Metabolic Considerations in Atrial Fibrillation　― Mechanistic Insights and Therapeutic Opportunities ―

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice and is associated with morbidity and mortality. Over the past 2 decades, there have been major advances in understanding AF pathophysiology, but important knowledge gaps, particularly about targetable basic mechanisms, remain. Recent metabolomic and proteomic studies have shown changes in the expression of molecules involved in metabolic pathways in human and experimental AF, indicating a role for metabolic alterations in AF pathophysiology. AF is characterized by irregular high-frequency excitation and contraction that affect atrial energy demands, circulation and oxygen supply, and change the balance between metabolic demand and supply, causing metabolic stress. Here, we review the information available about AF-induced metabolic changes and their pathophysiological contribution. We also discuss the possibilities of developing novel therapeutic strategies that act by modulating cardiac metabolic processes during AF.

Weighted gene co‑expression network analysis to identify key modules and hub genes associated with atrial fibrillation

“…Previous genomic, metabolomic and proteomic studies have also demonstrated that metabolic genes and products were notably altered in patients with AF compared to patients with SR (39,40). As a result of irregular high-frequency excitation and contraction, AF-associated metabolic stress occurs when there is a decreased capacity of energy to supplement the demands of atrial tissues, combined with an increase in metabolism of ketone bodies, AMPK activation, mitochondria dysfunction and reactive oxygen species generation, which accelerates gradual atrial remodeling (41). KEGG pathway analysis of the magenta module indicated that it was primarily associated with the Hippo signaling pathway.…”

Metformin Use is Associated with A Lower Incidence of Hospitalization for Atrial Fibrillation in Patients with Type 2 Diabetes Mellitus

“…On the other hand, microvascular dysfunction and relative ischemia with reduced oxygen/nutrient delivery and/or increased energy demand in the heart may lead to metabolic stress and induce AF [1]. Through the activation of 5'-adenosine monophosphate-activated protein kinase, metformin promotes fatty acid oxidation, increases ketone body metabolism, reduces lipid accumulation and induces the expression of glucose transporter in cardiomyocytes, thus facilitates more e cient energy use with reduction of metabolic stress [1,24]. Studies also suggested that metformin may reduce AF by alleviating the dysfunction of epicardial adipose tissue [25].…”

“…Pro-brotic biomarkers such as interleukin-6, transforming growth factor-beta one, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 are important biomarkers of atrial remodeling in AF [1,26]. Interestingly, metformin inhibits the signaling pathways of transforming growth factor-beta one [27].…”

“…Atrial brillation (AF) is a common arrhythmia that can lead to increased hospitalization, stroke, or even life-threatening thromboembolic events [1,2]. Risk factors of AF may include aging, male sex, smoking, alcohol consumption, diabetes mellitus, hypertension, obesity, thyroid dysfunction, obstructive sleep apnea, high-level physical training, left ventricular dysfunction, valvular disease, myocardial infarction and heart failure [2][3][4].…”

May the Force Not Be With You During Culture: Eliminating Mechano-Associated Feedback During Culture Preserves Cultured Atrial and Pacemaker Cell Functions

“…A highly efficient energy supply-and-demand matching process is essential to coordinate atrial mechanometabolic feedback cues during permanent changes in cardiac workload. In response to an increase in electrical stimulation, frequency, or Ca 2+ transient amplitude, Ca 2+ accumulates in the atrial mitochondria and then activates enzymes participating in ATP production (Harada et al, 2017). It is not known whether cAMP/PKA and CaMKII signaling regulate ATP production in atrial cells, as has been seen in pacemaker cells.…”