Pain-free Walking Time Research Articles

Purified CD34+ Cells Transplantation in Patients with Angiitis-Induced Chronic Limb-Threatening Ischemia: A Single-Center Retrospective Study over a 10-Year Period

Angiitis-induced chronic limb-threatening ischemia (AICLTI) is defined as chronic limb-threatening ischemia (CLTI) caused by thromboangiitis obliterans (TAO) or other arteritis-related autoimmunological diseases. In the current study, we aimed to report the 10-year outcomes of AICLTI patients who underwent purified CD34+ cells (PCCs) transplantation. AICLTI patients who underwent PCCs transplantation at our center from May 2009 to September 2011 were retrospectively enrolled. The main outcome was major amputation-free survival (MAFS); other outcomes included Rutherford classification, intolerable pain-free walking time (IPFWT), Wong-Baker Faces Pain Rating Scale (WBFPS), recurrence, new lesions, quality of life (QoL) and patients' posttransplantation work conditions. Twenty-four patients were enrolled with a mean age of 41.5±7.8 years. Three underwent major amputation during the follow-up, and the 10-year MAFS was 87.5%. Eight were observed to have recurrence, and 2 had new lesions; the 10-year recurrence-free rate was 66.1%. All patients were unable to work at admission, 17 (70.8%) patients were reemployed after transplantation. The current study further demonstrated satisfactory long-term efficacy of PCCs transplantation, with a 10-year MAFS of 87.5%. However, the 10-year recurrence-free rate of 66.1% suggested that strict and regular long-term follow-up is necessary.

Clinical evolution of patients with lower extremity peripheral artery disease during the COVID-19 pandemic (the COVID-PAD study).

Background: The COVID-19 pandemic has led to significant disruptions in chronic disease care and forced people to stay at home. The effects of such issues on outpatients with lower extremity peripheral artery disease (PAD) remain unknown. Patients and methods: Single-centre, retrospective-prospective study conducted in a Swiss University Hospital. Patients with PAD were included between May 1 and July 31, 2020, with a follow-up visit at 12 months. Upon both visits, the Leriche-Fontaine PAD stage was recorded, and study participants underwent ankle-brachial index (ABI) calculation to assess limb perfusion. Functional capacities were assessed through the 6-minute walking and treadmill tests. Major adverse cardiovascular (MACE) and limb events (MALE) were recorded. Data collected during the pandemic were compared with the pre-pandemic period (January 1, 2019-April 30, 2020). Results: Overall, 259 patients were included. Mean age was 69 years and male sex was prevalent (69.1%). Odds of experiencing a degradation in PAD stage were lower during the pandemic than before (odds ratio [OR]: 0.43; 95% confidence interval [CI]: 0.21-0.87; p = 0.018). No significant difference was found between periods in terms of ABI trends. Both pain-free walking time at treadmill test (p = 0.003) and maximal pain intensity at 6-minute walking test (p = 0.001) significantly improved during the pandemic. Compared with the pre-pandemic period, during the pandemic patients were hospitalized less frequently (p = 0.028) and were less likely to undergo elective limb revascularization (p<0.001). No significant difference was found between periods in terms of MALE (p = 0.311), whereas non-fatal strokes were less frequently reported during the pandemic (p = 0.043). Conclusion: In a cohort of outpatients with PAD, we found no evidence of clinical deterioration during the pandemic compared with the pre-pandemic period, though rates of adverse events were nonnegligible in both periods. In case of future pandemics, patients with PAD should be encouraged to maintain an active lifestyle while being closely monitored to avoid clinical worsening.

Effects of additional exercise therapy after a successful vascular intervention for people with symptomatic peripheral arterial disease.

Effects of additional exercise therapy after a successful vascular intervention for people with symptomatic peripheral arterial disease.

Wharton's jelly mesenchymal stem cells transplantation for critical limb ischemia in patients with type 2 diabetes mellitus: a preliminary report of phase I clinical trial.

Peripheral artery disease (PAD) affects more than 230 million people worldwide, with approximately 11% of patients presenting with advanced-stage PAD or critical limb ischemia (CLI). To avoid or delay amputation, particularly in no-option CLI patients with infeasible or ineffective revascularization, new treatment strategies such as regenerative therapies should be developed. Mesenchymal stem cells (MSCs) are the most popular cell source in regenerative therapies. They possess significant characteristics such as angiogenic, anti-inflammatory, and immunomodulatory activities, which encourage their application in different diseases. This phase I clinical trial reports the safety, feasibility, and probable efficacy of the intramuscular administration of allogeneic Wharton's jelly-derived MSCs (WJ-MSCs) in type 2 diabetes patients with CLI. Out of six screened patients with CLI, five patients were administered WJ-MSCs into the gastrocnemius, soleus, and the proximal part of the tibialis anterior muscles of the ischemic lower limb. The safety of WJ-MSCs injection was considered a primary outcome. Secondary endpoints included wound healing, the presence of pulse at the disease site, the absence of amputation, and improvement in visual analogue scale (VAS), pain-free walking time, and foot and ankle disability index (FADI). No patient experienced adverse events and foot or even toe amputation during the 6-month follow-up. Six months after the intervention, there were a significantly lower VAS score and significantly higher pain-free walking time and FADI score than the baseline, but no statistically significant difference was seen between other time points. In conclusion, allogeneic WJ-MSC transplantation in patients with CLI seems to be safe and effective.

IMMEDIATE EFFECT OF THREE METHODS OF NEURODYNAMIC TISSUE MOBILIZATION EXERCISES ON THE WALKING CAPACITY AMONG PATIENTS HAVING NEUROGENIC CLAUDICATION

Purpose: Neurogenic claudication presents itself as leg pain, paresthesia or cramp reproduced by walking and reduced by rest. It occurs more commonly in spinal canal Stenosis and the surgical decompression of the spine in this condition is rarely required. Nerve tissue may develop dynamic dysfunction such as adhesion and neural fibrosis can impair nerve mobility. Neurodynamic mobilization methods may enhance the neural tissue mobility and enhance physical function. The aim of this study was to explore the role of neural mobilization on the pain free walking distance (PFWD) and walking time among cases of spinal canal Stenosis presenting with neurogenic claudication. Methods: Forty eight patients diagnosed with neurogenic claudication were randomly and equally divided into any of the four groups: the “tensioner neural mobilization”; the “one ended slider neural mobilization” group; the “two ended slider neural mobilization” group; and the placebo group. The distance walked before pain onset and this pain-free walking time was recorded immediately before and after the neural mobilization intervention as per group’s protocol. Result: The “two ended slider method” of neural mobilization was more superior to the “one ended slider” or the “tensioner method” for improving walking capacity. Neither “single ended” slider neural mobilization nor placebo intervention caused any statistically significant improvement in the walking capacity among patients of neurogenic claudication. Conclusion: The “double slider method” of neural mobilization is most appropriate followed by “slider method” of neural mobilization and the “single ended slider method” for enhancing the walking distance and walking time among patients suffering from neurogenic claudication.

The addition of evolocumab to maximal tolerated statin therapy improves walking performance in patients with peripheral arterial disease and intermittent claudication (Evol-PAD study)

ObjectiveTo test the hypothesis that in patients with peripheral arterial disease (PAD) and claudication, treated with maximal tolerated statin therapy, the addition of a monthly subcutaneous injection of evolocumab for 6 months improves treadmill walking performance. BackgroundLipid lowering therapy improves walking parameters in patients with PAD and claudication. Evolocumab decreases cardiac and limb adverse events in patients with PAD; however, the effect of evolocumab on walking performance is not known. MethodsWe performed a double-blind, randomized, placebo-controlled study to compare maximal walking time (MWT) and pain free walking time (PFWT) in patients with PAD and claudication treated with monthly subcutaneous injections of evolocumab 420 mg (n = 35) or placebo (n = 35). We also performed measurements of lower limb perfusion, brachial flow mediated dilatation (FMD), carotid intima media thickness (IMT), and serum biomarkers of PAD disease severity. ResultsAfter six-months of treatment with evolocumab MWT increased by 37.7 % (87.5 ± 24 s) compared to 1.4 % (−21.7 ± 22.9 s) in the placebo group, p = 0.01. PFWT increased by 55.3 % (67.3 ± 21.2 s) in the evolocumab group compared to 20.3 % (8.5 ± 20.3 s) in the placebo group, p = 0.051. There was no difference in lower extremity arterial perfusion measurements. FMD increased by 42.0 ± 73.9 % (1.01 ± 0.7 %) in the evolocumab group and decreased by 16.29 ± 20.06 % (0.99 ± 0.68 %) in the placebo group (p < 0.001). IMT decreased by 7.16 ± 4.6 % (0.06 ± 0.04 mm) in the evolocumab group and increased by 6.68 ± 4.9 % (0.05 ± 0.03 mm) in the placebo group, (p < 0.001). ConclusionsThe addition of evolocumab to maximal tolerated statin therapy improves maximal walking time in patients with PAD and claudication, increases FMD, and decreases IMT. Condensed abstractPeripheral arterial disease (PAD) impairs quality of life by causing lower extremity intermittent claudication, rest pain, or amputation. Evolocumab is a monthly injectable monoclonal antibody medication that reduces cholesterol. In this study, we randomly treated patients with PAD and claudication, and on background statin therapy, with evolocumab or placebo, and found that evolocumab improves walking performance on a treadmill test by increasing maximal walking time. We also found that evolocumab decreases plasma MRP-14 levels, a marker of PAD severity.

Long-Term Outcomes of Peripheral Blood Mononuclear Cells in the Treatment of Angiitis-Induced No-Option Critical Limb-Threatening Ischemia

Background: Peripheral blood mononuclear cells (PBMNCs) showed encouraging short outcomes in the treatment of angiitis-induced no-option critical limb-threatening ischemia (AICLTI) in the pilot study. This study aimed to demonstrate the long-term outcomes of this treatment.Methods: From May 2014 to December 2018, patients diagnosed with AICLTI and treated by autotransplantation of PBMNCs in our center were enrolled and analyzed. The primary endpoint was major amputation-free survival (MAFS), the secondary endpoints included peak pain-free walking time (PPFWT), Wong-Baker FACES pain rating scale score (WFPRSS), labor recovery, ankle-brachial index (ABI), transcutaneous partial oxygen pressure (TcpO2), and SF-36v2 scores.Results: A total of 58 patients were enrolled. During a minimal follow-up of 36 months, the MAFS was 93.1% and the labor competence restored rate was 62.1%. The WFPRSS was decreased from 8.7 ± 1.6 to 1.6 ± 3.2, and PPFWT was significantly improved from 2.9 ± 4.2 min to 16.6 ± 6.9 min. The quality of life was also significantly improved at each follow-up point. Perfusion evaluating parameters, such as ABI and TcPO2, were also significantly improved. No critical adverse event was observed during the treatment and follow-up period.Conclusions: The treatment of AICLTI by autotransplantation of PBMNCs demonstrated encouraging long-term results. It could not only restore labor competence, improve the quality of life, but also significantly reduce the major amputation rate.

Effects of structured home-based exercise training on circulating endothelial progenitor cells and endothelial function in patients with intermittent claudication.

Exercise training improves walking capacity in patients with intermittent claudication (IC). Endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), and endothelial dysfunction could play a role in this process. We measured EPCs and EMPs in a group of 60 patients with IC, and in a control group of 20 individuals without IC, before a treadmill test and 2, 24, and 48 hours after the test. Thirty patients with IC were randomly assigned to perform a 12-week home-based exercise training program. The EPC count, flow-mediated dilation (FMD) of the brachial artery, pain-free walking time (PFWT), and maximum walking time (MWT) were measured at the baseline and after the exercise training program. In patients with IC, EMPs significantly increased 2 hours after the treadmill test, whereas EPCs significantly increased after 24 hours. Among the subjects assigned to complete the training program, we observed a significant increase in the number of EPCs after 12 weeks, as well as an improvement in FMD, PFWT, and MWT. A significant correlation between the variation of EPCs, FMD, and MWT was found. The increase of EPCs and FMD were independent determinants of the walking capacity improvement, without significant interaction. Our results suggest that EPCs mobilization contributes to the improvement of walking capacity in patients with IC undergoing structured physical training. A number of different, partly independent, mechanisms are involved in this process, and our results highlight the potential role of EMPs release and endothelial function improvement. ClinicalTrials.gov Identifier: NCT04302571.

Long-Term Outcomes of Peripheral Blood Mononuclear Cells in the Treatment of Angiitis-Induced No-Option Critical Limb-Threatening Ischemia

Background: Peripheral blood mononuclear cells (PBMNCs) showed encouraging short outcomes in the treatment of angiitis-induced no-option critical limb-threatening ischemia (AICLTI) in pilot study. We aimed to demonstrate the long-term outcomes of this treatment. Methods: From May 2014 to December 2018, patients diagnosed with AICLTI and treated by autotransplantation of PBMNCs in our center were enrolled and analyzed. The primary endpoint was major amputation-free survival (MAFS), the secondary endpoints included peak pain-free walking time (PPFWT), Wong-Baker FACES pain rating scale score (WFPRSS), labour recovery, ankle-brachial index (ABI), transcutaneous partial oxygen pressure (TcpO2), and SF-36v2 scores. Findings: A total of 58 patients were enrolled. During a minimal follow-up of 36 months, the MAFS was 93.1%, labour competence restored rate was 62.1%. The WFPRSS was decreased from 8.7 ± 1.6 to 1.6 ± 3.2, and PPFWT was significantly improved from 2.9 ± 4.2 minutes to 16.6 ± 6.9 minutes. The quality of life was also significantly improved at each follow-up point. Perfusion evaluating parameters, including ABI and TcPO2 were also significantly improved. No critical adverse event was observed during the treatment and follow-up period. Interpretation: The treatment of AICLTI by autotransplantation of PBMNCs demonstrated encouraging long-term results. It could not only restore the labour competence, improve the quality of life, but also significantly reduced the major amputation rate. Funding: National Nature Science Funds (81970407), the Training Program for Outstanding Academic Leaders of the Shanghai Health and Family Planning System (2018BR40); the Project of Outstanding Academic Leaders of Shanghai Science and Technology Commission (19XD1401200). Declaration of Interest: All of the authors declare no conflicts of interest. Ethical Approval: This study was approved by the Ethics Committee of the Zhongshan Hospital, Fudan University.

Autologous peripheral blood-derived stem cells transplantation for treatment of no-option angiitis-induced critical limb ischemia: 10-year management experience

BackgroundPrevious studies have demonstrated that no-option angiitis-induced critical limb ischemia (NO-AICLI) could be significantly improved by transplantation of peripheral blood-derived stem cells (PBDSCs). Additionally, a randomized controlled trial (RCT) recently conducted by us suggested that peripheral blood-derived purified CD34+ cells (PCCs) were not inferior to non-purified peripheral blood mononuclear cells (PBMNCs) at limb salvage in treatment of NO-AICLI. However, most of these clinical trials whether RCT or single-arm studies were characterized with a small sample size and absence of long-term outcomes.MethodsTo analyze long-term clinical outcomes of PBDSCs transplantation for NO-AICLI, we reviewed clinical data of patients with NO-AICLI receiving PBDSCs transplantation at our center during the past decade. Meanwhile, we first compared the long-term safety and efficacy of intramuscular transplantation of PCCs versus PBMNCs in a sizable number of patients with NO-AICLI.ResultsFrom May 2009 to December 2019, a total of 160 patients with NO-AICLI patients were treated by PBDSCs transplantation (82 with PCCs, 78 with PBMNCs) at our center. Baseline characteristics between two groups were similar. Up to June 2020, the mean follow-up period was 46.6 ± 35.3 months. No critical adverse events were observed in either group. There was one death during the follow-up period. A total of eight major amputations occurred. The cumulative major amputation-free survival (MAFS) rate at 5 years after PBDSCs transplantation was 94.4%, without difference between two groups (P = .855). Wound healing, rest pain, pain-free walking time, ankle-brachial index, transcutaneous oxygen pressure, and quality of life (QoL) also significantly improved after PBDSCs transplantation.ConclusionsAutologous PBDSCs intramuscular transplantation could significantly decrease the major amputation rates and improve the QoL in patients with NO-AICLI. Long-term observation of a large sample of patients confirmed that the clinical benefits of PBDSCs transplantation were durable, without difference between the PCCs and PBMNCs groups.

Feasibility study to evaluate cycloidal vibration therapy for the symptomatic treatment of intermittent claudication

IntroductionIntermittent claudication (IC) is the most common symptom of peripheral arterial disease. Previous research has suggested that cycloidal vibration therapy (CVT) may induce angiogenesis and improvements in circulation. The objective of this feasibility study was to explore trial design and acceptability of the protocol to provide data to estimate the parameters required to design a definitive randomised control trial. This feasibility study specifically aimed to assess recruitment rate; attendance rates at baseline and follow-up; and safety, tolerability, and compliance with therapy device and additionally, to consider the potential efficacy of CVT as a novel treatment for intermittent claudication.MethodsPatients with intermittent claudication (IC) were recruited and CVT was applied at home for 30 min twice a day for a period of 12 weeks. Primary outcomes were pain-free walking time (PFWT) and maximum walking time (MWT) after 12 weeks of treatment. Secondary outcomes included the ankle-brachial index and ankle systolic blood pressure. Participants were assessed during active therapy phase at baseline, week 4, week 8, and week 12.ResultsThirty-four participants with IC were recruited: 30 (88%) male and 4 (12%) female. The rate of recruitment was 2.4 participants per month from a standard-size district general hospital. No participants left the study during the activity therapy stage, and no participant failed to attend their follow-up appointment. The general compliance with CVT was high. No participants dropped out during the treatment phase. The mean age of all participants was 68 years (IQR 60–75 years). Substantive improvements were seen in a comparison of differences in times to PFWT and MWT, in ABPI, and in systolic leg pressure in the treated leg. There was no evidence of a substantive difference from baseline in systolic leg pressure in the untreated leg. There were no immediate or delated treatment safety concerns of documented adverse effects with the treatment, all patients completed the required 12-week course indicated a high degree of patient acceptability.ConclusionThe statistically significant and substantive improvements from baseline after 12 weeks observed in PFWT and MWT in participants experiencing IC are comparable to improvements seen from other treatment options such as supervised exercise as reported by Stewart et al. (N Engl J Med 347:1941–1951, 2002). The substantive improvement in systolic leg pressure in the treated leg and the concurrent absence of a substantive change in systolic leg pressure in the untreated leg over the same period suggests a causative effect.This study has provided novel information relating to the number of potential eligible participants for a further research trial and potential association between CVT and improved symptoms. Additionally, it has established that CVT treatment is highly acceptable, as indicated by no participant drop-out in the treatment phase, and may potentially offer an alternative treatment option for patients experiencing IC. Furthermore, this study has assessed the variability of the primary outcome measure which provides vital information needed to calculate sample sizes for any future studies.In conclusion, this study has established the feasibility of using CVT to improve patients’ symptoms of IC and provides essential information which will contribute to the design of future research investigating whether the improvements seen are directly related to CVT.

P4700Work during treadmill rehabilitation predicts clinical benefit and muscle mitochondrial improvements in intermittent claudication

Abstract Background Supervised exercise training is recommended for intermittent claudication in peripheral artery disease (PAD), but the relationship between work achieved during exercise and clinical outcomes is not well described. As in other training modalities, increased effort measured by cumulative work production is expected to be translate into to positive performance adaptations. In settings of constrained limb blood flow, this relationship is unknown. In addition, the impact of exercise on skeletal muscle oxygen use capacity changes is unknown. Near infrared spectroscopy (NIRS) offers a method of characterizing skeletal muscle mitochondrial adaptations before and after training programs. Methods We enrolled subjects (n=17, age 71±8.8 years, 20% female) with PAD and intermittent claudication (ankle brachial index [ABI]=0.76±0.21) in a 12-week supervised training program, randomized to traditional pain-based training strategy versus hypoxia-based training (using NIRS to direct training). Muscle work was calculated based on training performance. NIRS-based determination of mitochondrial capacity and microvascular flow were measured at baseline and after 12 weeks. Results Subjects trained for an average of 32.9±5.9 sessions walking at 54.4±13.4 m/min per session. Subjects achieved a mean of average workload of 4767±5112 kilogram force meter (kpm) per session and an aggregate of 148536±148020 kpm for the training program. Baseline pain-free walking time of 2.95±2.10 minutes increased by a mean of 3.74±2.47 minutes. Increase in walking time was proportional to the average work level achieved per session, with a correlating trend to the overall work level performed over 12 weeks (r=0.543, p=0.024). There was no increase in blood flow measured by ABI or limb microcirculation perfusion index over the training period. Skeletal muscle mitochondrial capacity increased over the training period and correlated with the overall work performed (r=0.573, p=0.016). Figure 1 Conclusions Treadmill exercise rehabilitation for intermittent claudication may be guided by total dose of exercise and NIRS-based indices of mitochondrial capacity rather than pain-levels achieved or changes in perfusion measures. Acknowledgement/Funding American Heart Association

Implementation of Electrical Auricular Acupuncture and Low Frequency Modulated Electric Current Therapy in Pain Management of Patients with Knee Osteoarthritis: A Randomized Pilot Trial.

Background: Knee osteoarthritis is a major cause of knee pain. Conservative therapy resources are limited due to adverse effects. Therefore, alternative non-invasive therapy approaches to reduce pain medications are gaining importance. The current study analyses if electrical auricular acupuncture (EAA) or low frequency modulated electric current therapy (LFMECT) could support analgesic treatment. Methods: In a randomized pilot trial patients with painful knee OA were treated with EAA (group 1) or LFMECT (group 2) additional to standard pharmacological analgesic treatment. In total 19 female and 10 male patients with a mean age of 59.1 years (standard deviation ± 13.6) and a mean BMI of 28.9 kg/m2 (± 5.2) were included. Patients were randomly assigned to one of the groups stratified for age, gender and BMI. Before starting of the active study period and collecting of the initial data on day 1, all patients received a pharmacological analgesic baseline therapy for one week. At the next study stage patients started their randomly assigned treatment protocol for 42 days and final follow-up was set on day 70. Patients recorded their pain intensity (numerical rating scale; NRS) using a standardized patient diary. The pain free walking time in min was recorded and range of motion was assessed. Results: Rescue medication intake was comparable between both groups on day 42 (p = 0.55) and day 70 (p = 0.35). After the active study period (day 42) pain scores decreased significantly in both groups (group 1 p = 0.02; group 2 p = 0.0006). At follow up median pain scores further decreased in group 1 (p = 0.0002) and remained at a low level in group 2 (p = 0.001). Level of pain decreased in about 50% in both groups and was comparable during the study period. Total mean range of motion (ROM) increased in both groups (group 1 p = 0.0003; group 2 p = 0.02). Group 1 had more improvement of mean total ROM compared to group 2 (p = 0.034). Pain-free walking time increased in both groups and was comparable between both groups (p = 0.31). Any adverse effects due to EAA or LFMECT were not observed. Conclusions: Data of the current study indicates that implementation of EAA or LFMECT seems to be beneficial to reduce knee pain and improve knee function in patients with knee osteoarthritis.

Using wearable monitors to assess daily walking limitations induced by ischemic pain in peripheral artery disease

To develop, assess the feasibility of, and determine the clinical validity of an event-based analysis method using wearable monitors to quantify walking pain manifestations (WPMs) and stops induced by walking pain (SIWPs) during daily life walking in people with peripheral artery disease (PAD). The following two conditions were studied: a standardized outdoor walking session (OWS) and a seven-day free-living measurement (FLM) period. The PAD participants (n=23) wore an accelerometer and a watch. They were asked to press the event marker button on the watch to indicate events related to WPMs and SIWPs. To assess the clinical validity of the method, the computed pain-free walking time (PFWT) and maximal walking time (MWT) were compared with the PFWT and MWT assessed using standard treadmill walking protocols, respectively. Following OWSs, the PFWT[OWS] and MWT[OWS] were significantly correlated with the PFWT[Strandness] (r=.955, P<.001) and MWT[Strandness] (r=.821, P<.001), respectively. During the FLM, PAD participants experienced only 2 WPMs/day and 1 SIWP/day, although severely limited on the treadmill and during the OWS. The average WPMs/day were moderately correlated with the PFWT[Strandness] (r=-.54, P=.016). The PFWT[FLM] was on average 12 times longer than the PFWT[Strandness] . Interestingly, the intensity of the walking bouts as assessed by the accelerometer counts during the FLM was significantly lower than that during the OWS (45±15 vs 66±20counts/s, P<.001). This new method offers opportunities for studies investigating the experience of living with PAD and the assessment of daily life walking capacity for both diagnostic and therapeutic purposes.

Effects of sildenafil on maximum walking time in patients with arterial claudication: The ARTERIOFIL study

BackgroundPatients with lower extremity peripheral artery disease (PAD) frequently experience claudication, a clinical symptom indicative of reduced walking capacity. Recommended care consists of exercise rehabilitation combined with optimal medical treatment and surgery. The effects of a single oral dose of sildenafil, a phosphodiesterase type-5 inhibitor, on patients with claudication are discussed. The aim of this study was to test the efficacy of a single 100 mg dose of sildenafil compared to placebo in terms of maximal walking time (MWT) in patients with claudication. MethodsThe ARTERIOFIL study is a crossover, double-blind, prospective, randomized, single-center study conducted at Angers University Hospital in France. MWT (primary endpoint) was assessed using a treadmill test (10% incline; 3.2 km/h). Secondary endpoints (pain-free walking time (PFWT), transcutaneous oximetry during exercise and redox cycle parameters and safety) were also studied. ResultsFourteen patients were included of whom two were ultimately excluded. In the 12 remaining patients, the MWT was significantly improved during the sildenafil period compared with the placebo period (300 s [95% CI 172 s–428 s] vs 402 s [95% CI 274 s–529 s] p < 0.01). Sildenafil had no significant effect on pain-free walking time or skin tissue oxygenation during exercise. According to redox cycle parameters, sildenafil significantly reduced blood glucose and pyruvate levels and the 3-hydroxybutyrate/acetoacetate ratio, while there was no significant effect on lactate, 3-hydroxybutyrate, acetoacetate and free fatty acid levels. Symptomatic transient hypotension was observed in two women. ConclusionsThe ARTERIOFIL study has shown that a single 100 mg oral dose of sildenafil had a significant effect on increase in MWT but had no significant effects on PFWT and oxygenation parameters in patients with claudication. A double-blind, prospective, randomized, multicenter study (VIRTUOSE©) is ongoing to evaluate the chronic effect of six month-long sildenafil treatment on MWT in PAD patients with claudication. Clinical trial registrationThis clinical trial was registered at clinicaltrials.gov, registration.number: NCT02832570, (https://clinicaltrials.gov/ct2/show/NCT02832570).

Near infrared spectroscopy-guided exercise training for claudication in peripheral arterial disease.

Supervised treadmill exercise for claudication in peripheral arterial disease is effective but poorly tolerated because of ischemic leg pain. Near infrared spectroscopy allows non-invasive detection of muscle ischemia during exercise, allowing for characterization of tissue perfusion and oxygen utilization during training. We evaluated walking time, muscle blood flow, and muscle mitochondrial capacity in patients with peripheral artery disease after a traditional pain-based walking program and after a muscle oxygen-guided walking program. Patients with peripheral artery disease trained thrice weekly in 40-minute-long sessions for 12 weeks, randomized to oxygen-guided training ( n = 8, age 72 ± 9.7 years, 25% female) versus traditional pain-based training ( n = 10, age 71.6 ± 8.8 years, 20% female). Oxygen-guided training intensity was determined by maintaining a 15% reduction in skeletal muscle oxygenation by near infrared spectroscopy rather than relying on symptoms of pain to determine exercise effort. Pain free and maximal walking times were measured with a 12-minute Gardner treadmill test. Gastrocnemius mitochondrial capacity and blood flow were measured using near infrared spectroscopy. Baseline pain-free walking time was similar on a Gardner treadmill test (2.5 ± 0.9 vs. 3.6 ± 1.0 min, p = 0.5). After training, oxygen-guided cohorts improved similar to pain-guided cohorts (pain-free walking time 6.7 ± 0.9 vs. 6.9 ± 1.1 min, p < 0.01 for change from baseline and p = 0.97 between cohorts). Mitochondrial capacity improved in both groups but more so in the pain-guided cohort than in the oxygen-guided cohort (38.8 ± 8.3 vs. 14.0 ± 9.3, p = 0.018). Resting muscle blood flow did not improve significantly in either group with training. Oxygen-guided exercise training improves claudication comparable to pain-based training regimens. Adaptations in mitochondrial function rather than increases in limb perfusion may account for functional improvement. Increases in mitochondrial oxidative capacity may be proportional to the degree of tissue hypoxia during exercise.

Human primary CD34+ cells transplantation for critical limb ischemia.

The goal of this study was to characterize the properties of human CD34+ cells in culture and investigate the feasibility and efficacy of CD34+ transplantation in a mouse model of limb ischemia and in patients with no-option critical limb ischemia. Human CD34+ cells isolated from peripheral blood and grown in culture for up to four passages stained positively for the surface markers CD34 and CD133 and showed high viability after cryopreservation and recovery. Seven days after surgery to induce limb ischemia, ischemic muscles of nude mice were injected with CD34+ cells. Two weeks later, mice were scored for extent of ischemic injury, and muscle tissue was collected for immunohistochemical analysis of vascular endothelial cells and RT-PCR analysis of cytokine expression. Injury scores of CD34+ -treated, but not control, mice were significantly different before and after transplantation. Vascular density and expression of VEGF and bFGF mRNAs were also significantly increased in the treated mice. Patients with severe lower extremity arterial ischemia were injected with their own CD34+ cells in the affected calf, foot, or toe. Significant improvements were observed in peak pain-free walking time, ankle-brachial index, and transcutaneous partial oxygen pressure. These findings demonstrate that growth of human CD34+ cells in vitro and cryopreservations are feasible. Such cells may provide a renewable source of stem cells for transplantation, which appears to be a feasible, safe, and effective treatment for patients with critical limb ischemia.

Supervised exercise therapy versus home-based exercise therapy versus walking advice for intermittent claudication.

Supervised exercise therapy versus home-based exercise therapy versus walking advice for intermittent claudication.

Home-based exercise programmes for individuals with intermittent claudication: A protocol for an updated systematic review and meta-analysis.

Background:The aim of this updated review is to consider the evidence base for the effectiveness of home-based exercise programmes as a treatment option for improving walking distance in patients with intermittent claudication.Methods:The Medline, EMBASE, CINAHL, PEDro and Cochrane CENTRAL databases will be searched for terms including ‘intermittent claudication’, ‘peripheral arterial disease’, ‘home-based exercise’ and ‘home-based walking’. No date restrictions will be used but only articles in the English language will be included. Both randomised and non-randomised trials of home-based exercise programmes versus a comparator arm will be included, and a meta-analysis using only the randomised controlled trials will be attempted if the assumptions of heterogeneity are met. Data extraction will include study details, sample description, intervention description, length of follow-up and outcomes measures. The primary outcome measure is objectively measured maximal walking distance or time, with secondary outcome measures including pain-free walking distance or time, changes in physical activity and quality of life. We will also provide a narrative description of the effective components of a home-based exercise intervention which can aid future recommendations.Conclusion:Overall, this proposed review and meta-analysis aims provide a comprehensive and complete overview of the evidence base for home-based exercise programmes, which can aid clinicians in the management of their patients.

Supervised Exercise Training for Symptomatic Peripheral Artery Disease

In May 2017 the Centers for Medicare and Medicaid Services (CMS) published a final decision memo for supervised exercise therapy for symptomatic peripheral artery disease. This was because there was sufficient evidence demonstrating the benefit of exercise training for improving pain-free and peak walking time. This training can take place in a clinic setting or within a cardiac rehabilitation program. There were specific instructions for what must take place during supervised exercise training during each session day a patient was present. The goal of this review is to provide background information about the research that led to this decision from CMS. It will also review specifics of a supervised exercise training session and conclude with specifics about the CMS decision memo language as it relates to implementing a supervised exercise training session.