Download Mechanism and significance of a decrease in ejection fraction

88
JACC Vol 3. No 1
January 1984 88-97
Mechanism and Significance of a Decrease in Ejection Fraction During
Exercise in Patients With Coronary Artery Disease and Left
Ventricular Dysfunction at Rest
MICHAEL B. HIGGINBOTHAM, MB, R. EDWARD COLEMAN, MD, ROBERT H. JONES, MD,
FREDERICK R. COBB, MD
Durham . North Carolina
The purpose of this study was to determine whether an
exercise-induced decrease in ejection fraction in patients
with coronary artery disease and left ventricular dysfunction at rest represents ischemia or the nonspecific
response of a compromised left ventricle to exercise stress.
Accordingly, radionuclide ejection fraction responses of
246 patients with coronary artery disease and an ejection
fraction at rest of less than 0.50 were compared with
those of a "nonischemic" control group of 48 patients
with idiopathic dilated cardiomyopathy and a similar
degree of ventricular dysfunction. The significance of
the ejection fraction response in the group with coronary
artery disease was further examined by relating it to the
angiographic extent of coronary artery disease, severity
of angina, incidence of chest pain and electrocardiographic ST segment depression during exercise and longterm prognosis.
The ejection fraction decreased by ~ 0.01 and ~ 0.05
during exercise in 48 and 28%, respectively, of the patients with coronary artery disease compared with only
8 and 2 %, respectively, of the patients with cardiomyopathy. When exercise was limited by fatigue at a
The demonstration of reversible myocardial ischenua In patients With coronary artery disease IS Important In the selecnon of appropnate therapy When left ventncular funcnon at rest is normal, Ischemia often can be detected dunng
exercise stress by the demonstration of electrocardiographic
From the Cardiovascular Divrsionof the Department of Medicine. and
the Department of Radiology, Durham Veterans Adrmrnstranon Medical
Center and Duke Umversny Medical Center, Durham. North Carolina
This study was supported m part by Research Grant HLl7670 from the
National Heart. Lung. and Blood Institute. Bethesda. Maryland Dr Hrggmbotham received support from the National Heart Foundation of Austraha, Woden, AustralianCapital Terntory, Australia Manuscnptreceived
March 22, 1983, revised manuscnpt received August 10, 1983, accepted
August 16, 1983
Address for repnnts Fredenck R Cobb, MD, Divisionof Cardiology
(lIlA), Durham Veterans Adrrnmstranon Medical Center, 508 Fulton
Street, Durham, North Carolma 27705
© 1984 by the Amencan College of Cardiology
submaximal heart rate, the ejection fraction decreased
in 25% of the patients with coronary artery disease but
in none of the patients with cardiomyopathy. Patients
with coronary artery disease whose ejection fraction decreased during exercise had a significantly higher incidence of three vesseldisease, exercise-induced chest pain
or ST depression and late mortality than did patients
whoseejection fraction did not decrease. These relations
were confirmed equally in subgroups of patients with
moderate (ejection fraction 0.30 to 0.49) and severe
(ejection fraction < 0.30) left ventricular dysfunction.
Thus, in patients with coronary artery disease and
left ventricular dysfunction at rest, a decrease in ejection
fraction during exercise is more likely to indicate ischemia than a nonspecific left ventricular response to exercise stress. In the individual patient, a decrease of 0.05
or greater, or a decrease during submaximal exercise,
appears to be highly specificfor ischemia. A decrease in
ejection fraction identifies a subgroup of patients with a
high prevalence of multivessel coronary artery disease
and a high risk of death during long-term follow-up on
medical therapy.
changes (1), changes In radionuchde Indexes of global and
regional left ventncular function (2-5), and thallium perfUSIOn defects (6,7) Specific diagnostic cntena have been
established by comparing the responses of patients With
coronary artery disease With those of normal control subjects. In patients who have depressed left ventncular funcnon at rest , the diagnosis of Ischemia may be more difficult
for the following reasons First, because previous myocardial mfarcuon usually results In electrocardiographic
changes and abnormalities of wall motion and myocardial
perfusion at rest, It IS difficult to Interpret additional changes
that may occur during exercise (8-11) Second, because the
ejection fracnon at rest IS an Important determinant of the
ejection fraction response to exercise In patients With coronary artery disease (10), the diagnostic cntena used In patients With normal left ventncular function at rest may not
0735-1097/84/$3 00
JACC Vol , No I
January 1984 88-97
89
HIGGINBOTHAM ET AL
EXERCISE RfWON5E WITH CARDIAC DYSFUNCTION I\T REST
be appropnate m patients with abnormal function at rest
Third. myocardial mfarction reduces the amount of myocardium available for mamtammg global left ventncular
function dunng exercise, a ventncle that I~ abnormal at rest
may be unable to respond to the added demands ot exercise.
and the ejection fraction may decrease even m the absence
of rscherma The concept that exercise stres-, may reveal
myocardial dysfunction not apparent at rest has been discussed by other mvestigators concerned with valvular ( 12)
and myocardial (13) disorders
The present study was performed to clanfy the mechamsm and significance of the ejection fraction re~pon~e to
exercise m patients with coronary artery disease and left
ventncular dysfunction at rest It was reasoned that the
followmg observations would support the hypothesr- that a
decrease m ejection fraction represents ischerma rather than
a nonspecific response to exercise stress I) Patients who
have left ventncular dysfunction but a very low probabihty
of developmg ischemia do not expenence a decrease m
ejection fraction dunng exercise 2) A decrease m ejection
fraction dunng exercise I~ related to chrucal and electrocardiographic mdicators of ischemia. angiographrc extent
of coronary artery disease and subsequent mortality To
examme these hypotheses, the results of rest and exercise
first pass radionuchde angiography performed in 246 consecunve patients with angrographically proven coronary artery disease and reduced left ventncular function were compared with those of 48 patients with idiopathic dilated
cardiomyopathy In addition, the ejection fracnon responses
m patients with coronary artery disease were correlated with
cluneal and electrocardiographic indexes of ischenua. extent
of anatomic coronary artery disease and subsequentmortality
Methods
Study patients. A consecutive series of 246 patients
with coronary artery disease and left ventricular dysfunction
as defined by a radionuchde ejection fraction of levs than
o 50 was studied Two hundred twenty of these patients
were men and 26 were women. ages ranged from 25 to 72
years (mean 51) Coronary artery disease was confirmed in
all patients by cardiac cathetenzation, It showed 75% or
greater dIameter narrowmg of three vessels In 119 patlenb.
of two vessels m 71 patlent~ and of one ve~"el In 56 patients
There wa~ a hIstory of chest pam m 236 patlent<, and ot
myocardIal mfarctlOn m 187 patlent~ The electrocardIogram at rest showed Q waves of 0 04 second or greater In
177 patIents Of the 246 patIent". 31 (I )I'k) had neIther a
documented hIstory of myocardIal mfarctlOn nor Q waves
of 0 04 second or greater on the electrocardIOgram
Control group To compare patIent~ WIth coronary artery
disease With patIents who had comparable left ventncular
dy~functlon but a very low probabIlIty of developmg I~ch­
emIa dunng exerCise, a group of 48 patIents WIth IdlO-
pathic dilated cardiomyopathy was abo studied In 16 of
these patients cardiomyopathy had been confirmed by cardiac cathetenzation and in 32 patients the diagnosis was
based on chmcal and electrocardrographrc cntena alone Of
the 16 patients who underwent cathetenzation, the procedure was performed to exclude valvular heart disease In 4,
In the remammg 12 patients. coronary angiography and left
ventriculography were performed a" avsociated procedures
dunng catheterization for myocardial biopsy The decrsion
to perform cardiac cathetenzanon wa-, made by the patient'<
physician and was not mfluenced by the results of the radionuclide angiogram All 32 patients diagnosed chrncally presented for radionuchde angiography WIth a provisional dragnovi-, of congestive cardiomyopathy All had a history of
congestive heart tailure Without chest pam, and none had
electrocardiographic Q waves of 0 04 second or greater
Because the purpose of this part of the study was to obtam
a "model" of left ventncular dysfunction Without ischerrua
to act a" a control group for the patients WIth coronary artery
disease. the group With cardiomyopathy was further "elected
on the baSI'> of their chmcal and electrocardiographic re<pon-e to exercise. nve panents who satisfied the preceding
critena were excluded because they had expenenced chest
pam or new or addinonal ST segment depression dunng
exercise testmg
Table I shows the basehne charactenstics of the patients
WIth cardiomyopathy who had and had not undergone cardiac cathetenzanon The two subgroups did not differ m
age. sex distnbutron. electrocardiographic findings or basehne lett ventricular function
Radionuclide angiography. All 246 pauents WIth coronary artery disease and 42 ot the 48 patients WIth cardiomyopathy were assessed by first pa~~ radionuclide angiography The remammg ~IX patients With cardiomyopathy
underwent mulugated radionuclide angiography We have
demonstrated that these two radionuchde techrnque-, provide
sinular mtormation concernmg the ejection fraction In a
Table I. Baselme Charactcnvnc- of 48 Pauent-, With
Nomschermc Cardiomyopathy
Cardiac Catheten7 allon
16)
(n =
AgelH)
Se\
Abnormal ECG
STT
LYH
LBBB
RBBB
REF
No Cardiac Cathetenzauon
32)
(n =
46 ± II
10 M 6 F
15
50 ± 14
~
17
3
3
5
I
029 ± 0 II
25 M 7 F
27
3
2
029 ± 0 II
ECG = e!ectrocardlllgram, F = female LYH = lett ventnLUlar hypertrophy LBBB and RBBB = lett and nght bundle branch bloc\., re'pectlvely REF = re,t eJecllon tracllon M = male, ST/T = ST-T wave
ahnormaltlle,
90
HIGGINBOTHAM ET AL
EXERCISE RESPONSE WITH CARDIAC DYSFUNCTION AT REST
study of 36 patients who had left ventncular function determmed by both techniques, the mcan difference (± standard deviation) between ejection fraction measurements WID>,
respectively, 0 05 ± 0 02 at rest/correlation coefficient Ir]
= 0.94) and 0 06 ± 004 dunng exercise (r = 091), the
change 10 ejection fraction from rest to exercise vaned by
o 04 ± 0 03 Despite minor differences 10 the exercise
protocol used for the two techniques, similar exercise end
pomts were used for all studies Beta-adrenergic block109
drugs were discontmued for at Icast 24 hours before the
exercise test 10 207 of the 246 patients, the rernammg 39
took propranolol on the day of the study at the request of
their personal physician
Exercise protocol After the acquismon of the radionuclide angiogram at rest, each subject performed upright
bicycle exercise sittmg on an isokmcnc bicycle ergometer
For first pass studies, exercise work load commencedat 200
kpm/rrun and was mcreased by 100 kpm/mm each minute
For equihbnum studies, exercise work load was mcreased
by 150 kpm/mm every 3 mmutes to allow adequate time
for data acquisruon A standard 12 lead electrocardiogram
was recorded before the exercise study Precordial leads Y5
and Y6 were momtored contmuously, and the standard limb
leads and leads Y-+ to Y6 were recorded dunng each mmute
of exercise Blood pressure was measured by cuff manometry and recorded at rest and every 2 rnmutes dunng exercise Exercise was continued until one of the followmg
end pomts was reached moderate chest pam, honzontal or
downslopmg ST segment depression of I mY or more (2
mY With ST changes at rest), a heart rate 85% or greater
than the age-predicted maximum (target heart rate) or severe
fatigue
Radtonucltde acquisition and data analysts First pass
radronuchdeangiography was performed 10 the antenor projection usmg methods previously descnbed (14,15) For
each radionuchde acquistion, 10 to IS mCI of technetium99m pertechnetate was dissolved 10 less than I cc normal
saline solution and was flushed 10 as a bolus With 10 to 20
cc normal saline solution Using a multicrystal gammacamera equipped With a I inch (2 54 ern) parallel hole colhrnater, counts were acquired at 25 ms mtervals for I mmute Data were processed USIng the computer and software
of the Baird-Atomic System 77 Data from three to SIX
individual beats produced an average or representative cycle
Ejection fraction was calculated from background-corrected
end-diastolic and end-systolic counts
Ejection
fraction = End-dIastolIc counts - End-systolIc counts
End-diastolic counts
Wall motion was assessed from a stanc display of the
supenmposed end-diastolic and end-systolic penmeters denved from the representative cycle The static Image was
JACC Vol 3, No I
January 1984 88-97
divided mto three segments corresponding to the antenor,
apical and mfenor walls of the left ventncle Wall motion
was graded for each segment from 0 to 6 where 0 = normal,
I = less than Y2 wall hypokmetrc, 2 = greater than Y2 wall
hypokmetic, 3 = less than Y2 wall akmetic, 4 = greater
than Y2 wall akinetic, 5 = less than Y2 wall dyskmetic and
6 = greater than Y2 wall dyskmetic To distmguish between
global and regional left ventncular dysfunction, asynergy
of wall motion was defined as a difference of at least two
grades between two segments Asynergy that was present
only dunng exercise and resultmg from a decrease 10 regional wall motion was termed exercise-induced asynergy
Equiltbrtum radionuchde angiography was performed after
10 VIVO labelmg of red blood cells WIth 30 mCI of technetlUm-99m A SIngle-crystal gamma-camera, equipped WIth
a high sensinvity collimator, was interfaced WIth a Medical
Data Systems A2 computer for data collection and subsequent analysis End-diastohc and end-systolic regions of
interest were Identified us109 a sermautomated edge detection algorithm, ejection fraction was calculated from background corrected end-diastolic and end-systolic count measurements Wall motion was assessed 10 the left antenor
obhque projection, septal, apical and posterolateral regions
were graded as hypokmetic. akmetic or dyskmetic 10 a manner Similar to that used for the first pass studies
Follow-up, Of the 246 patients With coronary artery dISease, 96 underwentcoronary artery bypass surgery All were
operated on wrthm 4 months (56% withm 4 weeks. 89%
within 8 weeks) and thus did not contribute significantly to
long-term follow-up The remammg ISO patients were treated
medically and constituted the medical follow-up group Information concernmg the mortahty of all patients had been
obtained within 3 months of the study, either by letter or
telephone call to the patient or by contactmg the patient's
personal physician Follow-up duration was less than 10
months 10 49 patients, 10 to 19 months 10 21 patients, 20
to 29 months 10 29 patients and 30 months or more 10 51
patients
Statistical analysis, Ejection fraction changes from rest
to exercise were analyzed by paired t tests The relation
between ejection fraction changes dunng exercise and at
rest 10 the group WIth coronary artery disease was exarmned
by lmear regression analysis Unpaired t tests were used for
all mtergroup compansons The overall distnbution of angma class and vessel disease 10 the patient groups was
compared by chi-square analysis A log rank test was used
to compare survival curves for patients With different ejecnon fraction responses PatientsWith coronary arterydisease
and an ejection fraction at rest of 0 30 or greater were termed
subgroup I and those With an ejection fraction at rest of less
than 0 30 were termed subgroup II All analyses were apphed to the total group of patients WIth coronary artery
disease and both subgroups All group values are expressed
as mean ± standard deviation
HIGGINBOTHAM ET AL
EXERCISE RESPONSE WITH CARDIAC DYSFUNCTION AT REST
JACC Vol 3, No I
January 1984 88-97
fracuon response to exercise /1l patients with coronary artery disease IS shown 111 Figure 2 Lmear regression analysis
Results
Exercise response. Maximal work load achieved was
similar for patients with coronary artery disease (638 ±
198 kpm/mm) and patients With cardiomyopathy (560 ±
188 kpm/rmn) Both groups exercised to sirrular maximal
heart rates (135 ± 27 and 137 ± 21 beats/nun, respecnvely) Patients with cardiomyopathy proven by cardiac
cathetenzation achieved a SImilar maximal work load (604
± 243 kpm/rmn) and heart rate (\36 ± 18 beats/mm) to
that of patients who did not have cardiac cathetenzanon
(548 ± 159 kpm/rnm and 137 ± 22 beats/mm, respectively) Of the 246 patients with coronary artery disease.
162 achieved 85% of the predicted maximal heart rate compared with 25 of 48 patients with cardiomyopathy Seventyrune patients with coronary artery disease expenenced chest
pam and 65 had diagnostic ST segment depression dunng
exercise, one patient with cardiomyopathy confirmed by cardiac cathetenzation complamed of chest pam, but none had
new or additional ST segment changes Exercise was lumted
by fatigue m 52 patients with coronary artery disease and
m all patients with cardiomyopathy
Ejection fraction response to exercise. lndrvidualejection fracnon responses to exercise are shown m FIgure I
Ejection fraction did not change from rest (0 34 ± 0 19)
to exercise (0 35 ± 0 12) in patients with coronary artery
disease, but mcreased from 0 29 ± 0 II to 0 36 ± 0 15
(probability [p] < 0 000 I) m patients with cardiomyopathy
The ejection fracnon decreased dunng exercise m 117(48%)
of the patients with coronary artery disease compared with
only 4 (8%) of the patients with cardiomyopathy A decrease
in ejection fraction of 0 05 or greater was seen m 69 panents
(48%) with coronary artery disease compared with only I
patient (2%) with cardiomyopathy Although the 39 patients
tested while receivmg propranolol achieved lower heart rates
than did patients not takmg propranolol (119 ± 28 compared
with 138 ± 34 beats/nun), the ejection fraction decreased
m a Similar proportion in the two groups (16 [41 %] of 39,
and 101 [49%] of 207, respectively)
revealed a significant negative correlation between ejection
fraction at rest and the change from rest to exercise (r =
- 0 26), the ejection fraction decreased durmg exercise m
100 (57%) of 179 patients whose ejecnon fraction at rest
was greater than 0 30 (subgroup I) , compared With 17 (24%)
of 67 patients whose ejection fraction at rest was less than
o 30 (subgroup II)
The relation between exercise end point and ejection
fraction response IS Illustrated /1l Table 2 Exercise was
stopped by fatigue before 85% of the predicted maximal
heart rate was achieved ("madequate" end pomt) in 52
(20%) of the 246 patients With coronary artery disease and
in 23 (50%) of the 48 patients With cardiomyopathy For
all patients, mcludmg both coronary artery disease subgroups,
the ejection fraction decreased less often when the exercise
end pomt was inadequate than when It was adequate However, differences m exercise end pomt clearly did not account for the difference m ejection fraction response between coronary artery disease and cardiomyopathy groups
when the end pomt was adequate the ejection fracnon decreased in 104 (53%) of 194 patients With coronary artery
disease compared WIth 4 (16%) of 25 patients WIth cardiomyopathy (p < 0 00 I) When exercise was madequate the
ejection fraction decreased in 13 (25%) of 52 patients With
coronary disease but m none of the patients With cardiomyopathy (p < 0001)
Wall motion. Of the 246 patients With coronary artery
disease, abnormal wall motion was seen m 239 patients at
rest and in 240 patients dunng exercise Asynergy, that IS,
a segmental wall motion abnormality. was present in 79
patients at rest and m 106 patients dunng exercise Exerciseinduced asynergy occurred in 30 patients and was accornparned by a decrease in ejection fracnon m 20
Abnormal wall motion was noted at rest III all 48 patients
WIth cardiomvopathv and during exercise In 45 Left ven-
tncular a~ynergy was seen m 12patients at rest and 9 patients
dunng exercise Exercise-induced asynergy was not seen in
the group With cardiomyopathy
The effect of the ejection fraction at rest on the ejection
z
o
CARDIOMYOPATHY
CO RO NARY ARTE RYDIS EASE
(0' 48 )
(0 ' 2461
v<r 80
SU BGROUP II:SUBG ROU PI
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I
-=l
-..
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o
o o
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t
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o- cc rd.cc cotheten zc non
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><
w
20
40
60
91
80
RESTI NG EJECTION
20
40
FRACTION
60
80
/
Figure 1. Ejection fraction at rest and dunng exercise In 48 patients WIth nomschermc cardiomyopathy (left panel) and 246 patients With coro nary artery disea se and ejection fraction at rest less
than 0 50 (right panel ) POIntsappeanng below the
hne of idennty Indicate a decrease In ejection fracnon from rest to exerci se, pomts on or above the
lme represent no change or an Increase In ejection
fraction Two coronary artery disease subgroups are
separated for descnptive purposes accordmg to
ejection fraction at rest above or below 0 30
HIGGINBOTHAM ET AL
EXERCISE RESPONSE WITH CARDIAC DYSFUNCTION AT REST
92
r'- 26, pcO 001
I
tI
SUBGROUP][
+ 20
I-
U
I
I
I
+10
«
Z
. . .:... ...l;: -; :':
0
0
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• " ' .. I·~ ';'
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c:er:
••••
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10
20
30
40
50
RESTING EJECTION FRACTION
Figure 2, Relation between ejection fraction atrest and the change
m ejection fraction from rest to exercise (Il ejection fraction) m
patients with coronary artery disease and ejection fraction at rest
less than 0 50 An ejection fraction at rest of 0 30, used for separanon of the two subgroups, IS intermediate between the highest
and lowest values seen
Relation of ejection fraction change to severity of angina in patients with coronary artery disease. The dIStnbunon of subjects according to the seventy of angina was
Similar for the total group and each subgroup (Table 3) In
the total group, the proportion of patients m each functional
class was the same for patients whose ejection fraction decreased as for patients whose ejection fraction increased or
did not change (Fig 3) Separate analysis of subgroups I
and II revealed a lower incidence of class II angina m panents of subgroup II whose ejection fraction decreased durmg exercise (p < 001) No other significant differences
were seen
Relation of ejection fraction change to exercise response in patients with coronary artery disease, Chest
pam was seen m 32% and ST depression m 26% of the
JACC Vol 3 No I
January 1984 88-97
patients with coronary artery disease (Table 4) The mCIdence of chest pam and ST segment depression tended to
be lower m subgroup II than m subgroup I, but this difference was not significant There was a strong association
between exercise indexes of Ischemia and the directron of
ejection fraction change dunng exercise (Fig 4) Both chest
pam and ST depression occurred m a larger proportion of
patients whose ejection fraction decreased than m those
whose ejection fracnon did not decrease, these differences
were seen m the total group and in each subgroup Among
the 117 patients whose ejection fraction decreased dunng
exercise, the decrease was accornpamed by either chest pam
or ST segment depression in 79 patients (68%)
The data m Table 4 and Figure 4 also Illustratethe higher
incidence of a decrease m ejection fraction dunng exercise
compared with chest pam and ST depression The ejection
fraction decreased m 117 patients and chest pam occurred
m 79 patients and ST depression m 65 patients Whereas
63 (54%) of the 117 patients whose ejection fraction decreased had no ST depressron, only 12 (18%) of the 65
patients with ST depression had no decrease in ejection
fraction
Relation of ejection fraction change to anatomic extent of coronary artery disease, Table 5 lists the number
of diseased vessels in the total group and in each subgroup
The distnbution was comparable, approximately 50% of
each group having three vessel coronary artery disease
Figure 5 shows the directional change m ejection fraction
dunng exercise as a function of the number of diseased
vessels Patients whose ejection fraction decreased had a
higher prevalence of three vessel disease and a lower prevalence of one vessel disease than did patients whose ejection
fracnon increased or remained unchanged The prevalence
of two vessel disease tended to be lower m patients whose
ejection fraction decreased None of the 14 patients who
had single vessel coronary artery disease and ejection fracnon at rest of less than 0 30 (subgroup II) showed a further
reduction m ejection fraction dunng exercise
Table 2. Proportion of Patients With a Decrease m Ejection Fraction During Exercise, Related to Quality of End Pomt
Group
Cardiomyopathy
Coronary artery disease
Subgroup I
(REF 0 30 to 0 49) (n = 178)
Subgroup II
(REF < 0 30) (n = 68)
Adequate"
End Pomt
1P < 0001
4/25
1041194~
89/148
15/46
Inadequate*
End Pomt
0123
1P < 0001
13152~
Adequate vs
Inadequate
(p value)
0035
< 0001
11/31
0030
2121
0022
*Exerclse was defined as adequate when limited by chest pam or ST segment depression, or when 85% of the predicted maximal heart rate was
achieved Exercise was madequate when limited by fatigue before achievement of the target heart rate REF = ejecnon fraction at rest
HIGGINBOTHAM ET AL
EXERCISE RESPONSE WITH CARDIAC DYSFUNCTION AT REST
JACC Vol 3, No I
January 198488-97
Table 3. Distnbution of Patients With Coronary Artery
Disease and Ejection Fracnon at Rest Less Than 0 50,
Accordmg to Angina Class
NYHA
Angina
cause of the small number of patients In this subgroup
(p = 0 10)
Class
II
III
IV
Total patients
(n = 246)
9%
(21)
23%
(57)
22%
(53)
46%
(115)
Subgroup I
8%
(14)
25%
(44)
19%
(33)
48%
(87)
10%
(7)
24%
(16)
24%
(16)
42%
(29)
(REF 0 30
(n =
to 0 49)
178)
Subgroup II
<
(REF
(n
0 30)
= 68)
Numbers mparentheses represent numbers of patients NYHA
York Heart Associanon, other abbreviations as before
93
=
New
Relation of ejection fraction change to mortality in
patients with coronary artery disease. Twenty-six (17%)
of the 150 patients who were treated medically died dunng
the follow-up penod. Figures 6 and 7 relate survival to
ejection fraction at rest and dunng exercise The degree of
left ventncular dysfunction at rest was highly predictive of
mortality; 10% of the patients m subgroup I died compared
with 33% of those in subgroup II (p < 0 001)
The ejection fraction response to exercise was related to
survival In the total group (p = 0002) Fourteen deaths
(23%) occurred in the 61 patients whose ejection fraction
decreased dunng exercise compared with 12 (13%) of 89
patients whose ejection fraction increased or remained the
same In subgroup I, mortality was high among patients
whose ejection fraction decreased (9 l20%] of 50 patients),
by companson, only 1 (2%) of 51 patients whose ejection
fraction mcreased or was unchanged died dunng the followup penod (p = 0 008) Although ejection fraction at rest
was the major detenmnant of the high mortality In subgroup
II, 5 (45%) of 11 patients whose ejection fraction decreased
died compared with 11 (31%) of 38 patients whose ejection
fraction Increased, this difference was not significant be-
Mortality differences between these subgroups cannot be
explained by differences m age, mean age was between 50
and 52 years
Discussion
The uutial question addressed m this study was whether
the presence of ventncular dysfunction at rest predisposes
patients to a further decrease m function dunng exercise
stress, with a consequent reduction in ejection fraction ThIS
question IS potentially Important not only for patients with
coronary artery disease, but also for the assessment and
follow-up of patients with valvular heart disease For example, Borer et al (12) and Peter and Jones (16) showed
that the ejection fraction may decrease dunng exercise in
many patients with chronic aortic regurgitation and no eVIdence of left ventncular dysfunction at rest, It has been
suggested that this may represent mild left ventncular dysfunction which IS unmasked by the added stress of exercise
However, these Investigators have not excluded the pOSSIbihty that a decrease in ejection fraction in patients with
valvular regurgitation may reflect myocardial Ischemia or
changes m ventncular loading rather than bemg a marker
of left ventncular dysfunction
Role of ischemia in the ejection fraction decrease during exercise. If a decrease in ejection fraction dunng exercise IS related to myocardial dysfunction Itself, one might
expect It to be independent of commonly accepted indexes
of myocardial Ischemia, and generally proportional to the
degree of left ventncular dysfunction The findings of the
present study suggest that the opposite IS true In patients
with coronary artery disease, a decrease in ejection fraction
became less frequent as left ventncular dysfunction became
more severe, and It was related to cluneal and electrocardiographic Indexes of left ventncular Ischemia and multivessel coronary artery disease Furthermore, It occurred Infrequently In pattents WIth cardiomyopathy, who had left
g~ } (NYHA)
Angina Class
80
~m
~nz:
TOTAL GROUP
~
tj 60
z
UJ
~
L!.J
40
""
Cl.
20
EF.
N' 117
SUBGROUP I:
RESTING EF 30 - 49
SUBGROUP II:
RESTING EF < 30
Figure 3. Relation between New York Heart AsSOCiatIOn (N Y H A ) functional class and the ejecnon fraction response to exercise m patients with
coronary artery disease and ejection fraction at rest
less than 0 50 The prevalence of each angina class
was compared between patients whose ejection
fraction decreased dunng exercise (EF t) and patients whose ejection fraction increased or did not
change (EF i -) Compansons were made for the
total group. and for each subgroup separately Sigrnficant differences are indicated *p < 0 02 versus
EF t N = number of patients
94
HIGGIN BOTHAM ET AL
EXERCISE RESPONSE WITH CARDIAC DYSFUNCTION AT REST
Table 4. Incidence of Exertional Chest Pam and ST Depression
10 Patients With Coronary Artery Disease and Ejection Fracuon
at Rest Less Than 0 50
JACC Vol 3. No I
January 1984 88-97
Tab le 5. Distnbunon of Patients With Coronary Artery DIsease
and Ejection Fraction at Rest Less Than 0 50. According to the
Number of Diseased Vessels
Exercise Response
Number of Diseased Vessels
Chest Pam
ST Depression
Total patients
(n = 246 )
32 %
(79)
26 %
(65 )
Total patient s
246 )
Subgroup 1
(REF 0 30 to 0 49 )
34 %
(6 1)
29 %
(52 )
Subgroup 1
(REF 0 30 to 0 49)
(n
=
178 )
=
25 %
(17)
19%
(13)
68)
Figure 4. Relation between the ejection fracnon response to exercise and exercise-Induced chest pam (open columns) or ST
depression (hatc hed columns), or both. 10 patients With coronary
artery disease and ejection fraction at rest less than 0 50 Companson groups and abbreviatrons are Similar to Ihose 10 FIgure 3
Symbols denote sigmficant differences compared with EF ! (* p
< 0 02, **p < 00001. t p < 001 , ttp < 0 05)
o Chest Poon
r:lI ST Depressron
80
TOTAL GROU P
Ql
c
60
Ql
"'C
vc
40
~
20
=
3
23%
(56)
29 %
(7 1)
48 %
(119 )
24'*
(42)
31 %
(56 )
45 %
(80)
21 %
(14)
23 %
(16)
56 %
(38)
(7 8)
68)
Abbrevianons as before
ventncular dysfunction but a very low probabihty of developing ischemia The Increase In ejection fraction In most
patients WIth ca rdiomyopathy suggests that abnormal but
noruscherruc myocardium usually responds to the surnuh
accompanying exercise With an Increase In contracnhty
Therefore, the decrease In ejection fraction dunng exercise
that was seen In 117 of 246 patients with coronary artery
disease was more likely to represent myocardial ischemia
than a nonspecific decompensation dunng stress
Criteria for di a gn osing isch emia d u r ing exe rcise. The
ability to detect a subgroup of panents With a hig h hkehhood
of having reversible myocardial ischerrua may be Important
In selectmg appropnate populations for the study of medical
or surgical Interventions However, the cluneal utihty of a
test depends on ItS rehabihty In mdividual patients The
interpretanon of an indrvidual response IS always more dif-
100
=
Subgroup II
(REF < 0 30)
(n
Abbrevrations as before
u
=
(n
Subgroup II
(REF < 0 30)
(n
(n
2
SUBGROU PI
RE STINGEf 30-4 9
SUBGRO UP IT :
RESTI NG Ef < 30
ficult than the separation of subgroups, partly because of
the techmcal hrmtanons Inherent 10 a Single measurement
and partl y because of the vanabrhty of biologic responses
However, two relanvely specific cntena for diagnosing ischemia can be Inferred from the responses In our gro up WIth
cardiomyopathy The first cntenon IS a decrease In ejection
fract ion dunng subrnaximal level s of exercise which was
seen In 25 % of the patients WIth coronary artery disease but
In no patient WIth cardiomyopathy, the second IS a decrease
In ejection fraction by 0 05 or greater WhICh was seen In
28 % of the group WIth coronary disease but In only 2%, or
1 of the 48 patients WIth cardiomyopathy Although the
aSSOCIatIOn between ejection fracnon change , chest pain and
ST segment depression dunng exercise and the number of
diseased vessels strongly supported the Idea of an ischermc
rather than noms chemic mechamsm for a decrease In ejecnon fraction In the total group With coronary artery disease,
the weak correlations did not Improve the mterpretation of
mdividual responses
Coronary a rtery d isease versus cardi omyopathy . A
selected group of patients With cardiomyopathy was used
In the present stud y specifically as a model of left ventncular
dy sfunction In the absence of ischerrua We thought that
this would be the best available control group for determining the relation between rscherrna and the ejection fraction response However, the companson of patients With
cardiomyopathy and patients With coronary artery disease
may not be entirely valid , SInce It assumes that a ventncle
With segmental dysfunction should, In the absence of Ischemia , respond the same as a ventncle WIth diffuse dysfunction Although It IS possible that differences In ventncular disease may result In different responses to exercise
despite the same overall degree of dysfunction, this appears
unlikely
EF.
N '1 17
Because the patients WIth cardiomyopathy who did not
undergo cardiac cathetenzation were selected to exclude
either coronary artery disease or exercise-ind uced ischemia,
JACC Vol 3, No I
January 198488-97
HIGGINBOTHAM ET AL
EXERCISE RESPONSE WITH CARDIAC DYSFUNCTION AT REST
01}
~~
100
!!.
80
Number of
Diseased Vessels
SUBGROUP II:
RESTI NG EF < 30
SUBGROUP I:
RESTING EF 30 - 49
TOTAL GROUP
w
u
z
<t 60
>
w
t
w
C£:
o,
t
40
I"'
**
*1""
r
.
I"'
'"
20
I""
Figure 5. Relation between anatomic extent of
coronary artery disease and the ejection fraction
response to exercise 10 patients with coronary artery
disease and ejection fraction at rest less than 0 50
Companson groups and abbreviations are similar to
those 10 Figures 3 and 4 Significant differences
versus EF t are indicated (*p < 0 02, **p <
oom, tp
< 001)
'---
EF.
N' 117
EF'"
EF.
129
101
EF.
EF'"
77
16
our data do not necessanly charactenze the ejection fraction
responses In a representative population with cardiomyopathy It IS entirely possible that some patients excluded
from the study because of chest pam or ST segment depression dunng exercise In fact had normal coronary artenes,
and may have demonstrated a decrease In ejection fraction
Clearly, however, the response In such patIents could not
have been Interpreted as nomschermc Studies aimed at descnbmg the response In cardiomyopathy would require a
prospectIve design In which a consecutIve group of patients
underwent cardiac cathetenzatIon and radionuchde
angiography
Clinical and electrocardiographic features ofischemia.
These features are seen Infrequently In patIents with coronary artery disease and left ventncular dysfunction dunng
Figure 7. Survival curves for 150 medically treated patients with
coronary artery disease and ejection fraction at rest less than 0 50,
related to the direction of ejection fraction change from rest to
exercise A poorer survival IS seen for patients whose ejection
dunng exercise than for those 10 whom
fraction decreased (EF
It mcreased or did not decrease (EF i ~) This IS confirmed for
each coronary artery disease subgroup
t)
CORONARY ARTERY DISEASE
TOTAL GROUP
100
89
EFf-.
-~1 ,~-~~~~~-"'-... ------~2...--1._"\. 3-L
80
'--li----'-----,_____
EF. 24
--
T
Figure 6. Cumulative survival
150 medically treated patients
In
with coronary artery disease and ejection fraction at rest less than
related to the ejecuon fraction response to exercise Data
are represented as In Figure I
o 50,
CORONARY ARTERY DISEASE
FOLLOW-UP
Z
f=
SUBGROUP .IT: SUBGROUP I
.
u
<J:
Ct:
LL
./
60
I
I.
Z
0
f=
uw
w
V)
U
Ct:
w
><
w
/
~"'o':'1{
20
::.4' ••• J
0'1
•
)(
.0,0
/
0/
/
/
/
/
/
/
/
SUBGROUP II
100
38
/
y ..,'
.( ·I:J°· .
~
/0
/'.
/
/
.;to..
I ' /-.:
...,w 40
/
.,Y
JI":~.
/
/
I
.' ALIVE
0 ' DEAD
BO
.'
P
60
i
T
1
10 20 30 40 50 60
70 80 90
RESTING EJECTION FRACTION
!
10
20
_
-----14------
60
0 80
95
,
30
FOLLOW-UP (MONTHS)
;0
0.002
96
HIGGINBOTHAM ET AL
EXERCISE RESPONSE WITH CARDIAC DYSFUNCTION AT REST
exercise stress testing (8,9) In the present study, chest pam
occurred m only 32%, and ST segment depression m only
26% of patients dunng exercise, the mcidence was slightly
lower m the subgroup of patients with an ejection fraction
at rest of less than 0 30 The finding that neither chest pam
nor ST segment depression was observed m 38 of 117 patients whose ejection fraction decreased dunng exercise appears to support earlier observations (17, 18) that changes
m left ventncular function are more sensitive to Ischemia
than are either chmcal symptoms or the electrocardiogram
The development of new or additional wall monon abnormalities dunng exercise also was uncommon m patients with
coronary artery disease and left ventncular dysfunction (30
of 246 patients) This low incidence of exercise-induced
asynergy may have resulted from the assessment of wall
motion In a single (antenor) projection, and from the difficulty of resolving a change in wall motion In the presence
of extensive preexistmg wall motion abnormalities
The responses In our patients wrth coronary artery disease
show clearly that Ischemia cannot be predicted by coronary
anatomy alone The cluneal , electrocardiographic and radionuclide responses were heterogeneous whether patients had
one, two or three vessel disease, some patients with one
vessel disease appeared to develop Ischemia and some with
three vessel disease did not
Prognostic impUcations. Left ventncular function at rest
IS a strong and independent predictor of mortality in patients
with coronary artery disease (19-21) In a study mvolvmg
1,214 medically treated patients with coronary artery disease, Hams et al (21) demonstrated a 2 year mortality rate
of 5% In patients with normal left ventncular funcnon, 15%
in patients with moderate and 40% in patients with severe
left ventncular dysfunction In the present study, subgroups
I and II correspond to moderate and severe left ventncular
dysfunction, mortality rate at 2 years in these subgroups
was approximately to and 33%, respectIvely The ejection
fraction response to exercise provided sigmficant prognostic
mformation In the present study, especially m patients with
an ejection fraction at rest of 0 30 or greater (subgroup I),
only 1 (2%) of 51 patients m this subgroup whose ejection
fraction increased or remained unchanged dunng exercise
died dunng the follow-up penod compared with 9 (18 %)
of 50 patients whose ejection fraction decreased
As ejection fraction at rest was a strong predictor of the
high mortality in subgroup II, the Influence of the ejection
fraction response to exercise was of less prognostic Importance, a decrease In ejection fraction dunng exercise Identified patients in subgroup II with a mortality of 45% compared with 31 % In those patients whose ejection fraction
increased or did not change Although the Identification of
a group of patients with reversible myocardial Ischemia and
a poor prognosis while undergoing medical therapy has potentially Important therapeutic imphcations, further studies
will be needed to define whether the ejection fraction re-
JACC Vol 3. No I
January 1984 88-97
sponse to exercise has independent predictive value in addinon to other cluneal, nonmvasive and cardiac catheterizanon data
Conclusions. The results of this study indicate that m
patients With coronary artery disease and abnormal left ventncular function, a further decrease m ejection fraction durmg exercise IS more likely to represent Ischemia than a
nonspecific response of the ventncle to exercise stress, even
In the presence of severe left ventncular dysfunction Such
a decrease in ejection fraction IS related to multivessel coronary artery disease and mortality during long-term followup on medical therapy
We acknowledge Jaruce WIlson and Sharon Kamash for their assistance
m the collection of data, and Catlue Collins for her excellent secretanal
work
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EXERCISE RESPONSE WITH CARDIAC DYSFUNCTION AT REST
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