1. No category

Prognostic Value of Dobutamine Stress Myocardial Contrast Perfusion
Echocardiography
Jeane M. Tsutsui, Abdou Elhendy, James R. Anderson, Feng Xie, Anna C. McGrain
and Thomas R. Porter
Circulation 2005;112;1444-1450; originally published online Aug 29, 2005;
DOI: 10.1161/CIRCULATIONAHA.105.537134
Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX
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Imaging
Prognostic Value of Dobutamine Stress Myocardial Contrast
Perfusion Echocardiography
Jeane M. Tsutsui, MD; Abdou Elhendy, MD, PhD; James R. Anderson, PhD; Feng Xie, MD;
Anna C. McGrain, RN, BSN; Thomas R. Porter, MD
Background—Myocardial perfusion (MP) imaging with real-time contrast echocardiography (RTCE) improves the
sensitivity of dobutamine stress echocardiography for detecting coronary artery disease. Its prognostic value is
unknown. We sought to determine the value of MP and wall motion (WM) analysis during dobutamine stress
echocardiography in predicting the outcome of patients with known or suspected coronary artery disease.
Methods and Results—We retrospectively studied 788 patients with RTCE during dobutamine stress echocardiography
using intravenous commercially available contrast agents. The incremental prognostic value of MP imaging over clinical
risk factors and other echocardiographic data was examined through the use of a log-likelihood test (Cox model). During
a median follow-up of 20 months, 75 events (9.6%) occurred (58 deaths, 17 nonfatal myocardial infarctions). Abnormal
MP had significant incremental value over clinical factors, resting ejection fraction, and WM responses in predicting
events (P⬍0.001). By multivariate analysis, the independent predictors of death and nonfatal myocardial infarction were
resting left ventricular ejection fraction ⬍50% (relative risk [RR], 1.9; 95% CI, 1.2 to 3.2; P⫽0.01), hypercholesterolemia (RR, 0.5; 95% CI, 0.3 to 0.9; P⫽0.01), and abnormal MP (RR, 5.2; 95% CI, 3.0 to 9.0; P⬍0.0001). The 3-year
event free survival was 95% for patients with normal WM and MP, 82% for normal WM and abnormal MP, and 68%
for abnormal WM and MP.
Conclusion—MP imaging during dobutamine stress RTCE provides incremental prognostic information in patients with
known or suspected coronary artery disease. Patients with normal MP have a better outcome than patients with normal
WM. (Circulation. 2005;112:1444-1450.)
Key Words: coronary artery disease 䡲 echocardiography 䡲 exercise test 䡲 prognosis
T
he prognostic value of stress echocardiography has been
demonstrated in different patient populations.1– 6 Previous studies have shown that stress-induced wall motion
(WM) abnormalities predict future cardiac events. Recently,
the feasibility and accuracy of myocardial perfusion (MP)
imaging after intravenous ultrasound contrast during stress
echocardiography have been demonstrated.7–9 Among the
different myocardial contrast imaging modalities, real-time
contrast echocardiography (RTCE) has the advantage of
using a low mechanical index that minimizes microbubble
destruction, permitting the simultaneous evaluation of MP
and WM during stress echocardiography. MP analysis during
dobutamine stress RTCE has been shown to increase the
sensitivity and accuracy for detecting angiographically significant coronary artery disease (CAD) compared with WM
analysis.9 –12 However, the prognostic value of myocardial
contrast perfusion imaging has not been examined. In the
present study, we sought to determine the prognostic value of
MP during dobutamine stress RTCE in predicting death and
nonfatal myocardial infarction.
See p 1382
Methods
Patients
We retrospectively studied 922 consecutive patients with known or
suspected CAD who were referred for dobutamine stress RTCE
using commercially available contrast agents in our laboratory from
January 2000 to September 2003. Reasons for referral were evaluation of chest pain or dyspnea in 454 (58%), preoperative risk
assessment in 217 (27%), evaluation of multiple cardiac risk factors
in 94 (12%), or functional assessment after myocardial infarction in
23 (3%). The study was approved by the Institutional Review Board
of the University of Nebraska Medical Center, and all patients gave
informed consent. Follow-up was completed in September 2004.
Because the results of the dobutamine stress echocardiography
(DSE) may have influenced whether the patients had a revascularization procedure that could have altered their subsequent event rate,
any patient who underwent a revascularization procedure within 3
months of the DSE was excluded.13 Follow-up was not available in
57 patients (6%). Thus, the final population consisted of 788 patients
(387 men, 49%). Mean age was 62⫾14 years. Patients were followed
up for a median of 20 months (maximum, 51 months). Risk factors
Received January 18, 2005; revision received May 3, 2005; accepted May 23, 2005.
From the Department of Internal Medicine, Section of Cardiology (J.M.T., A.E., F.X., A.C.M., T.R.P.) and Department of Preventive and Societal
Medicine (J.R.A.), University of Nebraska Medical Center, Omaha, Neb.
Correspondence to Thomas R. Porter, MD, University of Nebraska Medical Center, 981165 Nebraska Medical Center, Omaha, NE 68198-1165. E-mail
trporter@unmc.edu
© 2005 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.105.537134
1444
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by on May 19, 2008
Tsutsui et al
for CAD were diabetes mellitus in 387 (49%), systemic hypertension
in 535 (68%), hypercholesterolemia in 406 (51%), and cigarette
smoking in 253 (32%). One hundred forty-nine patients (19%) had a
history of a previous myocardial infarction, 111 (14%) had previous
CABG, and 106 (13%) had previous percutaneous interventions.
Two hundred sixty-three patients (33%) were taking ␤-blockers, and
209 (27%) were taking calcium channel blockers. Diabetes mellitus
was defined as a fasting glucose level ⱖ140 mg/dL or the need for
insulin or oral hypoglycemic agents. Hypercholesterolemia was
defined as total cholesterol ⱖ200 mg/dL or treatment with lipidlowering medications. Hypertension was defined as blood pressure
ⱖ140/90 mm Hg or use of antihypertensive medication.
RTCE Study
RTCE was performed with the commercially available albuminencapsulated microbubble Optison (GEAmersham) or the lipidencapsulated microbubble Definity (Bristol-Myers Squibb Medical
Imaging, Inc). The doses of contrast used for the assessment of MP
were the same doses recommended for left ventricular opacification
during stress testing.14 Optison was injected in doses of 0.2 to 0.3 mL
and Definity in doses of 0.1 mL for each apical window, followed by
a 3- to 5-mL saline flush.
RTCE was performed with commercially available ultrasound
scanners (HDI 5000 and Sonos 5500, Philips Medical Systems, or
Sequoia 6.0, Siemens Acuson). Each is equipped with lowmechanical-index real-time pulse sequence schemes that deploy
either interpulse amplitude modulation or interpulse phase and
amplitude modulation.15 The systems were adjusted to achieve
optimal nonlinear signals at a mechanical index ⱕ0.3 and frame rate
ⱖ25 Hz. Time gain compensation and 2D gain settings were
adjusted to suppress any nonlinear signals from tissue before contrast
injection. Equipment settings were then kept unchanged throughout
the study. Perfusion images were obtained in the apical 4-, 2-, and
3-chamber views at baseline and at peak stress. The RTCE images
were digitally acquired after peak myocardial opacification until
disappearance of contrast from the myocardium. All images were
recorded on videotape and digitized in continuous-loop format for
side-by-side analysis.
Stress Protocol
Dobutamine was infused at a starting dose of 5 ␮g · kg⫺1 · min⫺1,
followed by increasing doses of 10, 20, 30, and 40 ␮g · kg⫺1 · min⫺1
to a maximal dose of 50 ␮g · kg⫺1 · min⫺1 in 3- to 5-minute stages.16
Atropine (up to 2 mg) was injected in patients without symptoms or
signs of myocardial ischemia to achieve 85% of the age-predicted
maximal heart rate, calculated as 220 minus age in years. Blood
pressure and cardiac rhythm were monitored before and during the
dobutamine infusion. Twelve-lead ECGs were obtained at 3-minute
intervals. The stress ECG was considered positive for ischemia in the
presence of horizontal or downsloping ST-segment depression ⬎0.1
mV at 0.06 seconds after the J point. End points of the stress test
were achievement of target heart rate (85% of age-predicted maximal
heart rate), maximal dobutamine/atropine doses, development of
severe or extensive WM abnormalities, ST elevation ⬎0.1 mV at an
interval of 80 ms after the J point in non–Q-wave leads, sustained
arrhythmias, severe chest pain, and intolerable side effects.17 The
dobutamine stress test was considered diagnostic if the target heart
rate and/or inducible abnormalities were detected by analysis of WM
or MP. The tests were considered nondiagnostic if the patients failed
to achieve the target heart rate without inducible WM or MP
abnormalities.
Prognostic Value of Contrast Echocardiography
1445
divided in 17 segments according to the recommendations of the
American Society of Echocardiography.20,21 MP and WM were
evaluated by an experienced observer. The interobserver agreement
of RTCE in our laboratory is 84% for MP (␬⫽0.63) and 91% for
WM (␬⫽0.64) analysis.9
The study was considered abnormal by segmental WM criteria if
there was a resting or new WM abnormality in ⱖ2 segments.10
Myocardial contrast enhancement was analyzed during the period of
myocardial opacification after each injection of contrast, after
attenuation from left ventricular cavity contrast had resolved. Resting images were compared side by side with stress images using
digitally captured cardiac cycles for each apical view. MP was
considered abnormal when ⱖ2 segments exhibited a perfusion
defect, defined as a transmural or subendocardial decrease in contrast
enhancement. Patients with normal MP at both baseline and peak
stress were classified as having a normal MP study. Patients with
normal MP at baseline and a new perfusion defect with stress were
classified as having an inducible perfusion defect. Patients with a
perfusion defect at baseline associated with WM abnormality without extension observed at peak dobutamine stress were classified as
having a fixed perfusion defect, and those with a resting perfusion
abnormality who developed a new perfusion defect in other segments
were characterized as having fixed plus inducible perfusion defects.
Artifacts resulting from contrast or lung interference were considered
present if the endocardial and epicardial borders of a segment could
not be visualized and thus were not distinguishable from surrounding
tissues.9 Thus, a transmural defect was only considered present when
ⱖ2 segments exhibited a decrease in contrast enhancement but both
the endocardial and epicardial borders were still evident. WM
response was also described with these same criteria. In addition,
patients with a biphasic response of WM in segments with resting
abnormalities were considered to have both resting and inducible
WM abnormalities.
Patients were classified according to the extent of abnormality.
They were considered to have single-vessel abnormality when the
perfusion defect or WM abnormality involved only 1 coronary artery
territory and multivessel abnormality when the perfusion defect or
WM abnormality involved ⬎1 coronary artery territory. The left
ventricular apex, anteroseptal, distal septum, and anterior walls were
assigned to the left anterior descending coronary artery, the lateral
wall to the left circumflex, and the inferior wall and basal septum to
the right coronary artery. The posterior wall was considered an
overlap zone that could be assigned to either right coronary or left
circumflex artery.10 The results of both MP and WM analyses were
made available to the referring physicians.
Follow-Up
Follow-up was obtained by review of the patient’s hospital chart,
electronic records, and telephone interview with the patient. The
study end points were death from any cause and nonfatal myocardial
infarction.
Cardiac death was defined as death associated with known or
suspected myocardial infarction, life-threatening arrhythmia, or pulmonary edema. Sudden unexpected death occurring without another
explanation was included as cardiac death. Nonfatal myocardial
infarction was defined by means of a serial increase in cardiac
specific enzymes and/or development of new ECG changes. Patients
who underwent revascularization within 3 months after RTCE were
excluded. Patients who underwent CABG and percutaneous coronary intervention ⬎3 months after RTCE were censored at the time
of revascularization.
Statistical Analysis
Image Analysis
Baseline left ventricular ejection fraction was visually estimated after
review of contrast enhanced images. Ejection fractions estimated to
be ⬍50% were confirmed by the biplane Simpson’s formula using
contrast enhanced images to delineate endocardial borders.18,19
Patients were considered to have normal left ventricular function
when ejection fraction was ⱖ50% and abnormal left ventricular
function when ejection fraction was ⬍50%. The left ventricle was
Continuous variables are expressed as mean and SD; categorical
variables are expressed as proportions. The concordance of WM and
MP analyses during dobutamine stress RTCE was calculated as the
percentage of agreement and ␬ statistics. Kaplan-Meier curves were
used to estimate the distribution of time to death or nonfatal
myocardial infarction. The Cox model was used to estimate the
relative risk (RR) of events for each variable. Differences between
time-to-event curves were compared with the log-rank test. Age and
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Circulation
September 6, 2005
left ventricular ejection fraction were analyzed as qualitative variables because of their varying clinical significance at different cutoff
values. Additional clinical variables considered for both univariate
and multivariate analyses were defined according to the Framingham
risk score assessment.22 They included diabetes, hypercholesterolemia, and hypertension. Additional clinical variables included a
history of prior myocardial infarction. Echocardiographic parameters
were ejection fraction and WM and MP responses to dobutamine.
Multivariate predictors of events were determined by the Cox
proportional-hazards model. The incremental value of stress echocardiographic information over clinical data was assessed in 4
modeling steps. The first step consisted of fitting a multivariate
model of only clinical data. Baseline left ventricular ejection fraction
was then added to this model, followed by WM (normal versus
abnormal) and then MP data (normal or abnormal). The significance
of adding additional variables to previous modeling steps was based
on the change in model-based likelihood statistics, with degrees of
freedom equal to the number of additional variables. A value of
P⬍0.05 was considered significant.
Results
The mean maximal dose of dobutamine was 32⫾9 ␮g · kg⫺1
· min⫺1. Atropine was injected in 83% of patients with a mean
cumulative dose of 0.7⫾0.6 mg. Heart rate increased from
75⫾13 bpm at baseline to 145⫾13 bpm at peak stress
(P⬍0.001), and the rate-pressure product increased from
11 065⫾2950 mm Hg/min at baseline to 20 762⫾
5770 mm Hg/min at peak stress (P⬍0.0001). The mean
percentage maximal predicted heart rate achieved at peak
stress was 91⫾11%. Target heart rate was achieved in 701
patients (89%). The contrast agent Optison was used in 575
patients (73%). The mean cumulative dose was 2.8⫾0.9 mL.
Definity was used in 213 patients (27%). The mean cumulative dose was 1.1⫾0.4 mL.
The mean left ventricular ejection fraction was
58⫾12%. There were 131 patients (17%) with baseline left
ventricular ejection fraction ⬍50%; among them, 41 had
ejection fraction ⬍30%. Seventy-seven patients had either
percutaneous revascularization (n⫽51) or bypass surgery
(n⫽26) within 3 months of the DSE. Two of these patients
had normal WM and MP responses to DSE, 21 had normal
WM and abnormal MP, and 54 had both abnormal WM and
MP responses during DSE.
In the remaining patients, the stress echocardiogram was
interpreted as normal for WM in 587 patients (74%) and
abnormal in 201 patients (26%). MP was interpreted as
normal in 462 patients (59%) and abnormal in 326 (41%).
WM and MP analyses were concordant in 663 patients (84%;
␬⫽0.65). Both tests were normal in 462 and abnormal in 201
patients. There were 125 patients (16%) with normal WM but
abnormal MP. All patients with abnormal WM also had
abnormal MP. The distributions of the results of WM and MP
analysis are presented in Table 1.
Myocardial revascularization was performed in 84 patients
(29 CABG, 55 percutaneous coronary interventions) ⬎3
months after the stress test. Of these patients, 10 had normal
WM and MP (2% of all normal WM and MP studies), 29 had
normal WM but abnormal MP (23% of all normal WM but
abnormal MP studies), and 45 had both abnormal WM and
abnormal MP (22% of all abnormal WM and MP studies).
These patients were censored at the time of revascularization.
TABLE 1. Distribution of WM and MP Results in the
Study Population
Results
WM, n (%)
MP, n (%)
P
Normal
587 (74)
462 (59)
⬍0.0001
Abnormal
201 (26)
326 (41)
Inducible
82 (11)
215 (27)
Fixed
63 (8)
41 (5)
Fixed plus inducible
56 (7)
70 (9)
126 (16)
196 (25)
75 (10)
130 (16)
Type of abnormalities
⬍0.0001
Extent of abnormalities
Single vessel
Multivessel
⬍0.0001
Predictors of Death or Nonfatal
Myocardial Infarction
The median follow-up for patients who did not experience an
event was 19.9 months. A total of 75 (9.6%) patients had
events during the follow-up. Events occurred at a median of
12 months (range, 1 day to 46 months) after the dobutamine
stress test and included death in 58 patients (cardiac in 30
patients) and nonfatal myocardial infarction in 17 patients.
The clinical characteristics of patients with and without
subsequent events are presented in Table 2. No differences in
hemodynamic or ECG responses to dobutamine stress were
observed between patients with or without events (Table 3).
Outcome According to Extent and Type of
Perfusion Defect
The outcome of patients according to the type of perfusion
defect is depicted in Figure 1. The 3-year event-free survival
was 95% in patients with normal MP, 86% in patients with
fixed perfusion defects, 84% in patients with inducible
perfusion defects (both P⬍0.001 versus normal perfusion),
and 41% in patients with both fixed plus inducible perfusion
defects (P⬍0.001 versus other groups).
TABLE 2. Clinical Features of Patients With and Without
Subsequent Events
Patients Without
Events, n (%)
(n⫽713)
Patients With
Events, n (%)
(n⫽75)
Male gender
345 (48)
42 (56)
Hypertension
490 (69)
45 (60)
Cigarette smoking
228 (32)
25 (33)
Hypercholesterolemia
372 (52)
34 (45)
Diabetes mellitus
238 (33)
26 (35)
Previous myocardial infarction
Variables
123 (17)
26 (35)*
Previous CABG
91 (13)
20 (27)*
Previous percutaneous coronary intervention
91 (13)
15 (20)
␤-Blockers
322 (45)
41 (54)
Calcium channel blockers
194 (27)
15 (20)
Medications
Data are mean⫾SD.
*P⬍0.05 by log-rank test (see Table 5 for details).
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Tsutsui et al
TABLE 3. Dobutamine Stress Test Data in Patients With and
Without Events
Variables
Patients Without
Events (n⫽713)
Prognostic Value of Contrast Echocardiography
1447
TABLE 4. Annual Event Rate During 3-Year Follow-Up
According to WM and MP Results
Patients With
Events (n⫽75)
Cumulative Event Rate at
Follow-Up Intervals, %
Dobutamine dose, ␮g 䡠 kg⫺1 䡠 min⫺1
31⫾8
32⫾8
Pattern
1y
2y
3y
Atropine dose, mg
0.7⫾0.6
0.7⫾0.6
Normal MP
3
5
5
12
20
27
75⫾13
78⫾16
6
14
15
148⫾27
146⫾35
20
28
44
11 046⫾2895
11 250⫾3454
3
5
5
6
15
18
Heart rate, bpm
145⫾13
142⫾15
15
23
32
Systolic blood pressure, mm Hg
144⫾36
144⫾40
20 850⫾5714
19 886⫾6280
Baseline
Heart rate, bpm
Systolic blood pressure, mm Hg
Rate-pressure product, mm Hg/min
Abnormal MP
Peak stress
Rate-pressure product, mm Hg/min
Predicted maximal heart rate, %
ST depression ⬎0.1 mV, n (%)
Single vessel
Multivessel
Normal WM and MP
Normal WM and abnormal MP
91⫾10
91⫾12
54 (8)
8 (11)
Data are mean⫾SD.
The territorial extent of perfusion defect was an additional
determinant of prognosis (Figure 2). The 3-year event-free
survival was 85% in patients with a single-vessel perfusion
defect and 56% in patients with multivessel perfusion defects
(P⬍0.001). The cumulative event rate for each pattern of
abnormality is demonstrated in Table 4. The Kaplan-Meier
curves of event-free survival according to the results of WM
and MP are illustrated in Figure 3. The 3-year event-free
survival was 95% in patients with normal WM and MP, 82%
in patients with normal WM but abnormal MP, and 68% in
those patients with abnormal WM and MP. This difference in
event-free survival was significant between each of the 3
groups. The 3-year cumulative event rate in all patients who
had normal WM was estimated to be 7.3%. For the 78% of
these patients who also had normal MP, the 3-year cumulative event rate was 4.5%. Therefore, this group had nearly a
3% lower event rate over the three year period when
compared with the total population of patients with normal
WM studies.
Figure 1. Kaplan-Meier curves of patients with normal MP, fixed
perfusion defects, inducible perfusion defects, and fixed plus
inducible perfusion defects. The difference between curves is
statistically significant (P⬍0.001).
Abnormal WM and MP
Incremental Value of WM and MP for Predicting
Death and Nonfatal Infarction
Table 5 presents the univariate and multivariate predictors of
follow-up events. By univariate analysis, the predictors of
events were previous CABG, previous myocardial infarction,
resting left ventricular ejection fraction ⬍50%, abnormal
WM, and abnormal MP. By multivariate analysis, the only
independent predictors of events were hypercholesterolemia
(RR, 0.5; 95% CI, 0.3 to 0.9), left ventricular ejection fraction
⬍50% (RR, 1.9; 95% CI, 1.2 to 3.2), and an abnormal MP
(RR, 5.2; 95% CI, 3.0 to 9.0). After adjustment for MP, the
analysis of WM no longer had predictive value. Although
hypercholesterolemia was not a significant univariate predictor, it had a protective effect in the multivariate analysis. One
reason was a higher prevalence of hypercholesterolemia in
patients with abnormal MP (60%) than in those with normal
MP (40%). Assessment of the predictive value of clinical and
echocardiographic variables to predict exclusively cardiac
events (cardiac death or nonfatal myocardial infarction)
showed that the only independent predictor of these events
was abnormal MP (RR, 9.0; 95% CI, 3.1 to 26.3; P⬍0.0001).
The sensitivity and specificity of MP for the prediction of
death or nonfatal MI at 2 years were 72% and 63%,
respectively, compared with 54% and 73% for WM analysis.
Sequential Cox regression models were fit to test the
incremental value of MP analysis over clinical and echocardiographic variables (Figure 4). The presence of left ventric-
Figure 2. Kaplan-Meier curves of patients with normal MP and
abnormal MP according to the vascular extent of perfusion
defect. Differences between curves are statistically significant
(P⬍0.001).
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September 6, 2005
TABLE 5. Predictors of Death or Nonfatal Myocardial Infarction by Univariate
and Multivariate Analyses
Univariate
Multivariate
Variables
RR (95% CI)
P
Age ⬎70 y
1.6 (1.0–2.5)
0.05
Hypercholesterolemia
0.8 (0.5–1.2)
0.27
Hypertension
0.7 (0.4–1.1)
0.15
Diabetes mellitus
1.1 (0.7–1.7)
0.81
NS
Previous CABG
2.5 (1.5–4.2)
0.0003
NS
Previous myocardial infarction
2.2 (1.4–3.6)
0.0008
NS
Ejection fraction ⬍50%
1.9 (0.9–4.2)
⬍0.0001
Abnormal WM
4.1 (2.6–6.5)
⬍0.0001
Abnormal MP
5.3 (3.1–9.1)
⬍0.0001
ular ejection fraction ⬍50% increased the likelihood of death
or nonfatal infarction over the analysis of clinical variables
(␹2⫽8.9; P⬍0.005). Abnormal WM at dobutamine stress
RTCE increased the ␹2 of 16.3 compared with left ventricular
ejection fraction ⬍50% and clinical data (P⬍0.001). However, the addition of abnormal MP to all of these variables
added significant incremental value in predicting outcome
(␹2⫽42.7; P⬍0.001).
Discussion
In this study, we compared the ability of 2 different imaging
techniques during dobutamine stress to predict outcome and
demonstrated an incremental value of MP imaging over WM
analysis in predicting outcome in patients with known or
suspected CAD. MP abnormalities were independently predictive of death and nonfatal myocardial infarction. A normal
MP response during DSE identified a low-risk patient group
with a better outcome than patients with normal WM.
Several studies have demonstrated the prognostic value of
WM analysis during DSE.3,4,23–29 Our 3-year event-free
survival of 7.3% after a negative WM response is similar to
what was observed in these studies, in which normal WM
responses to dobutamine were associated with annualized
mortality rates up to 8% and cardiac event rates up to
Figure 3. Kaplan-Meier curves based on the combination of
WM and MP data. Differences between curves are statistically
significant (P⬍0.001).
RR (95% CI)
P
NS
0.5 (0.3–0.9)
0.01
NS
1.9 (1.2–3.2)
0.01
5.2 (3.0–9.0)
⬍0.0001
NS
3.6%.3,4,23–29 Annualized rates of death or nonfatal myocardial infarction after a negative dobutamine sestamibi SPECT
have ranged from 0.7% to 1.5%,30 –32 with higher event rates
when outcomes other than death or infarction are included.27
In all these studies, disease prevalence varied significantly,
which played a major role in positive or negative predictive
value of the test. In only 1 study was there a direct
comparison of an MP imaging technique (radionuclide
SPECT) and WM by echocardiography in the same patients.27
In this study, there were no differences in cardiac death (0.6%
to 0.7%) or cardiac event rates (3.3% to 3.6%) in patients
with normal SPECT versus normal WM responses. However,
an abnormal study (WM or MP) was seen in ⬎60% of the
patients compared with 41% with abnormal perfusion and
26% with abnormal WM responses in our study. Thus, at
higher disease prevalence rates, the additive predictive value
of perfusion over WM in predicting outcome may not be as
great as observed in our study.
Role of MP and WM Imaging With RTCE in
Predicting Events
The present study is the first to evaluate the role of RTCE as
a prognostic tool in patients with known or suspected CAD.
Figure 4. Incremental values (expressed on y axis as ␹2 values
with incremental degrees of freedom) of left ventricular ejection
fraction (EF), abnormal WM, and abnormal MP over the clinical
variables using a Cox model.
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Tsutsui et al
RTCE has advantages over myocardial scintigraphy, including no irradiation, higher resolution, shorter test duration,
immediate availability of results, the ability to perform stress
and rest images in the same setting, and the ability to have
real-time imaging of both MP and WM.
Studies comparing dobutamine stress RTCE with quantitative angiography have demonstrated a significant improvement in test sensitivity with MP imaging over WM analysis
and greater accuracy in identifying multivessel CAD.9,10,33
Therefore, MP imaging during dobutamine stress RTCE
appears better than WM analysis at identifying the amount of
myocardium at risk, a marker that consistently outperforms
other variables in predicting hard event rates.34,35 This was
affirmed in our study in that patients with a multivessel
pattern of perfusion abnormalities had the lowest event-free
survival of all patients in the study.
Despite the incremental value of MP imaging during
RTCE, our study indicates that assessing both WM and MP
during dobutamine stress is helpful in determining risk. First,
the Cox sequential regression model indicated that both WM
and MP analyses added significant value to the prediction of
outcome. Second, patients with both WM and MP abnormalities had the worst prognosis, indicating improved specificity
for the prediction of events when results of both techniques
are abnormal.
Using RTCE to evaluate WM and MP is a recently
developed technique; interpretation of results requires some
degree of expertise. MP was based on the analysis of
myocardial contrast enhancement after bolus injection of
contrast agents, which reflects the myocardial blood volume.
Although the analysis of microbubble kinetics using
destruction-replenishment sequences during a continuous infusion of contrast permits the analysis of myocardial blood
flow changes,11,36 we have previously demonstrated that the
analysis of myocardial blood volume with RTCE during
dobutamine stress is highly feasible and accurate for detecting angiographically significant CAD.9,10 Because WM during RTCE is analyzed at frame rates of 25 to 30 Hz, more
subtle WM abnormalities like tardokinesis may not have been
identified at these frame rates.37
However, the contrast-enhanced WM analysis performed
in our study has the advantage of permitting a better delineation of endocardial borders and detection of WM abnormalities. Contrast-enhanced WM scoring has been demonstrated to be superior to non– contrast-enhanced WM
compared with MRI.18,19 We have recently compared the
ability of WM analyzed with high-mechanical-index harmonic imaging at frame rates ⬎60 Hz without contrast
against low-mechanical-index RTCE with intravenous ultrasound contrast during DSE to detect ⬎50% diameter stenoses.38 In this study, the sensitivity of the 2 WM analysis
methods were not significantly different (33% without contrast, 40% with contrast). The sensitivities of both WM
techniques in this pilot study were 30% lower than MP
imaging.
Study Limitations
We censored patients who underwent revascularization after
the stress testing. Although we may have eliminated patients
Prognostic Value of Contrast Echocardiography
1449
who were more likely to have events, most of these patients
had abnormal MP and were evenly distributed between those
with normal WM and those with abnormal WM. Therefore,
the error incurred by not including these patients would have
been to underestimate the predictive value of assessing MP
during dobutamine stress RTCE.
Although abnormal MP during dobutamine stress echocardiography was the most significant independent predictor of
events, hypercholesterolemia and reduced ejection fraction
were significant predictors as well. The prognostic importance of ejection fraction is well known. The reason for the
association of hypercholesterolemia with reduced risk of
events is unclear. Although hyperlipidemia was not a significant univariate predictor, it had a protective effect in the
multivariate analysis. This phenomenon appears to have
occurred because there was a higher prevalence of hypercholesterolemia in patients with abnormal MP (60%) than in
those with normal MP (40%), resulting in a confounding of
the univariate comparison. Also, because we defined hypercholesterolemia to include patients who were on lipidlowering agents, the protective benefits of these agents in
patients with abnormal MP may have resulted in a proportionately better outcome in the patients with abnormal MP
studies.
Finally, our results are based on the analysis of studies in
a single center. Larger multicenter studies are necessary to
address the feasibility and reproducibility of this technique.
Conclusions
MP analysis during dobutamine stress RTCE provides independent information for predicting mortality and nonfatal
myocardial infarction in patients with known or suspected
CAD after adjustment for clinical data, ejection fraction, and
WM analysis. The extent of perfusion defects predicts outcome. Patients with abnormal WM and MP are at higher risk
for hard events. A normal MP study is associated with better
survival than a normal WM study.
Disclosure
Dr Porter has received grant support from and worked as a consultant
for ImaRx Therapeutics, Inc, Tucson, Ariz, and has received grant
support from Bristol-Myers Squibb Medical Imaging, North Billerica, Mass, and AVI BioPharma, Inc, Corvallis, Ore.
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