Download Exercise training improves conduit vessel function in patients with

J Appl Physiol 95: 20–25, 2003;
10.1152/japplphysiol.00012.2003.
translational physiology
Exercise training improves conduit vessel function in
patients with coronary artery disease
Jennifer H. Walsh,1 William Bilsborough,2,3 Andrew Maiorana,1,3,4 Matthew Best,3,4
Gerard J. O’Driscoll,1,3,4 Roger R. Taylor,2,4 and Daniel J. Green1,3,4
Departments of 1Human Movement and Exercise Science and 2Medicine, The University of Western Australia,
Crawley 6009; and 3Department of Cardiology and 4Cardiac Transplant Unit, Royal Perth Hospital and
Western Australia Institute for Medical Research, Perth 6000, Western Australia, Australia
Submitted 7 January 2003; accepted in final form 26 March 2003
IN ADDITION TO REGULATION of vascular tone, the vascular
endothelium influences the progression of atherosclerosis via anticoagulant, anti-inflammatory, and vascular remodeling properties (28). Several studies have
indicated that subjects with cardiovascular disease or
risk factors exhibit impaired endothelium-dependent
vasomotor responses (2, 5, 7, 29, 33) and attenuated
vascular NO bioactivity. Furthermore, interventions
such as lipid-lowering and angiotensin-converting enzyme (ACE) inhibitor therapy, which improve cardiovascular mortality and morbidity, are also associated
with improved NO-mediated vascular function (17, 25,
26). The clinical relevance of endothelial dysfunction
has been further highlighted by recent studies indicating that endothelial dysfunction is an independent
predictor of cardiac events in patients with and without established coronary artery disease (CAD) (24, 34).
Regular physical exercise improves endothelium-dependent vasodilation in a number of populations, including those with heart failure (11, 18, 21), Type 2
diabetes (20), and hypertension (13). Animal studies
indicate that changes in blood flow and, therefore,
endothelial shear stress during repetitive exercise result in upregulation of NO synthase expression (30)
and enhanced endothelium-mediated relaxation (32).
More recent evidence suggests that exercise training
not only improves vascular function in the exercising
musculature but also induces generalized improvement in endothelial function (16, 18, 20, 21), possibly
as a result of hemodynamic and shear stress-mediated
changes associated with exercise (10).
Exercise training for patients with stable CAD is
now generally accepted as a nonpharmacological intervention to improve functional capacity and provide risk
factor modification, although the mechanisms responsible for the salutary effects of exercise are not fully
understood (15, 31). Improvement in endothelial and
vascular function may explain, in part, the beneficial
effects of exercise training on functional capacity and
cardiovascular outcomes. Despite its importance, few
studies have examined the effect of exercise training on
endothelial function in patients with CAD; one study
found coronary endothelium-dependent dilation to be
improved (12), whereas another found a 10-wk program of leg exercise to increase flow-mediated dilation
(FMD) significantly in the posterior tibial artery but
insignificantly in the brachial artery (9). In view of this
and our laboratory’s previous study finding FMD to be
increased in the brachial artery by lower body exercise
Address for reprint requests and other correspondence: D. J.
Green, Dept. of Human Movement and Exercise Science, The Univ.
of Western Australia, 35 Stirling Highway, Crawley 6009, Western
Australia, Australia.
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. Section 1734
solely to indicate this fact.
endothelium; blood flow; nitric oxide; ultrasound
20
8750-7587/03 $5.00 Copyright © 2003 the American Physiological Society
http://www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.5 on May 7, 2017
Walsh, Jennifer H., William Bilsborough, Andrew
Maiorana, Matthew Best, Gerard J. O’Driscoll, Roger
R. Taylor, and Daniel J. Green. Exercise training improves conduit vessel function in patients with coronary
artery disease. J Appl Physiol 95: 20–25, 2003; 10.1152/
japplphysiol.00012.2003.—It is well established that endothelial dysfunction is present in coronary artery disease
(CAD), although few studies have determined the effect of
training on peripheral conduit vessel function in patients
with CAD. A randomized, crossover design determined the
effect of 8 wk of predominantly lower limb, combined aerobic
and resistance training, in 10 patients with treated CAD.
Endothelium-dependent dilation of the brachial artery was
determined, by using high-resolution vascular ultrasonography, from flow-mediated vasodilation (FMD) after ischemia.
Endothelium-independent vasodilation was measured after
administration of glyceryl trinitrate (GTN). Baseline function was compared with that of 10 control subjects. Compared with matched healthy control subjects, FMD and GTN
responses were significantly impaired in the untrained CAD
patients [3.0 ⫾ 0.8 (SE) vs. 5.8 ⫾ 0.8% and 14.5 ⫾ 1.9 vs.
20.4 ⫾ 1.5%, respectively; both P ⬍ 0.05]. Training significantly improved FMD in the CAD patients (from 3.0 ⫾ 0.8 to
5.7 ⫾ 1.1%; P ⬍ 0.05) but not responsiveness to GTN (14.5 ⫾
1.9 vs. 12.1 ⫾ 1.4%; P ⫽ not significant). Exercise training
improves endothelium-dependent conduit vessel dilation in
subjects with CAD, and the effect, evident in the brachial
artery, appears to be generalized rather than limited to
vessels of exercising muscle beds. These results provide evidence for the benefit of exercise training, as an adjunct to
routine therapy, in patients with a history of CAD.
EXERCISE, VASCULAR FUNCTION, AND CORONARY DISEASE
training (20), we studied a group of patients with
stable CAD.
METHODS
Table 1. Baseline (entry) characteristics of CAD
patients and healthy control subjects
Age, yr
Previous myocardial infarction, no.
Previous coronary angioplasty/stent,
no.
Previous coronary artery bypass
graft, no.
Peak oxygen consumption,
ml 䡠 kg⫺1 䡠 min⫺1
Resting heart rate, beats/min
Resting systolic blood pressure,
mmHg
Resting diastolic blood pressure,
mmHg
Body mass index, kg/m2
Plasma lipids, mmol/l
Total cholesterol
Low-density lipoprotein cholesterol
High-density lipoprotein cholesterol
Triglycerides
CAD
Patients
(n ⫽ 10)
Control
Subjects
(n ⫽ 10)
55 ⫾ 2
4
54 ⫾ 1
7
6
27.0 ⫾ 1.7
55 ⫾ 2
128 ⫾ 7
132 ⫾ 5
72 ⫾ 4
28.8 ⫾ 1.2
79 ⫾ 3
25.7 ⫾ 0.7
4.3 ⫾ 0.4
2.6 ⫾ 0.3
1.0 ⫾ 0.1
1.4 ⫾ 0.2
5.1 ⫾ 0.1
3.0 ⫾ 0.2
1.2 ⫾ 0.1
2.1 ⫾ 0.5
Values are means ⫾ SE; n, no. of subjects. Note that all but 1 of the
coronary artery disease (CAD) patients were on 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor therapy. No significant differences in baseline variables between CAD patients and control subjects were evident at the time of study.
J Appl Physiol • VOL
pressure, and lipid profile were not significantly different
from the CAD patients at the time of their recruitment. The
characteristics of CAD patients and healthy control subjects
enrolled in the study are presented in Table 1. The Royal
Perth Hospital Ethics Committee approved the protocol, and
all subjects gave written, informed consent.
Study design. All subjects underwent baseline assessment,
after which CAD patients were randomly assigned to either
remain sedentary or exercise train for 8 wk according to the
protocol outlined below. Assessments were then repeated,
and crossover occurred with final assessments made 16 wk
after entry. In previous studies with a similar 8-wk exercise
program, such a crossover design has proved satisfactory
with no evidence, by subgroup analysis, of persisting effects
of exercise in subjects randomized to train first (20, 21).
Patients were requested to maintain their normal diet and
other lifestyle behaviors for the duration of the study, and
this was confirmed with interview and questionnaire.
Assessments of vascular function were conducted in a
quiet, temperature-controlled laboratory after an 8-h fast,
12-h abstinence from caffeine, and 24-h abstinence from
alcohol and exercise. For individual patients, repeat assessments were performed at the same time of day and time of
medication use was standardized.
Assessment of peak reactive hyperemia. Measures of peak
reactive hyperemic blood flow were performed in eight CAD
patients before conduit vessel function assessment. Subjects
were positioned with elbows at heart level and hands at a
comfortable height to allow forearm venous drainage. Pneumatic cuffs (SC10 and SC5, D. E. Hokanson, Bellevue, WA)
and strain gauges (SG 24, Medasonics, Mountain View, CA)
were positioned for forearm blood flow measurements. Wrist
and upper arm cuffs were connected to rapid inflation devices
(E-20 and AG 101, D. E. Hokanson); strain gauges were
positioned 8–10 cm distal to the olecranon process of each
arm. Strain-gauge placement and hand and elbow elevation
were the same for repeat tests. An online microcomputer
(SPG 16, Medasonics) sampled amplified output from the
strain gauges at 75 Hz, which was displayed in real time. A
software program controlled cuff inflation and deflation as
well as data acquisition, storage, and display to ensure that
blood flow measurements were synchronized with upper arm
cuff inflation.
Five minutes after subject preparation was complete, upper arm cuffs were inflated to ⬎200 mmHg for a period of 10
min to provide a stimulus for reactive hyperemic blood flow
(RHBF10) in each forearm. Immediately before upper arm
cuff deflation, hand blood flow was occluded by inflation of
wrist cuffs to 200 mmHg. Peak vasodilator capacity was
taken as the maximal flow after upper arm cuff deflation, in
all cases, being within the first 30 s.
A 20-min rest period was observed to allow blood flow to
return to baseline before conduit vessel function assessments
were performed.
Assessment of conduit vessel function. Patients rested supine with the nondominant arm extended and immobilized
with foam supports at an angle of ⬃80° from the torso. Heart
rate was continuously monitored with a three-lead electrocardiograph, and mean arterial pressure was determined
from an automated sphygmomanometer (Dinamap 8100, Critikon, Tampa, FL) on the contralateral arm. A rapid inflation
and deflation pneumatic cuff was positioned on the imaged
arm immediately distal to the olecranon process to provide a
stimulus to forearm ischemia. A 10-MHz multifrequency
linear array probe attached to a high-resolution ultrasound
machine (Aspen, Acuson, Mountain View, CA) was used to
image the brachial artery in the distal third of the upper arm.
95 • JULY 2003 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.5 on May 7, 2017
Subjects. Ten men with a history of CAD were recruited
from hospital clinics or via public advertisement. To be eligible, patients must have had CAD requiring surgical (Coronary artery bypass graft) or nonsurgical revascularization
(Percutaneous transluminal coronary angioplasty). The
numbers having these interventions or having previous myocardial infarction are shown in Table 1. Patients who had
undergone surgery or coronary intervention or had myocardial infarction during the previous 3 mo were excluded, as
were those who had valvular heart disease, a left ventricular
ejection fraction ⬍40%, chronic obstructive lung disease, or
renal or hepatic dysfunction. Patients were also excluded if
they were current smokers; currently had diabetes, asthma,
hypertension (systolic blood pressure ⬎160 mmHg or diastolic blood pressure ⬎90 mmHg), or hypercholesterolemia
(total cholesterol ⬎6.0 mmol/l or low-density lipoprotein cholesterol ⬎4.0 mmol/l); or performed more than two sessions of
light-to-moderate exercise per week. All were taking aspirin,
nine took 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor (statin) therapy, seven took ␤-blocking therapy, five took
an ACE inhibitor, two took a proton pump inhibitor, and one
each took a diuretic, a calcium channel-blocking drug, and
cholestyramine. Medications did not change across the
course of the control or exercise training periods.
Ten age-matched healthy control male subjects, who had
been randomly selected from the electoral role in a community survey, were also recruited to undergo baseline ultrasound assessment without exercise training. Subjects were
excluded if they displayed any exclusion criteria listed for the
CAD patients or if history or examination revealed evidence
of coronary or valvular heart disease. No control subject was
taking medication, and age, body mass index, resting blood
21
22
EXERCISE, VASCULAR FUNCTION, AND CORONARY DISEASE
J Appl Physiol • VOL
RESULTS
Of the 10 CAD patients, 4 were randomized to receive exercise training for the first 8-wk period. All
patients completed 16 supervised training sessions and
8 home training sessions, and no adverse events were
experienced during the study period.
General training effects. The 8-wk exercise training
period significantly improved symptom-limited, maximum cycle ergometer exercise test duration from 991 ⫾
63 to 1,087 ⫾ 66 s (P ⬍ 0.01). However, despite a trend
toward improvement, peak oxygen consumption did
not significantly change. Cholesterol, trigylcerides,
fasting blood glucose levels, resting heart rate, and
blood pressures were unaltered by training (Table 2).
Peak reactive hyperemic responses. In the CAD patients, RHBF10 was not significantly altered with exercise training in either the dominant (28.4 ⫾ 4.1 vs.
29.4 ⫾ 3.6 ml 䡠 100 ml⫺1 䡠 min⫺1; P ⬎ 0.8) or nondominant (33.7 ⫾ 3.5 vs. 38.7 ⫾ 5.0 ml 䡠 100 ml⫺1 䡠 min⫺1;
P ⬎ 0.2) arm.
Conduit vessel function assessment. Flow- and GTNmediated dilator responses in patients in the untrained
state were compared with those of the healthy, untrained control subjects of similar age. Basal brachial
artery diameter was not significantly different between
the CAD patients and control subjects (4.2 ⫾ 0.1 vs.
3.9 ⫾ 0.1 mm; P ⬎ 0.05). FMD responses were significantly impaired in the CAD patients (3.0 ⫾ 0.8 vs.
5.8 ⫾ 0.8%; P ⬍ 0.05) as were GTN responses (14.5 ⫾
1.9 vs 20.4 ⫾ 1.5%; P ⬍ 0.05; Fig. 1).
In the CAD patients, basal brachial artery diameter
was not significantly different in the untrained and
trained states (4.2 ⫾ 0.1 vs. 4.1 ⫾ 0.1 mm; P ⬎ 0.2).
Exercise training significantly increased the FMD response to forearm ischemia (3.0 ⫾ 0.8 to 5.7 ⫾ 1.1%;
P ⬍ 0.05). Endothelium-independent dilation in response to GTN was not changed (14.5 ⫾ 1.9 vs 12.1 ⫾
1.4%; P ⬎ 0.21; Fig. 2). In keeping with previous
studies involving an 8-wk crossover design (20, 21), the
order in which patients trained did not significantly
affect responses to training, and FMD in the untrained
Table 2. Characteristics after trained
and untrained periods
Exercise test duration, s
Peak oxygen consumption,
ml 䡠 kg⫺1 䡠 min⫺1
Resting systolic blood pressure,
mmHg
Resting diastolic blood pressure,
mmHg
Resting heart rate, beats/min
Plasma lipids, mmol/l
Total cholesterol
Low-density lipoprotein cholesterol
High-density lipoprotein cholesterol
Triglycerides
Fasting blood glucose, mmol/l
Body mass, kg
Values are means ⫾ SE. * P ⬍ .01.
95 • JULY 2003 •
www.jap.org
Untrained
Trained
991 ⫾ 63
1,087 ⫾ 66*
26.6 ⫾ 1.8
28.0 ⫾ 1.9
126 ⫾ 6
121 ⫾ 6
70 ⫾ 3
56 ⫾ 3
70 ⫾ 4
52 ⫾ 3
4.5 ⫾ 0.3
2.8 ⫾ 0.2
1.1 ⫾ 0.1
1.5 ⫾ 0.2
4.9 ⫾ 0.2
88.4 ⫾ 5.3
4.5 ⫾ 0.3
2.7 ⫾ 0.2
1.1 ⫾ 0.1
1.6 ⫾ 0.2
5.2 ⫾ 0.2
88.6 ⫾ 5.4
Downloaded from http://jap.physiology.org/ by 10.220.33.5 on May 7, 2017
When an optimal image was attained, the probe was held
stable in a stereotactic clamp and the probe position relative
to the radiale was recorded for repeat sessions. Ultrasound
parameters were set to optimize longitudinal, B-mode images
of the lumen-arterial wall interface.
After a 20-min rest, baseline images were recorded on a
S-VHS video cassette recorder (SVO-9500 MDP, Sony, Tokyo,
Japan) over 2 min. The forearm cuff was then inflated to 200
mmHg for 5 min. Images were recorded 30 s before cuff
deflation and for 2 min after deflation. After a 10-min rest, to
allow arterial diameter to return to baseline, another 2-min
baseline recording was made before administration of a sublingual 400-␮g spray dose of GTN with images recorded for a
further 5 min.
Brachial artery diameters were analyzed at the time of the
ECG R wave, that is, at end diastole. The same experienced
sonographer performed the analysis by using custom-designed edge-detection and wall-tracking software, which
minimizes investigator bias and has the power to detect an
absolute change in FMD of 2.5% in a crossover design study
with only five subjects (36). The mean intraobserver coefficient of variation of repeated measures of FMD when this
software is used is 6.7%, which is significantly lower than
that for traditional manual methods (36).
Exercise training protocol. Patients attended two supervised combined aerobic and resistance, “circuit” training sessions at the Cardiac Gymnasium, Royal Perth Hospital, and
completed one home training session per week. The focus was
on the large muscles of the lower limbs. Upper body exercises
did not involve hand-gripping or forearm exercise, and patients were instructed on correct lifting techniques and to
avoid the Valsalva maneuver.
The 8-wk circuit training protocol involved a combination
of resistance training, cycle ergometry and treadmill walking
as described in recent publications (19–21). Eight resistance
exercises, performed on weight stack machines (Pulsestar,
Cheshire, UK), were alternated with eight cycle stations at a
work-to-rest ratio of 45:15 s. Therefore, the total time taken
to perform one complete circuit was 16 min. Subjects performed 1 lift every 3 s, completing 15 lifts in the 45-s work
period. The number of circuits performed gradually increased
from one to three complete circuits during the first 2–3 wk, as
tolerated. At completion of the circuits, subjects performed
an additional 5 min of treadmill walking. Resistance intensity commenced at 55% of pretraining 1 repetition maximum
and increased to 65% at week 4. The eight resistance exercises consisted of seated leg press, standing calf raise, left
and right hip flexion, pectoral exercise, seated abdominal
flexion, shoulder extension, and seated leg flexion. Cycling
and treadmill walking intensities were initially 70% of peak
heart rate (HRpeak), determined from a prestudy graded
maximal exercise test, and were increased up to 85% of
HRpeak at week 6.
Home training sessions were individually prescribed and
involved patients performing continuous aerobic exercise at
70–85% HRpeak for up to 45–60 min. To ensure compliance,
sessions were recorded in a diary and heart rates were
recorded with Polar heart rate monitors (Polar Electro Oy,
Kempele, Finland).
Data analysis. To compare trained and untrained data for
all variables, including FMD and GTN responses, Student’s
paired t-test was used. To compare the responses of CAD
patients and healthy control subjects, an unpaired t-test was
used. Data are reported as means ⫾ SE. Significance was
accepted at P ⬍ 0.05.
EXERCISE, VASCULAR FUNCTION, AND CORONARY DISEASE
23
state was not different between those who trained first
or second.
DISCUSSION
Fig. 2. Endothelium-dependent, flow-mediated dilation (A) and endothelium-independent, GTN-mediated dilation (B) of the brachial
artery in CAD patients in untrained (open bars) and trained (solid
bars) states. Values are means ⫾ SE. Eight weeks of training
significantly improved flow-mediated (P ⬍ 0.05) but not GTN-mediated responses. NS, not significant.
Fig. 1. Endothelium-dependent, flow-mediated dilation (A) and endothelium-independent, glyceryl trinitrate (GTN)-mediated dilation
(B) of the brachial artery in healthy control subjects (solid bars; n ⫽
10) and untrained coronary artery disease (CAD) patients (open
bars; n ⫽ 10). Values are means ⫾ SE. Both flow-mediated and
GTN-mediated dilator responses were impaired in the CAD patients
compared with the healthy control subjects (both P ⬍ 0.05).
J Appl Physiol • VOL
flow and vessel wall shear stress induces an increase in
the endothelial production of vasodilator compounds
(23). Animal studies have found that exercise training
is associated with an increase in vascular NO production (30, 32) and upregulation of NO synthase expression (30), again attributable to repeated episodes of
vascular wall shear stress. Furthermore, Green et al.
(10) recently demonstrated augmented NO bioactivity
in the upper limb vessels during an acute bout of lower
limb exercise in normal volunteers. Hence, our data
showing an increase in FMD in a conduit artery of a
nontrained muscle bed are consistent with many previous studies and concur with the thesis that recurrent
augmentation of vessel wall shear stress, as a consequence of repeated, exercise-induced hemodynamic
changes, results in a generalized increase in NO bioactivity throughout the vasculature (16, 18, 20, 21). It
is, however, possible that this results not only from
upregulation of NO production but also from other
phenomenon such as the quenching of NO by superoxide radicals (1).
Our findings are consistent with previous studies in
healthy subjects (4) and in subjects with heart failure
(11, 18), diabetes (20), and hypertension (13), which
demonstrated enhanced endothelium-dependent dilator function, without improvement in endothelium-
95 • JULY 2003 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.5 on May 7, 2017
Our randomized crossover design study found FMD
of the brachial artery improved after 8 wk of combined
aerobic and resistance exercise training in patients
with stable CAD, indicating enhanced endotheliumdependent vascular function in the brachial artery.
Because endothelial dysfunction appears to be an integral component of atherogenesis (28), and in light of
recent studies showing endothelial dysfunction to be
an independent predictor of future cardiac events in
patients with and without established CAD (24, 34),
these findings are of likely relevance in the management of patients with CAD. The exercise program was
supervised, outpatient gymnasium based, and designed to largely exclude upper limb exercise, but a
similar program of thrice weekly exercise could be
easily adapted for home implementation in suitable
stable patients.
The present study does not specifically address the
mechanisms responsible for the improvement in endothelium-dependent vasodilation, which remain speculative. Early studies found that an increase in blood
24
EXERCISE, VASCULAR FUNCTION, AND CORONARY DISEASE
J Appl Physiol • VOL
termined, level of ongoing exercise may be necessary to
maintain training-induced vascular function gains.
The possibility that differing drug regimes may have
affected vascular function cannot be excluded. However, the medications were typical of those taken by
patients with CAD, and no changes were made
throughout the study period. Therefore, the results are
likely to be widely applicable to CAD patients on standard therapies. Another possible limitation of the
study relates to the training program used: predominantly lower limb and gymnasium based. However, its
elements were generic and could be easily modified to
suit home- or community-based environments, although it is possible that different training intensities,
frequencies, or modalities may elicit other results and
that a longer term program would seem necessary for
sustained response. The propriety of a randomized
sequence of exercise and nonexercise periods also
arises. However, with a relatively short-duration exercise training program such as we used, our laboratory
has previously found no significant carryover effect of
exercise in those trained first (20, 21), as was also the
case in this study. Furthermore, if there were any such
effect, it would only serve to minimize the effect size
observed using a cross-over design.
The findings of this study provide further evidence
for the beneficial effect of an exercise training program
on endothelium-dependent vascular function in patients with stable CAD undergoing routine management. Furthermore, the benefit is not limited to the
vasculature of the trained muscle bed, because changes
in the brachial artery were observed as a result of
lower limb exercise. Exercise training-mediated improvement in vascular endothelial function may, in
part, explain the cardiovascular mortality and morbidity benefits attributed to exercise in the CAD population.
This study was supported by National Health and Medical Research Council of Australia Project Grant 211997.
REFERENCES
1. Cai H and Harrison D. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87: 840–844,
2000.
2. Celermajer DS, Sorensen KE, Bull C, Robinson J, and
Deanfield JE. Endothelium-dependent dilation in the systemic
arteries of asymptomatic subjects related to coronary risk factors
and their interaction. J Am Coll Cardiol 24: 1468–1474, 1994.
3. Clarkson P, Celermajer DS, Powe AJ, Donald AE, Henry
RMA, and Deanfield JE. Endothelium-dependent dilatation is
impaired in young healthy subjects with a family history of
premature coronary disease. Circulation 96: 3378–3383, 1997.
4. Clarkson P, Montgomery HE, Mullen MJ, Donald AE,
Powe AJ, Bull T, Jubb M, World M, and Deanfield JE.
Exercise training enhances endothelial function in young men.
J Am Coll Cardiol 33: 1379–1385, 1999.
5. Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ,
Coleman SM, Loscalzo J, and Dzau VJ. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest 86: 228–234, 1990.
6. DeSouza CA, Shairo LF, Clevenger CM, Dinenno FA,
Monahan KD, Tanaka H, and Seals DR. Regular aerobic
exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men. Circulation 102:
1351–1357, 2000.
95 • JULY 2003 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.5 on May 7, 2017
independent dilator function, after a period of exercise
training. They are also consistent with those of Hambrecht et al. (12), who showed that 4 wk of 10-min daily
cycle training performed six times per day improved
coronary endothelium-mediated dilator function, but
not endothelium-independent dilation, in patients with
CAD. The conclusions of Gokce et al.(9) are at minor
variance with ours. These authors studied the effect of
a 10-wk period of treadmill or stationary bicycle exercise in CAD patients having similar demographics to
our group, but they compared the results with a CAD
nonexercise group. FMD increased significantly in the
posterior tibial artery, by a mean of 2.0%, whereas the
1.9% increase in the brachial artery did not reach
significance. The initial FMD in our subjects was substantially lower, consistent with greater depression of
endothelial function, and the improvement was larger
but the apparent differences may also be methodological. As mentioned above, we consider the evidence
supports a systemic vascular effect of exercise to be
substantial.
We did not submit the normal, control subjects, used
for baseline comparative purposes, to an exercise program because of the previous observations in such
subjects (4). Compared with the healthy subjects, endothelium-independent dilator function, assessed by
the response to GTN administration, was impaired in
the CAD patients before training. This is consistent
with previous observations that subjects with early
vascular disease tend to exhibit endothelial but not
vascular smooth muscle dysfunction (3, 6, 33, 35),
whereas those with more advanced vascular disease
may manifest abnormality in both endothelial and
smooth muscle function (8, 11, 37). The lack of improvement in smooth muscle function after 8 wk of
training in CAD patients is also consistent with previous observations (11, 12, 20) and with our finding that
RHBF10, an index of vascular structure (27), was unaltered by training. These observations support the
concept that, whereas enhanced endothelium-mediated vasodilation can result from short-term training
and serve to buffer shear stress during early exercise
periods, longer term training may be necessary to stimulate changes in the vessel wall and, hence, improvement in endothelium-independent function or vessel
structure (22). At the same time, in this and other
studies, the apparent lack of improvement in this aspect of vascular function could depend on the assessment technique. That is, the dose of GTN conventionally administered may have interrogated the upper
end of the dose-response curve, and construction of a
dose-response relationship could be more revealing.
The order of training did not affect the vascular
response in the present study, and there was no difference in untrained data between those who trained first
or second. These findings are consistent with previous
crossover design studies that suggest that vascular
function follows a similar conditioning-deconditioning
time course to that of other exercise-induced physiological adaptations (20, 21) and that some, as yet unde-
EXERCISE, VASCULAR FUNCTION, AND CORONARY DISEASE
J Appl Physiol • VOL
21. Maiorana A, O’Driscoll G, Dembo L, Cheetham C, Goodman C, Taylor R, and Green D. Effect of aerobic and resistance exercise training on vascular function in heart failure.
Am J Physiol Heart Circ Physiol 279: H1999–H2005, 2000.
22. McAllister RM and Laughlin MH. Short-term exercise training alters responses of porcine femoral and brachial arteries.
J Appl Physiol 82: 1438–1444, 1997.
23. Miller VM and VanHoutte PM. Enhanced release of endothelium-derived factor(s) by chronic increases in blood flow. Am J
Physiol Heart Circ Physiol 255: H446–H451, 1988.
24. Neunteufl T, Heher S, Katzenschlager R, Wolfl G, Kostner
K, Maurer G, and Weidinger F. Late prognostic value of
flow-mediated dilation in the brachial artery of patients with
chest pain. Am J Cardiol 86: 207–210, 2000.
25. O’Driscoll G, Green D, Maiorana A, Stanton K, Colreavy F,
and Taylor R. Improvement in endothelial function by angiotensin-converting enzyme inhibition in non-insulin-dependent
diabetes mellitus. J Am Coll Cardiol 33: 1506–1511, 1999.
26. O’Driscoll G, Green D, and Taylor R. Simvastatin, an HMGcoenzyme A reductase inhibitor, improves endothelial function
within 1 month. Circulation 95: 1126–1131, 1997.
27. Patterson GC and Whelan RF. Reactive hyperaemia in the
human forearm. Clin Sci (Colch) 14: 197–211, 1955.
28. Ross R. Atherosclerosis—an inflammatory disease. N Engl
J Med 340: 115–126, 1999.
29. Schroeder S, Enderle MD, Ossen R, Meisner C, Baumbach
A, Pfohl M, Herdeg C, Oberhoff M, Haering HU, and
Karsch KR. Noninvasive determination of endothelium-mediated vasodilation as a screening test for coronary artery disease:
pilot study to assess the predictive value compared with angina
pectoris, exercise electrocardiography, and myocardial perfusion
imaging. Am Heart J 138: 731–739, 1999.
30. Sessa WC, Pritchard K, Seyedi N, and Hintze TH. Chronic
exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression.
Circ Res 74: 349–353, 1994.
31. Snell PG and Mitchell JH. Physical inactivity: an easily modified risk factor (Editorial). Circulation 100: 2–4, 1999.
32. Sun D, Huang A, Koller A, and Kaley G. Short-term daily
exercise acitivity enhances endothelial NO synthesis in skeletal
muscle arterioles of rats. J Appl Physiol 76: 2241–2247, 1994.
33. Suwaidi JA, Higano ST, Holmes DR, Lennon R, and Lerman A. Obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly disease
coronary arteries. J Am Coll Cardiol 37: 1523–1528, 2001.
34. Vita JA and Keaney JF. Endothelial function: a barometer for
cardiovascular risk (Editorial)? Circulation 106: 640–642, 2002.
35. Vita JA, Treasure CB, Nabel EG, McLenachan JM, Fish
RD, Yeung AC, Vekshtein VI, Selwyn AP, and Ganz P.
Coronary vasomotor response to acetylcholine relates to risk
factors for coronary artery disease. Circulation 81: 491–497,
1990.
36. Woodman R, Playford D, Watts G, Cheetham C, Reed C,
Taylor R, Puddey I, Beilin L, Burke V, Mori T, and Green
D. Improved analysis of brachial artery ultrasound using a novel
edge-detection software system. J Appl Physiol 91: 929–937,
2001.
37. Zhang X, Zhao SP, Li XP, Gao M, and Zhou QC. Endothelium-dependent and -independent functions are impaired in patients with coronary heart disease. Atherosclerosis 149: 19–24,
2000.
95 • JULY 2003 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.5 on May 7, 2017
7. Egashira K, Inou T, Hirooka Y, Yamada A, Maruoka Y, Kai
H, Sugimachi M, Suzuki S, and Takeshita A. Impaired
coronary blood flow response to acetylcholine in patients with
coronary risk factors and proximal atherosclerotic lesions. J Clin
Invest 91: 29–37, 1993.
8. Enderle MD, Schroeder S, Ossen R, Meisner C, Baumbach
A, Haering HU, Karsch KR, and Pfohl M. Comparison of
peripheral endothelial dysfunction and intimal media thickness
in patients with suspected coronary artery disease. Heart 80:
349–354, 1998.
9. Gokce N, Vita JA, Bader DS, Sherman DL, Hunter LM,
Holbrook M, O’Malley C, Keaney JF, and Balady GJ. Effect
of exercise on upper and lower extremity endothelial function in
patients with coronary artery disease. Am J Cardiol 90: 124–
127, 2002.
10. Green D, Cheetham C, Mavaddat L, Watts K, Best M,
Taylor R, and O’Driscoll G. Effect of lower limb exercise on
forearm vascular function: contribution of nitric oxide. Am J
Physiol Heart Circ Physiol 283: H899–H907, 2002.
11. Hambrecht R, Fiehn E, Weigl C, Gielen S, Hamann C,
Kaiser R, Yu J, Adams V, Niebauer J, and Schuler G.
Regular physical exercise corrects endothelial dysfunction and
improves exercise capacity in patients with chronic heart failure.
Circulation 98: 2709–2715, 1998.
12. Hambrecht R, Wolf A, Gielen S, Linke A, Hofer J, Erbs S,
Schoene N, and Schuler G. Effect of exercise on coronary
endothelial function in patients with coronary artery disease.
N Engl J Med 342: 454–460, 2000.
13. Higashi Y, Sasaki S, Kurisu S, Yoshimizu A, Sasaki N,
Matsuura H, Kajiyama G, and Oshima T. Regular aerobic
exercise augments endothelium-dependent vascular relaxation
in normotensive as well as hypertensive subjects: role of endothelium-derived nitric oxide. Circulation 100: 1194–1202, 1999.
14. Joannides R, Haefeli WE, Linder L, Richard V, Bakkali E,
Thuillex C, and Luscher TF. Nitric oxide is responsible for
flow-dependent dilation of human peripheral conduit arteries in
vivo. Circulation 91: 13114–11319, 1995.
15. Jolliffe JA, Rees K, Taylor RS, Thompson D, Oldridge N,
and Ebrahim S. (Editors). Exercise-based rehabilitation for
coronary heart disease (Cochrane Review). In: The Cochrane
Library. Oxford, UK: Update Software, 2001.
16. Kingwell BA, Sherrard B, Jennings GL, and Dart AM. Four
weeks of cycle training increases basal production of nitric oxide
from the forearm. Am J Physiol Heart Circ Physiol 272: H1070–
H1077, 1997.
17. Laufs U, La Fata V, Plutzky J, and Liao JK. Upregulation of
endothelial nitric oxide sythase by HMG CoA reductase inhibitors. Circulation 97: 1129–1135, 1998.
18. Linke A, Schoene N, Gielen S, Hofer J, Erbs S, Schuler G,
and Hambrecht R. Endothelial dysfunction in patients with
chronic heart failure: systemic effects of lower-limb exercise
training. J Am Coll Cardiol 37: 392–397, 2001.
19. Maiorana A, O’Driscoll G, Cheetham C, Collis J, Goodman
C, Rankin S, Taylor R, and Green D. Combined aerobic and
resistance exercise training improved functional capacity and
strength in CHF. J Appl Physiol 88: 1565–1570, 2000.
20. Maiorana A, O’Driscoll G, Cheetham C, Dembo L, Stanton
K, Goodman C, Taylor R, and Green D. The effect of combined aerobic and resistance exercise training on vascular function in type 2 diabetes. J Am Coll Cardiol 38: 860–866, 2001.
25