Notch1 deletion reduces arrhythmogenic remodeling after myocardial infarction

Myocardial infarction (MI) induces re-expression of fetal genes, including Notch1, which can modify the electrophysiological properties of cardiomyocytes.

This study aimed to evaluate the role of Notch1 signaling in the electrical remodeling of the injured heart.

Electrophysiological consequences of Notch1 gene deletion were evaluated in male and female conditional knockout (cKO) mice, with respect to corresponding wild-type (WT) animals. Mice were studied both in the naïve state and after MI.

Electrocardiographic recordings showed no arrhythmias in WT and cKO mice in the naïve state. However, 1 day after MI, 69% of WT mice exhibited ectopic beats compared with 31% of cKO animals, who also presented lower arrhythmia burden. To examine the effects of Notch1 loss on myocardial repolarization, monophasic action potentials (MAPs) were recorded in perfused hearts. In the myocardium of WT mice, MAP duration was prolonged after 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 voltage-gated potassium currents were comparable between WT and cKO cells. However, ∼2 weeks after MI, WT myocytes showed a significant reduction of total voltage-gated potassium currents, whereas cKO myocytes maintained levels similar to baseline.

Notch1 deficiency mitigates the electrophysiological remodeling of cardiomyocytes and is coupled with reduced arrhythmia susceptibility of the heart after MI.