altered vessel signalling molecules in subjects with down s syndrome

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Osteocalcin as a potential risk biomarker for cardiovascular and metabolic diseases

Clear evidence supports a role for circulating and locally-produced osteocalcin (OC) in the pathophysiology of cardiovascular (CV) lesions and CV risk, also in combination with metabolic changes, including type 2 diabetes mellitus (T2DM). Reduced plasma OC levels are associated with greater incidence of pathological CV changes, like arterial and valvular calcification, coronary and carotid atherosclerosis and increased carotid intima-media thickness. The actual relationship between OC levels and incidence of major CV events is, however, still unclear. Moreover, reduced circulating OC levels have been mostly associated with insulin resistance, metabolic syndrome or T2DM, indicating relevant OC actions on pancreatic \u3b2-cells and insulin secretion and activity. Based on these observations, this review article will attempt to summarize the current evidence on the potential usefulness of circulating OC as a biomarker for CV and metabolic risk, also evaluating the currently open issues in this area of research

PCSK9 Expression in Epicardial Adipose Tissue : Molecular Association with Local Tissue Inflammation

Epicardial adipose tissue (EAT) has the unique property to release mediators that nourish the heart in healthy conditions, an effect that becomes detrimental when volume expands and proinflammatory cytokines start to be produced. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a proinflammatory mediator involved in atherosclerosis, is also produced by visceral fat. Due to the correlation of inflammation with PCSK9 and EAT enlargement, we evaluated whether PCSK9 was expressed in EAT and associated with EAT inflammation and volume. EAT samples were isolated during surgery. EAT thickness was measured by echocardiography. A microarray was used to explore EAT transcriptoma. The PCSK9 protein levels were measured by Western Blot in EAT and ELISA in plasma. PCSK9 was expressed at both the gene and protein levels in EAT. We found a positive association with EAT thickness and local proinflammatory mediators, in particular, chemokines for monocytes and lymphocytes. No association was found with the circulating PCSK9 level. The expression of PCSK9 in EAT argues that PCSK9 is part of the EAT secretome and EAT inflammation is associated with local PCSK9 expression, regardless of circulating PCSK9 levels. Whether reducing EAT inflammation or PCSK9 local levels may have beneficial effects on EAT metabolism and cardiovascular risk needs further investigations

Hypertension in adult Fabry's disease: is cardiotrophin-1 a diagnostic biomarker?

Background: Cardiotrophin-1 (CT-1), a cytokine produced by cardiomyocytes and non-cardiomyocytes in conditions of stress, can be used as a biomarker of left ventricular hypertrophy and dysfunction in hypertensive patients. Hypertension is one of the main adverse events in the third and last phase of Fabry's disease (FD). We measured CT-1 in order to examine its correlation with the vascular and cardiac alterations at different ages and assess its potential for use as a biomarker of hypertension in FD. Findings: The level of CT-1 was clearly higher in hypertensive adults than in adult FD patients. FD patients show a small, non-significant decrease in plasma CT-1 with age, while in hypertensive patients CT-1 in plasma rises strongly and highly significantly with age. Conclusions: CT-1 can be considered a good biomarker of the progression of hypertension with age, but particular care is needed when following hypertension in FD patients, since CT-1 does not correlate the same way with this disease

The role of inflammation in patients with intraductal mucinous neoplasm of the pancreas and in those with pancreatic adenocarcinoma

Background: There are very few data regarding inflammation in patients with intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Aim: To evaluate the circulating concentrations of placental growth factor (PlGF), transforming growth factor-alpha (TGF-\u3b1), transforming growth factor-beta 1 (TGF-\u3b21), tumour necrosis factor receptor 1 (TNF-R1) and matrix metalloproteinase-2 (MMP-2) in patients with IPMNs and in those with pancreatic adenocarcinomas. Patients and Methods: Sixty-nine patients were enrolled: 23 (33.3%) had IPMNs and 46 (66.7%) had histologically confirmed pancreatic adenocarcinomas. Thirteen healthy subjects were also studied. PlGF, TGF-\u3b1, TGF-\u3b21, TNF-R1 and MMP-2 were determined using commercially available kits. Results: TNF-R1 (p=0.003) was the only protein significantly different among the three groups. Conclusion: Serum TNF-R1 was elevated in patients with IPMNs and in those with pancreatic adenocarcinomas, suggesting a high apoptotic activity in both groups of patients studied

Hypertrophic Epicardial Adipose Tissue is a Source of EPAC Proteins Directly Associate to ST2 Production and Heart Dilation and may be Potential Index of Heart Remodeling in CVDs Patients

Introduction: Epicardial adipose tissue (EAT) is a myocardial fat from which released molecules can directly reach the heart. In pathological conditions, the ubiquitously tissue hypertrophy mediators are the exchange proteins directly activated by cAMP (EPACs), named EPAC1 and EPAC2. In the heart the main protective signalling against detrimental remodelling is the ST2 and IL33 molecules. ST2 exists both as transmembrane receptor (ST2L) and soluble (sST2) form and in case of physiological stretch ST2L bind IL33 promoting anti-fibrotic signals. Contrarily in CVDs, sST2 is up regulated functioning as scavenger of IL33 and promoting heart dilatation. Interesting is that ST2 can be also produced by adipose tissue in normal condition. Due to EPACs properties to induce hyperplasia, our hypothesis is that larger EAT cells may also produce sST2 that can local amplify its detrimental role on myocardium. For these reasons we want to verified in CVDs patients first if larger EAT cells are able to up regulate EPAC proteins and second if EPACs may be associate to sST2 EAT production and heart dilatation. Methods: 50 CVD patients are enrolled and stratified according to EAT median thickness (8mm). plasma and EAT biopsies are collected during surgery. Indexed left ventricular mass (hLVM), end-diastolic posterior wall (EDPW), relative wall thickness (RWT), left ventricular mass (LVM) values are used as cardiac dilatation indexes commonly approved in clinical practice. Gene expression and protein assays are performed to investigate EPACs, ST2, IL33 mRNA and protein production. Results: Our data demonstrated that CVDs patients with EAT >8mm have significantly positive correlation with RWT and they also presented higher EPAC1 and ST2 mRNA and protein levels than CVDs patients 8mm and up-regulated in CVDs patients < 8mm. CVDs patients with hypertrophic EAT both EPAC1 and EPAC2presented positive correlation with hLVM, EDPW, LVM indexes and ST2 mRNA levels. Conclusion: Our results demonstrated that EPACs are directly associate to EAT hyperplasia and sST2 local production suggesting their implication in detrimental heart hyperplasia. From these results we can suggest that EAT thickness can be a potential newer parameter of detrimental heart remodelling in the prevention of CVDs complications

Regulated on activation, normal-T cell expressed and secreted (RANTES/CCL5) levels: an association with epicardial visceral fat thickness

Introduction: Epicardial adipose tissue (EAT), accumulated around the heart, is considered an index of visceral adiposity and a promising indicator of high cardio-metabolic risk. Evidences showing that EAT is a metabolically active organ and a source of inflammatory adipo-chemocytokines suggest a condition of chronic inflammation in this small cardiac fat depot. However, the potential links between cardiac adiposity and circulating levels of inflammatory adipo-chemokines, as markers of subclinical inflammation, are not completely understood. Our aim is to evaluate whether cardiac adiposity, measured as EAT thickness, is related to Regulated on activation, Normal T Cell Expressed and Secreted (RANTES/CCL5) levels, in obese patients. Methods: EAT thickness (meauserd by echocardiography, on the free wall of right ventricle), RANTES/CCL5 and other inflammatory markers (by ELISA kit) were measured in 36 women with uncomplicated obesity (OB) (BMI 41.6\ub15.6 kg/m2) and 15 normal-weight controls. Abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were assessed by computed tomography (CT). Results: OB patients had thicker EAT (6.8\ub10.9 vs. 1.3\ub10.3 mm, p<0.0001) (Fig.1) and higher RANTES/CCL5 levels (2468.9\ub1745.5 vs. 1272.1\ub1413.7 pg/ml, p<0.03) than controls (Fig. 2). The EAT thickness positively correlated with RANTES/CCL5 concentrations (r2=0.65, p<0.001) (Fig.3). Moreover, EAT thickness and RANTES/CCL5 concentration were directly correlated with indices of fat distribution (VAT, VAT/SAT and waist, p<0.001 for all). Notably, when using multiple regression analysis, RANTES/CCL5 levels most closely correlated with EAT thickness (t=3.93) and VAT areas (t=3.77), while other indices of fat distribution did not enter the model. Conclusions: EAT thickness, an indicator of cardiac adiposity, may be related to inflammatory adipo-chemokines in visceral-obese patients and might be used as a reliable marker of visceral adiposity. The elevated RANTES/CCL5 levels, contributing to the pro-inflammatory state, may also lead to cardio-metabolic disorders