Surrogate Marker Of Endothelial Function Research Articles

Apelin is expressed throughout the human kidney, is elevated in chronic kidney disease & associates independently with decline in kidney function.

Chronic kidney disease (CKD) is common and cardiovascular disease (CVD) is its commonest complication. The apelin system is a potential therapeutic target for CVD but data relating to apelin in CKD are limited. We examined expression of the apelin system in human kidney, and investigated apelin and Elabela/Toddler (ELA), the endogenous ligands for the apelin receptor, in patients with CKD. Using autoradiography, immunohistochemistry and enzyme-linked immunosorbent assay, we assessed expression of apelin, ELA and the apelin receptor in healthy human kidney, and measured plasma apelin and ELA in 155 subjects (128 patients with CKD, 27 matched controls) followed up for 5years. Cardiovascular assessments included blood pressure, arterial stiffness (pulse wave velocity) and brachial artery flow-mediated dilation. Surrogate markers of endothelial function (plasma asymmetric dimethylarginine and endothelin-1) and inflammation (C-reactive protein and interleukin-6) were measured. The apelin system was expressed in healthy human kidney, throughout the nephron. Plasma apelin concentrations were 60% higher in women than men (6.48 [3.62-9.89] vs. 3.95 [2.02-5.85] pg/mL; P< .0001), and increased as glomerular filtration rate declined (R= -0.41, P< .0001), and albuminuria rose (R= 0.52, P< .0001). Plasma apelin and ELA were associated with vascular dysfunction. Plasma apelin associated independently with a 50% decline in glomerular filtration rate at 5years. We show for the first time that the apelin system is expressed in healthy human kidney. Plasma apelin is elevated in CKD and may be a potential biomarker of risk of decline in kidney function. Clinical studies exploring the therapeutic potential of apelin agonism in CKD are warranted.

Impaired vascular endothelial function as a perioperative risk predictor \u2013 a prospective observational trial

BackgroundIn the recent years, an increasing number of patients with multiple comorbidities (e.g. coronary artery disease, diabetes, hypertension) presents to the operating room. The clinical risk factors are accompanied by underlying vascular-endothelial dysfunction, which impairs microcirculation and may predispose to end-organ dysfunction and impaired postoperative outcome. Whether preoperative endothelial dysfunction identifies patients at risk of postoperative complications remains unclear. In this prospective observational study, we tested the hypothesis that impaired flow-mediated dilation (FMD), a non-invasive surrogate marker of endothelial function, correlates with Days at Home within 30 days after surgery (DAH30). DAH30 is a patient-centric metric that captures postoperative complications and importantly also hospital re-admissions.MethodsSeventy-one patients scheduled for major abdominal surgery were enrolled. FMD was performed pre-operatively prior to major abdominal surgery and patients were dichotomised at a threshold value of 10%. FMD was then correlated with DAH30 (primary endpoint) and postoperative complications (secondary endpoints).ResultsDAH30 did not differ between patients with reduced FMD and normal FMD (14 (4) (median (IQR)) vs. 15 (8), P = 0.8). Similary, no differences between both groups were found for CCI (normal FMD: 21 (30) (median (IQR)), reduced FMD: 26 (38), P = 0.4) or frequency of major complications (normal FMD: 7 (19%) (n (%)), reduced FMD: 12 (35%), P = 0.12). The regression analyses revealed that FMD in combination with ASA status and surgery duration had no additional significant predictive effect for DAH30, CCI or Clavien-Dindo score.ConclusionFMD does not add predictive value with regards to DAH30, CCI or Clavien-Dindo score within our study cohort of patients undergoing abdominal surgery.Trial registrationThe study was registered in the German Clinical Trials Register (DRKS00005472), prospectively registered on 25/11/2013.

Improvement of microcirculatory impairment in patients with predialysis chronic kidney disease after AST-120 administration

BackgroundEndothelial dysfunction starts at an earlier stage in patients with chronic kidney disease (CKD), and induces macro- and microcirculatory impairments. We evaluated whether uremic toxin-lowering therapy could improve endothelial function in patients with CKD.MethodsWe performed a prospective interventional trial with 30 predialysis non-diabetic CKD patients who were administered oral adsorbent AST-120 (6 g/day) for 12 months. Surrogate markers of endothelial function including flow-mediated dilation (FMD) and skin perfusion pressure (SPP) were serially evaluated along with serum indoxyl sulfate (IS) levels and renal function. Renal function was evaluated based on blood urea nitrogen, serum creatinine (sCr) levels, and estimated glomerular filtration ratio (eGFR).ResultsMonthly decline in renal function (slope of reciprocal sCr) after AST-120 administration did not change compared to that during the pre-treatment period. However, serum IS levels significantly decreased at 3 months after AST-120 administration (p < 0.01), and it was sustained during the period of AST-120 administration (p < 0.01). Although FMD did not improve, SPP was constantly elevated after AST-120 administration, and was significantly higher at 12 months compared with baseline value (69.7 ± 14.6 vs. 78.8 ± 18.9 mmHg, p < 0.05). A significant correlation between the change of IS and SPP from baseline values was shown at 6 months after AST-120 administration (r = − 0.558, p = 0.02).ConclusionMicrocirculatory impairment was improved after AST-120 administration in patients with predialysis CKD.Trial registrationUMIN, UMIN000013577. Registered on March 31, 2014,

Effect on MicroRNA-92a in Atherosclerosis along with FlowMediated Vasodilation Study

Atherosclerosis has been regarded as an inflammatory disease. The vascular endothelium is considered as having multiple functions, regulating vascular tone, thrombosis, haematosis, permeability and cell adhesion. The emergence of microRNAs (miRNAs) as significant regulators of pathophysiological processes has indicated novel molecular insights and provided new therapeutic targets in atherosclerotic condition. Many studies have revealed that miRNA are associated with cardiovascular disease (CVD). With respect to miR-92a, miR -92a, a member of the miR-17 to miR-92 cluster, is expressed highly in endothelial cells (ECs) and regulated by shear stress. Both In vitro and vivo, miR-92a expression is highly induced in atheroprone regions compared with atheroresistant regions under disturbed flow (d-flow) condition. The clinical and experimental studies have suggested that inhibition of miR-92a can contribute to the improvement of endothelial dysfunction, inflammation, and oxidative stress in atherosclerosis. Recent reports showed that antimiR-92a as novel therapeutic options can be attributed to the endothelial cell autophagy and cardiomyocyte metabolism and that mechanistically, atherosclerotic status promote the packaging of functional miR-92a-3p into endothelial microvesicles, thereby promoting angiogenic response into recipient endothelial cells. It is strongly suggested that miR-92a-3p, having novel biological function and mechanism is a potent therapeutic target in atherosclerosis-related diseases. It is putative that flow-mediated vasodilation (FMD) study, early surrogate marker of endothelial function may in part reflect miR-92a, multifunctional biomarker

Effectiveness of a Novel Nutraceutical Compound Containing Red Yeast Rice, Polymethoxyflavones and Antioxidants in the Modulation of Cholesterol Levels in Subjects With Hypercholesterolemia and Low-Moderate Cardiovascular Risk: The NIRVANA Study.

Background: Red yeast rice supplements are broadly accepted as treatment for dyslipidaemia in subjects without high cardiovascular (CV) risk. Their effect on lipid profile is well known, but few data are available on their effect on endothelial function.Objectives: To study the effect of a novel nutraceutical compound (NC) containing low monacolin K dose, polymethoxyflavones and antioxidants on lipid profile, endothelial function and oxidative stress.Methods: Fifty-two subjects with low-moderate CV risk and dyslipidaemia (according to European guidelines) were enrolled and treated for 8 weeks with the NC. Blood samples were collected at baseline and at the end of treatment to assess changes in lipid profile, endothelial function and oxidative stress. The primary endpoint was the reduction of low density lipoprotein (LDL) cholesterol. Endothelial function was assessed through measurement of rate of apoptosis and nitric oxide (NO) production in human umbilical vein endothelial cells (HUVECs) treated with subject’s serum. High-sensitivity C-reactive protein, 4-hydroxynonenal (HNE) and oxidized LDL (oxLDL) were markers of oxidative stress.Results: Fifty subjects completed the study. The treatment caused a significant decrease in LDL (−15.6%, p < 0.001), oxLDL (−21.5%, p < 0.001), total cholesterol (TC), triglycerides, and ApoB. Apoptosis rate of HUVECs significantly decreased (−15.9%, p < 0.001). No changes were noted for NO levels and 4-HNE protein adducts. The reduction of the apoptosis rate was correlated to the reduction of oxLDL.Conclusion: An 8-week treatment based on a novel NC containing low manocolin K dose, polymethoxyflavones and antioxidants improved lipid profile in subjects with dyslipidaemia and low-moderate CV risk. Secondarily, we observed an improvement in surrogate markers of endothelial function that may result from the reduction of oxLDL (Registered at www.clinicaltrials.gov, NCT03216811).

Proof-of-Concept Study for an Enhanced Surrogate Marker of Endothelial Function in Diabetes

Diabetes mellitus affects distal small vessels earlier and to a greater extent than proximal vessels. Vascular disease starts from activation of the endothelial cells, which if prolonged may lead to reduced distensibility of the vessel when maximally stimulated. Hence a device which measures distensibility of a distal vessel should be a good biomarker for subclinical disease. We have developed a device capable of measuring reactive hyperaemia induced changes in the radial artery flow, volumetric changes and accompanying effects on the vessel wall. The measurement is based on the magnetic flux disturbance upon haemodynamic modulation as blood flows through a uniformly applied magnetic field, and generates what we have termed the radial artery maximum distensibility index (RA-MDI). In a proof-of-concept study we found significant correlations between RA-MDI and cardiovascular risk factors, scoring systems and carotid artery intima-media thickness. Further large scale prospective studies need to be conducted to ascertain the correlations with cardiovascular events.

Endothelial Nitric Oxide Pathways in the Pathophysiology of Dengue: A Prospective Observational Study.

Dengue can cause increased vascular permeability that may lead to hypovolemic shock. Endothelial dysfunction may underlie this; however, the association of endothelial nitric oxide (NO) pathways with disease severity is unknown. We performed a prospective observational study in 2 Vietnamese hospitals, assessing patients presenting early (<72 hours of fever) and patients hospitalized with warning signs or severe dengue. The reactive hyperemic index (RHI), which measures endothelium-dependent vasodilation and is a surrogate marker of endothelial function and NO bioavailability, was evaluated using peripheral artery tonometry (EndoPAT), and plasma levels of l-arginine, arginase-1, and asymmetric dimethylarginine were measured at serial time-points. The main outcome of interest was plasma leakage severity. Three hundred fourteen patients were enrolled; median age of the participants was 21(interquartile range, 13-30) years. No difference was found in the endothelial parameters between dengue and other febrile illness. Considering dengue patients, the RHI was significantly lower for patients with severe plasma leakage compared to those with no leakage (1.46 vs 2.00; P < .001), over acute time-points, apparent already in the early febrile phase (1.29 vs 1.75; P = .012). RHI correlated negatively with arginase-1 and positively with l-arginine (P = .001). Endothelial dysfunction/NO bioavailability is associated with worse plasma leakage, occurs early in dengue illness and correlates with hypoargininemia and high arginase-1 levels.

Evaluation of Endothelial Function by Flow-Mediated Dilation: a Comprehensive Review in Rheumatic Disease.

Flow-mediated dilation (FMD) represents a non-invasive marker of endothelial function to evaluate vascular homeostasis, which reflects the effects of several mechanisms, including vessel tone regulation, cell proliferation, and inflammatory responses. Beyond classical atherosclerotic risk factors such as arterial hypertension, diabetes mellitus, smoking, obesity, and dyslipidemia, chronic inflammation contributes to the endothelial dysfunction causing plaque formation and there is growing evidence of a significantly higher cardiovascular morbidity associated with autoimmune diseases. The endothelium reacts to several endogenous and exogenous stimuli, through surface receptors and intracellular signalling, and releases numerous vasoactive substances, including endothelins, prostacyclins, and nitric oxide (NO). Chronic inflammatory rheumatic diseases are commonly associated with decreased endothelial NO production, vascular damage, and premature atherosclerosis. Despite partially eclipsed by pulse wave velocity measure in the modern scientific literature, we provide a comprehensive overview and critically discuss the available data supporting FMD as a surrogate marker of endothelial function and, therefore, its potential role in predicting early atherosclerosis in patients with rheumatic diseases.

First report on the association of drinking water hardness and endothelial function in children and adolescents.

IntroductionThis study aims to investigate the relationship of water hardness and its calcium and magnesium content with endothelial function in a population-based sample of healthy children and adolescents.Material and methodsThis case-control study was conducted in 2012 among 90 individuals living in two areas with moderate and high water hardness in Isfahan County, Iran. The flow-mediated dilatation (FMD) of the brachial artery and the serum levels of soluble adhesion molecules (sICAM-1, sVCAM-1) were measured as surrogate markers of endothelial function, and high-sensitivity C-reactive protein (hs-CRP), as a marker of inflammation.ResultsData of 89 participants (51% boys, mean age 14.75 (2.9) years) were complete. Those participants living in the area with high water hardness had higher FMD, hs-CRP, and soluble adhesion molecules (sICAM-1, sVCAM-1) than their counterparts living in the area with moderate water hardness. Multiple linear regression analysis showed that after adjustment for confounding factors of age, gender, body mass index, healthy eating index and physical activity level, total water hardness, as well as water content of calcium and magnesium, had a significant positive relationship with FMD. The corresponding associations were inverse and significant with soluble adhesion molecules (p < 0.05).ConclusionsThis study, which to the best of our knowledge is the first of its kind in the pediatric age group, suggests that water hardness, as well as its calcium and magnesium content, may have a protective role against early stages of atherosclerosis in children and adolescents.

Effect of particulate air pollution and passive smoking on surrogate biomarkers of endothelial dysfunction in healthy children

Background:This study aimed to determine the association of ambient particulate matter (PM) on surrogate markers of endothelial function and inflammation in healthy children with or without exposure to second-hand smoke.Methods:This cross-sectional study was conducted in 2011 in Isfahan, which is the second largest and second most air-polluted city in Iran. The areas of the city with lowest and highest air pollution were determined, and in each area, 25 pre-pubescent boys with or without exposure to daily tobacco smoke at home were selected, i.e. 100 children were studied in total. Serum levels of C-reactive protein (CRP) and nitric oxide (NO) were measured.Results:Mean (SD) NO concentration was 7·87 (2·18) and 7·75 (2·04) μmol/L for participants not exposed and exposed to passive smoking, respectively, which is not statistically significant. The corresponding figures for CRP concentrations were 1·69 (0·89) and 2·13 (1·19) μg/ml (P = 0·04). Mean (SD) CRP concentration was significantly higher in children living in the highly polluted area than in those in the area of low pollution [2·11 (1·91) vs 1·60 (1·43) μg/ml, respectively, P = 0·02]. This difference was not significant for NO concentration. The regression analysis that examined the association between PM concentration (as independent variable) and CRP and NO levels (as dependent variables) in children not exposed to passive smoking demonstrated that increased PM was associated with a decrease in NO and an increase in CRP concentration. This finding shows that, regardless of passive smoking, PM10 concentration has a significant independent association with serum CRP and is inversely associated with NO levels.Conclusion:The findings suggest that in healthy children PM concentration has a significant independent association with biomarkers of endothelial dysfunction and inflammation.

Elevated Circulating Levels and Tissue Expression of Pentraxin 3 in Uremia: A Reflection of Endothelial Dysfunction

Elevated systemic pentraxin 3 (PTX3) levels appear to be a powerful marker of inflammatory status and a superior outcome predictor in patients with chronic kidney disease (CKD). As previous data imply that PTX3 is involved in vascular pathology and that adipose tissue mass may influence circulating PTX3 levels, we aimed to study the importance of adipose tissue expression of PTX3 in the uremic milieu and its relation to endothelial dysfunction parameters. Plasma PTX3 and abdominal subcutaneous adipose tissue (SAT) PTX3 mRNA levels were quantified in 56 stage 5 CKD patients (median age 57 [range 25–75] years, 30 males) and 40 age and gender matched controls (median age 58 [range 20–79] years, 27 males). Associations between PTX3 measures and an extensive panel of clinical parameters, including surrogate markers of endothelial function, were assessed. Functional ex vivo studies on endothelial status and immunohistochemical staining for PTX3 were conducted in resistance subcutaneous arteries isolated from SAT. SAT PTX3 mRNA expression correlated with plasma PTX3 concentrations (rho = 0.54, p = 0.0001) and was increased (3.7 [0.4–70.3] vs. 1.2 [0.2–49.3] RQ, p = 0.02) in CKD patients with cardiovascular disease (CVD), but was not significantly different between patients and controls. The association to CVD was lost after adjustments. SAT PTX3 mRNA levels were independently correlated to asymmetric dimethylarginine and basal resistance artery tone developed after inhibition with nitric oxide synthase and cyclooxygenase (rho = −0.58, p = 0.002). Apparent positive PTX3 immunoreactivity was observed in both patient and control arteries. In conclusion, fat PTX3 mRNA levels are associated with measures of endothelial cell function in patients with CKD. PTX3 may be involved in adipose tissue-orchestrated mechanisms that are restricted to the uremic milieu and modify inflammation and vascular complications in CKD patients.

English

Introduction Flow-mediated dilatation (FMD) is widely used as a non-invasive method to assess endothelial function. Vascular endothelium is a biological interface between blood and vessel wall and has a crucial role in vascular homeostasis. The endothelium is a large paracrine organ that secretes numerous factors regulating vasomotor function, cell growth, platelet and leukocyte interactions, inflammatory responses and thrombosis. It responds to various internal and external stimuli, through cell membrane receptors and signal transduction mechanisms, with numerous vasoactive substances released, including prostacyclins, endothelins, endothelial cell growth factors, interleukins, plasminogen inhibitors and nitric oxide (NO). In particular, NO is one of the most important molecules for its role as a vasodilator factor, inhibitor of inflammatory activity, vascular smooth muscle cell proliferation and platelet adhesion and aggregation. Classic and non-classic atherosclerotic risk factors such as hypertension, diabetes mellitus, smoking habit, obesity, dyslipidemia and systemic inflammation could lead to endothelial dysfunction and accelerated atherosclerosis. Chronic inflammatory rheumatic diseases have been associated with decreased endothelial function and accelerated atherosclerosis. This paper briefly reviews the role of FMD as a surrogate marker of endothelial function in rheumatic diseases. Conclusion FMD is a useful marker of endothelial function in chronic rheumatoid disease, but many factors can affect FMD assessment, and so further studies are needed to increase our understanding. Introduction Vessel homeostasis is determined by a balance between vasoconstrictor, vasodilator, proaggregating and antiaggregating molecules. Stimuli that alter vessel homeostasis can induce an altered endothelial function. This pathophysiological condition is associated with activated phenotype of endothelial cells, leading to increased expression of adhesion molecules, proinflammatory cytokines such as tumour necrosis factor (TNF) alpha, interleukin (IL)-1, IL-6 and interferon (IFN) gamma and prothrombotic factors. This process results in oxidative stress up-regulation, loss of vasodilatory ability and promotion of thrombosis, inflammation and cellular proliferation1. Several studies demonstrated that endothelial dysfunction plays a central role in the pathogenesis of atherosclerosis, promotes early atherosclerotic changes and is predictive for the development of cardiovascular events2,3. Thus, assessment of endothelium function, in the preclinical stage of atherosclerosis with non-invasive approaches, may serve as a valuable measure to be counted in the follow-up of patients with cardiovascular disease (CVD) risk. Among different methods, the assessment of flow-mediated dilatation (FMD) is one of the most used4. FMD depends on endothelium production of vasodilator molecules including nitric oxide (NO) and prostacyclin. Assessment of FMD is based on the reactive hyperaemia phenomenon that occurs when arterial blood flow is restored after a period of transient arterial occlusion5. Increased blood flow determines an enhancement in shear stress on the vessel wall that stimulates the release of NO5,6. Endothelial cell membrane contains calcium-activated potassium channels that open in response to shear stress. Potassium entrance hyperpolarizes the cell and increases calcium entry with activation of endothelial nitric oxide synthase (eNOS)7. FMD response is characteristically presented as a change in arterial baseline diameter after hyperaemia induced by applying sphygmomanometer cuff inflated to a pressure 25–50 mmHg above systolic arterial pressure. Usually, brachial artery can be assessed for its accessibility4 (Figures 1–3). * Corresponding author Email: a.spadaro.reuma@virgilio.it 1 Dipartimento di Medicina Interna e Specialita Mediche – UOC Reumatologia Sapienza – University of Rome, Italy 2 Dipartimento di Medicina e di Scienze per la Salute, University of Molise, Campobasso, Italy Figure 1: FMD execution technique: US probe was applied on the patient’s forearm to detect brachial artery.

Body Weight Loss by Very-Low-Calorie Diet Program Improves Small Artery Reactive Hyperemia in Severely Obese Patients

Endothelial dysfunction is a major underlying mechanism for the elevated cardiovascular risk associated with increased body weight. We aimed to assess the impact of weight loss induced by an intensive very-low-calorie diet (VLCD) on arterial wall function in severely obese patients (SOP). Thirty-four SOP were admitted to the metabolic ward of the hospital for a 3-week period. A VLCD characterized by a liquid diet providing 800 kcal/day was administered. The small artery reactivity to postischemic hyperemia index (saRHI), a surrogate marker of endothelial function, was assessed before and 1 week after hospital discharge. Anthropometry and biochemical parameters were also measured. Obese and non-obese age- and gender-matched groups were recruited for baseline comparisons. SOP had significantly lower saRHI compared with obese and non-obese individuals. SaRHI significantly increased after the intervention in SOP (1.595 ± 0.236 vs. 1.737 ± 0.417, p = 0.015). A significant improvement in glucose (p = 0.026), systolic blood pressure (p = 0.049), LDLc (p < 0.001), and inflammatory parameters was observed. Body weight loss was associated with a higher saRHI (r = -0.385, p = 0.033), and it was the main determinant of saRHI variation independently of confounders (β -0.049, IC 95 % -0.091-0.008, p = 0.021). Weight loss induced by a VLCD in SOP improved small artery reactivity, and it was associated with the amelioration of metabolic and inflammation markers. Endothelial dysfunction may be softened by body weight loss interventions and useful in the management of cardiovascular risk factors in SOP.

Sympathetic regulation of vascular function in health and disease

The sympathetic nervous system (SNS) is known to play a pivotal role in short- and long-term regulation of different functions of the cardiovascular system. In the past decades increasing evidence demonstrated that sympathetic neural control is involved not only in the vasomotor control of small resistance arteries but also in modulation of large artery function. Sympathetic activity and vascular function, both of which are key factors in the development and prognosis of cardiovascular events and disease, are linked at several levels. Evidence from experimental studies indicates that the SNS is critically influenced, at the central and also at the peripheral level, by the most relevant factors regulating vascular function, such as nitric oxide (NO), reactive oxygen species (ROS), endothelin (ET), the renin-angiotensin system. Additionally, there is indirect evidence of a reciprocal relationship between endothelial function and activity of the SNS. A number of cardiovascular risk factors and diseases are characterized both by increased sympathetic outflow and decreased endothelial function. In healthy subjects, muscle sympathetic nerve activity (MSNA) appears to be related to surrogate markers of endothelial function, and an acute increase in sympathetic activity has been associated with a decrease in endothelial function in healthy subjects. However, direct evidence of a cause-effect relationship from human studies is scanty. In humans large artery stiffness has been associated with increased sympathetic discharge, both in healthy subjects and in renal transplant recipients. Peripheral sympathetic discharge is also able to modulate wave reflection. On the other hand, large artery stiffness can interfere with autonomic regulation by impairing carotid baroreflex sensitivity.

A spontaneous, double-blind, double-dummy cross-over study on the effects of daily vardenafil on arterial stiffness in patients with vasculogenic erectile dysfunction

BackgroundIt is known that the incidence of endothelial dysfunction in patients with vascular erectile dysfunction (ED) is increased. The effects of daily vardenafil on endothelial function and arterial stiffness in patients with erectile dysfunction (ED) have never been investigated. Methods20 men complaining vascular ED (mean IIEF5=12±6 and peak systolic velocity-PSV=24±2cm/s) were enrolled in a 4-week, randomized, double-blind, double-dummy, crossover study (mean age 59±11) and received either vardenafil 10mg daily or 20mg on-demand with a two-week washout interval. Primary endpoints were variation from baseline of reactive hyperemia (RH) and augmentation index (AI) calculated by fingertip peripheral arterial tonometry (PAT) device. Secondary endpoints were variations of IIEF-5 and SEP3 scores from baseline and plasma surrogate markers of endothelial function, i.e. endothelin-1 (ET-1) and adrenomedullin (ADM). ResultsPatients who took daily vardenafil (vs. on-demand) reported significant (P<0.01) improvements in arterial stiffness as evaluated by AI and reduction of plasma ADM levels (p<0.05) but no improvement in average RH. When corrected for heart rate, ADM showed a strong direct relationship with AI (r2=0.22; p<0.005). The proportion of patients with an IIEF5 score of ≥22 or in SEP3 percentage of success rates were similar. Each treatment resulted in significantly greater IIEF5 scores (p<0.001) and better SEP3 response rates (p<0.0001) compared with baseline. ConclusionsWe demonstrated that daily vardenafil improves arterial stiffness and erectile function measurements in men with severe vasculogenic ED. This effect may be mediated, at least in part, by a reduction in ADM circulating levels.

Flow-mediated dilatation of the brachial artery is a poorly reproducible indicator of microvascular function in Type I diabetes mellitus

Flow-mediated dilatation (FMD) of the brachial artery is commonly measured as a surrogate marker of endothelial function. Its measurement is, however, technically demanding and reports regarding its reproducibility have not always been favourable. Two Type I diabetes and control group comparator studies were conducted to assess the reproducibility of FMD and to analyse blood flow data normally discarded during FMD measurement. The studies were sequential and differed only with regard to operator and ultrasound machine. Seventy-two subjects with diabetes and 71 controls were studied in total. Subjects had FMD measured conventionally. Blood velocity waveforms were averaged over 10 pulses post forearm ischaemia and their component frequencies analysed using the wavelet transform, a mathematical tool for waveform analysis. The component frequencies were grouped into 11 bands to facilitate analysis. Subjects were well-matched between studies. In Study 1, FMD was significantly impaired in subjects with Type I diabetes vs. controls (median 4.35%, interquartile range 3.10-4.80 vs. 6.50, 4.79-9.42, P < 0.001). No differences were detected between groups in Study 2, however. However, analysis of blood velocity waveforms yielded significant differences between groups in two frequency bands in each study. This report highlights concerns over the reproducibility of FMD measures. Further work is required to fully elucidate the role of analysing velocity waveforms after forearm ischaemia.

High-density lipoprotein cholesterol and apolipoprotein A1 levels strongly influence the reactivity of small peripheral arteries

ObjectiveReactive hyperaemia after shear stress is a surrogate marker of endothelial function. However, the mechanisms controlling the dilation capacity of small peripheral resistance arteries are not well characterised. We evaluated reactive hyperaemia by peripheral artery tonometry (PAT) in the acral arteries and studied their clinical and biochemical determinants. MethodsEight hundred sixteen subjects at intermediate to high cardiovascular risk were recruited. The reactive hyperaemia index (RHI) of small digital arteries was measured by PAT. Clinical history data, anthropometry and biochemical parameters were also analysed. We studied the associations between clinical and biochemical factors and small artery RHI. ResultsHDL cholesterol and apolipoprotein A1 levels were strongly and directly correlated with an increased dilation response. Metabolic syndrome components, such as increased waist circumference, hypertriglyceridaemia and smoking, were inversely associated with RHI as were serum markers of inflammation. The predictors of small peripheral artery RHI were HDL cholesterol, which had a protective effect, and smoking, which had a negative impact. ConclusionHDL cholesterol and apolipoprotein A1 levels had a strong, positive correlation with small artery reactive hyperaemia, whereas smoking, waist circumference and triglyceride levels were inversely associated. HDL cholesterol was the main determinant of RHI in small peripheral resistance arteries.

Endothelial progenitor cells as a new marker of endothelial function with respect to risk of cardiovascular disorders

The discovery of endothelial progenitor cells (EPC), over a decade ago, has refuted the previous belief that vasculogenesis only occurs during embryogenesis. The results of several studies revealed altered number and impaired function of EPC in hyperlipidemia, hypertension, diabetes, obesity as well as in rheumatoid arthritis. The population of developmental age is characterized by higher counts of EPC compared to adults. However, among young patients with chronic disorders that affect the vascular system, the number of EPC decreases. The reduced circulating concentration of EPC has become a surrogate marker of endothelial function and has been implicated in the pathogenesis of many vascular diseases. This article aims to review the biology and pathophysiology of EPC in the conditions of cardiovascular risk factors. The potential possibilities of increasing EPC number and function as well as the use of EPC in the treatment of vascular pathology will also be discussed.

The Many Faces of Endothelial Microparticles

Endothelial microparticles (EMP) are complex vesicular structures shed from activated or apoptotic endothelial cells. They play a remarkable role in coagulation, inflammation, endothelial function, and angiogenesis and thus disturb the vascular homeostasis, contributing to the progression of vascular diseases. As a cause or a consequence, elevated levels of EMP were found in plasma from patients with vascular diseases, where they serve as a surrogate marker of endothelial function. More recent data challenged the presumed deleterious role of EMP because they could promote cell survival, exert antiinflammatory effects, counteract coagulation processes, or induce endothelial regeneration. This review focuses on the ambivalent role of EMP in vascular homeostasis.

Effect of pioglitazone on endothelial function in impaired glucose tolerance

Flow-mediated dilation (FMD) is a surrogate marker of endothelial function, which has been proposed as a barometer of vascular health. Impaired microvascular response to reactive hyperaemia is thought to be the mechanism behind reduced shear stress and subsequently impaired FMD, which has been associated with cardiovascular events. This study aims to assess the effect of pioglitazone on the vasculature of patients with impaired glucose tolerance (IGT). Forty IGT patients with no cardiovascular disease were compared with 24 healthy age- and sex-matched controls. Endothelial function was assessed using FMD of the brachial artery. Adiponectin (ADN) levels were measured and insulin sensitivity was calculated using homeostasis model assessment of insulin resistance (HOMA-IR). A randomised double-blind placebo-controlled trial of the IGT subjects was then performed, with subjects receiving either pioglitazone 30 mg od or matched placebo for 12 weeks before the measurements were repeated. The IGT subjects had a significantly impaired FMD compared with the controls (p < 0.001). Diastolic shear stress (DSS) was also significantly reduced in IGT (p = 0.04). High molecular weight (HMW) ADN was significantly lower in the IGT group than in controls (p = 0.03). On analysis of the IGT group after 12 weeks treatment, FMD was significantly increased in the pioglitazone group compared with placebo (p = 0.03) as was endothelium-independent dilation (EID) (p = 0.03). A significant increase in total ADN (p < 0.001), HMW ADN (p < 0.001) and HMW/total ratio (p = 0.001) occurred in the pioglitazone group compared with placebo. Pioglitazone improved endothelial function in IGT. Treatment with pioglitazone may reduce the risk of cardiovascular disease in this patient group.