Impacts of a high-fat diet on the metabolic profile and the phenotype of atrial myocardium in mice

Abstract

Aims Obesity, diabetes and metabolic syndromes are risk factors of atrial fibrillation (AF). We tested the hypothesis that metabolic disorders have a direct impact on the atria favoring the formation of the substrate of AF. Methods & Results Untargeted metabolomic and lipidomic analysis was used to investigate the consequences of a prolonged high fat diet (HFD) on mouse atria. Atrial properties were characterized by measuring mitochondria respiration in saponin-permeabilized trabeculae, by recording action potential with glass microelectrodes in trabeculae and ionic currents in myocytes using the perforated configuration of patch clamp technique and by several immuno-histological and biochemical approaches. After 16 weeks of HFD, obesogenic mice showed a vulnerability to AF. The atrial myocardium acquired an adipogenic and inflammatory phenotypes. Metabolomic and lipidomic analysis revealed a profound transformation of atrial energy metabolism with a predominance of long-chain lipid accumulation and beta-oxidation activation in the obese mice. Mitochondria respiration showed an increased use of palmitoyl-CoA as energy substrate. Action potentials were short duration and sensitive to the K-ATP-dependent channel inhibitor, whereas K-ATP current was enhanced in isolated atrial myocytes of obese mouse. Conclusion HFD transforms energy metabolism, causes fat accumulation, and induces electrical remodeling of the atrial myocardium of mice that become vulnerable to AF. Translational perspective Understanding the link between metabolic diseases and atrial fibrillation is of major importance. One hypothesis claims that, in addition to shared co-morbidities, metabolic disorders favor the substrate of atrial fibrillation. Here we show that after prolonged high fat diet, the atrial myocardium becomes adipogenic, inflamed and vulnerable to atrial fibrillation. This tissue remodeling appears to result from an unbalance between uptake and oxidation of fatty acid resulting in long-chain lipid storage, activation of metabolic-sensitive potassium channels and action potential shortening. Therefore, diet appears to be an important link between metabolic disorders and atrial fibrillation.

High liver fibrosis scores in metabolic dysfunction-associated fatty liver disease patients are associated with adverse atrial remodeling and atrial fibrillation recurrence following catheter ablation

“…Despite these established epidemiological observations, mechanistic approaches are severely lacking. Recently, a study published by Suffee et al using a high-fat-diet mouse model showed a vulnerability to AF linked to a shorter action potential duration caused by enhanced K-ATP current in the context of obesity ( 19 ). Although interesting, such studies did not emphasize the liver phenotype so far.…”

“…AF pathogenesis encompasses a wide spectrum of mechanisms involving electrophysiological and structural remodeling of the left atrium (LA) ( 15 ). Furthermore, metabolic disorders have been previously associated with LA remodeling [e.g., mitochondrial dysfunction in diabetic patients ( 16 – 18 ) and enhanced LA fibrosis in the high-fat-diet-fed mice ( 19 )] but did not emphasize the liver phenotype. Therefore, data assessing the impact of MAFLD on LA remodeling are severely lacking.…”

Combined metabolomic and transcriptomic profiling approaches reveal the cardiac response to high-fat diet

“…Both Pdk4 and HMGcs2 are differentially expressed in obese human hearts with hypertrophy ( Newman et al., 2017 ), which underscores the potential relevance of our findings to some forms of human heart disease. Another group has recently reported metabolomic changes in mouse atrial tissue in response to 16 weeks of HFD ( Suffee et al., 2021 ). Similar to our results from ventricular tissue, this study showed accumulation of some fatty acids and increased use of fatty acid as a substrate.…”

The association between eicosanoids and incident atrial fibrillation in the Framingham Heart Study

“…Oxidized linoleic acid metabolites including 9-oxoODE were reduced 44 . Atrial fatty infiltration contributes to abbreviation of action potential duration and a substrate for AF, and oxidized lipid metabolites likely contribute to this process 45 .…”