Maximal Walking Time Research Articles

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.

Six-month combined aerobic and resistance exercise program enhances 6-minute walk test and physical fitness in people with peripheral arterial disease: A pilot study

BackgroundExercise therapy is a recognized non-pharmacological intervention for peripheral arterial disease (PAD); however, the effects of combined exercise remain under investigation. This study aimed to compare the effects of a 6-month combined supervised exercise program (SUP) with a usual care (UC) approach on walking ability, physical fitness, and peripheral blood flow in people with PAD and claudication. MethodsTwenty-three male participants (Age=64.1 ± 6.2years and ABI=0.58±0.07) with PAD and claudication were assigned to either the SUP group (n = 10), engaging in structured supervised treadmill walking combined with three resistance exercises, three times a week, or the UC group (n = 13), receiving advice to walk. The primary outcome measure was walking ability, with assessments conducted at baseline (M0), after 3 months (M3), and 6 months (M6). ResultsAfter the 6-month intervention, the SUP group exhibited significant improvements in absolute claudication time (ACT, p = 0.045), maximal walking time (MWT, p = 0.045), maximal walking distance (MWD, p = 0.027), and pause duration (p = 0.045) during the 6-minute walk test (6MWT), when compared to the UC group. Over time, a significant increase in walking speed during the 6MWT (Speed6MWT, p = 0.001) and walking speed without claudication (SpeedNoC, p < 0.001) was found, although no significant differences were found between the groups. The SUP group increased by 0.8 km/h in both Speed6MWT and SpeedNoC, while the UC group increased by 0.3 km/h and 0.6 km/h, respectively. Despite claudication consistently occurring at the same time, the SUP group demonstrated an improved tolerance to pain or a better understanding of pain, enabling them to walk longer distances at higher speeds. A positive effect of SUP was found for chair sit-and-reach test (p = 0.023), percentage of fat mass (p = 0.048), fat-free mass (p = 0.040), and total body water (p = 0.026), suggesting potential benefits attributed to the resistance strength exercises. ConclusionA 6-month combined treadmill and resistance exercise program improved walking ability, walking speed, lower body and lower back flexibility, and body composition in people with PAD and claudication.

The Review of Recent Trend for School Bus Routing Problem

The School Bus Routing Problem (SBRP) is a complex transportation challenge involving finding optimal bus routes. This review paper provides an overview of the recent developments in SBRP research and focuses on three sub-problems: Bus Route Generation, Bus Route Scheduling, and Bus Stop Selection. The paper examines recent publications from 57 relevant articles. It highlights the increasing focus on real-world and complex scenarios, as well as the growing popularity of metaheuristic approaches in addressing SBRP challenges. The analysis reveals the significance of bus route generation, bus route scheduling, and bus stop selection, showcasing the effectiveness of machine learning and heuristic or metaheuristic algorithms in improving route quality. This study also classifies SBRP problems based on the number of schools, service surroundings (urban or rural), mixed-load scenarios, and fleet mix (homogeneous or heterogeneous). Finally, the paper explores the objectives of SBRP research, including minimising the total cost, distance, time, and number of buses. Meanwhile, the constraints of this study are the capacity of a bus, the maximum riding time, time windows, the maximum walking time between two stops and so on. This comprehensive review paper aims to offer a framework for new researchers and provides valuable insights for future research directions in this transportation area.

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 Effects of Plantar Plate Therapy for Subtalar Joint Valgus Type for One Case Osteoarthritis of the Knee

There are many research reports showing that the effect of plantar plate on medial knee OA is effective in the short term, but there are few reports that it is effective for a long period of 6 months or longer. Also although there are many studies on plantar plate in the varus type of the subtalar joint, there are few studies in the valgus type of the subtalar joint. In this study, we investigated the long-term effect of wearing a plantar plate that guides the subtalar joint to a neutral position in patients with the subtalar joint valgus type. The case is an elderly female diagnosed with bilateral knee osteoarthritis. The case is an elderly female diagnosed with bilateral knee osteoarthritis. X-ray evaluation was right III, left III in KL grade.The plantar plate was evaluated by comparing the 10 m maximum effort walking time and pain evaluation VAS, the total consumption and the number of steps in one week without and immediately after wearing the plantar plate. In order to examine the long-term effects, functional evaluation was performed 3 months, 6 months, and 12 months after the installation of the plantar plate.As a result, 10m walking time and walking pain improved, suggesting improvement in long-term walking ability after 3 months, 6 months, and 12 months. In addition, SF36.v2, a health-related QOL evaluation scale, total consumption, and number of steps improved, and a weight loss effect was obtained. Based on the above, it is suggested that the manufactured plantar plate is effective for a long period of time. I thought For cases in which the subtalar joint is valgus, a plantar plate that induces varus to the subtalar joint is more suitable than a lateral wedge-shaped plantar plate that induces valgus to the subtalar joint.

Attendance at Supervised Exercise Sessions and Walking Outcomes in Peripheral Artery Disease: Results From 2 Randomized Clinical Trials.

Background Supervised exercise therapy (SET) is the first-line therapy for walking impairment in peripheral artery disease (PAD). This study evaluated the association between attendance at SET and improved walking performance, compared with a control group, in PAD. Methods and Results Data from 2 randomized clinical trials of SET for PAD were combined. In each trial, participants were randomized to 3 times weekly supervised treadmill exercise or an attention control group for 6 months (maximum, 77 exercise sessions). Participants randomized to SET were categorized into tertiles, according to the proportion of exercise sessions they attended. Results adjusted for age, sex, race, baseline walking performance, comorbidities, and other potential confounders. A total of 272 participants with PAD (mean age, 67.9±9.3 years; 44% women; 61% Black race) were included. For participants randomized to SET, tertiles of attendance rates at exercise sessions were as follows: 11% to 68% (N=45), 69% to <85% (N=46), and ≥85% (N=46). Compared with control, mean improvement in 6-minute walk was significantly greater in each SET tertile: mean (95% CI) for tertile 1, 27.9 m (1.3-54.4 m; P=0.04), tertile 2, 38.2 m (12.2-64.2 m; P=0.001), and tertile 3, 56.9 m (29.9-83.8 m; P<0.0001). Among participants randomized to SET, greater SET attendance was associated with greater improvement in 6-minute walk distance (overall P for trend=0.025). Compared with control, improvement in maximal treadmill walking time was greater in each SET attendance tertile: tertile 1 (3.3 minutes [95% CI, 1.7-4.8 minutes]; P<0.0001), tertile 2 (3.8 minutes [95% CI, 2.3-5.3 minutes]; P<0.0001), and tertile 3 (5.4 minutes [95% CI, 3.9-7.0 minutes]; P:<0.0001). Among participants randomized to SET, greater attendance at SET was not significantly associated with greater improvement in maximal treadmill walking time (overall P for trend=0.064). Conclusions Among people with PAD randomized to SET, better attendance at exercise sessions was associated with significantly greater 6-minute walk improvement. Among all participants with PAD, even relatively low SET attendance was associated with significantly greater improvement in walking performance, compared with a control group who did not exercise. Registration URL: https://clinicaltrials.gov/ct2/show/NCT01408901. URL: https://clinicaltrials.gov/ct2/show/NCT00106327.

Exercise Oximetry Correlates Better With Exercise-Induced Lactate Increase, than Ankle Brachial Index or Walking Time, in Vascular Claudicants.

In claudication, the correlation between walking-induced biomarkers and indices of clinical severity (e.g., walking distance or ankle brachial index (ABI)), is fair. We hypothesized that a correlation would be observed between the clinical estimation of ischemia severity with exercise transcutaneous oximetry (Ex-TcpO2) and lactate increase. A prospective study was performed among 377 patients with arterial claudication. We recorded age, sex, ABI, body mass index (BMI), systolic arterial blood pressure (SBP), and glycemia. Capillary blood lactate was measured at rest and 3min after a constant load treadmill test. We recorded maximum walking time (MWT), heart rate (HRmax), the sum of minimal decrease from oxygen values for buttocks, thighs and calves Ex-TcpO2 (DROPmin), as well as the amplitude of chest-TcpO2 decrease. A multilinear regression model was used to assess the variables associated with lactate increase. BMI, SBP, HRmax, the amplitude of decrease in chest-TcpO2 and DROPmin, but not age, sex, ABI, MWT, diabetes mellitus nor glycemia, were significantly associated to lactate increase in the model. Because it accounts for the severity and diffusion of lower-limb exercise-induced ischemia and detects exercise induced hypoxemia, TcpO2 may be preferable to ABI or MWT to estimate the metabolic consequences of walking in claudicants.

Cardiac Rehabilitation and Mortality Risk Reduction in Peripheral Artery Disease at 6-Month Outcome.

The management of patients with peripheral artery disease (PAD) is integrative and multidisciplinary, in which cardiac rehabilitation (CR) plays a prognostic role in terms of functional status, quality of life, and long-term impact on morbidity and mortality. We conducted a prospective cohort study on 97 patients with PAD admitted to a single tertiary referral center. Based on a prognostic index developed to stratify long-term mortality risk in PAD patients, we divided the cohort into two groups: low and low-intermediate risk group (45 cases) and high-intermediate and high risk group (52 cases). We analyzed demographics, clinical parameters, and paraclinical parameters in the two groups, as well as factors associated with cardiological reassessment prior to the established deadline of 6 months. Obesity (p = 0.048), renal dysfunction (p < 0.001), dyslipidemia (p < 0.001), tobacco use (p = 0.048), and diabetes mellitus (p < 0.001) are comorbidities with long-term prognostic value. Low-density lipoprotein cholesterol (p = 0.002), triglycerides (p = 0.032), fasting glucose (p = 0.011), peak oxygen uptake (p = 0.005), pain-free walking distance (p = 0.011), maximum walking time (p < 0.001), and maximum walking distance (p = 0.002) influence the outcome of PAD patients by being factors associated with clinical improvement at the 6-month follow-up. PAD patients benefit from enrollment in CR programs, improvement of clinical signs, lipid and carbohydrate profile, and weight loss and maintenance of blood pressure profile within normal limits, as well as increased exercise capacity being therapeutic targets.

Clinical prediction rule for locomotive syndrome in older adults: A decision tree model

BackgroundNo previous studies have proposed a clinical prediction rule that analyzes the factors related to the severity of locomotive syndrome. This study developed and assessed a clinical prediction rule for the severity of locomotive syndrome in older adults. MethodsA total of 186 patients were assessed using the locomotive syndrome risk test. Classification and regression tree methodologies were used to develop the clinical prediction rule. This study developed three prediction models based on the severity of the locomotive syndrome, of which Model 3 assessed the most severe condition. The following potential predictive factors were measured and entered into each model; single-leg standing time, grip strength, preferred and maximum walking time, and timed up and go test. ResultsThe single-leg standing test (≤59.4 or >59.4 s) was the best single discriminator for Model 1. Among those with a single-leg standing time >59.4 s, the next best predictor was grip strength (≤37.8 or >37.8 kg). In Model 2, the single-leg standing test was also the best single discriminator (≤12.6 or >12.6 s). Among those with a single-leg standing time ≤12.6, the next best predictor was TUG (≤7.9 or >7.9 s). Additionally, among those with a single-leg standing time >12.6, the next best predictor was single-leg standing time (≤55.3 or >55.3 s). In Model 3, predictive value in Model 2 was the best single discriminator (0 or 1). Among those with 1, the next best predictor was maximum walking time (≤3.75 or >3.75 s). The area under the receiver operating characteristic curves of Models 1, 2, and 3 were 0.737, 0.763, and 0.704, respectively. ConclusionsA clinical prediction rule was developed to assess the accuracy of the models. These results can be used to screen older adults for suspected locomotive syndrome.

Abstract 299: Microvessel Oxidative Stress Predicts Changes In Leg Function Of Patients With Peripheral Arterial Disease After Supervised Exercise Therapy

Our objective was to evaluate baseline oxidative stress in the microvessels of patients with Peripheral Arterial Disease (PAD) 1) in association with Heme Oxygenase-1 (HO-1), a critical cytoprotective molecule for oxidative stress 2) as a predictor of the functional and pathophysiologic changes that occur in response to six months of Supervised Exercise Therapy (SET). We hypothesized that accumulated oxidative stress in the microvessels of PAD at baseline would predict changes in walking performance, myofiber pathology, and limb function at the end of a six-month program of SET. Methods: Twelve claudicating patients received six months of SET per ACC/AHA guidelines. Before and after SET, patients were evaluated for leg biomechanics, overground walking capacity (six-minute walking distance, SMWD), and maximum walking time on a treadmill. Subsequently, their more affected calf muscle was biopsied for quantification of HO-1 and oxidative stress (carbonyl content) in both myofibers and microvessels. We evaluated the association between HO-1 expression and carbonyl content with correlation and multiple regression. Results: HO-1 expression and Carbonyl content were strongly associated in the microvessels (n=1400, r=0.98, p&lt;0.001). Increasing Carbonyl content in the microvessels of each subject was associated with increasing HO-1 expression. In a subset of patients, HO-1 expression increased more slowly with increasing carbonyl content. Pre-SET Oxidative Stress in microvessels was a significant predictor of SET mediated change in SMWD (r=-0.75, p=0.012) and plantarflexion torque (r=0.8571, p=0.0065). Conclusion: Carbonyl content (oxidative stress) in microvessels of each subject was positively associated with HO-1 expression. However, in a subset of patients HO-1 expression increased more slowly with increasing carbonyl content. Baseline oxidative stress in the microvessels, which may be a function of the quality of HO-1 expression, was a significant predictor of SET mediated change in SMWD and plantarflexion torque. The data suggest that microvessel oxidative damage may contribute uniquely to calf muscle pathology and leg dysfunction in PAD patients.

Most Falls of Active Elderly People are not Caused by Decreases in Physical Function

Several healthy, community-dwelling elderly people who live independently experience falls. However, their falls are not always attributed to decreased physical function. We aimed to examine the cause of falls in active elderly people. They were divided into fallers (n = 49) and non-fallers (n = 170) based on their fall experience during the previous year. The subjects participated in the following tests: transferring velocity during the sit-to-stand, one-leg stand time, functional reach, 10-m maximal walking time, muscle strength (foot grip, ankle plantar flexion, hip flexion, knee extension strength), systemic reaction time, agility stepping, and maximal side step length after completing the ADL questionnaire, fall risk assessment sheet, fall risk profile from Demura et al, and life-space assessment sheet. No significant differences were observed in physical functions, which were the basis of fall prevention (muscle strength, balance, and gait) and fall avoidance (systemic reactions, agility stepping, and maximal side step length) between both groups. A significant difference was observed in the ADL score but not between both fall risk scores, and the Life-Space Assessment scores. Moreover, no significant differences were observed between the high risk ratio for falls and nursing care based on each questionnaire. In conclusion, the differences in physical function and fall risk factors between the fallers and non-fallers in active, independent elderly people living in the community were not observed. The cause of these falls (22.4%) was not attributed to physical function decreases or other fall risk factors. These may mainly depend on accidents resulting from high activity.

Cerebellar Theta Burst Stimulation on Walking Function in Stroke Patients: A Randomized Clinical Trial.

Objectives: The objective of this study was to explore the efficacy of cerebellar intermittent theta burst stimulation (iTBS) on the walking function of stroke patients.Methods: Stroke patients with walking dysfunction aged 25–80 years who had suffered their first unilateral stroke were included. A total of 36 patients [mean (SD) age, 53 (7.93) years; 10 women (28%)] were enrolled in the study. All participants received the same conventional physical therapy, including transfer, balance, and ambulation training, during admission for 50 min per day during 2 weeks (10 sessions). Every session was preceded by 3 min procedure of cerebellar iTBS applyed over the contralesional cerebellum in the intervention group or by a similar sham iTBS in control group. The groups were formed randomly and the baseline characteristics showed no significant difference. The primary outcome measure was Fugl–Meyer Assessment–Lower Extremity scores. Secondary outcomes included walking performance and corticospinal excitability. Measures were performed before the intervention beginning (T0), after the first (T1) and the second (T2) weeks.Results: The Fugl–Meyer Assessment for lower extremity scores slightly improved with time in both groups with no significant difference between the groups and over the time. The walking performance significantly improved with time and between group. Two-way mixed measures ANOVA showed that there was significant interaction between time and group in comfortable walking time (F2,68 = 6.5242, P = 0.0080, η2partial = 0.276, ε = 0.641), between-group comparisons revealed significant differences at T1 (P = 0.0072) and T2 (P = 0.0133). The statistical analysis of maximum walking time showed that there was significant interaction between time and groups (F2,68 = 5.4354, P = 0.0115, η2partial = 0.198, ε = 0.734). Compared with T0, the differences of maximum walking time between the two groups at T1 (P = 0.0227) and T2 (P = 0.0127) were statistically significant. However, both the Timed up and go test and functional ambulation category scale did not yield significant differences between groups (P > 0.05).Conclusion: Our results revealed that applying iTBS over the contralesional cerebellum paired with physical therapy could improve walking performance in patients after stroke, implying that cerebellar iTBS intervention may be a noninvasive strategy to promote walking function in these patients. This study was registered at ChiCTR, number ChiCTR1900026450.

Body mass-normalized moderate dose of dietary nitrate intake improves endothelial function and walking capacity in patients with peripheral artery disease.

Peripheral artery disease (PAD) is characterized by the accumulation of atherosclerotic plaques in the lower extremity conduit arteries, which impairs blood flow and walking capacity. Dietary nitrate has been used to reduce blood pressure (BP) and improve walking capacity in PAD. However, a standardized dose for PAD has not been determined. Therefore, we sought to determine the effects of a body mass-normalized moderate dose of nitrate (0.11 mmol nitrate/kg) as beetroot juice on serum nitrate/nitrite, vascular function, walking capacity, and tissue oxygen utilization capacity in patients with PAD. A total of 11 patients with PAD received either nitrate supplement or placebo in a randomized crossover design. Total serum nitrate/nitrite, resting BP, brachial and popliteal artery endothelial function (flow-mediated dilation, FMD), arterial stiffness (pulse-wave velocity, PWV), augmentation index (AIx), maximal walking distance and time, claudication onset time, and skeletal muscle oxygen utilization were measured pre- and postnitrate and placebo intake. There were significant group × time interactions (P < 0.05) for serum nitrate/nitrite, FMD, BP, walking distance and time, and skeletal muscle oxygen utilization. The nitrate group showed significantly increased serum nitrate/nitrite (Δ1.32 μM), increased brachial and popliteal FMD (Δ1.3% and Δ1.7%, respectively), reduced peripheral and central systolic BP (Δ-4.7 mmHg and Δ-8.2 mmHg, respectively), increased maximal walking distance (Δ92.7 m) and time (Δ56.3 s), and reduced deoxygenated hemoglobin during walking. There were no changes in PWV, AIx, or claudication (P > 0.05). These results indicate that a body-mass normalized moderate dose of nitrate may be effective and safe for reducing BP, improving endothelial function, and improving walking capacity in patients with PAD.

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.

FC 107SNF472 ATTENUATES THE PROGRESSION OF FEMORAL ARTERY CALCIFICATION AND RECOVERS LIMB BLOOD PERFUSION AND WALKING ABILITY IN A RAT MODEL OF PERIPHERAL ARTERY DISEASE

Abstract Background and Aims Peripheral artery disease (PAD) is a common co-morbidity in end-stage kidney disease (ESKD) patients undergoing dialysis. The prominent vascular calcification in these patients is associated with severity of symptoms and adverse outcomes. Although there are medical therapies approved for PAD, none of them has been specifically approved por PAD-ESKD. For example, cilostazol is approved for PAD but its use is limited in PAD-ESKD patients. Surgical interventions are challenging in these patients due to their specific vascular calcification and show worse outcomes. Therefore, the aims of this study were to evaluate the effects of the investigational drug SNF472, a selective inhibitor of vascular calcification, on blood perfusion and limb functional recovery in a Vitamin D3 (VitD)-induced rat model of arterial calcification and limb ischemia. Method Three consecutives daily subcutaneous (s.c) doses of VitD were administered to 66 male Sprague Dawley rats to induce limb ischemia. Rats were randomized into four groups at day 5 after the start of VitD treatment (when all parameters were measured in a satellite group) and were treated for nine days with placebo s.c., placebo peroral (p.o.), SNF472 (40 mg/kg/day, s.c.) or cilostazol (40 mg/kg/day, p.o.). An additional control group did not receive VitD (sham) and was administered with placebo s.c. during these last nine days. Posterior limb blood perfusion was measured using laser Doppler imaging at baseline (before calcification induction), day 4 (before treatment start) and day 13 (end of treatment). Walking ability was evaluated by measuring Maximum Walking Distance (MWD) and Maximum Walking Time (MWT) using a rat treadmill at baseline, day 4 and day 11. Rats were sacrificed at day 13, and heart and femoral arteries were collected for calcium analysis. Results Administration of VitD induced heart and femoral artery calcification by day 5. This calcification was associated with decreased limb blood perfusion and impairment of walking ability (both MWT and MWD) compared to sham. Treatment with SNF472 inhibited calcification progression in femoral arteries by 41% and in heart by 56% compared to placebo. The inhibition of calcification progression by SNF472 led to a 29% increase in limb blood perfusion (p&amp;lt; 0.001) and a significant improvement in walking ability (49% in MWD and 43% in MWT; p&amp;lt; 0.05) compared to placebo. Calcification inhibition in femoral arteries was positively correlated with both MWD and MWT (p&amp;lt; 0.0001). No effects of cilostazol were observed in tissue calcification, limb blood perfusion or walking ability. Conclusion SNF472 attenuates the progression of vascular calcification and improves blood perfusion and the functional parameters MWT and MWD in a rat model of PAD vascular calcification. These results support investigation of SNF472 as a potential therapy for PAD-ESKD patients who have vascular dysfunction due to a high degree of arterial calcification.

Acute mitochondrial antioxidant intake improves endothelial function, antioxidant enzyme activity, and exercise tolerance in patients with peripheral artery disease.

Peripheral artery disease (PAD) is a manifestation of atherosclerosis in the leg arteries, which causes claudication. This may be in part due to vascular mitochondrial dysfunction and excessive reactive oxygen species (ROS) production. A mitochondrial-targeted antioxidant (MitoQ) has been shown to improve vascular mitochondrial function that, in turn, led to improved vascular function in older adults and animal models. However, the roles of vascular mitochondria in vascular function including endothelial function and arterial stiffness in patients with PAD are unknown; therefore, with the use of acute MitoQ intake, this study examined the roles of vascular mitochondria in endothelial function, arterial stiffness, exercise tolerance, and skeletal muscle function in patients with PAD. Eleven patients with PAD received either MitoQ or placebo in a randomized crossover design. At each visit, blood samples, brachial and popliteal artery flow-mediated dilation (FMD), peripheral and central pulse-wave velocity (PWV), blood pressure (BP), maximal walking capacity, time to claudication (COT), and oxygen utility capacity were measured pre- and-post-MitoQ and placebo. There were significant group by time interactions (P < 0.05) for brachial and popliteal FMD that both increased by Δ2.6 and Δ3.3%, respectively, and increases superoxide dismutase (Δ0.03 U/mL), maximal walking time (Δ73.8 s), maximal walking distance (Δ49.3 m), and COT (Δ44.2 s). There were no changes in resting heart rate, BP, malondialdehyde, total antioxidant capacity, PWV, or oxygen utility capacity (P > 0.05). MitoQ intake may be an effective strategy for targeting the vascular mitochondrial environment, which may be useful for restoring endothelial function, leg pain, and walking time in patients with PAD.NEW & NOTEWORTHY The results of this study reveal for the first time that acute oral intake of mitochondrial-targeted antioxidant (MitoQ, 80 mg) is effective for improving vascular endothelial function and superoxide dismutase in patients with peripheral artery disease (PAD). Acute MitoQ intake is also effective for improving maximal walking capacity and delaying the onset of claudication in patients with PAD. These findings suggest that the acute oral intake of MitoQ-mediated improvements in vascular mitochondria play a pivotal role for improving endothelial function, the redox environment, and skeletal muscle performance in PAD.

Mitochondrial Targeted Antioxidant Intake Improves Vascular Function And Exercise Tolerance In Peripheral Artery Disease Patients

Peripheral artery disease (PAD) is a manifestation of atherosclerosis in the lower leg arteries, which causes reduced blood flow and leg pain. This may be in part due to excessive mitochondria-produced reactive oxygen species (ROS) and attenuated mitochondrial respiratory function. Mitoquinol mesylate, a mitochondrial-targeted antioxidant, has been shown to scavenge ROS and improve vascular function in older adults and animal models. However, the impacts of mitoquinol on vascular function in patients with PAD are unknown. PURPOSE: To examine the impacts of acute mitoquinol intake (80mg) on endothelial function (flow mediated dilation, FMD), resting heart rate (RHR), blood pressure (BP), arterial stiffness (pulse wave velocity, PWV), and exercise tolerance in patients with PAD. METHODS: 10 patients with PAD (stage II-III) received either mitoquinol or placebo in a randomized crossover design. At each visit, measurements of RHR, central and peripheral BP, brachial and popliteal artery FMD, PWV, augmentation index (AIx), maximal walking capacity, and time to claudication (COT) were measured before and after mitoquinol and placebo. RESULTS: There were significant group by time interactions (p<0.05) for brachial FMD, popliteal FMD, and COT, which significantly increased (p<0.05). There were trends for decreases in diastolic BP (p=0.10), carotid-to-ankle PWV (p=0.08), and increases in maximal walking time (p=0.06), and maximal walking distance (p=0.06). There were no changes in RHR, systolic BP, central BP, deceleration time, max dP/dt, carotid-to-radial PWV, carotid-to-femoral PWV, or AIx (p>0.05). CONCLUSIONS: Mitoquinol intake may be an effective strategy for targeting mitochondrial ROS, which may be useful for treating endothelial dysfunction, leg pain, and improving walking time in patients with PAD.

Dietary Nitrate Intake Improves Vascular Function And Walking Capacity In Patients With Peripheral Artery Disease

Peripheral artery disease (PAD) is the manifestation of atherosclerosis in the arteries of the legs, which reduces blood flow to the lower extremities and impairs walking capacity. Dietary nitrate has been used to reduce blood pressure (BP) and increase exercise tolerance in PAD. However, a standard dose, body mass normalized nitrate, for PAD has yet to be determined. PURPOSE: To elucidate the impacts of a body mass-normalized dose of nitrate (0.11 mmol nitrate/kg) in the form of beetroot juice on resting heart rate (RHR), central and peripheral BP, vascular function, and exercise tolerance in patients with PAD. METHODS: In a randomized crossover design, 10 patients with PAD (stage II-III) received either the nitrate supplement or placebo. At each visit, measures of RHR, central and peripheral BP, brachial and popliteal artery endothelial function (flow-mediated dilation, FMD), arterial stiffness (pulse-wave velocity, PWV), augmentation index (AIx)), maximal walking capacity, and time to claudication (COT) were measured before and after nitrate and placebo. RESULTS: There were significant group by time interactions (p<0.05) for systolic BP, endothelial function, and maximal walking distance. Systolic BP was significantly reduced (p<0.05) while popliteal FMD, brachial FMD, and maximal walking time significantly increased (p<0.05). Nitrate intake reduced central systolic BP and increased maximal walking time (p<0.05). There were trends for decreased diastolic BP (p=0.15), central diastolic BP (p=0.06), and central pulse pressure (p=0.17). There were no changes in RHR, deceleration time, max dP/dt, carotid-to-radial PWV, carotid-to-femoral PWV, carotid-to-ankle PWV, AIx, or COT (p>0.05). CONCLUSIONS: These results indicate that a dose of nitrate (~0.11 mmol nitrate/kg) seems to be an effective dose for improving BP, vascular function, and walking capacity in patients with PAD.

Age-related Differences In Rapid Neuromuscular Parameters Of The Plantar Flexors And Correlations With Physical Function

Few studies have concurrently examined multiple rapid neuromuscular characteristics of the plantar flexors (PFs) in middle-aged (MM) and older (OM) males. Further, it is important to determine the association between these measures and physical function. PURPOSE:To compare rapid neuromuscular parameters of the PFs in MM and OM, and examine correlates of physical functioning. METHODS:Twenty-nine healthy, MM (n=14; 45.3±2.6 yrs) and OM (n=15; 65.3±3.2 yrs) performed fast, isotonic (IT) contractions with a load of 0.5 Nm and slow, isokinetic (IK; 60°·s-1) concentric contractions of the PFs using a dynamometer. Participants were instructed to push with the ball of their foot “as hard and fast as possible” prior to each contraction. Peak velocity (PV), rate of velocity development (RVDIT), and rate of electromyography rise (RER) were obtained from IT trials. During the IK trials, time to peak torque (TPT) and rate of velocity development (RVDIK) were acquired. RVD was obtained from the linear slope of the velocity-time curve (Δvelocity/Δtime)as the highest rolling 20 ms value. RER of the medial gastrocnemius was derived from the linear slope of the normalized electromyography signal as the highest rolling 50 ms value. Maximal walking velocity (MWV) and time to complete 5 chair rises (5CR) were also recorded. Group comparisons were made with independent samples t-tests, while Pearson correlation coefficients were calculated to examine select relationships. RESULTS:RVDITwas lower (MM=5202.83±510.23 vs. OM=4630.29±854.23°·s-2; p=0.037), and 5CR time greater (16%; p=0.022) in OM.RER was only correlated (r=0.431; p=0.026) with RVDIT. Only PV (r=0.396; p=0.033) and RVDIT(r=0.480;p=0.008) were correlated with MWV, while only TPT was correlated with 5CR time (r=0.451; p=0.014). CONCLUSIONS:Our findings suggest that rapid neuromuscular measures may be differentially influenced by age, and only particular parameters are associated with physical function.

P1234SNF472 IMPROVES LIMB BLOOD PERFUSION AND WALKING ABILITY IN A PERIPHERAL ARTERY DISEASE VASCULAR CALCIFICATION RAT MODEL

Abstract Background and Aims Peripheral Artery disease (PAD) is a common vascular disease associated with functional impairment and increased risk of cardiovascular events in End Stage Kidney Disease (ESKD) patients undergoing dialysis. Poor limb salvage outcomes and high post-amputation mortality in hemodialysis (HD) patients highlight the need for earlier medical therapies. Cilostazol and pentoxifylline are approved for PAD. Their use in HD patients stays limited and cilostazol use requires caution in this population. Clinical studies demonstrate associations between arterial calcification and adverse outcomes in PAD patients. SNF472, a selective calcification inhibitor that interferes in the formation and growth of hydroxyapatite, is in Phase 3 for calciphylaxis treatment. This study aims to evaluate the effects of SNF472 on limb functional recovery and blood perfusion in a Vitamin D3 (VitD)-induced arterial calcification rat model. Method Arterial calcification was induced in 32 Sprague Dawley rats by 3 consecutive daily s.c. doses of 120 kIU/kg VitD. Rats were divided into four groups and treated during 12 days by: placebo s.c, placebo p.o, SNF472 (20 mg/kg/day, s.c.) or cilostazol (20 mg/kg/day, p.o.). An additional group of 8 rats without VitD received vehicle only (sham). Efficacy was evaluated at day 12 and 17 (5 days after treatment stop). Posterior limb blood perfusion was measured using Laser Doppler Imaging and limb walking ability was evaluated by measuring Maximum Walking Distance (MWD) and Maximum Walking Time (MWT) using a treadmill. Rats were sacrificed at day 26 (14 days after treatment stop), and aortas were collected for calcium analysis. Results VitD-induced arterial calcification was associated with decreased blood perfusion and impairment of limb walking ability (MWT and MWD) compared to sham. SNF472 reduced aorta calcification by 41% compared to placebo. No effects of cilostazol on vascular calcification were observed. The inhibition of calcification in SNF472-treated animals was associated with significant higher limb blood perfusion compared to placebo or Cilostazol (1.28 and 1.37-fold higher, respectively at day 12: p&amp;lt; 0.001) and it was translated into a significant improvement in walking ability compared to placebo (515±114 meters vs 334±187 meters, respectively: p&amp;lt;0.05). Conclusion SNF472 shows improvements in vascular calcification, blood perfusion and a functional parameter like walking distance in a PAD vascular calcification rat model. These results suggest that SNF472 may represent a new therapeutic approach for the treatment of PAD associated with high vascular calcification such as in renal disease.