Minoxidil versus placebo in the treatment of arterial wall hypertrophy in children with Williams Beuren Syndrome: a randomized controlled trial.

BACKGROUND: Insufficient elastin synthesis leads to vascular complications and arterial hypertension in children with Williams-Beuren syndrome. Restoring sufficient quantity of elastin should then result in prevention or inhibition of vascular malformations and improvement in arterial blood pressure. METHODS: The aim of this study was to assess the efficacy and safety of minoxidil on Intima Media Thickness (IMT) on the right common carotid artery after twelve-month treatment in patient with Williams-Beuren syndrome. We performed a randomized placebo controlled double blind trial. All participants were treated for 12 months and followed for 18 months. The principal outcome was assessed by an independent adjudication committee blinded to the allocated treatment groups. RESULTS: The principal outcome was available for 9 patients in the placebo group and 8 patients in the minoxidil group. After 12-month treatment, the IMT in the minoxidil group increased by 0.03 mm (95% CI -0.002, 0.06) compared with 0.01 mm (95%CI - 0.02, 0.04 mm) in the placebo group (p = 0.4). Two serious adverse events unrelated to the treatment occurred, one in the minoxidil and 1 in the placebo group. After 18 months, the IMT increased by 0.07 mm (95% CI 0.04, 0.10 mm) in the minoxidil compared with 0.01 mm (95% CI -0.02, 0.04 mm) in the placebo group (p = 0.008). CONCLUSION: Our results suggest a slight increase after 12 and 18-month follow-up in IMT. More understanding of the biological changes induced by minoxidil should better explain its potential role on elastogenesis in Williams-Beuren syndrome. TRIALS REGISTRATION: US National Institutes of Health Clinical Trial Register (NCT00876200). Registered 3 April 2009 (retrospectively registered).

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.

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.

Past, present and future of arterial endofibrosis in athletes: a point of view.

Exercise-induced arterial endofibrosis (EIAE) is now a 20-year-old concept. Initially observed in highly trained cyclists, it has been found in many other male and female endurance athletes. Most stenoses are located on the first centimetres of the external iliac artery but other localisation may be found. The disease is defined by specific histological findings showing fibrosis of the intimal and medial wall of the artery. Ankle pressure measurement plays a key role in the diagnosis of EIAE provided that the exercise tests reproduce symptoms and are performed with the subject being highly trained, and that pressure measurements are performed early following exercise. Various cut-off values have been proposed in the literature. Magnetic resonance imaging or arteriography or ultrasound imaging should be performed by trained operators only. Surgical 'endofibrosectomy' is preferable in young cyclists generally associated with a saphenous enlargement patch. We do not recommend angioplasty. Athletes are generally allowed to return to competition within 3-4 months following surgery. Many unanswered questions remain, specifically about the pathophysiology of this disease. Mechanical and pressure strain play a central role in the development of EIEA, but nutritional and haemorrheological factors, hormonal changes and a genetic predisposition are likely to contribute. New techniques could facilitate the diagnosis of EIAE.

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.

The physiological response of ankle systolic blood pressure and ankle to brachial index after maximal exercise in athletes is dependent on age.

The development of sports activities in the over forties has increased the number of middle-aged patients performing heavy-load exercise. The normal response of ankle systolic blood pressure (ASBP) and ankle to brachial index (ABI) to intense exercise is known in young athletes, but little is known for other age groups. Three groups of 21 athletes: <20 (G1), 20-40 (G2), and >40 (G3) years old, respectively, were studied. ASBP and brachial systolic blood pressure (BSBP) were measured simultaneously before and after an incremental maximal cycle ergometer test. Rest ABI was higher in G3 compared to G1 (P<0.001: ANOVA, Bonferroni). Compared to respective resting values, BSBP, at 1 min of recovery, was increased for the three groups of age (P<0.001) whereas ASBP was unchanged for G1 and G2, and significantly increased for G3 (P<0.001). ASBP was significantly higher in G3 than in G1 and G2, ABI was lower in G1 and G2 compared to G3: 0.70+/-0.11, 0.76+/-0.09 and 0.91+/-0.14, respectively. This age-related ABI increase is consistent with the impaired vasodilator capacity observed in aging normal subjects but not with the decrease observed in ABI resting values in epidemiological studies. ABI is higher in older than in younger athletes at rest and after exercise. In aging athletes, aiming to detect mild to moderate arterial lesions, it is likely that normal limits defined in young athletes are not valid.

Early vasodilator response to anodal current application in human is not impaired by cyclooxygenase-2 blockade.

It is generally acknowledged that cutaneous vasodilatation in response to monopolar galvanic current application would result from an axon reflex in primary afferent fibers and the neurogenic inflammation resulting from neuropeptide release. Previous studies suggested participation of prostaglandin (PG) in anodal current-induced cutaneous vasodilatation. Thus the inducible cyclooxygenase (COX) isoform (COX-2), assumed to play a key role in inflammation, should be involved in the synthesis of the PG that is released. Skin blood flow (SkBF) variations induced by 5 min of 0.1-mA monopolar anodal current application were evaluated with laser-Doppler flowmetry on the forearm of healthy volunteers treated with indomethacin (COX-1 and COX-2 inhibitor), celecoxib (COX-2 inhibitor), or placebo. SkBF was indexed as cutaneous vascular conductance (CVC), expressed as percentage of heat-induced maximal CVC (%MVC). Urinalyses were performed to test celecoxib treatment efficiency. No difference was found in CVC values at rest: 14.3 +/- 4.0, 11.9 +/- 3.2, and 10.9 +/- 2.0% MVC after indomethacin, celecoxib, and placebo treatment, respectively. At 10 min after the onset of anodal current application, CVC values were 22.2 +/- 4.9% MVC (not significantly different from rest) with indomethacin, 85.7 +/- 15.3% MVC (P < 0.001 vs. rest) with celecoxib, and 70.4 +/- 13.1% MVC (P < 0.001 vs. rest) with placebo. Celecoxib significantly depressed the urinary prostacyclin metabolite 6-keto-PGF(1alpha) (P < 0.05 vs. placebo). Indomethacin, but not celecoxib, significantly inhibited the anodal current-induced vasodilatation. Thus, although they are assumed to result from an axon reflex in primary afferent fibers and neurogenic inflammation, these results suggest that the early anodal current-induced vasodilatation is mainly dependent on COX-1-induced PG synthesis.

Near-infrared spectroscopy and transcutaneous oxygen pressure during exercise to detect arterial ischemia at the buttock level: comparison with arteriography.

BACKGROUND: Noninvasive tests are required to detect (in both male and female subjects and side by side) arteries toward the hypogastric circulation that are likely to present significant lesions as a cause of buttock claudication. METHODS: We compared the accuracy of near-infrared spectroscopy (NIRS) and transcutaneous oxygen pressure (TCP o 2 ) on both buttocks during walking tests to detect lesions on the arteries toward the hypogastric circulation. NIRS was considered abnormal if recovery time to pre-exercise values was greater than 240 seconds for tissue oxygen saturation (absent data being coded 0), and TCP o 2 was coded abnormal if the minimal value of buttock changes minus chest changes was lower than -15 mm Hg. The study was conducted in a university hospital; there were 30 ambulatory patients with stage 2 claudication of the Fontaine classification. RESULTS: Angiography showed 36 abnormal (stenosis > 75%) and 24 normal arterial axes toward the buttocks circulation. NIRS and TCP o 2 provided respectively 55% (range, 41.6% to 67.9%) and 82% (range, 69.6% to 90.5%) accuracy (95% confidence interval) to predict the presence of arteriographically proven lesions; P < .05. CONCLUSIONS: Using available cut-off points proposed in the literature, NIRS showed a lower diagnostic accuracy than TCP o 2 for the prediction of lesions on the arterial tree to the hypogastric circulation. NIRS is a recent technique as compared with TCP o 2 , and its diagnostic accuracy might improve in the future. Currently, one should carefully weigh the advantages and limits of NIRS and TCP o 2 when a choice is to be made between them to monitor exercise-induced changes resulting from lower limb arterial disease at the proximal level.

Pain description in patients with isolated proximal (without distal) exercise-related lower limb arterial ischemia.

Among the last 250 claudicants referred to the laboratory for transcutaneous oxygen pressure recording at exercise, we analyzed the symptoms reported by the 36 patients who showed isolated proximal (without distal) ischemia. Among the symptomatic proximal sites cited by these patients, the hip and thigh represent 60%, whereas the buttock is cited in fewer than 25% of cases. Buttock symptoms are reported in only 31% of symptomatic patients. 'Buttock' claudication is probably not the dominant symptom in isolated proximal vascular ischemia. Assessing proximal lower limb ischemia through the sole detection of 'buttock pain' could contribute to the underestimation of proximal vascular ischemia.