Selim Kilic

Comparative effects of nebivolol and metoprolol on oxidative stress, insulin resistance, plasma adiponectin and soluble P-selectin levels in hypertensive patients

Objectives To determine the effects of nebivolol on oxidative stress, insulin resistance, adiponectin and plasma soluble P-selectin levels in hypertensive patients in comparison with metoprolol. Material and methods Eighty newly diagnosed hypertensive patients in grade 1 hypertension according to the European Society of Hypertension and European Society of Cardiology guidelines were enrolled in this prospective, blinded, randomized study. Seventy-two patients completed the study. After baseline assessment, each patient was randomly allocated to a 5 mg daily dose of nebivolol (n = 37, 20 male) or a 100 mg daily dose of metoprolol (n = 35, 18 male) and treated for 6 months. Blood pressure, heart rate, oxidative stress (malonyldialdehyde), homeostasis model assessment: insulin resistance, adiponectin and plasma soluble P-selectin levels were measured before and after treatment. Results At the end of treatment, nebivolol and metoprolol significantly decreased blood pressure and heart rate, with a more pronounced bradycardic effect of metoprolol. Nebivolol, but not metoprolol, significantly lowered oxidative stress (P = 0.03), the insulin resistance index (P = 0.003) and plasma soluble P-selectin levels (P = 0.008), and increased adiponectin levels (P = 0.04). Conclusion Nebivolol, in contrast to metoprolol, improved oxidative stress, insulin sensitivity, decreased plasma soluble P-selectin and increased adiponectin levels in hypertensive patients. These beneficial effects of nebivolol may contribute to a reduction in cardiovascular risk in hypertensive patients.

FGF-23 and vascular dysfunction in patients with stage 3 and 4 chronic kidney disease.

Studies in animals show that fibroblast growth factor (FGF)-23 interferes with vascular reactivity induced by the nitric oxide (NO) system. To investigate the relationship between circulating FGF-23 levels and the response of forearm blood flow to ischemia (flow-mediated vasodilatation, FMD) and nitroglycerin, we tested 183 patients with stage 3-4 chronic kidney disease (CKD). None of them had cardiovascular complications or were taking drugs interfering with vascular function. Patients with FGF-23 levels above the median had significantly lower glomerular filtration rate, FMD, and fetuin-A levels (an anti-inflammatory molecule and potent inhibitor of calcification). They also had higher proteinuria and phosphate levels when compared to patients whose FGF-23 levels were below the median. The response to nitroglycerin was not different between the two groups. Multiple regression analysis showed that the relationship between FGF-23 and FMD was only modestly sensitive to adjustment for classical risk factors, biomarkers of bone mineral metabolism, high-sensitivity C-reactive protein, and homeostatic model assessment index. Adjustment for asymmetrical dimethyl arginine (ADMA) weakened the strength of this link; however, it remained highly significant. There was no independent association between FGF-23 and nitroglycerin. Thus, attenuation of FMD by ADMA suggests that this endogenous inhibitor of NO synthase may, in part, mediate the vascular effects of FGF-23 in patients with CKD.

Comparison of Calcium Acetate and Sevelamer on Vascular Function and Fibroblast Growth Factor 23 in CKD Patients: A Randomized Clinical Trial

BACKGROUND Fibroblast growth factor 23 (FGF-23) is a marker of endothelial dysfunction and atherosclerotic complications in patients with chronic kidney disease (CKD). Because previous studies suggested that sevelamer may exert effects on FGF-23 level and endothelial function independently of its phosphate-lowering action, we tested the effect of sevelamer versus calcium acetate on vascular function and FGF-23 levels. STUDY DESIGN Randomized prospective open-label trial. SETTING & PARTICIPANTS Patients with stage 4 CKD with hyperphosphatemia (n = 100). INTERVENTION An 8-week intervention with sevelamer (n = 47) and calcium acetate (n = 53). OUTCOMES The primary study outcome was change in flow-mediated vasodilatation in the forearm. The secondary outcome was change in FGF-23 levels. RESULTS Serum phosphate levels decreased in both treatment arms (P < 0.001), but more markedly in the sevelamer group (P < 0.001). Flow-mediated vasodilatation increased from 6.1% to 7.1% (P < 0.001) in sevelamer-treated patients, whereas it was unchanged in the calcium-acetate group (6.0% vs 6.0%). In a combined analysis, treatment-induced changes in flow-mediated vasodilatation were (P < 0.001) associated with simultaneous changes in FGF-23 levels (-27.1% [-33.2% to -8.8%] for the sevelamer group; 3.5% [-8.4% to 12.1%] for the calcium acetate group), as well as with C-reactive protein and fetuin A levels. These relationships were confirmed in multiple regression analysis adjusting for changes in serum phosphate levels and other factors. LIMITATIONS Unblinded randomized controlled study that cannot establish mechanisms of effect. CONCLUSIONS In hyperphosphatemic patients with stage 4 CKD, treatment with phosphate lowering induces measurable improvements in flow-mediated vasodilatation. Furthermore, independently of serum phosphate level, FGF-23 level changes induced by phosphate binders are associated with simultaneous changes in flow-mediated vasodilatation. These observations are compatible with the hypothesis that FGF-23 may contribute to vascular dysfunction in this population.

Vascular health, systemic inflammation and progressive reduction in kidney function; clinical determinants and impact on cardiovascular outcomes

INTRODUCTION Systemic inflammation, endothelial dysfunction and arterial thickening contribute to the elevated cardiovascular risk of dialysis patients. However, the course of these derangements and their relative contribution to the cardiovascular risk of nondialysed chronic kidney disease (CKD) are scarcely investigated. METHODS Flow-mediated dilatation (FMD) and intima-media thickness (IMT) were assessed in 304 nondialysed CKD patients Stages 1-5 (mean age 46 ± 12 years, 158 men), together with routine biochemical measurements, C-reactive protein (CRP) and insulin resistance. Patients were then followed for time-to-event analysis of cardiovascular outcomes (fatal and nonfatal). RESULTS CRP and IMT increased, while FMD decreased in parallel with estimated glomerular filtration rate (eGFR) decline (P < 0.001 for all). CRP and intact parathormone, as well as eGFR, appeared as strong determinants of FMD and IMT in multivariate analyses. After a median follow-up of 41 (range 6-46) months, 30 fatal and 59 nonfatal cardiovascular events occurred. In univariate analysis, FMD, IMT and CRP were significant predictors of outcome. In a multivariate Cox model excluding IMT, both FMD [hazard ratios 0.52 (95% confidence intervals 0.37-0.73) per %] and CRP [1.07 (1.03-1.11) per mg/L] predicted cardiovascular outcomes independently of confounders. In a model excluding FMD, only CRP (and not IMT) was a significant predictor. CONCLUSIONS Endothelial dysfunction, arterial thickening and inflammation occur in parallel with the decline in eGFR, contributing to the increased cardiovascular risk of nondialysed CKD. Our results support the use of FMD over IMT measurements to monitor nondialysed CKD patients at risk.

Soluble TWEAK and PTX3 in nondialysis CKD patients: impact on endothelial dysfunction and cardiovascular outcomes.

BACKGROUND AND OBJECTIVES Chronic kidney disease (CKD) conveys high mortality rates. Soluble TNF-like weak inducer of apoptosis (sTWEAK) and long pentraxin 3 (PTX3) are predictors of mortality in dialysis patients and determinants of endothelial dysfunction. Now, we hypothesize that both sTWEAK and PTX3 act as biomarkers of cardiovascular outcomes in nondialysis CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Cross-sectional analysis in which flow-mediated dilation (FMD) and intima-media thickness (IMT) were assessed in 257 nondialysis stage 1 to 5 CKD patients (mean age, 52 ± 12 years; 130 men), together with biochemical measurements and sTWEAK and PTX3 assessments. Patients were followed for cardiovascular outcomes. RESULTS PTX3 and IMT increased, whereas FMD and sTWEAK decreased across CKD stages (P<0.001 for all). Both PTX3 and sTWEAK appeared as strong determinants of FMD in multivariate analysis. The univariate associations of sTWEAK and PTX3 with IMT were dependent on estimated GFR. After a median of 39 months (range, 2 to 43 months), 22 fatal and 57 nonfatal cardiovascular events occurred. In a Cox model excluding PTX3, decreasing sTWEAK concentration was associated with increased risk of cardiovascular events independently of basic confounders (age, gender, estimated GFR, C reactive protein, diabetes, and cardiovascular comorbidity) and FMD. In a model excluding sTWEAK, circulating levels of PTX3 were directly associated with cardiovascular outcomes independently of basic confounders, but this association was lost after adjustment for FMD. CONCLUSIONS Both PTX3 and sTWEAK levels associated with the endothelial dysfunction observed with progressive kidney failure. Additionally, both biomarkers impacted the predictability of cardiovascular outcomes.

Comparative effects of nebivolol and metoprolol on red cell distribution width and neutrophil/lymphocyte ratio in patients with newly diagnosed essential hypertension.

Abstract: High level of circulating red cell distribution width (RDW) and neutrophil/lymphocyte (N/L) ratio may reflect ongoing vascular inflammation and play an important role in pathophysiology of hypertension. We evaluate the effects of nebivolol and metoprolol on the RDW and N/L in new essential hypertensive patients. After baseline assessment, 72 patients were randomly allocated to 5 mg/d of nebivolol (n = 37, 20 men) or 100 mg/d of metoprolol (n = 35, 18 men) and treated for 6 months. Blood pressure (BP), heart rate (HR), RDW, and N/L were measured before and after treatment. BP significantly decreased with both drugs (P < 0.001). Analog reduction was observed for resting HRs (P < 0.001), but metoprolol caused greater HR fall as compared with nebivolol (P < 0.001). After 6 months of treatment, nebivolol significantly lowered not only RDW but also the total white blood cell and N/L (P < 0.001, P = 0.023, P = 0.017, respectively). No changes were observed in metoprolol group. Percent decrease in RDW was found to be significantly higher in nebivolol than in the metoprolol group (P = 0.001) and remained also after correction for confounders (P = 0.012). Nebivolol improved RDW and N/L to a greater extent than metoprolol in patients with hypertension. These favorable effects may participate, together with the BP reduction, at the favorable properties of the drug in hypertension.

Plasma Apelin and ADMA Levels in Patients with Essential Hypertension

Both apelin and asymetric dymethyl arginine (ADMA) regulate blood pressures. Low apelin and high ADMA levels have been reported in several cardiometabolic disorders. However, there is no data about ADMA and apelin levels in essential hypertension and any relationship between them. We investigated a group of newly diagnosed and untreated 30 young hypertensive men and 30 healthy controls. Apelin levels were significantly lower and the ADMA levels were significantly higher in the patients (p = 0.04 for both). Both ADMA and apelin were related to the systolic blood pressures (SBP) (beta = −0.393, p = 0.003; beta = 0.285, p = 0.03, respectively). Future studies are necessary in order to clearly define the role of ADMA and apelin in the pathogenesis of essential hypertension.

Sacrococcygeal pilonidal disease: analysis of previously proposed risk factors

PURPOSE Sacrococcygeal pilonidal disease is a source of one of the most common surgical problems among young adults. While male gender, obesity, occupations requiring sitting, deep natal clefts, excessive body hair, poor body hygiene and excessive sweating are described as the main risk factors for this disease, most of these need to be verified with a clinical trial. The present study aimed to evaluate the value and effect of these factors on pilonidal disease. METHOD Previously proposed main risk factors were evaluated in a prospective case control study that included 587 patients with pilonidal disease and 2,780 healthy control patients. RESULTS Stiffness of body hair, number of baths and time spent seated per day were the three most predictive risk factors. Adjusted odds ratios were 9.23, 6.33 and 4.03, respectively (p<0.001). With an adjusted odds ratio of 1.3 (p<.001), body mass index was another risk factor. Family history was not statistically different between the groups and there was no specific occupation associated with the disease. CONCLUSIONS Hairy people who sit down for more than six hours a day and those who take a bath two or less times per week are at a 219-fold increased risk for sacrococcygeal pilonidal disease than those without these risk factors. For people with a great deal of hair, there is a greater need for them to clean their intergluteal sulcus. People who engage in work that requires sitting in a seat for long periods of time should choose more comfortable seats and should also try to stand whenever possible.

Low Triiodothyronine Alters Flow-Mediated Vasodilatation in Advanced Nondiabetic Kidney Disease

Background/Aims: Subclinical or frank hypothyroidism is causally implicated in endothelial dysfunction. Since the plasma concentration of the active form of thyroid hormone, triiodothyronine (T3), is reduced in chronic kidney disease (CKD), where endothelial function is frequently altered, low T3 may be a factor implicated in this disturbance in CKD patients. Methods: We investigated the relationship between flow-mediated vasodilatation (FMD) and thyroid hormones in a series of 217 nondiabetic patients with stage 3–4 CKD. Results: The plasma concentration of free T3 (fT3) was closely associated with FMD (r = 0.38; p < 0.001). fT3 was also inversely associated with hemoglobin (r = –0.41; p < 0.001), systolic pressure (r = –0.28; p < 0.001) and the plasma concentration of the endogenous inhibitor of NO synthase, asymmetric dimethylarginine (ADMA; r = –0.18; p = 0.007). However, adjustment for ADMA markedly attenuated the fT3-FMD link, a phenomenon suggesting that raised plasma ADMA, possibly driven by low fT3, at least in part mediates the adverse effects of low T3 on endothelial function in CKD. Conclusions: Low T3 in patients with moderate-to-severe CKD is a marker of endothelial dysfunction. This study sets a solid rationale for designing specific intervention studies aimed at clarifying the nature (causal or not causal) of the endothelial function-T3 link in CKD.

Blockade of the renin-angiotensin system increases plasma adiponectin levels in type-2 diabetic patients with proteinuria.

Background/Aims: Adiponectin seems to be an important modulator for metabolic and vascular diseases. A case study was designed to measure plasma adiponectin levels and to investigate the effects of angiotensin-converting enzyme inhibitors on adiponectin levels in type-2 diabetic patients with proteinuria. Methods: Forty-nine patients (28 males, 21 females) and 23 healthy volunteers (13 males, 10 females) were included in the case study. Patients with proteinuria were treated with 5 mg/day ramipril (n = 21) for 4 weeks. Results: Adiponectin levels of patients were significantly lower than those of healthy volunteers (p < 0.001). There were significant negative correlations between adiponectin concentrations and insulin levels as well as the homeostasis model assessment (HOMA) index in the patient group (r = –0.655, p < 0.001; r = –0.469, p = 0.001, respectively). There was also a significant negative correlation between plasma adiponectin concentrations and the degree of proteinuria (r = –0.912, p < 0.001). Plasma adiponectin levels in patients with proteinuria (n = 21; 4.81 ± 3.17 µg/ml) were significantly lower than those without proteinuria (n = 28; 10.25 ± 2.03 µg/ml; p < 0.001). After the treatment period, adiponectin levels significantly increased (p < 0.001) and proteinuria, plasma insulin, and HOMA indexes significantly decreased in the treatment group (p < 0.001, p < 0.001, p = 0.002, respectively). Conclusions: The results suggest that adiponectin is inversely correlated with proteinuria and treatment with ramipril both corrects proteinuria and increases the low adiponectin levels in diabetic patients.