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Andersen S.,Steno Diabetes Center | Mischak H.,Glasgow Cardiovascular Research Center | Mischak H.,Mosaiques Diagnostics GmbH | Zurbig P.,Mosaiques Diagnostics GmbH | And 3 more authors.
BMC Nephrology | Year: 2010

Background. Previously the angiotensin II receptor blocker Irbesartan has been demonstrated to reduce the risk for progression from microalbuminuria to macroalbuminuria in type 2 diabetic patients. The purpose of this study was to evaluate the effect of treatment with Irbesartan in type 2 diabetic patients with microalbuminuria on the urinary proteome. Methods. High-resolution capillary-electrophoresis coupled to mass-spectrometry (CE-MS) was used to profile the low-molecular-weight proteome in urine of a subgroup of patients from a two year randomized irbesartan versus placebo therapy trial, which included hypertensive type 2 diabetic patients with microalbuminuria on ongoing antihypertensive medication (IRMA2-substudy). Results. We demonstrate that the therapy with 300 mg Irbesartan daily over a period of two years results in significant changes of the urinary proteome. Both, a classifier developed previously that consists of urinary peptides indicative of chronic kidney disease, as well as several individual peptides changed significantly after treatment. These changes were not observed in the placebo-treated individuals. Most prominent are changes of urinary collagen fragments associated with progression of diabetic nephropathy, indicating normalization in urinary peptides. Conclusion. CE-MS analysis of urine enabled identification of peptides as potential surrogate markers for renoprotection in microalbuminuric type 2 diabetic patients, which show persistent improvement after longterm treatment with Irbesartan. The results suggest that a major benefit of treatment by Irbesartan may be improvement of collagen turnover, reduction of fibrosis. They further suggest that urinary proteome analysis could be utilized to assess potential benefit of therapeutic intervention, providing statistically significant results even on a small population. © 2010 Andersen et al; licensee BioMed Central Ltd.

Adabag S.,Veterans Affairs Health Care System | Adabag S.,University of Minnesota | Rector T.S.,Veterans Affairs Health Care System | Rector T.S.,University of Minnesota | And 8 more authors.
European Journal of Heart Failure | Year: 2014

Aims Sudden cardiac death (SCD) accounts for ∼ 25% of all deaths in heart failure with preserved ejection fraction (HFpEF). However, strategies to identify HFpEF patients at a higher risk of SCD have not been developed.Methods and results We studied 4128 patients with HFpEF enrolled in the Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction (I-PRESERVE) trial. All SCDs were adjudicated by a clinical endpoint committee. Cumulative incidences of SCD were estimated counting other deaths as competing risks. Cox regression analysis was used to generate a risk model for SCD. During a mean follow-up of 4.1 years, 231 (5.6%) patients died suddenly and 650 (15.7%) died non-suddenly. A multivariable model in 3480 patients including age, gender, history of diabetes and myocardial infarction, LBBB on ECG, and the natural logarithm of NT-proBNP identified a subgroup of 837 (24%) patients with ≥10% cumulative incidence of SCD over 5 years, accounting for other deaths as competing risk (Harrell's C index 0.75). The 5-year cumulative incidences of SCD in the higher and lower risk groups were 11% and 4%, respectively. In the higher risk group, 32% of deaths were SCD compared with 26% in the entire I-PRESERVE cohort.Conclusions A multivariable prediction model identified patients with HFpEF who have a ≥10% risk of SCD over 5 years, similar to the risk of SCD in the Sudden Cardiac Death in Heart Failure (SCD-Heft) trial. This model may be useful for selecting patients with HFpEF for SCD prevention trials. © 2014 The Authors European Journal of Heart Failure.

Pihlstrom H.,University of Oslo | Dahle D.O.,University of Oslo | Mjoen G.,University of Oslo | Pilz S.,Medical University of Graz | And 8 more authors.
Transplantation | Year: 2015

BACKGROUND: Hyperparathyroidism is reported in 10% to 66% of renal transplant recipients (RTR). The influence of persisting hyperparathyroidism on long-term clinical outcomes in RTR has not been examined in a large prospective study. METHODS: We investigated the association between baseline parathyroid hormone (PTH) levels and major cardiovascular events, renal graft loss, and all-cause mortality by Cox Proportional Hazard survival analyses in 1840 stable RTR derived from the Assessment of LEscol in Renal Transplantation trial. Patients were recruited in a mean of 5.1 years after transplantation, and follow-up time was 6 to 7 years. RESULTS: Significant associations between PTH and all 3 outcomes were found in univariate analyses. When adjusting for a range of plausible confounders, including measures of renal function and serum mineral levels, PTH remained significantly associated with all-cause mortality (4% increased risk per 10 units; P = 0.004), and with graft loss (6% increased risk per 10 units; P < 0.001), but not with major cardiovascular events. Parathyroid hormone above the upper limit of normal (65 pg/mL) indicated a 46% (P = 0.006) higher risk of death and an 85% higher risk of graft loss (P < 0.001) compared with low/normal values. CONCLUSIONS: Hyperparathyroidism is an independent, potentially remediable, risk factor for renal graft loss and all-cause mortality in RTR. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Handberg A.,Aarhus University Hospital | Hojlund K.,University of Southern Denmark | Gastaldelli A.,CNR Institute of Neuroscience | Flyvbjerg A.,Aarhus University Hospital | And 4 more authors.
Journal of Internal Medicine | Year: 2012

Objectives. Insulin resistance is associated with increased CD36 expression in a number of tissues. Moreover, excess macrophage CD36 may initiate atherosclerotic lesions. The aim of this study was to determine whether plasma soluble CD36 (sCD36) was associated with insulin resistance, fatty liver and carotid atherosclerosis in nondiabetic subjects. Methods. In 1296 healthy subjects without diabetes or hypertension recruited from 19 centres in 14 European countries (RISC study), we determined the levels of sCD36, adiponectin, lipids and liver enzymes, insulin sensitivity (M/I) by euglycaemic-hyperinsulinaemic clamp, carotid atherosclerosis as intima-media thickness (IMT) and two estimates of fatty liver, the fatty liver index (FLI) and liver fat percentage (LF%). Results. IMT, FLI, LF%, presence of the metabolic syndrome, impaired glucose regulation, insulin and triglycerides increased across sCD36 quartiles (Q2-Q4), whereas adiponectin and M/I decreased (P≤0.01). sCD36 was lower in women than in men (P=0.045). Log sCD36 showed a bimodal distribution, and amongst subjects with sCD36 within the log-normal distribution (log-normal population, n=1029), sCD36 was increased in subjects with impaired glucose regulation (P=0.045), metabolic syndrome (P=0.006) or increased likelihood of fatty liver (P<0.001). sCD36 correlated significantly with insulin, triglycerides, M/I and FLI (P<0.05) after adjustment for study centre, gender, age, glucose tolerance status, smoking habits and alcohol consumption. In the log-normal population, these relationships were stronger than in the total study population and, additionally, sCD36 was significantly associated with LF% and IMT (P<0.05). Conclusions. In this cross-sectional study of nondiabetic subjects, sCD36 was significantly associated with indices of insulin resistance, carotid atherosclerosis and fatty liver. Prospective studies are needed to further evaluate the role of sCD36 in the inter-relationship between atherosclerosis, fatty liver and insulin resistance. © 2011 The Association for the Publication of the Journal of Internal Medicine.

Calvin C.M.,University of Edinburgh | Batty G.D.,University of Edinburgh | Batty G.D.,University College London | Batty G.D.,MRC Social and Public Health science Unit | And 3 more authors.
Health Psychology | Year: 2011

Objective: In a prospective cohort study the authors examined associations between childhood intelligence at age 11 and inflammatory and hemostatic biomarkers in middle age. Method: Participants were 9,377 men and women born in the United Kingdom in March 1958, and whose blood plasma samples at age 45 years were analyzed for levels of C-reactive protein (CRP), D-dimer, fibrinogen, tissue plasminogen activator (t-PA) antigen, and von Willebrand factor (VWF). Sex-adjusted linear regression models tested cognition-blood biomarker associations, with and without adjustment for potential confounding by parental socioeconomic status and potential mediation by cardiovascular disease (CVD) risk factors at midlife. Cognitive tests taken at age 50 enabled the inflammation-cognition association to be tested for reverse causation, by adjusting for age 11 intelligence. Results: Higher childhood intelligence test scores were significantly associated (p < .001) with lower adult levels of CRP (beta coefficient = -0.068), t-PA antigen (β = -0.014), D-dimer (β = -0.011), fibrinogen (β = -0.011), and VWF antigen (β = -0.008). Early life factors including parental socioeconomic status accounted for 24%-44% of these associations, whereas further adjustment for adult CVD risk factors largely attenuated the effects (82%-100%). The significant inverse associations between age 45 biomarker levels and age 50 cognition could be accounted for to a substantial degree by childhood intelligence (50%-100% attenuation). Conclusions: Childhood intelligence is predictive of inflammatory and hemostatic biomarker status at middle age, which may be largely explained by health behaviors. This highlights the need to consider possible bidirectional associations between cognition and inflammation (and hemostasis) in lifecourse models of CVD-related health. © 2011 American Psychological Association.

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