(Circulation. 2000;101:1255.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Enoximone Echocardiography for Predicting Recovery of Left Ventricular Dysfunction After Revascularization
A Novel Test for Detecting Myocardial Viability
Presented at the 70th scientific Sessions of the American Heart Association, Orlando, Florida, November 9–12, 1997.
From the Department of Cardiovascular Sciences, Istituto Scientifico/Università San Raffaele, Milan, Italy.
Correspondence to Chunzeng Lu, MD, PhD, Dept of Cardiovascular Sciences, Istituto Scientifico/University of San Raffaele, Via Olgettina 60, 20132 Milan, Italy. E-mail lu.chunzeng{at}hsr.it
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Abstract |
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Background—The possibility that enoximone, a nonglycoside, noncatechol, positive inotropic agent, in combination with 2-dimensional echocardiography may predict recovery of myocardial dysfunction after revascularization has not been yet evaluated.
Methods and Results—Forty-five patients with chronic
coronary artery disease and left ventricular
dysfunction underwent dobutamine (DE, 5 to 10 µg ·
kg-1 · min-1) and enoximone (EE, 1.5
mg/kg, over 10 minutes) echocardiography.
Myocardial wall motion was scored from 1 (normal) to 4 (dyskinesia): an
asynergic segment was considered to have contractile enhancement when
the score decreased by 
1 grade. Of 478 asynergic segments, 216 (45%)
exhibited functional recovery after
revascularization. Dobutamine- and
enoximone-induced contractile enhancement was observed in 41% and 46%
of segments, respectively. Compared with DE, EE had higher sensitivity
(88% versus 79%, P<0.01) and negative predictive
value (90% versus 84%, P<0.05) in predicting
functional recovery. The specificity (89% versus 90%) and positive
predictive value (87% for both EE and DE) were similar. Concordant
interpretation of EE and DE findings was found in 85% (406 of 478) of
affected segments. Prerevascularization
coronary angiography showed that stenosis severity of
vessels supplying areas which only improved with enoximone was
significantly greater (89.9%) than that of vessels (77.7%) supplying
areas that responded to both agents (P<0.02). Both
dobutamine and enoximone increased heart rate (16% and
10%, respectively), whereas enoximone did not cause changes in
systolic blood pressure that increased by 14% with
dobutamine.
Conclusions—Enoximone echocardiography provides a novel and reliable approach for the prediction of functional recovery after revascularization. Compared with dobutamine echocardiography, the test yields higher sensitivity and induces lesser hemodynamic alterations.
Key Words: echocardiography • dobutamine • enoximone • myocardial viability
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Introduction |
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The potential reversibility of chronic ischemic myocardial dysfunction is now well established, but the question remains about which tools available to most clinical centers are both reliable and cost effective.1 2 Positron emission tomography imaging of myocardial glucose utilization is a sensitive and accurate modality for identifying myocardial viability,3 4 but the technique is time-consuming, expensive, and only available to a few clinical centers. Thallium-201 single-photon emission computed tomography yields the highest sensitivity for detecting viability and is cost-effective and widely available for clinical use.1 5 However, this technique may lack specificity and overestimate the probability of functional recovery.6 7 8 More recently, the presence of contractile reserve as shown by improved function during dobutamine infusion has been proposed as a more suitable alternative.9 10 11 However, the inotropic response to adrenergic stimulation is attenuated in patients receiving ß-adrenoceptor blockers. Furthermore, in the presence of critical coronary stenosis, dobutamine, even at low doses, can sometimes induce ischemia that might mask a hibernating state by preventing the improvement of wall motion.12 13 14
Enoximone, a nonglycoside, noncatechol, positive inotropic agent that acts via selective inhibition of the cyclic adenosine monophosphate-specific phosphodiesterase, is widely used for the treatment of heart failure. This agent has also been shown not to increase myocardial oxygen demand15 16 17 18 and could represent a valid alternative for the detection of viable myocardium by means of 2-dimensional echocardiography.
The aim of the present study was to evaluate the sensitivity, specificity, tolerability, and safety of enoximone echocardiography (EE) for predicting functional recovery after revascularization. The optimal infusion modalities were also investigated and the results compared with those obtained with dobutamine echocardiography (DE).
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Methods |
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Study Population
We selected patients with chronic coronary artery disease and left ventricular dysfunction elected to percutaneous or surgical myocardial revascularization. Inclusion criteria were an ejection fraction of
45% on contrast ventriculography, the presence
of 2 or more akinetic or hypokinetic segments on resting
echocardiography, the absence of recent episodes of
unstable angina, and the absence of hemodynamically
significant valvular disease.
Forty-five patients (41 males) constituted the final study population:
their mean age was 59±10 years (range 35 to 75 years) and mean
angiographic left ventricular ejection fraction was 36%
(range 18% to 45%). One-vessel disease, defined as diameter
stenosis of at least 50%, was present in 12 patients; 13
patients had 2-vessel disease; and 20 had 3-vessel disease. Twenty-nine
patients had a previous myocardial infarction (9.7±8.6 months before
the study). In 19 patients, all medications were discontinued 48
hours before the echocardiographic study; the other 26
patients were examined while still receiving antianginal therapy, but
ß-adrenergic blocking agents were withdrawn at least 48 hours before
the study. Percutaneous transluminal
coronary angioplasty was performed in 21 patients and 24
underwent coronary artery bypass grafting.
Echocardiographic Protocol
Each patient underwent DE or EE within 1 week before
revascularization. The test sequence varied, but
normally DE was performed before EE in a separate session (>4 hours).
All patients gave written informed consent.
DE was performed using a low-dose protocol. Echocardiographic imaging was performed at baseline and during intravenous infusion of dobutamine (5 to 10 µg · kg-1 · min-1). Each step lasted 5 minutes. EE was performed using a dose of 1.5 mg/kg. Enoximone, diluted with saline to a concentration of 2.5 mg/mL, was infused over 10 minutes. The maximum infusion rate did not exceed 12.5 mg/min in order to avoid venous burning sensation. Echo images were recorded soon after the infusion.
During both DE and EE study, echo images were obtained from the standard parasternal long-axis and short-axis views as well as from the apical 4- and 2-chamber views; 12-lead ECG was monitored continuously and recorded on paper every 2 minutes. Blood pressure was measured with a cuff sphygmomanometer at 5-minute intervals.
In order to choose the optimal dose of enoximone, echo images, ECG, and blood pressure were also recorded at the end of 0.5-mg and 1.0-mg injections for the initial 12 patients.
All studies were performed with a Hewlett-Packard Sonos 2500 ultrasound system equipped with a 2.5/2.0 MHz transducer. Images were digitized from 4 views, using a commercially available stress program (Hewlett-Packard Sonos 2500 ultrasound system). The generated cineloops were stored on a HP Rewritable Optical Disk for later review.
Echocardiographic Image Processing and
Analysis
The images were interpreted by 2 investigators. In case of
disagreement, a third experienced cardiologist was consulted and a
majority decision was taken. The left ventricle was divided into 16
segments according to the recommendations of the American Society of
Echocardiography. For each segment,
systolic wall motion and thickening was visually graded with a
semiquantitative 4-grade scoring system (normal or hyperkinetic, 1;
hypokinesia, 2; akinesia, 3; and dyskinesia, 4). Because both normal
and hyperkinetic segments are given a score of 1,
dobutamine or enoximone-induced hyperkinesis in normal
segments cannot improve the wall motion score. Conversely, in hypo- or
akinetic segment, a decreased score 1 grade reflects improved
regional left ventricular function (eg, a hypokinetic
segment becoming normal or an akinetic segment becoming hypokinetic).
Deterioration in regional wall motion was considered to be due to
myocardial ischemia when the wall motion score increased by one
grade or more; however, akinesis becoming dyskinesis was not considered
a sufficient criterion for the occurrence of ischemia, as this
alteration can be due to passive stretching.19 In our
center, intra- and interobserver variabilities in the interpretation of
regional function are 7.1% and 4.2%, respectively.20
Echocardiographic Follow-Up
After revascularization (mean 3.2±0.4
months), regional wall motion was assessed by 2 experienced
echocardiographers who had no knowledge of the results of
the stress echocardiography. Segmental wall motion
was considered to have improved after
revascularization when endocardial excursion and
wall thickening (score 1 or 2) were observed in areas that were
akinetic or dyskinetic (score 3 or 4) at baseline, or when
contractility normalized (score 1) in areas of reduced
endocardial excursion and wall thickening (score 2).
Assignment of Myocardial Regions in Relation to Revascularized
Vessels
Coronary angiograms and bypass surgery reports were
reviewed for coronary anatomy and location of
revascularization. Basal and midanteroseptum, basal
and midanterior free wall, and 2 anteroapical segments were considered
as the distribution territory of the left anterior descending
coronary artery and its side branches; basal, midlateral, and
midposterior segments were designated as the distribution territory of
the left circumflex artery; finally, the basal and
midinferior wall and basal and midposterior septum were
assigned to the right coronary artery perfusion bed. Three
additional segments were assigned to overlapping regions: left anterior
descending/circumflex for the apicolateral region, left anterior
descending/right coronary for the inferoapical region, and
right coronary/circumflex for the posterobasal region. The
overlapping perfusion territories varied depending on the type of
coronary distribution.
Statistical Analysis
Sensitivity, specificity, and positive and negative predictive
value were calculated in the usual fashion. Differences between the
results of DE and EE were evaluated using the
2 test; a Fisher’s exact test was used when
appropriate. Continuous variables were expressed as mean±SD and
compared by a paired t test. We used the segment as the unit
of analysis for assessing concordance between DE and EE because
Sawada et al21 showed that a segment by segment
analysis was appropriate in the absence of any
consistent intrapatient correlation of the segment data.
P0.05 was considered statistically significant.
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Results |
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Preintervention Echocardiographic Findings
From a total of 720 left ventricular segments, 230 were classified as akinetic (8 segments were dyskinetic) and 286 as hypokinetic. Seventeen akinetic segments were excluded from the postintervention evaluation because of aneurysmectomy (n=10) or because they were not grafted or the vessel responsible for their perfusion had not been dilated (n=7). Of the 286 hypokinetic segments, 21 were excluded from the postintervention evaluation because of aneurysmectomy (n=6) or because revascularization had not been successful (n=15).
Dobutamine Versus Enoximone:
Hemodynamic Responses and Side Effects
The hemodynamic response to dobutamine
and enoximone is shown in Figure 1
. With
dobutamine, there was a significant increase in
systolic blood pressure (14%) and heart rate (16%), whereas
with enoximone, systolic blood pressure showed no change and
heart rate increased to a lesser extent (10%).
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No significant adverse effects nor chest pain or ECG and echocardiographic ischemic changes occurred during or after administration of enoximone. By contrast, dobutamine caused transient ischemia in 4 patients (chest pain, 2 of them associated with diagnostic ST-segment depression). Ventricular premature beats (Lown class 1 to 2) were observed in 8 patients with dobutamine and in 4 patients during enoximone. Five patients had vein pain during enoximone infusion and in 2 of them, enoximone had to be temporally washed out by physiological saline.
Dobutamine Versus Enoximone: Contractile
Responses
The contractile response to dobutamine and enoximone,
along with functional recovery after
revascularization are summarized in Figure 2. Of 213 akinetic segments that could be
successfully revascularized, 65 and 71 (41 patients) segments showed
improved wall motion during DE and EE, respectively (31% versus 33%,
P=NS). Wall motion improved during the infusion of
dobutamine and enoximone in 131 and 148, respectively, of
the 265 successfully revascularized hypokinetic segments (42 patients;
49% and 56%, P=NS). Thus, viability was detected more
frequently in hypokinetic than in akinetic segments
(P<0.01) with both DE and EE. The wall motion score index
was 2.07±0.32 at rest and improved significantly with
dobutamine (1.78±0.34, P<0.001 versus rest)
and enoximone infusion (1.74±0.34, P<0.001 versus rest,
P=NS versus dobutamine).
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Follow-Up Clinical Data and Rest Echocardiography
Three months after revascularization, no
patients had angina and 9 still complained of dyspnea on effort (NYHA,
class II). Follow-up coronary angiography was performed in 29
patients (20 had percutaneous angioplasty and 9 had
bypass surgery), of whom 4 had restenosis and were excluded
from the study. Of 20 patients not undergoing follow-up
coronary angiography, 11 had a negative exercise ECG test, 3
had negative results both on rest/stress myocardial
scintigraphy and on exercise ECG test, and 6 had a negative
stress echocardiogram.
Resting echocardiograms 3 months after
revascularization revealed improved wall motion in
216 (45%) of the 478 dyssynergic segments (Figure 2
). The
improvement was found in 75 (35%) of the 213 akinetic segments and in
141 (53%) of the 265 hypokinetic segments (P=0.01).
DE Versus EE: Prediction of Functional Recovery
The Table shows the sensitivity, specificity,
accuracy, and positive and negative predictive value of DE and EE for
predicting functional recovery after
revascularization.
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Postrevascularization improvement occurred in 170 of 196 (87%) and 190 of 219 (87%) segments that responded during DE and EE, respectively. Of 282 and 259 segments that had no response to dobutamine and enoximone, respectively, only 46 (16%) and 26 (10%) segments showed functional recovery at follow-up. Thus, the positive predictive value was the same (87%) for EE and DE. However, EE had a significant greater negative predictive value than DE (90% versus 84%, P<0.05). Similarly, there were no significant differences in specificity between the 2 methods (89% versus 90%). However, the sensitivity of EE (88%) was significantly higher than that of DE (79%, P<0.01).
Effects of Enoximone Dose (in 12 Patients)
The effects of enoximone on heart rate increased in a dose-related
fashion. Neither systolic nor diastolic pressure
were affected by increasing the enoximone dose (Figure 3).
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Contractile responses during enoximone were strongly dose-dependent.
The lowest dose of 0.5 mg/kg induced wall motion improvement in only
25% of dyssynergic segments, whereas 1.0 mg/kg and 1.5 mg/kg of
enoximone resulted in contractile enhancement in 43%
(P<0.01, versus 0.5 mg/kg) and 54% (P<0.01,
versus both 0.5 and 1.0 mg/kg) of dyssynergic segments, respectively.
Sensitivity increased in a dose-dependent fashion: 45% for 0.5 mg/kg,
70% for 1.0 mg/kg, and 87% for 1.5 mg/kg, respectively
(P<0.001 for all interdose differences). Accordingly,
specificity was highest with 0.5 mg/kg (98%) and progressively
decreased with 1.0 mg/kg (92%) and 1.5 mg/kg (88%) (Figure 4).
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Concordant Interpretation of DE and EE
Of a total of 478 involved segments, 167 (35%) showed improvement
and 239 (50%) were unchanged during both DE and EE. Thus, the global
interpretation of echo imaging for predicting functional recovery by DE
and EE was concordant in 406 (85%) of affected segments (Figure 5). Among the 72 (15%) segments
with discordant assessment by the 2 techniques, 22 improved with DE and
remained unchanged with EE; conversely, 50 segments were considered
viable by EE and necrotic by DE (21 segments in anterior, 19 in
lateral, 5 in posterior, and 5 in inferior wall). These 50
segments were present in 15 patients, with a mean 3.3 segments per
patient (2 patients had 2 segments, 8 patients had 3, 3 patients had 4,
and 2 patients had 5 segments). Fourteen of these 15 patients had
multiple vessel disease (4 had 2- and 10 had 3- vessel disease).
Stenosis severity of vessels supplying areas which only
improved with enoximone was significantly greater (89.9±7.7%) than
that of vessels (77.7±17.5%) supplying areas that responded to both
agents (P<0.02). The overall concordance of the 2 methods
was also high, both in functionally recovered (88%) and in unchanged
segments (83%).
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Discussion |
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The present study demonstrates the feasibility, tolerability, and accuracy of enoximone as a stressor for the echocardiographic assessment of myocardial viability, as well as its superior sensitivity to dobutamine for predicting functional recovery. Our findings have potential pathophysiological and clinical relevance.
Mechanism of Viability: Recognition by Enoximone
The effects of enoximone are mediated by inhibition of
phosphodiesterase III, which continuously degrades intracellular cAMP.
Intracellular increase in cAMP enhances the entry of calcium into cells
by activating membrane-bound calcium channels, therefore augmenting
inotropic state.15 16 22 23 24 25 In patients with congestive
heart failure,15 16 17 18 26 27 including those with
coronary artery disease,28 29 enoximone has been
shown to be extremely safe over a wide range of doses (0.25 to 3.0
mg/kg). Experimental and clinical studies have shown that enoximone
exerts a positive inotropic effect, not accompanied by a significant
increase in myocardial oxygen
consumption.17 18 26 30 31 Additionally,
the action of enoximone is not influenced by 
- or ß-adrenergic
blockade or by catecholamine depletion that may occur in
severe heart failure and can attenuate the response to
dobutamine. Therefore, enoximone in combination with
2-dimensional echocardiography appears particularly
suitable for the identification of viable myocardium.
EE Versus DE
Besides similar specificity and positive predictive value, EE
showed better sensitivity and negative predictive value than
dobutamine. This may be due to the different
cardiovascular properties of the 2 agents. When viable
myocardium is supplied by critically stenotic
coronary arteries, some asynergic but viable segments may show
no improvement even at low-dose dobutamine
infusion.12 13 In our study, dobutamine
infusion caused heart rate and systolic blood pressure to
increase significantly and induced severe ischemia in 4
patients. This confirms that dobutamine, even in relatively
low doses, can sometimes precipitate transient myocardial
ischemia in patients with severe coronary disease. Our
results agree with those of Afridi et al,14 who showed
that most segments deteriorate during dobutamine infusion
at doses 20 µg · kg-1 ·
min-1, but worsening of wall motion can also be
observed in some patients with doses as low as 7.5 µg ·
kg-1 · min-1.
Therefore, the possibility that DE may underestimate myocardial
viability has to be considered.
Unlike dobutamine, enoximone caused a lesser increase in
heart rate, did not induce any change in systolic blood
pressure, and did not precipitate transient acute ischemia. We
found that the vessels supplying the segments that showed viability by
enoximone alone had significantly more severe stenosis than
those supplying segments with a positive response to both stresses
(90% versus 78%, P<0.02). This finding confirms that the
superior sensitivity of enoximone in detecting viability probably
relates to the lesser increase in myocardial oxygen consumption.
Therefore, in the setting of restricted blood flow, enoximone may avoid
the development of superimposed ischemia, which may sometimes
occur with dobutamine12 13 14 and mask a
hibernating state by concealing the improvement of wall motion.
Furthermore, these segments considered viable by EE and necrotic by DE
were present in 33% of study patients, most of them showing
3 segments defined as viable by EE only. This figure is also in line
with currently used criterion for definition of contractile reserve
(presence of improved wall thickening or movement in at least 2
abnormal segments).9 14 32 Accordingly, on a per-patient
as well as on a per-segment basis, EE may substantially have a
sensitivity superior to DE.
In agreement with previous findings,6 7 11 32 the contractile response to inotropic stimulation was related to the degree of baseline dysfunction: more hypokinetic than akinetic segments manifested contractile enhancement during both dobutamine and enoximone stimulation. A previous study33 showed that viable hypokinetic segments retaining contractile reserve show minimal fibrosis on transmural myocardial biopsies, whereas akinetic segments lacking contractile reserve only contain islets of viable myocytes surrounded by extensive fibrosis.
Optimal Dose of EE Test
In agreement with previous studies,26 31 we found
that the inotropic response to enoximone is strongly dose-dependent.
Only 25% of dyssynergic segments improved
contractility at the dose of 0.5 mg/kg but the
contractile response increased progressively with increasing doses.
Accordingly, the sensitivity for predicting functional recovery was
only 45% for 0.5 mg/kg and increased to 70% and 87%, respectively,
for 1 and 1.5 mg/kg. Importantly, increasing the dose did not reduce
specificity, yielding an acceptable diagnostic
accuracy.
Previous studies26 31 have shown that enoximone improves
cardiac performance without significantly affecting blood
pressure and heart rate. Indeed, in our study both systolic and
diastolic pressure remained unaffected at any of the doses
we used. However, the effects of enoximone on heart rate were
dose-related, and significant increases occurred with high doses
(Figure 4). The discrepancy between our observation and those
reported in the literature may depend on different administration
schedules: to reach the target dose, we used shorter injection times
(10 minutes) than previously reported in clinical
studies.26 31
Limitations of the Study
Follow-up angiography was not performed in all patients. Thus
reocclusion, or restenosis entailing reduction of resting blood
flow and leading to underestimation of the tests’ specificity, cannot
be definitively excluded. Nevertheless, the specificity was excellent
for both DE and EE, suggesting that this potential problem did not play
any relevant role in our patients. In addition, all patients who had no
follow-up angiography remained asymptomatic and had
negative results on functional stress tests, suggesting persisting
vessel patency.
We used only low-dose dobutamine infusion at 5 and 10 µg · kg-1 · min-1 for detection of contractile reserve. Although this represents the first9 and the most frequently used protocol,6 7 10 11 32 other investigators have demonstrated the usefulness of higher doses for optimal evaluation.8 14 Therefore, the possibility that the dobutamine protocol we used could have resulted in a somewhat lower diagnostic accuracy cannot be completely ruled out.
Clinical Implications
Although pharmacological stress
echocardiography has gained increased
acceptance for the detection of myocardial viability, a
substantial limitation of stress echocardiography
is its less-than-ideal sensitivity. The present study shows that
enoximone in combination with 2-dimensional
echocardiography yields a better sensitivity than
DE, without loss in specificity. Furthermore, enoximone induces lesser
hemodynamic alterations and provides the potential for
a new and attractive approach for the detection of myocardial
viability. Importantly, the superior sensitivity of enoximone for
predicting functional recovery is based on its ability of inotropic
stimulation without increasing myocardial oxygen consumption. The
latter feature makes enoximone more appealing than
dobutamine in patients with critical stenosis and
ischemic left ventricular dysfunction, in whom the
presence and extent of residual viable tissue is sought. Besides the
practical advantage related to its easier administration, EE can also
be performed in patients receiving ß-adrenoceptor blockers without
the need to withdraw the medication, as is the case when
dobutamine is used.
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Acknowledgments |
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We are deeply indebted to Fabrizio Veglia, PhD, for statistical assistance.
Received May 11, 1999; revision received September 28, 1999; accepted October 7, 1999.
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