Claudication Onset Time Research Articles

Effects of short-term dietary nitrate supplementation on exercise and coronary blood flow responses in patients with peripheral artery disease.

Peripheral arterial disease (PAD) is a prevalent vascular disorder characterized by atherosclerotic occlusion of peripheral arteries, resulting in reduced blood flow to the lower extremities and poor walking ability. Older patients with PAD are also at a markedly increased risk of cardiovascular events, including myocardial infarction. Recent evidence indicates that inorganic nitrate supplementation, which is abundant in certain vegetables, augments nitric oxide (NO) bioavailability and may have beneficial effects on walking, blood pressure, and vascular function in patients with PAD. We sought to determine if short-term nitrate supplementation (via beetroot juice) improves peak treadmill time and coronary hyperemic responses to plantar flexion exercise relative to placebo (nitrate-depleted juice) in older patients with PAD. The primary endpoints were peak treadmill time and the peak coronary hyperemic response to plantar flexion exercise. Eleven PAD patients (52-80 yr.; 9 men/2 women; Fontaine stage II) were randomized (double-blind) to either nitrate-rich (Beet-IT, 0.3 g inorganic nitrate twice/day; BRnitrate) or nitrate-depleted (Beet-IT, 0.04 g inorganic nitrate twice/day, BRplacebo) beetroot juice for 4 to 6 days, followed by a washout of 7 to 14 days before crossing over to the other treatment. Patients completed graded plantar flexion exercise with their most symptomatic leg to fatigue, followed by isometric handgrip until volitional fatigue at 40% of maximum on day 4 of supplementation, and a treadmill test to peak exertion 1-2 days later while continuing supplementation. Hemodynamics and exercise tolerance, and coronary blood flow velocity (CBV) responses were measured. Although peak walking time and claudication onset time during treadmill exercise did not differ significantly between BRplacebo and BRnitrate, the diastolic blood pressure response at the peak treadmill walking stage was significantly lower in the BRnitrate condition. Increases in CBV from baseline to peak plantar flexion exercise after BRplacebo and BRnitrate showed a trend for a greater increase in CBV at the peak workload of plantar flexion with BRnitrate (p = 0.06; Cohen's d = 0.56). Overall, these preliminary findings suggest that inorganic nitrate supplementation in PAD patients is safe, well-tolerated, and may improve the coronary hyperemic and blood pressure responses when their calf muscles are most predisposed to ischemia.Clinical trial registration:https://clinicaltrials.gov/, identifier NCT02553733.

Is the Walking Impairment Questionnaire a surrogate marker of 6-minute walking test performance in patients with peripheral artery disease with different degrees of claudication symptoms?

To analyze the associations between the Walking Impairment Questionnaire (WIQ) and 6-minute walk test (6MWT) in absolute or relative performance in patients with peripheral artery disease (PAD) and different degrees of claudication symptoms. Two hundred and sixty-seven patients with PAD and claudication symptoms participated in the study. All patients underwent 6MWT and WIQ tests. Patients were divided into tertile groups according to their 6MWT performance (1st tertile = severe, 2nd = moderate, 3rd = mild). Multiple linear regression was performed to investigate the association between WIQ scores and the achievement of expected performance in the 6MWT. Claudication onset distance and time, total walking distance, and the percentage of the predicted values had a significant weak correlation (P < 0.01) with WIQ scores (distance, speed, and stair-climbing capacity). The correlations for almost all variables were slightly higher in the 1st tertile compared with the 2nd and 3rd tertiles (i.e. WIQ-distance and Claudication onset time, r = 0.25 and 0.12, WIQ-distance and Claudication onset distance, r = 0.34 and 0.18; WIQ-distance and total walking distance, r = 0.23 and 0.18, respectively). Multilinear regression confirmed a slightly superior relationship in the 1st tertile compared with the 2nd tertile (i.e. WIQ-distance and Claudication onset time, R2 = 0.24 and R2 = 0.01; WIQ-distance and Claudication onset distance, R2 = 0.25 and R2 = 0.03, respectively). WIQ is weakly associated with absolute and relative 6MWT performance in patients with PAD. Despite slightly better correlations in patients with severe claudication symptoms, WIQ scores must be used with care as a surrogate marker of 6MWT performance in this group.

Magnetic Resonance Imaging-Derived Microvascular Perfusion Modeling to Assess Peripheral Artery Disease.

Background Computational fluid dynamics has shown good agreement with contrast-enhanced magnetic resonance imaging measurements in cardiovascular disease applications. We have developed a biomechanical model of microvascular perfusion using contrast-enhanced magnetic resonance imaging signal intensities derived from skeletal calf muscles to study peripheral artery disease (PAD). Methods and Results The computational microvascular model was used to study skeletal calf muscle perfusion in 56 individuals (36 patients with PAD, 20 matched controls). The recruited participants underwent contrast-enhanced magnetic resonance imaging and ankle-brachial index testing at rest and after 6-minute treadmill walking. We have determined associations of microvascular model parameters including the transfer rate constant, a measure of vascular leakiness; the interstitial permeability to fluid flow which reflects the permeability of the microvasculature; porosity, a measure of the fraction of the extracellular space; the outflow filtration coefficient; and the microvascular pressure with known markers of patients with PAD. Transfer rate constant, interstitial permeability to fluid flow, and microvascular pressure were higher, whereas porosity and outflow filtration coefficient were lower in patients with PAD than those in matched controls (all P values ≤0.014). In pooled analyses of all participants, the model parameters (transfer rate constant, interstitial permeability to fluid flow, porosity, outflow filtration coefficient, microvascular pressure) were significantly associated with the resting and exercise ankle-brachial indexes, claudication onset time, and peak walking time (all P values ≤0.013). Among patients with PAD, interstitial permeability to fluid flow, and microvascular pressure were higher, while porosity and outflow filtration coefficient were lower in treadmill noncompleters compared with treadmill completers (all P values ≤0.001). Conclusions Computational microvascular model parameters differed significantly between patients with PAD and matched controls. Thus, computational microvascular modeling could be of interest in studying lower extremity ischemia.

Relation of non-exercise walking activity with exercise performance in patients with peripheral artery disease: NEW activity for PAD

IntroductionCommunity-based structured exercise training (CB-SET) programs are beneficial for patients with peripheral artery disease (PAD). However, the impact of lower levels of walking activity accumulated separately from formal exercise is unclear. The aim of this study was to determine the relation of non-exercise walking (NEW) activity with exercise performance in PAD. MethodsThis was a post hoc analysis from twenty patients with PAD enrolled in a 12 week CB-SET program using diaries and accelerometry. Formal exercise (3 sessions·week−1) was detected using patient-reported diary entries that corresponded with accelerometer step data. NEW activity was characterized as steps completed over five days each week, excluding steps achieved during formal exercise sessions. The primary exercise performance outcome was peak walking time (PWT) assessed on a graded treadmill. Secondary performance outcomes included claudication onset time (COT) from the graded treadmill and peak walking distance (PWD) achieved during the six-minute walk test (6MWT). Partial Pearson correlations evaluated the relation of NEW activity (step·week−1) with exercise performance outcomes using exercise session intensity (step·week−1) and duration (min·week−1) as covariates. ResultsNEW activity demonstrated a moderate, positive correlation with change in PWT (r=0.50, p=0.04). Other exercise performance outcomes were not significantly related to NEW activity (COT: r=0.14; 6MWT PWD: r=0.27). ConclusionsA positive association was demonstrated between NEW activity and PWT following 12 weeks of CB-SET. Interventions to increase physical activity levels outside of formal exercise sessions may be beneficial for patients with PAD.

Magnetic resonance imaging based superficial femoral artery velocity measurements in peripheral artery disease

Peripheral artery disease (PAD) causes lower extremity dysfunction and is associated with an increased risk of cardiovascular mortality and morbidity. In this study, we analyzed how non-invasive 2-dimensional-phase-contrast magnetic resonance imaging (2D-PC-MRI) measured velocity markers of the distal superficial femoral artery (SFA) are associated with clinical and functional characteristics of PAD. A total of 70 (27 diabetic and 43 non-diabetic) PAD patients were included in this secondary analysis of data collected from the Effect of Lipid Modification on Peripheral Artery Disease after Endovascular Intervention Trial (ELIMIT). Electrocardiographically (ECG)-gated 2D-PC-MRI was performed at a proximal and a distal imaging location of the distal SFA. Baseline characteristics did not differ between diabetic and non-diabetic PAD patients. Claudication onset time (COT) was shorter in diabetic PAD patients compared to non-diabetics (0.56 (inter quartile range (IQR): 0.3, 2.04) minutes vs. 1.30 (IQR: 1.13, 2.15) minutes, p = 0.025). In a pooled analysis of all 70 PAD patients, maximum velocity was significantly higher in the proximal compared with the distal SFA segment (43.97 (interquartile range (IQR): 20.4, 65.2) cm/s; vs. 34.9 (IQR: 16.87, 51.71) cm/s; p < 0.001). The maximum velocities in both the proximal and distal SFA segments were significantly higher in diabetic PAD patients compared with non-diabetics (proximal: 53.6 (IQR: 38.73, 89.43) cm/s vs. 41.49 (IQR: 60.75, 15.9) cm/s, p = 0.033; distal: 40.8 (IQR: 23.7, 71.90) cm/s vs. 27.4 (IQR: 41.67, 12.54) cm/s, p = 0.012). Intra-observer variability, as assessed by intraclass correlation (ICC) analysis, was excellent for SFA mean and maximum velocities (0.996 (confidence interval [CI]: 0.996, 0.997); 0.999 (CI: 0.999, 0.999)). In conclusion, 2D-PC-MRI SFA velocity measures are reproducible and may be of interest in assessing diabetic and non-diabetic PAD patients.

Acute Effects of Dietary Nitrate on Exercise Tolerance, Muscle Oxygenation, and Cardiovascular Function in Patients With Peripheral Arterial Disease

Previous studies have used supplements to increase dietary nitrate intake in clinical populations. Little is known about whether effects can also be induced through vegetable consumption. Therefore, the aim of this study was to assess the impact of dietary nitrate, through nitrate-rich vegetables (NRV) and beetroot juice (BRJ) supplementation, on plasma nitrate and nitrite concentrations, exercise tolerance, muscle oxygenation, and cardiovascular function in patients with peripheral arterial disease. In a randomized crossover design, 18 patients with peripheral arterial disease (age: 73 ± 8years) followed a nitrate intake protocol (∼6.5mmol) through the consumption of NRV, BRJ, and nitrate-depleted BRJ (placebo). Blood samples were taken, blood pressure and arterial stiffness were measured in fasted state and 150min after intervention. Each intervention was followed by a maximal walking exercise test to determine claudication onset time and peak walking time. Gastrocnemius oxygenation was measured by near-infrared spectroscopy. Blood samples were taken and blood pressure was measured 10min after exercise. Mean plasma nitrate and nitrite concentrations increased (nitrate; Time × Intervention interaction; p < .001), with the highest concentrations after BRJ (494 ± 110μmol/L) compared with NRV (202 ± 89μmol/L) and placebo (80 ± 19μmol/L; p < .001). Mean claudication onset time and peak walking time did not differ between NRV (413 ± 187s and 745 ± 220s, respectively), BRJ (392 ± 154s and 746 ± 176s), and placebo (403 ± 176s and 696 ± 222s) (p = .762 and p = .165, respectively). Gastrocnemius oxygenation, blood pressure, and arterial stiffness were not affected by the intervention. NRV and BRJ intake markedly increase plasma nitrate and nitrite, but this does not translate to improved exercise tolerance, muscle oxygenation, and/or cardiovascular function.

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.

Acute effects of leg heat therapy on walking performance and cardiovascular and inflammatory responses to exercise in patients with peripheral artery disease.

Lower‐extremity peripheral artery disease (PAD) is associated with increased risk of cardiovascular events and impaired exercise tolerance. We have previously reported that leg heat therapy (HT) applied using liquid‐circulating trousers perfused with warm water increases leg blood flow and reduces blood pressure (BP) and the circulating levels of endothelin‐1 (ET‐1) in patients with symptomatic PAD. In this sham‐controlled, randomized, crossover study, sixteen patients with symptomatic PAD (age 65 ± 5.7 years and ankle‐brachial index: 0.69 ± 0.1) underwent a single 90‐min session of HT or a sham treatment prior to a symptom‐limited, graded cardiopulmonary exercise test on the treadmill. The primary outcome was the peak walking time (PWT) during the exercise test. Secondary outcomes included the claudication onset time (COT), resting and exercise BP, calf muscle oxygenation, pulmonary oxygen uptake (V̇O2), and plasma levels of ET‐1, interleukin‐6 (IL‐6) and tumor necrosis factor‐alpha (TNF‐α). Systolic, but not diastolic BP, was significantly lower (~7 mmHg, p < .05) during HT when compared to the sham treatment. There was also a trend for lower SBP throughout the exercise and the recovery period following HT (p = .057). While COT did not differ between treatments (p = .77), PWT tended to increase following HT (CON: 911 ± 69 s, HT: 954 ± 77 s, p = .059). Post‐exercise plasma levels of ET‐1 were also lower in the HT session (CON: 2.0 ± 0.1, HT: 1.7 ± 0.1, p = .02). Calf muscle oxygenation, V̇O2, COT, IL‐6, and TNF‐α did not differ between treatments. A single session of leg HT lowers BP and post‐exercise circulating levels of ET‐1 and may enhance treadmill walking performance in symptomatic PAD patients.

Abstract 14802: Relation of Non-exercise Walking Activity With Exercise Performance in Patients With Peripheral Artery Disease

Introduction: Structured exercise programs in home settings are beneficial for patients with peripheral artery disease (PAD). However, the impact of lower levels of walking activity accumulated separately from formal home exercise in PAD is unclear. The aim of this study was to determine the relation of non-exercise walking (NEW) activity with exercise performance in PAD. Methods: This was a post-hoc analysis from twenty patients with PAD enrolled in a 12-week structured home-based walking exercise program using diaries and accelerometry. Formal exercise sessions (3 sessions·week -1 ) were detected using patient-reported diary entries that corresponded with accelerometer step data. NEW activity was characterized as steps completed over five days each week, excluding steps during formal exercise sessions. The primary outcome for the intent-to-treat analysis was peak walking time (PWT) assessed on a graded treadmill. Secondary outcomes were claudication onset time (COT) from the graded treadmill test and maximal distance achieved during the six-minute walk test (6MWT). Pearson correlations evaluated the relation between NEW activity (step·week -1 ) and exercise performance outcomes using intensity (step·week -1 ) and duration (min·week -1 ) from formal exercise sessions as covariates. Results: NEW activity demonstrated a strong, positive correlation with change in PWT (r=0.50, p=0.04) when controlling for exercise intensity and duration during the 12-week intervention. Other exercise performance outcomes were not significantly related to NEW activity (COT: r=0.14; 6MWT maximal distance: r=0.27). Conclusions: A positive association was demonstrated between NEW activity and the primary outcome of PWT following 12 weeks of structured home-based walking exercise. Interventions to improve physical activity outside of formal exercise sessions may be beneficial for patients with PAD.

Association between calf muscle oxygen saturation with ambulatory function and quality of life in symptomatic patients with peripheral artery disease

ObjectiveThe objective of this study was to determine whether calf muscle hemoglobin oxygen saturation (Sto2) obtained during a standardized treadmill test is associated with ambulatory function and health-related quality of life (HRQoL) in patients with symptomatic peripheral artery disease (PAD). We hypothesized that a rapid decline in calf muscle Sto2 during walking is associated with impaired ambulatory function and HRQoL and that these associations are independent of ankle-brachial index (ABI). MethodsCalf muscle Sto2, peak walking time, and claudication onset time were obtained during a treadmill test in 151 symptomatic men and women with PAD. Patients were further characterized by demographic variables, comorbid conditions, cardiovascular risk factors, ABI, 6-minute walk distance, daily ambulatory activity, Walking Impairment Questionnaire (WIQ) score, and Medical Outcomes Study 36-Item Short Form Health Survey physical function score to assess HRQoL. ResultsThe median calf muscle Sto2 value at rest was 52%, which declined to 22% after only 1 minute of walking during the treadmill test and reached a minimum value of 9% after a median time of 87 seconds of walking. Of the various calf muscle Sto2 measurements obtained during the treadmill test, the exercise time to the minimum calf muscle Sto2 value (log transformed) had the strongest univariate associations with peak walking time (r = 0.56; P < .001), claudication onset time (r = 0.49; P < .001), 6-minute walk distance (r = 0.31; P < .001), WIQ distance score (r = 0.33; P < .001), WIQ speed score (r = 0.39; P < .001), WIQ stair-climbing score (r = 0.37; P < .001), and Medical Outcomes Study 36-Item Short Form Health Survey physical function score (r = 0.32; P < .001). In adjusted multiple regression models, these associations persisted (P < .001) after adjustment for demographic measures, cardiovascular risk factors, comorbid conditions, and ABI. ConclusionsMore rapid decline in oxygen saturation of the calf musculature during walking, indicative of impaired microcirculation, is predictive of impaired ambulatory function and HRQoL in patients with symptomatic PAD. Of particular importance, these associations are independent of ABI and other common health burdens, highlighting the clinical relevance that the microcirculation has on ambulatory function and HRQoL in patients with symptomatic PAD.

Effects of heated water-based versus land-based exercise training on vascular function in individuals with peripheral artery disease.

Peripheral artery disease (PAD) is an atherosclerotic disease that is associated with poor vascular function, walking impairment, and reduced quality of life. Land-based exercise therapy (LBET) is frequently recommended to improve walking and reduce symptoms. Recently, evidence has suggested that heated-water exercise therapy (HWET) is an effective intervention for PAD. However, the efficacy of LBET versus HWET in PAD patients had not been elucidated. Therefore, we sought to compare effects of LBET with HWET on cardiovascular function, exercise tolerance, physical function, and body composition in PAD patients. PAD patients (n = 53) were recruited and randomly assigned to a LBET group (n = 25) or HWET group (n = 28). The LBET group performed treadmill walking, whereas the HWET group performed walking in heated water for 12 wk. Leg (legPWV) and brachial-to-ankle arterial stiffness (baPWV), blood pressure (BP), ankle-brachial index (ABI), 6-min walking distance (6MWD), claudication onset time (COT), physical function, and body composition were assessed before and after 12 wk. There were significant group-by-time interactions (P < 0.05) for legPWV, BP, 6MWD, COT, body composition, and resting metabolic rate (RMR). Both groups significantly reduced (P < 0.05) legPWV, BP, and body fat percentage, and HWET measures were significantly lower than LBET measures. Both groups significantly increased 6MWD, COT, and RMR, and HWET group measures were significantly greater than LBET measures. A time effect was noted for baPWV reduction in both groups (P < 0.05). These results suggest that both LBET and HWET improve cardiovascular function, exercise tolerance, and body composition, and HWET showed considerably greater improvements compared with LBET in patients with PAD.NEW & NOTEWORTHY The results of this study reveal for the first time that although land-based exercise therapy is effective for reducing arterial stiffness and blood pressure in patients with peripheral artery disease (PAD), heated-water exercise therapy demonstrates greater benefits on vascular function. The greater improvements in muscular strength, time to onset of claudication, and exercise tolerance after heated-water exercise therapy may have clinical implications for improving quality of life in patients with PAD. The heated-water exercise therapy intervention demonstrated relatively higher exercise training adherence (∼88%) compared with the land-based exercise intervention (∼81%).

Assessment of behavioral determinants influencing success of supervised exercise therapy in patients with intermittent claudication: A cross sectional survey

BackgroundSupervised exercise therapy is the first step in treatment of intermittent claudication. However, adherence to supervised exercise therapy is low. Limited access and reimbursement issues are known reasons, though lack of motivation is often leading. Behavioral determinants influencing motivation and thus adherence to supervised exercise therapy remain to be investigated. In this study we sought to determine which behavioral determinants would be of influence on the long-term adherence of supervised exercise therapy. Methods200 patients, newly diagnosed with peripheral arterial disease Rutherford classification II–III, were sent a questionnaire to assess motivation and behavior with regard to supervised exercise therapy. The questionnaire was constructed using the I-CHANGE model for explaining motivational and behavioral change. Baseline characteristics were acquired from medical records. Alpha Cronbach's was calculated to test reliability of the questionnaire. Results108 (54%) patients returned their questionnaire. A total of 79% patients followed supervised exercise therapy. Patients who increased their walking distance after supervised exercise therapy have significantly greater knowledge (p = 0.05), positive attitude (p = 0.03) and lower negative attitude (p = 0.01). Patients with a higher self-efficacy remained significantly more active after participating in supervised exercise therapy (p = 0.05). ConclusionIncreasing the determinants knowledge, attitude and self-efficacy will improve adherence to supervised exercise therapy and result in delayed claudication onset time.

Inflammation and Muscle Oxygen Saturation are Associated with Exercise Pressor Response in Peripheral Artery Disease

PURPOSE: To determine whether calf muscle oxygen saturation (StO2) and vascular biomarkers of inflammation and oxidative stress were associated with an exercise pressor response during treadmill walking in patients with symptomatic peripheral artery disease (PAD). METHODS: A total of 179 patients were characterized on demographic variables, comorbid conditions, cardiovascular risk factors, ankle/brachial index, peak walking time (PWT), claudication onset time (COT), and calf muscle oxygen saturation (StO2) during a graded maximal treadmill test. The exercise pressor response was measured as the change in blood pressure from rest to the end of the first 2-minute treadmill exercise work stage (2 mph, 0% grade). Patients were further characterized on endothelial effects of circulating factors present in the sera using a cell culture-based bioassay on primary human arterial endothelial cells, and on circulating inflammatory and vascular biomarkers. RESULTS: During the maximal treadmill test, patients experienced COT at 197±164 seconds (mean±SD) and PWT at 395±254 seconds. There was a wide range in the change in systolic blood pressure (-46 to 50 mm Hg) and in diastolic blood pressure (-23 to 38 mm Hg), with mean increases of 4.3 mm Hg and 1.4 mm Hg, respectively. In multiple regression analyses, significant predictors of systolic blood pressure included glucose (p<0.001) and insulin (p=0.039). The significant predictors of diastolic blood pressure included cultured endothelial cell apoptosis (p=0.019), the percentage drop in exercise calf muscle StO2 (p=0.023), high sensitivity C-reactive protein (p=0.032), and glucose (p=0.033). CONCLUSION: Higher levels in pro-inflammatory vascular biomarkers, impaired calf muscle StO2 during exercise, and elevated blood glucose were independently associated with greater exercise pressor response in patients with symptomatic PAD. The clinical implication is that exercise and nutritional interventions designed to improve inflammation, microcirculation, and glucose metabolism may ameliorate the exercise pressor response in patients with symptomatic PAD.

Beet the Best?

A primary goal of therapy for patients with peripheral artery disease (PAD) and intermittent claudication is increased ambulatory function. Supervised exercise rehabilitation was recently shown to confer superior walking benefits to pharmacological or surgical interventions. Increases in plasma inorganic nitrite, via oral nitrate, have been shown to increase exercise performance in both human and animal models, especially in hypoxic conditions. To determine whether a 36-session exercise rehabilitation program while consuming oral inorganic nitrate (4.2 mmol concentrated beetroot juice) would produce superior benefits over exercise plus placebo in pain-free walking and markers of increased skeletal muscle perfusion in patients with PAD and intermittent claudication. This was a randomized, double-blind, per-protocol study design. After the 12-week protocol, claudication onset time on a maximal treadmill test increased by 59.2±57.3 s for the exercise plus placebo group (n=13) and by 180.3±46.6 s for the exercise plus beetroot juice group (n=11; P≤0.05). This produced a between treatment medium to large standardized effect size (Cohen d) of 0.62 (95% CI, -0.23 to +1.44). The data for 6-minute walk distance showed a similar pattern with increases of 24.6±12.1 and 53.3±19.6 m ( P≤0.05) in the exercise plus placebo and exercise plus beetroot juice groups, respectively. Measures of gastrocnemius perfusion, including ankle-brachial index, peak reactive hyperemic blood flow, and tissue deoxygenation characteristics, during exercise (assessed my near-infrared spectroscopy) all changed significantly for the exercise plus beetroot juice group with moderate-to-large effect sizes over exercise plus placebo changes. Although it is premature to speculate on overall clinical utility of a nitrate-based therapy for PAD, this early pilot study evidence is encouraging. Specifically, our data suggests that increasing plasma nitrite before exercise may allow PAD subjects to train with less pain, at higher workloads for longer durations at each training session, thereby maximizing the beneficial peripheral vascular and skeletal muscle adaptations. URL: http://www.clinicaltrials.gov . Unique identifier: NCT01684930 and NCT01785524.

Greater Exercise Pressor Response Is Associated With Impaired Claudication Outcomes in Symptomatic Peripheral Artery Disease

We determined whether a greater exercise pressor response during a constant-load treadmill test was associated with lower peak walking time (PWT) and claudication onset time (COT) measured during a graded maximal treadmill test in 304 patients with symptomatic peripheral artery disease (PAD). The exercise pressor response was assessed by measuring heart rate and blood pressure (BP) at rest and during a constant-load treadmill test (speed = 2 mph, grade = 0%). After only 2 minutes of walking, mean heart rate increased by 26 beats/min from rest and mean systolic BP increased by 16 mm Hg. In adjusted analyses, increases in systolic BP ( P = .021), heart rate ( P = .002), mean arterial pressure ( P = .034), and rate-pressure product ( P < .001) from rest to 2 minutes of constant-load exercise were negatively associated with COT. Similarly, increases in heart rate ( P = .012) and rate-pressure product ( P = .018) from rest to 2 minutes of constant-load exercise were negatively associated with PWT. A greater exercise pressor response observed after only 2 minutes of walking at no incline was independently associated with impaired claudication outcomes in patients with symptomatic PAD. The implication is that the exercise pressor response is an important and easily obtained clinical measurement that partially explains differences in PWT and COT.

Effects of a 12-Week mHealth Program on FunctionalCapacity and Physical Activity in Patients With PeripheralArtery Disease

Supervised exercise is beneficial for peripheral artery disease (PAD) patients limited by intermittent claudication (IC). However, supervised exercise for PAD remains widely underutilized. Mobile health (mHealth) provides an intermediate solution between supervised and independent home-based exercise. The purpose of this study was to determine the effects on functional capacity and physical activity patterns of a 12-week mHealth program in PAD patients with IC. Twenty patients were randomized into usual care or a 12-week mHealth intervention consisting of patient education, smartphones, and physical activity trackers. Patient education was disseminated through smartphone and a daily exercise prescription was given based on steps per day. Primary outcomes were 12-week changes in peak VO2 and claudication onset time; and changes in physical activity measured by steps per/day and minutes of exercise per/week. mHealth patients significantly increased peak VO2 from 15.2 ± 4.3 to 18.0 ± 4.8 ml/kg/min (20.3 ± 26.4%; p ≤0.05), while usual care did not change from 14.3 ± 5.4 to 14.5 ± 5.7 ml/kg/min (1.0 ± 6.9%; NS). Comparison of these changes resulted in a significant difference between groups (p ≤0.05) for peak VO2. Claudication onset time significantly increased in mHealth (320 ± 226 to 525 ± 252 seconds; ≤ 0.05), while usual care demonstrated a worsening (252 ± 256 to 231 ± 196 seconds; NS). The comparison of these group changes resulted in a significant difference (p ≤0.05). Neither steps per day or minutes of activity reached significant differences between groups. In conclusion, a 12-week mHealth program in PAD patients with IC can improve peak VO2 and claudication onset time; and mHealth interventions represent a promising alternative therapy for those patients who cannot participate in supervised exercise.

Abstract 136: Near-Infrared Spectroscopy for Diagnosis and Characterization of Peripheral Artery Disease Severity

Background: Peripheral artery disease (PAD) frequently is undertreated. ABI is the standard for diagnosis of PAD but is limited in its ability to predict functional status and risk of disease progression. Previous work with Near-Infrared Spectroscopy (NIRS) has demonstrated impaired oxygen utilization in PAD muscle and may allow for improved diagnosis and stratification of disease severity. We hypothesize that exercise produces characteristic changes in lower-extremity muscle oxygenated heme percent (StO 2 ) which differentiates PAD from control and predicts PAD severity better than ABI. Methods: We recruited 31 PAD subjects with intermittent claudication (IC) (ABI &lt; 0.9) and 9 controls (ABI ≥ 0.9 and no IC). All subjects completed a Gardner maximal treadmill test. PAD subjects walked until IC was prohibitive (peak walking time, PWT) and controls walked for 540 seconds. StO 2 measurements were taken from the lateral gastrocnemius with the wireless MOXY NIRS monitor. StO 2 was documented at baseline, 60s, claudication onset time (COT), and PWT. For each subject, StO 2 values were expressed as percent of baseline to allow for comparison across subjects. Data were analyzed by student’s t-test and linear regression. Results: Mean baseline StO 2 values were 46±11% and 58±17%, respectively, for PAD and control subjects. Among controls, StO 2 dropped below baseline at 140±101s whereas PAD subjects dropped below baseline at 6±10s (P&lt;0.001). PAD StO 2 s at 60s, COT, and PWT were compared to control StO 2 s at the corresponding time points. PAD patients’ StO 2 at 60s, COT, and PWT were 65.2±37.9% (n=31), 66.4±35.5% (n=31), and 73.2±26.0% (n=25) lower than controls, respectively (P &lt; 0.001). PAD subjects were separated into tertiles of PWT. Relative to baseline, StO 2 decreased 84.2±18.4% (n=11) in the lowest tertile compared to 29.8±30.6% (n=10) in the highest tertile (P&lt;0.05). Percent decrease in StO 2 at 60s correlated to PWT (R 2 =0.56) in contrast to ABI (R 2 =0.018). Conclusion: During exercise, PAD patients exhibited a characteristic change in StO 2 . In contrast to ABI, StO 2 predicted PAD-related exercise limitation. These data suggest NIRS in conjunction with traditional methods could be used to guide diagnostic and treatment decisions.

Abstract 21129: Arterial Anatomy and Functional Performance in Peripheral Artery Disease: Cardiovascular Cell Therapy Research Network Patients With Intermittent Claudication Injected With ALDH Bright Cells: CCTRN PACE

Introduction: Claudication is characterized by the presence of a stenosis or occlusion of arteries in the lower extremities that limits walking endurance compared with healthy individuals. Magnetic Resonance (MR) based assessments of leg arterial anatomy may enable improved understanding of the underlying causes of functional impairment. Hypothesis: The severity of stenosis in the lower extremity arteries and collateral vessel density is associated with functional impairment. Methods: A total of 82 participants with claudication and infrainguinal PAD were recruited across 9 US sites as part of the National Heart, Lung, and Blood Institute-sponsored CCTRN PACE clinical trial. Baseline (pre-treatment) data for 78 participants were used for this analysis. Functional performance was assessed by treadmill test measures of peak walking time (PWT) and claudication onset time (COT). Contrast-enhanced time-resolved magnetic resonance angiography was used to assess maximum stenosis of the superficial femoral artery (SFA) in each leg. The extent of arterial collateralization at the thigh (nTC) and calf (nCC) was measured by counting the number of vessels that bypassed a stenosis and reconstituted the main conduit vessel. Linear regression was used to evaluate the association between PWT and COT as the dependent variable and maximum stenosis, nTC and nCC as independent variables. Results: The participants were 66±9 years old, 27% female. The mean pre-exercise ankle brachial index in the more symptomatic leg was 0.61± 0.12. Participants were primarily Rutherford 2 (54%) and 3 (44%). At baseline, mean PWT was 5.0±2.6 min, COT was 1.6±0.9 min, nTC was 3.4±3.3 and nCC was 1.1±1.9. The maximum thigh stenosis was ≥75% in 77/78 and 99-100% in 66/78 participants. In linear regression models, maximum stenosis and nTC were not associated with PWT or COT. The nCC was associated with the COT (beta=0.08, p=0.008), and weakly associated with PWT (beta= 0.16, p=0.07). The association with COT remained after adjustment for thigh stenosis and nTC (beta=0.08, p=0.01). Conclusions: In patients with claudication and significant SFA stenosis, calf collateralization was associated with superior functional performance.

Sarcopenia in Peripheral Arterial Disease: Prevalence and Effect on Functional Status

Objectives(1) To determine the prevalence of sarcopenia in older men with peripheral arterial disease (PAD); (2) to compare a subgroup of the group with age-, race-, sex-, and body mass index (BMI)–matched non-PAD control counterparts, and (3) to compare the functional status of those with PAD with and without sarcopenia. DesignCohort study. SettingMedical center. ParticipantsSedentary community-dwelling men (N=108; age, >50y) with a confirmed diagnosis of PAD (44% blacks; BMI, 27.8±0.4kg/m2; ankle-brachial index, .62±.01). InterventionsNot applicable. Main Outcome MeasuresDual-energy x-ray absorptiometry scans were used to assess appendicular lean mass and determine the prevalence of sarcopenia by/height2. Treadmill tests were used to determine claudication onset time, peak walking time, and claudication recovery time. 6-Minute walk distance was also measured. ResultsSarcopenia prevalence in our PAD cohort was 25%. The PAD subgroup (n=42) matched with control counterparts in terms of race, sex, age, and BMI had higher prevalence rates than did their non-PAD counterparts (23.8% vs 2.4%; P<.05). Individuals with sarcopenia (n=28) had a shorter 6-minute walk distance (326±18.8m vs 380±9.7m; P<.05) and higher claudication recovery time (592±98s vs 395±29s; P<.05) than did individuals with PAD but without sarcopenia (n=80). There was no difference in claudication onset time or peak walking time between the PAD groups. ConclusionsMen with PAD demonstrate a high prevalence of sarcopenia. Those with sarcopenia and PAD demonstrate decreased mobility function.

Combined Dietary Nitrate and Exercise Intervention in Peripheral Artery Disease: Protocol Rationale and Design.

BackgroundPeripheral artery disease (PAD) is caused by atherosclerotic occlusions in the legs. It affects approximately 8-12 million people in the United States alone, one-third of whom suffer from intermittent claudication (IC), defined as ischemic leg pain that occurs with walking and improves with rest. Patients with IC suffer a markedly impaired quality of life and a high perception of disability. Improving pain-free walking time is a primary goal of rehabilitation in this population.ObjectiveThe nitric oxide (NO)-PAD trial is designed to compare the effects that 12 weeks of supervised exercise training, in combination with a high inorganic nitrate-content (beetroot [BR] juice) beverage or placebo (PL) beverage, has on clinical outcomes of exercise and functional capacity in two groups of PAD+IC patients: exercise training plus beetroot (EX+BR) and exercise training plus placebo (EX+PL). The primary aims of this randomized controlled, double-blind pilot study are to determine group differences following 12 weeks of EX+BR versus EX+PL in the changes for (1) exercise capacity: pain-free walking time (claudication onset time, COT), peak walk time (PWT), and maximal exercise capacity (peak oxygen uptake, VO2peak) during a maximal-graded cardiopulmonary exercise test (max CPX) and (2) functional capacity: 6-minute walk (6MW) distance. The secondary aims will provide mechanistic insights into the exercise outcome measures and will include (1) gastrocnemius muscle oxygenation during exercise via near-infrared spectroscopy (NIRS); (2) gastrocnemius muscle angiogenesis: capillaries per unit area and per muscle fiber, and relative fraction of type I, IIa, IIb, and IId/x fibers; and (3) vascular health/function via brachial artery flow-mediated dilation, lower-limb blood flow via plethysmography, and pulse wave velocity and reflection.MethodsA total of 30 subjects between 40 and 80 years of age with PAD who are limited by IC will undergo exercise training 3 days per week for 12 weeks (ie, 36 sessions). They will be randomized to either the EX+BR or EX+PL group where participants will consume a beverage high in inorganic nitrate (4.2 mmol) or a low-nitrate placebo, respectively, 3 hours prior to each training session.ResultsData collection from this study has been completed and is in the process of analysis and write-up. While the study is too underpowered—EX+BR, n=11; EX+PL, n=13—to determine between-group differences in the primary outcomes of COT, PWT, and 6MW, preliminary observations are promising with Cohen d effect sizes of medium to large.ConclusionsExercise training is currently the most effective therapy to increase functional capacity in PAD+IC. If the addition of inorganic nitrate to an exercise regimen elicits greater benefits, it may redefine the current standard of care for PAD+IC.Trial RegistrationClinicalTrials.gov NCT01684930; https://clinicaltrials.gov/ct2/show/NCT01684930 (Archived by WebCite at http://www.webcitation.org/6raXFyEcP)