European Heart Journal (1997) 18, 1599-1605
Prognostic value of left ventricular volume response
during dobutamine stress echocardiography
C. Coletta, A. Galati, R. Ricci, A. Sestili, G. Guagnozzi, F. Re and V. Ceci
Department of Cardiology, S. Spirito Hospital, Rome, Italy
Aims An abnormal left ventricular volume response during
dobutamine echocardiography identified patients with
severe coronary artery disease. The aim of the study was to
assess the prognostic value of left ventricular volume
changes during dobutamine stress echocardiography in 136
patients.
Introduction
Pharmacological stress echocardiography is increasingly
being used to diagnose coronary artery disease, as a
complementary or alternative test in patients unable to
exercise or in the presence of an inconclusive exercise
ECG response1'"3'. Recently, dobutamine stress echocardiography has been found to be a reliable predictor
of unfavourable prognosis in patients with suspected'45'
or proven'6' coronary artery disease, and to be effective
in identifying patients with a strong probability of
peri-operative cardiac events during major vascular surgery'7'. The presence of inducible wall motion dyssynergies is needed for a positive result in dobutamine stress
echocardiography, while stress-induced angina and electrocardiographic abnormalities are considered ancillary
signs of ischaemia. Recent papers have evaluated the
anatomical and functional responses of the left ventricle
during dobutamine infusion in normal subjects'8"101 or in
patients without resting wall motion abnormalities'"'.
The relationship between an abnormal left ventricular
Revision submitted 11 April 1997, and accepted 25 April 1997.
Correspondence: Claudio Coletta, via Annia 26 00184 Rome, Italy.
0195-668X/97/101599+07 S18.00/0
Conclusion An abnormal end-diastolic volume response
during dobutamine stress echocardiography identifies
patients with an unfavourable outcome; they should be
considered for more accurate prognostic stratification.
(Eur Heart J 1997; 18: 1599-1605)
Key Words: Dobutamine echocardiography, left ventricular volume, prognosis.
volume response during dobutamine echocardiography
and a high probability of two- or three-vessel coronary
artery disease has been described'12'. Patients with multivessel coronary disease have a poor clinical outcome,
and left ventricular volume changes during dobutamine
infusion could provide useful prognostic information.
The aim of the study was to assess the role of the left
ventricular volume response during dobutamine stress
echocardiography, together with other clinical, electrocardiographic and echocardiographic parameters, in the
prognostic evaluation of patients with coronary heart
disease.
Methods
From June 1992 to December 1994, 294 consecutive
patients with known or suspected coronary artery disease scheduled for dobutamine echocardiography were
considered for the study. Patients with valvular heart
disease, congestive heart failure (NYHA III—IV class),
unstable angina, recent (<30 days) myocardial infarction complicated by angina, atrial fibrillation and left
bundle branch block were excluded. The study protocol
1997 The European Society of Cardiology
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Methods and results Endpoints were defined as spontaneous cardiac events at follow-up. Left ventricular
end-diastolic and end-systolic volume changes (abnormal
response: <10% and <20% decrease, respectively) were
compared with other clinical and stress test variables.
During 18 ±7 months of follow-up, 31 cardiac events
occurred: 12 hard events (cardiac death [n = 6], myocardial
infarction [n = 6]) and 19 soft events (unstable angina
[n = 16], congestive heart failure [n = 3]). End-diastolic volume response (/>=0006), diabetes (P=0008), inducible
wall motion abnormalities (/>=0024), end-systolic volume
response (P=0039) and inducible angina (/>=0-038) were
related to a greater likelihood of cardiac events. The Cox
regression analysis revealed end-diastolic volume response
(odds ratio: 30; CI 1-44-6-32) and diabetes (odds ratio: 2-7;
CI 1-28-5-69) to be independent predictors of spontaneous
cardiac events. Diabetes (odds ratio: 40; CI 1-26-12-80)
and <40% baseline ejection fraction (odds ratio: 2-21;
CI 1 -14—4-29) were independent predictors of hard events.
1600 C. Coletta et al.
The test was considered positive when wall motion
deteriorated one grade in at least two segments or two
grades in at least one segment; akinesia deteriorating to
dyskinesia was not considered for the result of the
test'14'. Agreement between the two observers was
required for test results to be interpreted as positive. In
case of disagreement, the judgement of a third observer
was conclusive. For each patient, the wall motion score
index (total score/16) at rest and peak stress and the
difference between the two values, as an index of severity
of ischaemia, were considered; in case of improvement,
the score of a resting abnormal segment was calculated
as unmodified. Finally, the rate-pressure product at the
onset of ischaemia was considered.
Dobutamine electrocardiography
The dobutamine stress ECG was interpreted as positive
for ischaemia if horizontal or downsloping ST segment
depression or elevation > 0 1 mV in at least two leads
with a normal baseline ST segment occurred. In case of
>0-5mV resting ST segment depression or elevation,
the ECG response was considered abnormal in the
presence of an increased ST segment shift >0-2 mV in at
least two leads. In patients with myocardial infarction,
ST segment elevation in Q leads was not considered a
positive criterion.
Dobutamine-atropine stress test
In resting conditions, a two-dimensional echocardiographic examination of the left ventricle was performed
using a wide-angle phased-array imaging system
(Hewlett Packard 77020, Sonos 1500 system) equipped
with a 2-25- or 3-5-MHz transducer and recorded on
SVHS videotape (Panasonic 7350 AG). A 12-lead ECG
was also recorded with the patient at rest. Dobutamine
was administered intravenously with an infusion pump,
starting at 5 ug . kg" ' body weight per min (stage I) and
increasing to 10 ug . kg" ' per min after 3 min (stage II)
and then incrementally every 3 min to 20 (stage III), 30
(stage IV) and 40 ug . kg" ' per min, and continued for
6 min (stage V). Atropine (0-25 to l-0mgi.v.) was
administered if heart rate at the 3rd min of stage V was
lower than the target level. During the test, the 12-lead
ECG was continuously monitored and recorded at the
end of each stage. Blood pressure was non-invasively
measured at rest and at each stage of the test. The
two-dimensional echocardiogram was continuously
monitored and recorded at rest and during the last
minute of each stage. As a rule, the infusion of
dobutamine was stopped in the presence of new wall
motion abnormalities.
Off-line analysis of echocardiographic images
was performed by two investigators in blind conditions.
The left ventricle was divided into 16 segments, and wall
motion in each was subjectively scored on a four-point
scale: 1= normal; 2 = hypokinetic; 3 = akinetic; 4=dyskinetic[13]; a reduction of systolic thickening was considered the only criterion for wall motion dyssynergy.
Eur Heart J, Vol. 18, October 1997
Left ventricular volume measurements
The apical two- and four-chamber views were reviewed
off-line for volume analysis by a single investigator in
blind conditions. End-diastolic and end-systolic volumes
were calculated at rest and at peak dobutamine infusion
using the biplane modified Simpson's formula'131 in the
frame coincident with the R wave (end-diastole) and in
the last frame before mitral valve opening (end-systole);
the procedure was performed on three consecutive beats
and the mean value was drawn. The percent changes
from baseline to peak infusion of end-diastolic and
end-systolic volumes were considered. Ejection fraction
values at rest and at peak dobutamine infusion and the
relative percent change were calculated. An abnormal
volume response was defined as a less than 10% decrease
in end-diastolic volume and as a less than 20% decrease
in end-systolic volume at peak dobutamine infusion; the
ejection fraction response was defined as abnormal in
the presence of a < 10% increase during the test. Alternative cut-off values were considered where defined
normality criteria were absent (end-diastolic volume:
<20% decrease; end-systolic volume: <30% decrease;
ejection fraction: <5% increase).
Variability analysis
Intra-observer variability, as regards calculation of left
ventricular volume, was assessed by the investigator in
the first 40 dobutamine stress tests of this study. At
baseline, mean percent variability values in two different
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was approved by the Hospital Ethics Committee, and all
patients gave written informed consent. In all patients,
beta-adrenergic blocking agents were withdrawn 48 h
and nitrates and calcium antagonists 24 h before the
study. Fifty-five patients had a prematurely interrupted
test in the absence of new wall motion abnormalities
(repetitive ventricular arrhythmias, >0-3 mV ST depression, systolic blood pressure fall >30mmHg, systolic
arterial pressure >220 mmHg, severe chest pain or
palpitations) and were excluded. Two hundred and
thirty-nine patients had a negative dobutamine stress
test at the end of the last stage or at the target heart rate
(220 - age x 0-85 in men; 200 - age x 0-85 in woman),
or a positive test for inducible wall motion abnormalities. In order to minimize technical problems, the
echocardiographic examinations, routinely recorded on
a SVHS tape, were reviewed by an experienced observer:
only 147 patients (62%) with a clear, complete endocardial definition in apical views were considered as
having optimal image quality and were admitted to the
follow-up study. In each patient, age, gender, clinical
history (myocardial infarction, angina), presence of
diabetes (need of long-term therapy), presence of hypertension (need of long-term treatment with antihypertensive drugs) and angina during the dobutamine stress test
were considered for subsequent analysis.
LV volume response during stress echo
blind evaluations performed 30 days apart for enddiastolic and end-systolic volumes were, respectively,
5 ± 4% and 5 ± 5%. At peak stress, mean percent values
were, respectively, 6 ± 4% and 7 ± 5%.
Follow-up data
Statistical analysis
Results are given as mean value ± SD. Relative differences were compared using the chi-square test with
Yates' correction, or the McNemar test when indicated.
Cumulative survival curves were calculated by means of
the product-limit method of Kaplan and Meier.
Statistical differences between curves were assessed with the log-rank or Mantel-Haenszel test. The
individual effect of variables on event-free survival was
evaluated with the use of the Cox regression model
(BMPD 2L, Department of Biomathematics, University
of California-Los Angeles, revised 1987), with an
unmodified forward-selection stepwise procedure. Variables selected were: age (continuous value), gender
(male/female), hypertension (yes/no), diabetes (yes/no),
history of myocardial infarction (yes/no), rest ejection
fraction (<40%; <50%), presence of rest wall motion
abnormalities (yes/no), rest wall motion score index
(<15; <2), inducible angina (yes/no), inducible ECG
abnormalities (yes/no), inducible wall motion abnormalities (yes/no), inducible wall motion abnormalities
at < 20-000 rate-pressure product (yes/no), >0-3 wall
motion score index peak-rest difference (yes/no), enddiastolic volume decrease (<10%; <20%), end-systolic
volume decrease (<20%; <30%) and ejection fraction
increase during the test (>10%; >5%). For multivariate
analysis, results are expressed as risk odds ratio. A
P value < 0-05 was considered statistically significant.
When appropriate, 95% confidence intervals (CI) are
described.
Results
One hundred and forty-seven patients had high-quality
echocardiograms and complete clinical and stress test
information. Of these, four were lost at follow-up and
seven underwent a coronary revascularization procedure
less than 6 months after admission to the study. Definite
follow-up information was available in 136 patients
(116 men, 20 women, mean age 61 years, range 33 to 75).
A history of myocardial infarction was present in 87
patients (64%): in 48 patients the myocardial infarction
was recent (35%; mean 18 ± 9 days); 49 patients (36%)
had stable angina. Hypertension was present in 60
patients (44%) and diabetes in 26 (19%).
Dobutamine stress echocat-diography
One hundred and three patients (76%) had wall motion
abnormalities at baseline echocardiography. Atropine
was administered in 43 patients (32%). New wall motion
abnormalities occurred in 68 patients (50%). Angina
during the test occurred in 41 patients (30%), and
inducible ECG abnormalities were observed in 31
patients.
Left ventricular volume response
An abnormal end-diastolic volume response was observed in 54 patients (40%); in 27 (20%) the volume
increased during the test. An abnormal end-diastolic
volume response was present in 43/68 patients with, and
in 11/68 patients without, inducible wall motion abnormalities (63% vs 16%; P<0001). An abnormal endsystolic volume response was observed in 47 patients
(35%); in 18 (13%) the volume increased during the test.
An abnormal end-systolic volume response was present
in 29/68 patients with, and in 18/68 patients without,
inducible wall motion abnormalities (43% vs 26%;
Cardiac events
Spontaneous cardiac events
During 18 ± 7 months of follow-up (range 1-44 months)
events occurred in 31 patients: 12 hard events (cardiac
death [n = 6], myocardial infarction [n = 6]) and 19 soft
events (unstable angina [n=16], congestive heart failure
[n = 3]).
Revascularization procedures
Twenty one revascularization procedures occurred during the follow-up (CABG: 15, PTCA: 6). Of these, eight
procedures (CABG: 6, PTCA: 2) were planned in the
absence of any spontaneous event.
Clinical and stress test variables vs events at
follow-up: univariate analysis
All events
Diabetes was the only clinical variable correlated with
spontaneous cardiac events. Eleven of 26 patients with
Eur Heart J, Vol. 18, October 1997
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Follow-up data were obtained from at least one of three
sources: (1) review of the patient's hospital record; (2)
communication with the patient's physician and review
of the patient's chart; (3) periodic outpatient clinical
evaluation. The outcome events were denned as: cardiac
death and non-fatal myocardial infarction for 'hard'
event-free survival; cardiac death, non-fatal myocardial
infarction, congestive heart failure with a >2 NYHA
class increase and unstable angina with ischaemic ECG
changes requiring hospital admission for spontaneously
occurring event-free survival. Only one event, the worst,
was considered in each patient. To avoid any possible
interference between test results and elective revascularization procedures, the follow-up times of patients
who had coronary revascularization procedures were
censored at the time of intervention. In the absence of
events, the minimum follow-up period accepted for the
study was 6 months.
1601
1602 C. Coletta et al.
Table 1 Sensitivity, specificity, positive predictive value
and negative predictive value of clinical and stress test
variables for spontaneous cardiac events
Variable
Diabetes
Inducible WMA
Inducible Angina
EDV Dec <10%
ESV Dec <20%
Sensitivity
Specificity
PPV
NPV
35%
68%
45%
65%
52%
86%
55%
75%
68%
70%
42%
31%
34%
37%
34%
82%
85%
82%
87%
83%
Dec=decrease; EDV=end-diastolic volume; ESV = end-systolic
volume; NPV = negative predictive value; PPV=positive predictive
value; WMA = wall motion abnormalities.
Hard events
Death or myocardial infarction occurred in five of 26
patients with, and in seven of 110 without, a history of
diabetes (P-0037; relative risk: 3-2). Five of 23 patients
with <40% and seven of 113 patients with >40%
baseline ejection fraction (P=Q-05; relative risk: 31) had
a hard event at follow-up. No other considered variables
were correlated with a higher probability of subsequent
hard events.
Cox stepwise regression analysis
All events
At stepwise regression analysis, an abnormal enddiastolic volume response during dobutamine stress test
Hard events
A history of diabetes (odds ratio: 402; 95% CI: 1-2612-80) and a less than 40% baseline ejection fraction
(odds ratio: 2-21; 95% CI: 1-14-4-29) were independent
predictors of cardiac death and non-fatal myocardial
infarction (Table 2).
Cardiac death
No clinical, baseline echocardiographic or stress test
variables were independent predictors of cardiac death
at follow-up.
Survival tables
Kaplan-Meier life tables of cardiac event-free survival in
relation to the response of end-diastolic volume and to
the presence of new wall motion abnormalities during
dobutamine stress tests are represented in Fig. 1. The
event-free survival rate at 36 months was significantly
higher in patients with a normal end-diastolic volume
response (a) and in patients without inducible wall
motion abnormalities (b).
Discussion
Several studies using dipyridamole or dobutamine stress
echocardiography have demonstrated that stressinduced ischaemia is associated with an adverse longterm outcome'15"201. The presence of inducible wall
motion abnormalities was always considered a positive
test result. In the present study, an abnormal decrease in
left ventricular end-diastolic volume during dobutamine
stress echocardiography was the most accurate predictor
of spontaneous cardiac events, both at univariate and
Cox multivariate regression analysis.
A left ventricular volume decrease during exercise echocardiography in normal subjects is a wellknown phenomenon'2'1, and a relationship between
an abnormal volume response during exercise and the
presence of residual coronary disease was observed in
revascularized patients'22'. In patients with multivessel
Table 2 Significant predictors of spontaneous cardiac events according to the Cox
stepwise regression model
All events
Variable
EDV Dec <10'Vo
Diabetes
Hard events
Odds Ratio
95% CI
Variable
Odds Ratio
95% CI
3 02
2-70
1-44-6-32
1-28-5-69
Diabetes
EF <40%
402
2-21
1-26-12-80
1-14-^-29
CI=confidence intervals: EF = baseline ejection fraction: other abbreviations as in Table 1.
Eur Heart J. Vol. 18, October 1997
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diabetes had a spontaneous cardiac event, in comparison
with 20/110 without (P=0008; relative risk: 2-3). An
adverse outcome was present in 20/54 patients with an
abnormal and in 11/82 patients with a normal enddiastolic volume response (/>=0006; relative risk: 2-8).
Twenty-one of 68 patients with, and 10/68 patients
without, new wall motion abnormalities (/*=0-025; relative risk: 21) had events at follow-up. An abnormal
end-systolic volume response (/>=0-039; relative risk:
20) and angina during dobutamine infusion (/>=OO38;
relative risk: 1-9) were the other variables related to a
higher probability of cardiac events. Values of sensitivity, specificity, positive and negative predictive values of
the aforementioned variables for spontaneous cardiac
events are represented in Table 1.
(odds ratio: 302; 95% CI: 1-44-6-32) and a history of
diabetes (odds ratio: 2-70; 95% CI: 1-28-5-69) were
independent predictors of spontaneous cardiac events
(Table 2).
L V volume response during stress echo 1603
(a)
100
90
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80
l
AAA
70
AA
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60
50
'AAAAA A
43%
40
30
20
10
18
24
30
36
42
(b)
GO
100
90 80
#
^AA
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*
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85%
AA
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70
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60 -
58%
50 40 30 20 10 1 , , , , , 1
12
1
18
1
24
Time (months)
1
30
1
36
| ,,
42
Figure 1 (a) Kaplan-Meier event-free survival curves in relation to normal/abnormal
left ventricular end-diastolic volume decrease during dobutamine stress echocardiography. •=end-diastolic volume decrease >10%, A = end-diastolic volume decrease <10%,
/ > <0-01. (b) Kaplan-Meier event-free survival curves in relation to the presence/absence
of inducible wall motion abnormalities during dobutamine stress echocardiography.
• = negative dobutamine stress echocardiography; • = positive dobutamine stress
echocardiography, /><0-01.
coronary disease, Aroesty et a/.'231 found an increase in
left ventricular end-diastolic pressure with abnormal
diastolic volume reduction preceding the appearance of
new wall motion abnormalities during pacing-induced
ischaemia. Perez et al.[24] first described an abnormal
decrease in left ventricular areas (end-diastole: <15%;
end-systole: <33%) during dobutamine stress test in a
group of patients with coronary artery disease. Olson
et al. found an abnormal end-diastolic volume change
during dobutamine stress echocardiography to be 100%
sensitive and 68% specific in the identification of patients
with multivessel disease'121. More recently, Dagianti
et al. failed to find a relationship between diastolic/
systolic volume index changes during dobutamine stress
tests and the presence of coronary disease'251, while in
patients with left main coronary disease Attenhofer et al.
observed a preserved volume reduction during dobutamine infusion'261. Therefore data are controversial,
but an abnormal response in left ventricular volume
seems more frequent in patients with multivessel disease,
and it could precede the onset of wall motion abnormalities during provocative stress tests. In a preliminary
report, Olson et al.l27\ in patients referred for dobutamine echocardiography, found that an abnormal
(<20%) decrease in end-diastolic volume at peak infusion was the only predictor of cardiac events (/>=0-02)
and cardiac death (P=0-004) at Cox multivariate regression analysis. In our study, an abnormal end-diastolic
Eur Heart J. Vol. 18, October 1997
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12
1604 C. Coletta et al.
volume response during dobutamine echocardiography
was significantly more frequent in patients with spontaneous cardiac events, while an abnormal end-systolic
volume response was a weak prognostic indicator. Endsystolic volume is related to the extension of inducible
wall motion abnormalities: the interruption of dobutamine infusion in the presence of new wall motion
abnormalities prevented further extension of ischaemia
and probably limited the value of such a variable as a
prognostic marker.
Hard events
Diabetes and baseline ejection fraction were significantly
predictive of cardiac death or myocardial infarction,
both at univariate and at Cox regression analysis, while
no stress test result was predictive of future hard events.
The reliability of the dobutamine stress test as an
indicator of death or reinfarction is controversial:
Kamaran et al.m found positive dobutamine echocardiography to be predictive of cardiac death in a group of
210 patients. Poldermans et a/.[5] described the absence
of correlation between a positive dobutamine stress test
and hard events in 430 patients, but in the subgroup of
patients with a normal resting wall motion the test was
predictive of cardiac death alone. Finally, in our study
no variable was predictive of cardiac death, but the low
number of events is the likely reason for this result.
Limitations of the study
Many patients were excluded from the study and the
results cannot be extrapolated to a general, unselected
population. However, a suboptimal acoustic window
was the prevailing criterion of exclusion, and this should
not constitute a selection bias. A high-quality echo
image was mandatory to minimize problems of left
ventricular volume calculation. The variability of our
study data were low enough for clinical application, but
the results need to be confirmed in patients whose echo
image quality is unselected. Coronary angiography was
performed in some patients, and the prognostic impact
of coronary artery disease was not analysed. However,
the aim of the study was to evaluate the prognostic value
of various non-invasive parameters; indications for
coronary angiography were questionable in the majority
of patients.
Eur Heart J, Vol. 18, October 1997
Dobutamine-atropine stress echocardiography has a
proven prognostic value and is a reasonable first-line
option in patients unable to exercise or with controversial ECG results. Our study demonstrated that an
abnormal left ventricular diastolic volume response during dobutamine stress echocardiography has an independent prognostic value, and could be helpful in predicting
cardiac events in patients with coronary heart disease.
We are grateful to Fulvia Seccareccia, MSc, for the invaluable
help in statistical analysis.
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