Atrial fibrillation (AF) is the most frequent arrhythmia observed in clinical practice. It affects approximately 1% of the population and has age, hypertension, obesity or myocardial infarction as risk factors. AF can lead to serious complications such as stroke and heart failure. AF therefore constitutes a major public health problem. Recently, a sarcomere-protein mutation was identified in the gene encoding an atrial-selective myosin light chain protein 4 (MYL-4) involved in cardiac contractility, causing a genetically inherited form of AF. Different signaling pathways have been implicated in causing these rhythm disorders, such as inflammation and atrial fibrosis. Conventional anti-inflammatory drugs are ineffective against AF. Bioactive endogenous autacoids, termed specialized pro-resolution mediators, including resolvin-D1 (RvD1), have been described to promote resolution of inflammation and potentially reduce the onset of AF.

Elucidating how Resolvin D1 affects disturbed electrophysiological functions linked to the Myl-4 mutation.

We developed a colony of male and female Sprague-Dawley Knock-In rats, mutated in the Myl-4 gene. A dose of 2μg/kg/d of RvD1 (or equivalent dose of vehicle) was administered to wild-type (WT) and MYL-4 rats for 21 days. AF-susceptibility was assessed with in vivo electrophysiological study and conduction by optical mapping. The structure of the atria was studied by echocardiography, histology, and electron microscopy. The expression levels of proteins (by Western blot) and genes (by qPCR) involved in inflammation and cell apoptosis were assessed in the right and left atria of MYL-4 rats versus WT.

RvD1 reduced AF inducibility in rats carrying the mutation compared to vehicle, while suppressing atrial inflammation (IL-1β), apoptosis-markers (Bax/Bcl2), and atrial structural remodeling (dilatation, hypertrophy).

This project highlights the potential therapeutic effects of RvD1 treatment to prevent AF in atrial cardiomyopathies.