Neurovascular Response to Pressure in Patients With Diabetic Foot Ulcer.

Diabetic foot ulcer (DFU) is a problem worldwide, and prevention is crucial. We hypothesized that the inability of the skin to respond to pressure is involved in DFU pathogenesis and could be an important predictive factor to take into account. We included 29 patients with DFU and 30 patients with type 2 diabetes without DFU. Neuropathy and skin blood flow at rest were assessed in response to acetylcholine, sodium nitroprusside, local heating (42°C), and to nonnoxious locally applied pressure. Results were compared with those obtained from 10 healthy age-matched control subjects. Vasodilatation in response to pressure was significantly impaired in both groups with diabetes compared with healthy subjects. The vasodilator capacity to pressure was significantly lower in patients with DFU compared with those without DFU, despite the absence of significant difference in cutaneous pressure perception threshold and vascular reactivity to acetylcholine, sodium nitroprusside, and heat. This pronounced alteration of neurovascular response to pressure in patients with DFU is a good marker of skin vulnerability and could be used to better predict individuals at risk.

VEGF-A promotes both pro-angiogenic and neurotrophic capacities for nerve recovery after compressive neuropathy in rats.

Nerve recovery following injury is usually incomplete, leaving functional deficits. Our aim was to investigate the neural changes in pro-angiogenic, pro-inflammatory and apoptotic factors during and after chronic nerve compression (CNC). Nerve function was impaired after CNC and was progressively restored after nerve decompression, while nerve blood flow was elevated. While the expression of the pro-inflammatory and pro-angiogenic cytokines IL-6, TNF-α and VEGF-A was high during and after CNC, we observed that inhibition of VEGF-A receptors strongly counteracted the angiogenic response induced by the ex vivo CNC. Activation of the pro-survival transcription factor nuclear factor-kappa B (NF-κB) increased during CNC, returning to control levels after nerve decompression. After nerve decompression, the downregulation of Mdm2 correlated well with an increased expression of pro-apoptotic transcription factor p53. All together, we bring novel evidence that CNC activates transcription factors such as NF-κB and p53, which are key effectors of the cellular stress response, suggesting a neuroprotective process associated with an increased VEGF-A-mediated neurotrophic effect. Our results highlight the role of pro-angiogenic and pro-inflammatory cytokines during CNC that are reinforced by increasing neurotrophic capacity during recovery to promote nerve regeneration.

Effect of ageing on tactile transduction processes.

With advancing age, a decline in the main sensory modalities including touch sensation and perception is well reported to occur. This review mainly outlines the peripheral components of touch perception highlighting ageing influences on morphological and functional features of cutaneous mechanical transducers and mechanosensitive ion channels, sensory innervation, neurotransmitters and even vascular system required to ensure efferent function of the afferent nerve fibres in the skin. This, in conjunction with effect of ageing on the skin per se and central nervous system, could explain the tactile deficit seen among the ageing population. We also discuss appropriate tools and experimental models available to study the age-related tactile decline.

Asic3 is a neuronal mechanosensor for pressure-induced vasodilation that protects against pressure ulcers.

Pressure-induced vasodilation (PIV) delays the decrease in cutaneous blood flow produced by local application of low pressure to the skin, a physiologically appropriate adjustment of local vasomotor function. Individuals without a normal PIV response have a high risk of ulceration. Here we demonstrate that acid-sensing ion channel 3 (Asic3) is an essential neuronal sensor for the vasodilation response to direct pressure in both humans and rodents and for protecting against pressure ulcers in mice.

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.

What can current stimulation tell us about the vascular function of endogenous prostacyclin in healthy rat skin in vivo?

In endothelial function, prostacyclin (PGI(2)) is as important as nitric oxide (NO); however, no test assesses specifically the vascular function of endogenous PGI(2). We hypothesized that PGI(2) has a dominant role in cathodal current-induced vasodilation (CIV) described in human skin. We thus aimed to study, in physiological conditions, the PGI(2) involvement in cathodal CIV in rats in order to use pharmacological blockers that could not be used in humans. CIV was reduced by cyclooxygenase (COX)-1 and PGI(2) synthase (PGIS) and PGI(2) receptor (IP) blockers, but was unchanged by COX-2 and NO synthase (NOS) blockers. The level of 6-ketoPGF(1)(α) present in skin biopsies, measured as endogenous PGI(2), was increased by cathodal current stimulation, except under COX-1 and PGIS inhibition. This study provides evidence that cathodal CIV mainly relies on the release of PGI(2) endogenously produced through the COX-1/PGIS pathway, and then acts on IP receptors to relax the cutaneous microvessels in healthy rats. In contrast, neither COX-2 nor NOS is involved in CIV and the endogenous PGI(2) release by current stimulation. This finding shows that cathodal current stimulation could be a valuable method to assess the vascular function of endogenous PGI(2) in healthy skin.

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.

Aging-associated sensory neuropathy alters pressure-induced vasodilation in humans.

Healthy skin is protected from pressure-induced ischemic damage because of the presence of pressure-induced vasodilation (PIV). PIV relies on small sensory nerve fibers and endothelial function. Since aging alters both nervous and vascular functions, we hypothesized that PIV is altered with aging. We compared PIV in non-neuropathic and neuropathic older subjects (60-75 years) with that of young subjects (20-35 years). Laser Doppler flowmetry was used to evaluate the cutaneous responses to local pressure application, acetylcholine, and local heating. Quantitative sensory tests were used to evaluate sensory-nerve-fiber function. The non-neuropathic older subjects had an impaired PIV (12+/-7% increase in blood flow with pressure) compared with young subjects (62+/-4%, P<0.001). In the presence of peripheral neuropathy, the older subjects were totally deprived of PIV, leading to early pressure-induced cutaneous ischemia (-31+/-10%, P<0.001). This inability of the skin to adapt to localized pressure in older subjects is related to the severity of the sensory-fiber dysfunction rather than to endothelial dysfunction, which was comparable between the non-neuropathic (141+/-19% increased blood flow with acetylcholine, P<0.05) and neuropathic older subjects (145+/-28% increase, P<0.05) compared with young subjects (234+/-25% increase).

A normal penile pressure cannot rule out the presence of lesions on the arteries supplying the hypogastric circulation in patients with arterial claudication.

Proximal claudication remains a difficult diagnosis. The ankle to brachial index may be insensitive in the case of isolated hypogastric lesions. Penile pressure represents an alternative method for proximal arteries. Surprisingly, the accuracy of penile pressure measurement in detecting lesions on the arteries supplying pelvic circulation in patients suffering claudication has rarely been studied. We aimed to evaluate the diagnostic accuracy of the penile brachial index < 0.60 (penile over brachial systolic pressure ratio) to non-invasively investigate arteriographic lesions on arteries supplying the hypogastric circulation in 88 male patients referred for Fontaine stage II. The receiver operating characteristic (ROC) curve was used to define the diagnostic performance of the penile brachial index and search for a specific cut-off point in this population. Accuracy was 69.3% (95% confidence interval: 58.6-78.7) for the detection of an arterial stenosis or occlusion on at least one side. The penile brachial index

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

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

OBJECTIVES: Endothelial 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.

Functional assessment at the buttock level of the effect of aortobifemoral bypass surgery.

BACKGROUND: Little is known about the prevalence of proximal (hip, buttock, lower back) claudication after aortobifemoral bypass (AF2B) grafting and its hemodynamic effects at the buttock level. METHODS: Forty-eight patients performed a treadmill test before and within 6 months after AF2B. The San Diego Claudication Questionnaire and the chest-corrected decrease from rest of transcutaneous oxygen pressure on buttocks were used to study exercise-induced proximal claudication and regional pelvic blood flow impairment. A decrease from rest of transcutaneous oxygen pressure value <-15 mm Hg was used to indicate regional blood flow impairment (RBFI). RESULTS: Patients had the following characteristics: 39 were men and 9 were women, 60 +/- 9 years, lowest ankle-to-brachial index (ABI) of 0.55 +/- 0.18 and maximal walking distance (MWD) on treadmill of 188 +/- 192 m at inclusion. ABI and MWD were significantly improved after surgery at 0.83 +/- 0.19 and 518 +/- 359 m (P < 0.0001). Unilateral or bilateral RBFI at the buttocks was found in 39 versus 29 patients before and after AF2B, respectively. Proximal claudication with underlying RBFI on one or both sides on treadmill were observed in 29 patients before AF2B, and in 9 of 26 (41%) versus 6 of 22 (23%) patients in end-to-end versus end-to-side proximal aorto-graft anastomosis of the AF2B, respectively (P < 0.05). CONCLUSION: A significant increase in MWD and ABI, but little improvement of proximal perfusion is observed after surgery, a finding that is expected from the absence of hypogastric artery revascularization. The prevalence of proximal claudication and proximal blood flow impairment is higher in case of end-to-end when compared with end-to-side proximal aorto-graft anastomosis, confirming the role of collaterals such as lumbar arteries in the buttock circulation during exercise in patients suffering from peripheral arterial disease. Proximal claudication on treadmill early after surgery affects almost one third of the patients and must not be underestimated among patients receiving AF2B. Attempts at hypogastric artery revascularization, if possible, might be preferable to decrease the risk of proximal claudication after AF2B.

Measurement of walking distance and speed in patients with peripheral arterial disease: a novel method using a global positioning system.

BACKGROUND: The maximal walking distance (MWD) performed on a treadmill test remains the "gold standard" in estimating the walking capacity of patients who have peripheral arterial disease with intermittent claudication, although treadmills are not accessible to most physicians. We hypothesized that global positioning system (GPS) recordings could monitor community-based outdoor walking and provide valid information on walking capacity in patients with peripheral arterial disease. METHODS AND RESULTS: We studied 24 patients (6 women) with arterial claudication (median [25th to 75th percentile] values: 57 years old [48 to 67 years], 169 cm tall [164 to 172 cm], weight 81 kg [71 to 86 kg], and ankle-brachial index 0.64 [0.56 to 0.74]). MWD on the treadmill was 184 m (144 to 246 m), which was compared with the results of self-reported MWD, the distance score from the Walking Impairment Questionnaire, MWD observed during a 6-minute walking test, and MWD measured over a GPS-recorded unconstrained outdoor walk in a public park. Self-reported MWD, Walking Impairment Questionnaire distance score, 6-minute walking test score, and GPS-measured MWD were 300 m (163 to 500 m), 28% (15% to 47%), 405 m (338 to 441 m), and 609 m (283 to 1287 m), respectively. The best correlation with MWD on the treadmill test was obtained with the MWD measured by the GPS (Spearman r=0.81, P<0.001). CONCLUSIONS: Outdoor walking capacity measured by a low-cost GPS is a potentially innovative way to study the walking capacity of patients with peripheral arterial disease. It opens new perspectives in the study of walking capacity for vascular patients with claudication under free-living conditions or for physicians who do not have a treadmill.

Endothelium-derived hyperpolarizing factor as an in vivo back-up mechanism in the cutaneous microcirculation in old mice.

There is now strong evidence that an endothelium-derived hyperpolarizing factor (EDHF), other than nitric oxide (NO) or prostaglandin (PG), exists for dilating arteries and arterioles. In vitro studies on isolated vessels pointed out a role for EDHF as a back-up mechanism when the NO pathway is impaired, but there was a lack of in vivo studies showing a functional role for EDHF. Ageing has pronounced effects on vascular function and particularly on endothelium-dependent relaxation, providing a novel situation in which to assess the contributions of EDHF. The purpose of the present study was thus to determine if, in vivo, there was a functional role for EDHF as a back-up mechanism in the cutaneous microcirculation in the ageing process. We investigated in vivo the contribution of each endothelial factor (NO, PG and EDHF) in the cutaneous vasodilatation induced by iontophoretic delivery of acetylcholine and local pressure application in young adult (6-7 months) and old (22-25 months) mice, using pharmacological inhibitors. The cutaneous vasodilator responses induced by acetylcholine and local pressure application were dependent upon NO and PG pathways in young adult mice, whereas they were EDHF-dependent in old mice. EDHF appears to serve as a back-up mechanism when ageing reaches pathological states in terms of the ability for NO and PG to relax cutaneous microvessels, allowing for persistent cutaneous vasodilatator responses in old mice. However, as a back-up mechanism, EDHF did not completely restore cutaneous vasodilatation, since endothelial responses were reduced in old mice compared to young adult mice.

Study of human outdoor walking with a low-cost GPS and simple spreadsheet analysis.

PURPOSE: To determine whether a low-cost, commercially available global positioning system (GPS) can be used to study outdoor walking of healthy subjects, allowing the detection of walking and resting (nonwalking) periods and the accurate estimation of speed and distance of each walking periods. METHODS: The same EGNOS-enabled GPS receiver was used for all experiments. In experiment 1, various signal-processing methodologies were tested for the detection of both walking and resting bouts from a prescribed walking protocol (PWP) that was performed 21 times by six healthy subjects on an outdoor athletic track. In experiment 2, the accuracies of these processing methodologies were then tested through a blinded analysis of different PWP for 10 other healthy subjects in a designated public park. In experiment 3, speed and distance calculated by the GPS receiver during series of 100-400 m on an outdoor athletic track were compared with actual speed and distance. RESULTS: Raw data were inaccurate, but the combination of a low-pass filter, an adapted high-pass filter, and artifact processing enabled one to detect walking and resting bouts with an accuracy of 89.8% (95% CI, 84.4-93.4). A manual post-processing methodology, used to complete previous automatic processing results, provided the highest concordance with the PWP, reaching an accuracy of 97.1% (95% CI, 93.5-98.8). There was an excellent relationship both between actual and processed distances (R2=1.000) and between actual and processed speeds (R2=0.947). CONCLUSION: Low-cost, commercially available GPS may be accurate in studying outdoor walking, provided that simple data processing is applied. Future validation in diseased subjects could allow for the study of free-living walking capacity, such as maximal walking distance in vascular patients.

Altered acetylcholine, bradykinin and cutaneous pressure-induced vasodilation in mice lacking the TREK1 potassium channel: the endothelial link.

The TWIK related K+ channel TREK1 is an important member of the class of two-pore-domain K+ channels. It is a background K+ channel and is regulated by hormones, neurotransmitters, intracellular pH and mechanical stretch. This work shows that TREK1 is present both in mesenteric resistance arteries and in skin microvessels. It is particularly well expressed in endothelial cells. Deletion of TREK1 in mice leads to an important alteration in vasodilation of mesenteric arteries induced by acetylcholine and bradykinin. Iontophoretic delivery of acetylcholine and bradykinin in the skin of TREK1+/+ and TREK1-/- mice also shows the important role of TREK1 in cutaneous endothelium-dependent vasodilation. The vasodilator response to local pressure application is also markedly decreased in TREK1-/- mice, mimicking the decreased response to pressure observed in diabetes. Deletion of TREK1 is associated with a marked alteration in the efficacy of the G-protein-coupled receptor-associated cascade producing NO that leads to major endothelial dysfunction.

High prevalence of proximal claudication among patients with patent aortobifemoral bypasses.

BACKGROUND: Proximal (ie, buttock, hip) claudication can result from impaired perfusion in the hypogastric area after aortobifemoral bypass (ABF) despite normal femorodistal blood flow provided by the patent bypass. The proportion of patients that experience proximal claudication after ABF is unknown, and arguments for the vascular origin of symptoms specifically at the proximal level have never been reported. METHODS: This was a prospective study set in an institutional practice of ambulatory patients referred for a systematic survey of their previous ABF bypass. Among the 131 eligible patients, 10 refused to participate and 16 were unable to walk on a treadmill. The 105 studied patients (94 men, 11 women) were a mean age of 63 +/- 10 years, and the median delay from surgery was 2 years (range, 4 months to 26 years). We used a modified version of the San Diego Claudication Questionnaire administered both at rest before the treadmill study and again after the treadmill test. Transcutaneous oxygen pressure (TcPO2) at the buttock level was used to evaluate blood flow impairment during exercise at the proximal level, with blood flow impairment defined as buttock minus chest TcPO2 decrease in excess of -15 mm Hg. RESULTS: Thirty patients reported proximal exercise-related pain consistent with vascular criteria by history before exercise. However, 59 patients (56%) reported symptoms compatible with proximal claudication, and TcPO2 values were abnormal on one or both sides in 52. The persistence of at least one (prograde or retrograde) pathway to the hypogastric circulation, determined by review of operative details from the aortobifemoral bypass and angiography, did not significantly decrease the proportion of patients reporting proximal claudication by history (26%) or on treadmill (55%) compared with those with bilateral hypogastric occlusion (33% by history, P = .51 compared with at least one prograde hypogastric pathway and 61% based on treadmill test, P = .65 compared with at least one prograde hypogastric pathway). CONCLUSION: The present study shows that (1) the proportion of ABF patients with a median bypass age of 2 years that report proximal claudication is high (28%), (2) this proportion is significantly higher when claudication is detected by treadmill exercise tests, (3) a vascular origin (or at least contribution) is likely 88% of the proximal symptoms observed on treadmill, (4) the presence of proximal claudication with associated abnormal TcPO(2) results increases the risk of walking impairment in affected patients, and (5) preservation of at least one internal iliac artery to allow prograde or retrograde flow to the hypogastric vascular bed does not decrease the risk of proximal claudication after ABF surgery. A vascular origin of (or at least contribution to) most of the proximal exercise-related symptoms should always be discussed in patients with patent ABF bypass.