The sodium channel Nav1.5, encoded by the Scn5a gene, is responsible for the excitability and the conduction velocity of electrical impulses through the heart. Nav1.5 mutations are involved in rhythmic or structural pathologies. During the acute phase of myocardial infarction (MI), arrhythmias were associated with an increased risk of mortality. Over time, progressive left ventricular remodeling will lead to heart failure.
Objectives: The association of polymorphisms and mutations carried by genes encoding for channels with acquired forms of arrhythmias and post-MI remodeling, are not well characterized. In this context, we have investigated the role of Nav1.5 genetic alterations in the occurrence of ventricular arrhythmias, structural remodeling and cardiac contraction abnormalities during the acute phase of MI.
Methods: The Nav1.5 contribution in this context was evaluated after permanent occlusion of coronary artery performed on mouse model invalidated at the heterozygous state for the Scn5a gene (Scn5a+/- mice; 10-12 weeks old). After validation of the infarction by echocardiography, these animals were studied in vivo by echocardiography and ECG and in vitro using molecular and biochemical investigations during the first 48 hours post-MI. These protocols were extended to a second transgenic model, animals carriers of a mutation in SCN5A identified in humans and leading to loss of function: the T220I mutation. This original model has never been studied in this pathophysiological context.
Results: Series of animals placed in this pathophysiological context, revealed that Scn5a+/− animals have a higher mortality due to arrhythmic events. In addition, the ECG recorded by telemetry during 48 hours post-MI revealed that Scn5a+/− mice present an increased incidence of premature ventricular beats (5.6±2.7 & 33.1±11 PVB/hour respectively for WT-MI and Scn5a+/−MI mice) without any difference in structural and functional remodelling compared to WT-MI. 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 Expression respectively) and IL-1β mRNA (1,8±0.3 & 4.6±0.8 RE respectively) and downregulation of Cx43 mRNA (0.61±0.08 & 0.39±0.03 RE 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.