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1 Section of Vascular Medicine, Divisions of 2 General Internal Medicine, 3 Geriatrics, and 4 Cardiology, University of Colorado Health Sciences Center, Denver, Colorado 80262; and 5 Department of Medicine, Harbor-UCLA Medical Center, Torrance, California 90509
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Patients with peripheral arterial disease (PAD) have arterial
occlusions that limit peripheral blood flow. This study evaluated the
dynamic response in O2 consumption
(
O2) at the onset of constant-load exercise (O2
kinetics) in patients with PAD. Eight patients with bilateral PAD,
seven patients with unilateral PAD, nine age-matched nonsmoking
controls, and seven smoking controls performed graded treadmill
exercise to assess peak O2.
Subjects also performed constant-load exercise tests at 2.0 miles/h at 0 and 4% grade to determine
O2 kinetics. Peak
O2 was reduced 50% in
patients with PAD compared with both control groups
(P < 0.05). At 4% grade,
phase 2 O2 kinetics were
significantly slowed for the PAD groups compared with controls (60.1 ± 15.7 and 58.7 ± 8.3 s, unilateral and bilateral PAD groups,
respectively; compared with 28.4 ± 19.3 and 27.9 ± 8.1 s,
nonsmoking and smoking controls, respectively;
P < 0.05). No relationship was found
between O2 kinetics and
disease severity. These data demonstrate that O2 kinetics are markedly
slowed in patients with PAD. The impairment in
O2 kinetics is not related
to smoking status or arterial disease severity and therefore may
reflect altered control of skeletal muscle metabolism.
heart rate; oxygen consumption; muscle metabolism
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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WITH THE TRANSITION from rest to constant-load
exercise, the rate of change in O2
uptake (O2 kinetics) reflects
the ability of the cardiopulmonary system to deliver
O2, as well as the rate at which
O2 is taken up and utilized by
exercising skeletal muscle. Changes in
O2 kinetics with
disease may provide insight into the alterations in physiological
regulation that are associated with an impairment in exercise
performance and functional capacity.
Cardiovascular diseases are associated with a profound impairment in
both submaximal and peak exercise performances. Slowed O2 kinetics have been well
documented in patients with cardiovascular diseases that affect the
central "cardiac" component of
O2 kinetics (coronary artery
disease and cyanotic congenital heart disease) as well as in disease
that exhibits both central and skeletal muscle defects (congestive
heart failure) (2, 8, 13, 24, 26, 34, 35, 38). These
observations are consistent with the concept that an impaired cardiac
output response to exercise limits
O2 delivery to skeletal muscle,
resulting in a slower response of
O2 to any externally imposed
work demand. This is in contrast to healthy subjects whose
O2 kinetics are limited by
either a maldistribution of blood flow to the working tissues or
inertia of oxidative enzyme activities (6, 15).
In patients with peripheral arterial disease (PAD), arterial occlusions
in the lower extremity limit peripheral blood flow; this results in
impaired functional walking ability (17, 28). Patients with
claudication typically have adequate resting blood flow to maintain
tissue viability. However, with walking exercise, the inadequate
delivery of O2 and substrate to
match metabolic demand results in muscle ischemia, claudication
pain, and alterations in skeletal muscle metabolism (17, 20).
Furthermore, these patients have on average a 50% reduction in peak
exercise performance as well as a decreased
O2-work rate slope during
incremental exercise (16). These observations suggest that the rate of
O2 adaptation to an increase
in work rate is attenuated in PAD and reflects an attenuation of the
dynamic response of O2 as
well as a defect in oxidative metabolism in meeting energy demands. Potentially, the obstruction of blood flow through the major conduit vessels, alterations in skeletal muscle metabolism associated with PAD,
or both, could slow the kinetic response of
O2 during the transition from
rest to exercise. To directly test the hypothesis that PAD is
associated with slowed O2
kinetics, we measured O2
kinetics in patients with unilateral and bilateral PAD, and in healthy,
nonsmoking subjects and otherwise healthy controls who smoked. The
specific aims of the present study were
1) to determine if
O2 kinetics were slowed in
patients with PAD compared with healthy, age-matched, nonsmoking
controls and otherwise healthy smoking controls,
2) to characterize
O2 kinetics in
patients with unilateral PAD vs. bilateral PAD, and
3) to determine whether the
hemodynamic severity of PAD could account, in part, for altered O2 kinetics.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. Thirty-one subjects were enrolled in this study: eight patients with bilateral PAD; seven patients with unilateral PAD; nine healthy, age-matched, nonsmoking controls; and seven smoking, but otherwise healthy, controls. The study was approved by the University of Colorado Multiple Institutional Review Board, and informed consent was obtained from all subjects.
PAD was confirmed by the measurement of the ankle-brachial index (ABI; described below). Patients with PAD were enrolled who had an ABI
0.85 in the worse affected leg (the most symptomatic had the lowest
ABI). All PAD patients had claudication, defined as aching in the calf
muscles that occurred only with exercise and was completely relieved
after 10 min of rest. Patients with bilateral disease exhibited
claudication symptoms and decreased ABIs in both legs. Patients with
unilateral disease were defined as exhibiting claudication symptoms
meeting ABI criteria for PAD in the worse affected leg, and with no
claudication symptoms and a normal ABI (>0.95 at rest) in their less
affected leg. All PAD patients were current smokers, with a
pack · yr history (packs/day × no. of yr of
smoking) of >30 yr. Of the 14 PAD patients accepted for study, 7 were
taking aspirin, 4 were treated with calcium channel blockers, 3 were
treated with diuretics, 2 with lipid-lowering drugs, 2 with
angiotensin-converting enzyme inhibitors, and 2 with nitrates. Patients
were excluded if they exhibited ischemic rest pain or were exercise
limited by symptoms other than PAD (heart failure, pulmonary disease,
angina). Patients with diabetes and patients taking medications which
may alter exercise responses (i.e., beta blockers) were also excluded
(30).
Nonsmoking control subjects had no chronic medical diseases (by history
and a normal physical exam), were taking no medications, and had no
cigarette smoking history. Nonsmoking control subjects had no history
of claudication, had normal ABIs at rest, and had normal
electrocardiograms (ECGs) at rest as well as during and after exercise.
Smoking controls were all current smokers with a self-reported history
of 
20 pack · yr, but they were otherwise healthy as
defined above. Smoking subjects were included in the study design to
aid in discrimination between potential effects of smoking vs. PAD on
the time constant of O2
kinetics (25, 33).
Exercise protocol. Subjects were not allowed to smoke within 60 min before the start of any of the exercise testing. After familiarization with the treadmill, all subjects were initially tested with a graded treadmill protocol. Patients with PAD (unilateral and bilateral) performed a graded treadmill test at a constant speed of 2.0 miles/h starting at 0% grade and increasing 2.0% every 2 min until maximal claudication pain occurred (14). Subjects without PAD (nonsmoking controls and smoking controls) performed a standard Bruce treadmill protocol to maximal effort (10). All tests were performed on a Quinton 4000 treadmill (Quinton Instruments, Seattle, WA). Heart rate (HR) was measured minute-by-minute by using 12-lead ECG recordings. Blood pressure was monitored by auscultation during every stage of graded exercise.
All subjects performed multiple exercise tests at a constant work rate from rest to 2.0 miles/h, 0% grade on 1 day and at 2.0 miles/h, 4% grade on another day that was separated from the first test by 1 wk. These workloads were chosen because they were well tolerated by all subjects and could be sustained for at least 6 min. These workloads elicited a 450-700 ml/min change in absoluteO2 from baseline. The
exercise at 4% grade corresponded to
O2 values well below the
ventilatory anaerobic threshold (VAT) for the healthy subjects. In
patients with PAD, the steady-state
O2 at 4% grade was below
the peak O2
(O2 peak) attained
during claudication- limited exercise. The VAT could not be measured in
PAD patients, because the incremental tests were terminated due to
claudication before attaining gas-exchange criteria for establishing
VAT. To minimize intertest variance, subjects were familiarized with
the testing protocol on the first day, with six to ten 30-s transitions
from rest to exercise. As part of the familiarization, each subject
initiated walking on a moving treadmill (2.0 miles/h) with the same
foot for each transition; one hand was on the handrail, the other was
held at the side. The tests for assessment of
O2 kinetics consisted of
obtaining 3 min of resting data, followed by 6 min of constant-rate
walking. Each of the 0 and 4% grade tests were repeated four times to
allow an average response to be calculated. Subjects rested for 20 min in a seated position between exercise tests.
Measurement of gas exchange.
With the use of a Medical Graphics CPX/D metabolic system (Medical
Graphics Corporation, St. Paul, MN), rates of
O2 and CO2 output
(CO2) were measured breath
by breath and averaged to 20-s intervals for the determination of
O2 peak.
O2 peak was defined
as the highest O2 achieved
during the graded test. Respiratory exchange ratio (RER) was calculated
as the ratio of CO2
to O2. Breath-by-breath
data for kinetic analysis were acquired for
O2 and minute ventilation
by using the same metabolic system. HR data were recorded and
calculated simultaneously with each ventilatory data point by the CPX/D
system via Transistor Type Logic signaling from the ECG recorder. All
breath-by-breath data collected were saved as ASCII files and were
stored to disk for later analysis.
Kinetic analysis.
Specific analytic software for the kinetic analysis was developed at
the University of Colorado Health Sciences Center Vascular Research
Metabolic Laboratory. Breath-by-breath
O2 and HR data from the
constant workload tests were time interpolated to 1-s intervals. The
four tests at each workload were then time aligned and averaged by the
superimposition of data files. A five-point filter was used to
eliminate aberrant breaths from the average response curve. For each
value in a response curve, two values preceding and two values after
the value in question were considered in the calculation of an expected
datum value. Rejection criteria were defined as a range of acceptable
values determined as a percentage of the calculated mean for each
time-interpolated interval. Rejection criteria and weighting of each of
the five points in the calculation were predetermined before filtering.
By using a statistical program [BMDP (1988), Los Angeles,
CA], two mathematical models were employed to fit to the
average-response curves by using nonlinear regression techniques. A
single-exponential model without a time delay was used to assess the
overall O2 kinetic response
at 2.0 miles/h, 0% grade because the
O2 response curve was
monophasic and no phase 1 was
observed. The curve is described by the formula
![<A><AC>V</AC><AC>˙</AC></A><SC>o</SC><SUB>2</SUB>(<IT>t</IT>) = <A><AC>V</AC><AC>˙</AC></A><SC>o</SC><SUB>2</SUB>(<IT>b</IT>) + <IT>A</IT><SUB>1</SUB>[1 − <IT>e</IT><SUP>−(−<IT>t</IT>/&tgr;)</SUP>]](/content/vol87/issue2/fulltext/809/img001.gif)
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(1) |
O2(t)
is the O2 at time
t,
O2(b)
is the resting baseline O2
(in ml/min) before exercise, A1 (in ml/min) is
the difference between the baseline value and the new steady state, and
(in s) is defined as the time constant representing the rate of
increase in O2 of the
exercise-response curve [equal to time (in s) to 63% of the
change in O2 from baseline
to steady-state exercise].
In contrast to the O2
responses at 0% grade, the test at 4% grade resulted in a much larger
increase in O2; thus a
phase 1 and
2 component of the curves were
observed. Multiexponential mathematical modeling was used to fit the
average O2 response curves
at 2.0 miles/h, 4% grade exercise and was utilized to describe three
distinct phases of O2
kinetics.
![<A><AC>V</AC><AC>˙</AC></A><SC>o</SC><SUB>2</SUB>(<IT>t</IT>) = <A><AC>V</AC><AC>˙</AC></A><SC>o</SC><SUB>2</SUB>(<IT>b</IT>) + <IT>A</IT><SUB>0</SUB>[1 − <IT>e</IT><SUP>−(−<IT>t</IT>/&tgr;<SUB>0</SUB>)</SUP>] <IT>phase 1</IT>](/content/vol87/issue2/fulltext/809/img002.gif)
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![+ <IT>A</IT><SUB>1</SUB>[1 − <IT>e</IT><SUP>−(−<IT>t</IT> − TD<SUB>1</SUB>)/&tgr;<SUB>1</SUB></SUP>] <IT>phase 2</IT>](/content/vol87/issue2/fulltext/809/img003.gif)
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![+ <IT>A</IT><SUB>2</SUB>[1 − <IT>e</IT><SUP>−(−<IT>t</IT> − TD<SUB>2</SUB>)/&tgr;<SUB>2</SUB></SUP>] <IT>phase 3</IT>](/content/vol87/issue2/fulltext/809/img004.gif)
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(2) |
O2 at the onset of
exercise, which represents an increase in pulmonary blood flow
(cardiodynamic phase of O2
kinetics: phase 1) (Fig. 1) (36). For comparisons of
phase 1,
0 (in s) described the rate of rise in O2
during phase 1, and
A0 described the
change in amplitude of
O2 (in ml/min).
After a time delay (TD1; in s),
the second exponential fit phase 2 of
the response curve, reflecting peripheral
O2 delivery and
O2 (6, 7, 36). Phase 2 comparisons between groups
were made by using 1 (the rate
of rise in O2 during
phase 2) and
A1 [the
change in amplitude of O2
(in ml/min) from the end of phase 1 to
the new steady state]. There was also the possibility of a third
exponential fit, phase 3 (the slow
component of O2 kinetics),
which would follow a second time delay
(TD2; in s). A
phase 3 increase in O2 would be expected under
exercise conditions of high intensity and accumulation of systemic
blood lactate (6, 7, 36). These conditions were not observed in PAD
patients at these low work rates (19).
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O2 data were also
derived at 4% grade, independent of curve-fit modeling techniques, by
the sum of breath-by-breath O2
(
O2) over several
intervals of exercise (from exercise onset to 60, 90, 120, 180, and 300 s). By using the raw breath-by-breath O2 data
(Bn, in ml/min) and the duration
of each breath (Dn, in s),
O2 was calculated as the
milliliters of O2 consumed
over a selected interval minus the product of resting baseline average
(O2x, in ml/min)
and the duration of the selected interval in minutes
(tint).
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(3) |
O2
was normalized to body weight to minimize the influences of weight on
absolute O2 requirements
during treadmill exercise.
ABI. The ABI was calculated in all subjects before exercise testing. ABIs in patients with PAD and in smoking controls were also obtained 1 min after graded exercise. The postexercise ABIs of nonsmoking control subjects were not measured. While subjects were in the supine position, systolic blood pressure was measured in both arms with a Doppler ultrasonic instrument (model 841, Parks Medical Electronics, Beaverton, OR). The pressures in the dorsalis pedis and posterior tibialis vessels of each ankle were also measured in duplicate. The ratio of ankle-to-brachial systolic pressure was determined by taking the highest arm pressure divided into the higher of the two vessels in each ankle.
Data analysis.
The data for all PAD patients (unilateral + bilateral) were combined
and compared against the combined control groups (nonsmoking + smoking)
for O2 analyses. This
was done to increase sample size and to provide better discrimination
between differences in the PAD and control groups. All
other analyses were made by using the means from each of the four
separate groups. Between-subject analysis of variance was used to test
for differences between groups at baseline. Paired differences were
described by using Tukey-Kramer post hoc tests. Paired
t-tests were used to compare changes
within group means. The alpha level was set to 0.05 for statistical
significance. Data are presented as means ± SD for each group.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subject characteristics.
Patients with PAD and control groups were similar in age and weight
(Table 1). Pack · yr of
cigarette use did not significantly differ between the smoking control,
unilateral PAD, or bilateral PAD groups but differed from the values
observed for the nonsmoking control group
(P < 0.05). ABIs differentiated PAD
patients with unilateral disease from those with bilateral disease. The
resting ABI in the less affected leg of unilateral PAD patients was
similar to the resting ABI of nonsmoking controls and smoking controls. However, the resting ABI in the worse affected leg of unilateral patients was comparable to the resting ABI values observed in both legs
of bilateral PAD patients. After peak exercise, ABIs decreased in the
worse affected legs of unilateral PAD patients by 44% and in both legs
of bilateral PAD patients (34% in the worse affected leg, 23% in the
less affected leg; all P < 0.05 vs.
rest, by paired t-tests). No decrease
in postexercise ABI was observed in the smoking control group or in the
less affected leg of unilateral PAD patients after peak exercise.
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Peak exercise performance.
Unilateral and bilateral PAD patients attained a lower claudication
limited
O2 peak (51 and 55%, respectively), lower
HRpeak (23 and 31%,
respectively), and lower RERpeak
values (20 and 18%, respectively) compared with the combined control
subjects (Table 2;
P < 0.05 for each PAD group vs.
Control). No differences in peak exercise performance variables were
observed between the nonsmoking and smoking control subjects or between
the unilateral and bilateral PAD groups.
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O2 kinetics, 0% grade.
Resting O2 was comparable
between all groups before exercise (Table
3). The overall
O2 kinetic responses of the
unilateral and bilateral PAD groups at 0% grade were monoexponential
(phase 2) and demonstrated a slowed
kinetic response compared with the nonsmoking and smoking control
groups (Table 3; P < 0.05). The change in O2 from rest to
steady state (A1) was
also similar between groups. There were no differences between the
kinetic responses of the nonsmoking and the smoking control groups, all of which were monoexponential.
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O2 kinetics, 4% grade.
There were no differences in resting
O2 between groups before
exercise at 4% grade. Phase 1 kinetic
parameters (0,
A0) were not
different between groups (Table 4). The
time delay (TD1) until the
beginning of phase 2 was comparable
between all groups. The phase 2 time
constant (1) was similar
between the unilateral and bilateral PAD groups (see individual data
points in Fig. 2), but a significant
slowing of the phase 2 time constant
was observed in the unilateral and bilateral PAD patients
compared with nonsmoking and smoking control subjects
(P < 0.05 for PAD groups vs.
combined control groups). The amplitude of phase
2 (A1) was not
different between the PAD and control groups. Kinetic parameters did
not differ between nonsmoking and smoking control groups. Under the exercise protocols that were used, steady-state exercise conditions were confirmed by a plateau of the
O2 response and the
absence of a phase 3 exponential
component of the curve fit for any subject in any group.
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O2
measures.
O2 measures at 4% grade
were lower in all patients with PAD compared with the combined control
groups from rest to 60, 90, and 120 s
(P < 0.05 for PAD group vs. combined
control group; Table 5). Measures from
exercise onset to 180 and 300 s did not differ between the PAD patient
population and the combined control subjects.
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HR responses.
Before exercise at 0% grade, resting HRs were comparable between the
smoking controls and the unilateral and bilateral PAD patients (Table
6), but resting HRs of nonsmoking controls
were lower compared with the other three groups
(P < 0.05). HR kinetic analyses for
0 and 4% grades were attempted by using monoexponential curve-fitting
techniques. However, the exercise-response curves for HR were neither
exponential nor linear and could not be fit reliably by using these
methods. Therefore, time constants or mean response times may not have
appropriately described the HR response. The mean steady-state HR
achieved at the end of the 0% grade exercise was lower in the
nonsmoking control group than in the smoking control and in the
unilateral and bilateral PAD groups (P < 0.05). The change in HR from resting to steady-state exercise
(
HR) was greater in the unilateral and bilateral PAD groups compared
with nonsmoking or smoking controls (PAD groups vs. control groups,
P < 0.05).
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Determinants of .
To determine whether PAD disease severity was related to
the kinetic response of O2
during exercise, we evaluated whether resting ABI in the worse affected
leg of each PAD patient was correlated to phase
2 time constants at 4% grade. No significant correlation was found (r = 
0.025, Fig. 3). Additionally,
phase 2 time constants at 4% grade
were not correlated with
O2 peak in patients
with PAD (r = 0.257). No correlations
of phase 2 time constants and
O2 peak
within the combined control groups were observed
(r = 0.11). Between-group
correlations were not assessed because of the distinct difference in
populations under investigation (diseased vs. nondiseased) and the
possibility of autocorrelation.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study demonstrates that during constant-load treadmill
exercise, the kinetics of O2
at the onset of exercise were markedly slowed in patients with PAD
compared with control subjects. The impaired
O2 kinetic responses in PAD
patients appeared to be related to the presence of vascular disease but not to the hemodynamic severity, because the prolongation in the O2 time constant was not
associated with the degree of reduction in ABI or whether one or both
legs were affected. Furthermore, the
O2 kinetic impairment in PAD
could not be explained by phase 1 kinetic differences, reduced HR responses, or current smoking status.
This suggests that neither central cardiac factors nor smoking status
could account for the marked slowing of the phase 2 time constant observed in patients with PAD.
Typically, to eliminate weight-bearing influences and allow accurate
measures of work rate, cycle exercise has been used to determine
O2 kinetics. Although less
optimal than cycle exercise, treadmill exercise was used in the present
study to assess the O2
kinetics, because walking is the activity that produces the claudication pain observed in patients with PAD. Differences in body
weight between groups were not significant and, therefore, were not
expected to confound O2
kinetic responses. In the present study, neither the total change in
O2 from resting to steady state at 0% grade
(A1) and 4%
grade (A0 + A1) nor the
absolute steady-state O2
achieved was different between groups. Therefore, the actual work rate
and walking efficiency appeared to be similar between groups. The
exponential curve fitting was influenced neither by differences in
steady-state O2 between PAD
and control groups nor by the presence of a slow component of
O2
(phase 3). Furthermore, phase 2 O2 kinetics have been shown
to be workload independent during cycling exercise at workloads below
the lactate threshold (6). An exponential phase
3 O2 kinetic
response (slow component) was not observed in any subject during either
0 or 4% grade exercise testing. The absence of a slow component was
due to the low level of walking exercise (sub-VAT) and was corroborated
by RER values well below 1.00. Although no direct measures of blood
lactate concentration were made, previous studies have reported only
small increases in systemic lactate levels, even at peak
claudication-limited exercise in PAD patients (18, 20). These
observations support the finding in the present study that lactate
accumulation and the presence of a phase 3 component of
O2 are not likely a
significant contributor to the slowed kinetics.
Kinetic responses.
Phase 1 O2 kinetics at 4% grade
(representing the cardiac component of
O2 kinetics) were not
different, as assessed by either the time constant
(0) or change in
O2
(A0) between
the PAD and control groups. However, a significantly greater dynamic HR
response from rest to steady state (HR) was apparent in the PAD
groups compared with the control groups. This could reflect greater
cardiac sympathetic stimulation in PAD patients compared with controls.
Importantly, a defect in the central cardiac component of
the O2 kinetic response is
possible, although the present data suggest that this may be unlikely.
O2
(TD1) observed in the present
study are longer compared with values observed during measurements made during cycling exercise (6, 7, 31, 36). Multiexponential modeling with
time delays of human O2
kinetics has not been previously described during low-level walking
exercise. Potentially, the mode of exercise (treadmill walking vs.
cycling), exercise intensity, or physiological changes associated with
aging (such as alterations in vascular conductance) may elicit an
exercise O2 response profile
that is different from that observed for cycle exercise.
Phase 2 O2 kinetic time constants
were notably slowed in patients with PAD during treadmill walking at
4% grade. These observations are consistent with the findings of a
reduced O2-work rate
relationship during incremental cycle exercise in patients with PAD
compared with normal controls (16). The
O2 kinetic data, from
curve-fitting procedures, also confirm observations by Auchincloss et
al. (2, 3) of a reduced 1-min
O2 in PAD patients
compared with controls. Auchincloss et al. concluded that the reduction
appeared to be the result of a primary impairment in peripheral flow,
because improvement of flow through surgical bypass interventions
improved 1-min O2 to nearly
normal values. However, if limited total peripheral blood flow is
solely responsible for the slowed
O2 response in PAD, a
relationship would be expected between the O2 kinetic response and
worsening degrees of disease severity (as conventionally measured by
ABI) as well as a difference between patients with unilateral vs.
bilateral disease. The data in the present study revealed no
differences in time constants () between the unilateral and
bilateral PAD groups, despite substantially different quantitative
amounts of total lower extremity flow limitation. Furthermore, there
was no correlation between worst affected leg ABI and tau in unilateral
and bilateral PAD patients. This implies that hemodynamic disease
severity (ABI) could not predict the degree of
O2 kinetic impairment.
Limited peripheral blood flow may only partially account for the
slowing of the time constant during phase
2. A second contributor to phase
2 O2 kinetics
is the responses intrinsic to the exercising muscle. The transition
from rest to a fixed workload requires an enhanced production of ATP to
meet an elevated ATP requirement. Immediately after the onset of
exercise, this energy demand is met by preformed ATP, and the rapid
conversion of creatine phosphate (CrP) to ATP. Neither of these energy
sources requires the catabolism of substrates or the consumption of
O2. However, the stores of these
high-energy phosphates can only support exercise for brief periods. As
ATP and CrP are consumed, the free ADP concentration in muscle
increases. Although the regulation of mitochondrial respiration in
muscle is complex, the ADP concentration is a potential major control
point for stimulating O2.
Thus mitochondrial respiration can be described as a function of ADP
concentration in vivo (23, 37). As ADP accumulates with the onset of
exercise, mitochondrial O2
consumption (and hence ATP production) increases until the ADP level
sustains an ATP production that matches the ATP demands of the imposed
workload. The time constant for the accumulation of ADP in muscle can
be equated with the respiratory
O2 kinetics (5). Therefore,
anything that alters the ADP vs. mitochondrial respiration relationship
will alter the kinetics of
O2. This concept has been
observed by the improvement of
O2 kinetics in older and
younger subjects after training and has been validated in patients with
mitochondrial myopathies by using
31P- nuclear magnetic resonance
spectroscopy (4, 23, 31).
Although peripheral blood flow at rest is normal in PAD patients, there
is considerable evidence that skeletal muscle metabolic regulation is
altered, secondary to the sequellae of muscle ischemia with
exercise (9). For example, skeletal muscle in patients with PAD has a
19-36% increase in expression of mitochondrial enzymes,
accumulation of oxidative intermediates, and evidence of acquired
mitochondrial DNA injury (8a, 11, 12, 18, 21, 23, 32). These metabolic
changes appear to be relevant, because they correlate with patients'
functional performance, in contrast to lack of correlation of
hemodynamic measurements (1, 20, 29). Importantly, the ADP vs.
mitochondrial respiration relationship is altered in PAD, and more ADP
is required than is needed by control subjects to sustain a given level
of mitochondrial function. The present demonstration of
slowed respiratory O2
kinetics in patients with PAD is in complete concordance with the
31P-nuclear magnetic resonance
spectroscopy of Kemp et al. (22). These data suggest that altered
muscle mitochondrial function may contribute to the delayed
O2 kinetic response, although a detraining effect may present an alternate contributor to the slowed
kinetic response in PAD patients. Taken together, these data support
the hypothesis that PAD is associated with an alteration in the ADP vs.
mitochondrial respiration relationship that potentially results from an
acquired mitochondrial myopathy and that strategies to improve
metabolic function may be an important therapeutic target (9).
O2.
O2 was used to evaluate
4% grade O2 kinetics in a
manner independent of curve-fit modeling techniques. This measure of O2 kinetics revealed
differences between the PAD groups and the combined control groups from
exercise onset to 60, 90, and 120 s but not from onset to 180 and 300 s. The loss of discrimination of
O2 at 180- and 300-s time
intervals suggests that the kinetic response is not well described by
time intervals beyond 120 s of exercise. Importantly,
O2 can differentiate
between diseased and nondiseased patients over the early portions of an
exercise transition and can confirm curve-fit analyses of the slowed
O2 kinetic response in PAD.
Effects of smoking.
Because most PAD patients are present or former cigarette smokers, a
control group of healthy smoking subjects was included to address the
impact of smoking status and pack · yr on the time constant of O2 kinetics.
Smoking status and pack · yr history may have
influenced the time constant of
O2 kinetics, either through
an acute impairment in O2-
carrying capacity by formation of carboxyhemoglobin or through systemic
changes in O2 utilization caused
by chronic cigarette use (25, 33). However, in smoking control
subjects, pack · yr and smoking status were not
associated with slowing of the
O2 time constants compared
with nonsmoking controls. Therefore, the impairment in
O2 kinetics observed in PAD
patients was not a direct function of smoking status or pack · yr history.
Summary.
The present data demonstrate that the
O2 kinetic
responses to low-level, constant-load treadmill exercise are slowed in patients with PAD. Further research will be necessary to definitively assess whether peripheral flow limitations or changes in the regulation of skeletal muscle oxidative function, or both, are responsible for the
observed response in patients with PAD.
| |
ACKNOWLEDGEMENTS |
|---|
We thank the patients who gave of their time. We also acknowledge Andria Vogelsong, Susan Smith, and Amy Thomas for their assistance with the study and Jan Ingebritsen for development of the kinetic analysis software.
| |
FOOTNOTES |
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: W. R. Hiatt, Section of Vascular Medicine, Univ. of Colorado Health Sciences Center, Box B-179, 4200 E. Ninth Ave., Denver, CO 80262 (E-mail: Will.Hiatt{at}UCHSC.edu).
Received 3 September 1998; accepted in final form 31 March 1999.
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TOP
ABSTRACT
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METHODS
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DISCUSSION
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, unilateral PAD patients; 
, bilateral
PAD patients.