The role of laser Doppler flowmetry tests, serum angiopoietin-2, asymmetric and symmetric dimethylarginine to predict outcome in chronic kidney disease

OBJECTIVE: The role of biochemical and functional markers of microvascular dysfunction to predict cardiovascular outcomes in nondialyzed chronic kidney disease (CKD) remains unclear. In this prospective cohort study, we assessed whether biochemical [serum level of angiopoietin-2 (Ang-2), asymmetric and symmetric dimethylarginin] and functional (laser Doppler flowmetry) measures of microvascular function predicted cardiovascular events, cardiovascular and all-cause mortality in CKD patients. METHODS: Postocclusive reactive hyperemia area (PORHHA), acetylcholine and sodium nitroprusside-mediated flow changes were estimated by laser Doppler flowmetry, and Ang-2, asymmetric and symmetric dimethylarginin were assessed in 105 CKD patients at baseline. Multiple failure time Cox-regression analyses with backward elimination were performed to determine the predictors of the combined endpoint of cardiovascular mortality and cardiovascular events or all-cause mortality and cardiovascular events during a median of 66.6 (interquartile range 39.8-80.4) months of follow-up. RESULTS: In univariate models lnAng-2 and lnPORHHA both predicted the cardiovascular outcome besides age, diabetes, baseline cardiovascular disease, brachial pulse pressure and log C-reactive protein. In multivariate analysis lnPORHHA [hazard ratio: 0.66 (95% confidence interval: 0.49-0.89) per ln(mU s)], age [1.03 (1.01-1.06) per year], log C-reactive protein [1.31 (1.06-1.64) per ln(mg/l)] and diabetes [3.33 (1.70-6.53)] remained significant predictors of the cardiovascular outcome, whereas lnAng-2 did not enter the model. Neither of the microvascular variables were an independent predictor of all-cause mortality and cardiovascular events. CONCLUSION: Among the functional and biochemical microvascular parameters PORHHA seems to improve cardiovascular risk assessment in CKD. Nevertheless the robustness of traditional risk factors seems to outweigh the role of microvascular biomarkers on all-cause mortality and cardiovascular events at this time

Dietary iron enhances colonic inflammation and IL-6/IL-11-Stat3 signaling promoting colonic tumor development in mice

Chronic intestinal inflammation and high dietary iron are associated with colorectal cancer development. The role of Stat3 activation in iron-induced colonic inflammation and tumorigenesis was investigated in a mouse model of inflammation-associated colorectal cancer. Mice, fed either an iron-supplemented or control diet, were treated with azoxymethane and dextran sodium sulfate (DSS). Intestinal inflammation and tumor development were assessed by endoscopy and histology, gene expression by real-time PCR, Stat3 phosphorylation by immunoblot, cytokines by ELISA and apoptosis by TUNEL assay. Colonic inflammation was more severe in mice fed an iron-supplemented compared with a control diet one week post-DSS treatment, with enhanced colonic IL-6 and IL-11 release and Stat3 phosphorylation. Both IL-6 and ferritin, the iron storage protein, co-localized with macrophages suggesting iron may act directly on IL-6 producing-macrophages. Iron increased DSS-induced colonic epithelial cell proliferation and apoptosis consistent with enhanced mucosal damage. DSS-treated mice developed anemia that was not alleviated by dietary iron supplementation. Six weeks post-DSS treatment, iron-supplemented mice developed more and larger colonic tumors compared with control mice. Intratumoral IL-6 and IL-11 expression increased in DSS-treated mice and IL-6, and possibly IL-11, were enhanced by dietary iron. Gene expression of iron importers, divalent metal transporter 1 and transferrin receptor 1, increased and iron exporter, ferroportin, decreased in colonic tumors suggesting increased iron uptake. Dietary iron and colonic inflammation synergistically activated colonic IL-6/IL-11-Stat3 signaling promoting tumorigenesis. Oral iron therapy may be detrimental in inflammatory bowel disease since it may exacerbate colonic inflammation and increase colorectal cancer risk

Aortic stiffness is related to left ventricular diastolic function in patients with diabetes mellitus type 1: assessment with MRI and speckle tracking strain analysis

Diabetes mellitus type 1 (DM1) is associated with aortic stiffening and left ventricular (LV) diastolic dysfunction, however the relationship between aortic stiffness and LV diastolic dysfunction in DM1 patients is still largely unknown. The purpose of this study was to evaluate whether an increased aortic stiffness, expressed by increased aortic pulse wave velocity (PWV), is associated with subclinical LV diastolic dysfunction and decreased left atrial (LA) compliance as assessed with speckle tracking strain analysis in patients with DM1. Aortic PWV was assessed with cardiovascular magnetic resonance in 41 DM1 patients. Patients underwent echocardiography for assessment of conventional LV diastolic function indices and LV and LA longitudinal strain and strain rate (SR) assessed with speckle tracking strain analysis. LV SR during the isovolumic relaxation period (SRIVR) and LA strain were recorded and the E-wave velocity to SRIVR velocity ratio (E/SRIVR) was calculated. Independent samples t test and multivariate linear regression analyses were used for statistical analyses. Aortic PWV significantly correlated with SRIVR (beta = -0.71, p 0.10). In DM1 patients, aortic stiffness is inversely associated with sensitive markers of LV diastolic function and decrease in LA compliance as measured with echocardiographic speckle tracking strain analysis