Enhanced Levels of Adiposity, Stretch and Fibrosis Markers in Patients with Coexistent Heart Failure and Atrial Fibrillation.

The coexistence of heart failure (HF) and atrial fibrillation (AF) worsens the prognosis of patients. We aimed to study the inflammation, metabolism, adiposity, and fibrosis markers on epicardial and subcutaneous fat and blood, and their relationship with HF and AF. Samples from 185 patients undergoing cardiac surgery were collected. Levels of multi-markers on fat biopsies and plasma were analyzed. Patients were grouped by HF or AF presence. Plasma adiposity markers were increased in AF patients, while increased stretch markers correlated with HF. Patients with both AF and HF had higher ANP and GDF-15 levels. After excluding AF patients, plasma FABP4 was identified as the main HF predictor. Fat biopsies from AF patients showed an enhanced inflammatory profile. Higher levels of adiposity markers are associated with AF or HF, and higher stretch and fibrosis markers with combined AF and HF, suggesting a role of adiposity-fibrosis pathway in HF and AF coexistence.

The role of pericardial fluid biomarkers in predicting post-operative atrial fibrillation, a comprehensive review of current literature.

Post-operative atrial fibrillation (POAF) is a common complication of cardiac surgery which is associated with longer hospital stay, diminished quality of life, and increased mortality. Yet, the pathophysiology of POAF is poorly understood and it is unclear which patients are at highest risk. Pericardial fluid (PCF) analysis is emerging as an important tool for the early detection of biochemical and molecular changes in the cardiac tissue. With the epicardium acting as a semi-permeable membrane, the composition of PCF reflects the activity of the cardiac interstitium. Emerging research on PCF composition has identified promising biomarkers which may help stratify the risk for developing POAF. These include inflammatory molecules, such as interleukin-6, mitochondrial deoxyribonucleic acid, and myeloperoxidase, as well as natriuretic peptides. Additionally, PCF appears to be superior to serum analysis in detecting changes in these molecules during the early postoperative period after cardiac surgery. The aim of the present narrative review is to summarize the current literature on the temporal changes in the levels of potential biomarkers in PCF after cardiac surgery and their association with the development of new-onset postoperative atrial fibrillation.

The Impact Of Active Chest Tube Clearance Technology On Surgical Outcomes After Cardiac Surgery: An Updated Systematic Review And Meta-Analysis.

OBJECTIVE: Active chest tube clearance technology (ACT) systems were introduced to improve the patency of chest tubes and to reduce the potential complications associated with inadequate mediastinal blood drainage after cardiac surgical procedures. The purpose of this study is to assess the impact of ACT on the incidence of chest tube clogging, retained blood syndromes (RBS), re-exploration for bleeding, and the incidence of postoperative atrial fibrillation (POAF) after cardiac surgical procedures. METHODS: A database search was conducted using Medline, Embase, Cochrane Library, and Web of Science. Only articles comparing the use of ACT to conventional chest tube drainage after cardiac surgery were screened. Included articles were restricted to adult patients and English language only. RESULTS: Nine of the 841 articles screened were included in this review. Two studies were randomized controlled trials (RCT) and seven were observational studies. Pooled estimates showed RBS, surgical re-exploration rates, and POAF were significantly less common in the ACT group. CONCLUSION: Our meta-analysis suggests that the use of ACT may be beneficial in reducing the incidence of postoperative complications associated with inadequate drainage of mediastinal blood after cardiac surgery. However, more robust evidence is required to endorse these findings and support the routing use of ACT in clinical practice.

Effectiveness of intra-operative topical amiodarone for prevention of postcardiac surgery new-onset atrial fibrillation: A review of current evidence.

BACKGROUND: Postoperative atrial fibrillation (POAF) is one of the most common complications following cardiac surgery and is associated with increased morbidity. Intraoperative topical amiodarone application on epicardial tissue has been shown to reduce systemic concentrations while maintaining therapeutic myocardial concentrations, thereby, lowering the risk of extracardiac adverse effects associated with oral and intravenous amiodarone therapy. However, the efficacy and safety of topical amiodarone in preventing POAF is unclear. OBJECTIVES: This study summarizes the clinical studies to-date that have investigated the efficacy and safety of topical amiodarone administration in preventing POAF following cardiac surgery. METHODS: A database search was conducted using Medline, Embase, and Cochrane Library to identify relevant studies. Abstracts were screened and data were extracted from relevant full-text articles that met the inclusion and exclusion criteria. RESULTS: The search returned four studies with variable findings on the effect of topical amiodarone therapy on the incidence of POAF, cardiac effects, extracardiac effects, and hospital length of stay. CONCLUSION: Prophylactic topical application of amiodarone may be effective and safe for preventing post-operative new-onset atrial fibrillation. Further investigation is required to evaluate the efficacy and safety of topical amiodadrone therapy before it can be widely integrated into current practice.

The use of sutureless and rapid-deployment aortic valve prosthesis in patients with bicuspid aortic valve: A focused review.

OBJECTIVE: The objective of this scoping review is to describe the postoperative outcomes and complications of patients with bicuspid aortic valve (BAV) treated with sutureless or rapid-deployment prosthesis. BACKGROUND: The use of sutureless and rapid-deployment prostheses is generally avoided in patients with BAV due to anatomical concerns and the elevated risk of para-prosthetic leaks. Multiple studies have reported the use of these prostheses into patients with BAV with varying degrees of success. The focus of this review is to consolidate the current available evidence on this topic. METHODS: A scoping review was conducted using a comprehensive search strategy in multiple databases (Medline, Embase, Cochrane Central Register of Controlled Clinical Trials) for relevant articles. All abstracts and full texts were screened by two independent reviewers according to predefined inclusion and exclusion criteria. Thirteen articles, including case reports and case series were ultimately included for analysis. RESULTS: Of 1052 total citations, 44 underwent full text review and 13 (4 case reports, 6 retrospective analyses, and 3 prospective analyses) were included in the scoping review. Across all 13 studies, a total of 314 patients with BAV were used for data analysis. In sutureless and rapid-deployment prostheses, the mean postoperative aortic valvular gradients were less than 15 mmHg in all studies with mean postoperative aortic valvular areas all greater than 1.3 cm.2 There were 186 total complications for an overall complication rate of 59%. Individual complications included new onset atrial fibrillation (n = 65), required pacemaker insertion (n = 24), intraprosthetic aortic regurgitation (n = 20), new onset atrioventricular block (n = 18), and new onset paravalvular leakage (n = 10). CONCLUSIONS: The use of sutureless and rapid deployment prostheses in patients with BAV showed comparable intraoperative and implantation success rates to patients without BAV. Postoperative complications from using these prostheses in patients with BAV included new onset atrial fibrillation, intraprosthetic aortic regurgitation, new onset atrioventricular block, and required pacemaker insertion. Various techniques have been described to minimize these complications in patients with BAV receiving sutureless or rapid deployment prostheses.

The Effect of Mineralocorticoid Receptor 3 Antagonists on Anti-Inflammatory and Anti-Fatty Acid Transport Profile in Patients with Heart Failure.

Epicardial fat thickness is associated with cardiovascular disease. Mineralocorticoid receptor antagonist (MRA), a pharmaceutical treatment for CVD, was found to have an effect on adipose tissue. Our aim was to analyse the main epicardial fat genesis and inflammation-involved cell markers and their regulation by risk factors and MRA. We included blood and epicardial or subcutaneous fat (EAT or SAT) from 71 patients undergoing heart surgery and blood from 66 patients with heart failure. Cell types (transcripts or proteins) were analysed by real-time polymerase chain reaction or immunohistochemistry. Plasma proteins were analysed by Luminex technology or enzyme-linked immunoassay. Our results showed an upregulation of fatty acid transporter levels after aldosterone-induced genesis. The MRA intake was the main factor associated with lower levels in epicardial fat. On the contrary, MRA upregulated the levels and its secretion of the anti-inflammatory marker intelectin 1 and reduced the proliferation of epicardial fibroblasts. Our results have shown the local MRA intake effect on fatty acid transporters and anti-inflammatory marker levels and the proliferation rate on epicardial fat fibroblasts. They suggest the role of MRA on epicardial fat genesis and remodelling in patients with cardiovascular disease. Translational perspective: the knowledge of epicardial fat genesis and its modulation by drugs might be useful for improving the treatments of cardiovascular disease.

High released lactate by epicardial fat from coronary artery disease patients is reduced by dapagliflozin treatment.

BACKGROUND AND AIMS: Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, improves glucose uptake by epicardial adipose tissue (EAT). However, its metabolism might raise the lactate production and acidosis under hypoxia conditions, i.e. coronary artery disease (CAD), or lipogenesis and, in consequence, expand adipose tissue. Since lactate secreted by adipose tissue is correlated with tissue stress and inflammation, our aim was to study glucose metabolism by epicardial fat in CAD and its regulation by dapagliflozin. METHODS: Paired EAT and subcutaneous adipose tissue (SAT) biopsies from 49 patients who underwent open-heart surgery were cultured and split into three equal pieces, some treated with and others without dapagliflozin at 10 or 100 µM for 6 h. Anaerobic glucose metabolites were measured in supernatants of fat pads, and acidosis on adipogenesis-induced primary culture cells was analysed by colorimetric or fluorescence assays. Gene expression levels were assessed by real-time polymerase chain reaction. RESULTS: Our results showed that dapagliflozin reduced the released lactate and acidosis in epicardial fat (p < 0.05) without changes in lipid storage-involved genes. In addition, this drug induced gene expression levels of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α), a mitochondrial biogenesis-involved gene in both EAT and SAT (p < 0.05). After splitting the population regarding the presence of CAD, we observed higher lactate production in EAT from these patients (2.46 [1.75-3.47] mM), which was reduced after treatment with dapagliflozin 100 µM (1.99 [1.08-2.99] mM, p < 0.01). CONCLUSIONS: Dapagliflozin improved glucose metabolism without lipogenesis-involved gene regulation or lactate production, mainly in patients with CAD. These results suggest an improvement of glucose oxidation metabolism that can contribute to cardiovascular benefits.

Nutrients restriction upregulates adiponectin in epicardial or subcutaneous adipose tissue: impact in de novo heart failure patients.

Background: Hyperadiponectinemia is an indicator of worse outcomes in advanced heart failure (HF), its role in de novo HF is less clear. Objective: Because this protein is a hormone with starvation properties, we wanted to know its association with nutritional state and its regulator factors in de novo HF. Methods: Adiponectin circulating levels were determined by ELISA at discharge in patients admitted for de novo HF (n=74). Nutritional status was determined by CONUT score. Univariate and multivariate Cox regression analyses were employed to calculate the estimated hazard ratio (HR) with 95% confidence interval (CI) for death or all-cause readmission. Stromal vascular cells (SVC) of EAT and subcutaneous adipose tissue (SAT) from patients (n=5) underwent heart surgery were induced to adipogenesis for 18 days. Then, cells were cultured with complete or starved medium for 8 hours. At the end, adiponectin expression levels were analysed by real time polymerase chain reaction. Results: Patients were grouped regarding nutritional status. There was a strong association between high adiponectin levels and failing nutritional status. Those patients with worse nutritional state had the highest adiponectin and proBNP levels at discharge (p<0.01). Both proteins were slightly correlated (p<0.05). However, only high adiponectin levels were independently associated with death or all-cause readmission. Nutrients starvation upregulated adiponectin expression levels in adipogenesis-induced SVC from EAT or SAT. Conclusions: Worse nutritional state in de novo HF patients is associated with higher adiponectin plasma levels. Their levels were upregulated in adipose cells after being nutrients-starved. These results may help us to understand the adiponectin paradox in HF.

Omentin treatment of epicardial fat improves its anti-inflammatory activity and paracrine benefit on smooth muscle cells.

OBJECTIVE: Epicardial adipose tissue (EAT) in coronary artery disease is insulin resistant and has a proinflammatory profile. This study examined the regulation of EAT by exogenous omentin and its consequence on vascular cells. METHODS: Stromal vascular cells (SC) of EAT and subcutaneous adipose tissue (SAT) from patients who underwent heart surgery were cultured and exposed to adipogenic factors with or without omentin. Proinflammatory cytokine regulation by omentin was analyzed in SC and mature adipocytes. Glucose uptake by EAT and SAT explants was determined after insulin, omentin, or combined treatment. Human vascular cells were exposed to secretomes of SC, with and without omentin treatment. Migration of smooth muscle cells and expression of adhesion molecules were determined by wound healing or real-time polymerase chain reaction, respectively. RESULTS: Omentin treatment raised adipogenesis-induced adiponectin levels on SC of EAT and reduced TNF-α expression levels (0.58 ± 0.14-fold change; P = 0.034) in mature adipocytes. Omentin improved the insulin activity of EAT and SAT explants from cardiovascular disease patients. Finally, secretomes of SC under omentin treatment reduced the migration of smooth muscle cells. CONCLUSIONS: Exogenous omentin might support a cardioprotective role through its effect on EAT regarding glucose uptake, anti-inflammatory response, and its paracrine role on smooth muscle cells.

Glucose and Inflammatory Cells Decrease Adiponectin in Epicardial Adipose Tissue Cells: Paracrine Consequences on Vascular Endothelium.

Epicardial adipose tissue (EAT) is a source of energy for heart that expresses the insulin-sensitizer, anti-inflammatory and anti-atherogenic protein, adiponectin. But, in coronary artery disease, adiponectin production declines. Our objective was to determine its regulation by glucose and inflammation in stromal cells from EAT and subcutaneous adipose tissue (SAT) and its paracrine effect on endothelial cells. Stromal cells of EAT and SAT were obtained from patients who underwent cardiac surgery. Adipogenesis was induced at 117, 200, or 295 mg/dl glucose, with or without macrophage-conditioned medium (MCM). Expression of adiponectin, GLUT-4 and the insulin receptor was analyzed by real-time PCR. The paracrine effect of stromal cells was determined in co-cultures with endothelial cells, by exposing them to high glucose and/or MCM, and, additionally, to leukocyte-conditioned medium from patients with myocardial infarction. The endothelial response was determined by analyzing vascular adhesion molecule expression. Our results showed a U-shaped dose-response curve of glucose on adiponectin in EAT, but not in SAT stromal cells. Conversely, MCM reduced the adipogenesis-induced adiponectin expression of EAT stromal cells. The presence of EAT stromal increased the inflammatory molecules of endothelial cells. This deleterious effect was emphasized in the presence of inflammatory cell-conditioned medium from patients with myocardial infarction. Thus, high glucose and inflammatory cells reduced adipogenesis-induced adiponectin expression of EAT stromal cells, which induced an inflammatory paracrine process in endothelial cells. This inflammatory effect was lower in presence of mature adipocytes, producers of adiponectin. These results contribute to understanding the role of EAT dysfunction on coronary atherosclerosis progression.

Orosomucoid secretion levels by epicardial adipose tissue as possible indicator of endothelial dysfunction in diabetes mellitus or inflammation in coronary artery disease.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is associated with fat and autonomic system dysfunction. Epicardial adipose tissue (EAT) plays an endocrine role over the heart. Since orosomucoid (ORM) has local actions around the coronaries, our aim was to assess the relationship between its secretion profile by EAT and its catecholaminergic regulation in patients with T2DM and coronary artery disease (CAD). METHODS: We obtained EAT, subcutaneous adipose tissue (SAT) and plasma from 55 patients undergoing cardiac surgery. Fat explants were stimulated with isoproterenol (ISO) 1 µM for 6 h. After, the fat explants released-ORM and plasma levels were analyzed by ELISA. mRNA or protein expression was analyzed by real time PCR or western blot, respectively. The effects of ORM on endothelial cells were analyzed by impedance and wound healing assays. RESULTS: We observed that EAT-released ORM levels were higher than SAT (328 ± 185 vs 58 ± 45 ng/mL; p < 0.001). Interestingly, EAT secretion was lower in patients with than those without T2DM (260 ± 141 vs 370 ± 194 ng/mL; p < 0.05) and this difference was enhanced after ISO stimulation (p < 0.01). However, plasma levels (412 ± 119 vs 594 ± 207 µg/mL) and EAT-released ORM levels were higher in patients with than those without CAD (384 ± 195 vs 279 ± 159 ng/mL; p < 0.05). ISO stimulation, also reduced the EAT released-ORM levels in patients with CAD. On human endothelial cells, ORM induced an increase of healing and proliferation in a dose-dependent manner. CONCLUSION: EAT-released ORM levels in patients with T2DM or CAD and its regulation by catecholamines might be the mirror of local endothelium dysfunction or inflammatory process in different cardiovascular disorders.

Impaired adipogenesis and insulin resistance in epicardial fat-mesenchymal cells from patients with cardiovascular disease.

The thickness of epicardial adipose tissue (EAT), which is an inflammatory source for coronary artery disease (CAD), correlates with insulin resistance. One trigger factor is impaired adipogenesis. Here, our aim was to clarify the underlying mechanisms of insulin resistance on EAT-mesenchymal cells (MC). EAT and subcutaneous adipose tissue (SAT) were collected from 19 patients who were undergoing heart surgery. Their dedifferentiated adipocytes (DAs) and/or MCs were cultured. After the induction of adipogenesis or stimulation with insulin, the expression of adipokines was analyzed using real-time polymerase chain reaction (PCR). Colorimetric assays were performed to measure glucose levels and proliferation rate. Proteins modifications were detected via the proteomic approach and Western blot. Our results showed lower adipogenic ability in EAT-MCs than in SAT-MCs. Maximum adiponectin levels were reached within 28-35 days of exposure to adipogenic inducers. Moreover, the adipogenesis profile in EAT-MCs was dependent on the patients' clinical characteristics. The low adipogenic ability of EAT-MCs might be associated with an insulin-resistant state because chronic insulin treatment reduced the inflammatory cytokine expression levels, improved the glucose consumption, and increased the post-translational modifications (PTMs) of the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1). We found lower adipogenic ability in EAT-MCs than in SAT-MCs. This lower ability level was dependent on gender and the presence of diabetes, obesity, and CAD. Low adipogenesis ability and insulin resistance in EAT-MCs might shed light on the association between EAT dysfunction and cardiovascular disease.

Changes in lipid transport-involved proteins of epicardial adipose tissue associated with coronary artery disease.

OBJECTIVE: Recent studies have focused on the potential role of epicardial adipose tissue (EAT) in the physiopathology of several metabolic and cardiovascular diseases, especially coronary artery disease (CAD). We aimed to study whether there are differences in the proteome and the secretome between epicardial and subcutaneous adipose tissue (SAT) from patients with and without CAD. METHODS: EAT and SAT samples were collected from 64 patients undergoing elective cardiac surgery either for coronary artery bypass grafting or valve surgery. One or two-dimensional electrophoresis were performed on tissue samples and media collected at 3, 6, 24 or 48 of tissue culture. Protein identification was performed with mass spectrometry, and the results were then validated with Western blot or enzyme immunoassay. mRNA expression levels were analysed by real time polymerase chain reaction. RESULTS: The release of several proteins was found to be higher in EAT that in SAT. Remarkably, there were higher levels of apolipoprotein A-I and glutation S-transferase P release, whereas mRNA expression of fatty acid binding protein 4 was lower in EAT. Although apolipoprotein A-I protein quantity in EAT was similar between CAD and non CAD patients, its released levels from this fat pad were lower in CAD. CONCLUSION: EAT and SAT show different profiles of protein release and a different pattern was also found in samples from patients with CAD. These findings might support the hypothesis that EAT plays an interesting role in the physiopathology of atherosclerosis and CAD.

Proteomic analysis of epicardial and subcutaneous adipose tissue reveals differences in proteins involved in oxidative stress.

Epicardial adipose tissue (EAT) is an endocrine organ adjacent to coronary arteries and myocardium without anatomy barriers. Locally produced adipokines may reflect or affect to cardiovascular physiology and pathology. Our aim was to study the protein expression profiles of EAT and subcutaneous adipose tissue (SAT) to identify local candidate molecules characterizing EAT in patients with cardiovascular disease. EAT and SAT samples were collected from 55 patients undergoing heart surgery. Proteins from these tissues were separated by two-dimensional (2D) gel electrophoresis, and differences between them were identified by MALDI-TOF/TOF spectra. Differences in protein levels were further investigated by real-time RT-PCR and Western blots, and production of reactive oxygen species (ROS) in EAT and SAT was evaluated by nitroblue tetrazolium chloride assays. ROS production was higher in EAT than SAT. We have found mRNA differences for catalase, glutathione S-transferase P, and protein disulfide isomerase, and 2D Western blots additionally showed post-translational differences for phosphoglycerate mutase 1; all four are related to oxidative stress pathways. EAT suffers greater oxidative stress than SAT in patients with cardiovascular diseases and exhibits associated proteomic differences that suggest the possibility of its association with myocardial stress in these patients.

Extension of coronary artery disease is associated with increased IL-6 and decreased adiponectin gene expression in epicardial adipose tissue.

UNLABELLED: Epicardial adipose tissue (EAT) expresses lower levels of adiponectin in patients with CAD and higher levels of inflammatory mediators such as IL-6 and leptin than subcutaneous adipose tissue. This showed one important role of EAT in coronary artery disease. However, the relationship of EAT adiponectin and IL-6 levels to the extension of coronary artery disease has not hitherto been determined. We sought to determine whether the levels of adiponectin and interleukin-6 (IL-6) mRNA in epicardial adipose tissue are associated with the extension of coronary artery disease (CAD). METHODS: Angiographic and hormones expression were evaluated from epicardial and subcutaneous adipose tissue. 92 patients (58 CAD, 34 non-CAD) who underwent cardiac surgery. Adiponectin and IL-6 mRNA levels were measured by real time RT-PCR in epicardial and subcutaneous adipose tissue (SAT) following angiographic evaluation of their coronary arteries. RESULTS: We found that epicardial adipose tissue of CAD expressed lower levels of adiponectin mRNA and higher levels of IL-6 mRNA than that of non-CAD patients. As the number of injured arteries rose, adiponectin mRNA levels decreased (r=-0.402, p<0.001) and IL-6 mRNA increased (r=0.514, p<0.001) in epicardial adipose tissue. CONCLUSIONS: The extension of CAD is significantly associated with the expression of adiponectin and IL-6 mRNA in EAT. These findings suggest that low adiponectin and high IL-6 expression by EAT may contribute to CAD extension.