Remodelage électrique cardiaque dans des modèles murins de cardiomyopathies

Cardiomyopathies are diseases of the myocardium that may have several causes and comes in different forms such as cardiac hypertrophy or dilatation. Cardiomyopathies are often progressive diseases that cause a loss of heart function and lead to heart failure. In addition, hypertrophy and heart failure are associated with increased morbidity and mortality mainly due to electrical remodeling and arrhythmias. Delayed repolarization associated with a decrease of K+ currents, is one of the most common cardiac disorders associated with cardiac remodeling.  Angiotensin II (Ang II) and norepinephrine, the main effectors of the renin-angiotensin system and of the sympathetic nervous system, can both act directly on the heart by binding the Ang II type 1 receptor (AT1) and the adrenergic receptors. Ang II and norepinephrine are both associated with the development of cardiomyopathy, cardiac remodeling and prolongation of action potential duration. Two transgenic mouse models overexpressing the AT1 receptors (AT1R mouse) or the α1B-adrenergic receptors (α1B-AR mouse) specifically in the myocardium have been developed to study the effects of these stimuli on the heart. These two mouse models developed cardiac remodeling such as hypertrophy for the AT1R mice (hypertrophic cardiomyopathy) and dilatation of cardiac chambers for α1B-AR mice (dilated cardiomyopathy). In advanced stage of the disease, the two transgenic mouse models exhibit heart failure. Preliminary data showed that both transgenic mouse models experience cardiac arrhythmias and have a prolongation of the action potential duration. Moreover, AT1R and α1B-AR mice die suddenly and prematurely, which suggested that in pathological conditions, activation of the Ang II type 1 receptor or of the α1B-adrenergic receptor may affect repolarization and can be responsible for the incidence of serious arrhythmias causing the death of these mice. Base on these informations, the objective of this project was to characterize the ventricular repolarization in AT1R and α1B-AR mice to see if an increase of the activation of the Ang II type 1 receptor or of the 1B-adrenergic receptor could directly affect electrophysiological parameters and lead to severe arrhythmias.  Results showed that both AT1R mice and α1B-AR mice have a delayed ventricular repolarization (prolongation of the QTc interval and action potential duration) caused by a decrease in outward K+ currents (responsible for the repolarization). In addition, the incidence of arrhythmias is higher in both groups of transgenic mice compared with their respective control. Finally, we have seen that repolarization disorders also occur in younger mice of both models of cardiomyopathy that do not present sign of hypertrophy and cardiac remodeling. These results suggest that under pathological conditions, the overactivation of the Ang II type 1 receptor or of the α1B-adrenergic receptor can directly promote the development of arrhythmias by delaying the repolarization independently of hemodynamic variations and pathological phenotype. The results of these studies can be useful to understand the mechanisms underlying the development of cardiac arrhythmias in patients suffering from cardiac hypertrophy or failure and may help to choose the best treatment for these patients.

Keyphrases: Cardiomyopathies, Angiotensin II type 1 receptor, Alpha1B-adrenergic receptor, Cardiac arrhythmias, Ion currents, Cardiomyopathy, Ventricular repolarization, Transgenic mouse