Download Effects of 12 Months of Intense Exercise Training on

Effects of 12 Months of Intense Exercise
Training on Ischemic ST-segment Depression
in Patients with Coronary Artery Disease
ALI A. EHSANI, M.D., GREGORY W. HEATH, D.H.SC., JAMES M. HAGBERG, PH.D.,
BURTON E. SOBEL, M.D., AND JOHN 0. HOLLOSZY, M.D.
SUMMARY This study was undertaken to determine whether adaptation to 12 months of intense endurance
exercise training could alter the relationship between the product of heart rate and systolic blood pressure
(double product) and the extent of ischemic ST-segment depression during exercise in patients with coronary
artery disease. True (i.e., not symptom-limited) maximum oxygen uptake capacity increased from 25.5 ± 4.2
ml/kg/min (mean ± SD) to 35.3 ± 4.4 ml/kg/min with training. The maximum degree of ST-segment depression during exercise averaged 0.20 + 0.04 mV before and 0.16 0.08 mV after training despite a 20% increase
in maximum double product. The double product at which ST depression (0.1 mV) first appeared was 22%
greater after training. The extent of ST-segment displacement at the same double product was less after training. These findings suggest that training, if sufficiently intense and prolonged, can result in a reduction in
myocardial ischemia at the same or a higher double product.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
EXERCISE is used widely in the rehabilitation of
patients with coronary artery disease, and often results in major improvements in work capacity.'-'
Exercise training can induce an increase in the minimum work rate required to induce ST-segment
depression4 or angina,' in some patients with coronary artery disease. A decrease in the magnitude of
ST displacement at a given submaximal level of exercise has also been reported.4 7 Among the adaptations to endurance exercise are a slower heart rate and
a lower systolic blood pressure during submaximal exercise.' As a consequence, myocardial oxygen consumption at the same submaximal work rate is
reduced after training.8
However, in a group of patients with coronary artery disease studied by Detry and Bruce,4 the quantitative relationship of ST depression to the product of
heart rate and systolic blood pressure (double product)
was unchanged by 3 months of training.4 If the degree
of ST depression reflects the severity of myocardial
ischemia, this finding argues against improved myocardial oxygen supply and favors the interpretation
that the increased exercise threshold for ischemia after
training is solely due to a reduction in myocardial oxygen requirement.
We speculated that the apparent failure of myocardial oxygenation to improve in response to training
may have been due to an insufficient exercise stimulus.
In studies on animals in which training appeared to
improve myocardial blood supply, moderately
strenuous exercise lasting 1-3 hours/day, 5 days/week
was used.>'2 In contrast, the exercise used in studies in
which training did not appear to improve myocardial
ischemia in patients with coronary artery disease was
generally mild, intermittent and brief.4,' 13 The present study was designed to evaluate the effect of a
prolonged program of exercise of increasing intensity,
duration and frequency on the relationship between
the double product and the extent of ischemic STsegment depression during exercise in patients with
coronary artery disease. A small number of patients
was included in this study because it is difficult to identify large numbers of persons who can participate with
the prolonged commitment required to attain the level
of exercise sought. Also, our purpose was to assess the
efficacy of a successfully completed intense and
prolonged exercise program rather than of conventional cardiac rehabilitation.
Methods
Patients
The 10 patients, ages 44-63 years, are the first
group to complete 12 months of participation in the
exercise program. Nine had sustained a single
myocardial infarction, documented by characteristic
chest pain, evolving electrocardiographic changes and
increases in plasma enzyme levels. The interval between myocardial infarction and enrollment in the
study ranged from 4 months to 5 years. One patient
was asymptomatic but had type II hyperlipoproteinemia, a strong family history for coronary artery disease, frequent premature ventricular depolarizations,
a positive exercise stress test and angiographically
documented severe three-vessel coronary disease.
Three patients were receiving modest doses of propranolol (40 mg daily). In two of these patients, propranolol was stopped during the study by their personal physicians. There were no other changes in
medications during the study. We believe that inclusion of the results from the two patients in whom
propranolol was discontinued is justified, because ,@adrenergic blockers decrease rather than increase the
From the Division of Applied Physiology, Irene Walter Johnson
Institute of Rehabilitation, Department of Preventive Medicine,
and the Cardiovascular Division, Department of Medicine,
Washington University School of Medicine, St. Louis, Missouri.
Supported by NIH research grant HL-22215.
Drs. Heath and Hagberg were postdoctoral research trainees supported by NIH training grant HL-07081.
Address for correspondence: Ali A. Ehsani, M.D., Department of
Preventive Medicine, Washington University School of Medicine,
4566 Scott Avenue, St. Louis, Missouri 63110.
Received September 25, 1980; revision accepted March 6, 1981.
Circulation 64, No. 6, 1981.
1116
EXERCISE TRAINING IN CAD/Ehsani et al.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
magnitude of exercise-induced ST-segment displacement." Thus, discontinuation would not be expected to diminish the ischemic ST-segment response
to exercise. Four patients were taking isosorbide
dinitrate because of chest pain, which occurred only in
the immediate weeks after acute myocardial infarction. However, none of the patients had effort angina
at the time of admission to or during the study. In addition, none had clinical or electrocardiographic
manifestations typical of variant angina with coronary
artery spasm.
We also studied the ischemic ST-segment response
at the beginning and end of a 12-month interval in
eight additional men with coronary artery disease,
who were suitable candidates for the training program
in terms of exercise capacity and cardiac status, but
who could not make the necessary time commitment
for participation. Six of these men had sustained a
well-documented myocardial infarction. The interval
between myocardial infarction and the initial exercise
test was 4, 5, 7, 22, 48 and 120 months. The other two
patients had angiographically documented, severe,
three-vessel coronary artery disease. These additional
patients were studied to obtain information regarding
the likelihood of spontaneous improvement in exercise-induced, ischemic ST-segment depression. Each
patient gave written consent after being informed of
the details, objectives and risks of the study.
Exercise Testing
Exercise testing was preceded by a history, physical
examination and ECG at rest. The exercise tests were
performed 2 hours after a light meal, and, in the five
patients on medication, 3 hours after the last dose of
medication. The exercise tests were performed in sequence, 1 week apart, before and after 12 months of
participation in the exercise program. A maximal
treadmill exercise test, using the Bruce protocol,"' was
performed to evaluate work capacity and the heart
rate, blood pressure, and ECG responses to exercise.
A maximal treadmill test was performed to determine
maximum oxygen uptake capacity (VO2max). After a
5-minute warmup, during which the subject walked on
the treadmill at 2.5 mph up a 5% grade, the speed and
grade were adjusted to match the next to the last stage
attained in the preceding Bruce treadmill test. The
work rate was then increased at 3-minute intervals
using the Bruce protocol. A progressive, maximal exercise test on a bicycle ergometer (Quinton Model 845)
was performed to obtain information regarding the
heart rate, blood pressure, VO2 and ECG response to
bicycle exercise. After a 5-minute warm-up at a work
rate of 200 kg-m/min, the work rate was increased by
200 kg-m/min every 3 minutes to maximum. The end
point for all exercise tests was exhaustion.
The patients in this study were not symptomlimited, so we could measure their true VO2max. The
"leveling off` criterion, i.e., no further increase in Vo2
with higher work rates, was used to establish that
VO,max had been attained. To measure V02, expired
air was collected in Douglas bags and analyzed with a
1117
Perkin Elmer MGA 1100 mass spectrometer. The
volume of expired air was measured with a Parkinson
Cowan dry gasmeter.
Before exercise testing, a standard 12-lead ECG and
Frank X, Y and Z orthogonal leads were recorded with
the subject recumbent. To determine the effect of the
upright position on the ST segment, tracings from
leads V,, V5 and V, and Frank X, Y and Z leads were
recorded also while the patients were standing on the
treadmill before exercise. The ECG was monitored
continuously during exercise. Throughout each exercise test, simultaneous tracings from leads V,, V5 and
V. and Frank X, Y and Z leads were recorded at 1minute intervals. Blood pressure was measured with a
mercury sphygmomanometer, 30 seconds before the
end of each stage of the exercise tests and also at the
time of appearance of ischemic ST-segment changes
(0.1 mV depression). The double-product threshold
for an ischemic ST-segment response was defined as
the product of systolic blood pressure and heart rate at
which ischemic ST-segment displacement first
appeared. A horizontal or downward sloping STsegment depression of 0.1 mV lasting for 0.08 second
in three consecutive ECG complexes in a given lead
was considered indicative of ischemia.
Echocardiographic Measurements
To assess the effect of endurance training on left
ventricular size, M-mode echocardiographic examinations were undertaken using an Ekoline-20A ultrasonoscope (Smith-Kline) with a 2.25-MHz unfocused
transducer, 1.25 cm in diameter, interfaced with a
Cambridge multichannel strip-chart recorder as previously described." Echocardiograms were obtained
after 15 minutes of rest with the subjects supine and
during held expiration. The patients were instructed
repeatedly to avoid the Valsalva maneuver. All echocardiograms were taken 3 hours after the last dose of
medications and 24 hours after the last exercise session. The transducer was placed parasternally in the
third or fourth left intercostal space with the ultrasonic beam passing through the left ventricle just distal to the tips of the mitral valve leaflets. Three to four
cardiac cycles were averaged for each measurement.
End-diastolic dimension was defined as the distance
between the left side of the interventricular septum
and the posterior wall endocardium at the onset of the
QRS complex of the simultaneously recorded ECG.
Left ventricular posterior wall thickness was measured
as the distance from the posterior wall endocardium to
the epicardium at the onset of the QRS. Left ventricular end-diastolic volume was estimated using the
method described by Teichholz'7 and left ventricular
mass was estimated using the standard formula.'8 To
minimize variability in the serial echocardiographic
examinations, special care was taken to use exactly
the same body position and intercostal space in subsequent examinations as were used in the initial evaluation. To enhance the reproducibility, the tracings
were examined carefully and the measurements were
made using the same anatomic landmarks.
VOL 64, No 6, DECEMBER 1981
CIRCULATION
1118
Exercise Program
period) was 30 minutes initially, and was
progressively increased until after about 6 months the
patients were exercising continuously for 50-60
minutes.
up
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
The 12-month training program consisted of endurance exercise. Each exercise session began with 10
minutes of light palisthenics, stretching and walking.
This was followed by a period of either alternate walking and jogging sequences, continuous jogging or bicycle ergometer exercise. During the first 3 months, the
intensity of the exercise was adjusted to require
50-70%o of the patient's VO2max. Thereafter, if the
patient was adapting well to the training (i.e., increase
in VO2max, decrease in heart rate), exercise intensity
was increased to 70-80% of VO2max, with two to
three intervals of exercise requiring 80-90% of
VO2max, and lasting 2-5 minutes interspersed
through the exercise session. The intensity of the exercise was related to the patients' VO2max by monitoring heart rate during the exercise sessions and adjusting running speed on the indoor track, or resistance on
the bicycle ergometer, to elicit the heart rate
equivalent to the desired percent of V02max. Heart
rate during the exercise sessions was measured initially by radiotelemetry and, when considered safe, by
periodic ECG monitoring and palpation of the pulse.
The relationship between heart rate and oxygen uptake was determined by measuring Vo2 and heart rate
during the submaximal and maximal stages of the
progressive treadmill and bicycle ergometer exercise
tests, which were performed at 2-3-month intervals.
Patients were expected to exercise three times per
week during the first 3 months, and four to five times
per week for the next 9 months. The duration of the
exercise sessions (not including the 10-minute warm-
Statistical Analysis
The significance of differences between data obtained before and after the 12 months of training was
assessed with the paired, two-tailed t test. Leastsquares linear regression analysis was used to evaluate
the test-retest reliability for the determination of the
double-product threshold for ischemic ST-segment
changes. Values are as mean ± SD.
Results
Adherence to the exercise program was excellent for
nine of the patients, with an average attendance of 4.5
days per week for the last 9 monthg of the program.
However, patient 6 (tables 1-3) was irregular in his
attendance after 6 months, and participated in an
average of 2.5 exercise sessions per week during the
last 6 months of the study. A weight loss from an
average of 78.7 i 11 kg to 73.9 + 10 kg (p < 0.01)
occurred over the 12-month period. Exercise performance progressively improved. During the last 3
months of the study, all the patients were running 4-5
miles continuously per exercise session or performing
an equivalent amount of exercise on the bicycle ergometer. None of the patients had complications
(angina, myocardial infarction, serious ventricular
arrhythmias or cardiac arrest) during the study.
TABLE 1. Effects of 12 Months of Training on Maximum Exercise Capacity and Maximum Exerciseinduced Ischemic ST-segment Displacement
V02 max
ST depression max
Treadmill exercise
Double product max
time* (seconds)
(HR X SBP X 10-3)
(ml/kg/min)
(mV)
Pt
Initial 12 months
Initial 12 months
Initial 12 months
Initial 12 months
Trained group
1
32
39
620
660
37.0
33.7
0.20
0.10
2
21
36
420
600
36.4
23.1
0.20
0.20
3
24
39
460
810
25.9
27.9
0.20
0.30
4
33
23
540
640
30.0
19.8
0.20
0.10
5
33
20
330
540
20.0
15.9
0.30
0.30
6
27
29
435
540
27.0
27.0
0.20
0.20
7
23
31
520
600
23.7
25.5
0.20
0.10
8
30
33
450
562
22.2
28.9
0.20
0.15
9
24
36
360
550
27.0
29.4
0.15
0.10
10
31
44
440
630
30.8
36.2
0.15
0.10
Mean
26
458
613t
24.9
29.8:
0.20
0.16
35t
±4
±4
±81
±77
±5.1
±5.4
Untrained group (n -8)
415
437
24.6
± 99
±SD
±72
±4.8
*Exercise time to exhaustion in the Bruce test.15
tInitial vs 12-month value: p < 0.001.
±7.2
±SD
Mean
-
-
23.7
±0.04
0.17
±0.04
±0.08
0.25+
±0.07
+p<O.01.
Abbreviations: V02 max - maximum oxygen uptake capacity; HR - heart rate; SBP
pressure; max = maximum.
=
systolic blood
EXERCISE TRAINING IN CAD/Ehsani et al.
1119
TABLE 2. Effects of 12 Months of Training on the Threshold for Ischemic ST-segment Displacement
Ischemic ST-segment depression threshold
Double product
Systolic blood
Heart rate
(HR X SBP X 10-3)
pressure (mm Hg)
(beats/min)
Age Period after
Pt
Initial 12 months
Initial 12 months
(years) MI (months) Initial 12 months
Trained group
33.7
31.7
208
206
162
154
1
9
58
23.9
21.1
199
111
190
120
2
44
24.0
19.3
170
180
47
14
141
107
3
24.9
15.0
178
140
140
6
107
4
63
15.1
12.4
111
136
124
5
62
8
100
20.7
19.2
182
186
114
60
103
6
57
24.9
17.7
174
158
7
4
112
143
58
23.7
16.0
111
150
144
158
54
48
8
21.7
18.9
152
140
143
135
51
5
9
27.0
24.8
180
170
150
54
146
5
10
19.6
173
164
138*
119
24.0t
54.8
Mean
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
±SD
±6
±18
±17
±25
±21
±5.2
±4.5
Untrained group (n = 8)
18.6
20.7
154
164
119
125
Mean
49.6
±5.2
±5.5
±29
±18
±7
±16
±19
±SD
*Initial vs 12 month: p < 0.01.
tInitial vs 12 month: p < 0.001.
tSee Methods section.
Abbreviations: MI = myocardial infarction; HR = heart rate; SBP = systolic blood pressure.
Maximal Oxygen Uptake Capacity
The VO2max increased an average of 34%, from
2.01 ± 0.43 1/min to 2.69 ± 0.58 1/min (p < 0.001) in
response to the 12 months of training. As a result of
the decrease in body weight, VO2max per kg body
weight, which is considered a better indicator of
aerobic exercise capacity, increased by an average of
38% (table 1).
Heart Rate
Resting heart rate decreased from 68 ± 9 to 58 i 7
beats/min (p < 0.01), and maximum heart rate was
158 ± 17 beats/min initially and 165 ± 13 beats/min
after 12 months of training. Because of large differences in response between individuals, the average increase in maximum heart rate was not statistically
significant. After training, heart rate at the end of the
first stage of the Bruce test was 12% lower (p < 0.05),
and at the end of the second stage was 15% lower (p <
0.05) than before training..
systolic pressure attained at the time of maximal
treadmill exercise was significantly higher (13%; p <
9.01) after 12 months'of exercise training (fig. 1). The
systolic blood pressure at'maximum'bicycle ergometer
exercise increased from 179 ± 26 to 197 ± 17 mm Hg
(p < 0.05) in' response to training. The exercise
program' had no significant effect on the diastolic
blood pressure response to exercise.,
Double Product
As a consequence of the slower heart rate and lower
systolic blood pressure, the double product was
significantly lower at the same submaximal work rates
after the 12-month exercise program (fig. 2).
However, the average maximum double product attained during treadmill exercise increased by 20%
(table 1). With bicycle exercise, it increased by 19%
over the 12 months. The eight untrained patients had
no significant change in maximum double product
(table l).
Ischemic ST-segment Changes
Blood Pressure
Resting blood pressure did not change. Systolic
pressure averaged 126 ± 15 mm Hg before and 121 ±
14 mm Hg after 12 months of training. Diastolic
pressure was 80 ± 14 mm Hg before and 78 ± 7 mm
Hg after training. Average systolic blood pressure at
the end of the first stage of the Bruce test was
significantly lower after training (153 ± 22 vs 129 +
19 mm Hg; p < 0.001). A similar difference was seen
after the second stage of the Bruce test..However, the
To determine the reproducibility of the doubleproduct threshold for ST-segment depression, we performed Bruce treadmill exercise tests 4 weeks 'apart on
seven of the patients, before admission to the exercise
program, and again after 12 months of training, when
they were on a constant maintenance exercise
program. The- double-product threshold for an ischemic ST-segment response was virtually identical
in the tests performed 4 weeks apart, before and after
training (fig. 3).
CIRCULATION
1120
VOL 64, No 6, DECEMBER 1981
TABLE 3. Effects of 12 Months of Training on QRS Voltage of the ECG at Rest
Rv5
svl
(mV)
Pt
1
2
3
4
5
6
7
8
9
10
Initial
1.0
1.9
0.8
0.7
1.0
0.6
1.1
1.2
0.6
0.9
12 months
1.3
2.0
0.7
0.6
1.3
0.8
1.0
1.5
0.8
1.5
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Mean
1.0
1.2*
±SD
±0.4
±0.4
*Initial vs 12 months: p < 0.05.
tlnitial vs 12 months: p < 0.01.
Initial
1.8
1.5
1.5
1.9
1.4
1.5
1.8
1.7
1.4
2.5
1.7
±0.3
The double-product threshold for ischemic STsegment depression (defined as the product of heart
rate times systolic blood pressure required to induce
0.1 mV of ST-segment depression) increased by an
average of 22% during the 12 months of training (table
2). The untrained group showed a small decrease in
220
Before training
;.j:: After training
180
I
E
E
__-
CD
co 140
100
FIGURE 1. Systolic blood pressure (SBP) at the time of
maximum treadmill exercise before and after 12 months of
endurance exercise training. Values are mean ± SD. *Before
training vs after training. p < 0.01.
(mV)
12 months
2.2
2.0
2.5
2.2
1.4
1.5
Sv1 + RV5
(mV)
12 months
1.5
1.4
2.8
Initial
2.8
3.4
2.3
2.6
2.4
2.1
2.9
2.9
2.0
3.4
2.0*
+0.5
2.7
±0.5
3.1t
+0.7
2.2
3.5
4.0
3.2
2.8
2.7
2.3
3.2
3.0
2.2
4.3
their double-product threshold for ST-segment
depression (table 2).
The extent of ST-segment depression in response to
a given submaximal work rate was smaller after training (fig. 2). This is not surprising; the double product
was lower during the same work rates after the
patients were trained. To control for this effect of
training on the double product, we examined the relationship between extent of ischemic ST-segment
depression and the double product at various work
rates during the progressive bicycle exercise test. STsegment displacement at the same double product was
less after 12 months of training (fig. 4).
Although the maximum double product attained
during exercise was 20% higher after 12 months of
training, the maximum ST-segment depression
decreased in six patients, did not change in three, and
increased in only one, and the mean for the group did
not change significantly (table 1). Over the same
period, maximum ST-segment depression increased
significantly in the untrained group, even though maximum double product did not change significantly
(table 1).
Resting ECG
QRS voltage in the precordial leads was increased
significantly after training (table 3). The sum of Svi
and Rv6 increased by 15% during the 12 months of exercise training as a result of increases in both Svl and
RV6 voltage. The increase in QRS voltage was not
associated with any repolarization changes.
Changes in the Left Ventricular Dimensions
To determine the reproducibility of the measurements, echocardiographic studies were performed 2
weeks apart on seven of the patients, both before
enrollment in the exercise program and after 12
months of training. The differences between the two
measurements made before or after training were
small (table 4).
EXERCISE TRAINING IN CAD/Ehsani et al.
Good-quality echocardiograms were obtained in
nine patients. Left ventricular end-diastolic dimension
and posterior wall thickness were significantly increased after training (table 5). The estimated left ventricular end-diastolic volume index increased from
66 ± 17 to 83 ± 23 mI/M2 (p < 0.01) and left ventricular mass index from 93 ± 17 to 135 + 35 g/m2
(p < 0.01).
Discussion
Sufficiently prolonged and intense exercise training
can elicit the following cardiac responses in patients
with antecedent myocardial ischemia, attributable to
coronary artery disease, with or without associated
spasm: elevation of the double-product threshold for
ischemic ST-segment depression; decrease in the ex-
30r
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
20
x
L/)
dow0~
0C
r - - -
10
.,x
L
Or_
E
0
I
n
%-~ 0~
C~ c~
c~ 0~
0~
99..'
c~ 0~ ce.
LL
L/)
I-
z
-0.2
0
fLI)
-0.3
1
I
TREADMILL STAGE
FIGURE 2. Double product and the extent of ischemic STsegment depression at two submaximal levels of treadmill
* ) and after
exercise (Bruce protocol) before ( *
(o---o) 12 months of exercise training. Values are
means
SBP
=
SD. *Before training vs after training: p < 0.01.
systolic blood pressure; HR = heart rate.
±
1 121
tent of ST-segment depression at the same double
product; and a reduced or unchanged maximum STsegment depression despite a large increase in maximum double product. These findings suggest that
myocardial ischemia is reduced at the same, or a
higher, double product as a result of the adaptation to
exercise training. Coronary blood flow and myocardial oxygen consumption (MVO.) have been shown to
parallel closely the double product in normal persons
and in patients with coronary artery disease during exercise. 19-21 The decrease in electrocardiographic
evidence of myocardial ischemia in our patients might
be explained by an exercise-induced improvement in
myocardial oxygenation. Alternatively, training could
have induced a reduction in MVO2 due to decreased
left ventricular volume or decreased contractility
associated with decreased sympathetic drive.
A reduction in left ventricular volume seems unlikely, considering our echocardiographic and electrocardiographic findings indicating that, as in young
healthy subjects,16' 22 the exercise training resulted in a
volume overload hypertrophy of the left ventricle in
our coronary patients. This increase in left ventricular size cannot be attributed solely to bradycardia, as
left ventricular wall thickness and estimated mass
were significantly increased. In contrast, slowing of
the heart rate, by itself, results in an increase in left
ventricular end-diastolic volume with a decrease in
wall thickness.23 We could not measure left ventricular volume during exercise in this study. However,
Hindman and Wallace24 found, using radionuclide
angiography, that left ventricular end-diastolic and
end-systolic volumes measured during submaximal
and maximal exercise testing were significantly increased by 6 months of exercise training in a group of
coronary patients. Decreased sympathetic drive also
seems unlikely. Although plasma catecholamines increase less at the same absolute submaximal work
rate, the plasma catecholamine response to maximum
exercise is increased by training.2' 26
Studies in animals have provided data suggesting
that exercise enhances myocardial blood supply.9 12
Training has been reported by others to raise the
double- or triple-product threshold for exertional
angina in some patients, suggesting an improvement
in myocardial oxygenation.3.6 However, studies in
which objective end points were used have not shown
an improvement in myocardial blood supply or a
decrease in myocardial ischemia in response to training in patients with coronary artery disease. Ferguson
et al.8 measured coronary sinus blood flow and left
ventricular oxygen consumption at various intensities
of exercise in patients with coronary artery disease
before and after 6 months of training. They found that
coronary sinus blood flow and left ventricular oxygen
consumption at the same double product were unchanged and that maximum coronary sinus blood flow
and left ventricular oxygen consumption were unaffected by the training.8
Nolewajka et al.18 evaluated the effects of a
program of exercise on intercoronary collaterals in
patients with coronary artery disease using coronary
angiography and infusion of labeled microspheres. No
VOL 64, No 6, DECEMBER 1981
CIRCULATION
1122
0f
41
J
1
LU-
I
I
tn
tn
LLJ
CY m
Z > -0.2-
IO
*
LUJ E
X
_-
W
U
^
u
i_x
L½
0
uLJ
(I)
(r
-0.4
-1
-
CO
1_
-~
~
~
~
~
20
SBPx HR xi1-3
10
U
I
U.)
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
40
30
20
10
0
ISCHEMIC ST SHIFT THRESHOLD
(SBPx HRx10-3)
FIGURE 3. Reproducibility of the double-product threshold for ischemic ST-segment depression (0.1 mV). Two'
treadmill exercise tests were performed 4 weeks apart on
seven patients before ( * ) and after (0) 12 months of exercise
training. Values plotted on the abscissa are from the first
and those on the ordinate are from the second exercise test.
The values were essentially the same (r = 0.98, p < 0.0001).
SBP = systolic blood pressure; HR = heart rate.
changes in the extent of collateralization or myocardial perfusion were evident after training. Detry and
Bruce' found that the double product and the
magnitude of ST-segment depression at the same submaximal work rate were less after training, but the
relationship between the magnitude of the ST-segment
depression and the double product were unchanged.
Maximum ST depression in Detry and Bruce's
patients was actually greater after training, probably
because they attained a higher double product.
These negative results suggested that the beneficial
effects of training on exercise capacity and exertional
angina threshold were mediated by adaptations in the
skeletal muscles and autonomic nervous system,
which result in a lower myocardial oxygen requirement during submaximal exercise3' 8, 27 and/or by an
increase in arterial oxygen content.27' 28 Despite such
evidence that exercise training did not improve
myocardial blood supply or ischemia at a given double
~~~_
_
A
30
FIGURE 4. The relationship between the extent of STdepression and the double product at different intensities of submaximal bicycle ergometer exercise before
* ) and after (O---O) 12 months of exercise
( *training. Values are means ± SD. *Before training vs after
training; p < 0.02. SBP = systolic blood pressure; HR =
heart rate.
segment
product, the training programs were generally mild
and of short duration. Typically, patients participated
in 30-50 minute sessions of intermittent, mild exercise
two to four times per week for 2-6 months. Because
patients with coronary artery disease generally have a
very low exercise tolerance when they begin training,
exercise must initially be mild and intermittent. It
usually takes 3-6 months before even highly
motivated patients who are not symptom-limited,
such as those in the present study, can perform
moderately hard exercise (i.e., 65-85% of VO2max)
continually for an hour per day, 4-5 days/week.
Therefore, the lack of improvement in myocardial
ischemia in previous studies may have been due to termination of exercise training before a sufficient adaptive stimulus was attained.
This possibility motivated us to investigate the
adaptive responses of patients with coronary artery
disease to a more prolonged program of exercise of
progressively increasing duration, frequency and intensity. This training program induced a large increase in VO2max. The average increase in real
V02max (these patients' V02max was not symptomlimited) of 38% is one of the largest reported with
training in any group not initially limited by angi-
TABLE 4. Reproducibility of Echocardiographic Measurements
LVEDD (mm)
LVPWT (mm)
Initial
12 months
Initial
12 months
1st measurement
9.0 ± 1.0
10.3 ± 1.0
52.7 ± 7.0
57.6 ± 8.0
2nd measurement
8.7 ± 1.0
10.1 ± 1.3
52.9 ± 7.0
57.3 ± 9.0
r
0.86
0.80
0.98
0.99
Values are mean ± SD for seven patients.
Abbreviations: LVEDD = left ventricular end-diastolic dimension; LVPWT = left ventricular posterior
wall thickness.
EXERCISE TRAINING IN CAD/Ehsani et al.
1123
TABLE 5. Echocardiographic Evaluation ofLeft Ventricular Size Before and After 12 Months of Training
Body surface area (m2)
LVPWT (mm)
LVEDD (mm)
Pt
1
2
3
4
5
7
8
9
10
Initial
45
49
67
48
49
47
48
58
51
12 months
47
52
76
54
52
51
52
61
59
Initial
10
9
8
8
7
10
9
10
10
12 months
11
11
11
9
8
10
10
11
11
Initial
1.94
1.89
2.40
1.92
12 months
1.94
1.80
1.58
1.85
2.06
1.81
1.96
2.30
1.86
1.54
1.84
2.03
1.76
1.90
1.89*
1.93
10*
9
56*
51
Mean
± 0.2
±7
±1
±1
±0.2
±9
±SD
An adequate echocardiogram could not be obtained on patient 6.
*Initial vs 12 month: p < 0.01.
Abbreviations: LVEDD = left ventricular end-diastolic dimension; LVPWT = left ventricular posterior
wall thickness.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
na.3' 29 The large increase in VO2max provides evidence that the training stimulus was substantial. Another adaptation to the training was a large increase in
peak systolic blood pressure, which was statistically
significant even if the two patients who discontinued
propranolol therapy are excluded from the averages.
The increase in the peak systolic blood pressure attained at the time of maximal exercise could reflect an
improvement in left ventricular performance, since
myocardial ischemia results in a lower peak systolic
pressure during exercise.30' 31 Exercise-induced hypertrophy (tables 3 and 5) of adequately oxygenated regions of the left ventricle might also have contributed
to the increase in maximum systolic blood pressure by
helping to compensate for loss of contracting myocardium as a consequence of previous myocardial infarction and scarring.
Our findings that prolonged and intense exercise
training increases the double-product threshold for
ST-segment depression, and results in a reduced or
unchanged maximum ST depression despite a higher
double product, are not necessarily in conflict with the
report of Detry and Bruce4 that the relationship
between the double product and ST-segment depression is unchanged after 3 months of training. Rather,
our data probably reflect a later stage in the adaptive
process or differences in the populations studied, as
our patients were selected in part on the basis of being
free from symptom-limited exercise. The available information is compatible with the view that adaptations in skeletal muscles and the autonomic nervous
system occur rapidly in response to relatively mild exercise in patients with coronary artery disease and
result in a lower double product during subm"-ximal
exercise as well as an improvement in exercise
capacity. The present results indicate that if training is
continued and increased in intensity, frequency and
duration, additional cardiac adaptations can also occur in some patients with coronary artery disease,
which result in an increase in the double-product
threshold for myocardial ischemia.
Acknowledgment
We thank Susan Bloomfield, M.Sc. and Judy Ponser, R.D. for
assistance.
References
1. Hellerstein HK: Exercise therapy in coronary disease. Bull NY
Acad Med 44: 1028, 1968
2. Mitchell JH: Exercise training in the treatment of coronary
heart disease. Adv Intern Med 20: 249, 1975
3. Clausen JP: Circulatory adjustments to dynamic exercise and
effect of physical training in normal subjects and in patients
with coronary artery disease. Prog Cardiovasc Dis 18: 459,
1976
4. Detry JM, Bruce RA: Effects of physical training on exertional
ST-segment depression in coronary heart disease. Circulation
44: 390, 1971
5. Redwood DR, Rosing DR, Epstein SE: Circulatory and symptomatic effects of physical training in patients with coronary
artery disease and angina pectoris. N Engl J Med 286: 959,
1972
6. Sim DN, Neill WA: Investigation of the physiological basis for
increased exercise threshold for angina pectoris after physical
conditioning. J Clin Invest 54: 763, 1974
7. Hellerstein HK, Burlando A, Hirsch EZ, Plotkin FH, Feil GH,
8.
9.
10.
11.
12.
13.
Winkler 0, Marik S, Margolis N: Active physical reconditioning of coronary patients. Circulation 32 (suppl II): 11-1 10, 1965
Ferguson RJ, Cote P, Gauthier P, Bourassa MG: Changes in
exercise coronary sinus blood flow with training in patients with
angina pectoris. Circulation 58: 41, 1978
Scheuer J, Tipton CM: Cardiovascular adaptations to physical
training. Annu Rev Physiol 39: 221, 1977
Heaton WH, Marr KC, Capurro NL, Goldstein RE, Epstein
SE: Beneficial effect of physical training on blood flow to
myocardium perfused by chronic collaterals in the exercising
dog. Circulation 57: 575, 1978
McElroy CL, Gissen SA, Fishbein MC: Exercise-induced
reduction in myocardial infarct size after coronary occlusion in
the rat. Circulation 57: 958, 1978
Wyatt HL, Mitchell J: Influences of physical conditioning and
deconditioning on coronary vasculature in dogs. J Appl Physiol
45: 619, 1978
Nolewajka AJ, Kostuk WL, Rechnitzer PA, Cunningham DA:
1124
14.
15.
16.
17.
18.
19.
20.
21.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
22.
23.
CI RCULATION
Exercise and human collateralization: an angiographic and
scintigraphic assessment. Circulation 60: 114, 1979
Gianelly RE, Triester BL, Harrison DC: The effect of
propranolol on exercise-induced ischemic ST-segment depression. Am J Cardiol 24: 161, 1969
Bruce RA, Hornsten TR: Exercise stress testing in evaluation
of patients with ischemic heart disease. Prog Cardiovasc Dis 11:
371, 1969
Ehsani AA, Hagberg JM, Hickson RC: Rapid changes in left
ventricular dimensions and mass in response to physical conditioning and deconditioning. Am J Cardiol 42: 52, 1978
Teichholz LE, Kreulen TH, Herman GR: Problems in echocardiographic volume determinations. Am J Cardiol 37: 7, 1976
Troy BL, Pombo J, Rackley C: Measurements of left ventricular mass by echocardiography. Circulation 45: 602, 1972
Kitamuro K, Jorgensen CR, Gobel FL, Taylor HL, Wang Y:
Hemodynamic correlates of myocardial oxygen consumption
during upright exercise. J Appl Physiol 32: 516, 1972
Gobel FL, Nordstrom LA, Nelson RR, Jorgensen CR, Wang
Y: The rate-pressure product as an index of myocardial oxygen
consumption during exercise in patients with angina pectoris.
Circulation 57: 549, 1978
Holmberg S, Wieslaw S, Varnauskas E: Coronary circulation
during heavy exercise in control subjects and patients with coronary heart disease. Acta Med Scand 190: 465, 1971
DeMaria AN, Neumann A, Lee G, Fowler W, Mason DT:
Alterations in ventricular mass and performance induced by exercise training in man evaluated by echocardiography. Circulation 57: 237, 1978
DeMaria AN, Neumann A, Schubart PJ, Lee G, Mason DT:
Systematic correlation of cardiac chamber size and ventricular
24.
25.
26.
27.
28.
29.
30.
31.
VOL 64, No 6, DECEMBER 1981
performance determined with echocardiography and alterations in heart rate in normal persons. Am J Cardiol 43: 1, 1979
Hindman MC, Wallace AG: Radionuclide exercise studies. In
Physical Conditioning and Cardiovascular Rehabilitation,
edited by Cohen LS, Mock MB, Ringqvist I. New York, John
Wiley and Sons, 1981, p 33
Winder WW, Hagberg JM, Hickson RC, Ehsani AA, McLane
JA: Time course of sympathoadrenal adaptation to endurance
exercise training in man. J Appl Physiol 45: 370, 1978
Ehsani AA, Heath GW, Hagberg JM, Branconi J, Holloszy
JO: Influence of exercise training on plasma catecholamines in
patients with coronary artery disease. (abstr) Circulation 61
(suppl III): 111-267, 1980
Detry JM, Rousseau M, Vandenbroucke G, Kusumi F,
Brasseur LA, Bruce RA: Increased arteriovenous oxygen
difference after physical training in coronary heart disease. Circulation 44: 109, 1971
Bruce RA, Kusumi F, Frederick R: Differences in cardiac function with prolonged physical training for cardiac rehabilitation. Am J Cardiol 40: 597, 1977
Hickson RC, Bomze HA, Holloszy JO: Linear increase in
aerobic power induced by a strenuous program of endurance exercise. J Appl Physiol 42: 372, 1977
Vatner SF, McRitchie RJ, Maroko PR, Patrick TA,
Braunwald E: Effects of catecholamines, exercise, and nitroglycerine on the normal and ischemic myocardium in conscious
dogs. J Clin Invest 54: 563, 1974
Tomoike H, Franklin D, McKown D, Kemper WS, Guberek
M, Ross J Jr: Regional myocardial dysfunction and hemodynamic abnormalities during strenuous exercise in dogs with
limited coronary flow. Circ Res 42: 487, 1978
Effects of 12 months of intense exercise training on ischemic ST-segment depression in
patients with coronary artery disease.
A A Ehsani, G W Heath, J M Hagberg, B E Sobel and J O Holloszy
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Circulation. 1981;64:1116-1124
doi: 10.1161/01.CIR.64.6.1116
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1981 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://circ.ahajournals.org/content/64/6/1116
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally
published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the
Editorial Office. Once the online version of the published article for which permission is being requested is
located, click Request Permissions in the middle column of the Web page under Services. Further
information about this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/