Physical activity, walking exercise, and calf skeletal muscle characteristics in patients with peripheral arterial disease

Physical activity, walking exercise, and calf skeletal muscle characteristics in patients with peripheral arterial disease Mary McGrae McDermott, MD, a,b Jack M. Guralnik, MD, PhD, c Luigi Ferrucci, MD, PhD, d Lu Tian, ScD, b William H. Pearce, MD, e Frederick Hoff, MD, f Kiang Liu, PhD, b Yihua Liao, MS, b and Michael H. Criqui, MD, MPH, g Chicago, Ill; Baltimore, Md; and San Diego, Calif Objective: This cross-sectional study was set in an academic medical center and conducted to identify associations of physical activity level and walking exercise frequency with calf skeletal muscle characteristics in individuals with lower extremity peripheral arterial disease (PAD). Methods: Calf muscle characteristics in 439 men and women with PAD were measured with computed tomography at 66.67% of the distance between the distal and proximal tibia. Physical activity was measured continuously during 7 days with a vertical accelerometer. Patient report was used to determine the number of blocks walked during the past week and walking exercise frequency. Results were adjusted for age, sex, race, comorbidities, ankle-brachial index, body mass index, smoking, and other confounders. Results: For both objective and subjective measures, more physically active PAD participants had higher calf muscle area and muscle density. Calf muscle area across tertiles of accelerometer-measured physical activity were first activity tertile, 5071 mm 2 ; second activity tertile: 5612 mm 2 ; and third activity tertile, 5869 mm 2 (P <.001). Calf muscle density across tertiles of patient-reported blocks walked during the past week were first activity tertile, 31.4 mg/cm 3 ; second activity tertile, 33.0 mg/cm 3 ; and third activity tertile, 33.8 mg/cm 3 (P <.001). No significant associations were found between walking exercise frequency and calf muscle characteristics. Conclusion: Among participants with PAD, higher physical activity levels, measured by accelerometer and by patientreported blocks walked per week, were associated with more favorable calf muscle characteristics. In contrast, more frequent patient-reported walking exercise was not associated with more or less favorable calf muscle characteristics. Results suggest that clinicians should encourage their patients to increase their walking activity during daily life. (J Vasc Surg 2007;46:87-93.) Individuals with lower extremity peripheral arterial disease (PAD) have reduced calf skeletal muscle area com- walking speed over 4 meters. Identifying clinical charac- distance achieved during the 6-minute walk test and faster 4 1-4 pared with those without PAD. This finding is not teristics associated with larger calf muscle area and other entirely explained by differences in physical activity levels more favorable calf muscle characteristics may ultimately between people with and those without PAD. Available help identify effective therapies for improving functioning data suggest that leg ischemia may have a direct, negative in individuals with PAD. effect on calf skeletal muscle area, independent of physical Clinical characteristics that are associated with more activity levels. 1,4 For example, among individuals with PAD favorable calf muscle characteristics in individuals with who have significant differences in the ankle-brachial index PAD are unknown. For example, although patientreported walking exercise is associated with slower rates of (ABI) between the right and left legs, the leg with the lower ABI has significantly lower calf muscle area than the leg functional decline in patients with PAD, associations of 1,4 with the higher ABI. patient-reported walking exercise with calf muscle area in Previous study demonstrates that among patients with 5 patients with PAD are unknown. It is similarly unclear PAD, larger calf muscle area is associated with greater whether higher levels of physical activity are associated with more favorable calf muscle characteristics among individuals with PAD. Individuals with PAD have significantly From the Departments of Medicine, a Preventive Medicine, b Surgery, e and Radiology, f Northwestern University s Feinberg School of Medicine; the Laboratories of Epidemiology, Demography, and Biometry c and Clinical Epidemiology, d National Institute on Aging; and the Department of Family and Preventive Medicine, University of California at San Diego. g Competition of interest: none. Supported by grants R01-HL58099, R01-HL64739, and R01-HL71223, from the National Heart Lung and Blood Institute and by grant #RR- 00048 from the National Center for Research Resources, National Institutes of Health. Reprint requests: Dr McDermott, 676 N St. Clair, Suite 200, Chicago, IL 60611 (e-mail: mdm608@northwestern.edu). 0741-5214/$32.00 Copyright 2007 by The Society for Vascular Surgery. doi:10.1016/j.jvs.2007.02.064 6,7 lower physical activity levels than those without PAD, and it is unknown whether differences in calf muscle characteristics are observed across the range of physical activity levels typically observed in patients with PAD. Walking activity during daily life is a distinct measure from walking exercise activity, in part because walking activity may be less intensive than walking exercise activity. People may also be very physically active during daily life without engaging in walking exercise. Therefore, the purpose of this study was to assess associations of greater 87

88 McDermott et al JOURNAL OF VASCULAR SURGERY July 2007 walking activity during daily life and more frequent patientreported walking exercise with calf muscle area and calf muscle density in people with PAD. METHODS Participants. The protocol was approved by the Institutional Review Board of Northwestern University Feinberg School of Medicine and Catholic Health Partners Hospitals. Participants gave informed consent. Participants included individuals attending their fourth annual follow-up visit in the Walking and Leg Circulation Study (WALCS) 8,9 and individuals newly identified for 10 the present study (WALCS II). Participants were aged 59 years. For both WALCS and WALCS II, PAD participants were identified consecutively from among patients diagnosed with PAD in three Chicago-area noninvasive vascular laboratories. The rest were identified from among consecutive patients in a general medicine practice at Northwestern. PAD was defined as an ABI 0.90. 8-10 Exclusion criteria have been described and include dementia, nursing home residence, inability to walk without a wheelchair, foot or leg amputation, and recent lower extremity revascularization. 10 These exclusion criteria were applied at the time of study entry for WALCS or WALCS II and were selected because they interfered with the participant s ability to respond accurately to study questionnaires or they severely impaired lower extremity functional performance. Because study staff members were not fluent in non-english languages, potential participants who did not speak English were excluded. Ankle-brachial index. After participants rested supine for 5 minutes, a hand-held Doppler probe (Nicolet Vascular Pocket Dop II, Golden, Colo) was used to measure systolic pressures in the right brachial, dorsalis pedis, and posterior tibial arteries and left dorsalis pedis, posterior tibial, and brachial arteries. Pressures were measured in the order listed and then in reverse order. The ABI was calculated by dividing average pressures in each leg by the 11,12 average of the four brachial pressures. This method of ABI calculation was used because it has previously been shown to be more closely correlated with lower extremity 11 performance than alternative methods. However, analyses were also performed in which the ABI was calculated using the highest pressure in each leg. Average brachial pressures in the arm with highest pressure were used when one brachial pressure was higher than the opposite brachial pressure in both measurement sets and the two brachial pressures differed by 10 mm Hg in at least one measurement set. 13 The lowest leg ABI was used in analyses. Measuring calf muscle characteristics. A computed tomography (CT) scanner (LightSpeed, General Electric Medical Systems, Waukesha, Wis) was used to obtain a 2.5-mm cross-sectional image of the calves at 66.7% of the 14 distance from the distal to the proximal tibia. Crosssectional images were analyzed using BonAlyse (BonAlyse Oy, Jyvaskyla- Finland), a software for processing CT images that identifies muscle tissue and uses validated meth- 14,15 ods to measure density and geometry. The muscle outline was traced manually, excluding subcutaneous fat, intermuscular fat, and bone. Digital CT images consist of pixels representing a three-dimensional unit of space (a cube) measured in voxels. Voxels on the CT images range from 1000 (the density of air) to 2000 (the density of bone). Zero voxels corresponds to the density of water. When measuring muscle area, BonAlyse software quantifies voxels within a range corresponding to muscle density (9 to 271 mg/cm 3 ), excluding voxels corresponding to fat ( 270 to 8 mg/ cm 3 ). These definitions for muscle density and fat density were determined before data collection was initiated and were based on prior study and consultation with a radiologist with expertise in CT scan measurements. CT scans 14 were performed in all participants. In 40 legs, the interrater reliability of muscle area was 0.99, and inter-rater reliability of muscle density was 0.99. Six-minute walk test. Following a standardized protocol, 8,9,16 participants walk up and down a 100-foot -hall way for 6 minutes after instructions to cover as much distance as possible. The 6-minute walk test was completed by 416 (95%) of the 439 participants. Test retest reliability of the 6-minute walk was 0.87 (P.001) in our laboratory among 81 PAD participants who completed the test approximately 1 to 2 weeks apart. 17 Four-meter walking velocity. Walking velocity was measured over 4 meters at usual pace. This measure assesses usual walking speed over short distances. In contrast, the 6-minute walk specifically measures walking endurance. As in previous studies that validated the 4-meter walking velocity, the walk was performed twice and the faster walk was used in analyses. 8,9,18 The 4-meter walk test was completed by 422 (96%) of the 439 participants. Test retest reliability was 0.82 (P.001) in our laboratory among 84 PAD participants who completed the test approximately 1 to 2 weeks apart. 17 Accelerometer-measured physical activity. Physical activity levels were measured objectively and continuously for 7 days by using a vertical accelerometer (Caltrac, Muscle 6,7,19 Dynamics Fitness Network Inc, Torrance, Calif). The Caltrac accelerometer is worn at the hip and measures vertical movement at the hip; thus, it primarily measures walking activity. After 7 days, participants reported the number of activity units displayed on the accelerometer by telephone to investigators and returned their accelerometer by mail. We programmed the accelerometer identically for all participants, which allowed us to compare physical activity levels between participants, irrespective of individual 6,7,19-21 variation in age, weight, height, and sex. Programmed in this way, the accelerometers measured activity units. 6,7,19-21 The validity of the Caltrac accelerometer for measuring physical activity in patients with PAD has been demonstrated previously. 6,7,19 For example, in one study, there were no differences in accelerometer scores between subjects with and without PAD for a fixed distance of 800 feet.

JOURNAL OF VASCULAR SURGERY Volume 46, Number 1 McDermott et al 89 After 7 days, however, PAD participants had substantially 7 lower Caltrac-assessed activity than non-pad participants. Of participants with PAD who were eligible for this study, 60% wore a Caltrac monitor for 7 days. Systematic data on reasons that some participants did not wear monitors were not collected. Some participants refused to wear monitors, others wore monitors but did not return them and could not be reached at 7-day follow-up, some monitors malfunctioned, and in some instances, no monitors were available. Patient-reported physical activity and walking exercise frequency. The number of blocks walked during the 19 previous 7 days was obtained from patient report. At the initial visit, participants were asked, During the last week, how many city blocks or their equivalent did you walk? Let 12 city blocks equal one mile. Previous study shows that Caltrac accelerometer-measured activity is significantly associated with the number of blocks walked during the past week. 19 For walking exercise, participants who responded affirmatively to the question, During the past two weeks, have you gone walking for exercise? were classified as current exercisers. 5 Participants were asked to report the number of times they went walking for exercise during the prior week. 5 A previous study that used these specific questions showed that PAD participants who go walking for exercise three or more times per week have less average annual functional decline than PAD participants who walk 5 less frequently for exercise or not at all. Leg symptoms. The San Diego Claudication Questionnaire 8,9,22 was used to classify leg symptoms into one of(0.01%) attended a visit but did not undergo CT scanning. 0.90 and were excluded from analyses. An additional 15 five groups: (1) intermittent claudication, (2) leg pain on exertion and rest, (3) atypical exertional leg pain/carry on, (4) atypical exertional leg pain/stop, and (5) asymptomatic. Comorbidities. Algorithms developed for the Women s Health and Aging Study were used to document comorbidities, in which data were combined from patient report, physical examination, medical record review, medications, labora- 23 tory values, and a primary care physician questionnaire. Comorbidities assessed were angina, diabetes mellitus, myocardial infarction, stroke, heart failure, pulmonary disease, cancer, spinal stenosis, and disk disease. American College of Rheumatology criteria were used to adjudicate knee and hip osteoarthritis. 24,25 Other measures. Height and weight were measured at the study visit. Body mass index (BMI) was calculated as 2 weight in kg/height in meters. Cigarette smoking history was based on self-report. Statistical analyses. Differences in calf muscle area and calf muscle density were evaluated across tertiles of each physical activity measure and across categories of walking exercise by using analyses of covariance, adjusting for age, race, sex, recruitment cohort (WALCS vs newly identified), and tibia length (muscle area analyses only). Analyses were repeated with additional adjustment for smoking, BMI, leg symptoms, and comorbidities. Analyses of muscle area were adjusted for tibia length because greater tibia length is associated with greater calf muscle area. These analyses were adjusted for both BMI and tibia length because BMI is a measure of obesity, and tibia length measures height. 26 Average performance on each functional measure was compared across tertiles of vertical accelerometer-measured physical activity by using analyses of covariance and adjusting for age, race, gender, cigarette smoking, BMI, leg symptoms, ABI, recruitment cohort, and comorbidities. To determine whether significant associations were potentially explained by associations between higher physical activity levels and more favorable calf muscle characteristics, analyses were repeated with additional adjustment for calf muscle area and tibia length and calf muscle density, respectively. All analyses involving the Caltrac vertical accelerometer were repeated using inverse weighting to adjust for missing data. Analyses were performed using SAS 9.0 statistical software (SAS Inc, Cary, NC). RESULTS The 439 PAD participants consisted of 214 consecutive WALCS cohort members attending their fourth annual follow-up visit and 225 who were newly identified. Participation rates for the WALCS cohort have been described. 8,9 Newly identified participants were recruited from among 1804 men and women contacted for potential participation. Of these, 176 (9.8%) met exclusion criteria, 131 (7.3%) refused participation, 1021 (57%) did not respond to letters inviting their participation, 74 (4.1%) did not show for their study appointment, and 162 had an ABI The average age of PAD participants was 74.9 8.2 years, and 47% were women. In addition, 16.9% were African American, 15.7% were current smokers, 31.7% had diabetes mellitus, and 57.9% had a history of coronary or cerebrovascular disease. The average ABI was 0.63 0.16. Of the 439 PAD participants, 263 (59.9%) wore a Caltrac accelerometer for 7 days. There were no differences between wearers vs nonwearers in age (74.7 8.3 years vs 75.4 8.2 years, P.392), ABI (0.63 0.15 vs 0.63 0.15, P.77) or prevalence of men (52.1% vs 54.5%, P.61) or African Americans (16.7% vs 17.0%, P.93). Participants who wore accelerometers had better 6-minute walk performance (1147 375 feet vs 1064 427 feet, P.039) compared with nonwearers. The 4-meter walking speed between accelerometer wearers and nonwearers was similar at 0.86 0.20 m/s vs 0.85 0.24 m/s (P.852). Analyses adjusting only for age, sex, race, recruitment cohort, and tibia length showed a nonstatistically significant trend toward higher calf muscle density among participants who engaged in more frequent walking exercise: no walking exercise, 32.2 mg/cm 3 ; walking exercise one or two times per week, 32.6 mg/cm 3 ; and walking exercise more than three times per week, 33.0 mg/cm 3 (P.095). No significant associations were observed between patientreported walking exercise and calf muscle area, adjusting for age sex, race, and recruitment cohort (data not shown). No significant relationships were found between walking exercise frequency with calf muscle outcomes, adjusting for

90 McDermott et al JOURNAL OF VASCULAR SURGERY July 2007 Calf Muscle Area (mm 2 ) 6,000 5,800 5,600 5,400 5,200 5,000 4,800 P <.001 P <.001 P=.275 Tertiles 1 st Tertile 2 nd Tertile 3 rd Tertile 4,6000 Accelerometermeasured 7 day physical activity level Blocks walked during the past week Frequency of walking exercise Vertical accelerometer tertiles: 1st tertile ( 499), 2nd tertile (499-828), 3rd tertile (>828) Blocks walked tertiles: 1st tertile ( 4), 2nd tertile (> 4-21), 3rd tertile (>21) Walking exercise frequency: 1st group- no walking exercise; 2nd group- walking exercise 1-2 times per week; 3rd group- walking exercise >3 times per week. Data are adjusted for age, sex, race, BMI, leg symptoms, comorbidities, study cohort, smoking, tibia length, and ABI. Fig 1. Adjusted associations of physical activity levels and walking exercise frequency with calf muscle area among 439 participants with peripheral arterial disease (n 263 for accelerometer data). Vertical accelerometer tertiles: 1st tertile ( 499) (light gray bars), 2nd tertile (499-828) (medium gray bars), 3rd tertile ( 828) (black bars). Blocks walked tertiles: 1st tertile ( 4), 2nd tertile ( 4-21), 3rd tertile ( 21). Walking exercise frequency: first group, no walking exercise; second group, walking exercise 1 to 2 times per week; third group, walking exercise 3 times per week. Data are adjusted for age, sex, race, body mass index, leg symptoms, comorbidities, study cohort, smoking, tibia length, and ankle-brachial index. Calf Muscle Density mg/cm 3 34 33.5 33 33 32.5 32 31.5 31 31 30.5 P <.001 P =.007 P=.970 Tertiles 1 st Tertile 2 nd Tertile 3 rd Tertile 300 Vertical accelerometermeasured 7 day physical activity level Blocks walked during the past 7 days Frequency of walking exercise Vertical accelerometer tertiles: 1st tertile ( 499), 2nd tertile (499-828), 3rd tertile (>828) Blocks walked tertiles: 1st tertile ( 4), 2nd tertile (> 4-21), 3rd tertile (>21) Walking exercise frequency: 1st group- no walking exercise; 2nd group- walking exercise 1-2 times per week; 3rd group- walking exercise >3 times per week. Data are adjusted for age, sex, race, BMI, leg symptoms, comorbidities, smoking, recruitment cohort, and ABI. Fig 2. Adjusted associations of physical activity levels and walking exercise frequency with calf muscle density among 439 participants with peripheral arterial disease (n 263 for accelerometer data). Vertical accelerometer tertiles: 1st tertile ( 499) (light gray bars), 2nd tertile (499-828) (medium gray bars), 3rd tertile ( 828) (black bars). Blocks walked tertiles: 1st tertile ( 4), 2nd tertile ( 4-21), 3rd tertile ( 21). Walking exercise frequency: first group, no walking exercise; second group, walking exercise 1 to 2 times per week; third group, walking exercise 3 times per week. Data are adjusted for age, sex, race, body mass index, leg symptoms, comorbidities, study cohort, smoking, tibia length, and ankle-brachial index. age, sex, race, tibia length (muscle area only), BMI, comorbidities, leg symptoms, recruitment cohort, smoking, and ABI (Fig 1, Fig 2). Higher physical levels for 7 days measured by vertical accelerometer and greater numbers of blocks walked during the past 7 days were associated with greater calf muscle area and higher calf muscle density, adjusting for confounders (Fig 1, Fig 2). Results in Fig 1 and Fig 2 for patient-reported and objectively measured physical activity were similar when results were repeated adjusting only for

JOURNAL OF VASCULAR SURGERY Volume 46, Number 1 McDermott et al 91 Table. Associations between physical activity levels and functional performance levels in participants with peripheral arterial disease* Test Activity units Tertile 1 Tertile 2 Tertile 3 P trend Six-minute walk test in feet (n 260) Model 1 1043 1172 1275.001 Model 2 1074 1165 1252.001 Model 3 1083 1163 1245.001 Four-meter walking velocity (usual pace) in m/s (n 261) Model 1 0.817 0.852 0.915.001 Model 2 0.842 0.847 0.896.037 Model 3 0.844 0.846 0.894.056 *Results shown represent average performance on each measure of lower extremity performance (dependent variable) according to tertiles of accelerometer-measured physical activity levels (independent variable), adjusting for confounders. The variables adjusted for in each model are: model 1 adjusted for age, sex, race, body mass index, smoking, recruitment cohort, leg symptoms, comorbidities, and ankle-brachial index; model 2 adjusted for variables in model plus muscle area and tibia length; model 3 adjusted for variables in model plus muscle density. N represents the number of participants with peripheral arterial disease in each analysis. N values are smaller than data in Fig 1 and Fig 2 because accelerometer data were available for 60% of PAD participants. Previous studies suggest that lower extremity ischemia 1-4 has a direct, negative effect on calf muscle area. In addition, lower calf muscle area among individuals with PAD is associated with poorer 6-minute walk performance 4 and slower walking speed. Clinical characteristics associ - ated with lower calf muscle area in people with PAD are largely unknown, however. Results reported here show that higher physical activity levels during daily life, measured both objectively and by patient report, are associated with higher calf muscle area and higher calf muscle density in participants with PAD. In contrast, these results suggest that no significant associations exist between walking exercise frequency and calf muscle characteristics in PAD par- age sex, race, recruitment cohort, and tibia length (muscle ticpants and that patient-reported walking exercise may area only). Results were similar when analyses in Fig 1 andneither benefit nor harm calf muscle characteristics in persons with PAD. Fig 2 for blocks walked during the prior 7 days and walking exercise frequency were repeated within the subset of participants who wore Caltrac vertical accelerometers (data not exercise vs physical activity with calf muscle characteristics The differences observed in associations of walking shown). have several potential explanations. Walking activity during Higher accelerometer-measured physical activity tertiles were associated with better 6-minute walk perforated with activity during daily life. Patients with PAD may exercise may be more intensive than casual walking associmance and faster 4-meter walking speed among PAD participants, adjusting for age, sex, race, BMI, smoking, walk only to the onset of exertional leg pain during daily walk to maximal leg pain during walking exercise, but may recruitment cohort, leg symptoms, comorbidities, and ABI physical activities. Because intensive walking to maximal leg (Table, model 1). To determine whether these associations were potentially explained by more favorable calf muscle characteristics among more physically active PAD participants, analyses were repeated with additional adjustment for calf muscle area (Table, model 2) and calf muscle density (Table, model 3). The association between higher physical activity levels and better 6-minute walk performance was not substantially changed after additional adjustment for each calf muscle characteristic. This finding suggests that significant associations between higher physical activity levels and better 6-minute walk performance are not likely to be attributable to the more favorable skeletal muscle characteristics among more physically active PAD participants. However, after additional adjustment for calf muscle characteristics, associations of higher physical activity levels and faster 4-meter walking speed were less marked and of borderline statistical significance (Table). These latter findings suggest that the greater calf muscle area and greater calf muscle density observed in more physically active PAD participants may be responsible for the associations of higher physical activity and faster 4-meter walking velocity (Table). Analyses in Fig 1 and Fig 2 and the Table that included Caltrac vertical accelerometer data were repeated, with additional adjustment for missing data using inverse weighting. Results were similar to those presented in Fig 1 and 2 and the Table (data not shown). Analyses for Fig 1 and 2 and the Table were repeated, in which the ABI covariate was calculated using the highest pressure in each leg for the analysis. Results were similar to those presented in Fig 1 and Fig 2 and the Table. DISCUSSION pain during exercise is expected to induce greater leg ischemia than more casual walking during daily activities, and greater lower extremity ischemia is associated with 4 adverse calf muscle characteristics, more intensive walking exercise may be associated with less favorable calf muscle characteristics compared with less intensive walking activity. Alternatively, the patient-reported measure of walking exercise frequency may be a less valid measure than accelerometer-measured physical activity or the patientreported physical activity measure of the number of blocks walked during the past week. It is not intuitively clear, however, why the patient-reported measure of number of blocks walked during the prior week would be a more valid measure than patient-reported walking exercise frequency. In addition, the patient-reported walking exercise question used has been previously demonstrated to be associated significantly with average annual decline in functional performance among individuals with PAD. 5

92 McDermott et al JOURNAL OF VASCULAR SURGERY July 2007 Our results have implications for lifestyle counseling of patients with PAD and suggest that increasing physical activity during daily life may have beneficial consequences for calf muscle in patients with PAD. These findings suggest that physicians should urge their patients with PAD to increase their walking physical activity, even if their patient does not engage in walking exercise behavior. Our results also suggest that more study is needed to determine whether less intensive walking exercise (ie, walking to the onset of exertional leg symptoms) may be more beneficial to calf skeletal muscle than more intensive walking exercise (ie walking to maximal leg symptoms) in patients with PAD. Findings reported here also suggest that more favorable calf muscle characteristics in study participants with PAD who are more physically active may partly explain the observed associations between higher physical activity levels and faster 4-meter walking velocity. In this case, increased physical activity may increase calf muscle area, which in turn may contribute to faster walking speed over short distances. However, significant associations between higher objectively measured physical activity and better 6-minute walk performance did not appear to be explained by more favorable calf muscle characteristics among more physically active study participants. The associations between higher physical activity levels and better 6-minute walk performance remained highly statistically significant even after taking into account calf muscle characteristics in statistical analyses. These results suggest that factors other than muscle area or density may explain the observed associations between higher objectively measured physical activity levels and better 6-minute walk performance. Potential alternative explanations for this observed association include more efficient muscle metabolism, improved cardiovascular fitness, or more efficient gait characteristics in more physically active PAD patients. Because the 6-minute walk is a measure of walking endurance, whereas the 4-meter walk measures speed over a short distance, mechanisms of better performance may differ between each of these two functional performance assessments. 27 Previous study by Hiatt et al demonstrated that treadmill walking exercise was associated with a higher percentage of denervated muscle fibers and increased muscle connective tissue content among 26 patients with intermittent claudication who were randomized to 12 weeks of treadmill exercise, strength training, or a control group. Treadmill exercise was not associated with changes in type I or type II fiber area in the leg with most severe PAD; however, type II fiber area significantly decreased in the leg with less severe PAD. No changes in muscle fiber denervation, number, or connective tissue content were observed in the strength-trained or control groups. 27 To our knowledge, no prior studies have assessed associations between walking exercise frequency or physical activity levels and CT-measured calf muscle characteristics in a large cohort of participants with PAD. This study has limitations. First, data are crosssectional. Associations reported here between greater physical activity levels and more favorable calf muscle characteristics may not be causal. Second, we did not collect data on intensity of walking activity or exercise. It is conceivable that differences in associations between physical activity and walking exercise with calf muscle characteristics may be due to differences in walking intensity between walking activity during daily life and walking during exercise. Third, because 60% of PAD participants wore the Caltrac vertical accelerometer, we cannot be certain that our findings are generalizable to the PAD participants who did not wear the Caltrac accelerometer. However, analyses performed using the technique of inverse weighting to adjust for missing data suggest that our results for the Caltrac vertical accelerometer are likely to be similar to results for the entire cohort. Fourth, our study design does not allow us to determine reasons for the discrepancy in findings between the physical activity and patient-reported walking exercise measures. Finally, this study focuses on associations between walking activity and calf muscle characteristics. Associations between other forms of activity and calf muscle characteristics were not evaluated. CONCLUSION PAD patients with higher physical activity levels during daily life have more favorable calf skeletal muscle characteristics than PAD patients with lower activity. More favorable calf muscle characteristics in more physically activity persons with PAD may explain some of the observed associations between greater physical activity levels and better lower extremity performance in individuals with PAD. In contrast, participants with PAD who reported regular walking exercise had neither more or less favorable calf muscle characteristics. Nonetheless, it is important to note that multiple prior clinical trials demonstrate significant improvement in walking endurance in response to supervised treadmill walking exercise in persons with PAD. 28 Our data also suggest that physicians should encourage patients with PAD to increase their walking activity during daily life. AUTHOR CONTRIBUTIONS Conception and design: MM, JG, LF, WP, FH, KL, MC Analysis and interpretation: MM, JG, LF, LT, WP, KL, YL, MC Data collection: MM, WP, FH, KL Writing the article: MM, JG, LF, FH, KL, MC, YL Critical revision of the article: MM, LF, LT, WP, MC Final approval of the article: MM, JG, LF, LT, WP, KL, YL, MC, FH Statistical analysis: LT, KL, YL Obtained funding: MM, JG, LF, FH, KL, MC Overall responsibility: MM, KL

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