Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR‐α/sirtuin 1/PGC‐1α pathway

Bai

et al. 2020

BMC Cardiovasc Disord

Background: 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. Methods: We 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.Results: The 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.Conclusions: Metformin improves lipid metabolism and reverses the Warburg effect in chronic AF via AMPK activation. It attenuates atrial electrical and structural remodeling.

Section: Discussionsupporting

confidence: 93%

“…Activation of PPAR-α induces FA uptake and oxidation through upregulating the gene expression of FAT/CD36, CPT-1, VLCAD, etc. Previous studies demonstrated decreased activation of PGC-1α/PPARα pathway in chronic AF [16]. AMPK, which can improve fatty acids metabolism via phosphorylation of PGC-1α, was also found decreased in AF [5].…”

Section: Discussionmentioning

confidence: 74%

Metformin improves lipid metabolism and reverses the Warburg effect in a canine model of chronic atrial fibrillation

Bai

et al. 2020

BMC Cardiovasc Disord

“…In addition to oxidative stress, abnormalities in calcium handling, mitochondria DNA damage, and mitochondrial dysfunction readily disrupt cardiac rhythms through depleting energy supply to the ion channels and transporters. An emerging body of evidence implicates disturbances of energy metabolism in the pathogenesis of AF . Recently, Yan et al found that adiponectin, a metabolism‐related protein secreted by adipose tissue that possesses potent cardioprotective effects, attenuated myocardial infarction injury and improved mitochondrial biogenesis by AMP‐activated protein kinase (AMPK)/peroxisome proliferator–activated receptor‐γ coactivator 1α (PGC‐1α) signaling in diabetic hearts.…”

Section: Introductionmentioning

confidence: 99%

Alogliptin, a Dipeptidyl Peptidase‐4 Inhibitor, Alleviates Atrial Remodeling and Improves Mitochondrial Function and Biogenesis in Diabetic Rabbits

Zhang

Zhao

et al. 2017

JAHA

BackgroundThere is increasing evidence implicating atrial mitochondrial dysfunction in the pathogenesis of atrial fibrillation. In this study, we explored whether alogliptin, a dipeptidyl peptidase‐4 inhibitor, can prevent mitochondrial dysfunction and atrial remodeling in a diabetic rabbit model.Methods and ResultsA total of 90 rabbits were randomized into 3 groups as follows: control group (n=30), alloxan‐induced diabetes mellitus group (n=30), and alogliptin‐treated (12.5 mg/kg per day for 8 weeks) diabetes mellitus group (n=30). Echocardiographic and hemodynamic assessments were performed in vivo. The serum concentrations of glucagon‐like peptide‐1, insulin, and inflammatory and oxidative stress markers were measured. Electrophysiological properties of Langendorff‐perfused rabbit hearts were assessed. Mitochondrial morphology, respiratory function, membrane potential, and reactive oxygen species generation rate were assessed. The protein expression of transforming growth factor β1, nuclear factor κB p65, and mitochondrial biogenesis–related proteins were measured by Western blot analysis. Diabetic rabbits exhibited left ventricular hypertrophy and left atrial dilation without obvious hemodynamic abnormalities, and all of these changes were attenuated by alogliptin. Compared with the control group, higher atrial fibrillation inducibility in the diabetes mellitus group was observed, and markedly reduced by alogliptin. Alogliptin decreased mitochondrial reactive oxygen species production rate, prevented mitochondrial membrane depolarization, and alleviated mitochondrial swelling in diabetic rabbits. It also improved mitochondrial biogenesis by peroxisome proliferator–activated receptor‐γ coactivator 1α/nuclear respiratory factor‐1/mitochondrial transcription factor A signaling regulated by adiponectin/AMP‐activated protein kinase.ConclusionsDipeptidyl peptidase‐4 inhibitors can prevent atrial fibrillation by reversing electrophysiological abnormalities, improving mitochondrial function, and promoting mitochondrial biogenesis.

“…Liu et al demonstrated that the protein expression of mCPT-1 and GLUT4 is decreased in atrial tissues from AF patients compared with sinus-rhythm patients, indicating reduced FA oxidation and glucose transport. 57 The protein expression of sirtuin1, PGC-1α, and PPAR-α was also decreased in AF. AF rabbits showed a similar decrease in these molecules; treatment with a PPAR-α agonist (fenofibrate) restored the expression of mCPT-1 and GLUT4 and the activation of the PPAR-α/sirtuin1/PGC-1α pathway, suppressing AF inducibility.…”

Section: Ppar-α/pgc-1α Pathwaymentioning

confidence: 95%

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

Harada

Mĕlka

Sobue

et al. 2017

Circ J

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.