Abstract
BackgroundPrevious studies demonstrated impaired lipid metabolism and augmented aerobic glycolysis in AF. The authors aimed to investigate whether the use of metformin, an AMPK activator, could reverse this metabolic remodeling in chronic AF and to explore the underlying mechanisms.MethodsWe conducted chronic AF animal models with 18 beagle dogs and divided them into SR (pacemaker implanted without pacing), AF (pacemaker implanted with sustained pacing at a frequency of 400 beats/min for 6 weeks), and metformin+AF group (daily oral administration of metformin was initiated 1 week before surgery and continued throughout the study period). After electrophysiological measurements, the left atrial appendage tissue samples were taken from the beating heart for further analysis. Protein expression, histological analysis, and biochemical measurements were conducted.ResultsThe AF groups showed decreased expression of FAT/CD36, CPT-1, VLCAD, increased concentration of free fatty acid and triglyceride, and increased lipid deposition. The activation of AMPK/PGC-1α/PPARα pathway was decreased. The key factors of the Warburg effect, including HIF-1α, GLUT-1, PDK1, HK, and LDH, increased in AF group compared to SR group. The expression of PDH decreased significantly, accompanied by increased atrial lactate production. The extent of fibrosis increased significantly in the left atrial appendage of AF group. dERP, ∑WOV, and AF inducibility increased while ERP decreased in AF group compared to SR group. The use of metformin attenuated all these changes effectively.ConclusionsMetformin improves lipid metabolism and reverses the Warburg effect in chronic AF via AMPK activation. It attenuates atrial electrical and structural remodeling.
Highlights
Previous studies demonstrated impaired lipid metabolism and augmented aerobic glycolysis in Atrial fibrillation (AF)
The concentration of free fatty acid (FFA) (FFA, SR vs AF: 69.82 ± 9.76 vs 125.91 ± 9.81 umol/gprot, P < 0.01) and TG (TG, SR vs AF: 0.07 ± 0.01 vs 0.20 ± 0.02 mmol/gprot, P < 0.01) in left atrial appendage (LAA) increased significantly at the AF group, both of which were alleviated by the use of metformin (FFA, AF vs MET+AF: 125.91 ± 9.81 vs 85.68 ± 7.50 umol/gprot, P < 0.01) (TG, AF vs MET+AF: 0.20 ± 0.02 vs 0.16 ± 0.05 mmol/gprot, P = 0.04) (Fig. 1a, b)
Metformin regulates protein expression of key fatty acid metabolic factors To investigate how metformin regulates fatty acid metabolism, we examined the protein expression of key fatty acid metabolic factors in LAA from three groups, including fatty acid transporter (FAT/CD36), carnitine palmitoyl transferase-1 (CPT-1), and very-long-chain acyl-CoA dehydrogenase (VLCAD)
Summary
Previous studies demonstrated impaired lipid metabolism and augmented aerobic glycolysis in AF. The authors aimed to investigate whether the use of metformin, an AMPK activator, could reverse this metabolic remodeling in chronic AF and to explore the underlying mechanisms. Electrical remodeling, structural remodeling, and autonomic remodeling have been demonstrated to play important roles in the pathogenesis of AF [1]. Each of these can result from cardiac disease conditions and promote the development of AF; AF in turn causes AF-. Recent studies have documented substantial changes in energy metabolism in human and experimental AF, indicating the role of metabolic remodeling [3]. Little is known regarding the underlying mechanisms and the impact of those changes upon the initiation/ persistence of AF
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