Improving Exercise Capacity in Chronic Obstructive Pulmonary Disease Patients Through Uphill Walking
Phase: NA
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: VA Office of Research and Development

 
 
 
Improving exercise capacity in chronic obstructive pulmonary disease patients 
through uphill walking 
 
 
 
 
 
 
 
September 14, 2023 
 
NCT04026529 

A. BACKGROUND AND SIGNIFICANCE 
A.1 COPD is an important Veteran health issue. COPD is currently the third leading cause of death in the 
United States and worldwide.5 The prevalence of COPD in the United States Veteran population, ranging from 
33%-43%, is approximately five-fold higher than among the general population of the United States.1, 2, 4 A two-
fold increase in risk of developing COPD was found in those working in the armed forces.6 Active smoking 
continues to be a significant risk factor for COPD in the Veteran population.7 Further, the prevalence of chronic 
lung disease (i.e., COPD, asthma, and interstitial lung disease) has steadily increased from 2003 to 2011 in VA 
care8 inferring that pulmonary disease will continue to be a major health concern for the VA. 
A.2 Exercise performance is limited in COPD and largely attributed to dyspnea (breathlessness) and 
dynamic hyperinflation (air trapping).9, 10  For a large number of patients, exercise is limited by reaching a 
maximal amount of additional air that can be drawn into the lungs (inspiratory reserve volume). Dynamic 
hyperinflation in the presence of expiratory airflow limitation is a characteristic of COPD. Increasing respiratory 
rate causes insufficient time for subsequent emptying. As a consequence, air becomes progressively retained 
in the lung (dynamic hyperinflation), and this is the primary cause of symptomatic breathlessness in COPD.11 
Skeletal muscle strength also limits exercise in COPD, and this is often the outcome of severe detraining (i.e., 
use it or lose it) that develops in COPD patients.12 
 
Exercise performance is the result of the interaction between intensity (power output) and exercise 
duration. Exercise intensity is characteristically limited by inspiratory capacity, which, in turn, can be 
compromised by dynamic hyperinflation and ensuing dyspnea. Our study is based on the observation that 
respiratory rate will increase if gait speed increases, since breathing and walking coupling is less likely to vary 
at a simple ratio (1 stride:1 breath) in patients with COPD. The key hypothesis we will test is that exercise on a 
slope will permit higher intensity exercise without increasing respiratory rate. This is important, as intensity is a 
major driver of training benefit.  
A.3 Coupling of walking and breathing presents a novel 
approach to increase exercise performance. Extensive research 
demonstrates the presence of entrainment of movement and 
respiration in humans.13-16 It is well established that locomotor and 
respiratory rhythms strongly influence each other.17-19 There have 
been several pathways proposed that may mediate this coupling.17, 
20-22 Importantly, when rhythms are optimally coupled, energy 
expenditure is economized.23, 24 Our work demonstrates that 
patients with COPD display an unvarying coupling pattern with very 
low ratios at a self-selected walking speed (e.g., 1 stride:1 breath;  
Figure 2).3 Further, we show that energy expenditure is increased 
during walking in patients with COPD and is associated with 
abnormal coupling of breathing and walking as compared to 
healthy controls.25 Thus, in COPD patients, faster treadmill speeds 
drive increased stepping cadence and increased respiratory rates 
with earlier onset of dynamic hyperinflation and dyspnea, ultimately 
contributing to shorter exercise duration.   
A.4 Walking uphill offers a unique approach to optimizing 
walking and breathing coupling. Walking uphill presents different 
mechanical and metabolic demands from level ground walking. 
Uphill walking introduces a new obstacle as compared to level 
walking because the body must expend more energy to fight the increased amount of work needed to move 
the body’s mass against gravity.26 Energy requirements, amount of work, and muscle activation increase with 
steeper uphill slopes. At slopes greater than 0.2%, the energy cost of walking becomes proportional to the 
slope.27 During uphill walking, self-selected speed decreases with increasing slope.28 This could be due to 
metabolic constraints and/or mechanical constraints that are altered during uphill walking.28-30  
Our preliminary work, as well as published literature, supports the overall hypothesis that having patients with 
COPD walk a slight slope at a slower walking speed may lower respiratory rate, mediated by optimized walking 
and breathing coupling, and result in a delayed onset of dynamic hyperinflation and dyspnea as compared to 
level treadmill walking that relies on increased speed to increase workload.  
B. PRELIMINARY STUDIES AND CURRENT STATUS OF THE FIELD 
Figure 2. The most frequently used coupling 
frequency ratios (strides:breath) from 17 
patients with COPD (black) and 23 control 
subjects (gray) while walking at a self-
selected walking speed.3 More patients with 
COPD use less complex ratios such as 1:1 
and 3:2. Patients with COPD do not use 
higher ratios such as 4:1 and 5:1. These 
results are consistent under various walking 
speeds. NOTE: NC=no coupling 
0
2
4
6
8
10
NC
1:1
3:2
2:1
5:2
3:1
4:1
5:1
Number of Subjects

B.1 Preliminary work 
In addition to our published work3, 25, 31 demonstrating abnormal 
coupling ratios and their association with energy expenditure in patients 
with COPD, we have conducted a preliminary study investigating the 
effects of uphill walking on coupling ratios. 
Walking on a slope alters coupling in older adults. The goal of this 
study was to investigate the effect of walking on a slope on energy 
expenditure and breathing and walking coupling in healthy young and 
healthy older adults. Ten healthy young adults (Mean(SD): 22.5(1.1) 
years) and 10 healthy older adults (67.9(3.9) years) were asked to walk 
at their preferred walking speed on a treadmill that was either level (0% 
slope) or sloped (10% slope). Energy expenditure, rating of perceived 
exertion, as well as breathing and walking coupling ratios were 
quantified. Older adults walked at a slower speed uphill as compared to 
young adults. Uphill walking increased energy expenditure (p<0.001) 
and rating of perceived exertion (p<0.001) above level walking. 
Breathing and walking coupling ratios became more variable in older 
adults during uphill walking as compared to level walking (Figure 3).  
B.2 Current status of the field 
A dearth of information exists on the effect of slope walking in patients with COPD. Previous focus, 
although limited, has been on downhill walking.32-34 Decline walking requires controlled, eccentric contractions 
of the lower-extremity musculature, considered a more stressful walking condition compared to level walking.35 
Eccentric muscle contractions lead to increased muscle damage, muscle soreness, and fatigue.36, 37 Recent 
research demonstrates improvements in exercise capacity after a downhill walking program; however, muscle 
soreness between training sessions was not measured and reported.32, 33 In addition, it has been shown that 
during decline walking, healthy young persons must tightly control their angular momentum as to maintain 
stability and this may be difficult for pathological populations, increasing their risk of falls.38 Our approach 
focuses on uphill walking at slight slopes. This approach increases exercise intensity through increased 
mechanical demand to move the body against gravity; however, this is done through concentric muscle 
contractions. For the most detrained individuals, this approach limits immediate effects of muscle damage, 
soreness, and fatigue, leading to increased confidence and efficacy in exercise performance.  
Other strategies have been explored to permit tolerable exercise at higher intensity in COPD. Interval 
exercise, for example, has been shown to increase exercise duration,39, 40 but has yet to show a superior 
training effect.41, 42 Bronchodilators, helium-oxygen, and oxygen supplementation have been shown to reduce 
dynamic hyperinflation.43-47 Our approach could be combined with any combination of these other interventions 
and offers a separate means to permit improved exercise performance in COPD. 
Current pulmonary rehabilitation programs vary but generally include exercise, most commonly on a 
treadmill, behavioral change, and educational and nutritional counseling components.48, 49 Rehabilitation 
improves exercise capacity primarily through muscle training; however, not all individuals benefit from 
rehabilitation.48, 50-52 Rehabilitation (or exercise training) has a positive impact on strength, exercise tolerance 
(measured in a laboratory setting), dyspnea, self-efficacy, and health-related quality of life; rehabilitation, 
however, does not improve lung function.48, 49, 53-56 Further, the activity levels of COPD patients are not 
consistently improved following conventional rehabilitation.50, 57-59 Improving the effectiveness of pulmonary 
rehabilitation will improve the outcomes for participants. In addition, many of those referred to 
rehabilitation are unable to continue and do not report benefit. Improving one’s ability to participate in 
rehabilitation will increase the percentage of COPD patients for whom rehabilitation will be beneficial.  
C. RESEARCH DESIGN AND METHODS 
C.1 Overall Design  
This study will utilize a cross-sectional design to determine if walking on a slope 1) results in less dynamic 
hyperinflation, 2), improves dyspnea, and 3) leads to more complex coupling as compared to walking faster. 
The study will be completed over four visits. A total of 25 patients (aged 45-80 years) with moderate to severe 
COPD will be enrolled in the study. Hereinafter the patients will be referred to as subjects. During visit 1, 
subjects with moderate to severe COPD, recruited and consented from the Omaha VAMC pulmonary and 
general medicine clinics, will undergo a maximal cardiopulmonary exercise test under medical supervision. 
Only those that are cleared for participation by a physician will be enrolled into the study. Subjects, stratified by 
0
2
4
6
8
NC
1:1
3:2
2:1
5:2
3:1
Number of Subjects
Figure 3. The most frequently used 
coupling frequency ratios (strides:breath) 
from 10 young (black) and 10 older 
adults (gray) while walking level (solid) 
and uphill (stripe). Older adults used 
more ratios (increased variability) when 
walking uphill as opposed to level 
walking. NOTE: NC=no coupling 

disease severity60 upon enrollment (Table 1), will complete 
experimental conditions. The second visit a cardiopulmonary exercise 
test will be used to determine a set speed and slope that equates to 
70%-80% of peak work rate using VO2 (volume of oxygen consumed). 
Specifically, the time course of work rate will be calculated from the 
cardiopulmonary exercise test. The speed and slope that corresponds 
to where 70%-80% of peak work rate was identified will be used. After sufficient rest, an additional constant 
work rate test will be given using increases in speed with a level treadmill to determine the speed that elicits a 
VO2 comparable to the previous walking test. In addition, subjects will be asked to a series of questionnaires to 
characterize their disease state. During the third and fourth visits, airflow, respiratory rate, oximetry, dynamic 
hyperinflation, and walking cadence will be recorded during the trials at the speed/no slope or speed/slope 
determined in the previous visit. Speed or slope conditions will be randomized across visits. At the end of each 
trial, dyspnea rating will be recorded. 
C.2 Subjects, Sample Size, and Inclusion Criteria 
C.2.a Sample size justification: For this proposal, we are requesting funding to recruit and enroll a pilot 
population of 25 subjects. Subjects will be recruited and screened until all 25 subjects are enrolled. Stratified 
sampling will be conducted as subjects are enrolled. Subjects will be stratified by disease severity (Table 1). 
According to Omaha VAMC patient numbers, more than 45,000 visits are documented in the pulmonary clinics 
and other general health clinics with over 2,000 pulmonary function tests yearly. We anticipate recruiting 3-4 
subjects/month during months 3-18. We anticipate meeting our enrollment goal of 1-2 enrolled/month. 
C.2.b Inclusion and exclusion criteria: Veterans from all sex/gender, 
race, and ethnicity will be recruited. All subjects will undergo post-
bronchodilator spirometry and be clinically stable. All subjects must have 
documented FEV1/FVC ratio of <0.7, and between 30% to 80% FEV1% 
predicted (Table 1).60 If subjects have non-qualifying spirometry, they will 
not be screened further. Subjects with qualifying spirometry will be 
screened further (Figure 4). Potential subjects must have a BMI of less 
than 35 kg/m2 and must be free from co-morbidities that may affect 
walking patterns (e.g., peripheral arterial disease, diabetes, low back 
pain). Subjects must also be free from other co-morbidities that may have 
confounding effects such as neurological or musculoskeletal disease. 
Those that meet the initial eligibility criteria will undergo a 
cardiopulmonary exercise test. Those that are cleared for participation by 
a physician will be enrolled in the study following informed consent. 
Based on the exercise test and the pulmonary function test, subjects will 
need to meet the following criteria for enrollment: have moderate to 
severe COPD and have no other pulmonary or cardiac issues that will 
pose a safety hazard when participating in the laboratory treadmill trials.  
C.2.c Recruitment of subjects: The PI conducts a Pulmonary Clinic at the Omaha VAMC every Wednesday. 
During clinic, a member of her research team, will be present. When a subject that fits the preliminary inclusion 
criteria, the PI will refer the patient to speak with the research team before leaving. The research team will also 
be allowed to recruit subjects through Veteran communications such as newsletters and, by accessing 
potential subject names through VINCI, with generic letters informing them of the study. 
C.3 Protocol – Common for all aims  
C.3.a Screening and eligibility (VISIT 1): All potential subjects will be consented and begin screening at the 
Omaha VAMC. Screening includes a comprehensive medical history and spirometry test. Potential subjects 
that meet the initial screening criteria will undergo a cardiopulmonary exercise test administered at the Omaha 
VAMC. The Porszasz treadmill protocol61 will be used. This treadmill protocol provides a linear increase in 
work rate and is appropriate for testing those with a low exercise tolerance. Medical professionals will oversee 
this test with all safety precautions in place (e.g., 12-lead ECG, crash cart). Potential subjects that are cleared 
to participate by a physician will be enrolled.  
C.3.b VISIT 2: Once eligibility is determined, subjects will come to the Biomechanics Research Building at the 
University of Nebraska at Omaha (VA-leased space). They will complete a series of questionnaires that will be 
used as covariates in the analysis. Health-related quality of life and activity-related dyspnea will be assessed 
through the Chronic Respiratory Disease Questionnaire62, 63 and SF-36.64 To assess severity of dyspnea, they 
Table 1. Stratification strategy 60 
Category 
Criteria 
Mild 
FEV1 ≥ 80% predicted 
Moderate 
50% ≤ FEV1 < 80% predicted 
Severe 
30% ≤ FEV1 < 50% predicted 
Very Severe 
FEV1 < 30% predicted 
Figure 4. Flow chart of enrollment 
process. 

will be asked to complete the modified British Medical Research Council Questionnaire. To assess the impact 
COPD has on their everyday life, subjects will be asked to complete the COPD Assessment Tool.65 To 
determine work rate, the time course of work rate (done against gravity) from the Porszasz treadmill protocol 
will be calculated. The speed and slope that corresponds to 70%-80% peak work rate will be used.  
Subjects will be outfitted with a face mask that covers their nose and mouth attached to a portable 
metabolic cart (K5, Cosmed USA, Inc., Chicago, IL). We previously have used this method to measure energy 
expenditure in COPD patients without reported adverse events. Resting heart rate, respiratory rates, and tidal 
volume will be recorded as well through this device. Subjects will stand quietly for five minutes while energy 
expenditure is collected through the metabolic unit. Subjects will have a transcutaneous oximeter attached to 
their abductor pollicis brevis (The Moxy Monitor System, Moxy, Minneapolis, MN). Subjects will walk at the 
speed and slope that corresponds to 70%-80% peak work rate. Subjects will maintain this level of exercise for 
one minute. If fatigued, they will be instructed to stop. (As exercise time at 80% VO2 max is generally six 
minutes, we anticipate most subjects will complete the test without difficulty.) After sufficient rest and the return 
of heart rate and respiratory rate to resting levels for at least 10 minutes, subjects will complete an additional 
constant work rate test. They will walk at increasing speeds until the same VO2 from the previous walking test 
is achieved. This speed will be recorded, and the subject will be asked to continue to exercise at this rate for 
one minute. 
C.3.c VISIT 3: Within seven days, subjects will return for their first experimental visit. Subjects will be prepared 
for data collection by wearing a form-fitting suit (i.e., wrestling singlet) and obtaining height and body weight. 
Retro-reflective markers will be placed bilaterally on anatomical locations of the feet, legs, and hips (Figure 5), 
in addition to 89 markers on the thorax and abdomen.66-69  Subjects will 
be outfitted with the portable metabolic cart and oximeter as in the 
previous visit. One of two treadmill trials will be performed: 1) at the 
speed and 2) at the slope +speed determined in the previous visit. Trial 
order will be randomized among subjects and across visits 3 & 4. For 
each trial, subjects will be asked to walk on a treadmill for up to 6 
minutes. Speed or slope will be increased every 30 seconds and they will 
be asked to walk for one minute at that speed or slope. Once they reach 
the speed or slope that was determined to be 70%-80% of peak work 
rate, they will walk for an additional one minute. This procedure will allow 
for multiple data points for interpolation. Immediately at the end of the 
trial, dyspnea will be assessed by Borg scale.70 Dynamic hyperinflation 
will be assessed through motion capture of the thorax and abdomen 
(optoplethysmography).66-69 
C.3.d VISIT 4: Within seven days, subjects will return for their last 
experimental visit. Methods will be similar to C.3.c. Subjects will 
complete the treadmill trial that was not completed in Visit 3, either the 
speed or the slope trial. The treadmill trial will be administered in the same manner between both visits. 
C.4 Instrumentation and Data Processing Measures (Table 2):  
C.4.a Questionnaires to be used as covariates 
Chronic Respiratory Disease Questionnaire:62, 63 A 20-item questionnaire in which items are scored from 1 
(most severe) to 7 (no impairment). There are four subscale areas tested: dyspnea, fatigue, emotion, and 
mastery. In the dyspnea section, the subject is asked to recall the five most important activities that caused 
dyspnea over the past two weeks. Items within each subsection can range from 1 to 7 or most severe to no 
impairment. A total score, as well as individual subscale scores, can be calculated.  
SF-36:64 A generic assessment of health-related quality of life from the subject’s perspective. The SF-36 
contains eight domains: physical functioning, role-physical, general health perceptions, vitality, social 
functioning, role-emotional, mental health, and health transition. Two composite scores result: physical health 
composite score and mental health composite score. Scores >50 indicate better physical or mental health than 
the mean and <50 indicate worse health. 22 
Modified British Medical Research Council Questionnaire:71-73 A five-level rating scale based on the patient’s 
perception of dyspnea in daily activities. Patients rate their level of perception of dyspnea on 5 grades, from 0 
to 4. A grade of 0 reflects, “I only get breathless with strenuous exercise”; whereas a grade of 4 reflects “I am 
too breathless to leave the house” or “I am breathless when dressing.” 
COPD Assessment Tool (CAT):65 A patient-completed instrument that complements existing approaches to 
assessing COPD. It is a simple and reliable measure of health status in COPD to quantifying the impact of 
Figure 5. Subject wearing form-fitting 
suit while walking on a level treadmill. 

COPD on the patient’s health. It is comprised of 
8 questions and scores range from 1-40. A 
score 5 is typical of a normal, healthy individual. 
A score <10 is considered low impact; 10-20 is 
considered medium impact; >20 is considered 
high impact; and >30 is considered very high 
impact on everyday life. 
C.4.b Aim 1: Identify differences in dynamic 
hyperinflation and dyspnea during speed v. 
slope walking.  
Dynamic hyperinflation: Dynamic hyperinflation 
will be assessed through opto-plethysmography, 
an established method of computing lung 
volumes, including dynamic hyperinflation.66-69, 
74-84 Opto-plethysmography uses three-
dimensional motion capture information to 
determine lung volumes. The 3-D coordinates of 
the 89 markers on the abdomen and thorax will 
be used to create a representation of the 
surface of the trunk (Motion Analysis Corp., Santa Rosa, CA; 120Hz). The volume of the trunk enclosed by the 
surface will be obtained through a custom computer code (MathWorks, Inc., Natick, MA). Dynamic 
hyperinflation will be considered to be present when end-expiratory chest wall volume increased in relation to 
resting values.75, 84 
Perceived dyspnea:70 Breathlessness will be measured based on a 0 to 10-point Borg scale at the end of the 
treadmill trials.  
C.4.c Aim 2: Compare differences in respiratory rate, oxygen uptake, and lung dead space from speed 
to slope walking. 
Respiratory rate: Respiratory rate will be analyzed using motion capture markers on the chest. With custom 
computer code, the markers will be identified to model a sphere. The volume of the sphere will be recorded 
over time. As the volume increases and decreases, respiratory flow will be identified, and respiratory rate can 
be calculated. 
Oxygen uptake: Heart rate and pulmonary gas exchange analysis will be recorded on a breath-by-breath basis 
(TrueOne2400; ParvoMedics, Sandy, Utah). This will provide an accurate measure of pulmonary gas 
exchange, including oxygen uptake, i.e. VO2, in real-time. Steady-state VO2 while walking will be averaged and 
normalized to standing metabolic rate. Heart rate is recorded via an interface with a Polar heart rate monitor 
and is synchronized to pulmonary gas exchange. 
Dead space: Tidal volume and expired carbon dioxide will be measured using the same equipment as oxygen 
uptake above. Partial pressure of arterial carbon dioxide will be measured using a transcutaneous sensor (The 
Moxy Monitor System, Moxy, Minneapolis, MN). Dead space is equal to tidal volume multiplied by the partial 
pressure of arterial carbon dioxide (PaCO2) minus partial pressure of expired carbon dioxide (PeCO2) divided by 
PaCO2. 
C.4.d Aim 3: Determine the complexity of walking and breathing coupling ratios between speed v. 
slope walking.  
Coupling: The laboratory is equipped with a 17-camera, digital motion capture system (Motion Analysis Corp., 
Santa Rosa, CA; 120Hz) to allow for collection of three-dimensional marker positions in real time. The marker 
position data will be analyzed using custom MATLAB code (MathWorks, Inc., Natick, MA) available in the 
laboratory. Data will be plotted to detect spikes and outliers. Spikes and data points greater than three 
standard deviations from the mean will be removed. A cubic spline will be used to interpolate the removed data 
points. All marker data are then normalized to the unit vector for comparison. 
Coupling is often quantified as frequency coupling.85, 86 Frequency coupling refers to how many heel 
strikes occur within a single cycle of respiration (one inhalation to the next); it is usually counted in integer or 
half-integer ratios, measured using discrete relative phase. Discrete relative phase values between 0º-360º 
have a 1:1 relationship, 360º-720º have a 2:1 relationship, 720º-1080º have a 3:1 relationship, and so on. Half-
integer couplings (expressed as 3:2, 5:2, 7:2, etc.) exist when the frequency alternates between two integers. 
The range of ratios and the percentage of time each ratio is utilized will be recorded.  
Table 2. Measures to be collected during the course of the study.  
General Descriptive 
Measures 
Measurement Domain 
Visit 
Demographics  
Description of subject population 
1 
FEV1/FVC 
Determination of presence of COPD 
1 
Medical history 
Determination of co-morbidities 
1 
Potential Covariates 
 
 
Chronic Respiratory 
Disease Questionnaire 
Health-related quality of life and 
activity-related dyspnea 
2 
mMRC 
Dyspnea severity 
2 
CAT 
Impact of COPD on everyday life 
2 
SF-36 
Health-related quality of life 
2 
Variables Collected 
 
 
Respiratory rate 
Exercise performance 
3,4 
VO2 
Oxygen uptake 
3,4 
Oxygenation 
Dead space 
3,4 
Opto-plethysmography 
Dynamic hyperinflation 
3,4 
Rate of perceived 
dyspnea 
Dyspnea 
3,4 
Breathing rhythm 
Coupling ratios 
3,4 
Walking rhythm 
Coupling ratios 
3,4 
NOTE: mMRC=modified British Medical Research Council 
Questionnaire; CAT=COPD Assessment Tool 

C.5 Statistical Analysis 
For sample size justification, please see section C.2.a. Demographic characteristics will be compared between 
groups using independent t-tests for continuous variables and Chi-square tests for categorical variables. For all 
aims, data transformations, non-parametric tests, or generalized linear mixed models will be performed as 
appropriate.  
Aim 1: A statistically significant decrease in dynamic hyperinflation and/or dyspnea during slope walking 
compared to speed walking will support our hypothesis. To determine the effectiveness of speed versus slope 
on dynamic hyperinflation and dyspnea in patients with COPD, linear mixed-effects models will be conducted. 
The model will include dynamic hyperinflation and dyspnea as the outcome variable and walking conditions as 
the independent variable, as well as possible confounders. Missing data will be explored in terms of the 
missing data mechanism, multiple imputations, or other missing data strategies will be considered depending 
on the extent of missing data.  
Aim 2: A statistically significant decrease in respiratory rate and dead space with an increase in oxygen uptake 
during slope walking will support our hypothesis. Similar to Aim 1, linear mixed-effects models will be used to 
identify differences between the two walking conditions. Confounding variables and missing data will be dealt 
with in the same manner as Aim 1. 
Aim 3: An increase in complexity of coupling during slope walking compared to speed walking will support our 
hypothesis. Similar to Aim 1, linear mixed-effects models will be used to identify differences in preferred ratios 
between the two walking conditions. Confounding variables and missing data will be dealt with in the same 
manner. 
C.6 Anticipated Results and Alternative Strategies 
We anticipate that dynamic hyperinflation and dyspnea will be reduced in patients with COPD due to slower 
walking and slower respiratory rates during sloped walking as compared to level speed walking. It is expected 
that this will be influenced by the complexity in breathing and walking coupling ratios.  
Although the preliminary data indicate that change does occur in breathing and walking coupling in 
healthy controls, the pathophysiology of COPD may prevent a similar change in breathing and walking 
coupling while walking on a slope. In this case, data regarding changes in dynamic hyperinflation and dyspnea 
will still prove to be beneficial. These data will provide clinically meaningful data with regards to alternative 
approaches to pulmonary rehabilitation. Meaningful changes in these measures will provide fundamental data 
that may be used to guide pulmonary rehabilitation approaches in the future. 
 There is the possibility that the patients with COPD that have less severe disease and are healthier 
could perform better than those with greater disease severity. Therefore, only those with moderate to severe 
disease will be included (Table 1). We have addressed this by stratifying subjects as they are enrolled in the 
study. It is possible that age may influence the results as well; however, we anticipate disease severity to be a 
larger confounding variable than age. There is no research, at this time, to support the notion that age will 
influence one’s ability to couple walking and breathing rhythms.  
C.7 Timeline  
The study will be divided into specific goals that will be targeted and achieved (Table 3). Every three months, 
intermediate objectives will be assessed, and decisions will be made regarding the course and direction of the 
continuing research effort.  
C.8 Future Directions 
In summary, our research proposal uses 
a novel theoretical approach and a shift 
in clinical research through a new 
method. By exploring an innovative 
approach to improving exercise 
performance in COPD, it may be possible to increase exercise training intensity and duration and thus, 
improve the benefits of training during rehabilitation. Results from this study, including the demonstration 
of physiologic and symptomatic benefits from the proposed method of slope walking, will set the stage 
for a rigorous, well-powered, full Merit award outcome study evaluating the effectiveness of a slope-
based training regimen as part of rehabilitation. This future Merit award clinical trial needs to demonstrate 
that physical activity and lung function, outcomes most associated with morbidity and mortality, improve after a 
sloped-based pulmonary rehabilitation approach. 
Table 3. Timeline 
Year 1 
Year 2 
 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Hire and train personnel 
 
 
 
 
 
 
 
 
Subject recruitment 
 
 
 
 
 
 
 
 
Data collection for all aims 
 
 
 
 
 
 
 
 
Data processing and analysis 
 
 
 
 
 
 
 
 
Manuscript preparation  
 
 
 
 
 
 
 
 
Grant preparation and submission