Analysis of microvascular integrity, contractile reserve, and myocardial viability after acute myocardial infarction by dobutamine echocardiography and myocardial contrast echocardiography

Analysis of Microvascular Integri)r, Contractile Reserve, and Myocardwd Viability After Acute Myocardial Infarction by Dobutamine Echocardiography and Myocardial Contrast Echocardiography Sabino Iliceto, MD, Leonarda Galiuto, MD, Alfred0 Marchese, MD, Daniela Cavallari, MD, Paolo Colonna, MD, Giuseppina Biasco, MD, and Paolo Rizzon,

MD

The purpose of this study was to evaluate, in postinfar&on dysfunctioning myocardium, the relative potential of m ocardial contrast and low-dose dobutamine echoca rcriogmph in detecting myocardial viability, and the relation L! tween microvascular in rity, contractile reserve, and functional recovery at“B allow-up. tients with recent myocardial infarction Twenty-four were studi err before hospital discharge with low-dose dobutamine and myocardial contrast echocardioginfarct area, wall motion mphy. In the dysfunctioni score index was calcula z! at baseline, during lowdose dobutamine, and at 3-month follow-up. Revascularization of the infarct-related artery was performed if clinically indicated. Eighteen patients (group A) had myocardial enhancement of the dysfunctioning infarct area at myocardial contrast echocardiography of *SO%, whereas the remaining patients (group B) had an increase of GO%. Wall motion score index was sim-

ilar at baseline in groups A and B (2.6 f 0.4 and 2.8 f 0.2; p = NS), but it improved during low-&se dobutamine and at follow-up only in group A (1.9 f 0.9 and 1.9 f 0.7, respectively; p
ysfunctioning, but viable, myocardium can be the D result of prolonged myocardial ischemia followed by reperfusion. Functional left ventricular recovery of

tegrity after acute myocardial infarction in preserving contractile reserve and ensuring functional recovery at follow-up.

viable myocardium can occur either spontaneously (stunned myocardium)‘12or after adequate reestablishment of coronary flow (hibernating myocardium).3,4 Echocardiographic recognition of viable myocardium can be obtained by means of left ventricular imaging during low-dose dobutamine infusion.“-s Myocardial contrast echocardiography, by using a microvascular tracer,can demonstratemicrovascular integrity,9-I3which correlates with regional functional recovery following ejr]yl4.15 or late1617 revascularization after acute myocardial infarction. Therefore, since low-dose dobutamine echocardiography and myocardial contrast echocardiography are both capable of identifying viable myocardiurn, although by different means (recognition of contractile reserve and microvascular integrity, respectively), this study was undertaken (1) to evaluate the respective potential of low-dose dobutamine and myocardial contrast echocardiography after acute myocardial infarction in predicting left ventricular functional recovery, and (2) to assessthe role of microvascular inFrom the lnstrtute of Cardrology, Clniverslty of Bori, Bari, Italy, and the Instirzte of Cardlolqy, University of CCI lio:i, Cagllari, Italy. Manuscript received May 18, 1995; revis J monvscript ece:ved October I 8, 1995, and acceptec October 20. Address for repr:n:s. Sabino Ilrcetc, MD, lnstiture of Cardiology, Urwewty of Cagllarl, Via San Giorgio, No. 12. Cogliari, Italy.

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MFTHODS Twenty-four consecutive patients with first acute myocardial infarction hospitalized in our institution entered the study. Diagnosis of myocardial infarction was made on the basis of chest pain lasting ~30 minutes and unresolved by nitroglycerin, 21.0 mm ST-segment elevation in 22 leads in the initial electrocardiogram, peak creatine kinase >2 SDS above normal, and wall motion abnormalities on echocardiography at hospital admission. All patients but 1 were men (mean age 56 f 9 years), 10had an anterior and 14an inferior infarction; 22 patients had a Q-wave and 2 a non-Q-wave infarction. Sixteen of 24 patients underwent intravenous thrombolysis. All 24 patients had high-quality echocardiographic imaging and underwent both low-dose dobutamine and myocardial contrast echocardiography during hospitalization and echocardiographic follow-up after discharge. All patients gave informed consent and the institutional committee on human researchapproved the study protocol. low-dose dobutamine e&cardiography: Low-dose dobutamine protocol was performed in all patients during echocardiographicmonitoring within 5 & 2 days aftet admission. Two-dimensional echocardiographywas performed ‘before, during, and after dobutamine infusion CWJlRASl

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medical therapy, 15 were successfully treated by percutaneoustransh.uninalcoronary angioplasty of the infarctrelated artery, and 1 underwent coronary artery bypass grafting. Revascularization was performed at 30 f 10 days after acute myocardial infarction; echocardiograms considered for follow-up evaluation were obtained within 3 weeks of the revascularization procedure.

using all available tomographic planes obtainable from the precordial and apical approach.Commercial echocardiographic equipment (Sonos 1500, Hewlett-Packard Co., Andover, Massachusetts) connected to a digital acquisition system(PreVue III, Nova Microsonics, Mahwah, New Jersey) was used. Once baseline echocardiographic imageswere obtained and acquired in digital format, dobutamine infusion was begun at 5 pg/kg/min for 5 minutes, and at 10 pg/kg/min for a further 5 minutes.5 The echocardiographic tomographic planes most frequently used were the apical 4- and 2-chamber views, apical long axis, and either the precordial long or short axis at the level of the papillary muscles. Echocardiographic planes, comparable to those visualized in baseline conditions, were also obtained at the end of the first stageof the dobutamine protocol (5 pg/kg/min for 5 minutes), at the second stage (10 pg/kg/min for a further 5 minutes) and during recovery. Echocardiographic images were digitally acquired on-line, and each tomographic plane was stored in quad screen cineloop format with simultaneousdisplay of baseline, first-, and second-stage dobutamine protocol, and recovery to facilitate review and interpretation. Continuous monitoring of previously acquired digital tine loop images ensuredcomparability of the tomographic planesobtained throughout the entire dobutamine protocol. Review and interpretation of dobutamine studies were performed by 2 experienced observers unaware of myocardial contrast echocardiography and angiographic results. During dobutamine testing, heart rate, blood pressure,and electrocardiogram were continuously monitored. All studies were performed and completed without complications. None of the 24 patients were taking P-blocker therapy. Myocardiil contrast echocardiogmphy: Myocardial contrast echocardiography, performed by manually injecting a small amount (2 to 3 ml) of sonicated contrast medium in both coronary arteries, was performed within 3 days of low-dose dobutamine echocardiography after coronary angiography. A commercially available sonicator (W-380 Heat Systems-Ultrasonics,Farmingdale, New York) with a 0.5-inch (1.27 cm) diameter horn was usedto generatemicrobubbles. The horn was placed at the bottom of a 50 ml truncated syringe containing 6 ml of ioxaglate (Hexabrix “320,” Byk Gulden). Sonication lasted 15 seconds,producing microbubbles of 4 to 6p (light microscope observation). Left ventricular echocardiographic imaging was achieved using standard tomographic planes obtained from the precordial and apical approach. Multiple tomographic planes were acquired to obtain the most complete imaging of postmyocardial infarction dysfunctioning left ventricular segmentsduring injection. Particular attention was paid to the acquisition of tomographic planes corresponding to those obtained during low-dose dobutamine echocardiography. During myocardial contrast echocardiography, heart rate, blood pressure,and electrocardiogram were continuously monitored. Echocardiographic follow-up: Clinical and echocardiographic evaluations were performed in all patients within 3 months after hospital discharge. Patientsunderwent revascularization if clinically indicated at the discretion of the referring physician. Eight patients received

purpose of low-dose dobutamine echocardiography, myocardial contrast echocardiography, and follow-up echocardiographic data analysis, a %-segment left ventricular model was used. Each segment was defined as being dyskinetic, akinetic, hypokinetic, normokinetic, or hyperkinetic on the basis of subjective evaluation of inward motion of the endocardium toward the center of .the left ventricle and the degree of myocardial thickening. For the analysis foreseen in this study, we considered only dysfunctioning (dyskinetic and akinetic; hypokinetic) myocardial segments within the theoretical maximal risk area according to a previously described 3-region schemeof coronary perfusion.ts A wall motion score index in the baseline dysfunctioning infarct area at the time of low-dose dobutamine echocardiography was obtained by assigning a semiquantitative score (1 = normokinesia, 2 = hypokinesia, 3 = akinesia, and 4 = dyskinesia) to all segmentswithin this area and dividing the sum of the individual segmentscoresby the number of those segments.In each patient, wall motion score index within the dysfunctioning infarct area was calculated at baseline dobutamine echocardiography and, within the sameleft ventricular area,also at dobutamine echocardiography (10 pg/kg/min) and follow-up. On the basis of dobutamine echocardiographic results, a single myocardial segment within the dysfunctioning infarct areawas defined as being dysfunctioning, but viable, if it was dyskinetic or akinetic and became at least hypokinetic, or if it was hypokinetic and became normokinetic during dobutamine echocardiography. A patient was considered improved at dobutamine echocardiography or follow-up if wall motion improved in 22 contiguous dysfunctioning segmentswithin the dysfunctioning infarct area (from dyskinesia and akinesia to at least hypokinesia, and from hypokinesia to normokinesia) during dobutamine echocardiography or at follow-up, respectively. A myocardial segmentwas consideredopacified during myocardial contrast echocardiography if contrast enhancementof the myocardium was observedafter contrast injection. A patient was considered to have adequate microvascular perfusion if >50% of segments within the dysfunctioning infarct area were opacified at myocardial contrast echocardiography. In all patients, the percent increase in enhanced myocardium after myocardial contrast echocardiography within the dysfunctioning infarct area was calculated as follows: number of segments enhanced at myocardial contrast echocardiography within dysfunctioning infarct area/number of considered segments within dysfunctioning infarct area X 100. Inter- and intraobserver variability: To assessinterand intraobserver variability in interpreting myocardial

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Analysis of low-dose dobutamine e&cardiography and myocardial contrast echocardiography data: For the

contrast echocardiography studies (enhanced, not enhanced),30 left ventricular myocardial segmentswere independently reviewed by 2 observers, and again by 1 observer 2 weeks later. Agreement between the 2 observers was 85% whereas in the same observer it was 95%. Similarly, 20 stresstest studies were evaluated by 2 observers,and again by 1 observer 2 weeks later. Interobserver agreement was 89% at rest and 84% during stress,and intraobserver agreementwas 92% at rest and 83% during stress. Disagreement was never more than grade 1 for a single segment. Coronary angiography: Coronary angiography was performed in all patients using the Seldinger technique. A stenosis was considered significant if a lumen narrowing of 250% was seen. Statistical analysis: All data are expressedas mean + SD. Statistical analysis of changesin wall motion score index from baseline to dobutamine echocardiography and follow-up was computed by l-way analysis of variance for repeatedmeasureswith implementation of Bonferroni’s correction. Comparisons between groups of wall motion score index values at baseline, dobutamine echocardiography,and follow-up were madeby unpaired Student’s t test. Correlations between wall motion score index at baseline, dobutamine echocardiography,and follow-up, and percentageof contrast enhancementin dysfunctioning segmentswere performed by linear regression analysis.Differencesbetweencomparisonswere considered statistically significant at a 2-sided p value <0.05. Sensitivity, specificity, and positive and negative predictive values relied on the standard deviation and are reported with the corresponding 95% confidence interval.

index was 2.6 f 0.4 in baseline conditions and improved significantly both at dobutamine echocardiography (1.9 -c 0.9, p ~0.001 vs baseline) and at follow-up (1.9 + 0.7, p ~0.001 vs baseline, p = NS vs dobutamine echocardiography). In contrast, in group B patients, wall motion score index did not change from baseline (2.8 f 0.2) to dobutamine echocardiography (2.7 + 0.4) or follow-up (2.8 it 0.2; both, p = NS vs baseline). Both at dobutamine echocardiography and at follow-up, wall motion score index in group A was Iower than that observed in group B (Figure 1). No significant correlation was found betweenpercent increasein dysfunctioning myocardium with opacification at myocardial contrast and resting wall motion score index (r = -0.4; p = NS), whereas a significant negative correlation was found between this extension and wall motion score index during dobutamine echocardiography (r = -0.6; p = 0.005) and at follow-up (r = -0.6; p = 0.001).

Mirovascular int+y, contraclile reserve, and functional recovery at follow-up: In patients with a more

A and B patients (my&a&l enhancement at myocbrdid co& trast echacardiimrhv rSW% or
Sensii and specific’~ dabutamine e&cardiography segment functiona! recopy

of myocardial contrast and in predicting myocardial at fdlow-up: Of the group

of 24 patients considered in this study, 135 segments were dysfunctioning; they were located in the theoretical maximal risk area and adequately visualized at both dobutamine and myocardial contrast echocardiography, and were therefore considered for analysis. An average of 8.2 +- 2.4 segments and 4.1 f 2.7 segments/patient was evaluated in the groups with anterior and inferior infarction, respectively. Ninety-two of 135 segments were opacified at myocardial contrast echocardiography (myocardial contrast echocardiography positive) and 43 were not (myocardial contrast echocardiography negative); 41 had a viable responseat dobutamine echocardiography (dobutamine echocardiography positive) and RESULTS Ten of the 24 patients had an occluded infarct-relat- 94 did not (dobutamine echocardiography negative). ed artery (right coronary artery in 9, and left anterior Functional recovery at follow-up was observed in 42 of descending artery in 1). Of the remaining 14patients, 13 92 segmentsconsidered positive on myocardial contrast had a significant stenosis of the infarct-related artery (6 echocardiography and in none of the negative segments. had l-vessel disease, 7 had multivessel disease) and 1 Moreover, functional recovery was observed in 30 of 41 had angiographically normal arteries. Collateral circulation to the infarct-related artery was observed in 11 patients, in 10of whom this artery was occluded. Twelve of the 24 patients had functional improvement at followup. Eighteen patients had myocardial contrast echocardiography enhancementincreased to >50% of the dysfunctioning infarct area (group A), whereas the remaining 6 had 150% (group B). Among patients with ~50% of the dysfunctioning area opdcified at myocardial contrast echo, 5 had a particularly large postinfarct dysfunction. In 2 of these patients, all the segments were negative at myocardial contrast, while in the other 3 the opacified segments were 50%, 20%, and 40% of the entire dysfunctioning area. Twelve group A patients and a Baseline u Dobutamine n Follow up no group B patient had functional improvement at follow-up. Ten of the 24 patients had a viable responseat dobutamine echo. Nine of 10 patients with and 3 of 14 FIGURE 1. Wall motion score index (WMSI) in the sfunctianwithout a viable response at dobutamine echocardiog- ing infarct area at baseline candiions, during low 2 se &butamine, and at fdlow-up (3 months after acute event) in group raphy had functional improvement at follow-up. extensive preservation of microvascular integrity after myocardial infarction (group A), the wall motion score CORONARY

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TABLE I Potential of Low-Dose Dobutamine and Myocardial Contrast Echocardiography in Identifying Dysfunctioning, but Viable, Segments After Acute Myocardiol Infarction

dobutamine echocardiography (Table w*

DISCUSSION

Recovery at Follow-up

Results of this study show that if microvascular integrity (as assessedby WI (“/I WI myocardial contrast echo) is preserved within the risk area after acute myol.DDE+ (41 seg.) 30 A: LDDE- (94 seg.] 12 cardial infarction, contractile reserve and functional recovery at follow-up ,0.5Z.S5) (O.KK94) [O.&M) (O.Kz.94) can be present. In fact, within the in50 MCE+ (92 seg.) 42 farct area, although regional left ven0 43 MCE- (43 seg.) tricular function (as assessedby region,o!~l) [0.3&6) (0.3~55) (o!E) al wall motion score index) at baseline Values in parentheses ore 95% confidence intewols. conditions was similarly impaired in UXJE+, LDDE- - positive and negatiw results, mspecttwh/, on kwdose dc4atimic-a echocardiography; both patients with extensive preservaMCE+, MCE- = positive and negative results, respectively, on myaardil contrast echomrdiography; tion and in those with limited preserNeg. PV - negative predictive v&e; Pas. W = positive pedictive value; sag. = segments; Sons. = sensitivity; Spec. - specificity. vation of microvasculature integrity, it improved significantly at both dobutamine echocardiography (expression of contractile reTABLE II Myocardial Contrast, Low-Dose Dobutamine, and serve) and at follow-up (expression of functional recovFollow-Up Echocardiography in 135 Myocardial Segments ery) only in patients with a greater extent of preserved in Dysfunctioning Infarct Area microvasculature integrity. Our data also demonstrate Follow-Up that the more extensive the preservation of myocardial microvasculature, the greater the regional contractile MCE LDDE Impcoved (“~1 Not Improved (%) reserve and functional recovery at follow-up. This is Positive 30/41 (73) 11/41 (27) Positive (92 seg.) likely due to the fact that the absenceof microvascular Negative 12/51 (24) 39/51 (76) integrity is an expression of a more extensive myocarNegative 143 seg.) Positive dial necrosis.*S21 Negative 43 (loo) In the group of myocardial segments nonopacified Abbreviations OS in Table I. after injection of contrast medium in both coronary arteries, neither a viable response at low-dose dobutamine segmentsconsidered positive on dobutamine echocardi- echocardiography nor functional recovery at follow-up ography and in only 12 of 94 negative segments.There- occurred. This suggeststhat if microvascular integrity is fore, in the identification of viable myocardial segments, not preserved, contractile reserve and functional recovmyocardial contrast echo had 100% sensitivity and 46% ery cannot be expected. Conversely, in the presenceof specificity, whereas low-dose dobutamine echo had 71% microvascular integrity, as shown by contrast enhancement, myocardium can still be.viable even if it is dyssensitivity and 88% specificity (Table I). According to myocardial contrast and dobutamine functioning at rest, and can increasecontractility during echocardiographic results, 41 segmentshad positive re- dobutamine infusion, recovering at follow-up. Thus, sults during myocardial contrast and dobutamine echo- microvascular integrity within postischemic dysfunccardiography (microvascular integrity and preserved tioning myocardium cannot, in itself, be consideredprecontractile reserve); 51 segments were positive during dictive of functional recovery at follow-up. In fact, myocardial contrast echocardiography, but negative at although the absence of intramyocardial perfusion is dobutamine echocardiography (microvasculature inte- strictly correlated to irreversible functional damageposgrity but no contractile reserve); in 43 segments myo- sibly due to a more extensive necrosis, the presenceof cardial contrast and dobutamine echocardiography were opacification at myocardial contrast echocardiography, negative (absence of both microvasculature inte-grity and thus of microvasculature anatomic integrity, can be and contractile reserve). In no patient was a segment observednot only in dysfunctioning but viable myocardifound to be positive at dobutamine echocardiography in urn with preserved contractile reserve and functional the absenceof myocardial contrast echo- cardiography recovery at follow-up, but also in myocardium without enhancement (Table II). Functional recovery was such characteristics. The reason for the apparent disobserved in most segments (30 of 41, 73%) with posi- crepancy between microvascular integrity and absence tive myocardial contrast and dobutamine echocardiog- of contractile reserve and functional recovery needs to raphy, and in only 12 of 51 segments(24%) with posi- be investigated. We hypothesized someexplanations for tive myocardial contrast echocardiography and negative this apparently contradictory finding. One possibility is dobutamine echocardiography.These segmentswere all that in some cases,the ischemic injury during the acute related to a stenotic coronary artery and came from phaseof myocardial infarction is sufficient in entity and patients with a large dysfunctioning area (82 segments), duration to produce necrosis in a large amount of whereas peak creatine phosphokinase was rather small myocytes,but is unable to irreversibly damagethe entire (662.3 + 124.2 U/L). Functional recovery was absent in microvasculature. Another possibility is that even if all the segmentswith negative myocardial contrast and microvascular flow is present at rest, its functional Results

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reserve can be reduced to such an extent as to be able to guarantee only a low degree of myocardial contractility in baseline conditions,22 but not its improvement at increasing dosage (even at low-dose) of dobutamine infusion. Furthermore, not only microvasculature function, but also abnormal infarct-related artery anatomic conditions can finally affect overall coronary flow reserve. In fact, inadequateblood supply to the risk area can blunt functional response to dobutamine of dysfunctioning, but viable, myocardium. Obviously all these possibilities can coexist in a single patient. Last, the maximal dobutamine dosage used in this study (10 pg/kg/min) may have been inadequate in some of our patients in eliciting contractile reserve of dysfunctioning, but viable, myocardium.23 Stvdy limitations: In this study, dobutamine echocardiography and myocardial contrast echocardiography were performed a few days apart. It is unlikely that microvascular conditions could have changed within such a short time interval becausepatients were in stable clinical conditions. As previously mentioned, it is possible that some of the false-negative results of lowdose dobutamine echocardiography could have been due either to a relatively inadequate or to excessiveinotropic stimulus.7 In our series of patients, the dobutamine stresstest was performed without administering P-blocking therapy. Because the inotropic response to dobutamine may be blunted by /3 blockers, it is important to withdraw, these agents before the test. Last, in patients who underwent angioplasty, no information on infarctrelated artery patency at 3-month follow-up was available. Therefore, absence of recovery in some of these patients could be causedby a reduced flow reserve due to coronary restenosis. Clinical implications: Results of this study show that myocardial contrast and dobutamine echocardiography have different diagnostic potentials in predicting functional recovery at follow-up. In our study group, sensitivity was higher for myocardial contrast echocardiography and specificity was higher for dobutamine echocardiography. Thesedifferencesmay be explained by the different characteristicsof these2 diagnostic procedures. In fact, myocardial contrast echocardiography explores microvascular integrity, which is fundamental in ensuring viability, but, for the previously mentioned reasons, does not necessarily imply the existence of a large amount of viable myocytes and/or adequateblood flows conditions capableof ensuring regional functional recovery. On the other hand, dobutamine echocardiography directly explores the capability of myocytes to increase contractility and therefore, their viability. The different and complementary diagnostic characteristics of myocardial contrast and dobutamine echocardiography in detecting the presenceof viable myocardium have potential clinical implications. Opacification of myocardium by myocardial constrast echocaxdiography is not influenced by coronary artery anatomy (infarct-related artery narrowing, presence/absenceof collateral circulation); therefore, myocardial contrast echocardiography can be particularly useful in detecting viability when dobutamine echocardiography is not feasible, is contraindicated (very early phase of actite myocardial infarction), or CORONARY

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is of less value becauseof coronary conditions limiting blood supply to the myocardium. Dobutamine echocardiography is useful in detecting myocardial viability either in the acute5s7or chronic phase of myocardial infarction to evaluate the effect of revascularization procedureson dysfunctioning myocardium.6s8The diagnostic potential of dobutamine echocardiography is greatly enhancedif information on coronary anatomy (coronary angiography) and source of blood supply to dysfunctioning myocardium (myocardial contrast echocardiography) are also provided. _ 1. Braunwald E, Khmer RA. The stunnedmyocardium:prolonged,postischemic ventricular dysfunction. Circu[arion 1982;6:1146-l 149. 2. Bolli R. Myocardial “stunning” in man. Circulation 1992;86:1671-1691. 3. Rahimtoola SH. A perspectiveof the three large multicenterrandomizedclinical trials of coronary bypass surgery for chronic stable angina. Circularion 1985;72(supplV):V-125-V-135. 4. RahimtoolaSH. The hibernatingmyocardium.Am Hear? .I 1989;117:21l-221. 5. Pierard LA, De LandsheereC, Berthe C, Rigo P. KulbertusH. Identification of viable myocardium by echocardiographyduriug dobutamineinfusion in patients with myocardial infarction after thrombolytic therapy: comparisonwith positron emissiontomography.I Am Co11 Car&l 1990;15:1021-1031. 6. Barilla F, GhcorghiadeM, Alam M, Khaja F, Goldstein S. Low-dose dobutamine in patientswith acutemyocardial infarction identifies viable but not contmctile myocardiumandpredictsthe magnitudeof improvementin wall motion abnormalitiesin responseto coronaryrevasculatizatlon.AmHeart J 1991;122:1522-1531. 7. Smart SC, SawadaS, Ryan T, SegarD, Atberton L, Berkovitz K, Bourdillou PDV, FeigenbaumH. Low-dose dobutamineechocardiographydetectsreversible dysfunction after thrombolytic therapy of acutemyocardial infarction. Circulation 1993;88:405-415. 8. Cigarroa CG, deFilippi CR, Brickner E, Alvarez LG. Wait MA, Graybum PA. Dobutamiuestressechocardiographyidentifies hibernating myocardium and predicts recovery of left ventricular function after coronary revascularization.Circulafion 1993;88:430-436. 9. Armstrong WF. Assessmentof myocardial perfusion with contrast enhanced echocardiography.Echocardiography 1986;3:355-370. IO. FeiusteinSB. Assessmentof myocardial perfusionusing contrastechocardiography. Echocardiography 1989;6:17-25. 11. ArmstrongWF, Mueller TM, Kinney EL, Tickner EG, Dillon JC, Feigenbaum H. Assessmentof myocardial perfusion abnormalitieswith contrast-enhancedtwodimensionalechocardiography.Circularion 198266:166-173. 12. Kaul S, Kelly P, Oliner JD, GlasheenWp, Keller MW, WatsonDD. Assessment of regional blood flow with myccardial contrasttwo-dimensionalechocardiography.J Am Co11 Cardiol 1989;13:468482. 13. FeinsteinSB, Lang RM, Dick C, NeumannA, Al-Sadii J, Chua KG, Car101I, FeldmanT, Borow KM. Contrastechocardiographyduring coronary arteriogmphy in humans:perfusion and anatomicstudies. JAm Co11 Cardiol 1988;11:59-65. 14. Ito H, Tomooka T, Sakai N, Yu H, Higashino Y, Fujii K, MasuyamaT, KitabatakeA, Minamino T. Lack of myccardial perfusion immediately after successful thmmbolysis.A predictor of poor recovery of left ventricular function in auterior myocardial infarction. Circulation 199285:1699-1705. 15. Ito H, Tomooka T, Sakai N, Higashino Y, Fujii K, Katoh 0, MasuyamaT, Kitabatake A, Minamino T. Time course of functional improvementin stunned myocardiumin risk areain patientswith rep&used anterior infarction. Circulation 1993;87:355-362. 16. SabiaPJ,PowersER, RagostaM, SarembockIJ, Burwell LR, Kaul S. An association betweencollateral blood flow andmyocardialviability in patientswith recent myocardial infarction. N Engl J Med 1992:327:1825-1831. 17. Sabia PJ, Powers ER, JayaweeraAR, RagostaM, Kaul S. Functional significance of collateral blood flow in patients with recent acute myocardial infarction. A study using myocardial contrast echocardiography.Circulation 199285: 2080-2089. 18. SawadaSG, SegarDS, Ryan T, Brown SE, Dohan AM, Williams R, Fineberg NS, ArmstrongWF, FeigenbaumH. Echocardiographicdetectionof coronary artery diseaseduring dohutamineinfusion. Circulation 1991;83:1605-1614. 19. Kloner RA, Rude RE, Carlson N, Maroko PR, Deboer LWV, Braunwald E. Ultrastmctumlevidenceof microvasculardamageand myocardial cell injury after coronary azteryocclusion: which comesfirst? Circularion 1980,62:945-952. 20. Reimer KA, JenningsRB. The “wavefront phenomenon”of myocardial cell death.Lab invest 1979:40:633-644. 21. Kloner RA, GanoteCE, JenningsRB. The “no reflow” phenomenonafter tempomry coronary occlusion in dogs.J Clin Invest 1974:54:1496-1508. 22..JeremyRW, Liis JM, Becker LC. Progressivefailure of coronary flow during reperfusionof myocardial infarction: documentationof the no reflow phenomenon with positron emissiontomography.J Am CON Cardiol 1990;16:695-704. 23. SklenarJ, Ismail S. Villanueva FS, GoodmanC, GlasheenWP, Kaul S. Dobutamine ecbocardiogmphyfor determining the extent of myocardial salvage after qcrfusion. An experimentalevaluation. Circulation 1994;90:1502-1512. CONTRAST AND DOBUTAMINE

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