Two-Year Results of Sleeve Gastrectomy Combined with Posterior Fundoplication for Obesity Patients with Gastroesophageal Reflux Disease.

INTRODUCTION: Currently, gastroesophageal reflux disease (GERD) is the main side effect after sleeve gastrectomy (SG), causing discomfort and potential long-term risks. Surgical techniques combining fundoplication with SG are being evaluated to limit postoperative GERD. METHODS: This single-center retrospective study evaluated patients who underwent SG with posterior fundoplication in the context of GERD between 2018 and 2021, with postoperative follow-up up to 24 months. The results were compared to a control group (ratio 1 to 4) who had SG without fundoplication. Observed total weight loss (TWL) was compared to predicted TWL using the Sophia multinational study's machine learning-based calculator. RESULTS: The series included 22 patients (mean body mass index 44.4 kg/m2) with GERD conditions: GERD symptoms (n = 15), hiatal hernia (n = 6), esophagitis (n = 7), and Barrett's esophagus (n = 5). Two patients required reoperation, including one for valve perforation. At 2 years, GERD was present in three patients (13.6%), including two who regularly took proton pump inhibitors. Compared to the control group (n=88), the frequency of GERD persisting at 2 years was significantly reduced in the SG with fundoplication group (p=0.05). The TWL at 12 and 24 months was 27.7% and 26.1%, respectively, with no significant difference compared to the weight predicted by the model, nor compared to the control group. CONCLUSION: The combination of posterior fundoplication with SG can be proposed in patients with GERD who have a contraindication to Roux-en-Y gastric bypass. Specific morbidity may exist at the beginning of the experience.

The aminosterol Claramine inhibits ß-secretase 1-mediated insulin receptor cleavage.

The cleavage of the insulin receptor by ß-secretase 1 (BACE1) in the liver increases during diabetes, which contributes to reduce insulin receptor levels and impair insulin signaling. However, the precise signaling events that lead to this increased cleavage are unclear. We showed that BACE1 cleaves the insulin receptor in the early secretory pathway. Indeed, coimmunoprecipitation experiments reveal the interaction of the proforms of the two proteins. Moreover, fragments of insulin receptor are detected in the early secretory pathway and a mutated form of BACE1 that retains its prodomain cleaves an early secretory pathway-resident form of the insulin receptor. We showed that BACE1 proform levels are regulated by proteasome and/or lysosome-dependent degradation systems whose efficiencies are dependent on the O-GlcNacylation process. Our results showed that enhanced O-GlcNacylation reduces the efficiency of intracellular protein degradation systems, leading to the accumulation of the proform of BACE1 in the early secretory pathway where it cleaves the precursor of the insulin receptor. All these dysregulations are found in the livers of diabetic mice. In addition, we performed a screen of molecules according to their ability to increase levels of the insulin receptor at the surface of BACE1-overexpressing cells. This approach identified the aminosterol Claramine, which accelerated intracellular trafficking of the proform of BACE1 and increased autophagy. Both of these effects likely contribute to the reduced amount of the proform of BACE1 in the early secretory pathway, thereby reducing insulin receptor cleavage. These newly described properties of Claramine are consistent with its insulin sensitizing effect.

Qualitative study of self-reported experiences of infertile women with polycystic ovary syndrome through on-line discussion forums.

OBJECTIVES: To highlight the self-reported experiences and disease perceptions of infertile women with polycystic ovary syndrome (PCOS). METHODS: A qualitative study using an inductive method was conducted on infertile women with PCOS who shared their self-reported experiences on French-speaking on-line forums. RESULTS: 785 comments by 211 women on 7 forums were analyzed. Women complained of late diagnosis and lack of information regarding PCOS. PCOS and infertility showed negative psychological impact on daily life. This impact appeared to be alleviated by the sharing of knowledge and experience enabled by these forums. CONCLUSION: The self-reported experience of infertile women with PCOS is interesting for health practitioners. The psychological impact of PCOS and perceptions of illness appear to be improved by sharing experiences between women with PCOS, suggesting a beneficial support role of online discussion forums.

Monocytopenia, monocyte morphological anomalies and hyperinflammation characterise severe COVID-19 in type 2 diabetes.

Early in the COVID-19 pandemic, type 2 diabetes (T2D) was marked as a risk factor for severe disease and mortality. Inflammation is central to the aetiology of both conditions where variations in immune responses can mitigate or aggravate disease course. Identifying at-risk groups based on immunoinflammatory signatures is valuable in directing personalised care and developing potential targets for precision therapy. This observational study characterised immunophenotypic variation associated with COVID-19 severity in T2D. Broad-spectrum immunophenotyping quantified 15 leucocyte populations in peripheral circulation from a cohort of 45 hospitalised COVID-19 patients with and without T2D. Lymphocytopenia and specific loss of cytotoxic CD8+ lymphocytes were associated with severe COVID-19 and requirement for intensive care in both non-diabetic and T2D patients. A morphological anomaly of increased monocyte size and monocytopenia restricted to classical CD14Hi CD16- monocytes was specifically associated with severe COVID-19 in patients with T2D requiring intensive care. Increased expression of inflammatory markers reminiscent of the type 1 interferon pathway (IL6, IL8, CCL2, INFB1) underlaid the immunophenotype associated with T2D. These immunophenotypic and hyperinflammatory changes may contribute to increased voracity of COVID-19 in T2D. These findings allow precise identification of T2D patients with severe COVID-19 as well as provide evidence that the type 1 interferon pathway may be an actionable therapeutic target for future studies.

Correction to: Clinical Practice Guidelines for Childbearing Female Candidates for Bariatric Surgery, Pregnancy, and Post-Partum Management after Bariatric Surgery.

In the original article, due to an XML tagging error the name of Véronique Taillard was omitted from the list of members of the French Study Group for Bariatric Surgery and Maternity (the BARIA-MAT Group). The correct list is as follows.

Celiac Disease and Obesity: Is Bariatric Surgery an Option?

Celiac disease is an immune-mediated enteropathy associated with malabsorptive syndrome and fat-soluble vitamin deficiencies. Celiac disease affects 1% of individuals but is largely underdiagnosed, as its multifaceted clinical presentations create challenging diagnostic scenarios. With the rise of the obesity epidemic, doctors are increasingly seeing celiac disease patients with overweight or obesity, which raises the question of bariatric surgery. However, few studies so far have investigated bariatric surgery in this patient population. Here, we provide a comprehensive review of the literature on celiac disease, its nutritional consequences and complications, and we discuss the possible impact of bariatric surgery on weight loss, nutritional deficiencies, response to gluten-free diet, and long-term post-operative complications. We also review the effect of bariatric surgery on the incidence of celiac disease.

Unraveling LMNA Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical Pitfalls.

This study details the clinical and cellular phenotypes associated with two missense heterozygous mutations in LMNA, c.1745G > T p.(Arg582Leu), and c.1892G> A p.(Gly631Asp), in two patients with early onset of diabetes mellitus, hypertriglyceridemia and non-alcoholic fatty liver disease. In these two patients, subcutaneous adipose tissue was persistent, at least on the abdomen, and the serum leptin level remained in the normal range. Cellular studies showed elevated nuclear anomalies, an accelerated senescence rate and a decrease of replication capacity in patient cells. In cellular models, the overexpression of mutated prelamin A phenocopied misshapen nuclei, while the partial reduction of lamin A expression in patient cells significantly improved nuclear morphology. Altogether, these results suggest a link between lamin A mutant expression and senescence associated phenotypes. Transcriptome analysis of the whole subcutaneous adipose tissue from the two patients and three controls, paired for age and sex using RNA sequencing, showed the up regulation of genes implicated in immunity and the down regulation of genes involved in development and cell differentiation in patient adipose tissue. Therefore, our results suggest that some mutations in LMNA are associated with severe metabolic phenotypes without subcutaneous lipoatrophy, and are associated with nuclear misshaping.

Glucagon-like Peptide 1 Receptor Agonists, Diabetic Retinopathy and Angiogenesis: The AngioSafe Type 2 Diabetes Study.

AIMS: Recent trials provide conflicting results on the association between glucagon-like peptide 1 receptor agonists (GLP-1RA) and diabetic retinopathy (DR). The aim of the AngioSafe type 2 diabetes (T2D) study was to determine the role of GLP-1RA in angiogenesis using clinical and preclinical models. METHODS: We performed two studies in humans. In study 1, we investigated the effect of GLP-1RA exposure from T2D diagnosis on the severity of DR, as diagnosed with retinal imaging (fundus photography). In study 2, a randomized 4-week trial, we assessed the effect of liraglutide on circulating hematopoietic progenitor cells (HPCs), and angio-miRNAs.We then studied the experimental effect of Exendin-4, on key steps of angiogenesis: in vitro on human endothelial cell proliferation, survival and three-dimensional vascular morphogenesis; and in vivo on ischemia-induced neovascularization of the retina in mice. RESULTS: In the cohort of 3154 T2D patients, 10% displayed severe DR. In multivariate analysis, sex, disease duration, glycated hemoglobin (HbA1c), micro- and macroangiopathy, insulin therapy and hypertension remained strongly associated with severe DR, while no association was found with GLP-1RA exposure (o 1.139 [0.800-1.622], P = .47). We further showed no effect of liraglutide on HPCs, and angio-miRNAs. In vitro, we demonstrated that exendin-4 had no effect on proliferation and survival of human endothelial cells, no effect on total length and number of capillaries. Finally, in vivo, we showed that exendin-4 did not exert any negative effect on retinal neovascularization. CONCLUSIONS: The AngioSafe T2D studies provide experimental and clinical data confirming no effect of GLP-1RA on angiogenesis and no association between GLP-1 exposure and severe DR.

Clinical Practice Guidelines for Childbearing Female Candidates for Bariatric Surgery, Pregnancy, and Post-partum Management After Bariatric Surgery.

Emerging evidence suggests that bariatric surgery improves pregnancy outcomes of women with obesity by reducing the rates of gestational diabetes, pregnancy-induced hypertension, and macrosomia. However, it is associated with an increased risk of a small-for-gestational-age fetus and prematurity. Based on the work of a multidisciplinary task force, we propose clinical practice recommendations for pregnancy management following bariatric surgery. They are derived from a comprehensive review of the literature, existing guidelines, and expert opinion covering the preferred type of surgery for women of childbearing age, timing between surgery and pregnancy, contraception, systematic nutritional support and management of nutritional deficiencies, screening and management of gestational diabetes, weight gain during pregnancy, gastric banding management, surgical emergencies, obstetrical management, and specific care in the postpartum period and for newborns.

An Experimental Study of Intraluminal Hyperpressure Reproducing a Gastric Leak Following a Sleeve Gastrectomy.

INTRODUCTION: A gastric leak (GL) represents the main post-operative complication following a sleeve gastrectomy (SG) and occurs most commonly at the top of the stapling, without any clear explanation. OBJECTIVE: This experimental study evaluates the biomechanical behavior of post-SG gastric specimens using both insufflation and tensile tests. MATERIALS AND METHODS: A total gastrectomy followed by an ex vivo SG was performed in 15 pigs. The "sleeved" stomachs were subjected to intraluminal hyperpressure until failure. Uniaxial circumferential and longitudinal tensile tests were performed using gastric strips obtained from the "resected" stomachs. All the deformations and burst pressures were recorded and analyzed. RESULTS: A GL appeared in the upper third of the stapling in 73% of cases. The mean burst pressure was 26.3 ± 5.3 mmHg and was significantly correlated with the volume of the "sleeved" stomachs (p = 0.02). The overall deformation of the "sleeved" stomachs was comparable in the frontal (38.3%) and profile (40.5%) planes. The greatest displacement was observed at the failure zone (11 mm on average). The biomechanical behavior of the stomach wall differed according to the strip orientation. The circumferential strips presented a higher strain-to-failure rate (97%) and a lower Young's modulus (0.99 MPa) when compared to the longitudinal strips (45% and 2.58 MPa, respectively). CONCLUSION: This preliminary study reproduced a GL in the same location as observed during clinical practice. The volume of the SG influenced the burst pressure. Further experimental studies and numerical simulations should evaluate the impact of shape modifications on an SG.

Lipodystrophy-like features after total body irradiation among survivors of childhood acute leukemia.

BACKGROUND/OBJECTIVE: The number of long-term survivors of childhood acute leukemia (AL) is substantially growing. These patients are at high risk for metabolic syndrome (MS), especially those who received total body irradiation (TBI). The consequences of children's irradiation on adipose tissue (AT) development in adulthood are currently unknown. The objective of this study is to assess the impact of TBI on AT of childhood AL survivors. DESIGN: We compared the morphological and functional characteristics of AT among survivors of childhood AL who developed MS and received (n = 12) or not received (n = 12) TBI. SUBJECTS/METHODS: Body fat distribution and ectopic fat stores (abdominal visceral and liver fat) were evaluated by DEXA, MRI and 1H-spectroscopy. Functional characteristics of subcutaneous AT were investigated by studying gene expression and pre-adipocyte differentiation in culture. RESULTS: Patients who have received TBI exhibited a lower BMI (minus 5 kg/m2) and a lower waist circumference (minus 14 cm), especially irradiated women. Despite the lower quantity of intra-abdominal AT, irradiated patient displayed a nearly two-fold greater content of liver fat when compared to non-irradiated patient (17 vs 9%, P = 0.008). These lipodystrophic-like features are supplemented by molecular abnormalities in subcutaneous AT of irradiated patients: decrease of gene expression of SREBP1 (minus 39%, P = 0.01) and CIDEA (minus 36%, P = 0.004) and a clear alteration of pre-adipocyte differentiation. CONCLUSIONS: These results strongly support the direct effect of irradiation on AT, especially in women, leading to specific nonalcoholic fatty liver disease, despite lower BMI. A long-term appropriate follow-up is necessary for these patients.

One-year impact of bariatric surgery on serum anti-Mullerian-hormone levels in severely obese women.

INTRODUCTION: Although bariatric surgery seems to increase spontaneous fertility by improving ovulatory function in young women, its impact on ovarian reserve remains largely unknown. OBJECTIVE: To evaluate changes in serum anti-Mullerian hormone (AMH) levels in reproductive-age severely obese women after bariatric surgery (BS). METHODS: AMH levels were measured retrospectively in 39 women (mean age 34.6 ± 1.1 years, range 18-45) that underwent a sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB) at baseline, and 6 and 12 months after BS. Metabolic and micronutrient status, including fasting plasma insulin and glucose, HOMA-IR, leptin, adiponectin, calcium, albumin, transthyretin, ferritin, vitamins (B9, B12, B1, A, E, D), zinc, and selenium, were assessed in all patients before and 1 year after BS. RESULTS: Of the patients, 79% had class-3 obesity. At 6 and 12 months, mean total weight losses (TWL) were 26 and 30%; mean excess weight losses (EWL) were 61.7 and 70.2%. Compared to baseline, AMH levels significantly decreased by 18% at 6 months, and 32% at 12 months post-operatively (p = 0.010 and p = 0.001, respectively). There was no correlation between AMH variation and changes in metabolic parameters or micronutrient levels. Remarkably, changes in AMH levels did not differ between sleeve and RYGB patients and were not correlated with EWL. CONCLUSION: This pilot study shows a drastic reduction in AMH levels at 1 year after BS in reproductive-age severely obese women, which was not related to weight loss: this suggests a negative impact of BS on ovarian reserve, at least in the short term.

Lean body weight is the best scale for venous thromboprophylaxis algorithm in severely obese patients undergoing bariatric surgery.

Severely obese patients undergoing bariatric surgery (BS) are at increased risk for venous thromboembolism (VTE). How standard low molecular weight heparin (LMWH) regimen should be adapted to provide both sufficient efficacy and safety in this setting is unclear. We aimed to compare the influence of four body size descriptors (BSD) on peak anti-Xa levels in BS obese patients receiving LMWH fixed doses to identify which one had the greatest impact. One hundred and thirteen BS obese patients [median body mass index (BMI), 43.3 kg/m2 (IQR, 40.6-48.7 kg/m2)] receiving subcutaneous dalteparin 5000 IU twice daily were included in this prospective monocenter study. Peak steady-state anti-Xa levels were measured peri-operatively following thromboprophylaxis initiation. Only 48% of patients achieved target anti-Xa levels (0.2-0.5 IU/ml). In univariate analysis, age, gender, total body-weight (TBW), lean body-weight (LBW), ideal body-weight (IBW), BMI and estimated glomerural filtration rate (eGFR) were associated with anti-Xa levels. The strongest negative association was observed with LBW (r = -0.56, p < .0001). Receiver operating characteristic curves indicated that among BSD, LBW (cut-off >55.8 kg) had the highest sensitivity (73%) and specificity (69%) to predict sub-prophylactic anti-Xa levels. In multivariate analysis, LBW and eGFR remained associated with anti-Xa levels (ß = -0.47 ±â€¯0.08, p < .0001 and ß = -0.19 ±â€¯0.08; p = .02, respectively). In BS morbidly obese patients receiving LMWH for thromboprophylaxis after BS, LBW and eGFR are the main determinants of anti-Xa level, and could be proposed in LMWH-based thromboprophylaxis dosing algorithms. The efficacy of a LBW-scale based dosing algorithm for optimal VTE prevention deserves further prospective randomized trials.

Preoperative Prediction of Small Bowel Length Using CT Scan and Tridimensional Reconstructions: a New Tool in Bariatric Surgery?

PURPOSE: During Roux-en-Y-gastric Bypass, the limb lengths are preoperatively determined regardless of individual small bowel length (SBL), which presents a great variability. Few studies highlighted anthropometric factors associated with SBL, and none attempted to predict SBL preoperatively. OBJECTIVE: The aim of this study is to evaluate factors correlated to SBL (anthropometric and radiologic) and to establish a preoperative SBL prediction. MATERIAL AND METHODS: In this single-center prospective study, 30 adult patients who underwent laparotomy with a preoperative CT scan were included. Intraoperative SBL measurement was performed with an umbilical tape. Anthropometric parameters were age, gender, height, and BMI. 2D radiological measurements consisted of subcutaneous thickness, abdominal diameters, waist circumference, and mesenteric root length. 3D radiological volumetric reconstructions consisted of whole small bowel and mesentery (WSBM), lean small bowel and mesentery (LSBM), and fat small bowel and mesentery (FSBM). RESULTS: Mean intraoperative measurement of SBL was 531 ± 105 cm. Among the clinical and radiological measurements, the FSBM volume presented the greatest dispersion. Height (p < 0.02) and LSBM volume (p < 0.01) were significantly correlated to the SBL in univariate analysis. LSBM volume was the only measurement significantly associated with SBL in multivariate analysis (p < 0.006). From the multivariate model, a formula was created to predict SBL. The mean percentage difference between predicted and intraoperative SBL measurements for all patients was 13.7%, and 8.4% for obese patients. CONCLUSION: LSBM volume is significantly correlated to the SBL. A preoperative SBL prediction with low percentage error could be performed with LSBM volume.

Perioperative thromboprophylaxis in severely obese patients undergoing bariatric surgery: insights from a French national survey.

BACKGROUND: Venous thromboembolism (VTE) is a leading cause of death in obese patients undergoing bariatric surgery (BS), but there is neither consensus nor high-level guidelines yet on VTE prophylaxis in this specific population. OBJECTIVE: We aimed to evaluate patterns of BS perioperative thromboprophylaxis practices. SETTING: French obesity specialized care centers (CSO), which are tertiary care referral hospitals for the most severe cases of obesity METHODS: A detailed questionnaire survey (11 opened, 15 closed questions) investigating their prophylactic schemes of anticoagulation (molecule, dose, weight-adjustment, duration, associated measures, follow-up) was sent to the 37 CSO. RESULTS: Completion rate was 92%. Over 90% of respondents indicated using low molecular weight heparin. Enoxaparin was the most commonly used molecule (89%), twice daily (71%), started mostly 6 hours after BS (74%), whereas fondaparinux (9%), dalteparin (6%), and tinzaparin (6%) were less often prescribed. Dosing varied significantly according to centers from 4000 to 12,000 IU/d, with the most commonly used dose being 8000 IU once daily, 83%, as well as treatment duration (1 week, 9%; 3 weeks, 47%). Half CSO adjusted low molecular weight heparin dose to weight. Biological monitoring was performed in 88%. Only 1 center followed systematically anti-Xa activity. Associated measures such as elastic stoking or intermittent pneumatic compression were used in 32% and 26%, respectively, and both were used in 39%. CONCLUSION: This study finds significant discrepancies in thromboprophylaxis practices in obese patients undergoing BS, particularly with respect to treatment duration and dose adjustment, highlighting the urgent need for improved implementation of existing clinical practice guidelines in this VTE high-risk population.

A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy.

ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD), Progeria or Mandibulo-Acral Dysplasia (MAD). We report here the phenotype of a patient referred for severe metabolic syndrome and cardiomyopathy, carrying a mutation in ZMPSTE24. The patient presented with a partial lipodystrophic syndrome associating hypertriglyceridemia, early onset type 2 diabetes, and android obesity with truncal and abdominal fat accumulation but without subcutaneous lipoatrophy. Other clinical features included acanthosis nigricans, liver steatosis, dilated cardiomyopathy, and high myocardial and hepatic triglycerides content. Mutated fibroblasts from the patient showed increased nuclear shape abnormalities and premature senescence as demonstrated by a decreased Population Doubling Level, an increased beta-galactosidase activity and a decreased BrdU incorporation rate. Reduced prelamin A expression by siRNA targeted toward LMNA transcripts resulted in decreased nuclear anomalies. We show here that a central obesity without subcutaneous lipoatrophy is associated with a laminopathy due to a heterozygous missense mutation in ZMPSTE24. Given the high prevalence of metabolic syndrome and android obesity in the general population, and in the absence of familial study, the causative link between mutation and phenotype cannot be formally established. Nevertheless, altered lamina architecture observed in mutated fibroblasts are responsible for premature cellular senescence and could contribute to the phenotype observed in this patient.

Time course of cardiometabolic alterations in a high fat high sucrose diet mice model and improvement after GLP-1 analog treatment using multimodal cardiovascular magnetic resonance.

BACKGROUND: Cardiovascular complications of obesity and diabetes are major health problems. Assessing their development, their link with ectopic fat deposition and their flexibility with therapeutic intervention is essential. The aim of this study was to longitudinally investigate cardiac alterations and ectopic fat accumulation associated with diet-induced obesity using multimodal cardiovascular magnetic resonance (CMR) in mice. The second objective was to monitor cardiac response to exendin-4 (GLP-1 receptor agonist). METHODS: Male C57BL6R mice subjected to a high fat (35 %) high sucrose (34 %) (HFHSD) or a standard diet (SD) during 4 months were explored every month with multimodal CMR to determine hepatic and myocardial triglyceride content (HTGC, MTGC) using proton MR spectroscopy, cardiac function with cine cardiac MR (CMR) and myocardial perfusion with arterial spin labeling CMR. Furthermore, mice treated with exendin-4 (30 µg/kg SC BID) after 4 months of diet were explored before and 14 days post-treatment with multimodal CMR. RESULTS: HFHSD mice became significantly heavier (+33 %) and displayed glucose homeostasis impairment (1-month) as compared to SD mice, and developed early increase in HTGC (1 month, +59 %) and MTGC (2-month, +63 %). After 3 months, HFHSD mice developed cardiac dysfunction with significantly higher diastolic septum wall thickness (sWtnD) (1.28 ± 0.03 mm vs. 1.12 ± 0.03 mm) and lower cardiac index (0.45 ± 0.06 mL/min/g vs. 0.68 ± 0.07 mL/min/g, p = 0.02) compared to SD mice. A significantly lower cardiac perfusion was also observed (4 months:7.5 ± 0.8 mL/g/min vs. 10.0 ± 0.7 mL/g/min, p = 0.03). Cardiac function at 4 months was negatively correlated to both HTGC and MTGC (p < 0.05). 14-day treatment with Exendin-4 (Ex-4) dramatically reversed all these alterations in comparison with placebo-treated HFHSD. Ex-4 diminished myocardial triglyceride content (-57.8 ± 4.1 %), improved cardiac index (+38.9 ± 10.9 %) and restored myocardial perfusion (+52.8 ± 16.4 %) under isoflurane anesthesia. Interestingly, increased wall thickness and hepatic steatosis reductions were independent of weight loss and glycemia decrease in multivariate analysis (p < 0.05). CONCLUSION: CMR longitudinal follow-up of cardiac consequences of obesity and diabetes showed early accumulation of ectopic fat in mice before the occurrence of microvascular and contractile dysfunction. This study also supports a cardioprotective effect of glucagon-like peptide-1 receptor agonist.

Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines.

AIMS: Recent studies have reported a relationship between the abundance of epicardial adipose tissue (EAT) and the risk of cardiovascular diseases including atrial fibrillation (AF). However, the underlying mechanisms are unknown. The aim of this study was to examine the effects of the secretome of human EAT on the histological properties of the myocardium. METHODS AND RESULTS: Samples of EAT and subcutaneous adipose (SAT), obtained from 39 patients undergoing coronary bypass surgery, were analysed and tested in an organo-culture model of rat atria to evaluate the fibrotic properties of human fat depots. The EAT secretome induced global fibrosis (interstitial and peripheral) of rat atria in organo-culture conditions. Activin A was highly expressed in EAT compared with SAT and promoted atrial fibrosis, an effect blocked using neutralizing antibody. In addition, Activin A levels were enhanced in patients with low left-ventricular function. In sections of human atrial and ventricular myocardium, adipose and myocardial tissues were in close contact, together with fibrosis. CONCLUSION: This study provides the first evidence that the secretome from EAT promotes myocardial fibrosis through the secretion of adipo-fibrokines such as Activin A.