Impact of Resolvin-D1 in the resolution of atrial inflammation and arrhythmogenic cardiac remodelling in a rat model of myosin light chain 4 (MYL-4) mutation

Abstract

Atrial fibrillation (AF) is the most common heart rhythm disorder. AF risk factors include age, hypertension, obesity, or myocardial infarction. AF can cause severe complications such as stroke and sudden death. Hence, AF is a major public health issue. Proteins called actins and myosins interact to allow myocardial contractions. A mutation affecting the gene encoding a myosin light chain type 4 (MYL-4) protein is associated with a genetically inheritable form of AF. Furthermore, we have recently demonstrated that MYL-4 rats develop atrial inflammation and fibrosis. Conventional anti-inflammatory medications are ineffective against AF. Bioactive endogenous autacoids, called specialized proresolving mediators, including resolvin-D1: RvD1, have been described to promoting inflammation-resolution and potentially reduce AF occurrence. To elucidate the impact of a triggered resolution of inflammation in the prevention of AF. Resolution of atrial inflammation by daily treatment with RvD1 prevents the development of AF in a rat model of MYL-4 mutation. We have developed a colony of male and female Sprague-Dawley Knock-In rats, mutated on the Myl-4 gene. A dose of 2 μg/kg/d RvD1 (or equivalent dose of vehicle) was administered to wild-type (WT) and MYL-4 rats for 21 days. AF was assessed by in vivo electrophysiological study. The structure of the atria was studied by echocardiography, histology and electron microscopy. The expression levels of proteins (by western blotting) and genes (by qPCR) involved in inflammation and cellular apoptosis have been assessed in the right and left atria of MYL-4 rats compared to WT. Compared to WT rat, MYL-4 mutation causes an increased risk of AF, associated with an inflammatory and apoptotic profile in the atria. We observed that daily treatment with RvD1 prevents atrial inflammation (IL-1β), reduces cell death (Bax, Bcl2) and attenuates atrial structural remodelling (dilation, hypertrophy). Inflammation plays a crucial role in the development of arrhythmogenic atrial remodeling observed in rats carrying MYL4 mutation. In addition, this project contributes to highlight the potential therapeutic effects of the RvD1 treatment, to resolve inflammation and prevent AF in the context of a rhythm disturbances provoked by cardiac mutations.