Remodelages électriques et structurels prédisposant à la fibrillation auriculaire dans un modèle murin de surexpression du récepteur de type 1 à l’angiotensine II

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with an increased risk of strokes and other morbidities. Atrial fibrillation has been associated with ionic currents remodeling, as well as structural remodeling, such as fibrosis and hypertrophy. These atrial remodeling can slow down atrial conduction velocity increasing the risk of atrial fibrillation.  Several risk factors have been associated with atrial fibrillation and elevated levels of angiotensin II are one of them. Angiotensin II is the primary effector of the renin-angiotensin system (RAS). Angiotensin II type 1 receptors (AT1R) are responsible for the several pathologies induced by RAS overactivity, such as hypertension, heart failure and atrial fibrillation. However, the direct effects of angiotensin II on the heart and its role in atrial fibrillation pathophysiology remain largely unexplored.  The objective of this research project is to study electrical and structural remodeling in transgenic mice overexpressing AT1R specifically in cardiomyocytes. These mice, identified as AT1R mice, do not have hemodynamic changes and are therefore suitable for studying the direct effect of RAS overactivation on the heart. Two age groups were used to distinguish the direct effects of AT1R on atrial electrophysiology (50-day-old mice) from those induced by structural remodeling (6-month-old mice). The presence of atrial fibrosis solely in 6 months old AT1R mice was confirmed using Picrosirius Red histological method. Characterizing electrical remodeling with and without structural remodeling is important since fibrosis is known to modulate cardiac electrophysiology and impair atrial conduction.  The hypothesis of this project is that AT1R overexpression induces atrial electrical remodeling which alters conduction, leading to atrial fibrillation. Structural remodeling is expected to worsen conduction defects, further increasing the risk of atrial fibrillation.  In this project, we measured an approximately 60% decrease in sodium current in 50 days old AT1R mice compared to controls (CTL). This change in sodium current was associated with an increase of PKCα protein expression in the sarcolemmal fraction. PKCα is a protein kinase able to phosphorylate Nav1.5 channels, resulting in a decrease in its function. Scn5a gene expression, encoding for Nav1.5 channels, was not changed at 50 days, suggesting an absence of transcriptional regulation of the sodium current. Moreover, a decrease in connexins 40 and 43 gene expression was observed in AT1R mice from the age of 50 days. Accordingly, a prolongation in P wave duration, which corresponds to atrial depolarization, is observed at 50 days in AT1R mice compared to CTL. At 6 months, structural remodeling did not worsen the reduction in sodium current or connexins induced by AT1R overexpression but was associated with a further prolongation of P wave duration. Susceptibility to AF was slightly increased in 50 days old AT1R mice and even more at 6 months.  In conclusion, AT1R overexpression directly induces electrical remodeling, which slows down atrial conduction, independently of structural remodeling. Structural remodeling further alters atrial conduction without changes in sodium current or connexins expression. This project provides knowledge on mechanisms by which angiotensin II alters atrial conduction and leads to atrial fibrillation, even in absence of angiotensin II-induced hemodynamic changes.

Keyphrases: Conduction, Angiotensin II, Angiotensin II type 1 receptor, Atrial fibrillation, Sodium current, Connexins, Atrium