New insights into antiphospholipid-related endothelial dysfunction by assessment of vascular glycocalyx layer: results from a preliminary cross-sectional study.

INTRODUCTION: Antiphospholipid syndrome (APS) is associated with greater atherothrombotic risk and endothelial dysfunction, suggesting that endothelial glycocalyx is impaired in this disease. OBJECTIVES: The aim was to investigate the endothelial glycocalyx and the relationship between glycocalyx markers, endothelial dysfunction parameters and atherosclerotic markers in APS. METHODS: A total of 15 primary arterial APS patients and healthy controls were included in the study. Glycocalyx was assessed in both groups by sublingual sidestream dark field imaging and syndecan-1 plasma level. Endothelial function was evaluated by brachial artery flow-mediated dilatation (FMD) and early atherosclerosis by carotid intima media thickness (IMT). Thrombotic profile was also performed by measuring the plasma level of the tissue factor (TF). RESULTS: APS patients had significantly increased syndecan-1 plasma level 38.6 ± 5.0 pg/ml vs. 19.1 ± 3.5 pg/ml; p < 0.01 and a reduced glycocalyx thickness 0.26 ± 0.03 µm vs. 0.75 ± 0.07 µm; p < 0.01 compared with control. FMD was impaired in APS patients compared with control, 5.68% ± 0.42 vs. 8.29 ± 0.30, p < 0.01, respectively. IMT was significantly increased in APS patients compared with control, 0.52 ± 0.13 mm vs. 0.40 ± 0.06 mm, p < 0.01, respectively. Soluble TF, thiobarbituric acid-reactive substances levels were increased in the sera from APS patients compared with control. CONCLUSIONS: This preliminary study supports, for the first time, that in APS patients endothelial glycocalyx is impaired, which could lead to thrombosis, endothelial dysfunction and early atherosclerosis.

[Cardiovascular consequences of chronic kidney disease, impact of modulation of epoxyeicosatrienoic acids]. / Conséquences cardiovasculaires de l'insuffisance rénale chronique, intérêt d'une modulation des acides époxyeicosatriénoïques.

Cardiovascular events are more prevalent in chronic kidney disease than in the general population, being the main cause of morbi-mortality. The physiopathology explaining this association remains complex. Thus, research for new therapies to prevent cardiovascular events in chronic kidney disease is a major issue. Epoxyeicosatrienoic acids, products of the arachidonic acid metabolism, are endothelium-derived hyperpolarizing factors with vasodilatory, anti-inflammatory, thrombolytic, pro-angiogenic and anti-apoptotic properties. A decrease in the bioavailability of epoxyeicosatrienoic acids has been observed in many cardiovascular diseases such as hypertension, myocardial infarction or diabetes. Moreover, human studies of genetic polymorphisms of soluble epoxide hydrolase, the enzyme degrading epoxyeicoatrienoic acids, have shown that allelic variants related to an increase in its activity is associated with higher risk of cardiovascular events. Modulation of epoxyeicosatrienoic acids by soluble epoxide hydrolase inhibitors in some cardiovascular diseases induces structural improvements in the heart, vessels and kidneys, including decrease in cardiomyocyte hypertrophy, reduction in cardiac and renal interstitial fibrosis, improvement in renal hemodynamics, and prevention of endothelial dysfunction. In this context, increasing the bioavailability of epoxyeicosatrienoic acids appears to be an interesting therapeutic option in the prevention of cardiovascular events related to chronic kidney disease.

[Assessment of endothelial function in autoimmune diseases]. / Évaluation de la fonction endothéliale au cours des maladies auto-immunes.

Numerous autoimmune-inflammatory rheumatic diseases have been associated with accelerated atherosclerosis or other types of vasculopathy leading to an increase in cardiovascular disease incidence. In addition to traditional cardiovascular risk factors, endothelial dysfunction is an important early event in the pathogenesis of atherosclerosis, contributing to plaque initiation and progression. Endothelial dysfunction is characterized by a shift of the actions of the endothelium toward reduced vasodilation, a proinflammatory and a proadhesive state, and prothrombic properties. Therefore, assessment of endothelial dysfunction targets this vascular phenotype using several biological markers as indicators of endothelial dysfunction. Measurements of soluble adhesion molecules (ICAM-1, VCAM-1, E-selectin), pro-thrombotic factors (thrombomodulin, von Willebrand factor, plasminogen activator inhibitor-1) and inflammatory cytokines are most often performed. Regarding the functional assessment of the endothelium, the flow-mediated dilatation of conduit arteries is a non-invasive method widely used in pathophysiological and interventional studies. In this review, we will briefly review the most relevant information upon endothelial dysfunction mechanisms and explorations. We will summarize the similarities and differences in the biological and functional assessments of the endothelium in different autoimmune diseases.

Immunosuppressant regimen based on sirolimus decreases aortic stiffness in renal transplant recipients in comparison to cyclosporine.

Whether or not a cyclosporine A (CsA)-free immunosuppressant regimen based on sirolimus (SRL) prevents aortic stiffening and improves central hemodynamics in renal recipients remains unknown. Forty-four patients (48 ± 2 years) enrolled in the CONCEPT trial were randomized at week 12 (W12) to continue CsA or switch to SRL, both associated with mycophenolate mofetil. Carotid systolic blood pressure (cSBP), pulse pressure (cPP), central pressure wave reflection (augmentation index, AIx) and carotid-to-femoral pulse-wave velocity (PWV: aortic stiffness) were blindly assessed at W12, W26 and W52 together with plasma endothelin-1 (ET-1), thiobarbituric acid-reactive substances (TBARS) and superoxide dismutase (SOD) and catalase erythrocyte activities. At W12, there was no difference between groups. At follow-up, PWV, cSBP, cPP and AIx were lower in the SRL group. The difference in PWV remained significant after adjustment for blood pressure and eGFR. In parallel, ET-1 decreased in the SRL group, while TBARS, SOD and catalase erythrocyte activities increased in both groups but to a lesser extent in the SRL group. Our results demonstrate that a CsA-free regimen based on SRL reduces aortic stiffness, plasma endothelin-1 and oxidative stress in renal recipients suggesting a protective effect on the arterial wall that may be translated into cardiovascular risk reduction.

[Role of vascular calcium-activated potassium channels in the regulation of human peripheral conduit artery diameter]. / Rô1e des canaux potassiques calcium-dépendants dans la régulation du diamètre basal des artères de conductance périphériques humaines.

The role of an endothelium-derived hyperpolarizing factor (EDHF), acting through the opening of vascular calcium-activated potassium (K(Ca)) channels, in the regulation of the basal diameter of human peripheral conduit arteries has never been investigated in vivo. We measured in 7 healthy subjects the effect of the local infusion of an inhibitor of K(Ca) channels, tetraethylammonium chloride (TEA, 9 micromol/min, 8 min), on radial artery diameter (echotracking) and flow (Doppler). Endothelium-independent dilatation was assessed before and after TEA using sodium nitroprusside (SNP: 5, 10 and 15 nmol/min, 3 min each). TEA induced a decrease in radial artery diameter (2.65 +/- 0.09 to 2.52 +/- 0.09 mm: p < 0.05) and flow (9.4 +/- 1.2 to 7.4 +/- 1.1 ml/min; p < 0.01) without modification in the radial artery dilatation in response to SNP (NS). The decrease in radial artery diameter was still significant even when the decrease in flow was taken as covariate into analysis (p < 0.05). These results demonstrate the role of vascular K(Ca) channels in the regulation of basal peripheral conduit artery diameter and arteriolar tone in human strongly suggesting the involvement of an EDHF a these two levels.

[Hand skin heating: a new method for the evaluation of conduit artery endothelial function in insulin-dependent diabetic patients]. / Le chauffa e cutané distal: une nouvelle méthode d'étude de la fonction endothéliale des artères de conductance périphériques chez le diabétique insulinodépendant.

The presence of an altered endothelium-mediated flow-dependent dilatation (FDD) of peripheral conduit arteries in insulin-dependent diabetic patients without microangiopathy is still controversial. We studied 10 normotensive and non atherosclerotic insulin-dependent diabetic patients (D group) without complication (neuropathy, microalbuminuria or neuropathy) and 10 control subjects (C group) matched for age, sex and BMI. Radial artery diameter (RAD, echotracking) and flow (RAF, Doppler) were measured at baseline and during FDD in response to distal hand skin heating (from 34 to 44 degrees C). a method developed to increase RAF by stable steps by decreasing gradually hand skin vascular resistance. Endothelium-independent dilatation was evaluated by administration of glyceryl trinitrate (GTN: 0.3 mg spray). At baseline, there was no difference between group for RAF (C: 18 +/- 5 vs D: 18 +/- 2 mL/min; NS) and RAD (C: 2.51 +/- 0.12 vs D: 2.54 +/- 0.07 mm; NS). Heating induced in the diabetic group a smaller increase in RAF (C: 473 +/- 126% vs D: 262 +/- 63%; p<0.05) and RAD (C: 22.6 +/- 2.6% vs D: 16.1 +/- 1.8%; p<0.01). This last result remains significant when the increase in RAF was included into the analysis of RAD variation during heating (p<0.05). GTN-induced dilatation was similar in the 2 groups. Our results obtained by use of the hand skin heating method demonstrate the presence of an abnormal arteriolar skin reactivity and an altered peripheral conduit artery endothelium-dependent dilatation in uncomplicated insulin-dependent diabetic patients. The early identification of these anomalies, with negative prognostic value, could contribute to the management of these patients.

[Role of endothelium-derived nitric oxide in sustained flow-dependent dilatation of human peripheral conduit arteries]. / Rôle du monoxyde d'azote dans la dilatation débit-dépendante des artères de conductance périphériques en réponse à une stimulation soutenue.

Endothelial dysfunction is involved in the pathogenesis of cardiovascular diseases and is generally associated to the decrease in arterial nitric oxide (NO) availability. In humans, endothelial function can be evaluated by the post-ischaemic flow-dependent dilatation (FDD) of peripheral conduit arteries which is mainly mediated by the NO release when short duration of reactive hyperaemia are used (3 to 5 min ischaemia). However, recent studies suggest that the role of NO in this response decreases as the duration of the hyperaemic stimulation increases. The aim of the present study was thus, to evaluate, in healthy subjects, the role of NO in the FDD of conduct arteries in response to a sustained stimulation. Radial artery diameter (echotracking) and flow (Doppler) were measured, 7 cm under the elbow line, at baseline and during post-ischaemic hyperaemia (10 min wrist cuff inflation) in 10 healthy subjects (age: 24 +/- 1 years) in control period and after acute blockade of the endothelial NO-synthase by local infusion of NG-monomethyl L-arginine (L-NMMA, brachial artery, 8 mumol/min, 7 min). Endothelium-independent dilatation was studied by mean of sodium nitroprusside infusion (SNP: 5, 10 and 20 nmol/min, 3 min each dose before and after L-NMMA). L-NMMA administration decreased radial artery blood flow at base (Control: 14 +/- 2 vs L-NMMA: 10 +/- 1 ml/min, P < 0.05) and increased radial artery vasodilatation in response to SNP (P < 0.05) thus, demonstrating NO-synthase inhibition. Therefore, after L-NMMA there was a small decrease in radial FDD (Control: base: 2.52 +/- 0.05 mm, FDD: 11.3 +/- 0.6% vs L-NMMA: base: 2.51 +/- 0.04 mm: FDD: 9.0 +/- 0.9%; p < 0.05) without change in hyperaemia. In conclusion, our results demonstrate, in contrast to those obtained after short duration of hyperaemia, that the relative implication of NO in the flow-dependent vasodilatation of peripheral conduit arteries in humans decreases in response to sustained stimulation and suggest, in these experimental conditions, an associated flow-dependent vasodilating mechanism that is unaffected by the NO-synthase inhibition.