Semaglutide modulates prothrombotic and atherosclerotic mechanisms, associated with epicardial fat, neutrophils and endothelial cells network.

BACKGROUND: Obesity has increased in recent years with consequences on diabetes and other comorbidities. Thus, 1 out of 3 diabetic patients suffers cardiovascular disease (CVD). The network among glucose, immune system, endothelium and epicardial fat has an important role on pro-inflammatory and thrombotic mechanisms of atherogenesis. Since semaglutide, long-acting glucagon like peptide 1- receptor agonist (GLP-1-RA), a glucose-lowering drug, reduces body weight, we aimed to study its effects on human epicardial fat (EAT), aortic endothelial cells and neutrophils as atherogenesis involved-cardiovascular cells. METHODS: EAT and subcutaneous fat (SAT) were collected from patients undergoing cardiac surgery. Differential glucose consumption and protein cargo of fat-released exosomes, after semaglutide or/and insulin treatment were analyzed by enzymatic and TripleTOF, respectively. Human neutrophils phenotype and their adhesion to aortic endothelial cells (HAEC) or angiogenesis were analyzed by flow cytometry and functional fluorescence analysis. Immune cells and plasma protein markers were determined by flow cytometry and Luminex-multiplex on patients before and after 6 months treatment with semaglutide. RESULTS: GLP-1 receptor was expressed on fat and neutrophils. Differential exosomes-protein cargo was identified on EAT explants after semaglutide treatment. This drug increased secretion of gelsolin, antithrombotic protein, by EAT, modulated CD11b on neutrophils, its migration and endothelial adhesion, induced by adiposity protein, FABP4, or a chemoattractant. Monocytes and neutrophils phenotype and plasma adiposity, stretch, mesothelial, fibrotic, and inflammatory markers on patients underwent semaglutide treatment for 6 months showed a 20% reduction with statistical significance on FABP4 levels and an 80% increase of neutrophils-CD88. CONCLUSION: Semaglutide increases endocrine activity of epicardial fat with antithrombotic properties. Moreover, this drug modulates the pro-inflammatory and atherogenic profile induced by the adiposity marker, FABP4, which is also reduced in patients after semaglutide treatment.

Nutritional status is related to heart failure severity and hospital readmissions in acute heart failure.

BACKGROUND: Malnutrition is common in hospitalized heart failure (HF) patients and predicts adverse outcomes. The relationship between nutritional status and outcomes in HF has been partially studied. Our aim was to determine the relationship between the nutritional status and the long-term prognosis in patients hospitalized for acute HF. METHODS: We analyzed 145 patients admitted consecutively to a cardiology department for acute HF. Nutritional status was measured with the CONUT method, a validated scale based on laboratory testing (albumin; cholesterol; lymphocytes) during hospitalization. Patients were classified as normal, mildly, moderately or severely malnourished, and followed in a HF clinic. RESULTS: The mean aged of the population was 69.6years and 61% of patients were men, 54 had previous HF hospitalization (37%), 112 had hypertension (77%), 67 were diabetic (46%) and 135 had class III or IV NYHA (93%). Forty eight patients (33%) had normal nutritional status, 75 were mildly malnourished (52%), and 22 were moderately or severely malnourished (15%). Age, sex, hypertension, diabetes mellitus, or NYHA class among the three groups were not statistically different. ProBNP was directly correlated with the nutritional status. After a mean follow-up of 326days, 27 had a HF hospitalization (19%) and 61 (42,1%) had a hospitalization not related to HF. The analysis by Kaplan-Meier curves and log rank test showed that these differences were statistically significant. CONCLUSION: Malnutrition is common in patients hospitalized for HF. It seems to be a mediator of disease progression and determines a poor prognosis especially in advanced stages.

Evidence for a role of advanced glycation end products in atrial fibrillation.

BACKGROUND: Recent studies suggested that advanced glycation end-products (AGEs) and their receptor (RAGE) interaction may be promoted by inflammation and oxidative stress. These processes could also contribute to the pathogenesis of atrial fibrillation (AF), but their roles remain poorly defined. We studied the association of AGE-RAGE axis with AF in diabetic and non-diabetic patients, since the axis appears to play a key role in the process. METHODS: Ninety-seven consecutive outpatients were included in this transversal study. Fifty-nine patients were in sinus rhythm (SR) and 38 in permanent AF. Plasma fluorescent AGEs and soluble RAGE (sRAGE) were measured and comparisons between patients with and without AF were performed. A multivariate logistic regression analysis was made to define the independent factors associated with AF. RESULTS: Fluorescent AGEs and sRAGE were higher in AF group (74.9 ± 25.6 vs. 61.8 ± 20.1a.u. for fluorescent AGEs, p=0.006; 1714.2 ± 1105.5 vs. 996.1 ± 820.7 pg/mL for sRAGE, p=0.001). These differences were specially marked in non-diabetic patients. Both AGEs and sRAGE directly correlated with left atrial dimensions (r=0.496; r=0.536 for atrial area and r=0.491; r=0.511 for atrial volume, for fluorescent AGEs and sRAGE, respectively, p<0.001). In a multivariate analysis, fluorescent AGEs and sRAGE resulted as markers of AF independent of left atrial distension, diabetes and other confounding variables. CONCLUSIONS: AGEs and sRAGE plasma levels were higher in patients with AF, independently of diabetes mellitus, and they positively correlated with atrial dimensions, indicating a role for the AGE-RAGE axis in the arrhythmogenic structural atrial remodelling.

Productos de glicación avanzada: nuevo marcador de disfunción renal en pacientes con insuficiencia cardíaca crónica / Advanced glycation end-products: new markers of renal dysfunction in patients with chronic heart failure

Background and objectives: Advanced glycation end-products (AGE) are implicated in the physiopathology and prognosis of heart failure (HF) and they accumulate in situations such as kidney failure (KF). Our objective was to analyze the relation between AGE and KF in patients with chronic HF. Materials and methods: 102 consecutive patients of our medical center were included. Clinical and analytical data were obtained, with measurement of glycated haemoglobin, brain natriuretic peptide, cystatin C and fluorescent AGE. Glomerular filtration rate (GFR) was estimated for each patient. Results: 40.2% of patients presented GFR < 60 mL/min/1.73m2 and 11.7% had hidden kidney disease(HKD). AGE correlated positively with creatinine (r = 0.685, p < 0.001) and cystatin C (r = 0.682, p < 0.001) and negatively with GFR (r = 0.720, p < 0.001). Medium value of fluorescent AGE in patients with KF was higher than those without KF (83.4 [3.3] URF vs 56.8 [2.1] URF, p < 0.001). With regard to the diagnostic value for HKD, fluorescent AGE presented an area under the ROC curve higher than otherparameters for KD such as cystatin C. In themultivariate analysis, fluorescent AGE were an independent biomarker of KD (OR 1.060; 95% CI 1.024-1.097; p = 0.001). Conclusions: AGE act as a biomarker of KD in patients with chronic HF, both diabetics and non diabetics, being better than cystatin C in the detection of HKD (AU)

Fundamento y objetivo: Los productos finales de glicación avanzada (AGE) están involucrados en la fisiopatología y pronóstico de la insuficiencia cardíaca (IC), acumulándose en situaciones como la insuficiencia renal (IR). El objetivo del estudio fue analizar la relación de AGE e IR en pacientes con IC crónica.Material y método: Se incluyeron un total de 102 pacientes de forma consecutiva procedentes de la consulta de IC. Se obtuvieron datos clínicos y analíticos, con medición de hemoglobina glicada, péptido natriurético cerebral, cistatina C y AGE fluorescente, estimándose de cada paciente la tasa de filtración glomerular (TFG).Resultados: El 40,2% de los pacientes presentaron una TFG < 60ml/min/1,73m2 y el 11,7% enfermedad renal oculta. Los AGE presentaron una clara correlación positiva con la creatinina (r=0,685, p<0,001) y la cistatina C (r=0,682, p<0,001) y negativa con la TFG (r=−0,720, p<0,001). La media de AGE fluorescentes en pacientes con IR fue mayor que en aquellos sin IR (media [DE] de 83,4 [3,3] URF frente a 56,8 [2,1] URF, p<0,001). En cuanto a su valor para el diagnóstico de enfermedad renal oculta, los AGE fluorescentes presentaron un área bajo la curva ROC superior a la de otros parámetros de IR, como la cistatina C. El análisis multivariado demostró que los AGE fluorescentes son un marcador independiente de IR (odds ratio [OR] 1,06; intervalo de confianza del 95% [IC 95%] 1,024-1,097; p=0,001).Conclusiones: Los AGE actúan como un marcador de IR en pacientes con IC crónica, tanto diabéticos como no diabéticos, siendo superiores a la cistatina C en la detección de enfermedad real oculta (AU)

[Advanced glycation end-products: new markers of renal dysfunction in patients with chronic heart failure]. / Productos de glicación avanzada: nuevo marcador de disfunción renal en pacientes con insuficiencia cardíaca crónica.

BACKGROUND AND OBJECTIVES: Advanced glycation end-products (AGE) are implicated in the physiopathology and prognosis of heart failure (HF) and they accumulate in situations such as kidney failure (KF). Our objective was to analyze the relation between AGE and KF in patients with chronic HF. MATERIALS AND METHODS: 102 consecutive patients of our medical center were included. Clinical and analytical data were obtained, with measurement of glycated haemoglobin, brain natriuretic peptide, cystatin C and fluorescent AGE. Glomerular filtration rate (GFR) was estimated for each patient. RESULTS: 40.2% of patients presented GFR < 60 mL/min/1.73 m(2) and 11.7% had hidden kidney disease (HKD). AGE correlated positively with creatinine (r=0.685, p<0.001) and cystatin C (r=0.682, p<0.001) and negatively with GFR (r=-0.720, p<0.001). Medium value of fluorescent AGE in patients with KF was higher than those without KF (83.4 [3.3] URF vs 56.8 [2.1] URF, p<0.001). With regard to the diagnostic value for HKD, fluorescent AGE presented an area under the ROC curve higher than other parameters for KD such as cystatin C. In the multivariate analysis, fluorescent AGE were an independent biomarker of KD (OR 1.060; 95% CI 1.024-1.097; p=0.001). CONCLUSIONS: AGE act as a biomarker of KD in patients with chronic HF, both diabetics and non diabetics, being better than cystatin C in the detection of HKD.

Relation of soluble receptor for advanced glycation end products to predict mortality in patients with chronic heart failure independently of Seattle Heart Failure Score.

Knowledge of the role of the soluble receptor for advanced glycation end products (sRAGEs) in chronic heart failure (CHF) is very limited. In the present study, we measured plasma sRAGE levels in patients with CHF and examined whether plasma sRAGE predicts prognosis in patients with HF independently of validated scores as the Seattle Heart Failure Score (SHFS). We measured plasma sRAGE in 106 outpatients with CHF. Patients were prospectively followed during a median follow-up period of 1.3 years with end points of cardiac death or rehospitalization. Plasma sRAGE level increased with advancing New York Heart Association functional class, SHFS, age, and ischemic cause. Plasma sRAGE level was also higher in patients with cardiac death and/or events than in event-free patients. In Cox multivariate proportional hazard analysis, SHFS, sRAGE, and N-terminal pro-B-type natriuretic peptide were independent risk factors for cardiac death (sRAGE hazard ratio 1.26, 95% confidence interval 1.09 to 1.45, p = 0.002) and/or cardiac events (sRAGE hazard ratio 1.07, 95% confidence interval 1.03 to 1.11, p = 0.002). Survival curves adjusted by Cox analysis clearly demonstrated that the high-sRAGE group (higher than median) had a significantly higher incidence of cardiac death than the low-sRAGE group (p = 0.001). In conclusion, sRAGE is a novel, highly sensitive, and specific prognostic marker in current optimally treated patients with CHF with an additive and independent value compared to the multimarker SHFS.

Soluble receptor of advanced glycation end products levels are related to ischaemic aetiology and extent of coronary disease in chronic heart failure patients, independent of advanced glycation end products levels: New Roles for Soluble RAGE.

AIMS: Knowledge of the role of advanced glycation end products (AGE), their receptor (RAGE), and the receptor's soluble form (sRAGE), in heart failure (HF) is very limited. We evaluated the clinical role of the AGE-RAGE system in HF and in particular any association it might have with ischaemic aetiology. METHODS AND RESULTS: We measured fluorescent AGE, glycated albumin and sRAGE in 103 patients with chronic HF. We showed that sRAGE but not AGE was related to ischaemic aetiology (1638.3 ± 207.4 ischaemic vs. 1065.1 ± 94.2 pg/mL non-ischaemic group; P =0.016) independent of age, sex, diabetes, renal function, clinical severity, or other variables (OR: 1.091; 95% CI (confidence interval): 1.032-1.153; P =0.007). Moreover, sRAGE was directly associated with extent of coronary disease (OR for three vessel disease compared with non-coronary lesions: 1.186; 95% CI: 1.065-1.322; P =0.002). We also found a correlation between sRAGE and severity of HF, which increased with New York Heart Association (NYHA) class (741.9 ± 88.9 pg/mL in class 1, 1195.9 ± 113.2 pg/mL in class II, and 1724.8 ± 245.7 pg/mL in class III (P < 0.05)) and brain natriuretic peptide (BNP) levels (667.4 ± 68.0 vs. 1344.5 ± 126.0 pg/mL for BNP < and ≥400 pg/mL, respectively). CONCLUSION: sRAGE is an indicator of chronic heart failure severity and an independent marker of coronary artery disease and its severity in patients with CHF.