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Background: The most common symptom of peripheral artery disease (PAD) is intermittent claudication that involves the calf, thigh, and/or buttock muscles. How the specific location of this leg pain is related to altered gait, however, is unknown., Objectives: We hypothesized that because the location of claudication symptoms uniquely affects different leg muscle groups in people with PAD, this would produce distinctive walking patterns., Methods: A total of 105 participants with PAD and 35 age-matched older volunteers without PAD (CTRL) were recruited. Participants completed walking impairment questionnaires (WIQ), Gardner-Skinner progressive treadmill tests, the six-minute walk test, and we performed an advanced evaluation of the biomechanics of their overground walking. Participants with PAD were categorized into 4 groups according to their stated pain location(s): calf only (C, n = 43); thigh and calf (TC, n = 18); buttock and calf (BC, n = 15); or buttock, thigh, and calf (BTC, n = 29). Outcomes were compared between CTRL, C, TC, BC and BTC groups using a one-way ANOVA with post-hoc comparisons to identify and assess statistically significant differences., Results: There were no significant differences between CTRL, C, TC, BC and BTC groups in distances walked or walking speed when either pain-free or experiencing claudication pain. Each participant with PAD had significantly dysfunctional biomechanical gait parameters, even when pain-free, when compared to CTRL (pain-free) walking data. During pain-free walking, out of the 18 gait parameters evaluated, we only identified significant differences in hip power generation during push-off (in C and TC groups) and in knee power absorption during weight acceptance (in TC and BC groups). There were no between-group differences in gait parameters while people with PAD were walking with claudication pain., Conclusions: Our data demonstrate that PAD affects the ischemic lower extremities in a diffuse manner irrespective of the location of claudication symptoms., Database Registration: ClinicalTrials.gov NCT01970332., (Copyright © 2023 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Objective: Supervised exercise therapy (SET) is a first-line treatment for patients with peripheral artery disease (PAD). The efficacy of SET is most commonly expressed by significant statistical improvement of parameters that do not clarify how each individual patient will benefit from SET. This study examined the minimal clinically important difference (MCID) in walking speed in claudicating patients with PAD after SET., Methods: A total of 63 patients with PAD-related claudication (Fontaine stage II PAD) participated in a 6-month SET program. Self-selected walking speed was measured before and after SET. Distribution and anchor-based approaches were used to estimate the MCID for small and substantial improvement. The ability to walk one block and the ability to climb one flight of stairs questions were chosen as anchor questions from the Medical Outcomes Study 36-item Short Form questionnaire. Receiver operating characteristics curve analyses were performed to detect the threshold for MCID in walking speed after treatment., Results: The distribution-based method estimated 0.03 m/s as a small improvement and 0.08 m/s as a substantial improvement after SET. Small and substantial improvements according to the anchor question walking one block were 0.05 m/s and 0.15 m/s, respectively. For the climbing one flight of stairs anchor question, 0.10 m/s was a small improvement. Receiver operating characteristics curve analyses identified an increase of 0.04 m/s and 0.03 m/s for improvement based on walking one block and climbing one flight of stairs, respectively., Conclusions: We report our findings for the MCID for walking speed among claudicating patients receiving SET. Claudicating patients who increase walking speed of 0.03 m/s or greater are more likely to experience a meaningful improvement in walking impairment than those who do not. The MCID reported in this study can serve as a benchmark for clinicians to develop goals and interpret clinically meaningful progress in the care of claudicating patients with PAD., (Copyright © 2021 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Peripheral artery disease (PAD), a severe atherosclerotic condition primarily of the elderly, afflicts 200 million individuals, worldwide, and is associated with lower extremity myopathy. Circulating markers of inflammation have been linked to risk and severity of PAD but the contribution of local inflammation to myopathy remains unknown. We evaluated, by ELISA, calf muscle of PAD patients (N = 23) and control subjects (N = 18) for local expression of inflammatory cytokines including Granulocyte/Monocyte Colony-Stimulating Factor (GM-CSF), Interleukin 17A (IL-17A), Interferon ϒ (IFN-ϒ), tumor necrosis factor α (TNF-α), and Interleukin 6 (IL-6). One or more of these cytokines were expressed in nineteen patients and 2 controls and coordinated expression of GM-CSF, IL-17A, IFN-ϒ, and TNF-α, a signature of activated, MHC Class II dependent autoreactive Th-cells, was unique to 11 patients. GM-CSF is the central driver of tissue-damaging myeloid macrophages. Patients with this cytokine signature had a shorter (P= 0.017) Claudication Onset Distance (17 m) compared with patients lacking the signature (102 m). Transforming Growth Factor β1 (TGFβ1) and Chemokine Ligand 5 (CCL5) were expressed coordinately in all PAD and control muscles, independently of GM-CSF, IL-17A, IFN-ϒ, TNF-α, or IL-6. TGFβ1 and CCL5 and their gene transcripts were increased in PAD muscle, consistent with increased age-associated inflammation in these patients. Serum cytokines were not informative of muscle cytokine expression. We have identified a cytokine profile of autoimmune inflammation in calf muscles of a significant proportion of claudicating PAD patients, in association with decreased limb function, and a second independent profile consistent with increased "inflammaging" in all PAD patients., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Background: Patients with peripheral artery disease (PAD) who experience intermittent claudication report a range of symptoms. Patients with symptoms other than classically described intermittent claudication may be at the highest risk for functional decline and mobility loss. Therefore, technologies allowing for characterization of PAD severity are desirable. Near-infrared spectroscopy (NIRS) allows for measurements of muscle heme oxygen saturation (StO 2 ) during exercise. We hypothesized lower extremities affected by PAD would exhibit distinct NIRS profiles as measured by a low-cost, wireless NIRS device and that NIRS during exercise predicts walking limitation., Methods: We recruited 40 patients with PAD and 10 control participants. All patients with PAD completed a computed tomographic angiography, 6-minute walk test, and a standardized treadmill test. Controls completed a 540-second treadmill test for comparison. StO 2 measurements were continuously taken from the gastrocnemius during exercise. Variables were analyzed by Fischer's exact, χ 2 , Wilcoxon rank-sum, and Kruskal-Wallis tests as appropriate. Correlations were assessed by partial Spearman correlation coefficients adjusted for occlusive disease pattern., Results: Patients with PAD experienced claudication onset at a median of 108 seconds with a median peak walking time of 288 seconds. The baseline StO 2 was similar between PAD and control. The StO 2 of PAD and control participants dropped below baseline at a median of 1 and 104 seconds of exercise, respectively (P < .0001). Patients with PAD reached minimum StO 2 earlier than control participants (119 seconds vs 522 seconds, respectively; P < .001) and experienced a greater change in StO 2 at 1 minute of exercise (-73.2% vs 8.3%; P < .0001) and a greater decrease at minimum exercise StO 2 (-83.4% vs -16.1%; P < .0001). For patients with PAD, peak walking time, and 6-minute walking distance correlated with percent change in StO 2 at 1 minute of exercise (r = -0.76 and -0.67, respectively; P < .001) and time to minimum StO 2 (r = 0.79 and 0.70, respectively; P < .0001)., Conclusions: In this initial evaluation of a novel, low-cost NIRS device, lower extremities affected by PAD exhibited characteristic changes in calf muscle StO 2 , which differentiated them from healthy controls and were strongly correlated with walking impairment. These findings confirm and expand on previous work demonstrating the potential clinical value of NIRS devices and the need for further research investigating the ability of low-cost NIRS technology to evaluate, diagnose, and monitor treatment response in PAD., (Copyright © 2019 Society for Vascular Surgery. All rights reserved.)

Objective: In patients with peripheral artery disease (PAD), supervised exercise therapy is a first line of treatment because it increases maximum walking distances comparable with surgical revascularization therapy. Little is known regarding gait biomechanics after supervised exercise therapy. This study characterized the effects of supervised exercise therapy on gait biomechanics and walking distances in claudicating patients with PAD., Methods: Forty-seven claudicating patients with PAD underwent gait analysis before and immediately after 6 months of supervised exercise therapy. Exercise sessions consisted of a 5-minute warmup of mild walking and stretching of upper and lower leg muscles, 50 minutes of intermittent treadmill walking, and 5 minutes of cooldown (similar to warmup) three times per week. Measurements included self-perceived ambulatory limitations measured by questionnaire, the ankle-brachial index (ABI), walking distance measures, maximal plantar flexor strength measured by isometric dynamometry, and overground gait biomechanics trials performed before and after the onset of claudication pain. Paired t-tests were used to test for differences in quality of life, walking distances, ABI, and maximal strength. A two-factor repeated measures analysis of variance determined differences for intervention and condition for gait biomechanics dependent variables., Results: After supervised exercise therapy, quality of life, walking distances, and maximal plantar flexor strength improved, although the ABI did not significantly change. Several gait biomechanics parameters improved after the intervention, including torque and power generation at the ankle and hip. Similar to previous studies, the onset of claudication pain led to a worsening gait or a gait that was less like healthy individuals with a pain-free gait., Conclusions: Six months of supervised exercise therapy produced increases in walking distances and quality of life that are consistent with concurrent improvements in muscle strength and gait biomechanics. These improvements occurred even though the ABI did not improve. Future work should examine the benefits of supervised exercise therapy used in combination with other available treatments for PAD., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Claudication is the most common manifestation of peripheral artery disease (PAD), producing significant ambulatory compromise. Limited information exists on the routine physical activity of claudicating patients. Our objective was to record the intensity/time profiles of physical activity and the timing and duration of sedentary behavior of a sample of community-dwelling claudicating patients., Methods: Forty-four claudicating patients referred to our vascular clinic were recruited. Physical activity was recorded using the ActiGraph GT1M activity monitor. The Actigraph monitor is a lightweight instrument designed to measure human movement through changes in acceleration, measured as counts over 1-minute time periods. Data from 7 consecutive days were used for the calculations. We processed the data using the ActiLife software program., Results: The average daily activity of the claudicating patients shows a steady increase beginning approximately 05:30 AM until a peak plateau from approximately 10:00 AM to 01:30 PM followed by a steady decrease until approximately 09:30 PM, when a sustained period of inactivity begins. The average claudicating patient takes 3586 steps per day at an average intensity of 1.77 metabolic equivalents of task (METs, a physiological measure expressing the energy cost of physical activities). Average physical activity intensity and peak intensity fluctuate very little during the day, and they rarely exceed the level of light activity (light = <3 METs maximum effort, such as casual walking or light housework). During awake time, approximately 7 hours are spent in sedentary behaviors (<1.5 METs), and sedentary time is spread throughout the day mostly in short intervals between periods of low-energy activity., Conclusions: Our study objectively demonstrates the reduced physical activity of claudicating patients and documents physical activity/duration profiles throughout the day. The intensity of the physical activity of the average claudicating patient fluctuates very little during the day and rarely exceeds a light intensity level. Claudicating patients spend approximately half of their awake time in sedentary behavior and when they walk they do it in short bursts followed by several minutes of rest. We anticipate that changes in routine physical activity/duration profiles of patients with PAD will provide relevant, sensitive, and direct measures of the effectiveness of therapeutic interventions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Peripheral artery disease (PAD) is a vascular disease caused by atherosclerosis, resulting in decreased blood flow to the lower extremities. The ankle-brachial index (ABI) is a standard PAD diagnostic test but only identifies reduced blood flow based on blood pressure differences. The early signs of PAD manifest themselves not only at a clinical level but also at an elemental and biochemical level. However, the biochemical and elemental alterations to PAD muscle are not well understood. The objective of this study was to compare fundamental changes in intracellular elemental compositions between control, claudicating, and critical limb ischemia muscle tissue., Materials and Methods: Gastrocnemius biopsies from three subjects including one control (ABI ≥ 0.9), one claudicating (0.4 ≤ ABI < 0.9), and one critical limb ischemia patient (ABI < 0.4) were evaluated using a scanning electron microscope and energy dispersive X-ray spectroscopy to quantify differences in elemental compositions. Spectra were collected for five myofibers per specimen. An analysis of variance was performed to identify significant differences in muscle elemental compositions., Results: This study revealed that intracellular magnesium and calcium were lower in PAD compared with control myofibers, whereas sulfur was higher. Magnesium and calcium are antagonistic, meaning, if magnesium concentrations go down calcium concentrations should go up. However, our findings do not support this antagonism in PAD. Our analysis found decreases in sodium and potassium, in PAD myofibers., Conclusions: These findings may provide insight into the pathologic mechanisms that may operate in ischemic muscle and aid in the development of specialized preventive and rehabilitative treatment plans for PAD patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Peripheral artery disease (PAD), a common manifestation of atherosclerosis, is characterized by lower leg ischemia and myopathy in association with leg dysfunction. Patients with PAD have impaired gait from the first step they take with consistent defects in the movement around the ankle joint, especially in plantar flexion. Our goal was to develop muscle strength profiles to better understand the problems in motor control responsible for the walking impairment in patients with PAD., Methods: Ninety-four claudicating PAD patients performed maximal isometric plantar flexion contractions lasting 10 seconds in two conditions: pain free (patient is well rested and has no claudication symptoms) and pain induced (patient has walked and has claudication symptoms). Sixteen matched healthy controls performed the pain-free condition only. Torque curves were analyzed for dependent variables of muscle strength and motor control. Independent t-tests were used to compare variables between groups, and dependent t-tests determined differences between conditions., Results: Patients with PAD had significantly reduced peak torque and area under the curve compared with controls. Measures of control differed between PAD conditions only. Load rate and linear region duration were greater in the pain condition. Time to peak torque was shorter in the pain condition., Conclusions: This study conclusively demonstrates that the plantar flexor muscles of the PAD patient at baseline and without pain are weaker in patients with PAD compared with controls. With the onset of claudication pain, patients with PAD exhibit altered muscle control strategies and further strength deficits are manifest compared to baseline levels. The myopathy of PAD legs appears to have a central role in the functional deterioration of the calf muscles, as it is evident both before and after onset of ischemic pain., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Peripheral artery disease (PAD), which affects an estimated 27 million people in Europe and North America, is caused by atherosclerotic plaques that limit blood flow to the legs. Chronic, repeated ischemia in the lower leg muscles of PAD patients is associated with loss of normal myofiber morphology and myofiber degradation. In this study, we tested the hypothesis that myofiber morphometrics of PAD calf muscle are significantly different from normal calf muscle and correlate with reduced calf muscle strength and walking performance., Methods: Gastrocnemius biopsies were collected from 154 PAD patients (Fontaine stage II) and 85 control subjects. Morphometric parameters of gastrocnemius fibers were determined and evaluated for associations with walking distances and calf muscle strength., Results: Compared with control myofibers, PAD myofiber cross-sectional area, major and minor axes, equivalent diameter, perimeter, solidity, and density were significantly decreased (P < 0.005), whereas roundness was significantly increased (P < 0.005). Myofiber morphometric parameters correlated with walking distances and calf muscle strength. Multiple regression analyses demonstrated myofiber cross-sectional area, roundness, and solidity as the best predictors of calf muscle strength and 6-min walking distance, whereas cross-sectional area was the main predictor of maximum walking distance., Conclusions: Myofiber morphometrics of PAD gastrocnemius differ significantly from those of control muscle and predict calf muscle strength and walking distances of the PAD patients. Morphometric parameters of gastrocnemius myofibers may serve as objective criteria for diagnosis, staging, and treatment of PAD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Previous studies have shown major deficits in gait for individuals with peripheral arterial disease before and after the onset of pain. However, these studies did not have subjects ambulate at similar velocities and potential exists that the differences in joint powers may have been due to differences in walking velocity. The purpose of this study was to examine the joint moments and powers of peripheral arterial disease limbs for subjects walking at similar self-selected walking velocities as healthy controls prior to onset of any symptoms. Results revealed peripheral arterial disease patients have reduced peak hip power absorption in midstance (p=0.017), reduced peak knee power absorption in early and late stance (p=0.037 and p=0.020 respectively), and reduced peak ankle power generation in late stance (p=0.021). This study reveals that the gait of patients with peripheral arterial disease walking prior to the onset of any leg symptoms is characterized by failure of specific and identifiable muscle groups needed to perform normal walking and that these gait deficits are independent of reduced gait velocity., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Peripheral arterial disease (PAD) is a manifestation of atherosclerosis resulting in intermittent claudication (IC) or leg pain during physical activity. Two drugs (cilostazol and pentoxifylline) are approved for treatment of IC. Our previous work has reported no significant differences in gait biomechanics before and after drug interventions when PAD patients walked without pain. However, it is possible that the drugs are more efficacious during gait with pain. Our aim was to use advanced biomechanical analysis to evaluate the effectiveness of these drugs while walking with pain. Initial and absolute claudication distances, joint kinematics, torques, powers, and gait velocity during the presence of pain were measured from 24 patients before and after 12 weeks of treatment with either cilostazol or pentoxifylline. We found no significant improvements after 12 weeks of treatment with either cilostazol or pentoxifylline on the gait biomechanics of PAD patients during pain. Our findings indicate that the medications cilostazol and pentoxifylline have reduced relevance in the care of gait dysfunction even during pain in patients with PAD.

Background: Recent research demonstrated that intermittent claudication patients have increased gait variability prior to the onset of claudication. However, it is unknown if these patients experience additional gait adaptations after the onset of claudication. Thus, we sought to determine how gait variability is affected by claudication in an effort to contribute to improved clinical management., Methods: Twenty-six intermittent claudication patients and 20 controls walked on a treadmill at self-selected speed; intermittent claudication patients were tested before (pain free) and after (pain) the onset of claudication. Variability of the ankle, knee, and hip joint angles was assessed using the largest Lyapunov exponent, standard deviation and coefficient of variation. Dependent t-tests were used to compare the pain free and pain conditions. Independent t-tests were used to compare intermittent claudication patients and controls., Findings: Pain free and pain conditions were not significantly different for any of the parameters evaluated except the ankle. Compared to controls, patients had significantly greater values for the largest Lyapunov exponent in both conditions for all joints., Interpretation: Gait variability was essentially the same before and after the onset of claudication at the knee and the hip, and was increased in both conditions compared to controls. This indicates altered cooperation between components of the locomotor system of intermittent claudication patients, likely due to the associated myopathy since differences were present even before the onset of claudication. This research helps provide essential biomechanical knowledge of intermittent claudication that contributes to improved clinical management., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: Claudication is the most common manifestation of peripheral arterial disease, producing significant ambulatory compromise. Our study evaluated patients with bilateral lower limb claudication and characterized their gait abnormality based on advanced biomechanical analysis using joint torques and powers., Methods: Twenty patients with bilateral claudication (10 with isolated aortoiliac disease and 10 with combined aortoiliac and femoropopliteal disease) and 16 matched controls ambulated on a walkway while 3-dimensional biomechanical data were collected. Patients walked before and after onset of claudication pain. Joint torques and powers at early, mid, and late stance for the hip, knee, and ankle joints were calculated for claudicating patients before and after the onset of claudication pain and were compared to controls., Results: Claudicating patients exhibited significantly reduced hip and knee power at early stance (weight-acceptance phase) due to decreased torques produced by the hip and knee extensors. In mid stance (single-limb support phase), patients had significantly reduced knee and hip power due to the decreased torques produced by the knee extensors and the hip flexors. In late stance (propulsion phase), reduced propulsion was noted with significant reduction in ankle plantar flexor torques and power. These differences were present before and after the onset of pain, with certain parameters worsening in association with pain., Conclusions: The gait of claudication is characterized by failure of specific and identifiable muscle groups needed to perform normal walking (weight acceptance, single-limb support, and propulsion). Parameters of gait are abnormal with the first steps taken, in the absence of pain, and certain of these parameters worsen after the onset of claudication pain., (Copyright (c) 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Pharmacological treatment has been used to alleviate the claudication symptoms and improve walking performance in peripheral arterial disease (PAD) patients. However, the effects of claudication treatments on gait mechanics have not been objectively identified with biomechanical techniques. For this study, 20 PAD patients were assigned to take either pentoxifylline (n=11) or cilostazol (n=9), the two FDA-approved pharmacological therapies used to treat intermittent claudication symptoms. All patients completed a gait evaluation protocol that involved the acquisition of kinematic and kinetic gait data before use of the medication and after 12 weeks of treatment. Results showed that treatment with either pentoxifylline or cilostazol resulted in limited overall improvement in gait parameters including joint angles and joint moments. Walking speed was unchanged, in either treatment group, as a result of the medication. These results suggest that to improve biomechanical walking parameters of PAD patients, clinicians cannot rely on drug therapies alone.

Objectives: Symptomatic peripheral arterial disease (PAD) results in significant gait impairment. In an attempt to fully delineate and quantify these gait alterations, we analyzed joint kinematics, torques (rotational forces), and powers (rotational forces times angular velocity) in patients with PAD with unilateral claudication for both the affected and nonaffected legs., Methods: Twelve patients with unilateral PAD (age, 61.69 +/- 10.53 years, ankle-brachial index [ABI]: affected limb 0.59 +/- 0.25; nonaffected limb 0.93 +/- 0.12) and 10 healthy controls (age, 67.23 +/- 12.67 years, ABI >1.0 all subjects) walked over a force platform to acquire gait kinetics, while joint kinematics were recorded simultaneously. Data were collected for the affected and nonaffected limbs during pain free (PAD-PF) and pain induced (PAD-P) trials. Kinetics and kinematics were combined to quantify torque and powers during the stance period from the hip, knee, and ankle joints., Results: The affected limb demonstrated significantly (P <.05) reduced ankle plantar flexion torque compared to controls during late stance in both PAD-PF and PAD-P trials. There were significant reductions in ankle plantar flexion power generation during late stance for both the affected (P <.05) and nonaffected limbs (P <.05) compared to control during PAD-PF and PAD-P trials. No significant differences were noted in torque comparing the nonaffected limbs in PAD-PF and PAD-P conditions to control for knee and hip joints throughout the stance phase. Significant reductions were found in knee power absorption in early stance and knee power generation during mid stance for both limbs of the patients with PAD as compared to control (P <.05)., Conclusion: Patients with PAD with unilateral claudication demonstrate significant gait impairments in both limbs that are present even before they experience any claudication symptoms. Overall, our data demonstrate significantly reduced ankle plantar flexion torque and power during late stance with reduced knee power during early and mid stance for the affected limb. Further studies are needed to determine if these findings are dependent on the location and the severity of lower extremity ischemia and whether the changes in the nonaffected limb are the result of underlying PAD or compensatory changes from the affected limb dysfunction., (Copyright 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: Claudication is the most common manifestation of peripheral arterial disease (PAD) producing significant ambulatory compromise. The purpose of this study was to use advanced biomechanical analysis to characterize the kinematic ambulatory pattern of claudicating patients. We hypothesized that compared with control subjects, claudicating patients have altered kinematic gait patterns that can be fully characterized utilizing advanced biomechanical analysis., Methods: The study examined fourteen PAD patients (age: 58 +/- 3.4 years; weight: 80.99 +/- 15.64 kg) with clinically diagnosed femoro-popliteal occlusive disease (Ankle Brachial Index (ABI): 0.56 +/- 0.03, range 0.45 to 0.65) and five healthy controls (age: 53 +/- 3.4 years; weight: 87.38 +/- 12.75 kg; ABI >or= 1). Kinematic parameters (hip, knee, and ankle joint angles in the sagittal plane) were evaluated during gait in patients before and after the onset of claudication pain and compared with healthy controls. Joint angles were calculated during stance time. Dependent variables were assessed (maximum and minimum flexion and extension angles and ranges of motion) and mean ensemble curves were generated. Time to occurrence of the discrete variables was also identified., Results: Significantly greater ankle plantar flexion in early stance and ankle range of motion during stance was observed in PAD patients (P < .05). Time to maximum ankle plantar flexion was shorter and time to maximum ankle dorsiflexion was longer in PAD patients (P < .05). These differences were noted when comparing PAD patients prior to and after the onset of claudication with healthy controls. The analysis of the kinematic parameters of the knee and the hip joints revealed no significant differences between PAD patients and controls., Conclusion: PAD patients with claudication demonstrate significant gait alterations in the ankle joint that are present prior to the onset of claudication pain. In contrast, the joint motion of the hip and knee did not differ in PAD patients when compared with controls. Further research is needed to verify our findings and assess the impact of more proximal disease in PAD patients as well as the effect of revascularization on joint kinematics.

Background: Claudication secondary to peripheral arterial disease leads to reduced mobility, limited physical functioning, and poor health outcomes. Disease severity can be assessed with quantitative clinical methods and qualitative self-perceived measures of quality of life. Limited data exist to document the degree to which quantitative and qualitative measures correlate. The current study provides data on the relationship between quantitative and qualitative measures of symptomatic peripheral arterial disease., Method: This descriptive case series was set in an academic vascular surgery unit and biomechanics laboratory. The subjects were symptomatic patients with peripheral arterial disease patients presenting with claudication. The quantitative evaluation outcome measures included measurement of ankle-brachial index, initial claudication distance, absolute claudication distance, and self-selected treadmill pace. Qualitative measurements included the Walking Impairment Questionnaire (WIQ) and the Medical Outcomes Study Short Form-36 (SF-36) Health Survey. Spearman rank correlations were performed to determine the relationship between each quantitative and qualitative measure and also between the WIQ and SF-36., Results: Included were 48 patients (age, 62 +/- 9.6 years; weight, 83.0 +/- 15.4 kg) with claudication (ABI, 0.50 +/- 0.20). Of the four WIQ subscales, the ankle-brachial index correlated with distance (r = 0.29) and speed (r = 0.32); and initial claudication distance and absolute claudication distance correlated with pain (r = 0.40 and 0.43, respectively), distance (r = 0.35 and 0.41, respectively), and speed (r = 0.39 and 0.39 respectively). Of the eight SF-36 subscales, no correlation was found for the ankle-brachial index, initial claudication distance correlated with Bodily Pain (r = 0.46) and Social Functioning (r = 0.30), and absolute claudication time correlated with Physical Function (r = 0.31) and Energy (r = 0.30). The results of both questionnaires showed reduced functional status in claudicating patients., Conclusions: Initial and absolute claudication distances and WIQ pain, speed, and distance subscales are the measures that correlated the best with the ambulatory limitation of patients with symptomatic peripheral arterial disease. These results suggest the WIQ is the most specific questionnaire for documenting the qualitative deficits of the patient with claudication while providing strong relationships with the quantitative measures of arterial disease. Future studies of claudication patients should include both quantitative and qualitative assessments to adequately assess disease severity and functional status in peripheral arterial disease patients.

Objective: Claudication is the most common manifestation of peripheral arterial disease (PAD), producing significant ambulatory compromise. The gait of claudicating patients has been evaluated using primarily temporal and spatial parameters. With the present study, we used advanced biomechanical measures to further delineate the ambulatory impairment of claudicating patients. We hypothesized that the claudicating legs of PAD patients have an altered kinetic gait pattern compared with normal legs from control subjects., Methods: Ambulation kinetics (ground reaction forces) were evaluated in claudicating patients and compared with age-matched healthy controls. Forces were analyzed in the vertical, anterior-posterior, and medial-lateral directions. Time from heel touch-down to toe-off (stance time) and time spent in double-limb support were also evaluated., Results: The study recruited 14 PAD patients (age, 58 +/- 3.4 years; weight, 80.99 +/- 15.64 kg) with femoropopliteal occlusive disease (ankle-brachial index [ABI], 0.56 +/- 0.03) and five controls (age, 53 +/- 3.4 years; weight, 87.38 +/- 12.75 kg; ABI, >or=1.00). Vertical force curve evaluation demonstrated significant flattening in claudicating patients resulting in a lower and less fluctuant center of mass when ambulating. In the anterior-posterior direction, claudicating patients demonstrated significantly decreased propulsion forces. In the medial-lateral direction, they had significantly increased forces consistent with wider steps and an inability to swing their legs straight through. Claudicating patients demonstrated a greater stance time and time in double limb support compared with healthy controls. Most importantly, gait abnormalities were present before the onset of claudication, with gait worsening after the onset of claudication., Conclusion: Claudicating patients demonstrate significant gait impairments that are present even before they experience any limb discomfort. These alterations may make them feel more stable and secure while attempting to minimize use of the affected limb. Advanced biomechanical analysis, using ambulation kinetics, permits objective and quantitative evaluation of the gaits of claudicating patients. Such evaluation may point to new rehabilitation strategies and provide objective measurement of functional outcomes after medical and surgical therapy.

Objective: Discrete morphologic, enzymatic and functional changes in skeletal muscle mitochondria have been demonstrated in patients with peripheral arterial disease (PAD). We examined mitochondrial respiration in the gastrocnemius muscle of nine patients (10 legs) with advanced PAD and in nine control patients (nine legs) without evidence of PAD., Methods: Mitochondrial respiratory rates were determined with a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles. Muscle samples were obtained from the anteromedial aspect of the gastrocnemius muscle, at a level 10 cm distal to the tibial tuberosity. Mitochondria respiratory rate, calculated as nanoatoms of oxygen consumed per minute per milligram of noncollagen protein, were measured at baseline (V(0)), after addition of substrates (malate and glutamate; (V(SUB)), after addition of adenosine diphosphate (ADP) (V(ADP)), and finally, after adenine nucleotide translocase inhibition with atractyloside (V(AT)). The acceptor control ratio, a sensitive indicator of overall mitochondrial function, was calculated as the ratio of the respiratory rate after the addition of ADP to the respiratory rate after adenine nucleotide translocase inhibition with atractyloside (V(ADP)/ V(AT))., Results: Respiratory rate in muscle mitochondria from patients with PAD were not significantly different from control values at baseline (0.31 +/- 0.06 vs 0.55 +/- 0.12; P =.09), but V(sub) was significantly lower in patients with PAD compared with control subjects (0.43 +/- 0.07 vs 0.89 +/- 0.20; P <.05), as was V(ADP) (0.69 +/- 0.13 vs 1.24 +/- 0.20; P <.05). Respiratory rates after atractyloside inhibition in patients with PAD were no different from those in control patients (0.47 +/- 0.07 vs 0.45 +/- P =.08). Compared with control values, mitochondria from patients with PAD had a significantly lower acceptor control ratio (1.41 +/- 0.10 vs 2.90 +/- 0.20; P <.001)., Conclusion: Mitochondrial respiratory activity is abnormal in lower extremity skeletal muscle in patients with PAD. When considered in concert with the ultrastructural and enzymatic abnormalities previously documented in mitochondria of chronically ischemic muscle, these data support the concept of defective mitochondrial function as a pathophysiologic component of PAD.

Objective: Previous morphologic studies and phosphorus nuclear magnetic resonance spectroscopy (31P MRS) have suggested a primary mitochondrial defect in claudicating skeletal muscle. We hypothesized that pentoxifylline may alleviate this defect., Methods: The response of calf muscle bioenergetics to pentoxifylline was evaluated in 10 male, nondiabetic claudicants with 31P MRS and standard treadmill testing before and after 12 weeks of pentoxifylline therapy. Phosphocreatine (PCr) and adenosinodiphosphate (ADP) recovery rate constants, two very sensitive measures of oxidative mitochondrial function, were measured., Results: Seven of the 10 subjects had abnormal baseline PCr (<0.015 s(-1)) and ADP (<0.024 s(-1)) recovery rate constants. These 7 had significant improvement in mitochondrial function with pentoxifylline; their PCr recovery rate constants increased from 0.009 +/- 0.002 to 0.013 +/- 0.002 s(-1) (P = 0.013) and their ADP recovery rate constants increased from 0.015 +/- 0.002 to 0.022 +/- 0.002 s(-1) (P = 0.004). The remaining 3 patients had normal baseline constants and demonstrated no improvement after pentoxifylline therapy. Baseline PCr and ADP recovery rate constants inversely correlated with their corresponding percentage of improvement after pentoxifylline (P < 0.05). In addition the percentage of improvement in the PCr and ADP recovery rate constants correlated with the percentage of improvement in initial claudication distance and maximum walking capacity (P < 0.05)., Conclusions: Pentoxifylline improves the mitochondriopathy of claudicating muscle, producing the most improvement in limbs with the worse baseline mitochondrial function. These results point to a potential new mode of action for pentoxifylline in the treatment of claudication and identify a subgroup of patients with the best potential for improvement with treatment., ((c)2001 Elsevier Science.)

Patients with peripheral artery disease (PAD) experience significant leg dysfunction. The effects of PAD on gait include shortened steps, slower walking velocity, and altered gait kinematics and kinetics, which may confound joint torques and power measurements. Spatiotemporal parameters and joint torques and powers were calculated and compared between 20 patients with PAD and 20 healthy controls using independent t tests. Separate analysis of covariance models were used to evaluate group differences after independently adjusting for gait velocity, stride length, and step width. Compared with healthy controls, patients with PAD exhibited reduced peak extensor and flexor torques at the knee and hip. After adjusting for all covariates combined, differences between groups remained for ankle power generation in late stance and knee flexor torque. Reduced walking velocity observed in subjects affected by PAD was closely connected with reductions in joint torques and powers during gait. Gait differences remained at the knee and ankle after adjusting for the combined effect of spatiotemporal parameters. Improving muscle function through exercise or with the use of assistive devices needs to be a key tool in the development of interventions that aim to enhance the ability of PAD patients to restore spatiotemporal gait parameters. [ABSTRACT FROM AUTHOR]

The most common symptom of peripheral artery disease (PAD) is intermittent claudication, which consists of debilitating leg pain during walking. In clinical settings, the presence of PAD is often noninvasively evaluated using the ankle–brachial index and imaging of the arterial supply. Furthermore, various questionnaires and functional tests are commonly used to measure the severity and negative effect of PAD on quality of life. However, these evaluations only provide information on vascular insufficiency and severity of the disease, but not regarding the complex mechanisms underlying walking impairments in patients with PAD. Biomechanical analyses using motion capture and ground reaction force measurements can provide insight into the underlying mechanisms to walking impairments in PAD. This review analyzes the application of biomechanics tools to identify gait impairments and their clinical implications on rehabilitation of patients with PAD. A total of 18 published journal articles focused on gait biomechanics in patients with PAD were studied. This narriative review shows that the gait of patients with PAD is impaired from the first steps that a patient takes and deteriorates further after the onset of claudication leg pain. These results point toward impaired muscle function across the ankle, knee, and hip joints during walking. Gait analysis helps understand the mechanisms operating in PAD and could also facilitate earlier diagnosis, better treatment, and slower progression of PAD. [ABSTRACT FROM AUTHOR]

Background: Pharmacological treatment has been advocated as a first line therapy for Peripheral Arterial Disease (PAD) patients suffering from intermittent claudication. Previous studies document the ability of pharmacological treatment to increase walking distances. However, the effect of pharmacological treatment on gait biomechanics in PAD patients has not been objectively evaluated as is common with other gait abnormalities. Methods: Sixteen patients were prescribed an FDA approved drug (Pentoxifylline or Cilostazol) for the treatment of symptomatic PAD. Patients underwent baseline gait testing prior to medication use which consisted of acquisition of ground reaction forces and kinematics while walking in a pain free state. After three months of treatment, patients underwent repeat gait testing. Results: Patients with symptomatic PAD had significant gait abnormalities at baseline during pain free walking as compared to healthy controls. However, pharmacological treatment did not produce any identifiable alterations on the biomechanics of gait of the PAD patients as revealed by the statistical comparisons performed between pre and posttreatment and between post-treatment and the healthy controls. Conclusions: Pharmacological treatment did not result in statistically significant improvements in the gait biomechanics of patients with symptomatic PAD. Future studies will need to further explore different cohorts of patients that have shown to improve significantly their claudication distances and/or their muscle fiber morphology with the use of pharmacological treatment and determine if this is associated with an improvement in gait biomechanics. Using these methods we may distinguish the patients who benefit from pharmacotherapy and those who do not. [ABSTRACT FROM AUTHOR]

Abstract: Abnormal mitochondrial function is present in patients with peripheral arterial disease and may contribute to its clinical manifestations. However, the specific biochemical mitochondrial defects and their association with increased oxidative stress have not been fully characterized. Gastrocnemius muscle was obtained from peripheral arterial disease patients (n = 25) and age-matched controls (n = 16) and mitochondrial parameters were measured. Complexes I through IV of the electron transport chain were individually evaluated to assess for isolated defects. Muscle was also evaluated for protein and lipid oxidative changes by measuring the levels of protein carbonyls, lipid hydroperoxides, and total 4-hydroxy-2-nonenal binding and for the activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. Mitochondrial electron transport chain complexes I, III, and IV in arterial disease patients demonstrated significant reductions in enzymatic activities and mitochondrial respiration compared to controls. Oxidative stress biomarker analysis demonstrated significantly increased levels of protein carbonyls, lipid hydroperoxides, and 4-hydroxy-2-nonenal compared to control muscle. Antioxidant enzyme activities were altered, with a significant decrease in superoxide dismutase activity and significant increases in catalase and glutathione peroxidase. Peripheral arterial disease is associated with abnormal mitochondrial function and evidence of significant oxidative stress. [Copyright &y& Elsevier]

Most patients with critical limb ischemia (CLI) from peripheral arterial disease (PAD) do not have antecedent intermittent claudication (IC). We hypothesized that transcriptomic analysis would identify CLI-specific pathways, particularly in regards to fibrosis. Derivation cohort data from muscle biopsies in PAD and non-PAD (controls) was obtained from the Gene Expression Omnibus (GSE120642). Transcriptomic analysis indicated CLI patients (N = 16) had a unique gene expression profile, when compared with non-PAD controls (N = 15) and IC (N = 20). Ninety-eight genes differed between controls and IC, 2489 genes differed between CLI and controls, and 2783 genes differed between CLI and IC patients. Pathway enrichment analysis showed that pathways associated with TGFβ, collagen deposition, and VEGF signaling were enriched in CLI but not IC. Receiver operating curve (ROC) analysis of nine fibrosis core gene expression revealed the areas under the ROC (AUC) were all >0.75 for CLI. Furthermore, the fibrosis area (AUC = 0.81) and % fibrosis (AUC = 0.87) in validation cohort validated the fibrosis discrimination CLI from IC and control (all n = 12). In conclusion, transcriptomic analysis identified fibrosis pathways, including those involving TGFβ, as a novel gene expression feature for CLI but not IC. Fibrosis is an important characteristic of CLI, which we confirmed histologically, and may be a target for novel therapies in PAD. [ABSTRACT FROM AUTHOR]

Objective: Claudication is the most common presentation of peripheral arterial disease (PAD), producing significant ambulatory compromise. Claudicating patients, most of whom are elderly, have reduced mobility and poor health outcomes, including an increased risk of falls. The gait of elderly fallers is characterized by increased variability. Increase in the variability of the locomotor system makes the gait more noisy and unstable. The purpose of this study is to investigate gait variability in patients with PAD. Methods: Nineteen symptomatic PAD patients (age, 63.6 ± 9.8 years; body mass, 82.1 ± 18.5 kg; height, 1.71 ± 0.06 m) walked on a treadmill in the absence of pain or claudication symptoms while joint flexion and extension kinematics were captured. Results were compared with results obtained from 17 matched healthy controls (age, 65.2 ± 12.5 years; body mass, 82.0 ± 25.9.5 kg; height, 1.73 ± 0.08 m). Relative joint angles were calculated for the ankle, knee, and hip flexion/extension, and the stride-to-stride variability of joint flexion and extension was calculated from at least 30 consecutive footfalls. Variability was expressed using the largest Lyapunov exponent, standard deviation, and coefficient of variation. Independent t tests were used to compare gait variability between groups. Results: Symptomatic PAD patients had significantly higher largest Lyapunov exponent values and coefficient of variation values for all joints, and higher standard deviation values at the ankle and the hip (P < .05). Conclusion: Symptomatic PAD patients have increased gait variability at the ankle, knee, and hip joints at baseline ambulation in the absence of claudication pain. Our findings indicate significant baseline deterioration in the locomotor system of symptomatic PAD patients. This deterioration results in increased noise and instability of gait and is a potential contributing factor to the falls and mobility problems experienced by symptomatic PAD patients. [Copyright &y& Elsevier]

Abstract: Background: Walking is problematic for patients with peripheral arterial disease. The purpose of this study was to investigate the frequency domain of the ground reaction forces during walking to further elucidate the ambulatory impairment of these patients. Methods: Nineteen bilateral peripheral arterial disease patients and nineteen controls were included in this study. Subjects were matched for age and gait speed. Participants walked over a force plate sampling at 600Hz. PAD patients were tested before (pain-free condition) after the onset of claudication symptoms (pain). We calculated median frequency, frequency bandwidth, and frequency containing 99.5% of the signal for the vertical and anterior–posterior ground reaction forces. Findings: Our results showed reduced median frequency in the vertical and anterior–posterior components of the ground reaction forces between the control group and both peripheral arterial disease conditions. We found reduced frequency bandwidth in the anterior–posterior direction between controls and the peripheral arterial disease pain-free condition. There were no differences in median frequency or bandwidth between peripheral arterial disease pain-free and pain conditions, but an increase in the frequency content for 99.5% of the signal was observed in the pain condition. Interpretation: Reduced frequency phenomena during gait in peripheral arterial disease patients compared to velocity-matched controls suggests more sluggish activity within the neuromotor system. Increased frequency phenomena due to pain in these patients suggest a more erratic application of propulsive forces when walking. Frequency domain analysis thus offers new insights into the gait impairments associated with this patient population. [Copyright &y& Elsevier]

Individuals with peripheral arterial disease (PAD) report difficulty walking and experience 73% more falls than their healthy counterparts, but no studies have investigated functional mechanisms contributing to increased falls. Minimum toe clearance (MTC) is the minimum vertical distance between the toe of the swinging leg and the walking surface when the leg is swinging, and decreased values are associated with an increased risk for falls. This study is the first such analysis in patients with PAD. Eighteen individuals with PAD and eighteen healthy controls walked on a treadmill before and after the onset of claudication pain. Mean MTC and the standard deviation of MTC values across the trial were calculated. Mean MTC was not different between groups in the pain-free ( P = 0.244) or pain conditions ( P = 0.565). MTC variability was increased for patients with PAD in pain-free ( P = 0.048) and pain conditions ( P = 0.019). No significant differences existed between conditions for MTC mean ( P = 0.134) or MTC variability ( P = 0.123). Increased MTC variability is present before and after the onset of claudication pain, and may be a useful assessment for treatment and rehabilitation efficacy in these patients. [ABSTRACT FROM AUTHOR]

Abstract: External work was utilized to measure differences between the unaffected and the affected limb in patients with unilateral peripheral arterial disease compared to healthy controls. Patients with unilateral peripheral arterial disease have shown deficits in peak joint powers during walking in the unaffected and affected legs. However, no research has detailed the amount of work that is being performed by each leg compared to healthy controls even though such an analysis would provide valuable information on the energy output from the affected and the unaffected legs. Two hypotheses were tested: (a) the unaffected and affected leg would perform less work than healthy controls in a pain-free state, and (b) the onset of symptomatic claudication pain would result in further changes in the external work. Results showed that during a pain-free state, both the unaffected and affected legs perform less work than the healthy controls. After onset of claudication pain, the work output by the affected limb becomes further decreased while the unaffected limb experiences changes in negative external work. These findings combined with recent evidence of decreased peak powers in both legs in unilateral peripheral arterial disease patients reflects altered pathomechanics in both limbs compared to healthy controls. [Copyright &y& Elsevier]