Microvascular endothelial function in obstructive sleep apnea: Impact of continuous positive airway pressure and mandibular advancement

ObjectivesEndothelial dysfunction has been proposed as a potential mechanism implicated in the pathogenesis of cardiovascular complications of obstructive sleep apnea syndrome (OSAS). This study aimed to evaluate the microvascular endothelial function (MVEV) in OSAS and the impact on MVEF of 2 months of treatment with continuous positive airway pressure (CPAP) and mandibular advancement device (MAD). Methods Microvascular reactivity was assessed using laser Doppler flowmetry combined with acetylcholine (Ach) and sodium nitroprusside (SNP) iontophoresis in 24 OSAS patients and 9 control patients. In 12 of the 24 OSAS patients, microvascular reactivity was reassessed after 2 months of CPAP and MAD using a randomized cross-over design. Results Ach-induced vasodilation was significantly lower in OSAS patients than in matched controls and correlated negatively with apnea hypopnea index (r = −0.49, p < 0.025) and nocturnal oxygen desaturations (r = −0.63, p < 0.002). Ach-induced vasodilation increased significantly with both CPAP and MAD. The increase in Ach-induced vasodilation under OSAS treatment correlated with the decrease in nocturnal oxygen desaturations (r = 0.48, p = 0.016). Conclusion Our study shows an impairment of MVEF in OSAS related to OSAS severity. Both CPAP and MAD treatments were associated with an improvement in MVEF that could contribute to improve cardiovascular outcome in OSAS patients

Effect of isoflurane on skin-pressure-induced vasodilation.

Since general anesthesia has been shown to attenuate endothelium-dependent vasodilation, it was of interest to verify whether general anesthesia would modify skin vasodilation in response to local pressure application, which is endothelium dependent. To study the effect of general anesthesia on pressure-induced vasodilation development, we examined the effects of low- and high-dose isoflurane. Skin blood flow was measured by laser Doppler flowmetry during 11.1 Pa s(-1) increases in locally applied pressure in anesthetized rats treated with low or high doses of isoflurane. Following the administration of low doses of isoflurane, skin blood flow increased from baseline, with increasing local pressure application (+37 +/- 10% at 2.0 kPa). The increase in skin blood flow was absent in rats treated with high doses (-20 +/- 5% at 2.0 kPa), even when the anesthesia-induced hypotension was corrected by gelofusine infusion (-20 +/- 10% at 2.0 kPa). Whereas sodium-nitroprusside-induced vasodilation developed following low and high doses of isoflurane, acetylcholine-induced vasodilation was impaired with high doses compared to low doses. These data show that pressure-induced vasodilation is abolished with high doses of anesthetics. It is not the anesthesia-induced hypotension, but the depth of anesthesia, which can lead to the disappearance of pressure-induced vasodilation by an alteration in endothelial function

Effect of head-upright tilt on the dynamic of cerebral autoregulation.

The effect of head-upright tilting on the rate of cerebral autoregulation was studied in 12 healthy volunteers (nine men and three women; age range 20-36 years). The dynamics of cerebral autoregulation was determined from the rate of change in cerebral resistance (RoR) during a drop in arterial blood pressure induced by rapid deflation of a 3-min ischaemic thigh cuff and from the ratio of changes in cerebral blood flow and arterial blood pressure (CAI) during the recovery period after the drop in arterial blood pressure. The test was performed supine and with 40 degrees head-up tilt (40 degrees HUT). Middle cerebral artery mean blood flow velocity was measured by transcranial Doppler simultaneously with peripheral arterial blood pressure using Finapres. The thigh cuff deflation induced a larger drop in arterial pressure during 40 degrees HUT [median -28% (25 percentile -36, 75 percentile -19)] than in the supine position [-16% (-23, -15)] (P < 0.01) and in cerebral resistance [supine: -12% (-15, -6); 40 degrees HUT: -15% (-20, -12); P < 0.05]. There was no significant change in RoR [15% s-1 (12, 15)] and CAI [1.9 (1.5, 3.1)] measured supine and during 40 degrees HUT [RoR: 13% s-1 (12, 15); CAI: 1.3 (0.99, 1.9)]. During the drop in arterial pressure, the relationship between arterial blood pressure and systolic peak-to-peak interval exhibited an hysteresis loop, indicating a cardiopulmonary and/or baroreflex activation that was not observed with cerebral resistance. The rate of autoregulation is an intrinsic property of the cerebral vascular bed and is not affected by the vasodilator state in the range of arterial blood pressure changes induced by the tight cuff method

Axon-reflex cutaneous vasodilatation is impaired in type 2 diabetic patients receiving chronic low-dose aspirin

Low-dose aspirin is largely but non-homogeneously used in primary prevention of cardiovascular complication in type-2 diabetic patients. We hypothesised that low-dose aspirin could interfere with the cutaneous neurovascular responses in type-2 diabetic patients. Galvanic current-induced vasodilatation (CIV) is an original non-noxious integrative model of neurovascular interaction and is impaired under low-dose aspirin in healthy subjects. Twenty type-2 diabetic patients (ten not receiving aspirin: D-NA and ten regularly receiving ≤ 150 mg/day aspirin: D-A), and ten age-, BMI-, and gender-matched non-diabetic control volunteers (MC), underwent macro- and microvascular investigations, including: CIV, acetylcholine (ACh) and sodium nitroprusside (SNP) iontophoresis, post-occlusive hyperemia (POH), neuropathy symptom (NSS) and disability (NDS) scores, and thermal and vibration sensory thresholds. Results are presented as median [25–75 centile] and microvascular results are expressed in multiple from baseline conductance (%Cb). CIV was 554 [349–769] %Cb in MC, 251 [190–355] %Cb in D-NA and 159 [136–202] %Cb in D-A (p < 0.05). No differences were observed between the three groups except for CIV, which is impaired in diabetic patients and further impaired in those regularly receiving low-dose aspirin, while other macrovascular, microvascular and clinical-sensitivity investigations show no significant difference. Potential clinical markers for the impairment of the neurovascular interaction are still required in diabetes. Correlation of the CIV response with the risk of cutaneous complications in diabetic patients remains to be tested

Chronic sciatic nerve injury impairs the local cutaneous neurovascular interaction in rats

Most studies of chronic nerve compression focus on large nerve function in painful conditions, and only few studies have assessed potential changes in the function of small nerve fibers during chronic nerve compression and recovery from compression. Cutaneous pressure-induced vasodilation is a neurovascular phenomenon that relies on small neuropeptidergic fibers controlling the cutaneous microvasculature. We aimed to characterize potential changes in function of these small fibers and/or in cutaneous microvascular function following short-term (1-month) and long-term (6-month) nerve compression and after release of compression (ie, potential recovery of function). A compressive tube was left on one sciatic nerve for 1 or 6 months and then removed for 1-month recovery in Wistar rats. Cutaneous vasodilator responses were measured by laser Doppler flowmetry in hind limb skin innervated by the injured nerve to assess neurovascular function. Nociceptive thermal and low mechanical thresholds were evaluated to assess small and large nerve fiber functions, respectively. Pressure-induced vasodilation was impaired following nerve compression and restored following nerve release; both impairment and restoration were strongly related to duration of compression. Small and large nerve fiber functions were less closely related to duration of compression. Our data therefore suggest that cutaneous pressure-induced vasodilation provides a non-invasive and mechanistic test of neurovascular function that gives direct information regarding extent and severity of damage during chronic nerve compression and recovery, and may ultimately provide a clinically useful tool in the evaluation of nerve injury such as carpal tunnel syndrome

Platelet inhibition by low-dose aspirin but not by clopidogrel reduces the axon-reflex current-induced vasodilation in humans

We previously showed a prolonged inhibition of current-induced vasodilation (CIV) after a single oral high dose of aspirin. In this study, we tested the hypothesis of platelet involvement in CIV. Nine healthy volunteers took 75 mg aspirin/day, 98 mg of clopidogrel bisulfate/day, or placebo for 4 days. CIV was induced by two consecutive 1-min anodal current applications (0.08 mA/cm2) through deionized water with a 10-min interval. CIV was measured with laser Doppler flowmetry and expressed as a percentage of baseline cutaneous vascular conductance: %Cb. In a second experiment in 10 volunteers, aspirin and placebo were given as in experiment 1, but a 26-h delay from the last aspirin intake elapsed before ACh iontophoresis and postocclusive hyperemia were studied in parallel to CIV. In experiment 1, the means ± SE amplitude of CIV was 822 ± 314, 313 ± 144, and 746 ± 397%Cb with placebo, aspirin (P < 0.05 from placebo and clopidogrel), and clopidogrel (NS from placebo), respectively. In experiment 2, CIV impairment with aspirin was confirmed: CIV amplitudes were 300 ± 99, and 916 ± 528%Cb under aspirin and placebo, respectively (P < 0.05), whereas vasodilation to ACh iontophoresis (322 ± 74 and 365 ± 104%Cb) and peak postocclusive hyperemia (491 ± 137 and 661 ± 248%Cb) were not different between aspirin and placebo, respectively. Low-dose aspirin, even 26 h after oral administration, impairs CIV, while ACh-mediated vasodilation and postocclusive hyperemia are preserved. If platelets are involved in the neurovascular mechanism triggered by galvanic current application in humans, it is likely to occur through the cyclooxygenase but not the ADP pathway. a significant increase in skin blood flow (SkBF) has been observed in response to non-noxious galvanic current application in humans. This current-induced vasodilation (CIV) has been described as the result of an axon reflex (3) and disappears in locally anesthetized or chronically capsaicin-treated skin. Then CIV depends on capsaicin-sensitive fibers and is an interesting model of the neurovascular interaction following non-noxious stimulation (11, 16). Prostaglandins are synthesized by cyclooxygenases (COX) and play a key role as mediators in the vascular response observed during CIV. COX are expressed in a large variety of human tissues, including endothelium, smooth muscles, nerves, and platelets (29). We recently reported a long-lasting inhibition of CIV (>5 days) following a single high (1,000 mg) oral dose of aspirin (11, 12, 40), which irreversibly blocks both isoforms of COX (COX-1 and COX-2). COX of neuronal origin does not seem responsible for this long-lasting effect (13). This long-lasting inhibition of CIV is consistent with the time required to resynthesize unblocked platelets after oral single-dose aspirin leading to the hypothesis that platelets participate in the vascular response to CIV. Indeed, a single oral high dose of aspirin irreversibly inactivates the platelet COX pathway for the duration of the life of the platelets (∼10 days) (1, 36). Indomethacin, a nonspecific COX inhibitor devoid of effect on vanilloid receptors and acid-sensing ion channels (41), abolished CIV, confirming that the inhibition of CIV by aspirin likely resulted from its effect on COX (and not on vanilloid receptors or on acid-sensing ion channels). Furthermore, the specific COX-2 inhibitor, celecoxib, failed to affect CIV, suggesting that CIV is mainly a COX-1-dependent phenomenon (39). Together, with the long-lasting effect of a single oral high dose of aspirin, the fact that COX-1 isoform participates in CIV raises the question of a possible platelet involvement in the axon-reflex CIV. Although there is, to date, no in vivo proof of a direct platelet-mediated vasodilation in humans, the hypothesis of a platelet involvement in axon-reflex vasodilation and other vasodilator mechanisms has previously been explored in vitro (15, 23, 31). Those authors provided evidence for a direct in vitro platelet-mediated endothelium-dependent vasodilation in preconstricted arteries but mainly by the ADP pathway. To investigate whether the platelet COX and ADP pathways are involved in vivo in CIV, we inhibited platelet function by aspirin (a platelet COX inhibitor) or clopidogrel (a platelet ADP-receptor inhibitor). Our hypothesis was that if platelets are involved, both clopidogrel and low-dose aspirin would impair the current-induced vasodilation

Low skin temperature impairs the cutaneous vasodilator response to local progressive pressure strain.

A pressure-induced vasodilation (PIV) was recently reported as a putative protective response in human skin. Therefore, we examined the influence of skin temperatures on cutaneous blood flow responses to local progressive pressure strain. Ten healthy volunteers were studied at different ambient temperatures leading to low (29.0 +/- 0.3 degrees C), intermediate (32.6 +/- 0.1 degrees C), high (33.9 +/- 0.1 degrees C) and very high (36.0 +/- 0.1 degrees C) skin temperatures. We measured cutaneous blood flow using laser Doppler flowmetry on the foot in response to a local progressive pressure increase of 5.0 mm Hg min(-1). Progressive pressure strain led to an almost linear cutaneous laser Doppler flow decrease at both low and intermediate skin temperatures (-40.1 +/- 6.6% and -31.2 +/- 6.5% from baseline at 30 +/- 1.25 mm Hg), whereas at both high and very high skin temperatures, subjects responded with a transient cutaneous vasodilation (+33.6 +/- 10.6% and +50.6 +/- 15.4% from baseline at 30 +/- 1.25 mm Hg). These findings suggest that high skin temperatures are required for the PIV to develop

Variability and short-term determinants of walking capacity in patients with intermittent claudication

OBJECTIVE: Global positioning system (GPS) recordings can provide valid information on walking capacity in patients with peripheral arterial disease (PAD) and intermittent claudication (IC) during community-based outdoor walking. This study used GPS to determine the variability of the free-living walking distance between two stops (WDBS), induced by lower-limb pain, which may exist within a single stroll in PAD patients with IC and the potential associated parameters obtained from GPS analysis.METHODS: This cross-sectional study of 57 PAD patients with IC was conducted in a university hospital. The intervention was a 1-hour free-living walking in a flat public park with GPS recording at 0.5 Hz. GPS-computed parameters for each patient were WDBS, previous stop duration (PSD), cumulated time from the beginning of the stroll, and average walking speed for each walking bout. The coefficient of variation of each parameter was calculated for patients with the number of walking bouts (N(WB)) >or=5 during their stroll. A multivariate analysis was performed to correlate WDBS with the other parameters. RESULTS: Mean (SD) maximal individual WDBS was 1905 (1189) vs 550 (621) meters for patients with N(WB) <5 vs N(WB) >or= 5, respectively (P < .001). In the 36 patients with N(WB) >or= 5, the coefficient of variation for individual WDBS was 43%. Only PSD and cumulated time were statistically associated with WDBS in 16 and 5 patients, respectively. CONCLUSIONS: A wide short-term variability of WDBS exists and likely contributes to the difficulties experienced by patients with IC to estimate their maximal walking distance at leisurely pace. Incomplete recovery from a preceding walk, as estimated through PSD, seems to dominantly account for the WDBS in patients with IC