Peripheral artery disease causes consistent gait irregularities regardless of the location of leg claudication pain.

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.

A comparison of the perceptions of wearing an ankle foot orthosis by individuals with peripheral artery disease according to their baseline-level of physical activity.

INTRODUCTION: Peripheral artery disease (PAD) is a prevalent cardiovascular disease that limits an individual's ability to walk. One potential way to improve physical activity for patients with PAD is an ankle foot orthosis (AFO). Previous research has found that various factors may influence an individual's willingness to wear AFOs. However, one factor that has been understudied is an individual's baseline physical activity level prior to wearing AFOs. Therefore, the purpose of this study was to compare the perceptions of wearing AFOs for 3 months among individuals with PAD according to their baseline level of physical activity. METHODS: Accelerometer-derived physical activity prior to AFO prescription was used to classify participants into either a higher or lower activity group. Semi-structured interviews were conducted at 1.5 and 3-months after wearing the AFOs to assess participants' perceptions of using the orthosis. Data were analyzed by a directed content analysis approach, then the percentage of respondents for each theme were calculated and compared between higher and lower activity groups. FINDINGS: Several differences were found. Participants in the higher activity group more often reported positive impacts from wearing the AFOs. Additionally, participants who were in the lower activity group more often reported the AFOs caused physical pain while participants in the higher activity group more often reported the device was uncomfortable during daily activities. CONCLUSION: Baseline physical activity levels may help to better understand barriers to wear and needed support to increase adherence to an AFO wear prescription, especially for patients with PAD with limited activity.

Assessing wear time and perceptions of wearing an ankle foot orthosis in patients with peripheral artery disease.

BACKGROUND: Peripheral artery disease (PAD) is a cardiovascular disease that affects walking ability. An ankle foot orthosis (AFO) may improve walking distances in those with PAD. Little research has explored if those with PAD wear a prescribed AFO and their perceptions of wearing the device. OBJECTIVE: To assess wear time of an AFO and explore perceptions of wearing the device in patients with PAD. DESIGN: Convergent mixed methods. SETTING: The study was conducted through a tertiary care medical center, and the research participants used the device in the community. PARTICIPANTS: Thirty-six patients, all older adult males, were enrolled in this study. Fourteen patients completed the study and 11 supplied sufficient accelerometer data to include in the analysis. INTERVENTIONS: An AFO was worn for 3 months. An accelerometer was placed on the AFO for 7 days at the midpoint (1.5 months) and endpoint of the intervention (3 months) to assess wear time. Semi-structured interviews explored patients' perceptions of wearing the AFO. MAIN OUTCOME MEASURE: The primary outcome measure was wear time measured objectively via accelerometer and subjectively via interview. RESULTS: Patients (n = 14) wore the AFO approximately 8 hours/day. Patients reported barriers such as challenges wearing the AFO during daily household activities (using stairs, being on uneven terrain), discomfort, clothing or footwear issues, and driving challenges. Positive effects of wearing the AFO were also reported, primarily the ability to walk further. CONCLUSIONS: An AFO may be an acceptable therapeutic intervention to improve perceived walking performance in older adult males with PAD. Addressing participants' perceptions of the AFO and barriers to wear are essential to increasing the positive effect the device has on participants' ambulatory activity.

Peripheral artery disease affects the function of the legs of claudicating patients in a diffuse manner irrespective of the segment of the arterial tree primarily involved.

Different levels of arterial occlusive disease (aortoiliac, femoropopliteal, multi-level disease) can produce claudication symptoms in different leg muscle groups (buttocks, thighs, calves) in patients with peripheral artery disease (PAD). We tested the hypothesis that different locations of occlusive disease uniquely affect the muscles of PAD legs and produce distinctive patterns in the way claudicating patients walk. Ninety-seven PAD patients and 35 healthy controls were recruited. PAD patients were categorized to aortoiliac, femoropopliteal and multi-level disease groups using computerized tomographic angiography. Subjects performed walking trials both pain-free and during claudication pain and joint kinematics, kinetics, and spatiotemporal parameters were calculated to evaluate the net contribution of the calf, thigh and buttock muscles. PAD patients with occlusive disease affecting different segments of the arterial tree (aortoiliac, femoropopliteal, multi-level disease) presented with symptoms affecting different muscle groups of the lower extremity (calves, thighs and buttocks alone or in combination). However, no significant biomechanical differences were found between PAD groups during the pain-free conditions with minimal differences between PAD groups in the claudicating state. All statistical differences in the pain-free condition occurred between healthy controls and one or more PAD groups. A discriminant analysis function was able to adequately predict if a subject was a control with over 70% accuracy, but the function was unable to differentiate between PAD groups. In-depth gait analyses of claudicating PAD patients indicate that different locations of arterial disease produce claudication symptoms that affect different muscle groups across the lower extremity but impact the function of the leg muscles in a diffuse manner generating similar walking impairments.

Muscle forces and power are significantly reduced during walking in patients with peripheral artery disease.

Patients with peripheral artery disease (PAD) have significantly reduced lower extremity muscle strength compared with healthy individuals as measured during isolated, single plane joint motion by isometric and isokinetic strength dynamometers. Alterations to the force contribution of muscles during walking caused by PAD are not well understood. Therefore, this study used simulations with PAD biomechanics data to understand lower extremity muscle functions in patients with PAD during walking and to compare that with healthy older individuals. A total of 12 patients with PAD and 10 age-matched healthy older controls walked across a 10-meter pathway with reflective markers on their lower limbs. Marker coordinates and ground reaction forces were recorded and exported to OpenSim software to perform gait simulations. Walking velocity, joint angles, muscle force, muscle power, and metabolic rate were calculated and compared between patients with PAD and healthy older controls. Our results suggest that patients with PAD walked slower with less hip extension during propulsion. Significant force and power reductions were observed in knee extensors during weight acceptance and in plantar flexors and hip flexors during propulsion in patients with PAD. The estimated metabolic rate of walking during stance was not different between patients with PAD and controls. This study is the first to analyze lower limb muscular responses during walking in patients with PAD using the OpenSim simulation software. The simulation results of this study identified important information about alterations to muscle force and power during walking in those with PAD.

Considerations for Implementation of an Ankle-Foot Orthosis to Improve Mobility in Peripheral Artery Disease.

OBJECTIVE: To explore the perceptions of wearing an ankle-foot orthosis (AFO) in patients with peripheral artery disease (PAD) who did and did not adopt the AFO intervention. This follows a clinical trial of the effectiveness of an AFO in improving walking distances for patients with PAD-related claudication. DESIGN: A randomized crossover trial of standard of care and an AFO for 3 months. Semistructured interviews were conducted 1.5 months into the AFO intervention to understand acceptability, demand, implementation, and practicality. Data were analyzed using a summative content analysis approach. SETTING: Vascular surgery clinic and biomechanics research laboratory. PARTICIPANTS: Patients (N=15; male, 100%; age, 71.9±.6.7y; body mass index [calculated as weight in kilograms divided by height in meters squared], 29.0±.5.5; ankle brachial index: AFO intervention withdrawal, 0.543; AFO intervention completion, 0.740) with claudication completed the study, and 6 withdrew prior to intervention completion. INTERVENTIONS: A certified orthotist fit participants with an AFO that was worn for 3 months. MAIN OUTCOME MEASURES: Qualitative analysis of the semistructured interviews. RESULTS: Key differences were reported between AFO intervention completion and AFO intervention withdrawal. Six of 14 of AFO intervention completion participants described their initial reactions to the AFO as negative vs 3 of 6 AFO intervention withdrawal participants. Only 5 of 15 AFO intervention completion participants reported minimal use of the AFO compared with 5 of 6 AFO intervention withdrawal participants. The AFO intervention withdrawal group reported higher levels of physical discomfort with the use of the AFO (4/6 vs 7/15) and preexisting health issues becoming a barrier to the use of the AFO (3/6 vs 5/15). Positive aspects reported included ease in standing and walking for AFO intervention withdrawal (4/6) and AFO intervention completion groups (13/15) as well as walking straighter and longer with less pain for AFO intervention withdrawal (3/6) and AFO intervention completion groups (9/15). CONCLUSIONS: Patients withdrawing prior to completion of AFO intervention tended to have more negative perceptions, more comorbidities, and more physical discomfort than those completing the intervention. Both groups reported positive aspects of the AFO. Implementation studies are needed to address barriers to AFO adoption.

Abnormal Microvascular Architecture, Fibrosis, and Pericyte Characteristics in the Calf Muscle of Peripheral Artery Disease Patients with Claudication and Critical Limb Ischemia.

Work from our laboratory documents pathological events, including myofiber oxidative damage and degeneration, myofibrosis, micro-vessel (diameter = 50-150 µm) remodeling, and collagenous investment of terminal micro-vessels (diameter ≤ 15 µm) in the calf muscle of patients with Peripheral Artery Disease (PAD). In this study, we evaluate the hypothesis that the vascular pathology associated with the legs of PAD patients encompasses pathologic changes to the smallest micro-vessels in calf muscle. Biopsies were collected from the calf muscle of control subjects and patients with Fontaine Stage II and Stage IV PAD. Slide specimens were evaluated by Quantitative Multi-Spectral and Fluorescence Microscopy. Inter-myofiber collagen, stained with Masson Trichrome (MT), was increased in Stage II patients, and more substantially in Stage IV patients in association with collagenous thickening of terminal micro-vessel walls. Evaluation of the Basement Membrane (BM) of these vessels reveals increased thickness in Stage II patients, and increased thickness, diameter, and Collagen I deposition in Stage IV patients. Coverage of these micro-vessels with pericytes, key contributors to fibrosis and BM remodeling, was increased in Stage II patients, and was greatest in Stage IV patients. Vascular pathology of the legs of PAD patients extends beyond atherosclerotic main inflow arteries and affects the entire vascular tree-including the smallest micro-vessels.

Supervised walking exercise therapy improves gait biomechanics in patients with peripheral artery disease.

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.

Muscle strength and control characteristics are altered by peripheral artery disease.

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.

Weekly vinorelbine and paclitaxel in older patients with advanced non-small cell lung cancer: A phase II Fred and Pamela Buffet Cancer Center Clinical Trials Network study.

OBJECTIVE: Platinum-based doublet chemotherapy is the standard for most patients with advanced non-small cell lung cancer (NSCLC). Toxicity concerns limit chemotherapy for patients over 70years. Vinorelbine and paclitaxel are effective as single agents in advanced NSCLC. This phase II study evaluates safety and efficacy of a combination of these two agents in patients >70years with advanced NSCLC. MATERIALS AND METHODS: Patients with treatment naïve metastatic NSCLC received two cycles comprising 6 weekly doses of vinorelbine and paclitaxel, with restaging scans at week 8. Patients with radiographic progression came off study. The estimated sample size was 29. Toxicity analyses were conducted after 10 patients and again after 19 patients were enrolled. Outcomes were safety and efficacy, progression free (PFS) and overall survival (OS) and quality of life (QOL). RESULTS: The study closed at second interim analysis as 6/19 patients had ≥grade 4 non-hematologic toxicity (respiratory failure, sepsis, ischemic encephalopathy, pneumonia, hypoxemia, cardiopulmonary arrest, neutropenic fever, death). Of the 16 evaluable patients, 7 completed the study. Disease control rate (partial response+stable disease) was 47% (n=9); 37% (n=7) progressed. No complete responses were seen. Median PFS was 3.5months (95% CI: 1.4, 5.5) and OS 7.8months (95% CI: 1.9, 13.6). QOL did not change compared to baseline, at week 9, but increased at week 17. CONCLUSIONS: Although the combination met its response end points, increased toxicity makes this combination unsuitable for older patients. While QOL improved over the study, the small sample hinders interpretation.

Transforming growth factor-beta 1 produced by vascular smooth muscle cells predicts fibrosis in the gastrocnemius of patients with peripheral artery disease.

BACKGROUND: Lower leg ischemia, myopathy, and limb dysfunction are distinguishing features of peripheral artery disease (PAD). The myopathy of PAD is characterized by myofiber degeneration in association with extracellular matrix expansion, and increased expression of transforming growth factor-beta 1 (TGF-ß1; a pro-fibrotic cytokine). In this study, we evaluated cellular expression of TGF-ß1 in gastrocnemius of control (CTRL) and PAD patients and its relationship to deposited collagen, fibroblast accumulation and limb hemodynamics. METHODS: Gastrocnemius biopsies were collected from PAD patients with claudication (PAD-II; N = 25) and tissue loss (PAD-IV; N = 20) and from CTRL patients (N = 20). TGF-ß1 in slide-mounted specimens was labeled with fluorescent antibodies and analyzed by quantitative wide-field, fluorescence microscopy. We evaluated co-localization of TGF-ß1 with vascular smooth muscle cells (SMC) (high molecular weight caldesmon), fibroblasts (TE-7 antigen), macrophages (CD163), T cells (CD3) and endothelial cells (CD31). Collagen was stained with Masson Trichrome and collagen density was determined by quantitative bright-field microscopy with multi-spectral imaging. RESULTS: Collagen density increased from CTRL to PAD-II to PAD-IV specimens (all differences p < 0.05) and was prominent around microvessels. TGF-ß1 expression increased with advancing disease (all differences p < 0.05), correlated with collagen density across all specimens (r = 0.864; p < 0.001), associated with fibroblast accumulation, and was observed exclusively in SMC. TGF-ß1 expression inversely correlated with ankle-brachial index across PAD patients (r = -0.698; p < 0.001). CONCLUSIONS: Our findings support a progressive fibrosis in the gastrocnemius of PAD patients that is caused by elevated TGF-ß1 production in the SMC of microvessels in response to tissue hypoxia.