Notch1 Deletion Reduces Arrhythmogenic Remodeling after Myocardial Infarction

ABSTRACTBackground Myocardial infarction (MI) induces re-expression of fetal genes, including Notch1, which can modify the electrophysiological properties of cardiomyocytes. Objective This study aimed to evaluate the role for Notch1 signaling in the electrical remodeling of the injured heart. Methods Electrophysiological consequences of Notch1 gene deletion were evaluated in male and female conditional knock-out (cKO) mice, with respect to corresponding wild-type (WT) animals. Mice were studied in both the naïve state and following MI. Results Electrocardiogram recordings showed no arrhythmias in WT and cKO mice in the naïve state. However, one day post-MI, 69% of WT mice exhibited ectopic beats, compared to 31% of cKO animals, who also presented lower arrhythmia burden. To examine the effects of Notch1 loss on myocardial repolarization, monophasic action potentials (MAP) were recorded in perfused hearts. In the myocardium of WT mice, MAP duration was prolonged post-MI, whereas this effect was attenuated in cKO hearts, resulting in shorter MAP duration in cKO hearts with respect to WT organs. To identify the ionic basis for this difference, patch-clamp recordings were performed on isolated left ventricular myocytes. In the naïve state, transient outward Kv currents were comparable between WT and cKO cells. However, ∼2 weeks post-MI, WT myocytes showed a significant reduction of total Kv currents, while cKO myocytes maintained levels similar to baseline. Conclusion Notch1 deficiency mitigates the electrophysiological remodeling of cardiomyocytes and is coupled with reduced arrhythmia susceptibility of the heart following myocardial infarction.