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Metformin regulates adiponectin signalling in epicardial adipose tissue and reduces atrial fibrillation vulnerability.

ABSTRACT: Epicardial adipose tissue (EAT) remodelling is closely related to the pathogenesis of atrial fibrillation (AF). We investigated whether metformin (MET) prevents AF-dependent EAT remodelling and AF vulnerability in dogs. A canine AF model was developed by 6-week rapid atrial pacing (RAP), and electrophysiological parameters were measured. Effective refractory periods (ERP) were decreased in the left and right atrial appendages as well as in the left atrium (LA) and right atrium (RA). MET attenuated the RAP-induced increase in ERP dispersion, cumulative window of vulnerability, AF inducibility and AF duration. RAP increased reactive oxygen species (ROS) production and nuclear factor kappa-B (NF-?B) phosphorylation; up-regulated interleukin-6 (IL-6), tumour necrosis factor-? (TNF-?) and transforming growth factor-?1 (TGF-?1) levels in LA and EAT; decreased peroxisome proliferator-activated receptor gamma (PPAR?) and adiponectin (APN) expression in EAT and was accompanied by atrial fibrosis and adipose infiltration. MET reversed these alterations. In vitro, lipopolysaccharide (LPS) exposure increased IL-6, TNF-? and TGF-?1 expression and decreased PPAR?/APN expression in 3T3-L1 adipocytes, which were all reversed after MET administration. Indirect coculture of HL-1 cells with LPS-stimulated 3T3-L1 conditioned medium (CM) significantly increased IL-6, TNF-? and TGF-?1 expression and decreased SERCA2a and p-PLN expression, while LPS + MET CM and APN treatment alleviated the inflammatory response and sarcoplasmic reticulum Ca2+ handling dysfunction. MET attenuated the RAP-induced increase in AF vulnerability, remodelling of atria and EAT adipokines production profiles. APN may play a key role in the prevention of AF-dependent EAT remodelling and AF vulnerability by MET.

SUBMITTER: Li B

PROVIDER: S-EPMC7348162 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Metformin regulates adiponectin signalling in epicardial adipose tissue and reduces atrial fibrillation vulnerability.

Li Biao B Po Sunny S SS Zhang Baojian B Bai Fan F Li Jiayi J Qin Fen F Liu Na N Sun Chao C Xiao Yichao Y Tu Tao T Zhou Shenghua S Liu Qiming Q

Journal of cellular and molecular medicine 20200522 14

Epicardial adipose tissue (EAT) remodelling is closely related to the pathogenesis of atrial fibrillation (AF). We investigated whether metformin (MET) prevents AF-dependent EAT remodelling and AF vulnerability in dogs. A canine AF model was developed by 6-week rapid atrial pacing (RAP), and electrophysiological parameters were measured. Effective refractory periods (ERP) were decreased in the left and right atrial appendages as well as in the left atrium (LA) and right atrium (RA). MET attenuat ...[more]

PMID: 32441464

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Project description:BackgroundThere are significant differences in the prevalence and prognosis of atrial fibrillation (AF) between sexes. Epicardial adipose tissue (EAT) has been found as a risk factor for AF. This study aimed to evaluate whether sex-based EAT differences were correlated with AF recurrence and major adverse cardiovascular events (MACE).MethodsIn this study, postmenopausal women and age, BMI, and type of AF matched men who had received first catheter ablation were included. EAT volume was quantified based on the pre-ablation cardiac computed tomography (CT) images. Clinical, CT, and echocardiographic variables were compared by sex groups. The predictors of AF recurrence and MACE were determined through Cox proportional hazards regression.ResultsWomen were found with significantly lower total EAT volumes (P < 0.001) but higher periatrial/total (P/T) EAT ratios (P = 0.009). The median follow-up duration was 444.5 days. As revealed by the result of the Kaplan-Meier survival analysis, the women were found to have a significantly higher prevalence of AF recurrence (log rank, P = 0.011) but comparable MACE (log rank, P = 0.507) than men. Multivariate analysis demonstrated that female gender (HR: 1.88 [95% CI: 1.03, 4.15], P = 0.032), persistent AF (HR: 2.46 [95% CI: 1.19, 5.05], P = 0.015), left atrial (LA) dimension (HR: 1.47 [95% CI: 1.02, 2.13], P = 0.041), and P/T EAT ratio (HR: 1.73 [95% CI: 1.12, 2.67], P = 0.013) were found as the independent predictors of AF recurrence. Sex-based subgroup multivariable analysis showed that the P/T EAT ratio was an independent predictor of AF recurrence in both men (HR: 1.13 [95% CI: 1.01, 1.46], P = 0.047) and women (HR: 1.37 [95% CI: 1.11, 1.67], P = 0.028). While age (HR: 1.81 [95% CI: 1.18, 2.77], P = 0.007), BMI (HR: 1.44 [95% CI: 1.02, 2.03], P = 0.038), and periatrial EAT volume (HR: 1.31 [95% CI: 1.01, 1.91], P = 0.046) were found to be independent of MACE.ConclusionWomen had a higher P/T EAT ratio and AF post-ablation recurrence but similar MACE as compared with men. Female gender and P/T EAT ratio were found to be independent predictors of AF recurrence, whereas age and periatrial EAT volume were found to be independent predictors of MACE.

Project description:PurposeThis study aimed to construct a radiomics signature of epicardial adipose tissue for predicting postoperative atrial fibrillation (POAF) after pulmonary endarterectomy (PEA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH).MethodsWe reviewed the preoperative computed tomography pulmonary angiography images of CTEPH patients who underwent PEA at our institution between December 2016 and May 2022. Patients were divided into training/validation and testing cohorts by stratified random sampling in a ratio of 7:3. Radiomics features were selected by using intra- and inter-class correlation coefficient, redundancy analysis, and Least Absolute Shrinkage and Selection Operator algorithm to construct the radiomics signature. The area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the discrimination, calibration, and clinical practicability of the radiomics signature. Two hundred-times stratified five-fold cross-validation was applied to assess the reliability and robustness of the radiomics signature.ResultsA total of 93 patients with CTEPH were included in this study, including 23 patients with POAF and 70 patients without POAF. Five of the 1,218 radiomics features were finally selected to construct the radiomics signature. The radiomics signature showed good discrimination with an AUC of 0.804 (95%CI: 0.664-0.943) in the training/validation cohort and 0.728 (95% CI: 0.503-0.953) in the testing cohorts. The average AUC of 200 times stratified five-fold cross-validation was 0.804 (95%CI: 0.801-0.806) and 0.807 (95%CI: 0.798-0.816) in the training and validation cohorts, respectively. The calibration curve showed good agreement between the predicted and actual observations. Based on the DCA, the radiomics signature was found to be clinically significant and useful.ConclusionThe radiomics signature achieved good discrimination, calibration, and clinical practicability. As a potential imaging biomarker, the radiomics signature of epicardial adipose tissue (EAT) may provide a reference for the risk assessment and individualized treatment of CTEPH patients at high risk of developing POAF after PEA.

Project description:Introduction: Epicardial adipose tissue (EAT) has been linked to incidence and recurrence of atrial fibrillation (AF), but the underlying mechanisms that mediate this association remain unclear. Circulating microRNAs (miRNAs) contribute to the regulation of gene expression in cardiovascular diseases, including AF. Thus, we sought to test the hypothesis that circulating miRNAs relate to burden of EAT. Methods: We examined the plasma miRNA profiles of 91 participants from the miRhythm study, an ongoing study examining associations between miRNA and AF. We quantified plasma expression of 86 unique miRNAs commonly expressed in cardiomyocytes using quantitative reverse transcriptase polymerase chain reaction (qPCR). From computed tomography, we used validated methods to quantify the EAT area surrounding the left atrium (LA) and indexed it to body surface area (BSA) to calculate indexed LA EAT (iLAEAT). Participants were divided into tertiles of iLAEAT to identify associations with unique miRNAs. We performed logistic regression analyses adjusting for factors associated with AF to examine relations between iLAEAT and miRNA. We performed further bioinformatics analysis of miRNA predicted target genes to identify potential molecular pathways are regulated by the miRNAs. Results: The mean age of the participants was 59 ± 9, 35% were women, and 97% were Caucasian. Participants in the highest tertile of iLAEAT were more likely to have hypertension, heart failure, and thick posterior walls. In regression analyses, we found that miRNAs 155-5p (p < 0.001) and 302a-3p (p < 0.001) were significantly associated with iLAEAT in patients with AF. The predicted targets of the miRNAs identified were implicated in the regulation of cardiac hypertrophy, adipogenesis, interleukin-8 (IL-8), and nerve growth factor (NGF) signaling. Conclusion: miRNA as well as EAT have previously been linked to AF. Our finding that iLAEAT and miRNAs 155-5p and 302a-3p are associated suggest a possible direct link to between these entities in the development and maintenance of AF. Further research is needed to study causal relationships between these biomarkers.

Dataset Information

Metformin regulates adiponectin signalling in epicardial adipose tissue and reduces atrial fibrillation vulnerability.

Publications

Metformin regulates adiponectin signalling in epicardial adipose tissue and reduces atrial fibrillation vulnerability.

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