Carmen Vasiliadou

Acute Systemic Inflammation Increases Arterial Stiffness and Decreases Wave Reflections in Healthy Individuals

Background— Aortic stiffness is a marker of cardiovascular disease and an independent predictor of cardiovascular risk. Although an association between inflammatory markers and increased arterial stiffness has been suggested, the causative relationship between inflammation and arterial stiffness has not been investigated. Methods and Results— One hundred healthy individuals were studied according to a randomized, double-blind, sham procedure-controlled design. Each substudy consisted of 2 treatment arms, 1 with Salmonella typhi vaccination and 1 with sham vaccination. Vaccination produced a significant (P<0.01) increase in pulse wave velocity (at 8 hours by 0.43 m/s), denoting an increase in aortic stiffness. Wave reflections were reduced significantly (P<0.01) by vaccination (decrease in augmentation index of 5.0% at 8 hours and 2.5% at 32 hours) as a result of peripheral vasodilatation. These effects were associated with significant increases in inflammatory markers such as high-sensitivity C-reactive protein (P<0.001), high-sensitivity interleukin-6 (P<0.001), and matrix metalloproteinase-9 (P<0.01). With aspirin pretreatment (1200 mg PO), neither pulse wave velocity nor augmentation index changed significantly after vaccination (increase of 0.11 m/s and 0.4%, respectively; P=NS for both). Conclusions— This is the first study to show through a cause-and-effect relationship that acute systemic inflammation leads to deterioration of large-artery stiffness and to a decrease in wave reflections. These findings have important implications, given the importance of aortic stiffness for cardiovascular function and risk and the potential of therapeutic interventions with antiinflammatory properties.

Arterial function and intima-media thickness in hypertensive patients with erectile dysfunction.

Objective Erectile dysfunction is a predictor of cardiovascular risk with high prevalence in hypertensive men. We investigated whether erectile dysfunction is related to arterial structure and function in hypertensive patients. Methods We evaluated arterial structural and functional characteristics and measured systemic endothelial/inflammatory markers in 52 hypertensive men with vasculogenic erectile dysfunction and in 34 hypertensive men with normal erectile function, matched for age, blood pressure, risk factors and treatment. Results Hypertensive patients with erectile dysfunction had higher common carotid intima-media thickness (0.95 ± 0.19 vs. 0.83 ± 0.18 mm, P = 0.003) and carotid–femoral pulse-wave velocity (8.89 ± 1.38 vs. 8.11 ± 1.10 m/s, P = 0.007), lower flow-mediated dilation of the brachial artery (absolute values of 2.96 ± 1.64 vs. 4.07 ± 1.68%, P = 0.003) and a higher level of the systemic endothelial dysfunction marker asymmetric dimethylarginine (0.67 ± 0.13 vs. 0.57 ± 0.16 μmol/l, P = 0.003), and the inflammatory markers high-sensitivity C-reactive protein [2.03 (1.16–2.89) vs. 1.23 (0.67–1.90) mg/l, P = 0.029] and interleukin-6 (4.13 ± 2.38 vs. 2.77 ± 1.92 pg/ml, P = 0.011). Multivariable analysis adjusting for age, mean pressure, other risk factors and treatment showed independent associations between erectile dysfunction and parameters of arterial structure and function. In the erectile dysfunction group, there were no significant relationships between the severity of erectile dysfunction (as expressed by the Sexual Health Inventory for Men score) and the above arterial indices and level of circulating markers (all P = NS). Conclusion In hypertensive men, the presence but not the severity of vasculogenic erectile dysfunction is associated with subclinical atherosclerosis, impairment of arterial function and systemic endothelial and inflammatory activation.

Effects of Ramipril on Endothelial Function and the Expression of Proinflammatory Cytokines and Adhesion Molecules in Young Normotensive Subjects With Successfully Repaired Coarctation of Aorta: A Randomized Cross-Over Study

OBJECTIVES The purpose of this study was to evaluate the effect of ramipril on endothelial function and inflammatory process in a group of normotensive subjects with successfully repaired coarctation of the aorta (SCR). BACKGROUND Subjects with SCR experience higher long-term cardiovascular risk as a result of the relapse of arterial hypertension or owing to nonreversible structural changes in the pre-coarctation arterial tree. These subjects experience endothelial dysfunction in the right forearm and appear to have elevated levels of proatherogenic inflammatory markers, even in the absence of arterial hypertension. METHODS Twenty young individuals age 27.3 +/- 2.4 years old with SCR 13.9 +/- 2.2 years previously, received ramipril 5 mg/day for 4 weeks in a randomized, cross-over, controlled trial. Endothelial function was evaluated in the right forearm by gauge-strain plethysmography, and serum levels of interleukin (IL)-1b, IL-6, soluble CD40 ligand (sCD40L), and soluble vascular cell adhesion molecule (sVCAM)-1 were determined by enzyme-linked immunosorbent assay. RESULTS Ramipril improved endothelial function (p < 0.001) and decreased the expression of proinflammatory cytokine IL-6 (p < 0.05) and sCD40L (p < 0.01). Furthermore, ramipril decreased serum levels of sVCAM-1 (p < 0.01) but failed to affect serum levels of C-reactive protein. These effects were independent of blood pressure lowering. CONCLUSIONS Ramipril reversed the impaired endothelial function and decreased the expression of proinflammatory cytokine IL-6, sCD40L, and adhesion molecules in normotensive subjects with SCR. These findings imply that ramipril treatment may have antiatherogenic effects in subjects with SCR, even in the absence of arterial hypertension.

Interaction between cytokines and sCD40L in patients with stable and unstable coronary syndromes

Background  Evidence suggests that soluble CD40‐ligand (sCD40L) is elevated in coronary artery disease (CAD) and is released from activated platelets during the acute myocardial infarction (AMI). Although sCD40L is part of immune response, the mechanisms regulating its release in different disease states remain unknown.

Vascular endothelium and inflammatory process, in patients with combined Type 2 diabetes mellitus and coronary atherosclerosis: the effects of vitamin C.

Aims  Type 2 diabetes mellitus (DM) and coronary artery disease (CAD) are both associated with endothelial dysfunction and elevated oxidative and inflammatory state. We examined the effect of vitamin C on endothelial function and levels of soluble vascular cell adhesion molecule (sVCAM‐1), interleukin‐6 (IL‐6) and tumour necrosis factor (TNF‐α), in DM patients with or without CAD and in non‐diabetic subjects.

Acute effects of different alcoholic beverages on vascular endothelium, inflammatory markers and thrombosis fibrinolysis system

BACKGROUND & AIM Mild alcohol consumption has been associated with decreased cardiovascular risk, although the underlying mechanisms are still unclear. We compared the acute effects of several alcoholic beverages on endothelial function, inflammatory process and thrombosis/fibrinolysis system in young adults. METHODS In this randomized intervention trial, healthy young individuals with no risk factor for atherosclerosis were randomized into 5 equally sized groups and received an equal amount of alcohol (30 g), as red wine (264 ml), white wine (264 ml), beer (633 ml), whisky (79 ml) or water (250 ml). Forearm blood flow was determined by gauge-strain plethysmography, at baseline, 1 and 4 h after alcohol intake. Levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP), fibrinogen (Fib), plasminogen activator inhibitor (PAI-1), von Willebrand factor (vWF) and tissue plasminogen activator (tPA) were determined at baseline and 4 h after alcohol consumption. RESULTS Reactive hyperemia was significantly increased 1 h after beer and red wine consumption (p<0.05 for both), while it returned at baseline at 4 h (p=ns vs baseline) but remained unchanged in all the other groups. vWF was decreased in the beer and red wine groups (p<0.05 for both) only. PAI-1/tPA ratio remained unchanged only in red wine and control group. Inflammatory markers remained unchanged in all the groups. CONCLUSIONS Acute consumption of red wine or beer improves endothelial function and decreases vWF levels, suggesting that the type of beverage may differently affect endothelial function and thrombosis/fibrinolysis system in healthy adults.

Effects of atorvastatin and vitamin C on forearm hyperaemic blood flow, asymmentrical dimethylarginine levels and the inflammatory process in patients with type 2 diabetes mellitus.

Type 2 diabetes mellitus (DM) is characterised by increased oxidative stress as a result of the hyperglycaemic state, leading to decreased nitric oxide bioavailability.1 Similarly, type 2 DM is characterised by increased levels of proatherogenic cytokines and adhesion molecules,1 while it has been shown that the endogenous endothelial nitric oxide synthase inhibitor, asymmetrical dimethyl arginine (ADMA), is also elevated in type 2 DM.2 Although ADMA synthesis is triggered by both oxidative stress and proinflammatory stimuli, the effect of antioxidant or anti-inflammatory treatment on its release is unclear. We compared the effects of atorvastatin (which has anti-inflammatory properties in atherosclerosis) and vitamin C (a well-known antioxidant) on the inflammatory process, endothelial function and the release of ADMA in normocholesterolaemic patients with type 2 DM. Forty-one patients with type 2 DM and no evidence of macroangiopathy were recruited (table 1). The absence of coronary artery disease (CAD) was established by a negative exercise stress test within the last 6 months before recruitment, while peripheral artery disease was defined as an ankle brachial index <0.90. All patients had cholesterol <5.4 mmol/l at baseline, and exclusion criteria were the use of statins, insulin, antioxidant supplements, hormone replacement therapy or anti-inflammatory medication during the past year, or the presence of any chronic disease or infection. All subjects had normal renal function (normal creatinine clearance as calculated by the Cockroft-Gault formula and no macroalbuminuria). Patients were randomly allocated into groups receiving atorvastatin (10 mg/day), vitamin C (2 g/day) or no …

Divergent effects of laughter and mental stress on arterial stiffness and central hemodynamics.

Objective: To investigate the effect of laughter and mental stress on arterial stiffness and central hemodynamics. Arterial stiffness and wave reflections are independent predictors of cardiovascular risk. Chronic psychological stress is an independent risk factor for cardiovascular events, whereas acute stress deteriorates vascular function. Methods: Eighteen healthy individuals were studied on three occasions, according to a randomized, single-blind, crossover, sham procedure-controlled design. The effects of viewing a 30-minute segment of two films inducing laughter or stress were assessed. Carotid-femoral pulse wave velocity was used as an index of arterial stiffness; augmentation index was used as a measure of wave reflections. Results: Laughter decreased pulse wave velocity (by 0.30 m/sec, p = .01), and augmentation index (by 2.72%, p = .05). Conversely, stress increased pulse wave velocity (by 0.29 m/sec, p = .05) and augmentation index (by 5.1%, p = .005). Laughter decreased cortisol levels by 1.67 &mgr;g/dl (p = .02), soluble P-selectin by 26 ng/ml (p = .02) and marginally von Willebrand factor (by 2.4%, p = .07) and increased total oxidative status (by 61 &mgr;mol/L, p < .001). Stress decreased interleukin-6 (by 0.11 pg/ml, p = .04) and increased total oxidative status (by 44 &mgr;mol/L, p = .007). Soluble CD40 ligand and fibrinogen remained unchanged. Conclusions: Positive (laughter) and negative (stress) behavioral interventions have divergent acute effects on arterial stiffness and wave reflections. These findings have important clinical implications extending the spectrum of lifestyle modifications that can ameliorate arterial function. FMD = flow-mediated dilatation; SD = standard deviation; PWV = pulse wave velocity; AIx = augmentation index; sP-selectin = soluble P-selectin; IL-6 = interleukin-6; sCD40L = soluble CD40 ligand; vWF = von Willebrand factor; TOS = total oxidative status; ANOVA = analysis of variance; ANCOVA = analysis of covariance; MAP = mean arterial pressure.

Relationship of fibrinogen with arterial stiffness and wave reflections.

Introduction Increased levels of fibrinogen have been related to target organ damage and cardiovascular outcomes. Arterial elastic properties are important determinants of cardiovascular performance and predictors of the corresponding risk. This study investigated whether the fibrinogen level is associated with arterial stiffness and wave reflections. Methods We studied 229 consecutive, non-diabetic patients with uncomplicated, never-treated essential hypertension (mean age 51 years, 149 men) and an age-matched control group of 159 normotensive individuals (mean age 50 years, 83 men). Carotid–femoral and carotid–radial pulse wave velocity (PWVc–f and PWVc–r) were measured as indices of elastic-type, aortic stiffness and muscular type, medium-sized arterial stiffness, respectively. The heart rate-corrected augmentation index (AIx75) was estimated as a composite marker of wave reflections and arterial stiffness. Plasma fibrinogen was measured using immunonephelometry. Results The fibrinogen level and arterial function indices (PWVc–f, PWVc–r, AIx75) were significantly higher in hypertensive patients than controls. In the whole population, fibrinogen level correlated with PWVc–f and AIx75 in univariable analysis, but not with PWVc–r. In multivariable analysis, an independent association was established between fibrinogen level and PWVc–f after adjusting for age, sex, mean pressure, heart rate, height, body mass index, smoking status, and total cholesterol. In contrast, no significant relationship was observed between fibrinogen and AIx75 after adjusting for confounders. Conclusion The plasma fibrinogen level is independently associated with aortic stiffening. This finding underlines the important role of fibrinogen as a marker of arterial damage, and implies a possible contribution of this compound to the pathophysiology of cardiovascular disease.

Antidepressive treatment as a modulator of inflammatory process in patients with heart failure: Effects on proinflammatory cytokines and acute phase protein levels

BACKGROUND Depression has been associated with increased inflammatory process. Although anti-depressive medication has anti-inflammatory effect in major depression, its role in patients with heart failure (HF) is unknown. In the present study we evaluated the impact of antidepressive medication on the expression of proinflammatory cytokines and acute phase response proteins, in patients with HF and major depression. METHODS The study population consisted of 250 patients with HF (154 suffering from major depression). Patients with major depression were under selective serotonin reuptake inhibitors (SSRIs, n=120) or tricyclic antidepressants (TCA) and/or serotonin/norepinephrine reuptake inhibitors (SNRIs) (n=34), for at least 6 months. RESULTS Levels of TNF-alpha, IL-6, CRP and fibrinogen were not significantly different between HF patients with depression under treatment and those without depression (p=NS for all). However, TNF-alpha and CRP levels were significantly lower in patients receiving TCA/SNRI compared to patients receiving SSRIs or those without depression (p<0.05 for all). Similarly, patients under TCA/SNRI had significantly lower heart rate compared to those treated with SSRIs or those without depression. In multivariate analysis, treatment with SNRI/TCA was an independent predictor for log(TNF-alpha) (beta=0.036(SE:0.016) and log(CRP) (beta=0.099(SE:0.048), p=0.041). CONCLUSIONS In the present study we demonstrate for the first time that treatment of patients with HF and major depression with TCAs/SNRIs, is associated with lower levels of TNF-alpha and CRP, suggesting that the type of antidepressive treatment may have a significant effect on the underlying inflammatory process.