Serum Markers Of Endothelial Dysfunction Research Articles

Optimization of the prevention of perinatal pathology in women with gestational endotheliopathy

Objectives: to evaluate the clinical effectiveness of the Metida for the prevention of perinatal pathology in pregnant women with gestational endotheliopathy and with the risk of preeclampsia.Materials and methods. 68 pregnant women with verified gestational endotheliopathy and with risk of preeclampsia > 1:150 participated in a prospective clinical comparative study. The patients were divided into subgroups: the first subgroup included 30 women who from 11–13 weeks of pregnancy received acetylsalicylic acid 100 mg/day and vitamin D 2000 IU/day; the II subgroup included 38 pregnant women who from 11–13 weeks of gestation received acetylsalicylic acid 100 mg/day, vitamin D 2000 IU/day and Metida (300 mg of elemental magnesium, 30 mg of vitamin B6). 28 practically healthy pregnant women of the control group received vitamin D 1000 IU/day. The clinical effectiveness of therapy was evaluated by comparing the number of cases of perinatal pathology; cases of intrauterine suffering of the fetus; the dynamics of indicators of laboratory-instrumental research methods (markers of the risk of perinatal pathology) and the pregnancy outcomes.Results. Metida as an additional preventive therapy made it possible to significantly reduce the number of cases of placental dysfunction (р = 0.01) and intrauterine suffering of the fetus (р = 0.02) compared to standard preventive therapy. There was also a 6-fold reduction in the incidence of preeclampsia and premature birth due to magnesium supplementation, compared to pregnant women who received only acetylsalicylic acid and vitamin D. There was a significant decrease in serum indicators of markers of endothelial dysfunction in women with gestational endotheliopathy as a result of taking magnesium: vascular endothelial growth factor (p < 0.00001), endoglin (p < 0.00001) compared to patients who did not receive magnesium, and there was also normalization of the of 25(OH)D level in blood serum compared to the control group (p = 0.33).Conclusions. Additional Mg supplementation during pregnancy may reduce the likelihood of perinatal pathology in high-risk patients and help normalize serum markers of endothelial dysfunction in women with high risk of preeclampsia.

TNF-α Inhibitors in Combination with MTX Reduce Circulating Levels of Heparan Sulfate/Heparin and Endothelial Dysfunction Biomarkers (sVCAM-1, MCP-1, MMP-9 and ADMA) in Women with Rheumatoid Arthritis.

Sulfated glycosaminoglycans (sGAGs) are likely to play an important role in the development and progression of rheumatoid arthritis (RA)-associated atherosclerosis. The present study investigated the effect of anti-tumor necrosis factor-α (anti-TNF-α) therapy in combination with methotrexate on plasma sGAG levels and serum markers of endothelial dysfunction. Among sGAG types, plasma chondroitin/dermatan sulfate (CS/DS) and heparan sulfate/heparin (HS/H) were characterized using electrophoretic fractionation. Serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9) and asymmetric dimethylarginine (ADMA) were measured by immunoassays. The measurements were carried out four times: at baseline and after 3, 9 and 15 months of anti-TNF-α therapy. All analyzed parameters, excluding ADMA, were significantly elevated in patients with RA before the implementation of biological therapy compared to healthy subjects. Performed anti-TNF-α treatment led to a successive decrease in HS/H levels toward normal values, without any effect on CS/DS levels in female RA patients. The treatment was also effective at lowering the serum levels of sVCAM-1, MCP-1, MMP-9 and ADMA. Moreover, a significant positive correlation was found between the circulating HS/H and the 28 joint disease activity score based on the erythrocyte sedimentation rate (DAS28-ESR, r = 0.408; p <0.05), MCP-1 (r = 0.398; p <0.05) and ADMA (r = 0.396; p <0.05) in patients before the first dose of TNF-α inhibitor. In conclusion, a beneficial effect of anti-TNF-α therapy on cell-surface heparan sulfate proteoglycans (HSPGs)/HS turnover and endothelial dysfunction was observed in this study. This was manifested by a decrease in blood HS/H levels and markers of endothelial activation, respectively. Moreover, the decrease in the concentration of HS/H in the blood of patients during treatment, progressing with the decline in disease activity, indicates that the plasma HS/H profile may be useful for monitoring the efficacy of anti-TNF-α treatment in patients with RA.

Endothelial Dysfunction: An Intermediate Clinical Feature between Urolithiasis and Cardiovascular Diseases.

An epidemiological relationship between urolithiasis and cardiovascular diseases has extensively been reported. Endothelial dysfunction is an early pathogenic event in cardiovascular diseases and has been associated with oxidative stress and low chronic inflammation in hypertension, coronary heart disease, stroke or the vascular complications of diabetes and obesity. The aim of this study is to summarize the current knowledge about the pathogenic mechanisms of urolithiasis in relation to the development of endothelial dysfunction and cardiovascular morbidities. Methods: A non-systematic review has been performed mixing the terms “urolithiasis”, “kidney stone” or “nephrolithiasis” with “cardiovascular disease”, “myocardial infarction”, “stroke”, or “endothelial dysfunction”. Results: Patients with nephrolithiasis develop a higher incidence of cardiovascular disease with a relative risk estimated between 1.20 and 1.24 and also develop a higher vascular disease risk scores. Analyses of subgroups have rendered inconclusive results regarding gender or age. Endothelial dysfunction has also been strongly associated with urolithiasis in clinical studies, although no systemic serum markers of endothelial dysfunction, inflammation or oxidative stress could be clearly related. Analysis of urine composition of lithiasic patients also detected a higher expression of proteins related to cardiovascular disease. Experimental models of hyperoxaluria have also found elevation of serum endothelial dysfunction markers. Conclusions: Endothelial dysfunction has been strongly associated with urolithiasis and based on the experimental evidence, should be considered as an intermediate and changeable feature between urolithiasis and cardiovascular diseases. Oxidative stress, a key pathogenic factor in the development of endothelial dysfunction has been also pointed out as an important factor of lithogenesis. Special attention must be paid to cardiovascular morbidities associated with urolithiasis in order to take advantage of pleiotropic effects of statins, angiotensin receptor blockers and allopurinol.

Ellisras Longitudinal Study 2017: elevated serum levels of carboxymethyl-lysine, an advanced glycation end-product, are associated with higher odds of developing endothelial dysfunction in black South African patients with type 2 diabetes mellitus (ELS 29).

This case-control study investigated the association between major types of serum advanced glycation end-products (AGEs) and selected serum/plasma markers of endothelial dysfunction in black patients with type 2 diabetes mellitus at Dr George Mukhari Academic Hospital. Serum AGEs were measured using either enzyme-linked immunosorbent assay (ELISA) or spectrofluoremetry. Serum markers of endothelial dysfunction were measured using either ELISA or calometry. The correlation and associations between major types of serum AGEs and markers of endothelial dysfunction were investigated using the Spearman correlation coefficient and bivariate logistic regression analysis, respectively. Although both serum total immunogenic AGEs and serum carboxymethyl-lysine (CML) were moderately and negatively associated with endothelial dysfunction, only serum CML was significantly associated with a higher odds for the development of endothelial dysfunction (low nitric oxide levels) in our diabetic subjects. It can therefore be concluded from this study that high serum levels of CML may predispose to endothelial dysfunction in black South Africans with type 2 diabetes.

IL-1α and IL-6 predict vascular events or death in patients with cerebral small vessel disease—Data from the SHEF-CSVD study

PurposeThe natural clinical course of cerebral small vessel disease (CSVD) was not thoroughly described. The aim of this single center cohort study was to establish biochemical predictors of vascular events and death in CSVD patients during a 24-month follow-up. Patients and methodsA total of 130 functionally independent patients with marked MRI features of CSVD and recent lacunar stroke (n = 52,LS), vascular Parkinsonism (n = 28,VaP) or dementia (n = 50,VaD) were prospectively recruited. Serum markers of endothelial dysfunction, inflammation and hemostasis were determined at baseline. The primary outcome was defined as occurrence of death or any vascular events during the observation. ResultsThe mean age was 72 ± 8.1 years, and 37.6% of the patients were women. The mean follow-up time was 22.3 ± 4.3 months, and 84.6% of patients had extensive white matter lesions on baseline MRI. The overall mortality rate was 6.9%, and vascular events or death occurred in 27% of the patients. Kaplan-Meier survival curves revealed no significant differences between CSVD groups (log rank p = 0.49). Cox regression analysis revealed that IL-1α (HR 1.4; 95%CI 1.09–1.8), IL-6 (1.4;1.1–2.2), hs-CRP (1.1;1.06–1.9), homocysteine (1.4;1.1–1.8), fibrinogen (1.4;1.05–2), and d-dimer (2.7;1.6–4.5) were significantly associated with the primary outcome. IL-1α (1.3;1.07–1.8), IL-6 (1.4;1.02–2.2), d-dimer (2.8;1.6–5) and homocysteine (1.4;1.1–1.8) remained significant after adjusting for age, sex and CSVD radiological markers. ConclusionsOur study demonstrated the important prognostic role of various circulation markers of inflammation in individuals with different clinical signs and radiological markers of CSVD. The strongest association occurred between IL-1α, IL-6 and recurrent stroke, other vascular events and death.

THE RELATIONSHIP BETWEEN LEVELS OF ALDOSTERONE, ESTRADIOL AND SERUM MARKERS OF ENDOTHELIAL DYSFUNCTION IN HYPERTENSIVE WOMEN

Objective: To study the relationship between plasma levels of aldosterone, estradiol and serum markers of endothelial dysfunction (ED) such as stable nitric oxide metabolites NO2-+NO3- (NOx), endothelin-1 (ET-1), homocysteine (HC), von Willebrand factor (vWF) in nondiabetic women with essential hypertension (EH). Design and method: We examined 79 hypertensive, nondiabetic women (mean age 51,4 ± 6,5y, mean EH duration 8,5 ± 7,6y). 28% of the group were smokers, 54% were obese, 76% - with dyslipidemia. Regular menstrual function had 30% of the women, the rest of the group – postmenopausal (median duration of postmenopause was 5,7 ± 3,5y). Circulating NOx levels were studied by spectrophotometry, ET-1, HC, vWF levels – by immunoenzyme assay, aldosterone and estrogen levels - by immunoenzyme assay. Statistical analysis was done using the Statistica 10.0 software. Results: We compared the levels of ED markers in women with a normal (56%), and elevated levels of aldosterone (44%), as well as in women with a normal (62%) and low levels of estradiol (38%). Women with hiperaldosteronemia had higher concentration of NOx (45.3 ± 17.6 and 38.8 ± 16.5 mmol/l, respectively, p < 0.05), E-1 (1.4 ± 1.1 and 0.9 ± 0.8 fmol/l, respectively, p < 0.05) and vWF (1.6 ± 0.8 and 1.3 ± 0.9 mg/dl, respectively, p < 0.05). Aldosterone levels correlated with NOx (r = 0.36, p < 0.05), E-1 (r = 0.3, p < 0.05) and vWF (r = 0.34, p < 0.05) levels. Women with hypoestrogenemia had higher NOx (46.3 ± 16.9 and 37.5 ± 16.0 mmol/l, respectively, p < 0.05), E-1 (1.5 ± 1.1 and 0.8 ± 0.4 fmol/l, respectively, p < 0.05) and vWF (1.6 ± 0.9 and 1.2 ± 0.7 mg/dl, respectively, p < 0.05) levels as well. Estradiol levels correlated with NOx (r = -0.6, p < 0.05) and vWF (r = -0.5, p < 0.05) levels. Conclusions: Our results suggest that women in perimemopausal period demonstrate hormonal disorders with elevation of aldosterone level and decline of estrogen level, which are related to the increase of a number of substances considered as the markers of endothelial dysfunction.

P.4.c.003 - Agomelatine reverses cognition-related behavior and hippocampal gene expression alterations induced by chronic social defeat stress in mice

Depression is recognized as a predictor of increased cardiac morbidity and mortality. In addition, depressed patients exhibit an increase in the serum markers of endothelial dysfunction and platelet activation involved in the cascade of events leading to atherosclerosis. The purpose of this study was to determine the early and late-onset expression of various vascular markers in a rodent model of depression. Male DBA (an inbred strain of mice)/2J mice were exposed to either 7 weeks of controlled living conditions or unpredictable chronic mild stress (UCMS), and subsequently given daily fluoxetine (10 mg/kg) or NaCl (9%) during the last 5 weeks of the experiment. Depressive-like behavior was evaluated by using motivational and self-care behavior, including the assessment of the animal's coat state and grooming behavior. Enzyme-linked immunoassay was used to quantify matrix metalloproteinase-9 (MMP-9), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and plasminogen activator inhibitor-1 (PAI-1) expression either immediately after the end of the UCMS procedure (short term condition) or 10 months later (long-term condition). Results indicate that 1) UCMS procedure induces a short-term depressive-like behavior in mice, defined as coat state deterioration, an effect that is prevented by fluoxetine treatment; 2) UCMS procedure has no effect on the short-term expression of the studied markers; however, UCMS increases expression of plasminogen activator inhibitor-1 only in the long-term group; 3) fluoxetine treatment is unable to counteract this UCMS-induced change; 4) aging induces behavioral perturbation, defined as a decrease in grooming motivation, and an increase of all the vascular markers in both control and UCMS groups and 5) pretreatment with fluoxetine has no protective effects on aging-induced behavioral and vascular alterations. Thus, in this model of depression-like behavior, UCMS appears to induce late-onset physiological changes, which are consistent with human studies indicating that depression is a risk factor for the development of heart disease.

Serum Markers of Endothelial Dysfunction and Inflammation Increase in Hypertension with Prediabetes Mellitus.

The aim of this study was to examine endothelial dysfunction and inflammation in hypertension and prediabetes by studying adhesion molecules and inflammatory factors. This study included 133 outpatients. Participants were categorized into three groups based on the presence or absence of hypertension and prediabetes: control subjects without prediabetes and hypertension (N group, n = 39); patients with hypertension only (H group, n = 34); and patients with hypertension and prediabetes (HD group, n = 60). Hypertension was diagnosed according to JNC7 criteria. Prediabetes was defined according to 2010 American Diabetes Association criteria. Plasma was isolated from overnight fasting blood samples for enzyme-linked immunosorbent assay (ELISA) analysis of concentrations of intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), P-selectin, and interleukin-6 (IL-6) as indicators of endothelial function and inflammation. We found that the H and HD groups showed significantly higher levels of all four biomarkers compared with the N group (all p < 0.01). The HD group also showed significantly higher levels of ICAM-1 (p = 0.042) and TNF-α (p < 0.01) compared with the H group; no significant differences in P-selectin (p = 0.59) and IL-6 (p = 0.70) levels were observed among these groups. Prediabetes and hypertension induce endothelial dysfunction and inflammation by elevating levels of soluble adhesion molecules and inflammatory cytokines. The comorbidity of these diseases may exacerbate inflammation and endothelial dysfunction by enhancing the expression of ICAM-1 and TNF-α.

Haptoglobin genotype is associated with increased endothelial dysfunction serum markers in type 1 diabetes.

To evaluate the genotype-driven effect of haptoglobin (Hp) in patients with type 1 diabetes without clinical cardiovascular (CV) disease, considering endothelial dysfunction (ED) and arterial stiffness (AS). About 137 patients with type 1 diabetes (duration ≥ 5 years) and 68 age- and sex-matched controls were evaluated for the following: (i) smoking, alcohol intake, BMI, blood pressure, fasting plasma glucose, HbA1c and lipid profile; (ii) microvascular complications; (iii) serum markers of ED (ICAM-1, VCAM-1 and E-selectin); (iv) AS, assessed as aortic pulse wave velocity (aPWV); and (v) Hp genotype. The prevalence of the 1/1, 2/1 and 2/2 Hp genotypes was 28.5%, 46.7% and 24.8% in patients with type 1 diabetes and 20.9%, 38.8% and 40.3% in controls, respectively. No differences were found in classical CV risk factors between patients homozygous for allele 2 and the remaining genotypes, both in patients with type 1 diabetes and controls. Patients with type 1 diabetes carrying the Hp2/2 genotype had higher concentrations of ICAM-1 (65.1 (56.7-76.0) ng/mL vs. 59.0 (51.7-69.3) ng/mL; P = 0.033) and sVCAM-1 (1133.1 (884.6-1458.6) ng/mL vs. 956.4 (738.5-1206.1) ng/mL; P = 0.040) than those without it. The Hp2/2 genotype remained independently associated with ED after adjusting for CV risk factors (P = 0.038). No significant differences were found for aPWV between Hp genotypes. Endothelial dysfunction may be influenced by Hp2/2 genotype in patients with type 1 diabetes with independence of classical CV risk factors.

Daily non-soy legume consumption reverses vascular impairment due to peripheral artery disease

ObjectivePeripheral artery disease (PAD) results from a decrease in blood flow to the limbs due to the presence of atherosclerotic plaque. It has been reported that isoflavones isolated from soybeans reduce arterial stiffness, a component of atherosclerotic disease. This study examined the effect of consuming whole legumes (non-soy) on arterial function in humans with PAD. MethodsTwenty-six individuals with PAD consumed ½ cup/day cooked legumes (beans, peas, lentils, chickpeas) daily for 8 weeks. Measurements of circulating factors and vascular function at baseline and study conclusion were compared. ResultsNo changes in were detected relative to baseline values for most parameters. Total and LDL-cholesterol were reduced by 5.0% and 8.7%, respectively. The ankle-brachial index (ABI) showed a 5.5% increase. Changes in ABI and LDL-cholesterol did not correlate. Serum markers of endothelial dysfunction and inflammation were unchanged, but short-chain acylcarnitine concentrations were significantly decreased. ConclusionsA legume-rich diet can elicit major improvements in arterial function and serum cholesterol in the absence of changes in either body mass or blood pressure, although the improvements in vascular function and serum lipids were unrelated. Although the positive results obtained with this dietary intervention were not explained by biomarkers of endothelial function and inflammation, altered acylcarnitine levels indicate an improvement in skeletal muscle metabolism due to enhanced tissue perfusion.

DYNAMICS OF CARDIOVASCULAR STATUS AND SERUM MARKERS OF ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH RHEUMATOID ARTHRITIS, TREATED WITH INFLIXIMAB

Aim. To assess the complex dynamics of the main parameters of cardiovascular status and serum markers of endothelial dysfunction (ED) in patients with rheumatoid arthritis (RA), who were treated with infliximab.Material and methods. The main group (MG) included 50 patients with seropositive RA, who received a combination of methotrexate and infliximab. The examination took place at baseline, as well as two, six, and 14 weeks after the treatment started. Comparison groups (CG) included healthy volunteers (n=25) and RA patients treated with methotrexate only (n=110). Serum levels of tumor necrosis factor-α (TNO-α), interleukin-10 (IL-10), tissue plasminogen activator (TPA), and von Willebrand factor (vWf) were measured, using ELISA. Left ventricular (LV) function and microvascular status were assessed with echocardiography and laser Doppler flowmetry (LDF), respectively.Results. The E/A ratio was reduced in all subgroups, and at Week 14 of infliximab therapy, it slightly increased. At baseline, LDF parameters, such as neurogenic arteriole tone and intravascular resistance, were increased. Infliximab therapy was associated with a moderate decline of these parameters. Throughout the study, serum vWf concentration was higher in MG patients than in healthy controls. TPA activity was reduced at baseline (496±173 pg/ml), increasing at Week 14 up to 705±157 pg/ml. Baseline concentrations of TNF-α and UL-10 were substantially elevated (357,1±34 and 453±42 pg/ml, respectively). At Week 6, TNF-α concentration decreased significantly. At Week 14, not only TNF-α level decreased, reaching 94±28 pg/ml, but also the ratio TNF-α/IL-10 decreased (from 0,78±0,5 to 0,4±0,2).Conclusion. In RA patients, infliximab was highly effective for the functional cytokine dysbalance correction, also demonstrating pleiotropic effects, such as correction of microvascular and endothelial dysfunction.

Abstract P081: Markers of Endothelial Function and Peripheral Arterial Disease among Women

Introduction: Markers of endothelial function may be associated with increased risk for cardiovascular disease; however, prospective data for peripheral arterial disease (PAD) are limited. We evaluated the hypothesis that serum markers of endothelial dysfunction are associated with an increased risk of PAD among women. Methods: We conducted a nested case-control study within an ongoing prospective cohort of U.S. female nurses (Nurses’ Health Study). Among 32,826 NHS participants who provided blood samples in 1989-1990, after excluding those who had myocardial infarction, coronary heart disease, stroke, or carotid artery surgery prior to the PAD diagnosis, we included all incident PAD cases that occurred between 1990 and 2008 and were confirmed by medical records. Each case was individually matched with three eligible controls using risk-set sampling, by age, smoking, date of blood draw, and fasting status. We evaluated the association between serum levels of soluble intercellular adhesion molecule (ICAM-1), E-selectin, and the risk of PAD, using conditional logistic regression analysis. Results: Complete biomarker data from 1990 was available for 144 cases and 431 controls. After accounting for matching factors, baseline ICAM-1 levels were associated with higher risk of PAD (RR for highest (T3) vs. lowest (T1) tertile=1.75, 95% CI: 1.05-2.90). The association was attenuated and no longer significant (RR T3 vs. T1=1.37, 95% CI: 0.75-2.49) after adjusting for serum levels of HDL and LDL-cholesterol, family history of myocardial infarction, relative weight, reported aspirin and cholesterol-lowering medication use, hypertension and diabetes diagnoses, physical activity, and pack-years of smoking. Additional adjustment for CRP levels further attenuated the relative risk (RR T3 vs. T1= 1.24, 95% CI: 0.67-2.29). We did not observe any significant association between baseline E-selectin levels and the risk of PAD (multivariate- and CRP-adjusted RR T3 vs. T1=0.93, 95% CI: 0.54-1.59). Conclusions: There was no association between ICAM-1 and E-selectin and subsequent PAD in this cohort of U.S women.

Arterial Erectile Dysfunction: Reliability of Penile Doppler Evaluation Integrated With Serum Concentrations of Late Endothelial Progenitor Cells and Endothelial Microparticles

We recently showed the diagnostic value of a new immunophenotype of blood endothelial progenitor cells (EPC) (CD45(-)/CD34(+)/CD144(+)) and endothelial microparticles (EMP) (CD45(-)/CD144(+)/annexin V(+)) in patients with arterial erectile dysfunction (AED), particularly in patients with associated late-onset hypogonadism and/or metabolic syndrome. In addition, we evaluated the effects of androgen replacement therapy, aerobic physical activity, and tadalafil administration on these markers. The aim of this study was to evaluate the serum concentrations of EPCs and EMPs in a large cohort of patients with AED according to severity of cavernous arterial insufficiency evaluated by penile Doppler. A total of 120 patients (aged 58.0 ± 6.0 years) with AED were enrolled in this study. Patients were classified into 3 groups based on value of peak systolic velocity (PSV). Group A: 37 patients with PSV <25 cm/s (severe arterial insufficiency); group B: 40 patients with PSV between 25 and 29 cm/s (moderate arterial insufficiency); group C: 43 patients with PSV between 30 and 34 cm/s (mild arterial insufficiency). Twenty patients (aged 60.0 ± 3.0 years) with psychogenic erectile dysfunction (PED) represented the control group. EPC and EMP blood concentrations were evaluated by flow cytometry. Patients with AED had significantly higher blood pressure, triglyceride levels, homeostasis model assessment index of insulin resistance, cavernous artery acceleration time, and intima-media thickness than those with PED, whereas International Index of Erectile Function score, high-density lipoprotein cholesterol level, and cavernous artery PSV were lower than those in PED. Both EPC and EMP levels were significantly higher in patients with AED compared with patients with PED. Among 3 groups of patients with AED, there were no significant differences in metabolic parameters examined, but group A showed significantly higher values of cavernous artery acceleration time and intima-media thickness than group B and group C. Finally, group A showed serum concentrations of EPCs and EMPs significantly higher compared with other groups with AED. Patients with AED showed worse metabolic parameters, cavernous artery parameters, and EPC and EMP levels compared with patients with PED. Among patients with AED, those with PSV <25 cm/s showed worse findings of endothelial dysfunction. This suggests that AED is an expression of endothelial damage and that this original immunophenotype of EPCs and EMPs may be considered a predictor of endothelial dysfunction in patients with AED. Finally, this study confirmed the reliability of penile Doppler evaluation integrated with these serum markers of endothelial dysfunction.

Early and Late-Onset Effect of Chronic Stress on Vascular Function in Mice: A Possible Model of the Impact of Depression on Vascular Disease in Aging

Depression is recognized as a predictor of increased cardiac morbidity and mortality. In addition, depressed patients exhibit an increase in the serum markers of endothelial dysfunction and platelet activation involved in the cascade of events leading to atherosclerosis. The purpose of this study was to determine the early and late-onset expression of various vascular markers in a rodent model of depression. Male DBA (an inbred strain of mice)/2J mice were exposed to either 7 weeks of controlled living conditions or unpredictable chronic mild stress (UCMS), and subsequently given daily fluoxetine (10 mg/kg) or NaCl (9%) during the last 5 weeks of the experiment. Depressive-like behavior was evaluated by using motivational and self-care behavior, including the assessment of the animal's coat state and grooming behavior. Enzyme-linked immunoassay was used to quantify matrix metalloproteinase-9 (MMP-9), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and plasminogen activator inhibitor-1 (PAI-1) expression either immediately after the end of the UCMS procedure (short term condition) or 10 months later (long-term condition). Results indicate that 1) UCMS procedure induces a short-term depressive-like behavior in mice, defined as coat state deterioration, an effect that is prevented by fluoxetine treatment; 2) UCMS procedure has no effect on the short-term expression of the studied markers; however, UCMS increases expression of plasminogen activator inhibitor-1 only in the long-term group; 3) fluoxetine treatment is unable to counteract this UCMS-induced change; 4) aging induces behavioral perturbation, defined as a decrease in grooming motivation, and an increase of all the vascular markers in both control and UCMS groups and 5) pretreatment with fluoxetine has no protective effects on aging-induced behavioral and vascular alterations. Thus, in this model of depression-like behavior, UCMS appears to induce late-onset physiological changes, which are consistent with human studies indicating that depression is a risk factor for the development of heart disease.

Ranolazine improves endothelial function in patients with stable coronary artery disease

We investigated the effect of ranolazine on endothelial-dependent vasodilatation (EDV), serum markers of endothelial dysfunction, and inflammation. Endothelial dysfunction has been shown to be independently associated with the occurrence of cardiovascular events. We sought to investigate whether ranolazine, a novel antianginal medication with no effect on heart rate or blood pressure, improves endothelial function in patients with stable coronary artery disease (CAD). Twenty-seven patients with stable CAD were randomly assigned to either 1000 mg twice daily of ranolazine or to matching placebo for 6 weeks and then crossed over for an additional 6 weeks in a double-blind design. EDV was assessed using reactive hyperemia peripheral arterial tonometry (RH-PAT) at baseline, 6, and 12 weeks. Markers of endothelial dysfunction and inflammation were also evaluated. After 6 weeks, treatment with ranolazine significantly increased the EDV RH-PAT index as compared with baseline (1.85+/-0.42 vs. 2.08+/-0.57, P = 0.037). EDV RH-PAT did not change while on placebo (1.69+/-0.35 vs. 1.78+/-0.41, P = 0.29). In addition, there was a significant drop in asymmetric dimethylarginine levels with ranolazine treatment (0.66+/-0.12 vs. 0.60+/-0.11 micromol/l, P = 0.02) and a near significant decrease in C-reactive protein levels (0.40+/-0.80 vs. 0.30+/-0.61 mg/dl, P = 0.05). Ranolazine improves endothelial function, asymmetric dimethylarginine, and C-reactive protein levels in a group of patients with stable CAD. Our results suggest a novel mechanism of action of ranolazine.

Increased consumption of legumes improves arterial stiffness in peripheral vascular disease independent of blood pressure, weight and serum cholesterol

BackgroundEating fibre‐rich, low glycemic legumes may benefit cardiovascular health by reducing plasma lipid levels. We therefore undertook a clinical study to address the hypothesis that increased legume consumption would improve arterial stiffness.MethodsIndividuals with peripheral arterial disease were given ½ cup mixed legumes daily for 8 wks.ResultsNo changes in glycated hemoglobin, blood pressure, body weight, triglycerides or HDL cholesterol were detected relative to baseline values, but there were significant decreases in total and LDL cholesterol. There was an improvement in ankle‐brachial index (ABI) and a corresponding decrease in arterial stiffness (by pulse wave analysis), but serum markers of endothelial dysfunction or inflammation remained constant. Interestingly, the improvements in ABI and cholesterol were not correlated.ConclusionsThese data indicate that a legume‐rich diet can elicit major improvements in arterial function in the absence of changes in either body mass or blood pressure. Furthermore, the lack of correlation with serum cholesterol levels suggests improved vascular function was not a consequence of the high fibre and low glycemic index properties of the legumes. Finally, the absence of changes in circulating markers of endothelial dysfunction suggests the positive effects on arterial stiffness are mediated by another mechanism.Funding from Pulse Canada.

Effect of spironolactone on endothelial dysfunction in rheumatoid arthritis

Objective: Chronic inflammation in rheumatoid arthritis (RA) is associated with vascular endothelial dysfunction. The aim of this study was to determine the effect of spironolactone on endothelial function in anti‐tumour necrosis factor (TNF)‐naive RA patients.Methods: Twenty‐four anti‐TNF‐naive RA patients (mean age 49±1.8 years; disease duration 8.5±5.8 years) with high disease activity [Disease Activity Score including a 28‐joint count (DAS28>5.1)] despite treatment with stable doses of conventional disease‐modifying anti‐rheumatic drugs (DMARDs) were investigated. Inflammatory disease activity [DAS28 and Health Assessment Questionnaire‐Disability Index (HAQ‐DI) scores, erythrocyte sedimentation rate (ESR), and C‐reactive protein (CRP)], serum markers of endothelial dysfunction, serum nitrite concentration, and endothelium‐dependent and ‐independent vasodilation of the brachial artery were measured before and after 12 weeks of therapy with oral spironolactone 2 mg/kg/day.Results: After treatment with spironolactone, flow‐mediated vasodilation (FMD) improved from 3.18±0.46% to 3.95±0.49% (p<0.001) whereas there was no significant change in endothelium‐independent vasodilation with nitroglycerin and baseline diameter (18.4±1.15% vs. 18.3±1.13%, p = 0.046, and 3.5±0.1 vs. 3.52±0.1 mm, p = 0.952, respectively); serum nitrite concentration was reduced significantly from 6.9±0.34 to 6.8±0.33 µmol/L (p<0.001), ESR from 59.90±4.86 to 51.22±4.26 mm in the first hour (p<0.001), and CRP level from 15.2±3.8 to 9.4±2.6 mg/dL (p = 0.019). DAS28 and HAQ‐DI scores were significantly reduced, from 6.9±0.25 to 4.1±0.31 (p<0.05) and from 1.47±0.09 to 0.69±0.1 (p<0.05), respectively.Conclusions: The study suggests that, in RA, endothelial dysfunction is part of the disease process and treatment with spironolactone improves both endothelial dysfunction and inflammatory disease activity in RA.

Diabetic Retinopathy and Risk of Heart Failure

The purpose of this study was to examine the association of diabetic retinopathy with incident heart failure (HF). Microvascular disease might play a more prominent role in the pathogenesis of diabetic cardiomyopathy, a major cause of HF in diabetes. Whether diabetic retinopathy, a microvascular complication of diabetes, predicts HF is unclear. A population-based study included 1,021 middle-aged type 2 diabetic persons with normal renal function and free of clinical coronary heart disease or HF at baseline. Diabetic retinopathy signs were graded from retinal photographs. Incident HF events were prospectively identified from hospital stay and death records. There were 125 (12.8%) participants with diabetic retinopathy. After 9-year follow-up, 106 (10.1%) participants developed incident HF events. Persons with retinopathy were more likely to develop HF (cumulative incidence of 21.6%) than those without retinopathy (cumulative incidence of 8.5%). After controlling for age, gender, race, smoking, diabetes duration, insulin use, blood pressure, lipid profile, and other risk factors, participants with retinopathy had more than 2.5-fold higher risk of developing HF than those without retinopathy (hazard ratio [HR] 2.71; 95% confidence interval [CI] 1.46 to 5.05). This association remained significant after further adjustments for glycemic control, carotid atherosclerosis, and serum markers of endothelial dysfunction (HR 2.20, 95% CI 1.08 to 4.47). The presence of diabetic retinopathy signifies an excess risk of HF, independent of known risk factors. This further supports a contribution of microvascular disease to the development of HF in people with diabetes.

Effects of low- and high-advanced glycation endproduct meals on macro- and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitus

Background: An advanced glycation endproducts (AGEs)–rich diet induces significant increases in inflammatory and endothelial dysfunction markers in type 2 diabetes mellitus (T2DM).Objective: The aim was to investigate the acute effects of dietary AGEs on vascular function in T2DM patients.Design: Twenty inpatients with T2DM [x̄ (±SEM) age: 55.4 ± 2.2 y; glycated hemoglobin: 8.8 ± 0.5%] were investigated. In a randomized crossover design, the effects of a low-AGE (LAGE) and high-AGE (HAGE) meal on macrovascular [by flow-mediated dilatation (FMD)] and microvascular (by Laser-Doppler flowmetry) function, serum markers of endothelial dysfunction (E-selectin, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1), oxidative stress, and serum AGE were assessed. The meals had identical ingredients but different AGE amounts (15.100 compared with 2.750 kU AGE for the HAGE and LAGE meals, respectively), which were obtained by varying the cooking temperature and time. The measurements were performed at baseline and 2, 4, and 6 h after each meal.Results: After the HAGE meal, FMD decreased by 36.2%, from 5.77 ± 0.65% (baseline) to 3.93 ± 0.48 (2 h), 3.70 ± 0.42 (4 h), and 4.42 ± 0.54% (6 h) (P < 0.01 for all compared with baseline). After the LAGE meal, FMD decreased by 20.9%, from 6.04 ± 0.68% (baseline) to 4.75 ± 0.48% (2 h), 4.69 ± 0.51% (4 h), and 5.62 ± 0.63% (6 h), respectively (P < 0.01 for all compared with baseline; P < 0.001 for all compared with the HAGE meal). This impairment of macrovascular function after the HAGE meal was paralleled by an impairment of microvascular function (−67.2%) and increased concentrations of serum AGE and markers of endothelial dysfunction and oxidative stress.Conclusions: In patients with T2DM, a HAGE meal induces a more pronounced acute impairment of vascular function than does an otherwise identical LAGE meal. Therefore, chemical modifications of food by means of cooking play a major role in influencing the extent of postprandial vascular dysfunction.

Benfotiamine Prevents Macro- and Microvascular Endothelial Dysfunction and Oxidative Stress Following a Meal Rich in Advanced Glycation End Products in Individuals With Type 2 Diabetes

Diabetes is characterized by marked postprandial endothelial dysfunction induced by hyperglycemia, hypertriglyceridemia, advanced glycation end products (AGEs), and dicarbonyls (e.g., methylglyoxal [MG]). In vitro hyperglycemia-induced MG formation and endothelial dysfunction could be blocked by benfotiamine, but in vivo effects of benfotiamine on postprandial endothelial dysfunction and MG synthesis have not been investigated in humans until now. Thirteen people with type 2 diabetes were given a heat-processed test meal with a high AGE content (HAGE; 15.100 AGE kU, 580 kcal, 54 g protein, 17 g lipids, and 48 g carbohydrates) before and after a 3-day therapy with benfotiamine (1,050 mg/day). Macrovascular flow-mediated dilatation (FMD) and microvascular reactive hyperemia, along with serum markers of endothelial disfunction (E-selectin, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1), oxidative stress, AGE, and MG were measured during both test meal days after an overnight fast and then at 2, 4, and 6 h postprandially. The HAGE induced a maximum reactive hyperemia decrease of -60.0% after 2 h and a maximum FMD impairment of -35.1% after 4 h, without affecting endothelium-independent vasodilatation. The effects of HAGE on both FMD and reactive hyperemia were completely prevented by benfotiamine. Serum markers of endothelial dysfunction and oxidative stress, as well as AGE, increased after HAGE. These effects were significantly reduced by benfotiamine. Our study confirms micro- and macrovascular endothelial dysfunction accompanied by increased oxidative stress following a real-life, heat-processed, AGE-rich meal in individuals with type 2 diabetes and suggests benfotiamine as a potential treatment.