- Email: [email protected]
Usefulness of real-time myocardial perfusion imaging in the evaluation of patients with first time chest pain
Usefulness of Real-Time Myocardial Perfusion Imaging in the Evaluation of Patients With First Time Chest Pain Grigorios Korosoglou, MD, Nina Labadze, MD, Alexander Hansen, MD, Christiane Selter, RN, Evangelos Giannitsis, MD, Hugo Katus, MD, and Helmut Kuecherer, MD In patients who have acute coronary syndrome (ACS), rapid and accurate risk stratification is crucial. Realtime myocardial contrast echocardiography (MCE) extends the evaluation of wall motion abnormalities by assessing myocardial perfusion. We investigated whether MCE could contribute to clinical and biochemical markers in identifying patients who have ACS when presenting to the emergency department. Consecutive patients (n ⴝ 100) who presented with first occurrence of chest pain underwent MCE to evaluate myocardial perfusion. Contrast images were also analyzed quantitatively off-line by measuring peak signal intensity (A) and slope of signal intensity increase () in 16 myocardial segments. Thirty-seven of 100 patients had ACS. MCE showed perfusion defects in 9 of 12 patients (75%) who had unstable angina and had high-grade stenotic lesions on an angiogram that were missed by assessment of troponin T. MCE iden-
tified all 6 patients who had non–ST-elevation myocardial infarction and no initial increase in troponin T and 17 of 19 patients who had non–ST-elevation myocardial infarction and an initial increase in troponin T. In 2 patients who had chest pain and increased troponin T, MCE excluded ACS by identifying perimyocarditis as the underlying cause. Multivariate logistic regression analysis showed that MCE was the strongest predictor of ACS, thus adding significant diagnostic value to conventional tests. Initial perfusion defect size correlated strongly with increased troponin T at 96 hours (r ⴝ 0.73, p <0.001) and with ejection fraction at 4 weeks of follow-up (r ⴝ ⴚ0.79, p <0.001). Thus, our data suggest that MCE can accurately identify patients who have ACS. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;94:1225–1231)
cute coronary syndromes (ACSs) encompass the clinical manifestation of ST-elevation myocardial A infarction, non–ST-elevation myocardial infarction
patible with myocardial ischemia. Inclusion criteria were pain duration ⬎20 minutes and occurrence of chest pain ⬍12 hours before presentation. Exclusion criteria were ST-elevation myocardial infarction, history of coronary artery disease, and historical or electrocardiographic evidence of previous infarction. The study protocol was approved by the local ethics committee, and all patients gave written informed consent. Study protocol: We prospectively performed MCE in the emergency department in 100 patients who had been admitted with chest pain. Personnel with skills to perform myocardial contrast echocardiographic studies was available during 5 days a week and from at least 8:00 A.M. to 8:00 P.M. The final diagnosis of ACS was made by an independent cardiologist who was aware of clinical, biochemical, and angiographic data but not of echocardiographic data and according to guidelines established by the American College of Cardiology and the American Heart Association.1 Because echocardiographic data were not used to define the presence or absence of the end point ACS, an established diagnosis of ACS was used as a reference to calculate the diagnostic value of 2-dimensional echocardiography and MCE. Electrocardiographic and biochemical markers: Abnormal electrocardiographic findings were defined as the presence of ST depression or T-wave inversion ⬎0.2 mV in ⱖ2 contiguous leads with pre-
(NSTEMI), and unstable angina.1 On the basis of clinical, electrocardiographic, and biochemical findings, only 20% to 30% of patients who have chest pain are clearly identified at presentation as having ACS.2– 4 Because patients who have suspected ACS present with a wide spectrum of risks for cardiac events, a noninvasive imaging technique may be useful for triaging these patients.5 Real-time myocardial contrast echocardiography (MCE) is an imaging technique that is applicable at the bedside and extends evaluation of wall motion abnormalities by assessing myocardial perfusion.6 – 8 This study investigated whether MCE adds value to clinical and biochemical markers for detection and risk stratification of patients who have acute chest pain.
METHODS
Patient population: In this prospective study, we included patients who had first-time chest pain comFrom the Department of Cardiology, University of Heidelberg, Heidelberg, Germany. Manuscript received June 4, 2004; revised manuscript received and accepted July 27, 2004. Address for reprints: Grigorios Korosoglou, MD, Department of Cardiology, Internal Medicine III, Im Neuenheimer Feld 410, 69115 Heidelberg, Germany. E-mail: [email protected]. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 94 November 15, 2004
0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.07.104
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FIGURE 1. Apical perfusion defect (bottom left) in a man with normal electrocardiographic findings and an initially normal level of troponin T. Two-dimensional echocardiogram shows hypokinesia of the apex (top right) and angiography (bottom right) shows significant 90% stenosis in the left anterior descending artery. Myocardial blood flows were 0.01 dB/s in the apical-lateral region and 0.05 dB/s in the apical-septal region, which were lower than the selected threshold of 0.12 dB/s.
dominant R waves.1 Troponin T was typically collected at presentation and 4, 8, and 96 hours after admission to estimate the extent of myocardial dam1226 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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age9 and was determined by a commercially available enzyme-linked immunosorbent assay (Cardiac Reader, Roche, Mannheim, Germany). Troponin T NOVEMBER 15, 2004
TABLE 1 Demographic and Clinical Characteristics ACS Characteristic Age (yrs), mean ⫾ SD Men Ejection fraction (%), mean ⫾ SD Men ⬎45 yrs, women ⬎55 yrs Hypertention High cholesterol level (LDL ⬎130 mg/dl) Tobacco use Diabetes mellitus TIMI risk score No resolution of chest pain on admission Dyspnea on admission Renal failure Blood pressure on admission (mm Hg) Systolic Diastolic Heart rate (beats/min) Cardiac medications Antihypertensives Antianginals Diuretics Digoxin Aspirin
Yes (n ⫽ 37)
No (n ⫽ 61)
p Value
65 ⫾ 12 27 (73%) 48 ⫾ 13 33 (89%) 21 (57%) 16 (43%) 24 (65%) 12 (32%) 4.1 ⫾ 1.5 27 (73%) 7 (19%) 2 (5%)
57 ⫾ 15 32 (52%) 62 ⫾ 5 32 (52%) 33 (54%) 35 (57%) 24 (39%) 13 (21%) 3.3 ⫾ 1.3 45 (74%) 9 (15%) 3 (5%)
0.02 0.04 ⬍0.001 0.05 NS NS 0.02 NS 0.007 NS NS NS
pulse of a higher mechanical index (flash) was transmitted to “clear” the myocardium of microbubbles. After returning immediately to low-power imaging, replenishment was visualized over 10 to 15 cardiac cycles. Images were analyzed visually and quantitatively off-line with a commercially available software tool (HDI Laboratory, Advanced Technology Laboratories, Bothell, Washington). Visual analysis of contrast echocardiography: Visual analysis was as-
sessed by 2 experienced observers who were blinded to each other and to other data. A third independent observer proved the variability of the 139 ⫾ 20 142 ⫾ 22 NS 83 ⫾ 10 82 ⫾ 12 NS first 2 observers and resolved differ76 ⫾ 11 75 ⫾ 17 NS ences in opinion by consensus of all 3. Regional myocardial opacification 13 (35%) 24 (39%) NS was graded visually with a 3-point 0 2 (3%) NS 8 (22%) 8 (13%) NS scale (3 ⫽ homogeneous, 2 ⫽ mildly 0 1 (2%) NS decreased, 1 ⫽ severely decreased, 8 (22%) 17 (28%) NS and 0 ⫽ no opacification), as previData presented as numbers of patients (percentages) or as mean ⫾ SD, unless otherwise indicated. ously described.7,8 Severely deLDL ⫽ low-density lipoprotein; TIMI ⫽ Thrombolysis In Myocardial Infarction. creased and absent perfusion was considered indicative for myocardial ischemia.8 For composite myocardial concentrations ⬎0.03 g/L were considered indic- contrast echocardiographic interpretation using wall ative of myocardial cell damage. Creatine kinase motion and perfusion, segments were graded as abactivity was determined by a Synchron LX-20 clin- normal if wall motion or perfusion was abnormal and ical chemistry system (Beckman Coulter, Krefeld, as normal if perfusion and wall motion were normal. Germany) at 25°C, and the upper limit of normal for Quantitative analysis of contrast echocardiogtotal creatine kinase activity was 75 IU/L. raphy: For quantitative analysis, regions of interest Two-dimensional echocardiography: Echocardio- were placed in each segment, from the epicardium to graphic imaging was performed in standard apical 2-, endocardium, and myocardial contrast intensity after 3-, and 4-chamber views with an ATL HDI 5000 flash was measured at end-systole to estimate capillary (Philips Medical System, Bothell, Washington) and at volume.11 Plots of contrast intensity versus time were 4 weeks of follow-up. Regional wall motion was as- constructed and fit to an exponential function: y ⫽ sessed by 2-dimensional echocardiography before A(1 ⫺ e⫺t).12 The plateau of signal intensity (A) and contrast administration. Analysis of wall motion was the slope of maximal signal intensity increase () assessed by 2 experienced observers who were were measured in each segment. The product of A ⫻ blinded to each other and to other data, and they used  was calculated by estimating myocardial blood the 16-segment left ventricular model of the American flow. Perfusion defect size was measured at end-sysSociety of Echocardiography and a semiquantitative tole by planimetry, 10 to 15 cardiac cycles after flash grade scale of 1 (normal), 2 (hypokinesia), 3 (akine- (Figure 1). For purposes of comparison with coronary sia), and 4 (dyskinesia).10 Ejection fraction was quan- angiography and analysis at the level of perfusion territories, segments were assigned to coronary territified using the biplane Simpson’s method.10 Myocardial contrast echocardiography: MCE was tories as previously described.7,13 performed in all patients in the emergency department Coronary angiography: Decisions to perform coroand as soon as possible after admission. Myocardial nary angiography were based on clinical grounds incontrast echocardiographic data were acquired over 5 dependent of echocardiographic data. Coronary anto 15 minutes. SonoVue (Bracco, ByK-Golden, Kon- giography was performed ⬍12 hours after admission stanz, Germany) was administered as a slow bolus to the emergency department. The angiograms were injection (1.0 to 1.5 ml/bolus) followed by a 5-ml analyzed by an independent observer blinded to other flush to obtain optimal visualization of the left ventri- data. The degree of stenosis was expressed as the cle. Myocardial contrast echocardiographic perfusion percent decrease of the internal luminal diameter in imaging was performed with an ATL HDI 5000 as relation to the normal reference. Coronary stenosis previously described.7,8 Briefly, imaging was per- was defined as ⱖ75% narrowing of the reference formed with a low mechanical index (between 0.14 lumen diameter. and 0.18) in color-coded harmonic power pulse inverStatistical analysis: Data are presented as mean ⫾ sion mode. When attenuation was minimized, a brief SD. Agreement between observers was assessed with CORONARY ARTERY DISEASE/CONTRAST ECHOCARDIOGRAPHY TO DETECT ACS
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TABLE 2 Detection of Acute Coronary Syndromes by Conventional Tests and by Echocardiography ACS (n ⫽ 37) Abnormal finding on electrocardiogram Increased initial troponin T Increased follow-up troponin T Abnormal wall motion (2D-echo) Abnormal perfusion (MCE) Abnormal wall motion or perfusion
23 19 25 19 31 33
NSTEMI (n ⫽ 25)
(62%) (51%) (68%) (51%) (83%) (89%)
16 19 25 17 23 24
Unstable angina (n ⫽ 12)
(64%) (76%) (100%) (68%) (92%) (96%)
7 (58%) 0 0 2 (17%) 8 (66%) 9 (75%)
No ACS (n ⫽ 61) 9 2 2 2 4 4
(15%) (3%) (3%) (3%) (7%) (7%)
2D-Echo ⫽ 2-dimensional echocardiography.
TABLE 3 Detection of Acute Coronary Syndromes by Echocardiography Sensitivity
Specificity
PPV
NPV
Accuracy
51% 84%* 71% 92% 89%*
97% 93% 93% 93% 93%
90% 89% 71% 85% 89%
77% 91% 93% 93% 93%
80% 90% 89% 93% 92%
94%
84%
94%
70%
93%
Visual assessment Wall motion (2D-echo) Perfusion (MCE) Perfusion (MCE), single-vessel CAD Perfusion (MCE), multivessel CAD Wall motion and perfusion Quantitative assessment Myocardial blood flow, threshold 0.12 dB/s
*p ⬍0.05, myocardial perfusion versus wall motion. CAD ⫽ coronary artery disease; NPV ⫽ negative predictive value; PPV ⫽ positive predictive value. Other abbreviation as in Table 2.
TABLE 4 Logistic Regression Model for Prediction of Acute Coronary Syndrome
Variable Model 1 for probability without real-time MCE* Intercept TIMI risk score Abnormal finding on electrocardiogram Abnormal follow-up level of troponin T Model 2 for probability with real-time MCE† Intercept TIMI risk score Abnormal finding on electrocardiogram Abnormal follow-up level of troponin T Real-time MCE
Wald’s Chi-square DF Coefficient Test p Value 1 1 1 1
⫺3.165 0.436 2.139 4.266
15.126 3.005 9.445 20.331
⬍0.001 0.083 0.002 ⬍0.001
1 1 1 1 1
⫺2.940 ⫺0.005 0.073 2.711 4.644
7.098 0.017 0.003 4.936 13.620
0.008 0.896 0.952 0.026 ⬍0.001
*Two-log likehood ⫽ 61.03 with 4 DF (p ⬍0.001). † Two-log likehood ⫽ 38.43 with 5 DF (p ⬍0.001). DF-degrees of freedom. Other abbreviation as in Table 1.
statistics. Inter- and intraobserver variabilities for measurement of quantitative myocardial contrast echocardiographic values were obtained by repeated analysis of 20 representative images. Logistic regression was performed to assess whether MCE would add diagnostic information over conventional tests, as previously described.13,14 The intercept and coefficients, which represented the relative weighting of each variable, were estimated using the logistic regression procedure of SPSS 11.0 (SPSS, Inc., Chicago, Illinois). Repeated measures analysis of variance with Bonferroni’s adjustment for multiple comparisons was used to compare quantitative myocardial contrast echocardiographic values. Statistical significance of differences in diagnostic value was evaluated by McNemar’s chi-square test.8 Receiver-operator 1228 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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characteristics were used to assess diagnostic characteristics of quantitative MCE. Perfusion defect size was compared with troponin T levels and ejection fraction using linear regression analysis. Differences were considered statistically significant at a p value of ⬍0.05.
RESULTS
Clinical and angiographic data:
Thirty-seven patients had a final diagnosis of ACS. Twelve of these patients had unstable angina defined as class IIIB according to Braunwald’s classification and showed high-grade stenotic lesions in ⱖ1 coronary artery. Twenty-five patients had NSTEMI with increased troponin T initially (n ⫽ 19) or at follow-up (n ⫽ 6), and 61 patients had non–ACS-related chest pain. Of these patients, 21 underwent angiography that showed no high-grade (ⱖ75%) lesions and 40 patients underwent stress testing that resulted in normal findings. Two of 61 patients who had non–ACS-related chest pain showed increased troponin T. In these 2 patients, angiograms showed normal coronary arteries, 2-dimensional echocardiograms showed pericardial effusion, and the increased troponin T was attributed to perimyocarditis. Two patients were excluded from analysis due to suboptimal echocardiographic windows. Thus, of 98 patients available for analysis, 12 had unstable angina, 25 had NSTEMI, and 61 had non–ACS-related chest pain, including the 2 patients who had perimyocarditis. Several clinical parameters NOVEMBER 15, 2004
Visual MCE achieved good sensitivity (84%) and high specificity (93%) for detection of ACS (Tables 2 and 3). MCE plus wall motion analysis further increased the sensitivity (89% vs 51%, p ⬍0.01) of the method and remained highly specific (93%) and predictive (89%; Table 3). Myocardial contrast echocardiograms identified 9 of 12 patients (75%) who had high-grade coronary lesions and normal levels of troponin T. Six of 25 patients (24%) who had NSTEMI showed troponin T levels that were initially normal and then high at 4-hour follow-up. MCE was performed before availability of follow-up troponin T levels in all 6 patients and successfully detected ACS in these patients before an increase in troponin T. ACS was detected in patients who had multivessel disease with a higher sensitivity than in patients who had 1-vessel disease (92% vs 71%). However, this difference did not reach statistical significance by McNemar’s chi-square test (Table 3). Multivariate logistic regression analysis: Abnormal findings on myo-
cardial contrast echocardiograms was the most significant test for detection of ACS and added independent diagnostic information to electrocardiograms and troponin T levels (Table 4). To investigate the incremental value of MCE, 2 regression logistic models were considered, 1 with and 1 without MCE. In model 1 FIGURE 2. A, , and A ⴛ  values decreased with worsening myocardial contractile [intercept (p/[1 ⫺ p]) ⫽ intercept ⫹ function (A) and were significantly lower in segments supplied by a stenotic coronary artery on angiography (B). (C) Ischemic segments with normal wall motion demonstrated A(Thrombolysis In Myocardial Insignificantly higher myocardial blood flow than did ischemic dysfunctional segments. *p farction score) ⫹ B(abnormal elec<0.01, normal versus hypokinetic; †p <0.01, ischemic segments versus ischemic and trocardiogram) ⫹ C(abnormal level ‡ dysfunctional segments; p <0.01, segments supplied by nonstenotic versus stenotic coroon follow-up troponin T)], electro# nary arteries; p <0.01, hypokinetic versus akinetic and dyskinetic. cardiograms and troponin T levels at follow-up were significantly predictive for ACS. When MCE was added differed significantly between patients who had and to this model (model 2) [intercept (p/[1 ⫺ p]) ⫽ intercept ⫹ A(Thrombolysis In Myocardial Infarction those who did not have ACS (Table 1). Analysis of wall motion: Wall motion analysis dem- score) ⫹ B(abnormal electrocardiogram) ⫹ C(abnoronstrated low sensitivity (51%) but high specificity mal level on follow-up troponin T) ⫹ D=(abnormal (97%) for detection of ACS (Tables 2 and 3). Two- myocardial contrast echocardiogram)], electrocardidimensional echocardiograms indicated perimyocardi- ography was no longer significant, whereas MCE reptis in 2 patients who had normal wall motion and resented the most powerful independent predictive parameter (p ⬍0.001 for MCE vs p ⫽ 0.026 for pericardial effusion. Combination of perfusion and wall motion data: MCE follow-up troponin T level). MCE added diagnostic plus wall motion analysis yielded good sensitivity information (chi-square 87.5) to the clinical (chi(89%) and accuracy (90%) for identifying ACS (Table square 28.4) and biochemical (chi-square 64.8) 3). MCE was initially performed in the emergency markers. department at 98 ⫾ 54 minutes (range 15 to 365) after Quantitative analysis of myocardial perfusion on a admission. Twenty-one patients underwent MCE be- segmental level: A, , and A ⫻  values decreased fore the availability of initial troponin T levels, and 95 with worsening myocardial contractile function and of 98 patients underwent MCE before the availability showed significantly lower values in segments supof follow-up troponin T levels. plied by stenotic (ⱖ75%) coronary arteries (Figure 2). CORONARY ARTERY DISEASE/CONTRAST ECHOCARDIOGRAPHY TO DETECT ACS
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FIGURE 3. Quantitative estimations of myocardial blood volume (A) and myocardial blood flow (B) by MCE provided good diagnostic characteristics for detection of segmental ischemia. The area of perfusion defect correlated strongly with troponin T level at 96 hours (C) and with EF at follow-up (D). AUC ⴝ area under the curve; cTnT ⴝ cardiac troponin T; EF ⴝ ejection fraction.
Further analysis demonstrated that, in segments supplied by stenotic arteries, myocardial blood flow was significantly lower when wall motion abnormalities were also present (Figure 2). Receiver-operating characteristics were used to assess prediction of myocardial ischemia on a segmental level by A, , and A ⫻  values (Figure 3). By selecting a threshold of 0.12 dB/s for myocardial blood flow (A ⫻ ), high accuracy (93%) was achieved for detection of segmental ischemia (Table 3). Perfusion defect size versus initial and peak levels of troponin T: Perfusion defect size in patients who had
ACS correlated strongly with troponin T levels at 96 hours and with global ejection fraction at 4-week follow-up (Figure 3). Observer variabilities of wall motion and perfusion:
Agreements between observers were 88% ( ⫽ 0.79) for interpreting perfusion and 91% ( ⫽ 0.82) for interpreting wall motion. The intra- and interobserver variabilities were 8% and 11% for quantification of A and 17% and 18% for quantification of . Intraobserver variability was 12% for planimetric quantification of the perfusion defect area.
DISCUSSION The results of this study show that MCE adds value to clinical and biochemical markers for detection of 1230 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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ACS and supports immediate risk stratification of patients who have chest pain. Radionuclide imaging is the most investigated modality in patients who have chest pain, and its detection of ACS is reasonable, in particular for technetium-99m tracers.15,16 However, nuclear imaging shows low spatial and limited temporal resolution. Magnetic resonance imaging has recently demonstrated diagnostic characteristics suitable for triaging of patients who have acute chest pain.13 However, magnetic resonance imaging is not applicable in high-risk patients because transportation away from the emergency department is necessary. Twodimensional echocardiography has been shown to reliably identify patients who have acute infarction in the emergency department.17,18 In a recent study that evaluated myocardial perfusion in a relative small group of patients and used older intermittent techniques,19 visual MCE showed good agreement with radionuclide imaging. In contrast to triggered imaging modalities that are time consuming and sensitive to motion artifacts, recent real-time techniques20 may be more efficient for detection of ACS in humans. This is the first study to demonstrate that MCE can detect ACS in patients who have chest pain as they present to the emergency department. MCE was the strongest predictor of ACS and added significant diNOVEMBER 15, 2004
agnostic value to clinical and biochemical markers, particularly in patients who had unstable angina. Furthermore, MCE accurately detected ACS in all 6 patients who had NSTEMI and normal levels of troponin T on admission and correctly excluded ACS in 2 patients who had chest pain and increased troponin T by identifying perimyocarditis. Myocardial perfusion was superior for detection of ACS compared with wall motion analysis, which may have a pathophysiologic explanation. In ACS, rupture of atherosclerotic plaques with subsequent peripheral microvascular embolization and thrombosis may decrease myocardial tissue perfusion.21 As demonstrated in experimental studies,22 myocardial blood flow may diminish to a level at which perfusion defects of subendocardial tissue are present but wall motion abnormalities are not detectable by 2-dimensional echocardiography. In the present study, 34 segments showed isolated perfusion abnormalities in 12 patients who had ACS. In these segments, myocardial blood flow decreased to a level that allowed detection of perfusion defects by MCE, but, as illustrated by quantitative data (Figure 2), another significant decrease in blood flow was necessary to cause wall motion abnormalities detectable by 2-dimensional echocardiography. Because ACS would have been missed in 12 of 33 patients (36%) just by assessment of wall motion, it is not surprising that myocardial perfusion was the most powerful parameter for identification of patients who had ACS. We previously demonstrated that estimation of myocardial blood flow by real-time MCE is useful to evaluate myocardial perfusion during adenosine stress testing in patients who had suspected coronary artery disease.7 However, because the patients in this study included those at high risk of evolving myocardial infarction, we did not use pharmacologic stress testing for safety reasons. Visual analysis of myocardial perfusion images was performed by 2 experienced echocardiographers (GK and AH) and yielded high specificity and accuracy and low interobserver variability. Observer variability may be higher and accuracy of perfusion imaging lower if visual analysis is performed by less experienced observers. However, newer automated myocardial parametric quantification methods that provide color-encoded quantification of myocardial blood flow23 may decrease observer variability and improve the reproducibility and the practicability of the method. This report demonstrates the added value of MCE to conventional testing for detecting ACS and highlights the prognostic value of this method. Because the initial perfusion defect size correlates strongly with the grade of myocardial damage, this may represent a novel variable for risk stratification in patients who have ACS. 1. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman
JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, et al (Committee on the Management of Patients With Unstable Angina). ACC/AHA guideline update for the management of patients with unstable angina and non–ST-segment elevation
myocardial infarction—2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Circulation 2002;106:1893–1900. 2. Lee TH, Cook EF, Weisberg M, Sargent RK, Wilson C, Goldman L. Acute chest pain in the emergency room. Identification and examination of low-risk patients. Arch Intern Med 1985;145:65– 69. 3. Rouan GW, Lee TH, Cook EF, Brand DA, Weisberg MC, Goldman L. Clinical characteristics and natural history of patients with acute myocardial infarction sent home from the emergency room. Am J Cardiol 1987;60:219 –224. 4. Antman EM, Braunwald E. Acute myocardial infarction. In: Braunwald E, ed. Heart Disease: A Textbook in Cardiovascular Medicine, 5th Ed. Philadelphia: WB Saunders, 1997:1184 –1288. 5. Antman EM, Tanasijevic MJ, Thompson B, Schactman M, McCabe CH, Cannon CP, Fischer GA, Fung AY, Thompson C, Wybenga D, Braunwald E. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335:1342–1349. 6. Kaul S, Senior R, Dittrich H, Raval U, Khattar R, Lahiri A. Detection of coronary artery disease with myocardial contrast echocardiography: comparison with 99mTc-sestamibi single-photon emission computed tomography. Circulation 1997;96:785–792. 7. Korosoglou G, da Silva KG Jr, Labadze N, Dubart AE, Hansen A, Rosenberg M, Zehelein J, Kuecherer H. Real-time myocardial contrast echocardiography for pharmacological stress testing. Is quantitative estimation of myocardial blood flow reserve necessary? J Am Soc Echocardiogr 2004;17:1–9. 8. Korosoglou G, Hansen A, Hoffend J, Gavrilovic G, David W, Zehelein J, Haberkorn U, Kuecherer H. Comparison of real-time myocardial contrast echocardiography for the assessment of myocardial viability with fluorodeoxyglucose-18 positron emission tomography and dobutamine stress echocardiography. Am J Cardiol 2004;94:31–37. 9. Remppis A, Ehlermann P, Giannitsis E, Greten T, Most P, Muller-Bardorff M, Katus HA. Cardiac troponin T levels at 96 hours reflect myocardial infarct size: a pathoanatomical study. Cardiology 2000;93:249 –253. 10. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I. Recommendations for quantification of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;2:358 –367. 11. Iwanaga S, Ewing SG, Husseini WK, Hoffman JI. Changes in contractility and afterload have only slight effects on subendocardial systolic flow impediment. Am J Physiol 1995;269:H1202–H1212. 12. Wei K, Jayaweera AR, Firoozan S, Linka A, Skyba DM, Kaul S. Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation 1998;97:473– 483. 13. Kwong RY, Schussheim AE, Rekhraj S, Aletras AH, Geller N, Davis J, Christian TF, Balaban RS, Arai AE. Detecting acute coronary syndrome in the emergency department with cardiac magnetic resonance imaging. Circulation 2003;107:531–537. 14. Horton NJ, Laird NM. Maximum likelihood analysis of logistic regression models with incomplete covariate data and auxiliary information. Biometrics 2001;57:34 – 42. 15. Heller GV, Stowers SA, Hendel RC, Herman SD, Daher E, Ahlberg AW, Baron JM, Mendes de Leon CF, Rizzo JA, Wackers FJ. Clinical value of acute rest technetium-99m tetrofosmin tomographic myocardial perfusion imaging in patients with acute chest pain and nondiagnostic electrocardiograms. J Am Coll Cardiol 1998;31:1011–1017. 16. Hilton TC, Thompson RC, Williams HJ, Saylors R, Fulmer H, Stowers SA. Technetium-99m sestamibi myocardial perfusion imaging in the emergency room evaluation of chest pain. J Am Coll Cardiol 1994;23:1016 –1022. 17. Sabia P, Afrookteh A, Touchstone DA, Keller MW, Esquivel L, Kaul S. Value of regional wall motion abnormality in the emergency room diagnosis of acute myocardial infarction. A prospective study using two-dimensional echocardiography. Circulation 1991;84:85–92. 18. Kontos MC, Kurdziel K, McQueen R, Arrowood JA, Jesse RL, Ornato JP, Paulsen WH, Tatum JL, Nixon JV. Comparison of 2-dimensional echocardiography and myocardial perfusion imaging for diagnosing myocardial infarction in emergency department patients. Am Heart J 2002;143:659 – 667. 19. Kontos MC, Hinchman D, Cunningham M, Miller JJ, Cherif J, Nixon JV. Comparison of contrast echocardiography with single-photon emission computed tomographic myocardial perfusion imaging in the evaluation of patients with possible acute coronary syndromes in the emergency department. Am J Cardiol 2003;91:1099 –1102. 20. Becher H, Burns PN. Contrast agents for echocardiography: principles and instrumentation. In: Becher H, Burns PN, eds. Handbook of Contrast Echocardiography. New York: Springer-Verlag, 2000:2– 44. 21. Fuster V, Corti R, Fayad ZA, Schwitter J, Badimon JJ. Integration of vascular biology and magnetic resonance imaging in the understanding of atherothrombosis and acute coronary syndromes. J Thromb Haemost 2003;1:1410 –1421. 22. Lafitte S, Matsugata H, Peters B, Togni M, Strachan M, Kwan OL, DeMaria AN. Comparative value of dobutamine and adenosine stress in the detection of coronary stenosis with myocardial contrast echocardiography. Circulation 2001; 103:2724 –2730. 23. Yu EH, Skyba DM, Leong-Poi H, Sloggett C, Jamorski M, Garg R, Iwanochko RM, Siu SC. Incremental value of parametric quantitative assessment of myocardial perfusion by triggered low-power myocardial contrast echocardiography. J Am Coll Cardiol 2004;43:1807–1813.
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tified all 6 patients who had non–ST-elevation myocardial infarction and no initial increase in troponin T and 17 of 19 patients who had non–ST-elevation myocardial infarction and an initial increase in troponin T. In 2 patients who had chest pain and increased troponin T, MCE excluded ACS by identifying perimyocarditis as the underlying cause. Multivariate logistic regression analysis showed that MCE was the strongest predictor of ACS, thus adding significant diagnostic value to conventional tests. Initial perfusion defect size correlated strongly with increased troponin T at 96 hours (r ⴝ 0.73, p <0.001) and with ejection fraction at 4 weeks of follow-up (r ⴝ ⴚ0.79, p <0.001). Thus, our data suggest that MCE can accurately identify patients who have ACS. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;94:1225–1231)
cute coronary syndromes (ACSs) encompass the clinical manifestation of ST-elevation myocardial A infarction, non–ST-elevation myocardial infarction
patible with myocardial ischemia. Inclusion criteria were pain duration ⬎20 minutes and occurrence of chest pain ⬍12 hours before presentation. Exclusion criteria were ST-elevation myocardial infarction, history of coronary artery disease, and historical or electrocardiographic evidence of previous infarction. The study protocol was approved by the local ethics committee, and all patients gave written informed consent. Study protocol: We prospectively performed MCE in the emergency department in 100 patients who had been admitted with chest pain. Personnel with skills to perform myocardial contrast echocardiographic studies was available during 5 days a week and from at least 8:00 A.M. to 8:00 P.M. The final diagnosis of ACS was made by an independent cardiologist who was aware of clinical, biochemical, and angiographic data but not of echocardiographic data and according to guidelines established by the American College of Cardiology and the American Heart Association.1 Because echocardiographic data were not used to define the presence or absence of the end point ACS, an established diagnosis of ACS was used as a reference to calculate the diagnostic value of 2-dimensional echocardiography and MCE. Electrocardiographic and biochemical markers: Abnormal electrocardiographic findings were defined as the presence of ST depression or T-wave inversion ⬎0.2 mV in ⱖ2 contiguous leads with pre-
(NSTEMI), and unstable angina.1 On the basis of clinical, electrocardiographic, and biochemical findings, only 20% to 30% of patients who have chest pain are clearly identified at presentation as having ACS.2– 4 Because patients who have suspected ACS present with a wide spectrum of risks for cardiac events, a noninvasive imaging technique may be useful for triaging these patients.5 Real-time myocardial contrast echocardiography (MCE) is an imaging technique that is applicable at the bedside and extends evaluation of wall motion abnormalities by assessing myocardial perfusion.6 – 8 This study investigated whether MCE adds value to clinical and biochemical markers for detection and risk stratification of patients who have acute chest pain.
METHODS
Patient population: In this prospective study, we included patients who had first-time chest pain comFrom the Department of Cardiology, University of Heidelberg, Heidelberg, Germany. Manuscript received June 4, 2004; revised manuscript received and accepted July 27, 2004. Address for reprints: Grigorios Korosoglou, MD, Department of Cardiology, Internal Medicine III, Im Neuenheimer Feld 410, 69115 Heidelberg, Germany. E-mail: [email protected]. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 94 November 15, 2004
0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.07.104
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FIGURE 1. Apical perfusion defect (bottom left) in a man with normal electrocardiographic findings and an initially normal level of troponin T. Two-dimensional echocardiogram shows hypokinesia of the apex (top right) and angiography (bottom right) shows significant 90% stenosis in the left anterior descending artery. Myocardial blood flows were 0.01 dB/s in the apical-lateral region and 0.05 dB/s in the apical-septal region, which were lower than the selected threshold of 0.12 dB/s.
dominant R waves.1 Troponin T was typically collected at presentation and 4, 8, and 96 hours after admission to estimate the extent of myocardial dam1226 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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age9 and was determined by a commercially available enzyme-linked immunosorbent assay (Cardiac Reader, Roche, Mannheim, Germany). Troponin T NOVEMBER 15, 2004
TABLE 1 Demographic and Clinical Characteristics ACS Characteristic Age (yrs), mean ⫾ SD Men Ejection fraction (%), mean ⫾ SD Men ⬎45 yrs, women ⬎55 yrs Hypertention High cholesterol level (LDL ⬎130 mg/dl) Tobacco use Diabetes mellitus TIMI risk score No resolution of chest pain on admission Dyspnea on admission Renal failure Blood pressure on admission (mm Hg) Systolic Diastolic Heart rate (beats/min) Cardiac medications Antihypertensives Antianginals Diuretics Digoxin Aspirin
Yes (n ⫽ 37)
No (n ⫽ 61)
p Value
65 ⫾ 12 27 (73%) 48 ⫾ 13 33 (89%) 21 (57%) 16 (43%) 24 (65%) 12 (32%) 4.1 ⫾ 1.5 27 (73%) 7 (19%) 2 (5%)
57 ⫾ 15 32 (52%) 62 ⫾ 5 32 (52%) 33 (54%) 35 (57%) 24 (39%) 13 (21%) 3.3 ⫾ 1.3 45 (74%) 9 (15%) 3 (5%)
0.02 0.04 ⬍0.001 0.05 NS NS 0.02 NS 0.007 NS NS NS
pulse of a higher mechanical index (flash) was transmitted to “clear” the myocardium of microbubbles. After returning immediately to low-power imaging, replenishment was visualized over 10 to 15 cardiac cycles. Images were analyzed visually and quantitatively off-line with a commercially available software tool (HDI Laboratory, Advanced Technology Laboratories, Bothell, Washington). Visual analysis of contrast echocardiography: Visual analysis was as-
sessed by 2 experienced observers who were blinded to each other and to other data. A third independent observer proved the variability of the 139 ⫾ 20 142 ⫾ 22 NS 83 ⫾ 10 82 ⫾ 12 NS first 2 observers and resolved differ76 ⫾ 11 75 ⫾ 17 NS ences in opinion by consensus of all 3. Regional myocardial opacification 13 (35%) 24 (39%) NS was graded visually with a 3-point 0 2 (3%) NS 8 (22%) 8 (13%) NS scale (3 ⫽ homogeneous, 2 ⫽ mildly 0 1 (2%) NS decreased, 1 ⫽ severely decreased, 8 (22%) 17 (28%) NS and 0 ⫽ no opacification), as previData presented as numbers of patients (percentages) or as mean ⫾ SD, unless otherwise indicated. ously described.7,8 Severely deLDL ⫽ low-density lipoprotein; TIMI ⫽ Thrombolysis In Myocardial Infarction. creased and absent perfusion was considered indicative for myocardial ischemia.8 For composite myocardial concentrations ⬎0.03 g/L were considered indic- contrast echocardiographic interpretation using wall ative of myocardial cell damage. Creatine kinase motion and perfusion, segments were graded as abactivity was determined by a Synchron LX-20 clin- normal if wall motion or perfusion was abnormal and ical chemistry system (Beckman Coulter, Krefeld, as normal if perfusion and wall motion were normal. Germany) at 25°C, and the upper limit of normal for Quantitative analysis of contrast echocardiogtotal creatine kinase activity was 75 IU/L. raphy: For quantitative analysis, regions of interest Two-dimensional echocardiography: Echocardio- were placed in each segment, from the epicardium to graphic imaging was performed in standard apical 2-, endocardium, and myocardial contrast intensity after 3-, and 4-chamber views with an ATL HDI 5000 flash was measured at end-systole to estimate capillary (Philips Medical System, Bothell, Washington) and at volume.11 Plots of contrast intensity versus time were 4 weeks of follow-up. Regional wall motion was as- constructed and fit to an exponential function: y ⫽ sessed by 2-dimensional echocardiography before A(1 ⫺ e⫺t).12 The plateau of signal intensity (A) and contrast administration. Analysis of wall motion was the slope of maximal signal intensity increase () assessed by 2 experienced observers who were were measured in each segment. The product of A ⫻ blinded to each other and to other data, and they used  was calculated by estimating myocardial blood the 16-segment left ventricular model of the American flow. Perfusion defect size was measured at end-sysSociety of Echocardiography and a semiquantitative tole by planimetry, 10 to 15 cardiac cycles after flash grade scale of 1 (normal), 2 (hypokinesia), 3 (akine- (Figure 1). For purposes of comparison with coronary sia), and 4 (dyskinesia).10 Ejection fraction was quan- angiography and analysis at the level of perfusion territories, segments were assigned to coronary territified using the biplane Simpson’s method.10 Myocardial contrast echocardiography: MCE was tories as previously described.7,13 performed in all patients in the emergency department Coronary angiography: Decisions to perform coroand as soon as possible after admission. Myocardial nary angiography were based on clinical grounds incontrast echocardiographic data were acquired over 5 dependent of echocardiographic data. Coronary anto 15 minutes. SonoVue (Bracco, ByK-Golden, Kon- giography was performed ⬍12 hours after admission stanz, Germany) was administered as a slow bolus to the emergency department. The angiograms were injection (1.0 to 1.5 ml/bolus) followed by a 5-ml analyzed by an independent observer blinded to other flush to obtain optimal visualization of the left ventri- data. The degree of stenosis was expressed as the cle. Myocardial contrast echocardiographic perfusion percent decrease of the internal luminal diameter in imaging was performed with an ATL HDI 5000 as relation to the normal reference. Coronary stenosis previously described.7,8 Briefly, imaging was per- was defined as ⱖ75% narrowing of the reference formed with a low mechanical index (between 0.14 lumen diameter. and 0.18) in color-coded harmonic power pulse inverStatistical analysis: Data are presented as mean ⫾ sion mode. When attenuation was minimized, a brief SD. Agreement between observers was assessed with CORONARY ARTERY DISEASE/CONTRAST ECHOCARDIOGRAPHY TO DETECT ACS
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TABLE 2 Detection of Acute Coronary Syndromes by Conventional Tests and by Echocardiography ACS (n ⫽ 37) Abnormal finding on electrocardiogram Increased initial troponin T Increased follow-up troponin T Abnormal wall motion (2D-echo) Abnormal perfusion (MCE) Abnormal wall motion or perfusion
23 19 25 19 31 33
NSTEMI (n ⫽ 25)
(62%) (51%) (68%) (51%) (83%) (89%)
16 19 25 17 23 24
Unstable angina (n ⫽ 12)
(64%) (76%) (100%) (68%) (92%) (96%)
7 (58%) 0 0 2 (17%) 8 (66%) 9 (75%)
No ACS (n ⫽ 61) 9 2 2 2 4 4
(15%) (3%) (3%) (3%) (7%) (7%)
2D-Echo ⫽ 2-dimensional echocardiography.
TABLE 3 Detection of Acute Coronary Syndromes by Echocardiography Sensitivity
Specificity
PPV
NPV
Accuracy
51% 84%* 71% 92% 89%*
97% 93% 93% 93% 93%
90% 89% 71% 85% 89%
77% 91% 93% 93% 93%
80% 90% 89% 93% 92%
94%
84%
94%
70%
93%
Visual assessment Wall motion (2D-echo) Perfusion (MCE) Perfusion (MCE), single-vessel CAD Perfusion (MCE), multivessel CAD Wall motion and perfusion Quantitative assessment Myocardial blood flow, threshold 0.12 dB/s
*p ⬍0.05, myocardial perfusion versus wall motion. CAD ⫽ coronary artery disease; NPV ⫽ negative predictive value; PPV ⫽ positive predictive value. Other abbreviation as in Table 2.
TABLE 4 Logistic Regression Model for Prediction of Acute Coronary Syndrome
Variable Model 1 for probability without real-time MCE* Intercept TIMI risk score Abnormal finding on electrocardiogram Abnormal follow-up level of troponin T Model 2 for probability with real-time MCE† Intercept TIMI risk score Abnormal finding on electrocardiogram Abnormal follow-up level of troponin T Real-time MCE
Wald’s Chi-square DF Coefficient Test p Value 1 1 1 1
⫺3.165 0.436 2.139 4.266
15.126 3.005 9.445 20.331
⬍0.001 0.083 0.002 ⬍0.001
1 1 1 1 1
⫺2.940 ⫺0.005 0.073 2.711 4.644
7.098 0.017 0.003 4.936 13.620
0.008 0.896 0.952 0.026 ⬍0.001
*Two-log likehood ⫽ 61.03 with 4 DF (p ⬍0.001). † Two-log likehood ⫽ 38.43 with 5 DF (p ⬍0.001). DF-degrees of freedom. Other abbreviation as in Table 1.
statistics. Inter- and intraobserver variabilities for measurement of quantitative myocardial contrast echocardiographic values were obtained by repeated analysis of 20 representative images. Logistic regression was performed to assess whether MCE would add diagnostic information over conventional tests, as previously described.13,14 The intercept and coefficients, which represented the relative weighting of each variable, were estimated using the logistic regression procedure of SPSS 11.0 (SPSS, Inc., Chicago, Illinois). Repeated measures analysis of variance with Bonferroni’s adjustment for multiple comparisons was used to compare quantitative myocardial contrast echocardiographic values. Statistical significance of differences in diagnostic value was evaluated by McNemar’s chi-square test.8 Receiver-operator 1228 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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characteristics were used to assess diagnostic characteristics of quantitative MCE. Perfusion defect size was compared with troponin T levels and ejection fraction using linear regression analysis. Differences were considered statistically significant at a p value of ⬍0.05.
RESULTS
Clinical and angiographic data:
Thirty-seven patients had a final diagnosis of ACS. Twelve of these patients had unstable angina defined as class IIIB according to Braunwald’s classification and showed high-grade stenotic lesions in ⱖ1 coronary artery. Twenty-five patients had NSTEMI with increased troponin T initially (n ⫽ 19) or at follow-up (n ⫽ 6), and 61 patients had non–ACS-related chest pain. Of these patients, 21 underwent angiography that showed no high-grade (ⱖ75%) lesions and 40 patients underwent stress testing that resulted in normal findings. Two of 61 patients who had non–ACS-related chest pain showed increased troponin T. In these 2 patients, angiograms showed normal coronary arteries, 2-dimensional echocardiograms showed pericardial effusion, and the increased troponin T was attributed to perimyocarditis. Two patients were excluded from analysis due to suboptimal echocardiographic windows. Thus, of 98 patients available for analysis, 12 had unstable angina, 25 had NSTEMI, and 61 had non–ACS-related chest pain, including the 2 patients who had perimyocarditis. Several clinical parameters NOVEMBER 15, 2004
Visual MCE achieved good sensitivity (84%) and high specificity (93%) for detection of ACS (Tables 2 and 3). MCE plus wall motion analysis further increased the sensitivity (89% vs 51%, p ⬍0.01) of the method and remained highly specific (93%) and predictive (89%; Table 3). Myocardial contrast echocardiograms identified 9 of 12 patients (75%) who had high-grade coronary lesions and normal levels of troponin T. Six of 25 patients (24%) who had NSTEMI showed troponin T levels that were initially normal and then high at 4-hour follow-up. MCE was performed before availability of follow-up troponin T levels in all 6 patients and successfully detected ACS in these patients before an increase in troponin T. ACS was detected in patients who had multivessel disease with a higher sensitivity than in patients who had 1-vessel disease (92% vs 71%). However, this difference did not reach statistical significance by McNemar’s chi-square test (Table 3). Multivariate logistic regression analysis: Abnormal findings on myo-
cardial contrast echocardiograms was the most significant test for detection of ACS and added independent diagnostic information to electrocardiograms and troponin T levels (Table 4). To investigate the incremental value of MCE, 2 regression logistic models were considered, 1 with and 1 without MCE. In model 1 FIGURE 2. A, , and A ⴛ  values decreased with worsening myocardial contractile [intercept (p/[1 ⫺ p]) ⫽ intercept ⫹ function (A) and were significantly lower in segments supplied by a stenotic coronary artery on angiography (B). (C) Ischemic segments with normal wall motion demonstrated A(Thrombolysis In Myocardial Insignificantly higher myocardial blood flow than did ischemic dysfunctional segments. *p farction score) ⫹ B(abnormal elec<0.01, normal versus hypokinetic; †p <0.01, ischemic segments versus ischemic and trocardiogram) ⫹ C(abnormal level ‡ dysfunctional segments; p <0.01, segments supplied by nonstenotic versus stenotic coroon follow-up troponin T)], electro# nary arteries; p <0.01, hypokinetic versus akinetic and dyskinetic. cardiograms and troponin T levels at follow-up were significantly predictive for ACS. When MCE was added differed significantly between patients who had and to this model (model 2) [intercept (p/[1 ⫺ p]) ⫽ intercept ⫹ A(Thrombolysis In Myocardial Infarction those who did not have ACS (Table 1). Analysis of wall motion: Wall motion analysis dem- score) ⫹ B(abnormal electrocardiogram) ⫹ C(abnoronstrated low sensitivity (51%) but high specificity mal level on follow-up troponin T) ⫹ D=(abnormal (97%) for detection of ACS (Tables 2 and 3). Two- myocardial contrast echocardiogram)], electrocardidimensional echocardiograms indicated perimyocardi- ography was no longer significant, whereas MCE reptis in 2 patients who had normal wall motion and resented the most powerful independent predictive parameter (p ⬍0.001 for MCE vs p ⫽ 0.026 for pericardial effusion. Combination of perfusion and wall motion data: MCE follow-up troponin T level). MCE added diagnostic plus wall motion analysis yielded good sensitivity information (chi-square 87.5) to the clinical (chi(89%) and accuracy (90%) for identifying ACS (Table square 28.4) and biochemical (chi-square 64.8) 3). MCE was initially performed in the emergency markers. department at 98 ⫾ 54 minutes (range 15 to 365) after Quantitative analysis of myocardial perfusion on a admission. Twenty-one patients underwent MCE be- segmental level: A, , and A ⫻  values decreased fore the availability of initial troponin T levels, and 95 with worsening myocardial contractile function and of 98 patients underwent MCE before the availability showed significantly lower values in segments supof follow-up troponin T levels. plied by stenotic (ⱖ75%) coronary arteries (Figure 2). CORONARY ARTERY DISEASE/CONTRAST ECHOCARDIOGRAPHY TO DETECT ACS
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FIGURE 3. Quantitative estimations of myocardial blood volume (A) and myocardial blood flow (B) by MCE provided good diagnostic characteristics for detection of segmental ischemia. The area of perfusion defect correlated strongly with troponin T level at 96 hours (C) and with EF at follow-up (D). AUC ⴝ area under the curve; cTnT ⴝ cardiac troponin T; EF ⴝ ejection fraction.
Further analysis demonstrated that, in segments supplied by stenotic arteries, myocardial blood flow was significantly lower when wall motion abnormalities were also present (Figure 2). Receiver-operating characteristics were used to assess prediction of myocardial ischemia on a segmental level by A, , and A ⫻  values (Figure 3). By selecting a threshold of 0.12 dB/s for myocardial blood flow (A ⫻ ), high accuracy (93%) was achieved for detection of segmental ischemia (Table 3). Perfusion defect size versus initial and peak levels of troponin T: Perfusion defect size in patients who had
ACS correlated strongly with troponin T levels at 96 hours and with global ejection fraction at 4-week follow-up (Figure 3). Observer variabilities of wall motion and perfusion:
Agreements between observers were 88% ( ⫽ 0.79) for interpreting perfusion and 91% ( ⫽ 0.82) for interpreting wall motion. The intra- and interobserver variabilities were 8% and 11% for quantification of A and 17% and 18% for quantification of . Intraobserver variability was 12% for planimetric quantification of the perfusion defect area.
DISCUSSION The results of this study show that MCE adds value to clinical and biochemical markers for detection of 1230 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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ACS and supports immediate risk stratification of patients who have chest pain. Radionuclide imaging is the most investigated modality in patients who have chest pain, and its detection of ACS is reasonable, in particular for technetium-99m tracers.15,16 However, nuclear imaging shows low spatial and limited temporal resolution. Magnetic resonance imaging has recently demonstrated diagnostic characteristics suitable for triaging of patients who have acute chest pain.13 However, magnetic resonance imaging is not applicable in high-risk patients because transportation away from the emergency department is necessary. Twodimensional echocardiography has been shown to reliably identify patients who have acute infarction in the emergency department.17,18 In a recent study that evaluated myocardial perfusion in a relative small group of patients and used older intermittent techniques,19 visual MCE showed good agreement with radionuclide imaging. In contrast to triggered imaging modalities that are time consuming and sensitive to motion artifacts, recent real-time techniques20 may be more efficient for detection of ACS in humans. This is the first study to demonstrate that MCE can detect ACS in patients who have chest pain as they present to the emergency department. MCE was the strongest predictor of ACS and added significant diNOVEMBER 15, 2004
agnostic value to clinical and biochemical markers, particularly in patients who had unstable angina. Furthermore, MCE accurately detected ACS in all 6 patients who had NSTEMI and normal levels of troponin T on admission and correctly excluded ACS in 2 patients who had chest pain and increased troponin T by identifying perimyocarditis. Myocardial perfusion was superior for detection of ACS compared with wall motion analysis, which may have a pathophysiologic explanation. In ACS, rupture of atherosclerotic plaques with subsequent peripheral microvascular embolization and thrombosis may decrease myocardial tissue perfusion.21 As demonstrated in experimental studies,22 myocardial blood flow may diminish to a level at which perfusion defects of subendocardial tissue are present but wall motion abnormalities are not detectable by 2-dimensional echocardiography. In the present study, 34 segments showed isolated perfusion abnormalities in 12 patients who had ACS. In these segments, myocardial blood flow decreased to a level that allowed detection of perfusion defects by MCE, but, as illustrated by quantitative data (Figure 2), another significant decrease in blood flow was necessary to cause wall motion abnormalities detectable by 2-dimensional echocardiography. Because ACS would have been missed in 12 of 33 patients (36%) just by assessment of wall motion, it is not surprising that myocardial perfusion was the most powerful parameter for identification of patients who had ACS. We previously demonstrated that estimation of myocardial blood flow by real-time MCE is useful to evaluate myocardial perfusion during adenosine stress testing in patients who had suspected coronary artery disease.7 However, because the patients in this study included those at high risk of evolving myocardial infarction, we did not use pharmacologic stress testing for safety reasons. Visual analysis of myocardial perfusion images was performed by 2 experienced echocardiographers (GK and AH) and yielded high specificity and accuracy and low interobserver variability. Observer variability may be higher and accuracy of perfusion imaging lower if visual analysis is performed by less experienced observers. However, newer automated myocardial parametric quantification methods that provide color-encoded quantification of myocardial blood flow23 may decrease observer variability and improve the reproducibility and the practicability of the method. This report demonstrates the added value of MCE to conventional testing for detecting ACS and highlights the prognostic value of this method. Because the initial perfusion defect size correlates strongly with the grade of myocardial damage, this may represent a novel variable for risk stratification in patients who have ACS. 1. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman
JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, et al (Committee on the Management of Patients With Unstable Angina). ACC/AHA guideline update for the management of patients with unstable angina and non–ST-segment elevation
myocardial infarction—2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Circulation 2002;106:1893–1900. 2. Lee TH, Cook EF, Weisberg M, Sargent RK, Wilson C, Goldman L. Acute chest pain in the emergency room. Identification and examination of low-risk patients. Arch Intern Med 1985;145:65– 69. 3. Rouan GW, Lee TH, Cook EF, Brand DA, Weisberg MC, Goldman L. Clinical characteristics and natural history of patients with acute myocardial infarction sent home from the emergency room. Am J Cardiol 1987;60:219 –224. 4. Antman EM, Braunwald E. Acute myocardial infarction. In: Braunwald E, ed. Heart Disease: A Textbook in Cardiovascular Medicine, 5th Ed. Philadelphia: WB Saunders, 1997:1184 –1288. 5. Antman EM, Tanasijevic MJ, Thompson B, Schactman M, McCabe CH, Cannon CP, Fischer GA, Fung AY, Thompson C, Wybenga D, Braunwald E. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335:1342–1349. 6. Kaul S, Senior R, Dittrich H, Raval U, Khattar R, Lahiri A. Detection of coronary artery disease with myocardial contrast echocardiography: comparison with 99mTc-sestamibi single-photon emission computed tomography. Circulation 1997;96:785–792. 7. Korosoglou G, da Silva KG Jr, Labadze N, Dubart AE, Hansen A, Rosenberg M, Zehelein J, Kuecherer H. Real-time myocardial contrast echocardiography for pharmacological stress testing. Is quantitative estimation of myocardial blood flow reserve necessary? J Am Soc Echocardiogr 2004;17:1–9. 8. Korosoglou G, Hansen A, Hoffend J, Gavrilovic G, David W, Zehelein J, Haberkorn U, Kuecherer H. Comparison of real-time myocardial contrast echocardiography for the assessment of myocardial viability with fluorodeoxyglucose-18 positron emission tomography and dobutamine stress echocardiography. Am J Cardiol 2004;94:31–37. 9. Remppis A, Ehlermann P, Giannitsis E, Greten T, Most P, Muller-Bardorff M, Katus HA. Cardiac troponin T levels at 96 hours reflect myocardial infarct size: a pathoanatomical study. Cardiology 2000;93:249 –253. 10. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I. Recommendations for quantification of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;2:358 –367. 11. Iwanaga S, Ewing SG, Husseini WK, Hoffman JI. Changes in contractility and afterload have only slight effects on subendocardial systolic flow impediment. Am J Physiol 1995;269:H1202–H1212. 12. Wei K, Jayaweera AR, Firoozan S, Linka A, Skyba DM, Kaul S. Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation 1998;97:473– 483. 13. Kwong RY, Schussheim AE, Rekhraj S, Aletras AH, Geller N, Davis J, Christian TF, Balaban RS, Arai AE. Detecting acute coronary syndrome in the emergency department with cardiac magnetic resonance imaging. Circulation 2003;107:531–537. 14. Horton NJ, Laird NM. Maximum likelihood analysis of logistic regression models with incomplete covariate data and auxiliary information. Biometrics 2001;57:34 – 42. 15. Heller GV, Stowers SA, Hendel RC, Herman SD, Daher E, Ahlberg AW, Baron JM, Mendes de Leon CF, Rizzo JA, Wackers FJ. Clinical value of acute rest technetium-99m tetrofosmin tomographic myocardial perfusion imaging in patients with acute chest pain and nondiagnostic electrocardiograms. J Am Coll Cardiol 1998;31:1011–1017. 16. Hilton TC, Thompson RC, Williams HJ, Saylors R, Fulmer H, Stowers SA. Technetium-99m sestamibi myocardial perfusion imaging in the emergency room evaluation of chest pain. J Am Coll Cardiol 1994;23:1016 –1022. 17. Sabia P, Afrookteh A, Touchstone DA, Keller MW, Esquivel L, Kaul S. Value of regional wall motion abnormality in the emergency room diagnosis of acute myocardial infarction. A prospective study using two-dimensional echocardiography. Circulation 1991;84:85–92. 18. Kontos MC, Kurdziel K, McQueen R, Arrowood JA, Jesse RL, Ornato JP, Paulsen WH, Tatum JL, Nixon JV. Comparison of 2-dimensional echocardiography and myocardial perfusion imaging for diagnosing myocardial infarction in emergency department patients. Am Heart J 2002;143:659 – 667. 19. Kontos MC, Hinchman D, Cunningham M, Miller JJ, Cherif J, Nixon JV. Comparison of contrast echocardiography with single-photon emission computed tomographic myocardial perfusion imaging in the evaluation of patients with possible acute coronary syndromes in the emergency department. Am J Cardiol 2003;91:1099 –1102. 20. Becher H, Burns PN. Contrast agents for echocardiography: principles and instrumentation. In: Becher H, Burns PN, eds. Handbook of Contrast Echocardiography. New York: Springer-Verlag, 2000:2– 44. 21. Fuster V, Corti R, Fayad ZA, Schwitter J, Badimon JJ. Integration of vascular biology and magnetic resonance imaging in the understanding of atherothrombosis and acute coronary syndromes. J Thromb Haemost 2003;1:1410 –1421. 22. Lafitte S, Matsugata H, Peters B, Togni M, Strachan M, Kwan OL, DeMaria AN. Comparative value of dobutamine and adenosine stress in the detection of coronary stenosis with myocardial contrast echocardiography. Circulation 2001; 103:2724 –2730. 23. Yu EH, Skyba DM, Leong-Poi H, Sloggett C, Jamorski M, Garg R, Iwanochko RM, Siu SC. Incremental value of parametric quantitative assessment of myocardial perfusion by triggered low-power myocardial contrast echocardiography. J Am Coll Cardiol 2004;43:1807–1813.
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