Download Ejection Fraction Response to Exercise in Patients with

Ejection Fraction Response to Exercise
in Patients with Chest Pain and
Normal Coronary Arteriograms
RAYMOND J. GIBBONS, M.D., KERRY L. LEE, PH.D., FREDERICK COBB, M.D.,
AND ROBERT H. JONES, M.D.
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SUMMARY In this study we describe the ejection fraction response to upright exercise using first-pass
radionuclide angiocardiography in a group of 60 patients with chest pain, normal coronary arteriograms and
normal resting ventricular function. A wide range of resting function (heart rate and ejection fraction) and exercise function (heart rate, ejection fraction, peak work load and estimated peak oxygen uptake) were measured. The ejection fraction response to exercise demonstrated wide variation, ranging from a decrease of 23%
to an increase of 24%. Six of 22 clinical and radionuclide angiocardiographic variables (resting ejection fraction, peak work load, age, sex, body surface area and the change in end-diastolic volume index with exercise)
were significant univariate predictors of the ejection fraction response to exercise. Multivariable analysis identified resting ejection fraction, the change in end-diastolic volume index with exercise and either sex or peak
work load as variables that provided significant independent predictive information. These observations indicate that the ejection fraction response to exercise is a complex response that is influenced by multiple physiologic variables. The wide variation in this population suggests that the ejection fraction response to exercise is
not a reliable test for the diagnosis of coronary artery disease because of its low specificity.
GATED EQUILIBRIUM and first-pass radionuclide angiocardiography (RNA) have been validated
as accurate, noninvasive methods for measuring ejection fraction (EF).1-- Using either technique, the
changes in EF with exercise have been reported to be
useful in the diagnosis of coronary artery disease.4 5
However, these studies have reported observations in
only a small number of patients with chest pain and
normal coronary arteriograms.4 6 The normal,
healthy subjects that have been used for additional
comparison to patients with coronary artery disease
may not be representative in terms of age, sex or
physical conditioning of the population in whom the
noninvasive diagnosis of coronary artery disease is
sought. The purpose of this study is to report our experience with upright rest and exercise first-pass RNA
in a group of 60 patients with chest pain, normal coronary arteriograms and normal resting ventricular
function and to identify factors other than coronary
artery disease that influenced the EF response to exercise in this population.
Methods
Study Population
The study group consisted of patients with chest
pain and normal coronary arteriograms who un-
derwent RNA between January 1, 1978 and December
1, 1979. The decision to have these patients undergo
arteriography was based on clinical indications and
was usually made before an RNA was performed. All
patients underwent RNA within 3 months of coronary angiography and satisfied the following criteria:
(1) No evidence of significant or insignificant coronary
artery disease. Minor irregularities of the coronary
arteries (less than 25% diameter narrowing) were considered grounds for exclusion. (2) Normal resting left
ventricular function, i.e., a rest EF . 50% by both
RNA and contrast left ventriculography. (3) Technically satisfactory RNA studies. Five patients were
excluded because of technical difficulties - supraventricular tachycardia during exercise in one patient,
premature ventricular complexes during the left ventricular phase of the bolus passage in two patients and
inadequate bolus injection in two patients. (4) No
pulmonary hypertension, i.e., systolic pulmonary
artery pressure < 35 mm Hg and mean pulmonary
artery pressure < 20 mm Hg. (5) No definite previous
myocardial infarction. A focal wall motion abnormality at catheterization and either ECG Q waves or
positive cardiac isoenzyme measurements were required for the diagnosis of a definite infarction.
Sixty patients (36 females and 24 males) were identified who satisfied these criteria. The median age was
48 years (range 29-74 years).
In patients under treatment with propranolol, the
drug was generally tapered and discontinued 24 hours
before the RNA study. However, eight patients (six
females and two males) had taken propranolol within
24 hours of the study because of the severity of their
symptoms.
From the Departments of Medicine, Surgery, and Community
and Family Medicine, Duke University Medical Center, Durham,
North Carolina.
Supported by research grant HL-17610, NHLBI; training grant
LM-07003, National Library of Medicine; and grants from the Prudential Insurance Company of America and the Kaiser Family
Foundation.
Dr. Lee is the recipient of Career Development Award LM00042, National Library of Medicine.
Dr. Cobb is an Established Investigator of the American Heart
Association.
Address for correspondence: Raymond J. Gibbons, M.D., Mayo
Clinic, 200 First Street Southwest, Rochester, Minnesota 55901.
Received September 24, 1980; revision accepted January 29,
1981.
Circulation 64, No. 5, 1981.
Study Acquisition
All studies were performed with the patient sitting.
A modified V5 electrocardiographic lead was monitored throughout and used to measure heart rate.
Blood pressure was measured indirectly with a
952
953
NORMAL EF RESPONSE TO EXERCISE/Gibbons et al.
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sphygmomanometer. After RNA at rest, exercise was
performed on a bicycle ergometer (Fitron, Lurer,
Inc.). Subjects began exercise at a work load of 200
kpm/min. The work load was progressively increased
by 100 kpm/min each minute until the subjects
achieved 85% of maximum predicted heart rate or had
moderate chest pain, positive ECG changes (> 0.1 mV
of downsloping or horizontal ST depression), or
severe fatigue. Exercise terminated for the first three
reasons was designated adequate; exercise terminated
by severe fatigue was considered inadequate. Patients
who achieved 85% of maximum predicted heart rate
were said to have achieved target heart rate. At peak
exercise, RNA was repeated and heart rate, blood
pressure and peak work load were recorded. The oxygen uptake at peak exercise (V02) was calculated from
the formula VO2 (ml/kg/min) = (300 + [peak work
load X 21)/kg.6
The details of the RNA procedure have been
reported.7-9 An anterior projection and a multicrystal
gamma camera (Baird System Seventy-seven) with a
1-inch, parallel-hole collimator were used. Ten to 15
mCi of technetium-99m pertechnetate were used for
each of the rest and exercise studies. Injections of the
isotope were made through a 1-inch, 20-gauge Teflon
catheter into an external jugular vein. The isotope was
dissolved in'less than 1 ml of normal saline and injected as a bolus with 10-20 ml of saline. Counts were
recorded over the anterior chest wall in binary form at
20-msec intervals for 1 minute.
Data Processing
Radionuclide data
were
processed using the
com-
puter and software of the Baird System Seventy-seven
and previously described techniques.2 7 Corrections
made for background immediately before injection, electronic dead-time count loss and detector nonuniformity. Count changes within the left ventricle
were' used to identify end-systolic and end-diastolic
frames. Addition of data from three to six sequential
beats produced an average or representative cardiac
cycle. EF was calculated from the background-corrected representative cardiac cycle as ([ED
ES]/ED) X 100, where ES = end-systolic counts and
ED = end-diastolic counts. A computer program outlined the end-diastolic and the end-systolic perimeters. In accordance with previous phantom measurements and patient validation studies, the end-diastolic
perimeter was chosen at the 21% isocount contour of
the end-diastolic image.'0 The aortic valve plane was
identified both from dynamic images and from the
zone in which counts did not change between end-systole and end-diastole. The end-diastolic image was
used to calculate an end-diastolic volume (EDV) by
the area-length method of Sandler and Dodge." The
EDV index (EDVI) was determined by dividing EDV
by body surface area (BSA). Validity studies for left
ventricular EF (LVEF) and EDV have been described.8' 9 The EF response to exercise was defined as
exercise EF minus rest EF. The ch-ange in EDVI'with
exercise (EXREDVI) was defined as exercise EDVI
minus rest EDVI. Regional left ventricular function
were
was assessed by analysis of wall motion through both
the cinematic display of the representative cycle and
the static display of the end-diastolic and end-systolic
perimeters.
Cardiac Catheterization
The cardiac catheterization procedure has been reported.12 Selective coronary cineangiograms were obtained in multiple left anterior oblique and right
anterior oblique views. Angiograms were interpreted
by at least two experienced angiographers who arrived
at a consensus reading.
Statistical Techniques
Clinical and RNA variables were examined to
determine their relationship to EF response to exercise. Univariate linear and rank correlations were
determined for each variable. Multivariable analysis
consisted of the determination of multiple regression
models using both a forward stepwise algorithm and a
backward elimination algorithm. Group differences
were evaluated by a Wilcoxon two-sample test.'. A p
< 0.05 was considered statistically significant.
Results
General
The study population was compared with all other
patients who were evaluated for chest pain between
January 1, 1973 and December 1, 1979 and found to
have normal coronary arteries and normal resting ventricular function (table 1). The study population was
not significantly different from this larger group of 797
patients in terms of sex distribution or treadmill performance. The study population was slightly older and
tended to have typical angina more frequently (p
= 0.07).
The study population demonstrated a wide range in
resting function and exercise performance (table 2).
The median resting heart rate was 80 beats/min
(range 52-120 beats/min), and the median resting EF
was 64.5% (range 50-81%). Exercise heart rate, EF,
TABLE 1. Comparison of Study Group with 797 Patients
with Normal Coronary Arteries and Normal Ventricular
Function
Other
group normals
(n = 60) (n = 797)
57%
60%
47
48
Study
Characteristic
Female
Median age (years)
Pain description
Typical angina
Atypical angina
Nonanginal pain
Treadmill performed
Treadmill interpretation positive
Treadmills stopped
before Bruce stage 3
p
NS
0.05
25%
49%
26%
72%
14%
58%
28%
76%
7%
10%
NS
33%
34%
NS
0.07
NS
CIRCULATION
954
TABLE 3. Distribution of Rest-to-exercise Change in Ejection Fraction (EXREF)
n EXREF < 0 EXREF = 0-4 EXREF > 5
Group
Men
24
3
4
17
Women
36
10
10
16
Overall
60
13 (22%)
14 (23%)
33 (55%)
TABLE 2. Distribution of Rest and Exercise Variables
Variable
Median
Range
81
Rest heart rate
52-120
150
Exercise heart rate
90-180
64.5
Resting ejection fraction
50-81
70.5
Exercise ejection fraction
47-89
EXREF
6.5
-23 to 24
27
Exercise V02 (mg/kg/min)
12-43
600
Peak work load (kpm/min)
300-1200
Abbreviations: EXREF = ejection fraction response to
exercise.
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V02 and peak work load all varied greatly in this population.
Thirty-six patients achieved 85% of maximum predicted heart rate during exercise. Exercise was terminated because of moderate chest pain in one patient
and because of positive ECG changes in one patient.
Twenty-two patients stopped exercise because of
severe fatigue.
The EF response to exercise ranged from -23 to 24
(median +6.5). The distribution of EF response to
exercise is displayed in figure 1 and table 3. In 13
patients (22%) (three men and 10 women) EF in
response to exercise decreased. In 33 patients (55%)
(17 men and 16 women), EF increased by at least 5
points. Regional wall motion was normal at rest in all
patients. With exercise, regional wall motion was abnormal in four patients (7%) and normal in the
remaining 56 patients (93%).
Univariate Analysis
Twenty-two clinical and RNA variables (table 4)
were examined for evidence of univariate correlation
with EF response to exercise. Six of these variables
had significant linear correlation coefficients (table 5).
The most significant single variable, rest EF, was
negatively correlated with EF response to exercise (fig.
2). The slope of the simple linear regression line was
-0.55, indicating that for each 10-point increase in
resting EF, EF response to exercise decreases approximately 5.5 points.
1.01
r-
0.8
CUMULATIVE
FREQUENCY
0.6
0.4
0.2
n
v,
.-
-20
.
9
1
-10
0
EXREF
a
10
a
1
5
20
FIGURE 1. Cumulative frequency of ejection fraction
exercise (EXREF). EXREF was less than O for
22% of the patients and 5 or more for 55% of the patients.
response to
VOL 64, No 5, NOVEMBER 1981
Peak work load was positively correlated with EF
response to exercise. (fig. 3). The slope of the simple
linear regression line was 0.016, indicating that for
each 100-kpm increase in work load, EF response to
exercise increases approximately 1.6 points.
Women had significantly (p = 0.005) lower values
of EF response to exercise than men (fig. 4). The median value for women was 4, compared with 10 for the
men. EF response to exercise was 5 or more for 71% of
the men but only 44% for the women. Rest and exercise heart rate blood pressure and heart rate-blood
pressure product did not correlate significantly with
EF response to exercise.
Multivariable Analysis
When all 22 variables were considered together, two
multiple regression models with similar predictive accuracy (multiple correlation r = 0.64, p = 0.0001)
were obtained. In the first model (table 6), rest EF,
work load and change in EDVI with exercise were
TABLE 4. Clinical and Radionuclide Angiographic Variables
Age
Sex
History of hypertension
Body surface area
Propranolol within last 24 hours
Rest heart rate
Rest ejection fraction
Rest systolic blood pressure
Rest diastolic blood pressure
Rest end-diastolic volume index
Exercise heart rate
Exercise systolic blood pressure
Exercise diastolic blood pressure
Peak work load
"Adequate" exercise
"Achieved target rate"
EXREDVI
RESTHR X RESTSYS
EXHR X EXSYS
EXHR/RESTHR
(EXHR X EXSYS)/(RESTHR X RESTSYS)
V02
Abbreviations: EXREDVI = (exercise end-diastolic
volume index - rest end-diastolic volume index); RESTHR
= rest heart rate; RESTSYS = rest systolic blood pressure;
EXHR = exercise heart rate; EXSYS = exercise systolic
blood pressure; V02 = maximal oxygen consumption.
NORMAL EF RESPONSE TO EXERCISE/Gibbons et al.
TABLE 5. Significant Variables Variable
Rest ejection fraction
Peak work load
Age
Sex (0 = male, 1 = female)
3Or-
Univariate Analysis
r
p
-0.44
0.0004
+0.40
0.001
-0.38
0.003
-0.37
0.003
+0.30
0.02
Body surface area
-0.27
0.04
EXREDVI
Abbreviations: EXREDVI = (exercise end-diastolic volume index - rest end-diastolic volume index).
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TABLE 6. Multivariable Analysis 1 - Significant Variables (r = 0.64, p = 0.0001)
Regression
coefficient
p
Variable
-0.53
0.0001
Rest ejection fraction
0.014
0.001
Peak work load
-0.16
0.008
EXREDVI
Abbreviations: EXREDVI = (exercise end-diastolic volume index - rest end-diastolic volume index).
TABLE 7. Multivariable Analysis 2 - Significant Variables (r = 0.64, p = 0.0001)
Regression
Variable
coefficient
p
-0.52
0.0001
Rest ejection fraction
Sex (0 = male, 1 = female)
-6.5
0.002
-0.19
0.003
EXREDVI
Abbreviations: EXREDVI = (exercise end-diastolic volume index - rest end-diastolic volume index).
independently correlated with EF response to exercise. Rest EF and change in EDVI with exercise were
negatively correlated with EF response to exercise;
peak work load was positively correlated with EF
response to exercise. The second model (table 7) included sex rather than peak work load. The associated regression coefficients for rest EF and change in
EDVI with exercise were very similar to those in the
first model. Since sex was coded 0 for males and 1 for
females, the regression coefficient of -6.5 for sex indicated that women had values of EF response to exercise that were 6.5 points lower than those for men
after rest EF and change in EDVI with exercise were
taken into account. According to the second model,
EF change with exercise (EXREF) could be estimated
from the following equations:
(males) EXREF = 45.0 - (0.52 X resting EF) -
(0.19
(females) EXREF =
(0.19
EXREDVI)
38.5 - (0.52 X resting EF)
X EXREDVI)
955
X
-
Discussion
Previous studies of rest and exercise EF measurements obtained by both gated equilibrium and firstpass RNA have reported on only a limited number of
patients with chest pain and normal coronary arteries.4" The present study reports on our experience
y
r
*S
20O
0
10
~~~~~
0*
-5-
.
-.55 X + 41
-0.44
0
--.
OF
EXREF
=
=
n = 60
-10 _
0
0
*
0
-20H_
.
30',~
.60
.70
RESTING EJECTION FRACTION
.80
FIGURE 2. Correlation ofejection fraction response to exercise (EXREF) with resting ejection fraction. The linear
correlation coefficient was modest, -0.44, indicating that
other factors may contribute to the variability of EXREF.
with rest and exercise first-pass RNA in a group of 60
patients with chest pain who at cardiac catheterization were found to have normal coronary arteries and
normal resting ventricular function. This study group
appeared similar to all other patients with chest pain
and normal coronary arteries evaluated at this institution except that the study group was slightly older.
Our study population demonstrated a wide range in
resting heart rate and resting EF. This variability may
reflect differences in physical conditioning, volume
status, anxiety levels and medications. These same
factors may account for the wide range of heart rate,
EF, work load and estimated VO2 observed during exercise.
The EF response to exercise has been reported by
others to be highly specific in the noninvasive
diagnosis of coronary artery disease." Our results
demonstrate a wide range in EF response to exercise.
In particular, the EF decreased with exercise in 13% of
the men and 28% of the women. Thus, EF response to
exercise would not be a very specific test for the
diagnosis of coronary artery disease in this group, particularly in these women. Caldwell et al.,14 using gated
blood pool imaging and supine exercise, reported
similar findings in a small group of patients; two of 11
y
r
30
-
.016X -5.1
+ 0.40
n -= 60
-
20
0
*
0
10
t
_--
EXREF
C
.
S
a
*
_
.
.~~~~~
3
-ID
-20
-30
I
200
400
600
800
PEAK WORKLOAD (kpm/min)
1000
1200
FIGURE 3. Correlation of ejection fraction response to exercise (EXREF) with peak work load. The linear correlation coefficient was modest, 0.40, indicating that other factors may contribute to the variability of EXREF.
CIRCULATION
956
1.0
~~MALE
r-1
fl!
--FEMALE
0.8
rzrJ
0.6h
CUMULATIVE
FREQUENCY
,
0.4
0.2
ri
r,
.
_
r'--i
H~~~1
__
r
i
J~~~~~~~~~~~~~~~~~~~~
_.
l
__,
I l
l l
I~~~~~~~~~~~~~~~~~~~~
A
mE
*
i
a
I
-20
-10
0
10
20
EXREF
FIGURE 4. Cumulative frequency of ejection fraction
response to exercise (EXREF) displayed by sex. The women
have lower values than the men (p = 0.005).
Downloaded from http://circ.ahajournals.org/ by guest on June 12, 2017
patients with normal coronary arteries decreased their
EF with exercise.
Our results appear to differ markedly from those of
Borer et al.,4 who reported that the EF invariably increases with exercise in patients with chest pain and
normal coronary arteries. However, differences in
study methods and patient population may have contributed to this discrepancy. In their study, a gated
equilibrium technique was used, exercise was performed in the supine position and the patients underwent a practice session of bicycle exercise. We
studied more patients and, in particular, more women.
Borer et al. had only seven women in their study while
we had 36. For men alone, we found that 21 of 24 subjects increased their EF with exercise (EF response to
exercise > 0); this was not significantly different from
the 14 of 14 men found by Borer to increase their EF
with exercise (p = 0.28).
Six variables were significant univariate predictors
of EF response to exercise, although the individual
correlation coefficients were very modest (0.44 or
less). Multivariable analysis demonstrated the presence of several factors that were independently associated with EF response to exercise. The most significant determinant of EF response to exercise was
resting EF, which had a negative regression coefficient. Thus, the higher the EF at rest, the less the
EF increases with exercise. The fact that stroke
volume cannot exceed end-diastolic volume places an
absolute ceiling on exercise EF of 100%. (The left ventricle does not obliterate during systole, so the highest
exercise EF recorded in this study, 89%, probably
represents the physiologic maximum of EF). Therefore, there is less difference between a high resting EF
and the absolute ceiling. Resting EF ranged from
50-81%; thus, the maximum possible increase with exercise ranged from 19-50% in our study population.
The change in EDVI from rest to exercise was also
a significant determinant of EF response to exercise.
The correlation was negative, indicating that as EDVI
increases with exercise, EF response to exercise decreases. The heart can increase its stroke volume with
exercise by both increasing EF and increasing EDV.
Our results suggest that the degree to which these two
VOL 64, No 5, NOVEMBER 1981
mechanisms are used in an individual subject are inversely related.
Finally, the third independent determinant of EF
response to exercise was either sex or peak work load.
Both variables provided equivalent statistical informationl in terms of modeling the performance of the population with regard to EF response to exercise.
Therefore, we could not determine which was the important physiologic variable. As a group, the women
achieved lower peak work loads than the men (p =
0.0001), which may reflect differences in physical conditioning and/or body weight (fig. 5). It is important
to note that the peak work load achieved during bicycle ergometer exercise is directly related to body
weight.6 However, both BSA and V02, a measure of
physical conditioning, were included in the multivariable analysis; neither one emerged as a significant
variable.
None of the other 22 variables considered in the
multivariable analysis showed a significant association
with EF response to exercise. Age and BSA, both
significant univariate predictors of EF response to exercise, were no longer significant once resting EF, the
change in EDVI from rest to exercise and either sex or
peak work load were taken into account. Rest and
exercise heart rate, blood pressure and heart
rate-blood pressure product were not significant in
either the univariate or multivariable analysis. The use
of propranolol within 24 hours of the RNA and the
achievement of "adequate" exercise also did not significantly influence EF response to exercise.
The predictive accuracy achieved by the two models
is modest (r = 0.64), indicating that other unidentified
factors may contribute to the variability of EF
response to exercise. One possibility is the inherent
variability in the measurement of EF. Upton et al.9
showed that repeat EF determinations may vary by as
much as 8% at rest and 5% during exercise in normal
subjects. A second possibility is the presence of an unidentified pathology within the study group. This
seems unlikely because of the relatively strict criteria
for entry into the study group, and previous studies at
I.Or
-----
MALE
FEMALE
r-
0.8k
CUMULATIVE
FREQUENCY
--
0.6F
0.4[
0.2
O-
200
_.
400 600 800 1000 1200
PEAK WORKLOAD (kpm/min)
FIGURE 5. Cumulative frequency of peak work load displayed by sex. The women have lower values ofpeak work
load than the men (p = 0.0001).
NORMAL EF RESPONSE TO EXERCISE/Gibbons et al.
this institution that have shown an excellent prognosis for similar patients."'
In conclusion, in a population of 60 patients with
chest pain, normal coronary arteriograms and normal
ventricular function, the EF at rest and the change in
EF with exercise were highly variable. In the absence
of coronary artery disease, resting EF, exercise-induced changes in ventricular volume and either peak
work load or sex were all independent determinants of
the EF response to exercise. The physiologic complexity and wide variation of the EF response to exercise in
this population with normal coronary arteriograms
may limit the value of this response in the noninvasive
diagnosis of coronary artery disease.
References
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Ejection fraction response to exercise in patients with chest pain and normal coronary
arteriograms.
R J Gibbons, K L Lee, F Cobb and R H Jones
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Circulation. 1981;64:952-957
doi: 10.1161/01.CIR.64.5.952
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1981 American Heart Association, Inc. All rights reserved.
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