Correlation between increased atrial expression of genes related to fatty acid metabolism and autophagy in patients with chronic atrial fibrillation.

Yasushige Shingu,Suguru Kubota,Hiroki Katoh,Takashi Yokota,Akira Yamada,Shingo Takada,Ryosuke Shirakawa,Yoshiro Matsui,Tomonori Ooka,Tomohiko Ai

doi:10.1371/journal.pone.0224713

Yasushige Shingu, Suguru Kubota + Show 8 more

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https://doi.org/10.1371/journal.pone.0224713

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Abstract

Atrial metabolic disturbance contributes to the onset and development of atrial fibrillation (AF). Autophagy plays a role in maintaining the cellular energy balance. We examined whether atrial gene expressions related to fatty acid metabolism and autophagy are altered in chronic AF and whether they are related to each other. Right atrial tissue was obtained during heart surgery from 51 patients with sinus rhythm (SR, n = 38) or chronic AF (n = 13). Preoperative fasting serum free-fatty-acid levels were significantly higher in the AF patients. The atrial gene expression of fatty acid binding protein 3 (FABP3), which is involved in the cells' fatty acid uptake and intracellular fatty acid transport, was significantly increased in AF patients compared to SR patients; in the SR patients it was positively correlated with the right atrial diameter and intra-atrial electromechanical delay (EMD), parameters of structural and electrical atrial remodeling that were evaluated by an echocardiography. In contrast, the two groups' atrial contents of diacylglycerol (DAG), a toxic fatty acid metabolite, were comparable. Importantly, the atrial gene expression of microtubule-associated protein light chain 3 (LC3) was significantly increased in AF patients, and autophagy-related genes including LC3 were positively correlated with the atrial expression of FABP3. In conclusion, in chronic AF patients, the atrial expression of FABP3 was upregulated in association with autophagy-related genes without altered atrial DAG content. Our findings may support the hypothesis that dysregulated cardiac fatty acid metabolism contributes to the progression of AF and induction of autophagy has a cardioprotective effect against cardiac lipotoxicity in chronic AF.

Highlights

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its presence is associated with increased risks of death, heart failure, and stroke [1,2,3]
Our findings demonstrated that the atrial expression of a gene involved in fatty acid metabolism, fatty acid binding protein 3 (FABP3), was upregulated in patients with chronic AF compared to the sinus rhythm (SR) patients
Our study is the first to demonstrate that compared to patients with SR, the atrial expression of FABP3 gene was upregulated in association with autophagy-related genes in patients with chronic AF

Summary

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its presence is associated with increased risks of death, heart failure, and stroke [1,2,3]. Prior research has shown that an elevated level of circulating FFAs is a strong risk factor for AF and AF-related stroke [6, 10] and can be a trigger of cardiac lipotoxicity, which is defined as the excess accumulation of toxic fatty acid metabolites such as diacylglycerol (DAG) in the heart. This may occur when the influx of FFAs exceeds the intracellular fatty acid oxidation, which leads to cardiac dysfunction, cardiac remodeling, and arrhythmias [11].

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