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Peripheral Artery Disease

Association Between Daily Steps at Moderate Cadence and Vascular Outcomes in Patients With Claudication

Gardner, Andrew W. PhD; Montgomery, Polly S. MS; Wang, Ming PhD; Shen, Biyi MS

Author Information
Journal of Cardiopulmonary Rehabilitation and Prevention: January 2022 - Volume 42 - Issue 1 - p 52-58
doi: 10.1097/HCR.0000000000000606
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Peripheral artery disease (PAD) is a significant medical concern, as it is highly prevalent worldwide,1 costly,2 and associated with a high rate of all-cause and cardiovascular mortality.3 The most common symptom of PAD is claudication,4 defined as lower extremity pain that is reproducibly induced by walking and relieved with rest and which is secondary to inadequate blood flow to the exercising leg musculature. Consequently, claudication impairs ambulation,5,6 physical function,7–9 daily physical activity,10,11 and health-related quality of life.12

Walking is the most common form of exercise performed by older adults13–15 and is the primary activity that elicits claudication in patients with PAD. Given that steps are a basic unit of locomotion that can also quantify intensity,16 daily steps and step rate (ie, cadence) are clinically relevant and appropriate metrics to evaluate daily activity levels in patients with PAD. Updated physical activity guidelines for US adults provide strong evidence for an inverse dose-response relationship between moderate-intensity physical activity and all-cause and cardiovascular disease mortality, and with incidence in vascular events such as cardiovascular disease, stroke, and heart failure.17 Moderate-intensity exercise for adults is equivalent to walking at a cadence of 100 steps/min,18 but this walking cadence exceeds the maximal rate of walking in patients with claudication in the community-based setting.11,19,20 Walking at a cadence of >60 steps/min represents a level beyond purposeful stepping in adults18,21 and is equivalent to a moderate intensity of walking in patients with claudication compared with their maximal cadence of approximately 95 steps/min during a 6-min walk test.22 Although moderate-intensity exercise is associated with better vascular health and fitness outcomes,17,23 it is not clear whether community-based walking at a cadence equivalent to moderate intensity is associated with better vascular function and biomarkers in patients with claudication. The current investigation is focused to addresses this knowledge gap.

The aims of this investigation were to determine whether patients with claudication grouped according to tertiles of community-based daily steps taken at a moderate cadence had differences in vascular function and biomarkers and whether group differences in vascular function and biomarkers persisted after adjusting for demographic variables, comorbid conditions, and severity of PAD. We hypothesized that patients who were in the upper and middle tertiles would have significantly better vascular function and biomarkers than patients who were in the lowest tertile, and these differences would persist after adjustment for demographic variables, comorbid conditions, and severity of PAD.

METHODS

The procedures of this study were approved by the institutional review board from the University of Oklahoma Health Sciences Center (HSC). Written informed consent was obtained from each patient before beginning the investigation.

Patients with PAD who had claudication (Fontaine stage II)4 were recruited from the University of Oklahoma HSC vascular clinic and vascular laboratory for possible enrollment into the study. Patients were evaluated in the Clinical Research Center and were screened on inclusion and exclusion criteria that have been used previously24 and which are listed in the following text.

Patients with PAD and claudication were included in this study if they met the following criteria: a history of claudication, claudication confirmed by a screening treadmill exercise test,5 and an ankle/brachial index (ABI) ≤0.90 at rest25 or ≤0.73 after exercise.26 Patients were excluded for the following conditions: absence of PAD (ABI >0.90 at rest and ABI >0.73 after exercise), noncompressible vessels (ABI >1.40), asymptomatic PAD,25 critical limb ischemia due to PAD, use of medications indicated for the treatment of claudication (cilostazol or pentoxifylline) initiated ≤3 mo prior to investigation, exercise limited by other diseases or conditions, active cancer, stage 5 chronic kidney disease (end stage), as defined by an estimated glomerular filtration rate <15 mL/min per 1.73 m,27 a calf skin fold measurement >20 mm because of the potential interference with the light path of the near-infrared spectroscopy probe from penetrating the subcutaneous tissue, pulse arterial oxygen saturation of the index finger <95% because of potential deleterious effects on oxygen delivery to the calf muscle due to poor pulmonary gas exchange, and failure to complete all of the tests within 3 wk.

TESTS, OUTCOME MEASUREMENTS, AND PHYSICAL ACTIVITY GROUP DETERMINATION

On the initial study visit, patients arrived at the Clinical Research Center in the morning fasted but were permitted to take their usual medications. Vital signs, demographic information, education level, height, weight, body mass index, anthropometric measurements, waist circumference, and ABI were obtained according to standard guidelines.28 Subsequently, patients had blood samples drawn, which were then sent to a central laboratory for analyses for fasting blood chemistries, including a complete metabolic panel, a lipid panel, and measurements of glucose, insulin, high-sensitivity C-reactive protein, and fibrinogen.

Patients then underwent a medical history and physical examination by study physicians, in which claudication history, comorbid conditions, cardiovascular disease risk factors, and current medications were recorded. On the basis of this battery of baseline assessments, patients were coded on cardiovascular disease risk factors according to standard definitions for hypertension, dyslipidemia, diabetes, obesity, abdominal obesity, and metabolic syndrome, as previously described.29,30 Coronary artery disease, cerebrovascular disease, and chronic kidney disease 27,31 were coded according to standard definitions, as previously described.32 Patients were further characterized on the history and symptoms of arthritis, chronic obstructive pulmonary disease, and PAD.

Patients performed a standardized Gardner-Skinner graded treadmill protocol5 during the baseline study visit to determine study eligibility and then repeated the test on a following visit within 1 wk for the purpose of recording the outcome measures of claudication onset time and peak walking time.5 Prior to the treadmill test, patients rested in the supine position for 10 min. Systolic blood pressure was measured in the posterior tibial and dorsalis pedis arteries of both legs, and in the brachial artery of both arms, by Doppler ultrasound technique according to standard guidelines.28 After completion of the treadmill test, patients returned to the supine position and ABI was measured 1 min after exercise. Calf muscle oxygen saturation (StO2) was continuously measured over the medial gastrocnemius muscle of the more symptomatic leg before and during the treadmill test using a continuous-wave, near-infrared spectrometer system,33 as previously described.34

Daily walking was measured using a StepWatch3 activity monitor (Orthoinnovations, Inc), as previously described.11,19,20,35–37 Walking was measured during 7 consecutive days in which patients were instructed to wear the monitor during waking hours and to remove it before retiring to bed and while showering. The patients were further instructed to engage in their normal routine daily activities and were not given any daily step goals to attain. The step activity monitor does not display the number of steps taken, thereby blinding patients to their daily steps. Only valid days with >10 hr of wear time were included in the analyses, as determined by identifying the first step recorded in the morning and the last step recorded in the evening of each day.38 During this period, we excluded durations in which patients may have removed the monitor by deleting time periods with no recorded steps for 180 consecutive min.38 All patients had ≥6 valid days of monitoring. We quantified the number of daily steps taken at a moderate cadence (ie, intensity) in the community setting for patients with claudication, defined as exceeding a cadence of 60 steps/min.11 Patients were then tertiled into low (group 1), intermediate (group 2), and high (group 3) groups based on the number of daily steps taken at moderate cadence.

STATISTICAL ANALYSES

Summary statistics including mean ± SD for continuous variables and frequencies with percentage (%) for categorical variables were presented by group (Table 1). Three-group comparisons were performed on the basis of analysis of variance tests or Kruskal-Wallis tests for continuous variables and Pearson's chi-square tests or Fisher's exact tests for categorical variables, as appropriate. The normality assumption for continuous variables was checked on the basis of Shapiro-Wilk tests, and if necessary, log transformation was applied. For each of the primary outcomes, we conducted four models to evaluate pairwise group differences (group 2 vs group 1; group 3 vs group 1), including univariable and multivariable logistic regression analyses adjusted for different sets of confounding variables. Noting that age, sex, race, and education were selected as covariates due to their significance based on our prior studies and the remaining ones were selected because they were significantly different between groups or were associated with daily steps in patients with PAD. The P values in model 1 and model 2 were obtained from Wald tests. All hypothesis tests were two-sided with the significance level of .05. Data were analyzed using SAS 9.4 Software (SAS Institute).

Table 1 - Demographic and Clinical Characteristics of Patients With Peripheral Artery Disease and Claudication Grouped According to Tertiles of Daily Steps Taken at a Moderate Cadencea
Variables Group 1 (n = 88) Group 2 (n = 87) Group 3 (n = 88) P Value
Age, yr 65.0 ± 10.0 65.4 ± 10.2 66.7 ± 9.9 .26
Weight, kg 81.0 ± 19.8 85.1 ± 19.7 81.5 ± 14.8 .85
Height, cm 165.8 ± 9.2 169.5 ± 9.3 169.4 ± 9.1 .01
Body mass index, kg/m2 29.3 ± 6.2 29.6 ± 6.3 28.5 ± 5.5 .35
Ankle/brachial index 0.62 ± 0.24 0.68 ± 0.25 0.72 ± 0.22 <.01
Claudication onset time, sec 155 ± 120 220 ± 193 287 ± 211 <.01
Peak walking time, sec 267 ± 162 414 ± 270 585 ± 318 <.01
Total daily steps, steps/d 4 079 ± 1 670 6 063 ± 1 480 10 065 ± 3 159 <.01
Daily steps at moderate cadence, steps/d 449 ± 202 1 110 ± 229 3 030 ± 1 583 <.01
Sex, men 26 (30) 50 (58) 56 (64) <.01
Race, Caucasian 44 (50) 47 (54) 52 (59) .48
Education, high school graduate 72 (82) 68 (78) 75 (85) .38
Coronary artery disease 36 (42) 29 (33) 27 (31) .34
Cerebrovascular disease 17 (19) 9 (10) 17 (19) .18
Chronic kidney disease 23 (26) 18 (21) 21 (24) .71
Lower extremity revascularization 41 (47) 43 (49) 38 (43) .71
Current smoking 35 (40) 35 (40) 26 (30) .26
Hypertension 77 (88) 77 (89) 77 (88) .97
Dyslipidemia 81 (92) 82 (94) 73 (83) .03
Diabetes 43 (49) 48 (55) 18 (20) <.01
Obesity 43 (49) 40 (46) 30 (34) .11
Abdominal obesity 51 (58) 50 (58) 34 (39) .01
Metabolic syndrome 73 (83) 73 (84) 65 (74) .18
Arthritis 56 (64) 40 (46) 51 (58) .05
Chronic obstructive pulmonary disease 29 (33) 14 (16) 26 (30) .03
aData are presented as mean ± SD or n (%).

RESULTS

By definition, the groups were significantly different on the number of daily steps taken at moderate cadence (P < .01) and on total daily steps (P < .01) (Table 1). In addition, groups were significantly different on ABI (P < .01), claudication onset time (P < .01), peak walking time (P < .01), height (P = .01), and sex (P < .01) and on the prevalence of dyslipidemia (P = .03), diabetes (P < .01), abdominal obesity (P = .01), arthritis (P = .05), and chronic obstructive pulmonary disease (P = .03).

As shown in Table 2, the ABI measured at rest, 1 min after treadmill exercise, and the percentage change in ABI after exercise were significantly different between group 3 and group 1 in unadjusted analyses (model 1) and in analyses adjusting for demographic variables (model 2), adjusting for model 2 plus comorbid conditions (model 3), and adjusting for model 3 plus the time taken to reach minimum calf muscle StO2 during exercise (model 4). For the comparison between group 2 and group 1, only the ABI measured at rest was significantly different between groups in adjusted models 2, 3, and 4, and ABI measured at 1 min after exercise was significantly different between groups in model 3.

Table 2 - Ankle/Brachial Index Measured Before and After a Treadmill Test in Patients With Peripheral Artery Disease and Claudication Grouped According to Tertiles of Daily Steps Taken at a Moderate Cadencea
Outcome Variables Group 1 (n = 88) Group 2 (n = 87) Group 3 (n = 88) Model Group 2 vs Group 1, P Value Group 3 vs Group 1, P Value
ABI at rest 0.62 ± 0.24 0.68 ± 0.25 0.72 ± 0.22 1 .06 <.01
2 .04 <.01
3 .01 .01
4 .04 .01
ABI at 1 min after exercise 0.34 ± 0.25 0.38 ± 0.27 0.44 ± 0.28 1 .25 .01
2 .15 .01
3 .04 .01
4 .14 .02
Absolute change in ABI after exercise −0.28 ± 0.15 −0.30 ± 0.18 −0.28 ± 0.20 1 .43 .97
2 .54 .71
3 .59 .94
4 .66 .89
Change in ABI after exercise, % −49 ± 27 −47 ± 25 −42 ± 29 1 .64 .05
2 .41 .02
3 .22 .03
4 .32 .03
Abbreviation: ABI, ankle/brachial index.
aData are presented as mean ± SD. Model 1: unadjusted. Model 2: adjusted for age, sex, race, and education. Model 3: adjusted for model 2 plus diabetes, dyslipidemia, abdominal obesity, arthritis, and chronic obstructive pulmonary disease. Model 4: adjusted for model 3 plus log-transformed exercise time to the minimum calf muscle oxygen saturation.

The exercise time to the minimum calf muscle StO2 of the three groups is displayed in the Figure and was significantly longer in group 3 than in group 1 in all four models (Table 3). In this case, model 4 consisted of adjusting for model 3 plus rest ABI. Similarly, the exercise time to the minimum calf muscle StO2 was significantly longer in group 2 than in group 1 in all four models.

F1
Figure.:
Box plot with scatter points of the exercise time to minimum calf muscle oxygen saturation (StO2) in patients with peripheral artery disease and claudication grouped according to tertiles of daily steps taken at a moderate cadence. This figure is available in color online (www.jcrpjournal.com).
Table 3 - Calf Muscle Tissue Oxygen Saturation Outcomes Before and During a Treadmill Test in Patients With Peripheral Artery Disease and Claudication Grouped According to Tertiles of Daily Steps Taken at a Moderate Cadencea
Outcome Variables Group 1 (n = 88) Group 2 (n = 87) Group 3 (n = 88) Model Group 2 vs Group 1, P Value Group 3 vs Group 1, P Value
StO2 at rest, % saturation 50 ± 19 50 ± 19 55 ± 16 1 .93 .10
2 .37 .63
3 .25 .44
4 .39 .27
StO2 at 1 min during exercise, % saturationb 25 ± 23 26 ± 26 26 ± 21 1 .82 .68
2 .47 .83
3 .35 .74
4 .13 .30
Minimum exercise StO2, % saturation 18 ± 20 17 ± 21 14 ± 17 1 .94 .28
2 .73 .18
3 .62 .42
4 .36 .19
Exercise time to minimum StO2, secb 127 ± 127 251 ± 266 310 ± 323 1 <.01 <.01
2 .01 <.01
3 .01 <.01
4 .03 .01
StO2 at peak walking time, % saturationb 24 ± 23 21 ± 21 19 ± 20 1 .83 .58
2 .51 .28
3 .48 .37
4 .18 .10
Abbreviation: StO2, calf muscle tissue oxygen saturation.
aData are presented as means ± SD. Model 1: unadjusted. Model 2: adjusted for age, sex, race, and education. Model 3: adjusted for model 2 plus diabetes, dyslipidemia, abdominal obesity, arthritis, and chronic obstructive pulmonary disease. Model 4: adjusted for model 3 plus ankle-brachial index.
bData were log transformed for model assessment.

Fibrinogen was significantly lower in group 3 than in group 1 in unadjusted analyses of model 1 and in adjusted analyses of models 3 and 4, with a trend toward significance in model 2 (Table 4). Plasma glucose was significantly lower in group 3 than in group 1 for models 1 and 2 but not after adjusting for comorbid conditions and ABI in models 3 and 4. For the comparisons between group 2 and group 1, no significant differences were found.

Table 4 - Vascular Biomarkers in Patients With Peripheral Artery Disease and Claudication Grouped According to Tertiles of Daily Steps Taken at a Moderate Cadencea
Outcome Variables Group 1 (n = 88) Group 2 (n = 87) Group 3 (n = 88) Model Group 2 vs Group 1, P Value Group 3 vs Group 1, P Value
High-sensitivity C-reactive protein, mg/L 6.2 ± 7.0 6.0 ± 6.1 4.5 ± 6.1 1 .83 .09
2 .93 .14
3 .98 .26
4 .98 .28
Fibrinogen, g/L 3.5 ± 1.2 3.6 ± 1.5 3.0 ± 1.1 1 .75 .02
2 .43 .06
3 .25 .04
4 .25 .05
Plasma glucose, mg/dL 110 ± 45 109 ± 48 94 ± 22 1 .80 .01
2 .90 .01
3 .46 .49
4 .69 .73
aData are presented as mean ± SD. Model 1: unadjusted. Model 2: adjusted for age, sex, race, and education. Model 3: adjusted for model 2 plus diabetes, dyslipidemia, abdominal obesity, arthritis, and chronic obstructive pulmonary disease. Model 4: adjusted for model 3 plus ankle/brachial index.

DISCUSSION

To our knowledge, this is the first study to determine the association between community-based daily steps taken at a moderate cadence and vascular function and biomarkers in patients with claudication. A major finding was that compared with patients in the lowest tertile of daily steps taken at a moderate cadence, patients in the second and third tertiles had better calf muscle StO2 and ABI values during and immediately after exercise. A second major finding was that the most active group had lower fibrinogen levels than the least active group. These group differences persisted even after adjusting for demographic measures, comorbid conditions, and severity of PAD.

GROUP DIFFERENCES IN EXERCISE CALF MUSCLE StO2

During the treadmill test, calf muscle StO2 declines rapidly during the first minute of walking in patients with claudication, indicating that the increased oxygen utilization by the calf muscle exceeds the increase in oxygen delivery and peripheral blood flow.33,34 This pattern of accelerated decline in calf muscle StO2 during the early phase of exercise is a hallmark characteristic of patients with claudication, whereas relatively little change in calf muscle StO2 occurs during exercise in control subjects.39–42 Calf muscle StO2 continues to decline during the treadmill test until reaching a minimum value.34 We have previously found that the most important characteristic of calf muscle StO2 during treadmill exercise in patients with claudication is the exercise time to reach the minimum StO2 value, as this measure was positively associated with claudication onset time and peak walking time in smaller cohorts,33,43 and this association persists even after adjusting for ABI,43 which agrees with current findings.

In the current study, we found that in both unadjusted and adjusted analyses, the patients in the second and third tertiles of community-based daily steps taken at a moderate cadence had a longer exercise time to the minimum calf muscle StO2 value than patients in the first tertile. This finding supports our previous observations that a slower decline in calf muscle StO2 during an exercise treadmill test was associated with higher claudication onset time and peak walking time33,34,43 and suggests that higher levels of community-based daily steps taken at a moderate cadence are associated with better microcirculation of the calf muscle throughout exercise, which may be a potential mechanism for delayed symptoms while walking. It is important to note that the association between higher daily steps taken at a moderate cadence and longer exercise time to the minimum calf muscle StO2 was independent of demographic variables, comorbid conditions, and ABI in multivariable regression models, indicating that daily steps at moderate cadence play an important role in the microcirculation of the calf musculature during exercise in patients with PAD. Furthermore, the fact that this association was observed after adjustment of ABI indicates that the link between daily steps at moderate cadence and microcirculation of the calf musculature was evident regardless of the severity of PAD.

GROUP DIFFERENCES IN POST-EXERCISE ABI

After treadmill exercise, ankle systolic blood pressure and ABI were measured to assess the impairment in the peripheral circulation and ischemic response to exercise. A decrease in ankle systolic pressure and ABI immediately following treadmill exercise is a hallmark characteristic in patients with PAD first observed in early classic studies.44–47 The reduction in ABI following exercise reflects a steal of blood flow via vasodilation into the ischemic proximal musculature and away from the more distal location of the ankle. The finding in the current study that patients in the third tertile of community-based daily steps taken at a moderate cadence had a higher post-exercise ABI and a lower percentage decline from rest ABI than patients in the first tertile suggests that greater daily steps taken at a moderate cadence is associated with lower impairment in the peripheral macrocirculation from exercise. The better post-exercise ABI values of the third tertile than the first tertile of daily steps taken at a moderate cadence were evident in both unadjusted and adjusted multivariable models, indicating that community-based daily steps taken at a moderate cadence had an independent and beneficial association with post-exercise ABI even after controlling for differences in demographic variables, comorbid conditions, and exercise time to the minimum calf muscle StO2.

GROUP DIFFERENCES IN COAGULATION

Patients in the third tertile of community-based daily steps taken at a moderate cadence had a 14% lower plasma fibrinogen level than patients in the first tertile, suggesting that higher step values were associated with a lower state of coagulation. This group difference in fibrinogen was significant in both unadjusted and fully adjusted analyses, indicating that the association between higher daily steps taken at a moderate cadence and lower coagulation was independent of demographic variables, comorbid conditions, and severity of PAD. These findings are supported by a previous report from our laboratory that higher sedentary time was independently associated with higher fibrinogen levels in patients with claudication.48 Interestingly, the association between daily steps taken at a moderate cadence and fibrinogen in the current study was not evident when comparing the patients in the first and second tertiles of activity. This observation may suggest that a higher volume of daily steps taken at moderate cadence may be needed to improve plasma fibrinogen and thus may be a therapy for patients within the reference range for fibrinogen who would not be considered for anticoagulation therapy. We speculate that the beneficial association between daily steps taken at moderate cadence and plasma fibrinogen might provide some benefits in survival, as a longitudinal follow-up study found that changes in fibrinogen was the strongest predictor of mortality in patients with claudication, as an increase in fibrinogen of 1 g/L was associated with nearly a two-fold increase in the probability of death within the subsequent 6 yr.49

LIMITATIONS

There may have been a self-selection bias regarding study participation, and the current results are only generalizable to patients with claudication. There are limitations associated with the cross-sectional study design. Significant group differences found in the variables do not provide evidence of causality, even with statistical adjustment of covariates in multivariable models. Although statistical adjustment was performed, it is possible that statistically significant findings are due to confounding variables that were not measured or due to residual confounding. There is a limitation associated with our assessment of daily step counts, which does not measure other potential physical activities performed throughout the day such as non–weight-bearing and nonambulatory activities. However, we believe this limitation is minimal because walking is required to complete many activities of daily living and walking is the most common form of exercise of older adults.14 There are limitations associated with the measurement of calf muscle StO2, as we have previously described.33 Finally, although medication information was recorded to better define hypertension, dyslipidemia, and diabetes, other medications that may influence fibrinogen, such as anticoagulants and antiplatelets, were not included in the analyses.

CONCLUSIONS

Compared with patients with claudication in the lowest tertile of community-based daily steps taken at a moderate cadence, patients in the second and third tertiles had better calf muscle StO2 and ABI values during and immediately after exercise. Second, the most active group had lower fibrinogen levels than the least active group. This study provides preliminary evidence that a greater number of community-based daily steps taken at a moderate cadence are positively associated with better vascular outcomes in patients with claudication.

ACKNOWLEDGMENTS

This study was supported by grants from the National Institute on Aging (R01-AG-24296) and the General Clinical Research Center (M01-RR-14467) sponsored by the National Center for Research Resources.

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Keywords:

claudication; exercise; fibrinogen; near-infrared spectroscopy; physical activity

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