Download The effect of 7 years of intense exercise training on patients

321
JACC Vol. 10, NO.2
August 1987:321-6
The Effect of 7 Years of Intense Exercise Training on Patients With
Coronary Artery Disease
MARC A. ROGERS, PHD, CHIKASHI YAMAMOTO, MS, JAMES M. HAGBERG, PHD,
JOHN O. HOLLOSZY, MD, ALI A. EHSANI, MD, FACC
St. Louis. Missouri
The purpose of this study was to evaluate the effects of
long-term exercise training on maximal aerobic exercise
capacity, evidence of myocardial ischemia and plasma
lipid-lipoprotein concentrations in patients with coronary artery disease. Nine men with coronary artery disease, aged 57 ± 2 years, who had completed 12 months
of supervised intense exercise training were restudied
after 6 additional years during which they continued to
exercise. The first 12 months of training resulted in a
44% increase in maximal oxygen consumption CV0 2max)
from 25.0 ± 1.3 to 35.9 ± 1.5 ml'kg-I'min- ' (p <
0.001). The V0 2max after 6 additional years (total 7
years) of intense training was 36.8 ± 2.4 ml·kg-'·min- I.
Plasma high density lipoprotein (HDL)-cholesterol
concentration increased from 38 ± 3 to 45 ± 4 mg-dl ' '
Endurance exercise training often increases maximal attainable oxygen uptake capacity (V0 2 max) and exercise performance and decreases exercise-induced myocardial ischemia in patients with coronary artery disease (1-4). These
beneficial effects had previously been attributed to peripheral adaptations that result in a larger oxygen extraction by
the trained skeletal muscles and a lower myocardial oxygen
demand during submaximal exercise (2,3,5). It is now clear,
however, that central adaptations can also occur in some
patients with coronary artery disease if a sufficient training
stimulus is applied. Previous studies from this laboratory
(4,6,7) suggest that high intensity exercise training can imFrom the Section of Applied Physiology and the Cardiovascular Division. Department of Internal Medicine and the Irene Walter Johnson
Institute of Rehabilitation, Washington University School of Medicine. St.
Louis, Missouri. This study was supported by Research Grants HL-22215
and HL-17646 from the National Institutes of Health. Specialized Center
of Research in Ischemic Heart Disease. Bethesda. Maryland. Dr. Rogers
is a postdoctoral research trainee supported by Training Grant HL-07456
from the National Heart, Lung, and Blood Institute, National Institutes of
Health.
Manuscript received October 14, 1986; revised manuscript received
January 27,1987, accepted February 19, 1987.
Address for reprints: Ali A. Ehsani, MD, Applied Physiology Section.
Box 8113, 2nd Floor West Building, Washington University School of
Medicine, St. Louis, Missouri 63110.
(01987 by the American College of Cardiology
at 12 months and rose further to 53 ± 5 mg-dl" ' at 6
years of follow-up (p < 0.05). The atherogenic index
(total cholesterol/HDL-cholesterol ratio) decreased from
5.8 ± 0.4 to 4.9 ± 0.4 by 12 months (p < 0.01) and to
4.1 ± 0.4 after 6 additional years of training (p < 0.05).
Although the maximal heart rate-pressure product was
14% higher after 12 months of training, maximal ST
segment depression was significantly less, 0.27 ± 0.06
versus 0.19 ± 0.04 mV (p < 0.05); this improvement
was maintained after 6 years of additional training.
These data provide evidence that the beneficial effects
of a program of intense exercise training can be maintained for long periods in some motivated patients with
coronary artery disease who continue to exercise.
(J Am Coil CardioI1987;10:321-6)
prove myocardial oxygenation and left ventricular function
during exercise. Furthermore, several short-term studies
(8-10) have shown that moderate exercise training can increase plasma high density lipoprotein (HDL) cholesterol
concentration and reduce the atherogenic index, that is, the
total cholesterollHDL cholesterol ratio. However, little is
known about the long-term effects of training on patients
with coronary artery disease. In particular, it is not known
whether the beneficial effects of high intensity training on
V0 2 max, myocardial ischemia and plasma lipid profiles can
be maintained if patients continue to train.
Therefore, in the present study, we assessed the effect
of 6 additional years of regular exercise training on V0 2max,
electrocardiographic (ECG) evidence of myocardial ischemia and the plasma lipid-lipoprotein profile in nine patients
with coronary artery disease who had completed a 12 month
program of intense, supervised exercise training.
Methods
Study subjects. Nine men with coronary artery disease
(aged 57 ± 2 years, mean ± SE) participated in the study
after giving written informed consent. The study was ap0735-1097/87/$3.50
322
JACC Vol. 10, No.2
Aogust 1987:321-6
ROGERS ET AL.
LONG-TERM EXERCISE AND CORONARY ARTERY DISEASE
proved by the Human Studies Committee at Washington
University School of Medicine. These patients had completed 12 months of exercise training in our coronary rehabilitation program 6 ± 0.4 years previously (4) and had
continued to exercise regularly. Seven of the patients had
had a single, previous myocardial infarction documented by
characteristic symptoms, ECG changes and increases in cardiac enzyme activity. Of the other two patients who did not
have a myocardial infarction, one had chronic, stable effort
angina and the other had a positive exercise ECG; both of
these patients had angiographically documented coronary
artery disease. The seven patients who had a myocardial
infarction were initially evaluated 14.0 ± 5.7 (range 3.5
to 52) months after the infarction. Four patients were taking
long-acting nitrates (5 to 20 mg/day) throughout the first
year of training but discontinued this medication thereafter.
Of the four patients who were initially taking propranolol
(20 to 40 mg/day), one discontinued it and one patient's
dosage was reduced from 40 to 20 mg/day. The remaining
two subjects continued to take propranolol throughout the
study.
These 9 patients were among 15 who had completed a
12 month program of endurance exercise training and who
continued to participate in the training program for an additional 6 years (total 7 years). Of the other six patients
(who were not retested), two moved away from St. Louis,
one died from carcinoma of the stomach, two reduced their
training because of lack of motivation and one required
coronary artery bypass graft surgery because of the recurrence of effort angina after 3 years of regular exercise that
consisted of jogging an average of 16 miles/week. Cardiac
catheterization and selective coronary arteriography in this
patient revealed normal left ventricular performance at rest,
and two vessel coronary disease (>70% stenosis).
Exercise testing. The exercise tests were performed at
least 2 hours after a light meal and approximately 3 hours
after the last dose of medication. A graded treadmill exercise
test was performed using the Bruce protocol (II). The exercise was terminated because of exhaustion (eight patients)
or angina (one patient). A second maximal treadmill test
was performed approximately 2 weeks later to determine
maximal oxygen uptake CVOzmax) using a protocol described previously (12). Briefly, after a 5 minute warm-up
period, the subjects either walked at a rate between 3 and
4 mph or ran at a rate between 4.75 and 7.5 mph (depending
on their level of training) at a constant rate on a treadmill
at a level grade. Every 2 minutes the grade was increased
by 2% until the subjects could no longer continue to exercise
because of fatigue or angina.
Oxygen consumption (VO z) was measured by collecting
expired air in neoprene meteorologic balloons and analyzing
the oxygen and carbon dioxide fractions with a Perkin-Elmer
MGA 1100 mass spectrometer. The volume of expired air
was measured with a Tissot gasometer. To assure that a true
VOzmax had been attained the following two criteria had
to be met: 1) no further increase in VOz with increasing
work rate, that is, the "leveling off criterion," and 2) a
respiratory exchange ratio e 1.10. The patient whose VOzmax
test was terminated because of angina had a respiratory
exchange ratio of 1.21.
Plasma lipoprotein-lipid determinations. A 10 ml venous blood sample was obtained in the morning, after the
subject had fasted for 12 hours, for determination of plasma
lipid and lipoprotein concentrations according to the standard protocol ofthe Lipid Research Clinics (13). All subjects
had participated in a typical exercise session on the day
before the lipid determination. No dietary control was imposed before the 12 month or 7 year determination.
Exercise training program. The 12 month exercise
training program has been described previously (4). Briefly,
the program consisted of a 10 minute warm-up of walking
and stretching followed by endurance exercise in the form
of jogging and cycling. The frequency, intensity and duration of the exercise were progressively increased so that
after 6 months of the program the subjects were training for
about 50 to 60 minutes/day, 4 to 6 times/week at a level
requiring 70 to 90% of VOzmax. After completion of the
12 month exercise program, the subjects continued to exercise for 6 more years at the same or a slightly lower
intensity, either on their own (n = 3) or in our supervised
program (n = 6). At the time of the 7 year evaluation, the
intensity of a typical exercise session was determined in all
subjects on several occasions by collection of expired air
during training.
Statistics. The significance of differences among data
obtained before and after 12 months and after 6 additional
years of exercise training was determined with a repeated
measures analysis of variance using the general linear models
procedure. The source of the difference was determined
using least square means (14). Values are expressed as mean
values ± SE.
Results
Intensity of exercise, By the end of the initial 12 months
of training, the subjects were jogging 18 ± 3 miles/week
at an intensity that elicited 81 ± 4% of maximal heart rate.
The subjects continued to exercise regularly for 6.0 ± 0.4
years (range 4.4 to 7.0), at which time they were jogging
about 26 miles/week at an intensity equivalent to 85 ± 4%
of maximal oxygen uptake (VOzmax) (Table I). The only
patient who had effort angina before training became asymptomatic after 12 months of training and remained symptom
free throughout the remaining 6 years of follow-up. No
major cardiac events occurred during the follow-up period.
Adaptations to maximal exercise. VOzmax increased
from 1.93 ± 0.14 to 2.64 ± 0.17 liters'min- t after 12
months of training. After 6 additional years of regular training, the subjects' VOzmax was 2.72 ± 0.21 liters' min - I
lACC Vol. 10, No.2
ROGERS ET AL.
LONG-TERM EXERCISE AND CORONARY ARTERY DISEASE
August 1987:321-6
323
Table l. Age and Current Exercise Training Data in Nine Study Patients
Age
Training
Heart Rate
(yr)
57.0
±2.3
(beats-min ")
Percent of Maximal
Heart Rate
Training VOz
(mHg-1'min ')
Percent of
VOzmax
Training
Mileage
(per week)
141
±5
83.4
±2.l
30.9
± 1.9
84.4
±3.6
25.5
± 3.1
Results are mean ± SE.
and 36.8 ± 2.4 ml-kg- "-min- I, neither of which was different from the values attained after the first 12 months of
training (Table 2). Heart rate during maximal exercise was
159 ± 6 before training, 170 ± 5 (p < 0.05) after 12
months of training and 168 ± 7 beats/min after 6 additional
years of training. Maximal oxygen pulse, defined as maximal oxygen uptake divided by heart rate measured at the
same time as VOzmax, increased by 33% (12 ± 1 to 16
± I ml-beat"') in response to the initial 12 months of
training and did not change further with the additional 6
years of training.
The subjects' graded treadmill exercise test time was the
same after 12 months and after 6 years of additional training
(Table 3); both times were significantly longer than the
initial test time. The maximal rate-pressure product, defined
as the product of heart rate and systolic blood pressure at
maximal exercise, was the same after 12 months and 6
additional years of regular training; both values were significantly higher than the initial value (Table 3, Fig. I). The
respiratory exchange ratio during measurement of VOzmax
was 1.27 ± 0.04, 1.19 ± 0.05 and 1.13 ± 0.03 during
the initial, 12 month and 6 year tests, respectively.
Adaptations to submaximal work. After 12 months of
training, heart rate, systolic blood pressure and the ratepressure product were significantly lower during submaximal exercise at any given work rate (Fig. I). The submaximal heart rate, systolic blood pressure and rate-pressure
product responses after 6 additional years of training remained lower than the initial values and were not significantly different from the values attained after 12 months.
ST segment changes during exercise. Eight of the nine
patients had a positive graded exercise test before entry into
the study as assessed by criteria reported previously (4).
After 12 months of training, one of these eight patients had
a negative test that remained negative after 6 years of followup. An additional subject's exercise ECG became negative
only at the 7th year follow-up, whereas the initial and 12
month tests showed significant ST segment depression. The
mean ST segment depression during maximal exercise decreased significantly from 0.27 ± 0.06 to 0.19 ± 0.04 mY
even though the rate-pressure product attained was 14%
higher after 12 months of training (Fig. 2). Furthermore, at
the 7 year follow-up, ST segment depression during maximal exercise was similar in magnitude to that observed
after 12 months of training but was significantly less than
that before training despite the higher rate-pressure product
(Fig. I).
Total plasma lipid-lipoprotein concentrations (Table
4). Body weight did not change significantly during the
course of the study. Total plasma cholesterol and low density
lipoprotein (LDL) cholesterol concentrations did not change
after training. High density lipoprotein (HDL) cholesterol
concentration increased 18% after the initial 12 months of
training (difference not significant because of subject variability). After 6 years of additional training, plasma HDL
levels had increased another 18% (p < 0.05). This increase
in HDL cholesterol concentration, along with the unchanged
total cholesterol concentration, resulted in a significantly
lower total cholesterollHDL cholesterol ratio at 12 months.
The total cholesterol/HDL cholesterol ratio improved further
Table 2. Maximal Treadmill Exercise Data in Nine Patients
Variable
VOzmax (liters-min I)
VOzmax (ml-kg-- 'min . I)
HRmax (beats' min ')
Oxygen pulse max (nil-beats-min-I)
Initial
Value
After 12
Months of
Training
After 7
Years of
Training
1.93
±O.14
25.0
±1.3
159
±6
12
±I
2.64*
±O.17
35.9*
± 1.5
l70t
±5
16*
±I
2.72*
±0.2l
36.8*
±2,4
168t
±7
16*
±l
*p < 0.01 vs. initial value: tp < 0.05 vs. initial value. Values are mean ± SE. VOzmax = maximal
oxygen uptake; HRmax = maximal heart rate; Oxygen pulse max = maximal oxygen pulse.
324
lACC Vol. 10. No.2
ROGERS ET AL.
LONG-TERM EXERCISE AND CORONARY ARTERY DISEASE
August 1987:321~6
Table 3. Hemodynamic Data During Graded Exercise in Nine Patients
Variable
HR peak (beats-min -I)
SBPmax (mm Hg)
RPPmax (SBP x HR x 10-')
GXT duration (s)
Initial
Values
After 12
Months of
Training
After 7
Years of
Training
146
±7
160
±6
23.5
±1.7
468
±25
16lt
±5
166
±6
26.8t
±2.l
621*
±22
l61t
±5
162
±11
26.2t
±2.2
614*
±34
*p < 0.01 vs. initial value; tp < 0.05 vs. initial value. Values are mean ± SE; SBPmax = maximal
systolic blood pressure; RPPmax = maximal rate-pressure product; GXT = graded exercise test, Bruce protocol;
other abbreviations as in Table 2.
to 4.1 ± 0.4 (p < 0.05) after 6 additional years of endurance
exercise training.
Discussion
Maximal oxygen uptake. Prolonged, strenuousexercise
training has been shown to elicit large increases in maximal
oxygen uptake (V0 2 max) in patients with coronary artery
disease (3,4,15). The 12 month exercise program of progressively increasing duration, frequency and intensity used
in our studies has resulted in average V0 2 max increases of
34 to 44% (4,6,7). In the presentstudy, the subjects' V02max
did not decrease between 12 months and 6 years of training,
indicating that the training stimulus was substantial enough
to maintain the large initial increase in V0 2 max.
There have been no previous long-term follow-up studies
on the effect of intense exercise training on maximal aerobic
capacity in patients with ischemic heart disease except for
a study by Kavanagh et al. (IS), who used submaximal
Figure 1. Heart rate and blood pressure responses during stages
I and II of the Bruce protocol initially (filled circles) and after 12
months (open circles) and a total of 7 years (open squares) of
exercise training. Results aremean values ± SE. *p < 0.05 versus
initial value; tp < 0.01 versus initial value. HR = heart rate;
RPP = rate-pressure product; SBP = systolic blood pressure.
130
_110
-;c
E
"0., 90
.£l
""J::
:~:
70
0
II
r
r
Figure 2. Maximal STsegment depression initially (filled circles)
and after 12 months (open circles) and a total of 7 years (open
squares) of exercise training. Results are mean values ± SE.
*p < 0.05 versus initial value. RPP = rate-pressure product.
0
>
E
~
':!::
160
Ol
J::
1 140
0-
al
<f)
120
I
24
180
testing to predict the V0 2 max of cardiac patients who were
training for a marathon race. However, in healthy 55 year
old men, Kasch et al. (17) found that V0 2 max was maintained after 10 years of training in a program that consisted
of moderate exercise similar to that used in our study. In
contrast, Mackeen et al. (I8) found a 16%decline in V0 2max
over a 13 year period in 40 to 60 year old men who were
inactive. In general, there is an approximately IO%/decade
decline in V0 2 max attributable to primary aging after the
age of 25 years (19-21). The decline in V0 2 max in middleaged men with coronary artery disease is probably attributable to I) the primary aging process, 2) the underlying
coronary artery disease with myocardial ischemia or scar,
or both, causing depressed left ventricular function (22),
and 3) a sedentary life-style. The V0 2 max in our patients
remained elevated for 6 years despite an expected age-related decline in V0 2max of about 2 mlkg Imin -1. The
large increase in V0 2 max after training cannot be solely
due to peripheral adaptations because the increase in arte-
o
~
I
-02
I
20
U')
1
~
Z
52
x
00-
I
~
LU
::E -04
16
o
LJ.J
""
U')
~
U')
12
0
II
TREADMILL TEST (Bruce Protocol)
-06
I
II
1
I
22
26
RPP
x
10 3
I
1
30
34
ROGERS ET AL.
LONG-TERM EXERCISE AND CORONARY ARTERY DISEASE
lACC Vol. 10. No. 2
August J987:32 J- 6
325
Table 4. Effects of Training on Plasma Lipid and Lipoprotein Concentrations in Nine Patients
Time
Initial value
After 12 months
of training
After 7 years of
training
HDL Cholesterol
Total Cholesterol
(rng-dl I)
LDL Cholesterol
(rng-dl I )
218 ± 13
208 ± 7
150 ± 14
140 :!: 5
38 ± 3
45 :!: 4
210 ± 8
127
53
:!:
6
(rng-dl t' )
:!:
5*t
Total CholesteroliHDL
Cholesterol Ratio
5.8 ± OA
4.9 :!: OAt
4. 1
:!:
OA*t
TG
(rngdl 1)
184 ± 66
lOS :!: 18
123 ± 21
Results are mean ± SE; *p < 0.05 vs. 12 months; t p < n.u l vs. initial value. HDL == high density lipoprotein; LDL == low density lipoprotein;
TG == triglycerides.
riovenous oxygen difference that can be induced by exercise
training is not sufficiently great to account for the entire
increase in V0 2max (23). Therefore, central adaptations
(6,7) must have played a role in bringing about and maintaining the elevated V0 2max in our subjects.
Effect of training on myocardial ischemia. The ratepressure product is a reasonably reliable noninvasive estimate of myocardial oxygen demand (MV0 2 ) in healthy persons and patients with coronary artery disease (24. 25) even
though it may not precisely reflect MV0 2 • A significant
reduction in maximal ST segment depression both after 12
months and after 6 additional years of intense exercise training despite a 14% increase in maximal rate-pressure product
is compatible with the interpretation of improved myocardial
oxygenation after training. We have previously shown an
increase in rate-pressure product threshold for ischemic ST
segment depression after 12 months of intense training (4).
a decrease in the extent of ST segment depression at the
same rate-pressure product and a reduced or unchanged
maximal ST segment depression despite a large increase in
rate-pressure product. Laslett et al. (26) also reported an
increased rate-pressure product threshold for myocardial
ischemia after 6 months of moderate training; however, they
did not report the effect of training on ST segment depression or rate-pressure product during maximal exercise. The
present study extends these observations and further suggests that an adequate training stimulus can result in lessening of myocardial ischemia despite a higher index of
MV0 2 in some patients, and that this adaptation can be
maintained for several years with continued training.
In addition to rate-pressure product, MV0 2 is also affected by contractility and left ventricular wall stress. which
is in tum related to radius. wall thickness and pressure. We
have recently shown (7) that left ventricular end-diastolic
volume and ejection fraction, two other variables affecting
MV0 2 , were higher at a comparable rate-pressure product
after intense training. Moreover, we have reported (27) a
higher concentration of plasma norepinephrine at maximal
exercise, which is likely to raise MV0 2 after training. Therefore, the reduction of ECG evidence of myocardial ischemia
at maximal exercise cannot be attributed exclusively to a
reduced MV0 2 and favors the interpretation that improved
myocardial oxygenation may, in part, be responsible for our
findings.
Long-term training and lipid-lipoproteins. Endurance
exercise training generally results in minimal changes in
total plasma cholesterol, whereas triglyceride concentrations
decrease markedly only in individuals with hypertriglyceridemia (28). The total plasma cholesterol and total triglyceride concentrations were not altered significantly by either
12 months or 6 additional years of training in the current
study, thus indicating that diet probably had little impact
on the alteration in HDL cholesterol concentration. The total
increase (39%) in plasma HDL cholesterol concentration in
this study is one of the largest reported; previously, typical
HDL cholesterol increases of 10 to 16% were found after
training in patients with coronary artery disease (8 to 10.29).
The plasma HDL cholesterol concentration after the total
of 7 years of training in our patients is similar to that reported
for young athletes (55 ± 2 mg'dl - ' ) studied in our laboratory but less than that of highly trained healthy endurance
athletes (66 ± 3 mg-dl I) the same age as our study patients
(30).
The total cholesterollHDL cholesterol ratio is clinically
useful as an atherogenic index in epidemiologic studies
(3 1.32). In the present study, this ratio improved significantly with 12 months of intense exercise training primarily
as a result of increased plasma HDL cholesterol concentration. After 7 years of training. the ratio had improved further
to 4.1 ± 0.4. a ratio very similar to that seen in older, lean
untrained subjects who were clinically free of coronary artery disease (30 ,33). Conceivably. this improvement in the
atherogenic index and HDL cholesterol concentration could
have a protective effect against progression of coronary
atherosclerosis. However, further studies are needed to examine its effect on prognosis.
Clinical implications. Our results suggest that regularly
performed. vigorous endurance exercise training can induce
large increases in V0 2m ax and exercise capacity and reduce
myocardial ischemia and that these changes appear to be
due in part to exercise-induced improvements in myocardial
oxygenation in some patients with coronary artery disease.
In addition, prolonged training results in a progressive, large
increase in HDL cholesterol concentration and a reduction
326
ROGERS ET AL.
LONG-TERM EXERCISE ANDCORONARY ARTERY DISEASE
JACC Vol. 10. No.2
in the atherogenic index . The results also show that these
improvements can be maintained with no apparent clinical
deterioration even in the presence of ST segment depression
in some highly motivated patients with coronary artery disease who are willing and able to perform relatively intense
exercise . Of course, this form of intervention may be unsuitable or even hazardous for many patients with coronary
artery disease . Further studie s are required to assess the
effect of long-term training on left ventricular function and
to determine the threshold necessary to elicit these adaptations .
14. Barr AI, Goodnight 1, Sail, IP, Blair WHo Chilco DM. The SAS
User's Guide. Raleigh, NC: SAS Institute, 1979:113-8 .
15. KavanaghT, Shephard RJ, Kennedy1. Characteristicsof postcoronary
marathon runners. Ann NY Acad Sci 1977;301:455-62.
August 1987:321-6
16. Hickson RC, Bomze HA, Holloszy JO. Linear increase in aerobic
power induced by a strenuous program of endurance exercise. 1 Appl
Physiol 1977;42:372-6 .
17. Kasch FW, WallaceIP, VancampSP. Effects of 18 years of endurance
exercise on the physical working capacity of older men. 1 Cardiopulmonary Rehabil 1985;5:308-12 .
18. Mackeen PC, RosenbergerlL , Slater JS, Nicholas WC, Buskirk EL.
A 13 year followup of a coronary heart disease risk factor screening
and exercise program for 40-59 year old men. J Cardiopulmonary
Rehabil 1985;5:510-23.
19. Hagberg, JM. The effect of training on the decline of V02max with
aging. Fed Proc 1987;46:1830-3 .
References
20. Heath GW, Hagberg JM, Ehsani AA, Holloszy 10. A physiological
comparison of young and older endurance athletes. J Appl Physiol
1981 ;51:634-40.
I. Vamauskas E, Bergman H, Houk P, Bjomtorp P. Hemodynamic effects of physical training in coronary patients. Lancet 1966;2:8-12 .
21. Buskirk EL. Decline in V02max with aging. Fed Proc 1987;46:
1824-9 .
2. Mitchell JH. Exercise training in the treatment of coronary heart disease. Adv Intern Med 1975;20:249-72.
3. Clausen IP. Circulatory adjustments to dynamic exercise and effect
of physical training in normal subjects and in patients with coronary
artery disease. Prog Cardiovasc Dis 1976;18:459-95 .
4. Ehsani AA, Heath GW, Hagberg1M, Sobel BE, Holloszy 10. Effects
of 12 months of intense exercise training on ischemic ST segment
depression in patients with coronaryartery disease. Circulation 1981 ;64:
1116-24.
22. Ehsani AA, Biello D, Seals DR, Austin MB, Schultz J. The effect
of left ventricular systolic function on maximal aerobic exercise capacity in asymptomatic patients with coronary artery disease. Circulation 1984;70:552-60.
5. Bergman H, Vamauskas E. The hemodynamic effects of physical
training in coronary patients. In: Brunner D, loki E, eds. Physical
Activity and Aging. Basel: Karger, 1970: 138-47 (Medicine and Sport,
vol 4).
6. Hagberg1M, Ehsani AA, Holloszy 10 . Effect of 12months of intense
exercise training on stroke volume in patients with coronary artery
disease. Circulation 1983;67:1194-9 .
23. BlomqvistCG, Saltin B. Cardiovascular adaptations to physical training. Annu Rev Physiol 1983;45:169-89 .
24. Kitamura K, Jorgensen CR, Gobel FL, Taylor HL, Wang Y. Hemodynamic correlates of myocardial oxygen consumption during upright
exercise. 1 Appl Physiol 1972;32:516-22 .
25. Holmberg S, Wieslaw S, Varnauskas E. Coronary circulation during
heavy exercise in control subjects and patients with coronary heart
disease. Acta Med Scand 1971 ;190:465-80.
26. Laslell U, Paumer L, Amsterdam EA. Increase in myocardialoxygen
consumption indexes by exercise training at onset of ischemia in patients with coronary artery disease. Circulation 1985;71:958-62.
10. Streja D, Mymin D. Moderate exercise and high-density lipoprotein
cholesterol. lAMA 1979;242:2190-2 .
27. Ehsani AA, Heath GW, Martin WH, Hagberg JM, Holloszy 10.
Effects of intense exercise training on plasma catecholamines in coronary patients. 1 App! Physiol 1984;57:154-9 .
28. Haskell WL. The influence of exercise on the concentrations of triglyceride andcholesterol in humanplasma. ExercSportSci Rev 1984;12:
205-44 .
29. Heath GW, Ehsani AA, Hagberg JM, Hinderliter JM, Goldberg AP.
Exercise training improves lipoprotein lipid profiles in patients with
coronary artery disease. Am Heart 1 1983;105:889-95.
30. Seals DR, Allen WK, Hurley BF, Dalsky GP, Ehsani AA, Hagberg
JM. Elevated high-density lipoprotein cholesterol levels in older endurance athletes. Am 1 Cardiol 1984;54:390-3 .
II . Bruce RA, Homsten TA. Exercise stress testing in the evaluation of
patients with ischemic heart disease. Prog Cardiovasc Dis 1969;11:
371-90.
31. Kannel WB, Castelli WP, Gordon T. Cholesterol in the prediction of
atherosclerotic disease: new perspectives based on the Framingham
study. Ann Intern Med 1979;90:85-9 1.
12. Costill DL, Fox EL. Energetics of marathon running. Med Sci Sports
1969;1:81 -6.
32. Malaspina IP , Bussiere H, LeCalve G. The total cholesterol/HDL
cholesterolratio: a suitable atherogenesis index. Atherosclerosis 1981 ;40:
373-5.
33. Seals DR, HagbergJM, Hurley BF, Ehsani AA, Holloszy 10. Effects
of endurance training on glucose tolerance and plasma lipid levels in
older men and women. JAMA 1984;252:645-9.
7. Ehsani AA, Biello DR, Schultz 1, Sobel BE, Holloszy 10. Improvement of left ventricular contractile function by exercise training in
patients with coronary artery disease. Circulation 1986;74:350-8.
8. Ballantyne FC, Clark RS, Simpson HS, Ballantyne D. The effect of
moderate physical exercise on the plasma lipoprotein subfractions of
male survivors of myocardial infarction. Circulation 1982;65:913-8.
9. Hartung GH, Squires WG, Gotto AM. Effect of exercise training on
plasma high-density lipoprotein cholesterol in coronary disease patients. Am Heart 11981 ;101 :181-4.
13. Lipid Research Clinics Program. Manual of laboratory operations:
lipid and lipoprotein analysis. National Heart and Lung Institute, Nationallnstitutes of Health Publication 75-628 . Bethesda, MD: United
States Department of Health, Education and Welfare, 1974, vol I.