Abstract Body: Background: Myocardial infarction (MI) induces re-expression of Notch1 receptor, which is normally restricted to the fetal heart and can modify the electrophysiological properties of myocytes.
Hypothesis: We hypothesized that reactivation of Notch1 signaling contributes to the electrical remodeling of the of the injured heart.
Methods: MI was induced by permanent coronary artery ligation in male and female conditional knock-out (cKO) mice with inducible deletion of Notch1 gene and compared to corresponding wild-type (WT) animals. Cardiac function was evaluated before and after MI by echocardiography and pressure-volume loop analysis. ECGs were collected to evaluate arrhythmia occurrence, while Langendorff-perfused hearts and isolated cardiomyocytes were used to assess myocardial electrical properties and ionic currents. A subgroup of mice overexpressing the active intracellular domain of Notch1 receptor (NICD) was also studied.
Results: Compared with naïve mice, animals at 2 and 4 weeks after MI exhibited chamber dilation and reduced functional parameters. These changes were similar in WT and cKO mice and were supported by comparable infarct sizes. ECG recordings showed that cKO mice had lower levels of arrhythmia at 1 day after MI, compared with WT mice. Similarly, inducibility of arrhythmias by programmed electrical stimulation at 1 day and 4 weeks post-MI was reduced in perfused hearts from cKO mice compared with WT. Importantly, at both time points, epicardial monophasic action potentials displayed shorter repolarization times in cKO hearts than in WT. To identify the ionic basis for this difference, patch-clamp recordings were performed in 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 in total Kv currents, whereas cKO myocytes maintained levels similar to baseline. Notably, myocytes from mice with cardiac-restricted NICD overexpression exhibited reduced Kv currents compared with WT cells.
Conclusion: Notch1 deficiency attenuates electrophysiological remodeling of cardiomyocytes and is associated with reduced arrhythmia susceptibility following myocardial infarction.