Aurélien Wauters

Acute Exposure to Diesel Exhaust Impairs Nitric Oxide–Mediated Endothelial Vasomotor Function by Increasing Endothelial Oxidative Stress

Exposure to diesel exhaust was recently identified as an important cardiovascular risk factor, but whether it impairs nitric oxide (NO)–mediated endothelial function and increases production of reactive oxygen species (ROS) in endothelial cells is not known. We tested these hypotheses in a randomized, controlled, crossover study in healthy male volunteers exposed to ambient and polluted air (n=12). The effects of skin microvascular hyperemic provocative tests, including local heating and iontophoresis of acetylcholine and sodium nitroprusside, were assessed using a laser Doppler imager. Before local heating, skin was pretreated by iontophoresis of either a specific NO–synthase inhibitor (L-N-arginine-methyl-ester) or a saline solution (Control). ROS production was measured by chemiluminescence using the lucigenin technique in human umbilical vein endothelial cells preincubated with serum from 5 of the subjects. Exposure to diesel exhaust reduced acetylcholine-induced vasodilation (P<0.01) but did not affect vasodilation with sodium nitroprusside. Moreover, the acetylcholine/sodium nitroprusside vasodilation ratio decreased from 1.51±0.1 to 1.06±0.07 (P<0.01) and was correlated to inhaled particulate matter 2.5 (r=−0.55; P<0.01). NO–mediated skin thermal vasodilatation decreased from 466±264% to 29±123% (P<0.05). ROS production was increased after polluted air exposure (P<0.01) and was correlated with the total amount of inhaled particulate matter <2.5 &mgr;m (PM2.5). In healthy subjects, acute experimental exposure to diesel exhaust impaired NO–mediated endothelial vasomotor function and promoted ROS generation in endothelial cells. Increased PM2.5 inhalation enhances microvascular dysfunction and ROS production.

L-NAME iontophoresis: a tool to assess NO-mediated vasoreactivity during thermal hyperemic vasodilation in humans.

Background: Decreased endothelial Nitric oxide (NO) bioavailability is one of the earliest events of endothelial dysfunction. Assessment of microvascular blood flow using a Laser Doppler Imager during local noninvasive administration of L-N-Arginine-Methyl-Ester (L-NAME) by skin iontophoresis may help discriminate the relative contributions of NO and non-NO pathways during a skin thermal hyperemic test. Methods: In healthy nonsmokers, the effects of thermal vasodilation and sodium nitroprusside–mediated vasodilation were tested on skin pretreated with 0.9% saline solution, 2% L-NAME iontophoresis (n = 12), or intradermal injection of 25 nmol L-NAME (n = 10). The effects of L-NAME iontophoresis were also measured in a group of smokers (n = 10). Results: L-NAME iontophoresis and intradermal injection of L-NAME decreased the skin response to local heating to a similar degree (−41% ± 4% vs. −44% ± 6%). L-NAME iontophoresis site-to-site and day-to-day coefficients of correlation were 0.83 and 0.76, respectively (P < 0.01). The site-to-site and day-to-day coefficients of correlation of L-NAME injection were lower than those of iontophoresis at 0.66 (P < 0.05) and 0.12, respectively (P = not significant). Sodium nitroprusside–induced skin hyperemia was not affected by L-NAME administration. L-NAME iontophoresis–mediated inhibition of skin thermal hyperemia was greater in smokers than in nonsmokers (P < 0.05). Conclusions: Laser Doppler Imager assessment of skin thermal hyperemia after L-NAME iontophoresis provides a reproducible and selective bedside method of qualitatively analyzing the contribution of the NO pathway to microvascular vasomotor function.

At high cardiac output, diesel exhaust exposure increases pulmonary vascular resistance and decreases distensibility of pulmonary resistive vessels.

Air pollution has recently been associated with the development of acute decompensated heart failure, but the underlying biological mechanisms remain unclear. A pulmonary vasoconstrictor effect of air pollution, combined with its systemic effects, may precipitate decompensated heart failure. The aim of the present study was to investigate the effects of acute exposure to diesel exhaust (DE) on pulmonary vascular resistance (PVR) under resting and stress conditions but also to determine whether air pollution may potentiate acquired pulmonary hypertension. Eighteen healthy male volunteers were exposed to ambient air (AA) or dilute DE with a particulate matter of <2.5 μm concentration of 300 μg/m(3) for 2 h in a randomized, crossover study design. The effects of DE on PVR, on the coefficient of distensibilty of pulmonary vessels (α), and on right and left ventricular function were evaluated at rest (n = 18), during dobutamine stress echocardiography (n = 10), and during exercise stress echocardiography performed in hypoxia (n = 8). Serum endothelin-1 and fractional exhaled nitric oxide were also measured. At rest, exposure to DE did not affect PVR. During dobutamine stress, the slope of the mean pulmonary artery pressure-cardiac output relationship increased from 2.8 ± 0.5 mmHg · min · l (-1) in AA to 3.9 ± 0.5 mmHg · min · l (-1) in DE (P < 0.05) and the α coefficient decreased from 0.96 ± 0.15 to 0.64 ± 0.12%/mmHg (P < 0.01). DE did not further enhance the hypoxia-related upper shift of the mean pulmonary artery pressure-cardiac output relationship. Exposure to DE did not affect serum endothelin-1 concentration or fractional exhaled nitric oxide. In conclusion, acute exposure to DE increased pulmonary vasomotor tone by decreasing the distensibility of pulmonary resistive vessels at high cardiac output.

Pro-thrombotic effect of exercise in a polluted environment: a P-selectin- and CD63-related platelet activation effect

Exposure to diesel exhaust is an important cardiovascular risk factor and may promote atherothrombotic events. Some data suggest that polluted air exposure could affect haemostasis through platelet activation. The aim of the study was to investigate the effects of acute exposure to diesel exhaust on platelet activation and platelet function. We tested the hypothesis in a randomised, crossover study in 25 healthy men exposed to ambient and polluted air; 11 of the subjects also performed exercise during exposure sessions. Platelet activation was evaluated by surface expression of CD62P (P-selectin) and CD63 (dense granule glycoprotein) using flow cytometry of labelled platelets. Platelet function was measured using the PFA-100 platelet function analyser and by Multiplate whole blood impedance platelet aggregometry. Acute diesel exhaust exposure had no effect on platelet activation at rest, but exercise in polluted air increased the collagen-induced expression of CD62P and CD63 (both p< 0.05). The increase in the expression of CD62P and CD63 was related to the total amount of PM2.5 inhaled during the exercise sessions (r=+0.58 and +0.60, respectively, both p< 0.05). Platelet aggregation was not impaired after polluted air exposure at rest or during exercise. In conclusion, in healthy subjects, diesel exhaust exposure induces platelet activation as illustrated by a dose-response increase in the release of CD62P and CD63. This platelet priming effect could be a contributor to the triggering of atherothrombotic events related to air pollution exposure.

Does third generation left ventricular assist device alter heart failure-related microvascular dysfunction?

Background Left ventricular assist device (LVAD) is a promising new therapy in patients with advanced heart failure. Previous studies suggested that continuous blood flow impairs endothelial function. Whether the third-generation LVAD (HeartWareR, HeartWare Inc., Framingham, MA, USA) system affects endothelial regulation of microvascular flow, endothelial nitric oxide (NO) bioavailability and endothelial production of vWF is not known.Methods Fifteen LVAD-supported heart failure patients and 13 age/body mass index matched heart failure patients (HF) were included. The microvascular endothelial function of skin vessels was assessed with laser Doppler imager (LDI) using 3 different hyperaemic challenges: acetylcholine (Ach) iontophoresis, sodium nitroprusside (SNP) iontophoresis and local heating to 44°C. NO-mediated vasodilation was further evaluated by comparing heating hyperaemic response in skin area pretreated either by a saline solution (control) or a specific NO-synthase inhibitor (L-N-arginine-methy...