Endothelial Function Parameters Research Articles

Pharmacogenetics of statin therapy and the endothelial function parameters in patients with type 2 diabetes mellitus

Aim. To investigate the association of variation in lipid-lowering response and endothelial function (EF) parameters after atorvastatin therapy in patients with type 2 diabetes mellitus (T2DM) with genetic markers of atherosclerosis.Methods. We included 97 patients with T2DM who were prescribed atorvastatin. Fasting lipid profiles and EF parameters were assessed before and after 12 months of statin therapy. For EF evaluation, we performed pulse-wave analysis during reactive hyperaemia. The genotypes for polymorphic markers were identified by real-time polymerase chain reaction with TaqMan probes. The statistical analysis included Wilcoxon, Mann–Whitney and Kruskal–Wallis tests. P-values 0.05 were considered statistically significant.Results. With statin therapy, PPARG2Pro/Pro patients had significantly lower TC and LDL-C levels than PPARG2 Pro/Ala and PPARG2 Ala/Ala patients (TC: 20.74% vs. 4.6% and 5.61%; p = 0.04 and LDL-C: 26.00% vs. 6.11% and 7.32%; p = 0.029). Patients with АРОЕЕ4/Е4 had significantly lower TC and TG levels than other АРОЕ patients (TC: -46.25% for Е4/Е4 vs. +33.33% for Е4/Е2, +5.73% for Е3/Е2, +11.80% for Е3/Е4, -10.92% for Е3/Е3, р = 0,01; TG: -56.52% for Е4/Е4 vs. +24.43% for Е4/Е2, +19.63% for Е3/Е2, +8.05% for Е3/Е4, -20.00% for Е3/Е3, р = 0.04). The patients with GG for TNFα G(238)A and GA for TNFα G(308)A had significantly greater amplitude of post-occlusive wave increase (Apw) than patients with GA for TNFα G(238)A and GG for TNFα G(308)A (+8.16 % vs. -0.93%, р = 0,04; +44% vs. -4.4%, p = 0.004, respectively).Conclusion. PPARG2Pro12Ala and АРОЕE2/Е3/Е4 polymorphism contributed to the between-patient variability in the response to statin therapy in patients with T2DM. Significant associations of the TNFαgene polymorphism with EF in patients with T2DM suggest an important role of inflammation in the pathogenesis of MVD.

Effects of selenium supplement on atherogenesis of ApoE-knockout mice fed high fat diet

To investigate the effects of selenium supplement on atherogenesis and endothelial function in ApoE-knockout mice fed high fat diet. ApoE-knockout mice fed with selenium-deficient and high fat diet were randomly allocated into 3 groups based on random number table including control group (not supplied with sodium selenite, n=10), low dosage selenium supplement group (supplied water with 0.1 mg/L sodium selenite, n=10) and high dosage selenium supplement group (supplied water with 0.2 mg/L sodium selenite, n=10). After 15 weeks, the following values were measured: the concentrations of selenium in heart and liver, the levels of serum lipid, the parameters of antioxidant function including activities of superoxide dismutase(SOD) and glutathion peroxidase (GSH-Px) and malondialdehyde (MDA) level in serum, the parameters of endothelial function including serum nitric oxide (NO), endothelin 1(ET-1), and vascular endothelial growth factor (VEGF) levels, and ET-1 and VEGF levels in aorta roots. The atherosclerotic lesions in aorta roots were analyzed with oil red O staining. (1) The selenium concentrations in heart and liver were significantly higher in high dosage and low dosage selenium supplement groups compared to control group (both P<0.05). (2) The levels of triglyceride, total cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol and high-density lipoprotein cholesterol were similar among groups (all P>0.05). (3) The activity levels of serum SOD were significantly higher in low dosage ((113.8±12.5)U/ml) and high dosage selenium supplement group ((152.3±11.3)U/ml) compared to control group ((90.7±10.7)U/ml, all P<0.05). The activity levels of serum GSH-Px were significantly higher in low dosage ((53.9±7.2)U/ml) and high dosage ((69.6±8.7)U/ml) selenium supplement groups than that of control group ((36.4±5.6)U/ml, all P<0.05). The serum MDA levels in low dosage ((4.73±1.05)nmol/ml) and high dosage ((4.13±1.21)nmol/ml) selenium supplement groups were significantly lower than that of control group ((5.97±1.08)nmol/ml, all P<0.05). (4) The serum NO concentrations in low dosage ((61.5±12.8)μmol/L) and high dosage ((79.0±14.6)μmol/L)selenium supplement groups were significantly higher than that of control group((42.7±9.1)μmol/L, all P<0.05). The concentrations of serum ET-1 in low dosage ((52.8±6.3)ng/L)and high dosage ((46.3±4.7)ng/L)selenium supplement groups were significantly lower than that of control group((72.2±6.3)ng/L, P<0.05). The concentrations of serum VEGF in low dosage ((97.4±16.5)ng/L)and high dosage ((83.5±22.0)ng/L)selenium supplement groups were significantly lower than that of control group((125.8±18.6)ng/L, P<0.05). The expression levels of ET-1 and VEGF in aorta roots among low dosage and high dosage selenium supplement groups were significantly lower compared to control group (all P<0.05). (5) The plaque area of aorta roots in low dosage ((0.95±0.19)×10(5) μm(2))and high dosage selenium supplement ((0.75±0.15)×10(5) μm(2)) groups were significantly smaller than that of control group((1.13±0.23)×10(5) μm(2)), and the plaque area in high dosage selenium supplement group was significantly smaller than in low dosage selenium supplement group (P<0.05). Supplement of selenium can attenuate atherogenesis in ApoE-knockout mice fed high fat diet, which is possibly mediated via reducing lipid peroxidation and improving endothelial functions.

Calcium Channel Blockade and Peroxisome Proliferator Activated Receptor γ Agonism Diminish Cognitive Loss and Preserve Endothelial Function During Diabetes Mellitus.

Diabetes mellitus is considered as a main risk factor for vascular dementia. In the past, we have reported the induction of vascular dementia (VaD) by experimental diabetes. This study investigates the efficacy of a nifedipine, a calcium channel blocker and pioglitazone in the pharmacological interdiction of pancreatectomy diabetes (PaD) induced vascular endothelial dysfunction and subsequent VaD in rats. Attentional set shifting (ASST) and Morris water-maze (MWM) test were used for assessment of learning and memory. Vascular endothelial function, blood brain barrier permeability, serum glucose, serum nitrite/nitrate, oxidative stress (viz. aortic superoxide anion, brain thiobarbituric acid reactive species and brain glutathione), brain calcium and inflammation (myeloperoxidase) were also estimated. PaD rats have shown impairment of endothelial function, blood brain barrier permeability, learning and memory along with an increase in brain inflammation, oxidative stress and calcium. Administration of nifedipine and pioglitazone significantly attenuated PaD induced impairment of learning, memory, blood brain barrier permeability, endothelial function and biochemical parameters. It may be concluded that nifedipine, a calcium channel blocker may be considered as a potent pharmacological agent for the management of PaD induced endothelial dysfunction and subsequent VaD.

A Single Session of Neuromuscular Electrical Stimulation Enhances Vascular Endothelial Function and Peripheral Blood Circulation in Patients With Acute Myocardial Infarction

This study aimed to investigate whether a single session of neuromuscular electrical stimulation (NMES) can enhance vascular endothelial function and peripheral blood circulation in patients with acute myocardial infarction (AMI). Thirty-four male patients with AMI were alternately assigned to 2 groups, and received NMES with muscle contraction (NMES group, n = 17) or without muscle contraction (control group, n = 17) after admission. NMES was performed for quadriceps and gastrocnemius muscles of both legs for 30 minutes. We measured systolic blood pressure as a parameter of cardiovascular responses and the low-frequency component of blood pressure variability as an index of sympathetic activity. Reactive hyperemia peripheral arterial tonometry (RH-PAT) index and transcutaneous oxygen pressure in foot (Foot-tcPO2) were also measured as parameters of vascular endothelial function and peripheral blood circulation, respectively. All patients completed the study without severe adverse events. Systolic blood pressure and the low-frequency component increased significantly during the NMES session in both groups (P < 0.01 and P < 0.05, respectively). However, elevation from systolic blood pressure at rest was < 10 mmHg in both groups. In the NMES group, the RH-PAT index and Foot-tcPO2 increased significantly after NMES (P < 0.05 and P < 0.001, respectively). No significant changes were observed in these parameters throughout the session in the control group. In conclusion, a single session of NMES with muscle contraction enhanced vascular endothelial function, leading to improvement in peripheral blood circulation without inducing excessive cardiovascular and autonomic responses in patients with AMI (UMIN000014196).

Изменение показателей эндотелиальной функции и жесткости артериального русла у больных ревматоидным артритом на фоне терапии лефлуномидом

The article presents the results of evaluation of leflunomide impact on endothelial function and vascular stiffness parameters in patients with rheumatoid arthritis (RA), but without cardiovascular diseases. 46 patients with RA satisfying ACR (1987) or ACR/EULAR (2010) classification criteria were examined. Investigations of endothelial function and arterial stiffness, based on the pulse wave contour analysis and the reactive hyperemia test (“AngioScan-01” device used), were conducted before the treatment and 12 months thereafter. It was determined that patients with RA suffered from subclinical damage of large arteries, characterized by endothelial dysfunction at micro- and macrocirculatory levels, and the increase in augmentation (AIp), stiffness (SI), and reflection (RI) indices, whose value correlated with RA duration, DAS28 activity index, RF level, and ACCP concentration. Leflunomide use in patients with RA was accompanied by statistically significant decrease in DAS28 index. It was shown that along with high anti-inflammatory activity leflunomide is also able of decreasing the signs of subclinical arterial damage, which is confirmed by the restoration of the endothelial function both in the system of small resistant vessels (increase in amplitude occlusion index) and large muscular arteries (increase in the value of phase shift between channels), and the decrease in stiffness of large arteries.

Protective effect with vascular endothelium of Danhong injection on unstable angina after coronary intervention in patients

Objective To observe the protective effects with vascular endothelium of Danhong injection for unstable angina (UA) after percutaneous coronary intervention in patients. Methods 180 patients with UA were randomly divided into two groups, and patients undergoing percutaneous coronary intervention (PCI) therapy.In addition, 90 cases in the control group were treated with conventional western medicine treatment, 90 cases in the observation group were treated with conventional western medicine treatment and Danhong injection therapy.The serum superoxide dismutase (SOD), malondialdehyde (MDA) and brachial artery flow-mediated endothelium-dependent vasodilation (FMD), von Willebrand factor (vWF), plasma nitric oxide (NO), endothelin-1 (ET-1) levels and other indicators before and after treatment were detected. Results The total effective rate of the observation group was 96.67%, which was significantly higher than 75.56% of the control group (χ2=9.23, P<0.05). The endothelial function parameters NO(73.66±11.58)μmol/L, ET-1(64.75±6.83)ng/L, vWF(114.58±16.24)%, FMD (6.54±0.88)% of the observation group after treatment were significantly improved than before treatment (t=8.04, 7.90, 8.44, 7.67, all P<0.05), which of the control group were (62.78±10.42)μmol/L, (92.31±8.67)ng/L, (152.64±18.75)%, (4.18±0.72)%, there were significant differences(t=6.78, 7.34, 7.70, 6.56, all P<0.05). The serum SOD (154.62±21.37)U/mL and MDA (4.18±0.79)nmol/L levels of the observation group were significantly improved than before treatment(t=7.58, 8.67, all P<0.05), which of the control group were (132.45±26.89)U/mL, (5.27±1.16)nmol/L, there were significant differences (t=7.22, 7.81, all P<0.05). Conclusion Danhong injection for the treatment of UA stasis syndrome can be widely promoted by reducing oxidative stress on vascular endothelial damage, and improving endothelial function in patients after PCI, has great clinical value. Key words: Danhong injection; Unstable angina; Percutaneous coronary intervention; Vascular endothelial function

Abstract 17081: Long-term Administration of Eicosapentaenoic Acid Ameliorates Vascular Endothelial Dysfunction Through the Renin-angiotensin-aldosterone System Inhibition Resulting in the Improvement of Muscle Oxygen Metabolism in Patients With Lifestyle Related Disease

Background: Elevated activity of renin-angiotensin-aldosterone system (RAAS) is known to induce vascular endothelial dysfunction in patients with lifestyle related disease such as diabetes mellitus (DM), hypertension (HT) and dyslipidemia (DL). Because the vascular endothelial dysfunction disturbs an appropriate blood flow to skeletal muscles, it is considered that the oxygen metabolism is impaired in them. Although eicosapentaenoic acid (EPA) has been reported to inhibit the RAAS, it is unclear whether EPA ameliorates vascular endothelial dysfunction via the RAAS inhibition resulting in the improvement of muscle oxygen metabolism. This study investigated the effects of EPA on vascular endothelial function and muscle oxygen metabolism during exercise in patients with lifestyle related disease. Methods: Ninety-two patients (68±8 years, 50 males) were divided into two groups based on the EPA administration in crossover method, after their DM, HT and/or DL were optimally treated. When patients took 1,800 mg of EPA daily for 8 months or not, they were in the EPA(+) group or in the EPA(-) group. In the end of each treatment period, cardiopulmonary exercise test was performed to measure oxygen uptake (VO 2 ) at anaerobic threshold (VO 2 AT ), peak VO 2 and the time from the start of the test to the AT (Time AT ) and endpoint (Time EP ). We measured serum EPA, plasma renin activity (PRA), aldosterone (ALD), adrenalin (ADRN) and noradrenalin (NORA), and reactive hyperemia index (RHI). We used the changes in PRA, ALD, ADRN and NORA before and after a cycle ergometer exercise test (ΔPRA, ΔALD, ΔADRN and ΔNORA) as neurohumoral factors, RHI as a parameter of vascular endothelial function and Time EP as an exercise capacity. Results: There were no significant differences in ΔPRA, ΔALD, ΔNORA, peak VO 2 and Time EP between the two groups. The PRA, ALD and ΔADRN were significantly lower in the EPA(+) group than in the EPA(-) group (P&lt;0.05, respectively). The RHI, VO 2 AT and Time AT were significantly higher in the EPA(+) group than in the EPA(-) group (P&lt;0.05, respectively). Conclusion: Long-term administration of EPA ameliorated vascular endothelial dysfunction via the RAAS inhibition resulting in the improvement of muscle oxygen metabolism in lifestyle related disease patients.

Abstract 13273: Long-term Administration of Eicosapentaenoic Acid Prevents an Excessive Blood Pressure Elevation During Exercise Simulating Ordinary Activities of Daily Living via the Improvement of Vascular Endothelial Dysfunction in Patients With Hypertension

[Background] Excessive blood pressure (BP) elevation was frequently observed during exercise even at low or moderate intensity in patients with hypertension (HT), although their BP at rest was successfully controlled with antihypertensives. Several studies documented that vascular endothelial dysfunction induced excessive BP elevation in their ordinary activities of daily living (ADL). On the other hands, eicosapentaenoic acid (EPA) reduces oxidative stress and vascular inflammation resulting in the improvement of vascular endothelial dysfunction. However, it is still unknown whether long-term administration of EPA ameliorates excessive BP elevation in ordinary ADL. This study aimed to investigate the influence of EPA on vascular endothelial dysfunction and excessive BP elevation during exercise at moderate intensity in HT patients. [Methods] We recruited 60 HT outpatients whose resting blood pressure was successfully controlled below 140/90 mmHg. Patients were assigned to EPA(+) group or EPA(-) group in crossover method. They were administered antihypertensives with or without 1,800 mg of EPA daily for 10 months in the EPA(+) and EPA(-) groups, respectively. We measured serum concentrations of EPA, arachidonic acid (AA) and EPA/AA ratio. We assessed reactive hyperemia index (RHI) and thrombomodulin (TM) as a parameter of vascular endothelial function. BP elevation during exercise was determined as the difference from systolic BP (SBP) at rest to peak SBP during a cycle ergometer exercise test (SBP). The exercise intensity was given as 75% of peak heart rate (HR) obtained from a treadmill exercise test, which indicates the intensity of ordinary ADL. We compared all parameters between the two groups and analyzed the relationship between RHI and SBP. [Results] EPA, EPA/AA ratio and RHI were significantly higher in the EPA(+) group than in the EPA(-) group (P&lt;0.01, respectively). SBP and TM were significantly lower in the EPA(+) group than in the EPA(-) group (P&lt;0.05, respectively). RHI was negatively correlated with SBP (r=-0.313, P&lt;0.05). [Conclusion] Long-term administration of EPA prevented an excessive BP elevation during exercise simulating ordinary ADL via the improvement of vascular endothelial dysfunction in HT patients.

Lack of correlation between the optimal glycaemic control and coronary micro vascular dysfunction in patients with diabetes mellitus: a cross sectional study.

BackgroundCoronary microvascular dysfunction (CMD) is associated with cardiovascular events in type 2 diabetes mellitus (T2DM). Optimal glycaemic control does not always preclude future events. We sought to assess the effect of the current target of HBA1c level on the coronary microcirculatory function and identify predictive factors for CMD in T2DM patients.MethodsWe studied 100 patients with T2DM and 214 patients without T2DM. All of them with a history of chest pain, non-obstructive angiograms and a direct assessment of coronary blood flow increase in response to adenosine and acetylcholine coronary infusion, for evaluation of endothelial independent and dependent CMD. Patients with T2DM were categorized as having optimal (HbA1c < 7 %) vs. suboptimal (HbA1c ≥ 7 %) glycaemic control at the time of catheterization.ResultsBaseline characteristics and coronary endothelial function parameters differed significantly between T2DM patients and control group. The prevalence of endothelial independent CMD (29.8 vs. 39.6 %, p = 0.40) and dependent CMD (61.7 vs. 62.2 %, p = 1.00) were similar in patients with optimal vs. suboptimal glycaemic control. Age (OR 1.10; CI 95 % 1.04–1.18; p < 0.001) and female gender (OR 3.87; CI 95 % 1.45–11.4; p < 0.01) were significantly associated with endothelial independent CMD whereas glomerular filtrate (OR 0.97; CI 95 % 0.95–0.99; p < 0.05) was significantly associated with endothelial dependent CMD. The optimal glycaemic control was not associated with endothelial independent (OR 0.60, CI 95 % 0.23–1.46; p 0.26) or dependent CMD (OR 0.99, CI 95 % 0.43–2.24; p = 0.98).ConclusionsThe current target of HBA1c level does not predict a better coronary microcirculatory function in T2DM patients. The appropriate strategy for prevention of CMD in T2DM patients remains to be addressed.

Incipient renal transplant dysfunction associates with tubular syndecan-1 expression and shedding.

Syndecan-1 is a transmembrane heparan sulfate proteoglycan involved in regenerative growth and cellular adhesion. We hypothesized that the induction of tubular syndecan-1 is a repair response to incipient renal damage in apparently stable, uncomplicated renal transplant recipients. We quantified tubular syndecan-1 in unselected renal protocol biopsies taken 1 yr after transplantation. Spearman rank correlation analysis revealed an inverse correlation between tubular syndecan-1 expression and creatinine clearance at the time of biopsy (r = -0.483, P < 0.03). In a larger panel of protocol and indication biopsies from renal transplant recipients, tubular syndecan-1 correlated with tubular proliferation marker Ki67 (r = 0.518, P < 0.0001). In a rat renal transplantation model, 2 mo after transplantation, mRNA expression of syndecan-1 and its major sheddase, A disintegrin and metalloproteinase-17, were upregulated (both P < 0.03). Since shed syndecan-1 might end up in the circulation, in a stable cross-sectional human renal transplant population (n = 510), we measured plasma syndecan-1. By multivariate regression analysis, we showed robust independent associations of plasma syndecan-1 with renal (plasma creatinine and plasma urea) and endothelial function parameters (plasma VEGF-A, all P < 0.01). By various approaches, we were not able to localize syndecan-1 in vessel wall or endothelial cells, which makes shedding of syndecan-1 from the endothelial glycocalyx unlikely. Our data suggest that early damage in transplanted kidneys induces repair mechanisms within the graft, namely, tubular syndecan-1 expression for tubular regeneration and VEGF production for endothelial repair. Elevated plasma syndecan-1 levels in renal transplantation patients might be interpreted as repair/survival factor related to loss of tubular and endothelial function in transplanted kidneys.

Some markers of endothelial dysfunction in patients with chronic prostatitis

Objective. To study some markers of endothelial dysfunction depending on the type of autonomic system activity in patients with chronic prostatitis. Design and methods. Altogether 183 patients with chronic prostatitis were enrolled. The following parameters of endothelial function were assessed: endotheliocyte count, nitrate and nitrite content, concentration of von Willebrand factor. Results. Autonomic imbalance was found, and increased sympathetic activity (sympathotony) was verified in 70% cases. The level of nitrates and nitrites is decreased, while the concentrations of von Willebrand factor, endothelin and homocystein were increased. Reactive hyperemia test showed lower brachial artery dilation in patients with increased sympathetic activity, as well as the decreased sensitivity of brachial artery to the shear stress. Conclusion. Endothelial dysfunction is characterized by the increased level of von Willebrand factor, endothelin and homocystein in patients with chronic prostatitis. The activation of sympathetic nervous system plays the key role in the pathogenesis of endothelial dysfunction in patients with chronic prostatitis.

P.5.f.008 New DSM-5 mild neurocognitive disorder – what changes in therapeutic intervention?

The study was designed to investigate the efficacy of bosentan a dual endothelin (ETA and ETB) receptor antagonist in experimental diabetes induced vascular endothelial dysfunction and associated dementia. Diabetes was induced in rats by administration of a single dose (50 mg/kg, i.p.) of streptozotocin (STZ). Drug treatment was started after 1 month of STZ administration and treatment was continued until the end of the study. Morris water maze (MWM) test was employed for testing spatial learning and memory. Endothelial function was measured on isolated aortic rings using student physiograph. Serum glucose, body weight, serum nitrite/nitrate, brain thiobarbituric acid reactive species (TBARS), reduced glutathione (GSH) levels, and brain acetylcholinesterase activity were also tested. STZ treatment resulted in significant development of cognitive and vascular endothelial deficits, manifested in the terms of endothelial dysfunction, impairment of learning and memory, reduction in body weight and serum nitrite/nitrate levels along with increase in serum glucose, brain acetylcholinesterase activity, TBARS, and decreased GSH levels. Treatment of bosentan attenuated diabetes induced impairment of learning, memory, endothelial function, and various biochemical parameters. It may be concluded that bosentan has shown efficacy in STZ induced cognitive and vascular endothelial deficits. Thus, endothelin receptors can be considered as a potential pharmacological target for the management of experimental diabetes induced vascular endothelial dysfunction and associated dementia.

Effects of magnesium supplements on blood pressure, endothelial function and metabolic parameters in healthy young men with a family history of metabolic syndrome

Background and aimsMagnesium plays an important role in the modulation of vascular tone and endothelial function and can regulate glucose and lipid metabolism. Patients with hypertension, metabolic syndrome (MetS) and diabetes mellitus (T2DM) have low body magnesium content; indeed, magnesium supplementation has been shown to have a positive effect on blood pressure (BP) and gluco-metabolic parameters. The aim of our study was to evaluate the effect of magnesium supplements on hemodynamic and metabolic parameters in healthy men with a positive family history of MetS or T2DM. Methods and resultsIn a randomized, double-blind, placebo-controlled 8-week crossover trial with a 4 week wash-out period, oral supplements of 8.1 mmol of magnesium-pidolate or placebo were administered twice a day to 14 healthy normomagnesemic participants, aged 23–33 years. The primary endpoint was office BP, measured with a semiautomatic oscillometric device. Secondary endpoints included characteristics of the MetS, namely endothelial function, arterial stiffness and inflammation. Plasma and urinary magnesium were measured in all participants while free intracellular magnesium was measured only in a subsample.There was no significant difference in either systolic and diastolic BP in participants post-magnesium supplementation and post-placebo treatment when compared to baseline BP measurements. Further, the metabolic, inflammatory and hemodynamic parameters did not vary significantly during the study. ConclusionsOur study showed no beneficial effect of magnesium supplements on BP, vascular function and glycolipid profile in young men with a family history of MetS/T2DM (trial registration at clinicaltrial.gov ID: NCT01181830; 12th of Aug 2010).

Efficacy of bosentan, a dual ETA and ETB endothelin receptor antagonist, in experimental diabetes induced vascular endothelial dysfunction and associated dementia in rats

The study was designed to investigate the efficacy of bosentan a dual endothelin (ETA and ETB) receptor antagonist in experimental diabetes induced vascular endothelial dysfunction and associated dementia. Diabetes was induced in rats by administration of a single dose (50mg/kg, i.p.) of streptozotocin (STZ). Drug treatment was started after 1month of STZ administration and treatment was continued until the end of the study. Morris water maze (MWM) test was employed for testing spatial learning and memory. Endothelial function was measured on isolated aortic rings using student physiograph. Serum glucose, body weight, serum nitrite/nitrate, brain thiobarbituric acid reactive species (TBARS), reduced glutathione (GSH) levels, and brain acetylcholinesterase activity were also tested. STZ treatment resulted in significant development of cognitive and vascular endothelial deficits, manifested in the terms of endothelial dysfunction, impairment of learning and memory, reduction in body weight and serum nitrite/nitrate levels along with increase in serum glucose, brain acetylcholinesterase activity, TBARS, and decreased GSH levels. Treatment of bosentan attenuated diabetes induced impairment of learning, memory, endothelial function, and various biochemical parameters. It may be concluded that bosentan has shown efficacy in STZ induced cognitive and vascular endothelial deficits. Thus, endothelin receptors can be considered as a potential pharmacological target for the management of experimental diabetes induced vascular endothelial dysfunction and associated dementia.

Effects of clopidogrel, prasugrel and ticagrelor on endothelial function, inflammatory and oxidative stress parameters and platelet function in patients undergoing coronary artery stenting for an acute coronary syndrome. A randomised, prospective, controlled study

IntroductionParticularly in the setting of acute coronary syndromes, the interplay between vascular and platelet function has been postulated to have direct clinical implications. The present trial is designed to test...

Endothelial dysfunction and brachial intima-media thickness: long term cardiovascular risk with claudication related to peripheral arterial disease: a prospective analysis.

ObjectiveEndothelial dysfunction plays a key role in the development, progression, and clinical manifestation of atherosclerosis, and in symptomatic peripheral arterial disease, endothelial dysfunction and enlarged intima-media thickness might be associated with increased cardiovascular risk. Flow-mediated dilatation and serologic parameters are used to evaluate individual endothelial function. Brachial intima-media thickness, a less recognized parameter of cardiovascular risk, is independently associated with coronary artery disease. The aim of this study was to evaluate the prognostic value of ultrasound and serologic parameters of endothelial function in relation to cardiovascular mortality in peripheral arterial disease.Designmonocentric, prospective cohort study.MethodsFlow mediated dilatation and brachial intima-media thickness were assessed in 184 (124 male) patients with peripheral arterial disease (Rutherford stages 2–3). Serologic parameters of endothelial function included asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and L-homoarginine. Cardiovascular events were recorded during a follow-up of 99.1±11.1 months. Subjects who died of noncardiovascular causes were excluded from further analysis.ResultsEighty-two patients (44.6%) died during follow-up after a mean duration of 49.7±28.3 months. There were 49 cardiovascular deaths (59.8%) and 33 other deaths (40.2%). Flow mediated dilatation was associated with cardiovascular death [1.17% (0.0, 4.3) vs. 4.1% (1.2, 6.4), p<0.001]. Intima-media thickness was greater in patients who succumbed to cardiovascular disease [0.37 mm (0.30, 0.41)] than in survivors [0.21 mm (0.15, 0.38), p<0.001]. Brachial intima-media thickness above 0.345 mm was most predictive of cardiovascular death, with sensitivity and specificity values of 0.714 and 0.657, respectively (p<0.001). Furthermore, ADMA levels above 0.745 µmol/l and SDMA levels above 0.825 µmol/l were significantly associated with cardiovascular death (p<0.001 and 0.030).ConclusionIn symptomatic peripheral arterial disease, decreased flow mediated dilatation, enlarged intima-media thickness, and elevated levels of ADMA and SDMA were associated with increased cardiovascular risk.

0291: Circulating markers of vascular endothelial dysfunction in obese patients

Obesity is a major worldwide health problem associated with several metabolic, inflammatory and oxidative troubles which represent major cardiovascular risk factors. The endothelial dysfunction plays a central role in the physiopathology of cardiovascular diseases. This critical function is generally evaluated through in vivo functional assessment, but emerging new biomarkers, like cell-derived microparticles (MPs,) reflecting alteration of the endothelium are increasingly studied. The aim of this study was to assess the level of circulating MPs in normal weight and obese patients and their relation with different oxidative, inflammatory and endothelial function parameters. Normal weight subjects (n=29, BMI<25kg/m 2 ) and obese patients (n=53, BMI>30 kg/m 2 ), were recruited at F. Hached Hospital (Sousse, Tunisia). Vascular endothelial function was assessed by the exploration of the endotheliumdependent vasodilatation by Laser Doppler Flowmetry and flow cytometry analysis was used for the quantification of circulating MPs. Obese subjects presented an endothelium-dependant vasodilatation significantly lower (21,26+2,89) than in normal weight patients (32,40+6,35) (p=0,008), characteristic to a vascular endothelial dysfunction. Furthermore, obese patients displayed a significantly higher number of circulating MPs (37579+4766 MPs/μl) in comparison to normal weight subjects (12099+934 MPs/μl) (p<0,001). Circulating MPs were positively correlated with anthropometric parameters BMI (r=0,504; p=0,02) and waist-hip ratio (WHC) (r=0,476; p=0,14). A positive correlation was also observed with parameters of inflammation (C-reactive protein (CRP) r=0,374; p=0,045) and oxidative stress (advanced oxidation protein product (AOPP) r=0,487; p=0,04 and total thiols r=0,551; p=0,01). These data demonstrated that circulating MPs could be a good biomarker of vascular endothelial dysfunction in obese patients, however the precise role of MPs in inflammation and oxidative stress has still to be clarified in further studies. Obesity, endothelial dysfunction, microparticles.

Circadian Variability of Fibrinolytic Markers and Endothelial Function in Patients with Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is strongly associated with cardiovascular disease, including stroke and acute coronary syndromes. Plasminogen activator inhibitor-1 (PAI-1), the principal inhibitor of tissue-type plasminogen activator (t-PA), has a pronounced circadian rhythm and is elevated in both OSA and cardiovascular disease and may be an important link between the two conditions. Endothelial dysfunction is one of the underlying pathophysiological mechanisms of cardiovascular disease, and may be altered in OSA. Our primary aim was to compare circadian variability of PAI-1 and t-PA in patients with OSA and normal controls by determining the amplitude (peak level) and mesor (rhythm adjusted mean) of PAI-1 and t-PA in serial blood samples over a 24-h period. The secondary aim was to measure markers of endothelial function (brachial and radial artery flow) in patients with OSA compared with normal controls. Cross-sectional cohort study. Subjects age 18 y or older, with a body mass index of 25-45 kg/m(2), with or without evidence of untreated OSA. Plasma samples were collected every 2 h, in OSA patients and matched controls, over a 24-h period. PAI-1 and t-PA antigen and activity were measured. The presence or absence of OSA (apnea-hypopnea index of 5 or greater) was confirmed by overnight polysomnography. Endothelial function was measured via brachial artery flow mediated vasodilatation and computerized arterial pulse waveform analysis. The rhythm-adjusted mean levels of PAI-1 antigen levels in the OSA group (21.8 ng/mL, 95% confidence level [CI], 18 to 25.7) were significantly higher as compared to the non-OSA group (16 ng/mL, 95% CI, 12.2 to 19.8; P = 0.03). The rhythm-adjusted mean levels of PAI-1 activity levels in the OSA group (23.9 IU/mL, 95% CI, 21.4 to 26.5) were also significantly higher than in the non-OSA group (17.2 IU/ mL, 95% CI, 14.6 to 19.9; P < 0.001).There were strong correlations between amplitude of PAI-1 activity and severity of OSA as measured by AHI (P = 0.02), and minimum oxygen levels during sleep (P = 0.04). Endothelial function parameters did not differ significantly between the two groups. The presence of obstructive sleep apnea adversely affects circadian fibrinolytic balance with higher mean plasminogen activator inhibitor-1 activity and antigen, and significantly lower mean tissue-type plasminogen activator activity compared with controls. This perturbation may be an important mechanism for increased cardiovascular events in patients with obstructive sleep apnea. Intermittent hypoxia and changes in circadian clock gene activity in obstructive sleep apnea may be responsible for these findings and warrant further study. Favorable changes in fibrinolytic balance may underlie the reduction in cardiovascular events observed with the treatment of obstructive sleep apnea.

Investigating the cardio-protective abilities of supplemental L-arginine on parameters of endothelial function in a hypercholesterolemic animal model.

Endothelial dysfunction is now widely recognized as an early marker of cardiovascular disease, making its treatment, or complete avoidance, an emerging, interesting therapeutic target. This study investigated the ability of the highly intriguing amino acid L-arginine to influence endothelial function. Its therapeutic potential is also compared to that of known cardiovascular medications, namely nitroglycerin [a nitric oxide (NO) donor] and enalapril [an angiotensin-converting enzyme (ACE) inhibitor]. Fifty male New Zealand rabbits were included in the study, divided into 5 equal groups: control, hypercholesterolemia (untreated), hypercholesterolemia (+L-arginine), hypercholesterolemia (+enalapril), and hypercholesterolemia (+nitroglycerin). Biochemical investigations included measurement of circulating NOx, malondialdehyde (MDA), and lipid profile markers, as well as dimethylarginine dimethylaminohydrolase (DDAH) and ACE activities. Furthermore, aortic ACE activity and blood platelet aggregation were estimated. A histopathological examination and intimal thickness measurement were also conducted. Compared to the untreated hypercholesterolemic group, all agents were capable of positively influencing MDA levels, platelet aggregation and intimal thickness; however, only the L-arginine group was capable of beneficially and significantly altering both NOx levels and serum and aortic ACE activities. No agents were capable of modulating serum DDAH activity inhibited by hypercholesterolemia. Based on the results of this study, L-arginine appears to be a novel cardio-protective agent, illustrated by its ability to ameliorate the deleterious effects of hypercholesterolemia on endothelial function, in a manner comparable to, and sometimes more potent than, commonly used cardiovascular medications.

The influence of physical training on endothelial function in patients with stable coronary artery disease.

Endothelial damage is the key factor in the pathophysiology of atherosclerosis. Regular physical activity exerts beneficial direct and indirect effects on, among others, cardiovascular system, locomotor system, lipids, carbohydrate and hormonal balance, maintenance of aproper body weight as well as immunological system. The aim of the study included evaluating the effect of aregular, two-month physical training on endothelial function parameters in patients with stable coronary artery disease. The study involved 61patients after coronary angioplasty, 13women and 48men aged 62.8±8.7years. The control group included 21 subjects aged 63.2±9.7years, 17 of whom had hypertension which was well controlled pharmacologically. Blood for VCAM-1 and ICAM-1 was collected with the subjects remaining for 30min in supine position, through avenous access inserted in the basilica vein. In the patients' group the blood was collected twice, prior to and after aphysical training cycle. In controls the blood was collected once. The investigated groups differ slightly but not in astatistically significant way with regard to the hemodynamic parameters BP 124.4/75.9 vs. 123.4/76.3mmHg, p=ns., HR 66.2±6.8 vs. 68.8±6.3 bpm, p=ns., left ventricular ejection fraction -EF 60.1±7.6 vs. 63.7±5.2 %, p<0.05 and did not differ with regard to the incidence of hypertension or BMI value. The level of soluble ICAM-1 prior to physical training was higher in the investigated group (289.0±97.1 vs. 230.2±47.1ng/mL, p<0.01) and after the training it decreased but remained higher than in control group (252.4±100.8ng/mL, p<0.05. vs. control group). The level of soluble VCAM-1 did not differ initially between the groups, nor did it change significantly after the training. Moderately intense physical training only slightly affects the investigated parameters of the endothelial function in patients with coronary artery disease. Abeneficial effect of training on endothelial function was observed as adecrease of the level of soluble ICAM-1. 8-week, moderately intense physical training is sufficient to cause aclinically significant decrease in arterial blood pressure.