Function In Non-diabetic Patients Research Articles

SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the acetylation of endothelium Notch1

BackgroundEndothelial–mesenchymal transition (EndMT) plays a crucial role in promoting myocardial fibrosis and exacerbating cardiac dysfunction. Dapagliflozin (DAPA) is a sodium–glucose-linked transporter 2 (SGLT-2) inhibitor that has been shown to improve cardiac function in non-diabetic patients with heart failure (HF). However, the precise mechanisms by which DAPA exerts its beneficial effects are yet to be fully elucidated.MethodsIsoproterenol (ISO) was used to generate a HF model in mice. For in vitro experiments, we used TGF-β1-stimulated human umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs).ResultsBoth our in vivo and in vitro results showed that EndMT occurred with decreased SIRT1 (NAD+-dependent deacetylase) protein expression, which could be reversed by DAPA therapy. We found that the protective effect of DAPA was significantly impaired upon SIRT1 inhibition. Mechanistically, we observed that SIRT1 phosphorylation, a required modification for its ubiquitination and degradation, was reduced by DAPA treatment, which induces the nucleus translocation of SIRT1 and promotes its binding to the active intracellular domain of Notch1 (NICD). This interaction led to the deacetylation and degradation of NICD, and the subsequent inactivation of the Notch1 signaling pathway which contributes to ameliorating EndMT.ConclusionsOur study revealed that DAPA can attenuate EndMT induced by ISO in non-diabetic HF mice. This beneficial effect is achieved through SIRT1-mediated deacetylation and degradation of NICD. Our findings provide greater insight into the underlying mechanisms of the therapeutic effects of DAPA in non-diabetic HF.Graphical

Effect of Colchicine on Neutrophil to Lymphocyte Ratio and Cardiac Function in Non-Diabetic Patients Post STEMI Using Speckle Tracking Imaging

Effect of Colchicine on Neutrophil to Lymphocyte Ratio and Cardiac Function in Non-Diabetic Patients Post STEMI Using Speckle Tracking Imaging

Effect of colchicine on Neutrophil to Lymphocyte ratio and Cardiac Function in Non-Diabetic Patients Post STEMI Using Speckle Tracking Imaging

Effect of colchicine on Neutrophil to Lymphocyte ratio and Cardiac Function in Non-Diabetic Patients Post STEMI Using Speckle Tracking Imaging

MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol

BackgroundPeripheral artery disease (PAD) affects over 230 million people worldwide and is due to systemic atherosclerosis with etiology linked to chronic inflammation, hypertension, and smoking status. PAD is associated with walking impairment and mobility loss as well as a high prevalence of coronary and cerebrovascular disease. Intermittent claudication (IC) is the classic presenting symptom for PAD, although many patients are asymptomatic or have atypical presentations. Few effective medical therapies are available, while surgical and exercise therapies lack durability. Metformin, the most frequently prescribed oral medication for Type 2 diabetes, has salient anti-inflammatory and promitochondrial properties. We hypothesize that metformin will improve function, retard the progression of PAD, and improve systemic inflammation and mitochondrial function in non-diabetic patients with IC.Methods200 non-diabetic Veterans with IC will be randomized 1:1 to 180-day treatment with metformin extended release (1000 mg/day) or placebo to evaluate the effect of metformin on functional status, PAD progression, cardiovascular disease events, and systemic inflammation. The primary outcome is 180-day maximum walking distance on the 6-min walk test (6MWT). Secondary outcomes include additional assessments of functional status (cardiopulmonary exercise testing, grip strength, Walking Impairment Questionnaires), health related quality of life (SF-36, VascuQoL), macro- and micro-vascular assessment of lower extremity blood flow (ankle brachial indices, pulse volume recording, EndoPAT), cardiovascular events (amputations, interventions, major adverse cardiac events, all-cause mortality), and measures of systemic inflammation. All outcomes will be assessed at baseline, 90 and 180 days of study drug exposure, and 180 days following cessation of study drug. We will evaluate the primary outcome with linear mixed-effects model analysis with covariate adjustment for baseline 6MWT, age, baseline ankle brachial indices, and smoking status following an intention to treat protocol.DiscussionMOBILE IC is uniquely suited to evaluate the use of metformin to improve both systematic inflammatory responses, cellular energetics, and functional outcomes in patients with PAD and IC.Trial Registration: The prospective MOBILE IC trial was publicly registered (NCT05132439) November 24, 2021.

Hypoglycemia induces vascular endothelial dysfunction in subjects with normal glucose tolerance

This prospective study determined the effects of hypoglycemic stimulation on vascular endothelial function in non-diabetic patients using reactive hyperemia peripheral arterial tonometry (RH-PAT). The study included non-diabetic patients who were hospitalized for an insulin tolerance test (ITT) for the diagnosis of hypoadrenocorticism or hypopituitarism. Vascular endothelial function was assessed using the reactive hyperemia index (RHI) measured by the RH-PAT. We also measured the levels of anterior pituitary hormone, adrenaline, noradrenaline, and dopamine at the time of hypoglycemia. The primary endpoint was a change in the RHI at 120 min after insulin administration. The study included 27 patients. ITT was associated with significant increases in systolic blood pressure, pulse rate, and the blood levels of adrenocorticotropic hormone, cortisol, growth hormone, adrenaline, noradrenaline, and dopamine. RHI significantly decreased after ITT from 2.24 ± 0.51 to 1.71 ± 0.42. A significant inverse correlation was observed between the change in RHI and change in adrenaline (r = − 0.670, p = 0.012). We concluded that hypoglycemic stimulation altered vascular endothelial function, as measured by RH-PAT, even in patients free of glucose intolerance. The observed deterioration in vascular endothelial function correlated with increases in catecholamine levels during hypoglycemia.Trial registration: UMIN000033244.

Endothelial dysfunction, subclinical atherosclerosis and LDL cholesterol are the independent predictors of left atrial functions in hypertension.

Left atrial function has an important role in determining optimal performance of the heart. Increase of left atrial dysfunction and volume are poor prognostic factors. In this study, we investigated independent determinants of left atrial function in non-diabetic patients with de novo hypertension. The study included 124 consecutive non-diabetic patients with de novo hypertension. Brachial artery flow-mediated dilatation, carotid intima-media thickness, transthoracic echocardiography, 24-h rhythm holter, and aortic stiffness measurements were recorded. In echocardiography, left atrial maximum (LAMaV) and minimum (LAMiV) volumes were calculated. Left atrium total emptying fraction (LATEF) and total emptying volume (LATEV) were divided into two groups according to the mean levels. Multivariate analysis was performed after correlation analysis for LATEV and LATEF mean levels. By logistic regression analysis, systolic blood pressure (OR 0.882, 95% CI 0.784-0.992, p = 0.036), percent of flow-mediated dilation (OR 0.747, 95% CI 0.595-0.938, p = 0.012), and presence of carotid plaque (OR 0.014, 95% CI 0.001-0.188, p = 0.001) were found as independent variables that determine LATEF. Age (OR 0.879, 95% CI 0.795-0.972, p = 0.012), smoking (OR 23.739, 95% CI 2.699-208.810, p = 0.004), left ventricular mass index (OR 1.052, 95% CI 1.012-1.094, p = 0.011), mitrale E-wave velocity (OR 1.108, 95% CI 1.031-1.191, p = 0.005) and LDL (low-density lipoprotein) cholesterol (OR 0.942, 95% CI 0.911-0.974, p = 0.001) were independent predictors of LATEV. In non-diabetic patients with de novo hypertension endothelial dysfunction, subclinical atherosclerosis and LDL cholesterol levels independently affect left atrial function.

Early Alterations in Glycemic Control and Pancreatic Endocrine Function in Nondiabetic Patients With Chronic Pancreatitis.

Diabetes mellitus is a frequent consequence of chronic pancreatitis (CP). Little is known about pancreatic endocrine function before the development of diabetes mellitus in CP, particularly in females, or those without calcific and/or alcoholic pancreatitis. Twenty-five nondiabetic adult patients with CP (19 female; mean [SE] age, 34.2 [2.4] years) were compared with 25 healthy controls matched for age, sex, and body mass index. Subjects underwent frequent sample intravenous glucose tolerance testing (FSIVGTT) and mixed meal tolerance testing (MMTT). Mean (SE) fasting glucose was higher in patients with CP (89.5 [2.3] mg/dL) than in controls (84.4 [1.2] mg/dL, P = 0.04). On MMTT, patients with CP had a higher area under the curve (AUC) glucose and AUC glucagon compared with controls (P ≤ 0.01). The AUC C-peptide was equivalent (P = 0.6) but stimulated C-peptide at 30 minutes was lower in patients with CP (P = 0.04). Mean insulin sensitivity index calculated from the FSIVGTT was lower in CP group, indicating reduced insulin sensitivity (P ≤ 0.01). Disposition index (insulin secretion adjusted for insulin sensitivity on FSIVGTT) was lower in patients with CP (P = 0.01). Patients with CP had higher fasting and MMTT glucose levels, without a compensatory increase in insulin secretion suggesting subtle early islet dysfunction. Our cohort had relative hyperglucagonemia and was less insulin sensitive than controls.

Abstract 19179: Effects of Systemic Insulin Resistance on Redox State and Endothelial Nitric Oxide Bioavailability in the Human Vascular Wall

Background: Insulin resistance (IR) and diabetes mellitus (DM) are associated with increased risk of cardiovascular disease. We explored the specific effects of insulin resistance on vascular redox state and endothelial function in non-diabetic patients with coronary atherosclerosis. Methods: The study population consisted of 383 patients undergoing coronary bypass surgery (CABG). Endothelial function was estimated using non-invasive imaging (brachial Flow-Mediated Dilatation -FMD) preoperatively. During surgery, segments of human saphenous vein (SV)were obtained and used to quantify nitric oxide bioavailability (ex vivo vasorelaxations in response to acetylcholine) and NADPH oxidase-derived superoxide (O2-) by lucigenin chemiluminescence (using NADPH at 100μM). Glucose and insulin were measured in plasmas for calculation of HOMA-IR, the homeostatic model assessment of IR status. Results: The presence of IR (HOMA-IR>2.9) was associated with impaired FMD (A), reduced vasorelaxations of human vessels in response to acetylcholine (B) and elevated vascular O2- generation (C). Conclusions: IR is associated with impaired endothelial function and increased oxidative stress in human vessels. This is the first study demonstrating a direct effect of systemic insulin resistance on key mechanisms of atherogenesis in human vessels, highlighting it as a specific therapeutic target in non-diabetic patients with atherosclerosis.

Admission glucose and left ventricular systolic function in non-diabetic patients with acute myocardial infarction.

Carbohydrate metabolism disorder in patients hospitalized due to acute ST-segment elevation myocardial infarction (STEMI) is associated with poor outcome. The association is even stronger in non-diabetic patients compared to the diabetics. Poor outcome of patients with elevated parameters of carbohydrate metabolism may be associated with negative impact of these disorders on left ventricular (LV) function. The aim of the study was to determine the impact of admission glycemia on LV systolic function in acute phase and 6 months after myocardial infarction in STEMI patients treated with primary angioplasty, without carbohydrate disorders. The study group consisted of 52 patients (9 female, 43 male) aged 35-74 years, admitted to the Department of Cardiology and Internal Medicine, Collegium Medicum in Bydgoszcz, due to the first STEMI treated with primary coronary angioplasty with stent implantation, without diabetes in anamnesis and carbohydrate metabolism disorders diagnosed during hospitalization. Echocardiography was performed in all patients in acute phase and 6 months after MI. Plasma glucose were measured at hospital admission. In the subgroup with glycemia ≥7.1 mmol/l, in comparison to patients with glycemia <7.1 mmol/l, significantly lower ejection fraction (EF) was observed in acute phase of MI (44.4 ± 5.4 vs. 47.8 ± 6.3 %, p = 0.04) and trend to lower EF 6 months after MI [47.2 ± 6.5 vs. 50.3 ± 6.3 %, p = 0.08 (ns)]. Higher admission glycemia in patients with STEMI and without carbohydrate metabolism disturbances, may be a marker of poorer prognosis resulting from lower LV ejection fraction in the acute phase and in the long-term follow-up.

Metformin Does Not Improve Diastolic Function in Nondiabetic Patients with STEMI

Metformin has no effect on diastolic function following acute myocardial infarction (MI) in nondiabetic patients. The disappointing finding from the Glycometabolic Interventions in Patients Presenting With ST-Segment Elevation Myocardial Infarction trial [GIPS-III; Lexis CP et al. JAMA 2014] is discussed in this article.

Abstract 19037: Impact of Stress Hyperglycemia on Coronary Flow Reserve Following Successfully Recanalized Primary Acute Myocardial Infarction in Non-Diabetic Patients

Background: Stress hyperglycemia (SH) is associated with adverse outcome and reduction in myocardial salvage after acute myocardial infarction (AMI), especially in non-diabetic patients. However, no relationship has been identified between admission blood glucose level and coronary flow reserve (CFR) as an index of microvascular function in non-diabetic patients with AMI. Methods: This study assessed 73 consecutive patients with a first anterior AMI who underwent successful percutaneous coronary intervention within 24 h from onset of symptoms. Plasma blood glucose was measured on admission. SH was defined as blood glucose ≥10 mmol/L (180 mg/dl). We excluded the patients with a previous or current diagnosis of diabetes or an abnormal oral glucose tolerance test (OGTT, 75-g) 5 days after admission. CFR was calculated as the ratio of hyperemic, which was induced by intravenous adenosine administration, to baseline diastolic coronary flow velocity of the left anterior descending artery using transthoracic echocardiography 7 days after AMI. Results: In 73 non-diabetic patients (mean age: 65 years, 48 males), 14 patients showed SH (218±48mg/dl). Baseline diastolic coronary flow velocity in patients with SH (24±11cm/s) was higher than those without SH(19±6 cm/s, p=0.04), while there was no significant difference in hyperemic coronary flow velocity between the patients with (50±26 cm/s) and without SH (48±20 cm/s). Calculated CFR of the patients with stress hyperglycemia (2.0±0.4) was significantly lower than those without stress hyperglycemia (2.4±0.6, p=0.02). Conclusions: CFR was impaired in non-diabetic patients with hyperglycemia on admission. Impaired coronary microcirculation may partly contribute to reduced myocardial salvage and adverse outcome in patients with SH.

Renal Resistive Index and Parathyroid Hormone Relationship with Renal Function in Nondiabetic Patients

Introduction. The renal resistive index (RRI) reflects intrarenal vascular resistance and stiffness, which are associated with chronic kidney disease. The links connecting renal function, intrarenal arterial resistance, and parathyroid hormone (PTH) with hypertension and metabolic factors remain elusive. The aim of this study is to investigate the possible relationship of RRI with glomerular filtration rate, PTH, hypertension, obesity (body mass index and waist-to-hip ratio), bioelectrical impedance analysis in body composition assessment, serum lipids, and insulin resistance assessed by homoeostasis model insulin resistance index. Patients and methods. This study was carried out on 387 (246 women, 141 men) nondiabetic patients, between >25 and <75 years, referred to an Internal Medicine Clinic and Day Hospital for essential hypertension, overweightness–obesity, and/or dyslipidemia. Lower salt/lower calorie Mediterranean diet, physical activity increase, smoking withdrawal, and lifestyle counseling, provided by a health psychologist support, were prescribed. Results. Higher hypertension risk, present in 42.5% of the overall group of eligible patients (164/387), is associated with high PTH and high RRI, along with greater renal insufficiency, insulin resistance, and obesity. There is a straight linear relationship of RRI to PTH (0.202; p = 0.009) in arterial hypertension, which is not observed in normal blood pressure patients. By gender-adjusted multiple linear regression analysis, it was found that fat mass, waist-to-hip ratio, and PTH account significantly for 62.3% of the variance to RRI in hypertensive patients. Conclusion. Increased arterial stiffness and intrarenal arterial resistance are associated with higher PTH in arterial hypertension; obesity (defined by greater fat mass and waist-to-hip ratio) and PTH are the independent conditions that account significantly for higher RRI.

Effect of Pioglitazone and Ramipril on Biomarkers of Low-Grade Inflammation and Vascular Function in Nondiabetic Patients with Increased Cardiovascular Risk and an Activated Inflammation: Results from the PIOace Study

This study investigated the effects of pioglitazone (PIO), ramipril (RAM), or their combination (PIRA) on low-grade inflammation in nondiabetic hypertensive patients with increased cardiovascular risk. Patients enrolled in this placebo-controlled, double-blind, randomized, parallel trial (72 male, 77 female, aged 60 ± 9 years, body mass index 30.4 ± 4.7 kg/m(2), duration of hypertension 9 ± 8 years) were treated with either 30/45 mg PIO (dose titration), 2.5/5 mg RAM, or their combination for 12 weeks. A reduction in high-sensitivity C-reactive protein was observed with PIO (-0.89 ± 1.98 mg/liter; -25%) and PIRA (-0.49 ± 2.11 mg/liter; -16%), while an increase was seen with RAM (0.58 ± 2.13 mg/liter; +20%, p < .05 vs PIO and PIRA). The 24-hour blood pressure profile showed a small increase with both monotherapies but a decrease with PIRA (p < .05 vs PIO). Improvements in biomarkers of chronic systemic inflammation and insulin resistance (IR) were observed in the PIO and PIRA arms only [PIO/RAM/PIRA: homeostasis model of assessment of IR: -0.78 ± 1.39 (-29%)/0.15 ± 1.03 (+5%)/ -1.44 ± 2.83 (-40%); adiponectin: 8.51 ± 5.91 (+104%)/ 0.09 ± 2.63 (+1%)/ 8.86 ± 6.37 mg/liter (+107%); matrix metallo-proteinase-9: -48 ± 127 (-12%)/-1 ± 224 (0%)/-60 ± 210 ng/ml (-13%), p < .05 for RAM vs PIO or PIRA in all cases]. Our 3-month study in nondiabetic hypertensive patients showed a decrease in biomarkers of IR and chronic systemic inflammation with the PIO monotherapy and the PIRA combination only, which may help to explain some findings in other cardiovascular outcome trials.

Effect of losartan on proteinuria and urinary angiotensinogen excretion in non-diabetic patients with chronic kidney disease

PurposeActivation of the rennin–angiotensin system (RAS) is thought to contribute to hypertension and proteinuria, and eventually to the progression of chronic kidney disease (CKD). Recent evidence suggests that urinary angiotensinogen...

Serum glucose level at hospital admission correlates with left ventricular systolic dysfunction in nondiabetic, acute coronary patients: the Hellenic Heart Failure Study

The purpose of this work was to evaluate the relation between serum glucose levels at hospital admission and left ventricular systolic function in nondiabetic patients with an acute coronary syndrome (ACS). Of the 1000 ACS patients who were consecutively enrolled during 2007-2008, 583 (63 +/- 13 years, 20% females) nondiabetic patients were studied in this work. Of these, 254 presented left ventricular systolic dysfunction (ejection fraction <40%). Biochemical measurements and detailed medical information were recorded in all participants. Patients having glucose levels at hospital admission in the highest tertile (>155 mg/dl) had lower left ventricular ejection fraction (40% vs 45%, P = 0.003), were older (66 +/- 11 vs 61 +/- 13, P = 0.004) and less physically active (49% vs 63%, P = 0.02), had higher troponin (14.7 +/- 39.7 vs 5.6 +/- 13.5, P = 0.03), higher brain natriuretic peptide (510.39 +/- 932.33 vs 213.4 +/- 301.14, P = 0.008), higher C-RP (42.26 +/- 55.26 vs 26.46 +/- 38.18, P = 0.04), lower creatinine clearance levels (68 +/- 33 vs.81 +/- 31, P = 0.009), higher white blood cell count (13 416 +/- 16 420 vs 9310 +/- 3020, P = 0.001), and lower body mass index (26.8 +/- 4 vs 27.2 +/- 4.4, P = 0.07), compared to those in the lowest tertile (<114 mg/dl). The multiadjusted logistic regression analysis revealed that a 10 mg/dl difference in glucose levels was independently associated with 8% (95% confidence interval 2%-14%) higher likelihood of left ventricular systolic dysfunction. Low glucose concentrations at hospital admission in nondiabetic post-ACS patients is a predictor for the appearance of left ventricular dysfunction, and could be a target marker for risk stratification.

Impact of insulin sensitivity treatment with pioglitazone on endothelial function in non-diabetic patients with arterial hypertension

The thiazolidindione (TDZ) pioglitazone reduces insulin resistance and blood pressure in non-diabetic patients with arterial hypertension as previously reported [Füllert et al. 2002]. The question is still not answered whether it is a direct effect on the endothelial wall or it is related with improvement of insulin sensitivity. The present investigation is the first placebo controlled study which examines the effect of TDZ induced changes of insulin sensitivity (SI) on endothelial function and blood pressure in in non-diabetic patients with high blood pressure. Insulin sensitivity indices (SI indices) were obtained by analyzing fasting glucose and insulin concentration with homeostasis model assessment (HOMA), the glucose and insulin profiles after 75 g dextrose oral glucose tolerance tests (OGTT, Matsuda-Index) and euglycemic hyperinsulinemic clamp (m-value) in a double-blind placebo-controlled study in 60 patients with arterial hypertension before and after 4 months treatment with Pioglitazone 45 mg (PIO45). Flow-mediated dilatation of brachial artery (FMD) after reperfusion was used to determine endothelial function. Blood pressure in the morning of every visit (casual blood pressure, RRc) and 24-h ambulatory blood pressure (24RR) were measured. Antihypertensive treatments were equally distributed in the placebo and PIO45 group. All SI indices were closely related to with alanine-aminotransferase activities (ALAT): HOMA r = 0.1041, p < 0.05, Matsuda-Index r = 0.4242, p < 0.01, M value r = 0.1944, p < 0.01. There were no relationships of SI indices with FMD, RRc and 24RR in the study population with treated arterial hypertension. FMD was closely related to the nocturnal systolic and diastolic 24hRR (systolic r = 0.0943, p < 0.05, diastolic r = 0.0947, p < 0.05). SI indices improved after 4-month therapy with PIO45 when compared with controls: HOMA 65% (p < 0.01), Matsuda-Index 60% (p < 0.01) and M value 17.7% (p = 0.008). FMD did not change after PIO45. Casual diastolic blood pressure (p = 0.016) and systolic blood pressure were lower (p = 0.053) under PIO45. No significant changes of 24-h blood pressure were found after treatment with TDZ. 4-month treatment with PIO45 improves SI, liver function and lowers casual blood pressure (RRc. No effects on 24-h ambulatory blood pressure and on endothelial function after PIO45 therapy were observed. The higher insulin sensitivity was not related to lower blood pressure. Thus, PIO45 appears to have a direct effect on the arterial system which cannot be explained by changes of endothelial function or improved SI in non-diabetic patients with treated high blood pressure.

Impact of pioglitazone on coronary endothelial function in non-diabetic patients with coronary artery disease

Pioglitazone has been shown to exert multiple antiatherosclerotic actions independent from its glycemic effects. We studied the hypothesis that pioglitazone improves coronary endothelial dysfunction in non-diabetic patients with coronary artery disease (CAD) in a randomized, placebo-controlled, double-blind trial. Fifty non-diabetic patients with CAD were randomized to 6 months treatment with pioglitazone 30 mg daily or placebo. Coronary endothelial function was tested at baseline and after 6 months with intracoronary infusion of adenosine, acetylcholine (0.072; 0.72; 7.2, and 36 microg/min), glyceroltrinitrate, and cold pressor test (CPT). The primary endpoint was the mean effect of treatment compared with placebo on acetylcholine-induced coronary vascular response for all acetylcholine dosages, based on percent change in luminal area measured by quantitative coronary angiography. There was no difference in baseline coronary endothelial function. The primary endpoint was significantly different between the groups with a 1.8% +/- 2.0% increase in luminal area between baseline and follow-up with pioglitazone and a 7.6% +/- 2.4% decrease in the placebo group (P < 0.008). At follow-up, there was a trend for a difference in CPT (P = 0.057). No difference was observed regarding intracoronary glyceroltrinitrate or adenosine. Pioglitazone treatment in non-diabetic patients with CAD was associated with a significantly better coronary endothelial function compared to placebo.

Serum Neutrophil Gelatinase-Associated Lipocalin as a Marker of Renal Function in Non-Diabetic Patients with Stage 2–4 Chronic Kidney Disease

The current Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines advocate creatinine-based equations for estimating GFR to identify patients with potential kidney disease and classify them into different stages due to the fact that serum creatinine is very insensitive to changes in the glomerular filtration rate. Very few biomarkers exist for monitoring chronic kidney disease. The aim of the study was to assess whether NGAL could represent a novel, sensitive marker of kidney function in adult patients with CKD. The study was performed on 92 non-diabetic patients with CKD stages 2–4. Serum and urinary NGAL as well as serum cystatin C were measured using commercially available kits. Serum NGAL was related, in univariate analysis, to serum creatinine, urinary NGAL, hemoglobin, hematocrit, leukocyte count, eGFR, and cystatin C. Urinary NGAL correlated with age, hemoglobin, hematocrit, serum creatinine, and eGFR. In multiple regression analysis, predictors of serum NGAL were creatinine (beta value = 0.97, p = 0.005), cystatin C (beta = 0.34, p = 0.01), and eGFR (beta value = 1.77, p = 0.001). In the healthy volunteers, serum NGAL correlated with age, serum creatinine, eGFR, leukocyte count, and cystatin C. Taking into consideration the fact that the recent DOQI (Dialysis Outcomes Quality Initiative) states that individuals with reduced GRF (glomerular filtration rate) are at greater risk for CVD and cardiac deaths, precise evaluation of renal function is important in order to select the appropriate strategy to reduce the cardiovascular risk. NGAL should be investigated as a potential early and sensitive marker of kidney impairment/injury.

Pioglitazone Improves Endothelial Function in Non-Diabetic Patients with Coronary Artery Disease

Objective: To test the hypothesis that pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, will improve endothelial function in non-diabetic subjects with coronary artery disease, we conducted a prospective study to evaluate the effect of this medication on the brachial artery vasomotor function and circulating markers of endothelial activation. Methods: Baseline characteristics were collected. After initial endothelial function assessment, patients were treated with pioglitazone hydrochloride 30 mg daily. The medication was continued for 12 weeks and endothelial function was reassessed as well as the inflammatory markers. The study medication then was stopped, and all the tests were repeated 12 weeks later. Results: Seventeen subjects completed all three-study phases. Mean age was 58 (range: 36–77 years). Compared with the baseline, the endothelium-dependent vasodilation improved significantly with the treatment (p < 0.001) from 4.4 ± 3.9 to 8.4 ± 4.1%, a relative increase of 91%. After withdrawal of treatment, the endothelium-dependent vasodilation returned towards baseline values. There was no change in endothelium-independent vasodilatation (12.27 ± 6.35 to 13.9 ± 9.23%, to 12.42 ± 5.35%, p = 0.177). The urine asymmetric dimethlyarginine levels decreased significantly with the treatment, but also returned to the initial values after the wash-out period (1.27 ± 0.5 µmol/ml to 0.97 ± 0.3 µmol/ml to 1.34 ± 0.5 µmol/ml, p = 0.017). No difference in the lipid profile, C-reactive protein, erythrocyte sedimentation rate, or fibrinogen levels was seen. Conclusion: Pioglitazone rapidly improves endothelial function in non-diabetic patients with coronary artery disease. This improvement is associated with a change in mean urinary asymmetric dimethylarginine levels, although a cause and effect cannot be determined from this investigation.

Peroxisome Proliferator–Activated Receptor-γ Activation With Pioglitazone Improves Endothelium-Dependent Dilation in Nondiabetic Patients With Major Cardiovascular Risk Factors

Patients with cardiovascular risk factors have endothelial dysfunction, a key element in the pathogenesis of atherosclerosis. The thiazolidinediones have been shown to exert multiple antiatherosclerotic actions in diabetic patients. This study tested the hypothesis that pioglitazone improves endothelial function in nondiabetic patients with major risk factors. The study had a randomized, double-blind, placebo-controlled, crossover design. Eighty patients with either hypertension or hypercholesterolemia were enrolled. Insulin sensitivity was assessed by the Quantitative Insulin Sensitivity Check Index (QUICKI), and patients were further classified as insulin sensitive or insulin resistant. In each treatment phase, patients received either pioglitazone 45 mg daily or placebo for 8 weeks. Endothelial function and laboratory tests were performed at the end of each 8-week period. Treatment with pioglitazone significantly lowered plasma insulin (-22.9%; P<0.001), improved QUICKI insulin sensitivity index (3.7%; P<0.001), increased HDL cholesterol (8.2%; P<0.001), and reduced triglycerides (-15.1%; P=0.003), free fatty acids (-14%; P=0.005), and C-reactive protein (-28.6%; P=0.001). Pioglitazone treatment significantly improved endothelium-dependent dilation to bradykinin (P=0.01) without affecting the response to sodium nitroprusside (P=0.31). In multivariable analysis, only changes in total cholesterol were predictors of improved endothelial reactivity with pioglitazone. In nondiabetic patients with cardiovascular risk factors, pioglitazone treatment enhances insulin sensitivity, decreases C-reactive protein, and improves endothelial vasodilator function. These effects do not appear to be closely related, suggesting that pioglitazone may have beneficial vascular properties independent of its effect on insulin sensitivity and inflammation.