Abstract 17996: Study of the Role of Scn5a in the Occurrence of Arrhythmic Events During Myocardial Infarction and Post-ischemic Remodeling

Abstract

The sodium channel Nav1.5, encoded by the Scn5a gene, is responsible for the excitability and the conduction of electrical impulses through the heart. Nav1.5 mutations are involved in rhythmic or structural pathologies. During the acute phase of myocardial infarction (MI), ventricular arrhythmias were associated with an increased risk of mortality. Over time, progressive left ventricular remodeling such as dilation, hypertrophy and fibrosis, will lead to heart failure. Objectives: The association of mutations carried by genes encoding for cardiac channels with acquired forms of ventricular arrhythmias and post-ischemic myocardial remodeling, are not well characterized. This project studied the role of Nav1.5 channel alterations in the occurrence of ventricular arrhythmias, structural and contraction abnormalities during the acute phase of MI. Methods: The Nav1.5 contribution in this pathological context was evaluated after permanent occlusion of left anterior descending coronary artery performed on mouse invalidated at the heterozygous state for the Scn5a gene (Scn5a+/-; 10-12 w old). After MI validation by echocardiography, they were studied in vivo by echo and electrocardiography and in vitro using molecular investigations during 48 hours post-MI. Results: Scn5a+/--MI mice present a higher mortality due to arrhythmic events. In addition, the ECG recorded by telemetry revealed that they present an increased incidence of premature ventricular beats (5.6±2.7 & 33.1±11 PVB/hour respectively for WT & Scn5a+/--MI) without any difference in structural and functional remodelling. However, mRNA expression revealed that Scn5a+/--MI mice have an increased up-regulation of pro-inflammatory factors IL-6 (3.7±0.9 & 17.4±9.3 Relative Quantity respectively) and IL-1β mRNA (1,8±0.3 & 4.6±0.8 RQ respectively) and downregulation of Cx43 mRNA (0.61±0.08 & 0.39±0.03 RQ respectively) without interstitial fibrosis induction. Conclusions: These observations, 48 hours post-MI, suggest that Scn5a+/- mice present factors for the establishment of a more severe post-ischemic heart failure. In addition, preliminary results obtained on small series of animals revealed that Scn5a+/- mice seem to have a more pronounced LV remodelling at 4 weeks post-MI.