Endothelin(B) receptor blocker inhibits high glucose-induced synthesis of fibronectin in human peritoneal mesothelial cells.

BACKGROUND: Long-term peritoneal dialysis using glucose-based dialysates is associated with peritoneal fibrosis. The object of this study was to investigate the hypothesis that endothelin (ET)-1, which is known to play an important role in various fibrotic diseases, may also be involved in peritoneal fibrosis using human peritoneal mesothelial cells (HPMC). METHODS: HPMC were cultured with 4% D- or L-glucose, or loaded with 10 nmol/L ET-1. In some experiments, the ETA receptor antagonist BQ-123, the ETB receptor antagonist BQ-788, and antioxidants 4-hydroxy-2,2,6,6-tetramethyl-piperidine 1-oxyl (TEMPOL) and diphenyleneiodium chloride (DPI) were used. mRNA expression of ET-1, ETA receptor, ETB receptor, and fibronectin (FN) was analyzed by real-time polymerase chain reaction (real-time PCR). The protein levels for FN and ET-1 were measured by ELISA. CM-H2DCFDA-sensitive reactive oxygen species (ROS) were evaluated by flow cytometry. RESULTS: D-Glucose significantly induced mRNA expression of ET-1 and the ETB receptor but not the ETA receptor. FN production under high glucose conditions was inhibited by BQ-788. ET-1 directly stimulated H PMC to increase mRNA expression of FN and CM-H2DCFDA-sensitive ROS production. BQ-788, TEMPOL, and DPI inhibited mRNA expression of FN induced by ET-1. CONCLUSION: The present study suggests that high-glucose-induced FN synthesis is mediated by the ET-1/ETB receptor pathway and, therefore, an ETB receptor antagonist may be usefulin preventing FN production in HPMC.     

Diet quality in association to lipidaemic profile in adults of families at high-risk for type 2 diabetes in Europe: The Feel4Diabetes study

Background and aimsThe role of diet in blood lipids is scarcely investigated in adults at risk of Type 2 Diabetes Mellitus (T2DM) and even less studied regarding their socioeconomic status (SES). This study aimed to investigate the associations of diet quality with blood lipids in adults from families at high-risk for developing T2DM from six European countries, considering their SES.Methods and resultsIn total 2049 adults (67% women) from relatively low-SES regions and high T2DM risk families were enrolled. Dietary habits, sedentary behaviour and sociodemographic characteristics were assessed using standardised questionnaires. The associations of tertiles of healthy diet score (HDS) with blood lipids were tested by univariate analysis of variance (UNIANOVA). HDL-Cholesterol (HDL-C) was positively (B 1.54 95%CI 0.08 to 2.99) and LDL-Cholesterol (LDL-C) (B ?4.15 95%CI ?7.82 to ?0.48), ratio of total cholesterol to HDL-C (B ?0.24 95%CI ?0.37 to ?0.10), ratio of LDL-C to HDL-C (B ?0.18 95%CI ?0.28 to ?0.08) and Atherogenic Index of Plasma (B ?0.03 95%CI ?0.06 to 0.00) inversely associated with the highest tertile of diet score compared to the lowest tertile independently of age, sex, Body Mass Index, total screen time and smoking. In sub-analysis of education (<14 and ≥ 14 years of education), these findings were only significant in the high-SES group.ConclusionWhile diet quality was poorer in the low-SES group, an association between diet quality and lipidemic profile was not found, as increased central obesity and smoking prevalence might have confounded this association. These findings indicate the need for tailor-made interventions, guided by the specific risk factors identified per population sub groups.     

Rationale--Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): evolving the management of cardiovascular risk in patients with chronic kidney disease

BACKGROUND: Patients with chronic kidney disease (CKD) have a high burden of mortality and cardiovascular morbidity. Additional strategies to modulate cardiovascular risk in this population are needed. Data suggest that anemia is a potent and potentially modifiable risk factor for cardiovascular disease in patients with CKD, but these data remain unsubstantiated by any randomized controlled trial (RCT). Furthermore, the clinical practice guidelines for anemia management in patients with CKD are based on limited data. The need for new RCTs to address critical knowledge deficits, particularly with regard to the impact of anemia therapy on cardiovascular disease and survival, is recognized within the guidelines and independent comprehensive reviews of the existing published trial data. STUDY DESIGN: The Trial to Reduce Cardiovascular Events with Aranesp (Amgen Inc, Thousand Oaks, Calif) (darbepoetin alfa) Therapy (TREAT) is a 4000-patient, multicenter, double-blind RCT, designed to determine the impact of anemia therapy with darbepoetin alfa on mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetes mellitus. Subjects will be randomized in a 1:1 manner to either darbepoetin alfa therapy to a target hemoglobin (Hb) of 13 g/dL or control, consisting of placebo for Hb > or =9 g/dL or darbepoetin alfa for Hb <9 g/dL until Hb is again Hb > or =9 g/dL. TREAT is event-driven and has a composite primary end point comprising time to mortality and nonfatal cardiovascular events, including myocardial infarction, myocardial ischemia, stroke, and heart failure. TREAT will provide data that are critical to evolution of the management of cardiovascular risk in this high-risk population.     

Malnutrition-associated high bleeding risk with low thrombogenicity in patients undergoing percutaneous coronary intervention

Background and aimsAlthough antithrombotic treatments are established for coronary artery disease (CAD), they increase the bleeding risk, especially in malnourished patients. The total thrombus-formation analysis system (T-TAS) is useful for the assessment of thrombogenicity in CAD patients. Here, we examined the relationships among malnutrition, thrombogenicity and 1-year bleeding events in patients undergoing percutaneous coronary intervention (PCI).Methods and resultsThis was a retrospective analysis of 300 consecutive CAD patients undergoing PCI. Blood samples obtained on the day of PCI were used in the T-TAS to compute the thrombus formation area under the curve. We assigned patients to two groups based on the geriatric nutritional risk index (GNRI): 102 patients to the lower GNRI group (≤98), 198 patients to the higher GNRI group (98<). The primary endpoint was the incidence of 1-year bleeding events defined by Bleeding Academic Research Consortium criteria types 2, 3, or 5. The T-TAS levels were lower in the lower GNRI group than in the higher GNRI group. Kaplan-Meier analysis showed worse 1-year bleeding event-free survival in the lower GNRI group compared with the higher GNRI group. The combined model of the GNRI and the Academic Research Consortium for High Bleeding Risk (ARC-HBR) had good calibration and discrimination for bleeding risk prediction. In addition, having a lower GNRI and ARC-HBR positivity was associated with 1-year bleeding events.ConclusionA lower GNRI could reflect low thrombogenicity evaluated by the T-TAS and determine bleeding risk in combination with ARC-HBR positivity.     

Pigment Epithelium‐Derived Factor as a New Predictor of Mortality Among Chronic Kidney Disease Patients Treated With Hemodialysis

Pigment epithelium‐derived factor (PEDF) plays a protective role against atherosclerosis. Although serum PEDF level is increased in patients undergoing regular hemodialysis (HD), the pathophysiological role of PEDF in HD patients is unknown. We measured serum PEDF levels in 74 HD patients, and the association between serum PEDF and adverse events such as all‐cause death and cardiovascular accident was evaluated prospectively. During the follow up of 45.4 ± 25.1 months, 24 patients (32.4%) experienced cardiovascular accident and 18 (24.3%) died. Significantly higher incidences of all‐cause mortality and cardiovascular accident were observed in the lower PEDF group than in the higher PEDF group. After adjusting for propensity score calculated from multiple confounding factors (age, gender, systolic blood pressure, history of previous cardiovascular disease, level of carbonyl content, albumin, hemoglobin, total cholesterol, creatinine, C‐reactive protein, dialysis vintage, Kt/V‐urea and history of diabetes), lower predialytic PEDF was a significant risk factor for all‐cause mortality (relative hazard = 6.060, standard error = 0.68467, P = 0.0085). Lower levels of predialytic PEDF was associated with an increased risk of mortality.     

Parental history of type 2 diabetes, TCF7L2 variant and lower insulin secretion are associated with incident hypertension. Data from the DESIR and RISC cohorts

Aims/hypothesis

The relationship between insulin secretion and the incidence of hypertension has not been well characterised. We hypothesised that both a parental history of diabetes and TCF7L2 rs7903146 polymorphism, which increases susceptibility to diabetes because of impaired beta cell function, are associated with incident hypertension. In a separate cohort, we assessed whether low insulin secretion is related to incident hypertension.

Methods

Nine year incident hypertension was studied in 2,391 normotensive participants from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort. The relationship between insulin secretion and 3 year incident hypertension was investigated in 1,047 non-diabetic, normotensive individuals from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort. Insulin secretion during OGTT was expressed in relation to the degree of insulin resistance, as assessed by a hyperinsulinaemic–euglycaemic clamp.

Results

In the DESIR cohort, a parental history of diabetes and the TCF7L2 at-risk variant were both associated with hypertension incidence at year 9, independently of waist circumference, BP, fasting glucose, insulin levels and HOMA-IR at inclusion (p?=?0.02 for parental history, p?=?0.006 for TCF7L2). In the RISC cohort, a lower insulin secretion rate during the OGTT at baseline was associated with both higher BP and a greater risk of hypertension at year 3. This inverse correlation between the insulin secretion rate and incident hypertension persisted after controlling for baseline insulin resistance, glycaemia and BP (p?=?0.007).

Conclusions/interpretation

Parental history of diabetes, TCF7L2 rs7903146 polymorphism and a reduced insulin secretion rate were consistently associated with incident hypertension. A low insulin secretion rate might be a new risk factor for incident hypertension, beyond insulin resistance.