Abstract 12119: Silencing of Notch Signaling Tempers the Occurrence of Arrhythmic Events in the Post-Infarcted Heart

Abstract

Notch1 receptor signaling is active during cardiac development and is upregulated in the adult myocardium following ischemic damage. We previously documented that Notch1 signaling modulates the electrical activity of myocytes, but whether activation of the Notch receptor system contributes to the functional properties of the injured heart remains to be clarified. In the current study, we assessed the consequences of silencing of Notch1 signaling on electrical activity and arrhythmogenic behavior of the mouse heart, in physiological condition and following myocardial infarction (MI). For this purpose, mice with cardiac-restricted, inducible deletion of Notch1 gene (conditional knock-out, cKO) and corresponding control (Ctrl) mice were studied at baseline and up to one month after permanent coronary artery ligation. By echocardiography, left ventricular (LV) mass, chamber volume, and systolic function were comparable in both male and female naïve cKO and Ctrl mice. At ~2 and ~4 weeks after MI, chamber dilation occurred and ejection fraction was equally reduced in cKO and Ctrl animals. By electrocardiographic recordings in the conscious state over a period of 10 minutes, no arrhythmic events were observed in naïve Ctrl and cKO mice. In contrast, at one day after MI, a large fraction of Ctrl mice developed premature ventricular complexes (PVCs, 72%, n=18) and ventricular tachycardia (VT, 28%), but the fraction of cKO mice with PVCs was substantially reduced (31%, n=32) and VT was not observed. From 3-~30 days after MI, arrhythmic events occurred sporadically and no major differences were detected between the two groups of mice. Following euthanasia at 30 days after MI, infarcted hearts were perfused in a Langendorff system and monophasic action potential and pseudo-ECGs collected. Spontaneous VT were found in both Ctrl (18%, n=11) and cKO (7% n=14) hearts in sinus rhythm. Importantly, programmed electrical stimulation (S1-S2 protocol) induced PVCs and/or VT in 55% of Ctrl infarcted hearts (n=11), but only in 23% of cKO organs (n=13). Collectively, these findings support the possibility that Notch1 signaling modulates the electrical activity of the injured heart and its propensity to develop arrhythmias.