of WT mice (n=26), but only in 31% of cKO animals (n=42, P<0.01 vs. WT). Quantitatively, infarcted cKO mice had lower aggregate arrhythmia score with respect to WT animals with MI. Similar results were observed in male and female animals. To evaluate the effects of loss of Notch1 on the electrical repolarization of the myocardium, monophasic action potentials (MAP) were measured in perfused hearts from naïve and infarcted mice. Duration of the MAP was comparable in the myocardium of WT and cKO naïve mice. After MI, repolarization was prolonged in WT hearts, but this effect was attenuated in cKO organs, for the two sexes. Thus, the MAP duration was shorter in infarcted hearts from cKO mice with respect to WT animals. To define the ionic basis for the preserved repolarization properties of infarcted cKO hearts, patch-clamp studies were conducted using isolated left ventricular myocytes. The outward K⁺ repolarizing current was comparable in myocytes from WT and cKO animals in the naïve state. But at ~2 weeks after MI, WT myocytes had a 37% reduction of total K⁺ currents with respect to cells from naïve mice, whereas no significant alterations were detected in cKO myocytes. Collectively, these findings indicate that silencing of Notch1 in mice attenuates cardiac electrophysiological remodeling occurring after myocardial infarction.