Epicardial Adipose Tissue Ceramides Are Related to Lipoprotein Lipase Activity in Coronary Artery Disease: Unfolding a Missing Link.

BACKGROUND: Epicardial adipose tissue (EAT) contributes to coronary artery disease (CAD). EAT presents a specific lipidomic signature, showing increased ceramides and other proinflammatory lipids content. Besides, LPL (lipoprotein lipase) activity in EAT would contribute to its expansion, supplying fatty acids to the tissue. Our aim was to evaluate the relations between LPL activity, regulators of LPL, and ceramides in EAT from CAD patients. METHODS: We studied patients undergoing coronary bypass graft (CAD, n=25) and patients without CAD (no CAD, n=14). EAT and subcutaneous AT (SAT) were obtained, tissue LPL activity and its regulator's expression (ANGPTL4, GPIHBP1 [glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1], and PPARγ [peroxisomal proliferator-activated receptor γ]) were assessed. Tissue lipidomes were evaluated by UHPLC-MS, in positive and negative ionization modes. RESULTS: LPL activity was higher in EAT from CAD (P<0.001), and in EAT than SAT in both groups (P<0.001). ANGPTL4 levels were lower, GPIHBP1 and PPARγ levels were higher in EAT from CAD (P<0.001). In both groups, EAT exhibited more ceramide (P=0.01), directly associated with LPL activity, being the strongest association with Cer18:1/24:1 (P<0.001). EAT Cer18:1/16:0 to Cer18:1/24:0 and Cer18:1/24:1 to 18:1/24:0 ratios were higher in CAD (P=0.03; P<0.001, respectively), the latter directly associated with LPL activity (r=0.63, P<0.001) GPIHBP1 levels (r=0.68, P<0.001), and inversely to EAT ANGPTL4 expression (r=-0.49, P=0.03). Pairwise partial correlation network showed associations among bioactive lipids and LPL and its regulators (P<0.001 in all cases). CONCLUSIONS: The association between LPL activity, total ceramide, and the atherogenic ceramide ratios highlights the importance of the enzyme and these bioactive lipids contributing to the different metabolic profile of EAT in CAD.

Untargeted Multiomics Approach Coupling Lipidomics and Metabolomics Profiling Reveals New Insights in Diabetic Retinopathy.

Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus (DM) which is the main cause of vision loss in the working-age population. Currently known risk factors such as age, disease duration, and hemoglobin A1c lack sufficient efficiency to distinguish patients with early stages of DR. A total of 194 plasma samples were collected from patients with type 2 DM and DR (moderate to proliferative (PDR) or control (no or mild DR) matched for age, gender, diabetes duration, HbA1c, and hypertension. Untargeted lipidomic and metabolomic approaches were performed. Partial-least square methods were used to analyze the datasets. Levels of 69 metabolites and 85 lipid species were found to be significantly different in the plasma of DR patients versus controls. Metabolite set enrichment analysis indicated that pathways such as metabolism of branched-chain amino acids (methylglutaryl carnitine p = 0.004), the kynurenine pathway (tryptophan p < 0.001), and microbiota metabolism (p-Cresol sulfate p = 0.004) were among the most enriched deregulated pathways in the DR group. Moreover, Glucose-6-phosphate (p = 0.001) and N-methyl-glutamate (p < 0.001) were upregulated in DR. Subgroup analyses identified a specific signature associated with PDR, macular oedema, and DR associated with chronic kidney disease. Phosphatidylcholines (PCs) were dysregulated, with an increase of alkyl-PCs (PC O-42:5 p < 0.001) in DR, while non-ether PCs (PC 14:0-16:1, p < 0.001; PC 18:2-14:0, p < 0.001) were decreased in the DR group. Through an unbiased multiomics approach, we identified metabolites and lipid species that interestingly discriminate patients with or without DR. These features could be a research basis to identify new potential plasma biomarkers to promote 3P medicine.

Untargeted Lipidomics Reveals a Specific Enrichment in Plasmalogens in Epicardial Adipose Tissue and a Specific Signature in Coronary Artery Disease.

OBJECTIVE: Epicardial adipose tissue (EAT) is an active endocrine organ that could contribute to the pathophysiology of coronary artery disease (CAD) through the paracrine release of proatherogenic mediators. Numerous works have analyzed the inflammatory signature of EAT, but scarce informations on its lipidome are available. Our objective was first to study the differences between EAT and subcutaneous adipose tissue (SAT) lipidomes and second to identify the specific untargeted lipidomic signatures of EAT and SAT in CAD. Approach and Results: Subcutaneous and EAT untargeted lipidomic analysis was performed in 25 patients with CAD and 14 patients without CAD and compared with paired plasma lipidomic analysis of isolated VLDL (very low-density lipoprotein) and HDL (high-density lipoprotein). Lipidomics was performed on a C18 column hyphenated to a Q-Exactive plus mass spectrometer, using both positive and negative ionization mode. EAT and SAT had independent lipidomic profile, with 95 lipid species differentially expressed and phosphatidylethanolamine 18:1p/22:6 twenty-fold more expressed in EAT compared with SAT false discovery rate =3×10-4). Patients with CAD exhibited more ceramides (P=0.01), diglycerides (P=0.004; saturated and nonsaturated), monoglycerides (P=0.013) in their EAT than patients without CAD. Conversely, they had lesser unsaturated TG (triglycerides; P=0.02). No difference was observed in the 295 lipid species found in SAT between patients with and without CAD. Fifty-one lipid species were found in common between EAT and plasma lipoproteins. TG 18:0/18:0/18:1 was found positively correlated (r=0.45, P=0.019) in EAT and HDL and in EAT and VLDL (r=0.46, P=0.02). CONCLUSIONS: CAD is associated with specific lipidomic signature of EAT, unlike SAT. Plasma lipoprotein lipidome only partially reflected EAT lipidome.

Endoscopic treatment of fistulas after sleeve gastrectomy: a comparison of internal drainage versus closure.

BACKGROUND AND AIMS: Fistulas after sleeve gastrectomy are major adverse events of bariatric surgery. The endoscopic management strategy evolved from closure to internal drainage after 2013. The main objective of our study was to evaluate and compare these different approaches. METHODS: This retrospective study included all patients treated for fistulas after sleeve gastrectomy in a referral center. Closure management was defined as initial treatment that used a covered metal stent and/or endoclips. Internal drainage management was defined as initial treatment by nasocystic drain and/or a double-pigtail stent. RESULTS: A total of 100 patients (women N = 78, mean [± standard deviation {SD}] age 42 ± 12 years) were included between 2007 and 2015. The mean (± SD) delay between sleeve gastrectomy and the first endoscopy was 82 ± 125 days. The overall success of endoscopic treatment was 86% within 6 ± 27 months. Two patients died. The primary success of internal drainage and closure management occurred in 19 of 22 (86%) and 49 of 77 (63%) patients, respectively. Among patients in failure for closure management, 22 had secondary internal drainage (18 being successful). Success of initial management was significantly higher for internal drainage (P = .043). Factors associated with failure of closure management were in multivariable analysis: collection >5 cm (P = .013). Factors associated with a time >6 months for achieving leakage closure were in multivariable analysis: reoperation before endoscopy (P = .044) and purulent flow at endoscopy (P = .043). CONCLUSIONS: Endoscopic management of fistulas after sleeve gastrectomy was successful in 86% of cases. In cases of collections >5 cm, internal drainage should be proposed first. Surgical reintervention before endoscopy delays treatment success.

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.

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.

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.

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.

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.

Human epicardial adipose tissue contains innate and adaptive lymphoid cells and a higher proportion of innate type 2 lymphoid cells compared to other adipose tissues.

IMPORTANCE: Epicardial adipose tissue (EAT) is a biologically active organ surrounding myocardium and coronary arteries that has been associated with coronary artery disease (CAD) and atrial fibrillation. Previous work has shown that EAT exhibits beige features. OBJECTIVE: Our objective was to determine whether the stromal vascular fraction of the human EAT contains innate or adaptive lymphoid cells compared to thoracic subcutaneous (thSAT), visceral abdominal (VAT) and subcutaneous abdominal (abSAT). PARTICIPANTS: New pangenomic microarray analysis was performed on previous transcriptomic dataset using significance analysis of microarray and ingenuity pathway analysis (n=41) to identify specific immune signature and its link with browning genes. EAT, thSAT, VAT and abSAT samples from explanted patients with severe cardiomyopathies and multi-organ donor patients (n=17) were used for flow cytometry (FC) immunophenotyping assay. Patients were on average 55±16 years-old; 47% had hypertension and 6% CAD. Phenotypic adaptive and innate immune profiles were performed using a TBNK panel and a specific ILC1-2-3 panel including CD127, CD117, CRTH2 (CD294) and activation markers such as CD25 and CD69. RESULTS: Transcriptomic analysis showed a significant positive correlation between the TH2 immune pathway (IL-4, IL-5, IL-13, IL-25, IL-33) and browning genes (UCP-1, PRDM16, TMEM26, CITED1, TBX1) in EAT versus thSAT (R=0.82, P<0.0001). Regarding adaptive immune cells, a preponderance of CD8T cells, a contingent of CD4T cells, and a few B cells were observed in all ATs (P<0.0001). In innate lymphoid cells (ILCs), an increase was observed in visceral ATs (i.e. EAT; VAT 35±8ILCs/g of tissue) compared to their subcutaneous counterpart (i.e. thSAT+abSAT: 8±3 ILCs/g of AT, P=0.002), with a difference in the proportion of the 3 subtypes of ILCs (ILC1>ILC3>ILC2). In addition, we observed an increase in EAT-ILC2 compared to other ATs and almost all these EAT-ILC2 expressed CD69 and/or CD25 activation markers (99.75±0.16%; P<0.0001). We also observed more NKs in EAT and VAT (1520±71 cells/g of AT) than in SATs (562±17 cells/g of AT); P=0.01. CONCLUSION: This is the first study to provide a comparison between innate and adaptive lymphoid cells in human epicardial versus abdominal or thoracic adipose tissues. Further studies are ongoing to decipher whether these cells could be involved in EAT beiging. TRIAL REGISTRATION: CODECOH No. DC-2021-4518 The French agency of biomedicine PFS21-005.

Human epicardial fat has a beige profile and contains higher type 2 innate lymphoid cells than subcutaneous fat.

OBJECTIVE: Epicardial adipose tissue (EAT) is a visceral fat that has been associated with coronary artery disease and atrial fibrillation. Previous work has revealed that EAT exhibits beige features. METHODS: First, a new pan-genomic microarray analysis was performed on previously collected paired human EAT and thoracic subcutaneous AT (thSAT) from the EPICAR study (n = 31) to decipher a specific immune signature and its link with browning genes. Then, adaptive (T and B cells) and innate lymphoid cell (ILC1, ILC2, and ILC3) immunophenotyping assay panels, including CD127, CD117, and prostaglandin D2 receptor 2, were performed on prospectively collected paired human multiorgan donors (n = 18; INTERFACE study). RESULTS: In the EPICAR study, a positive correlation between the T helper cell subtype Th2 immune pathway and browning genes was found in EAT versus thSAT (r = 0.82; p < 0.0001). In the INTERFACE study, this correlation was also observed (r = 0.31; p = 0.017), and a preponderance of CD4+T cells, CD8+T cells, and a few B cells was observed in all ATs (p < 0.0001). An increase in ILCs was observed in visceral AT (VAT) (i.e., EAT + VAT; 30 ± 5 ILCs per gram of AT) compared with subcutaneous counterparts (i.e., thSAT + abdominal SAT; 8 ± 2 ILCs per gram of AT; p = 0.001), with ILC1 being the most frequent (ILC1 > ILC3 > ILC2). Numbers of ILCs per gram of AT correlated with several Th2 or browning genes (IL-13, TNF receptor superfamily member 9 [TNFRSF9], and alkaline phosphatase, biomineralization associated [ALPL]). Interestingly, a specific increase in EAT-ILC2 compared with other ATs was observed, including a significant proportion expressing CD69 and/or CD25 activation markers (97.9% ± 1.2%; p < 0.0001). Finally, more natural killer cells were observed in EAT + VAT than in thSAT + abdominal SAT (p = 0.01). Exclusion of patients with coronary artery disease in the EPICAR and INTERFACE studies did not modify the main findings. Gene expression phenotyping confirmed specific upregulation of Th2 pathway and browning genes (IL-33 and uncoupling protein 1 [UCP-1]) in EAT. CONCLUSIONS: This is the first study, to our knowledge, to provide a comparison between innate and adaptive lymphoid cells in human EAT. Further studies are ongoing to decipher whether these cells could be involved in EAT beiging.

High prevalence of laminopathies among patients with metabolic syndrome.

Constitutional laminopathies, such as the Dunnigan familial partial lipodystrophy, are severe diseases caused by mutations in A-type lamins and share several features with metabolic syndrome (MS). In this study, we hypothesized that MS may be, in some cases, a mild form of laminopathies and use the abnormal cell nucleus phenotype observed in these diseases as a primary screening test in patients suffering from common MS. Nuclear shape and lamin A nucleoplasmic distribution abnormalities were systematically searched in lymphoblastoid cells of 87 consecutive patients with MS. In parallel, five genes encoding either the A-type lamins or the enzymes of the lamin A maturation pathway were systematically sequenced (LMNA, ZMPSTE24, ICMT, FNTA and FNTB). We identified 10 MS patients presenting abnormal nuclear shape and disturbed lamin A/C nuclear distribution. These patients were not clinically different from those without nuclear abnormalities except that they were younger, and had higher triglyceridemia and SGPT levels. Three of them carry a heterozygous mutation in LMNA or in ZMPSTE24, a gene encoding one of the lamin A processing enzymes. All three mutations are novel missense mutations predicted to be damaging. Both lymphoblastoid cells and skin fibroblasts from the patient carrying the mutation in ZMPSTE24, showed accumulation of lamin A precursor, indicating an alteration of the lamin A processing, confirmed by functional study. Together, these results show for the first time, that a significant proportion of MS patients exhibits laminopathies and suggest that systematic investigation of lamin A and its partners should be performed at the diagnosis of this syndrome.

Diet modulates endogenous thrombin generation, a biological estimate of thrombosis risk, independently of the metabolic status.

OBJECTIVE: High endogenous thrombin potential (ETP) is associated with venous and arterial thrombosis. Better knowledge of environmental influences on ETP may help to prevent thrombosis. METHODS AND RESULTS: Weaning rats exhibited high ETP values that decreased in low-fat diet and remained elevated on high-fat diet. In adult rats, high-fat diet-induced ETP increase was independent of coagulation factors, obesity, and insulin resistance and negatively associated with polyunsaturated fatty acid levels. Switching from high-fat diet to low-fat diet reversed the procoagulant phenotype with a slower kinetic than the normalization of hyperinsulinemia. In humans, ETP was independent of body weight whereas it was negatively associated with nutritional markers such as the percentage of energy provided by proteins, the protein:fat ratio, circulating phenolic compounds, and omega-3 polyunsaturated fatty acid. A recommended 3-month healthy diet with reduced energy density, including lipids, decreased ETP (-21%; P<0.0001). Changes in ETP were not associated with body weight, insulin sensitivity, or coagulation factor variations, but correlated negatively with plasma docosahexaenoic acid, a nutritional status sensitive fatty acid, and compounds reflecting vegetable intake. CONCLUSIONS: Diet plays a pivotal role in regulating ETP, independently of obesity and insulin resistance. Global nutritional recommendations could be useful in primary prevention of venous thrombosis.

Contributory role of the tongue and mandible in modulating the in-mouth air cavity at rest.

OBJECTIVES: The tongue-to-palate distance influences the volume of the in-mouth air cavity (IMAC), thus conditioning the entry of aromatic compounds to the olfactory mucosa site. This study was set out to record the IMAC volume by measuring tongue-to-palate distance at rest. MATERIALS AND METHODS: Twelve young adults in good general health were tested--lips contacting, with at-rest posture of the tongue and jaw during a silent reading task. Observations in this study were limited to pre- and post-swallowing sequences. The tongue-to-palate distance was measured using three electromagnetic sensors placed on the tongue upper surface. IMAC volume was evaluated from a geometrical model, taking into account the tongue-to-palate distance, the IMAC transversal distance measured from dental casts and historic data giving the anterior-posterior distance of the oral cavity. RESULTS: (1) In the at-rest posture, the tongue-to-palate distance was significantly greater at the posterior sensor level. (2) A vertical shift in tongue posture at rest frequently appeared following deglutition. The upward shifts were of larger amplitude and more frequent than the downward shifts. (3) Evaluation of the IMAC volume gave an approximate value of 12 ml at rest. (4) The chin sensor at rest was 2.8 ± 0.8 mm below its position when in occlusion. CONCLUSION: The tongue and mandible contribute to shaping the IMAC volume. CLINICAL RELEVANCE: These and other results suggest that deglutition changes tongue-to-palate distance and influences aroma release during mastication/deglutition acts through modulation of the IMAC volume.

Is increased myocardial triglyceride content associated with early changes in left ventricular function? A 1H-MRS and MRI strain study.

Background: Type 2 diabetes (T2D) and obesity induce left ventricular (LV) dysfunction. The underlying pathophysiological mechanisms remain unclear, but myocardial triglyceride content (MTGC) could be involved. Objectives: This study aimed to determine which clinical and biological factors are associated with increased MTGC and to establish whether MTGC is associated with early changes in LV function. Methods: A retrospective study was conducted using five previous prospective cohorts, leading to 338 subjects studied, including 208 well-phenotyped healthy volunteers and 130 subjects living with T2D and/or obesity. All the subjects underwent proton magnetic resonance spectroscopy and feature tracking cardiac magnetic resonance imaging to measure myocardial strain. Results: MTGC content increased with age, body mass index (BMI), waist circumference, T2D, obesity, hypertension, and dyslipidemia, but the only independent correlate found in multivariate analysis was BMI (p=0.01; R²=0.20). MTGC was correlated to LV diastolic dysfunction, notably with the global peak early diastolic circumferential strain rate (r=-0.17, p=0.003), the global peak late diastolic circumferential strain rate (r=0.40, p<0.0001) and global peak late diastolic longitudinal strain rate (r=0.24, p<0.0001). MTGC was also correlated to systolic dysfunction via end-systolic volume index (r=-0.34, p<0.0001) and stroke volume index (r=-0.31, p<0.0001), but not with longitudinal strain (r=0.009, p=0.88). Interestingly, the associations between MTGC and strain measures did not persist in multivariate analysis. Furthermore, MTGC was independently associated with LV end-systolic volume index (p=0.01, R²=0.29), LV end-diastolic volume index (p=0.04, R²=0.46), and LV mass (p=0.002, R²=0.58). Conclusions: Predicting MTGC remains a challenge in routine clinical practice, as only BMI independently correlates with increased MTGC. MTGC may play a role in LV dysfunction but does not appear to be involved in the development of subclinical strain abnormalities.

Early humoral response to COVID-19 vaccination in patients living with obesity and diabetes in France. The COVPOP OBEDIAB study with results from the ANRS0001S COV-POPART cohort.

BACKGROUND: Patients with diabetes and obesity are populations at high-risk for severe COVID-19 outcomes and have shown blunted immune responses when administered different vaccines. Here we used the 'ANRS0001S COV-POPART' French nationwide multicenter prospective cohort to investigate early humoral response to COVID-19 vaccination in the sub-cohort ('COVPOP OBEDIAB') of patients with obesity and diabetes. METHODS: Patients with diabetes (n = 390, type 1 or 2) or obesity (n = 357) who had received two vaccine doses and had no history of previous COVID-19 infection and negative anti-nucleocapsid (NCP) antibodies were included and compared against healthy subjects (n = 573). Humoral response was assessed at baseline, at one month post-first dose (M0) and one-month post-second dose (M1), through percentage of responders (positive anti-spike SARS-CoV-2 IgG antibodies (Sabs), geometric means of Sabs; BAU/mL), proportion of individuals with anti-RBD antibodies, and proportion of individuals with anti-SARS-CoV-2-specific neutralizing antibodies (Nabs). Potential clinical and biological factors associated with weak response (defined as Sabs < 264 BAU/mL) and presence of non-reactive anti-RBD antibodies at M1 were evaluated. Univariate and multivariate regressions were performed to estimate crude and adjusted coefficients with 95 % confidence intervals. Poor glycemic control was defined as HbA1c ≥ 7.5 % at inclusion. RESULTS: Patients with diabetes, particularly type 2 diabetes, and patients with obesity were less likely to have positive Sabs and anti-RBD antibodies after the first and second dose compared to controls (p < 0.001). At M1, we found Sabs seroconversion in 94.1 % of patients with diabetes versus 99.7 % in controls, anti-RBD seroconversion in 93.8 % of patients with diabetes versus 99.1 % in controls, and Nabs seroconversion in 95.7 % of patients with diabetes versus 99.6 % in controls (all p < 0.0001). Sabs and anti-RBD seroconversion at M0 and M1 were also significantly lower in obese patients than controls, at respectively 82.1 % versus 89.9 % (p = 0.001; M0 Sabs), 94.4 % versus 99.7 % (p 0.001; M1 Sabs), 79.0 % vs 86.2 % (p = 0.004 M0 anti-RBD), and 96.99 % vs 99.1 % (p = 0.012 M1 anti-RBD). The factors associated with low vaccine response (BAU < 264/mL) in patients with diabetes were chronic kidney disease (adjusted OR = 6.88 [1.77;26.77], p = 0.005) and poor glycemic control (adjusted OR = 3.92 [1.26;12.14], p = 0.018). In addition, BMI ≥ 40 kg/m2 was found to be associated with a higher vaccine response (adjusted OR = 0.10 [0.01;0.91], p = 0.040) than patients with BMI < 40 kg/m2. CONCLUSION: COVID-19 vaccine humoral response was lower in patients with obesity and diabetes one month after second dose compared to controls, especially in diabetic patients with CKD or inadequate glycemic control. These findings point to the need for post-vaccination serological checks in these high-risk populations.

Time-course changes of muscle protein synthesis associated with obesity-induced lipotoxicity.

The object of the study was to investigate the sequential changes of protein synthesis in skeletal muscle during establishment of obesity, considering muscle typology. Adult Wistar rats were fed a standard diet for 16 weeks (C; n = 14), or a high-fat, high-sucrose diet for 16 (HF16; n = 14) or 24 weeks (HF24; n = 15). Body composition was measured using a dual-energy X-ray absorptiometry scanner. The fractional synthesis rates (FSRs) of muscle protein fractions were calculated in tibialis anterior (TA) and soleus muscles by incorporation of l-13C-valine in muscle protein. Muscle lipid and mitochondria contents were determined using histochemical analysis. Obesity occurred in an initial phase, from 1 to 16 weeks, with an increase in weight (P < 0.05), fat mass (P < 0.001), muscle mass (P < 0.001) and FSR in TA (actin: 5.3 ± 0.2 vs. 8.8 ± 0.5% day−1, C vs. HF16, P < 0.001) compared with standard diet. The second phase, from 16 to 24 weeks, was associated with a weight stabilization, a decrease in muscle mass (P < 0.05) and a decrease in FSR in TA (mitochondrial: 5.6 ± 0.2 vs. 4.2 ± 0.4% day−1, HF16 vs. HF24, P < 0.01) compared with HF16 group. Muscle lipid content was increased in TA in the second phase of obesity development (P < 0.001). Muscle mass, lipid infiltration and muscle protein synthesis were differently affected, depending on the stage of obesity development and muscle typology. Chronic lipid infiltration in glycolytic muscle is concomitant with a reduction of muscle protein synthesis, suggesting that muscle lipid infiltration in response to a high-fat diet is deleterious for the incorporation of amino acid in skeletal muscle proteins.