- Email: [email protected]
Usefulness of Real-Time Myocardial Perfusion Imaging to Evaluate Tissue Level Reperfusion in Patients With Non–ST-Elevation Myocardial Infarction
Usefulness of Real-Time Myocardial Perfusion Imaging to Evaluate Tissue Level Reperfusion in Patients With Non–ST-Elevation Myocardial Infarction Grigorios Korosoglou, MD, Nina Labadze, MD, Evangelos Giannitsis, MD, Raffi Bekeredjian, MD, Alexander Hansen, MD, Stefan E. Hardt, MD, Christiane Selter, RN, Roger Kranzhoefer, MD, Hugo Katus, MD, and Helmut Kuecherer, MD Microvascular integrity is a prequisite for functional recovery in patients who have myocardial infarction after recanalization of the infarct-related coronary artery. In this study, we investigated whether impaired myocardial perfusion is present in patients who have non–STelevation myocardial infarction and whether the extent and time course of myocardial tissue reperfusion as assessed by myocardial contrast echocardiography (MCE) are related to functional recovery. Consecutive patients (n ⴝ 32) who presented with a first non–STelevation myocardial infarction were included in our study. MCE was performed on admission, 1 to 4 hours after angioplasty, and at 24 hours, 4 days, and 4 weeks of follow-up. Contrast images were analyzed visually and quantitatively. Myocardial blood flow was estimated by calculating the product of peak signal intensity and the slope of signal intensity increase. Improvement of wall motion on follow-up echocardiograms after 4 weeks served as a reference for functional recovery of impaired left ventricular function. Of 496 segments available for analysis, 128 (26%) were initially dys-
functional and 96 (75%) recovered at 4 weeks of follow-up. Myocardial tissue reperfusion occurred gradually, expanding over the first 24 hours after percutaneous coronary intervention (myocardial blood flow of 0.4 ⴞ 0.3 initially, 0.6 ⴞ 0.4 at 24 hours, and 1.6 ⴞ 0.7 dB/s at 4 weeks of follow-up, p <0.001). Extent of tissue reperfusion was closely related to grade of improvement of global ejection fraction (r2 ⴝ 0.76, p <0.001). MCE predicted functional recovery with a sensitivity of 81%, a specificity of 88%, and accuracy of 83% on a segmental level. Thus, impaired microvascular integrity is suggested by MCE in patients who present with non–ST-elevation myocardial infarction. Improvement of regional tissue perfusion after revascularization is closely related to functional recovery. This information may aid risk stratification and allow monitoring of the effectiveness of reperfusion therapy in these patients. 䊚2005 by Excerpta Medica Inc. (Am J Cardiol 2005;95:1033–1038)
reatment of patients who have acute coronary syndromes aims at preservation of flow in the infarctT related artery and the corresponding myocardial tis-
phenomenon in patients who have non-STEMI (NSTEMI). Further, most previous studies have used a categorical definition of microvascular integrity. Because no-reflow is a complex phenomenon that can expand over time,9 serial estimation of tissue level reperfusion is necessary. We and others have shown that MCE can be used to assess microvascular integrity.10 –12 In this study, we investigated whether impaired myocardial perfusion is present in patients who have NSTEMI and whether the extent and the time course of tissue reperfusion are related to functional recovery.
sue.1 However, restoration of epicardial blood flow may not necessarily guarantee functional recovery when impaired microvascular integrity is present.1,2 Distal embolization of plaque material3 and vascular reperfusion injury4 may compromise myocardial perfusion. Extent of tissue reperfusion is related to functional recovery and is associated with clinical outcomes.5 Impaired microvascular integrity (no reflow) has been observed by myocardial contrast echocardiography (MCE), nuclear scintigraphy, and magnetic resonance imaging in patients who have ST-elevation myocardial infarction (STEMI).6 –9 However, there are no data about the functional implications of this From the Department of Cardiology, University of Heidelberg, Heidelberg, Germany. Manuscript received October 6, 2004; revised manuscript received and accepted December 16, 2004. Address for reprints: Grigorios Korosoglou, MD, Department of Cardiology, Im Neuenheimer Feld 410, 69115 Heidelberg, Germany. E-mail: [email protected]. ©2005 by Excerpta Medica Inc. All rights reserved. The American Journal of Cardiology Vol. 95 May 1, 2005
METHODS
Patient population: In this prospective study, we included consecutive patients who presented with a first NSTEMI. Inclusion criteria were chest pain lasting ⬎20 minutes compatible with myocardial ischemia ⱕ12 hours before presentation and high levels of troponin T (⬎0.03 g/L) at initial presentation or at 4 to 8 hours of follow-up. Exclusion criteria were ST elevation and electrocardiographic signs or history of 0002-9149/05/$–see front matter doi:10.1016/j.amjcard.2004.12.055
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TABLE 1 Demographic and Clinical Characteristics (n ⫽ 32) Age (yrs) Men Interval between onset of chest pain and admission (min) TIMI flow grade 0 before PCI TIMI flow grade 1 or 2 before PCI TIMI flow grade 3 before PCI Multivessel CAD Advanced age (men ⬎45 yrs old, women ⬎55 yrs old) Hypertension Elevated cholesterol level (LDL ⬎130 mg/dl) Family history of CAD Tobacco use Diabetes mellitus Peak CK (U/L) 96-h troponin T level (g/L) Antihypertensive therapy Diuretic therapy Aspirin therapy
65 ⫾ 12 22 312 ⫾ 220 3 10 19 17 30 21 20 16 20 9 377 ⫾ 612 0.87 ⫾ 1.20 13 11 7
Values are numbers of patients or mean ⫾ SD, unless otherwise indicated. CAD ⫽ coronary artery disease; CK ⫽ creatine kinase; LDL ⫽ low-density lipoprotein; PCI ⫽ percutaneous coronary intervention.
infarction. The study protocol was approved by the local ethics committee, and all patients gave written informed consent. Two-dimensional echocardiography: Imaging was performed from standard apical 2-, 3-, and 4-chamber views using an ATL HDI 5000 system (Philips Medical System, Bothell, Washington). To avoid bias by simultaneous interpretation of regional wall motion and perfusion, wall motion was assessed before contrast administration using a semi-quantitative grade scale of 1 to represent normal wall motion, 2 to represent hypokinesia, 3 to represent akinesia, and 4 to represent dyskinesia.12,13 Wall motion and myocardial opacification were assessed initially, at 1 to 4 hours after angioplasty, at 24 hours, at 4 days, and at 4 weeks of follow-up. Recovery of regional contractile function was defined as an improvement of ⱖ1 grade in wall motion at 4-week follow-up.12,14 The wall motion score was serially calculated for initially dysfunctional segments, and ejection fraction was serially measured using the biplane Simpson’s method.13 Because the mean ⫾ SD of differences in ejection fraction judged by 2 independent observers was 0.04 points (4%), we defined a 2 SD value of 8% as a relevant improvement of ejection fraction at 4-week follow-up. Myocardial contrast echocardiography: Myocardial contrast echocardiographic perfusion imaging was performed as previously described11,12,15 using a low mechanical index (0.14 to 0.18) in harmonic power pulse inversion mode. SonoVue (Bracco, Byk-Gulden, Konstanz, Germany) was applied as a slow bolus injection (1.0 to 1.5 ml/bolus) to obtain optimal visualization of the left ventricle. When attenuation was minimized, a brief pulse of higher mechanical index was transmitted to “clear” the myocardium of microbubbles. Returning immediately to low power imag1034 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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ing, 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 myocardial opacification: Myocardial opacification was analyzed by 2 independent observers. A third observer proved the variability of the 2 first observers and resolved differences in opinion by consensus of all 3. Myocardial opacification was graded as 3 to represent homogeneous opacification, 2 to represent mildly decreased or patchy opacification, 1 to represent severely decreased opacification, and 0 to represent absent opacification.11,12 We previously reported that segments with absent (score 0) and severely decreased (score 1) perfusion have a low probability of recovering contractile function in patients who have ischemic heart disease.12 Therefore, in this study, improvement of regional perfusion in dysfunctional segments was defined as an increase from absent (score 0) to patchy (score 2) or to normal (score 3) or as an increase from severely decreased (score 1) to patchy (score 2) or to normal (score 3). An increase from absent (score 0) to severely decreased (score 1) was not considered an indication of improved myocardial perfusion. Quantitative analysis: Regions of interest were placed in each segment from the epicardium to the endocardium to analyze replenishment kinetics from end-systolic frames.16 Plots of contrast intensity versus time were constructed and fit to an exponential function, y ⫽ A*(1 ⫺ e⫺t), as described by Wei et al.17 The plateau of signal intensity (A) and the slope of maximal intensity increase () were measured, and the product of A* was calculated to estimate myocardial blood flow. Perfusion defect size was measured by planimetry of end-systolic frames, when maximal intensity was reached, usually 10 to 15 cardiac cycles after a “flash.” Coronary angiography: Selective coronary angiography was performed ⱕ12 hours after admission. Angiograms were analyzed and quantitated by an independent cardiologist. Degree of stenosis was expressed as percent decrease in internal luminal diameter in relation to the normal reference. Coronary stenosis was defined as ⱖ75% narrowing of the reference lumen diameter. Thrombolysis In Myocardial Infarction (TIMI) flow grade was assessed visually.18 Statistical analysis: Data are presented as mean ⫾ SD. Agreement between observers was assessed with statistics.19 Inter- and intraobserver variabilities for the estimation of the myocardial blood flow (A*) were obtained by double-blinded observers by repeating analysis of 20 representative myocardial contrast echocardiograms. Repeated measures analysis of variance with Bonferroni’s adjustment for multiple comparisons was used to compare wall motion and perfusion parameters. Temporal changes in perfusion defect size were compared with ejection fraction changes using linear regression analysis. Statistical significance of differences in diagnostic value was evaluated by McNemar’s chi-square MAY 1, 2005
plete occlusion of the infarct-related artery (left circumflex coronary artery in 2 patients and right coronary artery in 1 patient), resulting in TIMI flow grade 0 before angioplasty. All 32 patients underwent successful mechanical reperfusion, including stent placement, achieving TIMI grade flow 3 and ⬍50% residual stenosis. TIMI flow before angioplasty was not significantly related to initial perfusion defect size by MCE, to peak creatine kinase values, or to follow-up ejection fraction (r2 ⬍0.1, p ⫽ NS). Twenty of 32 patients had high levels of troponin T on admission (0.14 ⫾ 0.26 g/L), and all patients had high levels of troponin T at follow-up (0.87 ⫾ 1.2 g/L at 96 hours after admission). Clinical, biochemical, and angiographic data are listed in Table 1. No effects of SonoVue were noted on rhythm and blood pressure, and no allergic reactions were observed during and 30 minutes after contrast agent administration. Temporal course of myocardial perfusion and wall motion: Wall mo-
tion analysis was feasible in 496 of 512 segments (97%), and abnormal wall motion was detected initially in 128 of 496 segments (26%), including 83 hypokinetic and 45 akinetic and dyskinetic segments. Wall motion score improved initially at 4 days after angioplasty and showed further improvement at 4-week folFIGURE 1. (A) Wall motion started to improve at 4-day follow-up in segments that low-up (Figure 1). Similarly, global showed tissue reperfusion. (B) Similarly, global ejection fraction initially occurred 4 ejection fraction started to recover at days after angioplasty. (C) Improvement of myocardial perfusion occurred sooner, at 4 days and further improved at 24 hours, and improved more at 4-day and 4-week follow-up. *p <0.05, initially 4-week follow-up (Figure 1). Conversus 24 hours; #p <0.05, 24 hours versus 4 days; ‡p <0.05, 4 days versus 4 weeks. PCI ⴝ percutaneous coronary intervention. versely, perfusion score improved in segments with functional recovery at 24 hours and showed a further intest.11,12,15 Differences were considered significant at a p crease at 4 days and at 4-week follow-up (Figure 1). Thus, recovery of wall motion at rest followed myovalue ⬍0.05. cardial tissue reperfusion. Improved perfusion and lack of wall motion recovery, a condition suggestive of myocardial “stunning,” was seen in 62 of 128 RESULTS Clinical, angiographic, and safety data: Forty con- initially dysfunctional segments (48%) at 24-hour folsecutive patients fulfilled the inclusion criteria, but 8 low-up and in 52 of 128 segments (41%) at 4-day were excluded from analysis for the following reasons: 4 follow-up (Table 2). Visual assessment of perfusion was feasible in 476 patients were scheduled for urgent coronary artery bypass grafting so that serial myocardial contrast echocar- of 512 segments (93%), and quantification was feasidiograms were missed, and perfusion defects could not ble in 449 segments (87%). Estimation of myocardial be detected by MCE in 4 patients, including 2 who had blood flow showed similar temporal patterns with the extremely poor echocardiographic windows. Of the 32 visually assessed perfusion score. Thus, A* signifiremaining patients who serially underwent myocardial cantly increased at 24 hours and showed further imcontrast echocardiographic studies, 19 showed high- provement at 4-day and 4-week follow-up, reaching grade flow-limiting stenotic lesions (TIMI flow 1 or 2) values similar to those of segments with normal wall and 10 showed non–flow-limiting stenotic lesions motion (Figure 2). Conversely, A* remained un(ⱖ75%) before angioplasty. Three patients showed com- changed in segments without functional recovery. CORONARY ARTERY DISEASE/MCE IN NON–ST-ELEVATION MYOCARDIAL INFARCTION
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TABLE 2 Temporal Course of Myocardial Wall Motion and Perfusion in 128 Initially Dysfunctional Segments by Visual Myocardial Contrast Echocardiography After PCI
24 Hours
4 Days
4 Weeks
4 0 4
68 6 62
82 30 52
107 96
Improved myocardial perfusion Improved myocardial WM Improved perfusion but lack WM recovery (stunning) WM ⫽ wall motion. Other abbreviation as in Table 1.
TABLE 3 Detection of Functional Recovery by Real-time Myocardial Contrast Echocardiography
MCE at 24 hours MCE at 4 days
Sensitivity
Specificity
PPV
NPV
Accuracy
60% 81%*
69% 88%
85% 95%
37% 61%*
63% 83%*
*p ⬍0.05 for MCE at 24 hours versus 4 days. NPV ⫽ negative predictive value; PPV ⫽ positive predictive value.
(83% vs 63%, p ⬍0.05) for prediction of functional recovery compared with MCE at 24 hours (Table 3). Figure 3 shows a patient whose reperfusion spontaneously occurred 24 hours to 4 days after angioplasty. Thus, correct prediction of functional recovery was achieved by MCE at 4-day follow-up. Analysis by patients: Change of perfusion defect area at 4 days correlated closely (r2 ⫽ 0.76, p ⬍0.0001) with changes in ejection fraction after 4 weeks (Figure 4). Twenty-four patients showed an increased ejection fraction of ⱖ8% at 4 weeks (42 ⫾ 5% initially vs 58 ⫾ 8% at 4 weeks, p ⬍0.001). In these patients, perfusion defect size significantly decreased at 24 hours and showed further decreases at 4 days and at 4 weeks (Figure 2). In patients who did not show increased ejection fraction (n ⫽ 8), perfusion defect size remained unchanged. Inter- and intraobserver variabilities: Agreements between observers were 92% ( ⫽ 0.81) for interpreting myocardial contrast echocardiograms and 89% ( ⫽ 0.78) for interpreting wall motion. Intra- and interobserver variabilities were 13% and 17%, respectively, for assessment of A* and 12% and 7%, respectively, for planimetric quantification of the perfusion defect area.
FIGURE 2. (A) Myocardial blood flow significantly increased at 24 hours and showed a further improvement at 4 days and at 4 weeks in segments that showed functional recovery. (B) Similarly, perfusion defect area significantly decreased at 24 hours and showed a further decrease at 4 days and at 4 weeks in patients who showed improvement of global ejection fraction (>8%) at 4-week follow-up. *p <0.05, initially versus 24 hours; # p <0.05, 24 hours versus 4 days; ‡p <0.05, 4 days versus 4 weeks. Abbreviation as in Figure 1.
Prediction of regional functional recovery: Because myocardial tissue reperfusion occurred continuously, expanding over the first 24 hours, MCE at 4 days was more sensitive (81% vs 60%, p ⬍0.05) and accurate 1036 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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DISCUSSION This study demonstrates that impaired microvascular integrity is present in patients who have NSTEMI and that its extent and temporal course are related to recovery of wall motion. Real-time MCE can accurately predict functional recovery in these patients. Temporal course of myocardial reperfusion in NSTEMI:
Most patients (60% to 80%) who present with acute coronary syndromes in the emergency department show no ST elevation on their electrocardiogram.20 In this study, we have described for the first time the temporal course of myocardial reperfusion in patients who have NSTEMI and undergo successful angioplasty. Myocardial reperfusion is a complex phenomenon that expands over the first 24 hours after revasMAY 1, 2005
stable ischemic heart disease.12 In this study, MCE demonstrated good accuracy for prediction of functional recovery in patients who have acute NSTEMI. The phenomenon of myocardial stunning, defined as the presence of postischemic dysfunction without necrosis, is well established in the setting of acute infarction.5,6 In this study, a considerable number of segments (41% to 48%) demonstrated improved perfusion but abnormal wall motion at 24-hour and 4-day follow-up, a condition compatible with stunning. On a patient level, contractile function started improving after 4 days, whereas myocardial tissue reperfusion was seen 24 hours after angioplasty. Thus, these data prove the principle of myocardial stunning in patients who have NSTEMI and suggest that MCE can accurately identify stunned tissue with high probability for functional recovery. Previous studies that investigated myocardial reperfusion after myocardial infarction focused on prediction of functional recovery on a segmental level.5,6,24 However, because residual left ventricular function after infarction is a primary determinant of long-term survival, prediction of global improvement is more important for patient risk stratificaFIGURE 3. Myocardial reperfusion of the apex occurred spontaneously in a pation. In this study, we have shown tient who had acute anterior NSTEMI 24 hours to 4 days after revascularization for the first time that temporal of the left anterior descending artery. Assessment of myocardial perfusion 4 days after revascularization correctly predicted functional recovery at 4-week followchanges of myocardial reperfusion in up. patients who have NSTEMI can be assessed quantitatively by real-time MCE and are closely related to excularization, and its temporal patterns are closely tent of improvement in global ejection fraction. related to functional recovery. Galiuto et al21 and Study limitations: The number of patients studied Bronchet et al22 reported that reperfusion can sponta- was relative small. Because most patients studied neously occur between 24 hours and 6 to 9 days after showed functional recovery at 4-week follow-up, the STEMI. In accord with these results, in the present sensitivity of MCE may have been overestimated. study, myocardial perfusion improved spontaneously However, the aim of this study was to investigate in 30% of dysfunctional segments between 24 hours functional recovery, which is more probable in paand 4 weeks. Quantitative estimation of myocardial tients who have NSTEMI than in those who have blood flow confirmed visual findings, showing imSTEMI. We used slow bolus injections for adminisprovement (1.5-fold to 2-fold) after 24 hours and a further increase (3-fold) after 4 days. These findings tration of contrast agent, where delivery of micromay be explained by coronary spasm of the infarct- bubbles is not constant and may confound calculations related artery or through microvascular embolization of the peak rate of increase in contrast intensity. The after successful angioplasty that resolves in later use of continuous infusion may have provided more stages of reperfusion.23 Because myocardial tissue accurate results for estimation of myocardial blood reperfusion was not limited to the first 24 hours, flow. However, we and others have shown that calcuprediction of functional recovery was more accurate lation of replenishment kinetics is still feasible by by performance of MCE at 4-day follow-up. We pre- slow bolus injections during optimal myocardial viously reported that myocardial perfusion imaging opacification,12,15,25 which may, therefore, represent a can detect myocardial viability in patients who have more practical approach in routine clinical settings. CORONARY ARTERY DISEASE/MCE IN NON–ST-ELEVATION MYOCARDIAL INFARCTION
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FIGURE 4. (B) Decrease in perfusion defect area at 4 days correlated strongly with improvement of global ejection fraction at 4-week follow-up (r2 ⴝ 0.76, p <0.001). (A) A weaker correlation (r2 ⴝ 0.22, p <0.01) was found at 24-hour follow-up.
1. Anderson JL, Karagounis LA, Becker LC, Sorensen SG, Menlove RL. TIMI perfusion grade 3 but not grade 2 results in improved outcome after thrombolysis for myocardial infarction. Ventriculographic, enzymatic, and electrocardiographic evidence from the TEAM-3 Study. Circulation 1993;87:1829 –1839. 2. Lepper W, Hoffmann R, Kamp O, Franke A, de Cock CC, Kuhl HP, Sieswerda GT, Dahl J, Janssens U, Voci P, et al. Assessment of myocardial reperfusion by intravenous myocardial contrast echocardiography and coronary flow reserve after primary percutaneous transluminal coronary angioplasty (correction of angiography) in patients with acute myocardial infarction. Circulation 2000 23;101:2368 –2374. 3. Davies MJ. A macro and micro view of coronary vascular insult in ischemic heart disease. Circulation 1990;82:38 – 46. 4. Neumann FJ, Ott I, Gawaz M, Richardt G, Holzapfel H, Jochum M, Schomig A. Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation 1995;92:748 –755. 5. Ito H, Maruyama A, Iwakura K, Takiuchi S, Masuyama T, Hori M, Higashino Y, Fujii K, Minamino T. Clinical implications of the ‘no reflow’ phenomenon. A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation 1996;93:223–238. 6. Ito H, Tomooka T, Sakai N, Yu H, Higashino Y, Fujii K, Masuyama T, Kitabatake A, Minamino T. Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation 1992;1699 –1705. 7. Porter TR, Li S, Oster R, Deligonul U. The clinical implications of no reflow demonstrated with intravenous perfluorocarbon containing microbubbles follow-
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ing restoration of Thrombolysis In Myocardial Infarction (TIMI) 3 flow in patients with acute myocardial infarction. Am J Cardiol 1998;82:1173–1177. 8. Schofer J, Montz R, Mathey DG. Scintigraphic evidence of the “no reflow” phenomenon in human beings after coronary thrombolysis. J Am Coll Cardiol 1985;5:593–598. 9. Wu KC, Kim RJ, Bluemke DA, Rochitte CE, Zerhouni EA, Becker LC, Lima JA. Quantification and time course of microvascular obstruction by contrastenhanced echocardiography and magnetic resonance imaging following acute myocardial infarction and reperfusion. J Am Coll Cardiol 1998;32:1756 –1764. 10. 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. 11. Korosoglou G, Da Silva KG, 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. 12. 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 18fluordeoxyglucose positron emission tomography and dobutamine stress echocardiography. Am J Cardiol 2004;94:570 –576. 13. 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. 14. Pagano D, Bonser RS, Townend JN, Ordoubadi F, Lorenzoni R, Camici PG. Predictive value of dobutamine echocardiography and positron emission tomography in identifying hibernating myocardium in patients with postischaemic heart failure. Heart 1998;79:281–288. 15. Korosoglou G, Labadze N, Hansen A, Selter C, Giannitsis E, Katus H, Kuecherer H. Usefulness of real-time myocardial perfusion imaging in the evaluation of patients with first time chest pain. Am J Cardiol 2004;94:1225–1231. 16. 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:H1202–1212. 17. 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. 18. Gibson CM, Cannon CP, Murphy SA, Marble SJ, Barron HV, Braunwald E. TIMI Study Group. Relationship of the TIMI myocardial perfusion grades, flow grades, frame count, and percutaneous coronary intervention to long-term outcomes after thrombolytic administration in acute myocardial infarction. Circulation 2002;105:1909 –1913. 19. Kramer MS, Feinstein AR. Clinical biostatistics: the biostatistics of concordance. Clin Pharmacol Ther 1981;29:111–123. 20. Steg PG, Goldberg RJ, Gore JM, Fox KA, Eagle KA, Flather MD, Sadiq I, Kasper R, Rushton-Mellor SK, Anderson FA. GRACE Investigators. Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE). Am J Cardiol 2002 15;90:358 –363. 21. Galiuto L, Lombardo A, Maseri A, Santoro L, Porto I, Cianflone D, Rebuzzi AG, Crea F. Temporal evolution and functional outcome of no reflow: sustained and spontaneously reversible patterns following successful coronary recanalisation. Heart 2003;89:731–737. 22. Brochet E, Czitrom D, Karila-Cohen D, Seknadji P, Faraggi M, Benamer H, Aubry P, Steg PG, Assayag P. Early changes in myocardial perfusion patterns after myocardial infarction: relation with contractile reserve and functional recovery. J Am Coll Cardiol 1998;32:2011–2017. 23. Villanueva FS, Camarano G, Ismail S, Goodman NC, Sklenar J, Kaul S. Coronary reserve abnormalities in the infarcted myocardium. Assessment of myocardial viability immediately versus late after reflow by contrast echocardiography. Circulation 1996;94:748 –754. 24. Kereiakes DJ. Adjunctive pharmacotherapy before percutaneous coronary intervention in non–ST-elevation acute coronary syndromes: the role of modulating inflammation. Circulation 2003 21;108:III22–III27. 25. Lindner JR, Villanueva FS, Dent JM, Wei K, Sklenar J, Kaul S. Assessment of resting perfusion with myocardial contrast echocardiography: theoretical and practical considerations. Am Heart J 2000;139:231–240.
MAY 1, 2005
functional and 96 (75%) recovered at 4 weeks of follow-up. Myocardial tissue reperfusion occurred gradually, expanding over the first 24 hours after percutaneous coronary intervention (myocardial blood flow of 0.4 ⴞ 0.3 initially, 0.6 ⴞ 0.4 at 24 hours, and 1.6 ⴞ 0.7 dB/s at 4 weeks of follow-up, p <0.001). Extent of tissue reperfusion was closely related to grade of improvement of global ejection fraction (r2 ⴝ 0.76, p <0.001). MCE predicted functional recovery with a sensitivity of 81%, a specificity of 88%, and accuracy of 83% on a segmental level. Thus, impaired microvascular integrity is suggested by MCE in patients who present with non–ST-elevation myocardial infarction. Improvement of regional tissue perfusion after revascularization is closely related to functional recovery. This information may aid risk stratification and allow monitoring of the effectiveness of reperfusion therapy in these patients. 䊚2005 by Excerpta Medica Inc. (Am J Cardiol 2005;95:1033–1038)
reatment of patients who have acute coronary syndromes aims at preservation of flow in the infarctT related artery and the corresponding myocardial tis-
phenomenon in patients who have non-STEMI (NSTEMI). Further, most previous studies have used a categorical definition of microvascular integrity. Because no-reflow is a complex phenomenon that can expand over time,9 serial estimation of tissue level reperfusion is necessary. We and others have shown that MCE can be used to assess microvascular integrity.10 –12 In this study, we investigated whether impaired myocardial perfusion is present in patients who have NSTEMI and whether the extent and the time course of tissue reperfusion are related to functional recovery.
sue.1 However, restoration of epicardial blood flow may not necessarily guarantee functional recovery when impaired microvascular integrity is present.1,2 Distal embolization of plaque material3 and vascular reperfusion injury4 may compromise myocardial perfusion. Extent of tissue reperfusion is related to functional recovery and is associated with clinical outcomes.5 Impaired microvascular integrity (no reflow) has been observed by myocardial contrast echocardiography (MCE), nuclear scintigraphy, and magnetic resonance imaging in patients who have ST-elevation myocardial infarction (STEMI).6 –9 However, there are no data about the functional implications of this From the Department of Cardiology, University of Heidelberg, Heidelberg, Germany. Manuscript received October 6, 2004; revised manuscript received and accepted December 16, 2004. Address for reprints: Grigorios Korosoglou, MD, Department of Cardiology, Im Neuenheimer Feld 410, 69115 Heidelberg, Germany. E-mail: [email protected]. ©2005 by Excerpta Medica Inc. All rights reserved. The American Journal of Cardiology Vol. 95 May 1, 2005
METHODS
Patient population: In this prospective study, we included consecutive patients who presented with a first NSTEMI. Inclusion criteria were chest pain lasting ⬎20 minutes compatible with myocardial ischemia ⱕ12 hours before presentation and high levels of troponin T (⬎0.03 g/L) at initial presentation or at 4 to 8 hours of follow-up. Exclusion criteria were ST elevation and electrocardiographic signs or history of 0002-9149/05/$–see front matter doi:10.1016/j.amjcard.2004.12.055
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TABLE 1 Demographic and Clinical Characteristics (n ⫽ 32) Age (yrs) Men Interval between onset of chest pain and admission (min) TIMI flow grade 0 before PCI TIMI flow grade 1 or 2 before PCI TIMI flow grade 3 before PCI Multivessel CAD Advanced age (men ⬎45 yrs old, women ⬎55 yrs old) Hypertension Elevated cholesterol level (LDL ⬎130 mg/dl) Family history of CAD Tobacco use Diabetes mellitus Peak CK (U/L) 96-h troponin T level (g/L) Antihypertensive therapy Diuretic therapy Aspirin therapy
65 ⫾ 12 22 312 ⫾ 220 3 10 19 17 30 21 20 16 20 9 377 ⫾ 612 0.87 ⫾ 1.20 13 11 7
Values are numbers of patients or mean ⫾ SD, unless otherwise indicated. CAD ⫽ coronary artery disease; CK ⫽ creatine kinase; LDL ⫽ low-density lipoprotein; PCI ⫽ percutaneous coronary intervention.
infarction. The study protocol was approved by the local ethics committee, and all patients gave written informed consent. Two-dimensional echocardiography: Imaging was performed from standard apical 2-, 3-, and 4-chamber views using an ATL HDI 5000 system (Philips Medical System, Bothell, Washington). To avoid bias by simultaneous interpretation of regional wall motion and perfusion, wall motion was assessed before contrast administration using a semi-quantitative grade scale of 1 to represent normal wall motion, 2 to represent hypokinesia, 3 to represent akinesia, and 4 to represent dyskinesia.12,13 Wall motion and myocardial opacification were assessed initially, at 1 to 4 hours after angioplasty, at 24 hours, at 4 days, and at 4 weeks of follow-up. Recovery of regional contractile function was defined as an improvement of ⱖ1 grade in wall motion at 4-week follow-up.12,14 The wall motion score was serially calculated for initially dysfunctional segments, and ejection fraction was serially measured using the biplane Simpson’s method.13 Because the mean ⫾ SD of differences in ejection fraction judged by 2 independent observers was 0.04 points (4%), we defined a 2 SD value of 8% as a relevant improvement of ejection fraction at 4-week follow-up. Myocardial contrast echocardiography: Myocardial contrast echocardiographic perfusion imaging was performed as previously described11,12,15 using a low mechanical index (0.14 to 0.18) in harmonic power pulse inversion mode. SonoVue (Bracco, Byk-Gulden, Konstanz, Germany) was applied as a slow bolus injection (1.0 to 1.5 ml/bolus) to obtain optimal visualization of the left ventricle. When attenuation was minimized, a brief pulse of higher mechanical index was transmitted to “clear” the myocardium of microbubbles. Returning immediately to low power imag1034 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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ing, 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 myocardial opacification: Myocardial opacification was analyzed by 2 independent observers. A third observer proved the variability of the 2 first observers and resolved differences in opinion by consensus of all 3. Myocardial opacification was graded as 3 to represent homogeneous opacification, 2 to represent mildly decreased or patchy opacification, 1 to represent severely decreased opacification, and 0 to represent absent opacification.11,12 We previously reported that segments with absent (score 0) and severely decreased (score 1) perfusion have a low probability of recovering contractile function in patients who have ischemic heart disease.12 Therefore, in this study, improvement of regional perfusion in dysfunctional segments was defined as an increase from absent (score 0) to patchy (score 2) or to normal (score 3) or as an increase from severely decreased (score 1) to patchy (score 2) or to normal (score 3). An increase from absent (score 0) to severely decreased (score 1) was not considered an indication of improved myocardial perfusion. Quantitative analysis: Regions of interest were placed in each segment from the epicardium to the endocardium to analyze replenishment kinetics from end-systolic frames.16 Plots of contrast intensity versus time were constructed and fit to an exponential function, y ⫽ A*(1 ⫺ e⫺t), as described by Wei et al.17 The plateau of signal intensity (A) and the slope of maximal intensity increase () were measured, and the product of A* was calculated to estimate myocardial blood flow. Perfusion defect size was measured by planimetry of end-systolic frames, when maximal intensity was reached, usually 10 to 15 cardiac cycles after a “flash.” Coronary angiography: Selective coronary angiography was performed ⱕ12 hours after admission. Angiograms were analyzed and quantitated by an independent cardiologist. Degree of stenosis was expressed as percent decrease in internal luminal diameter in relation to the normal reference. Coronary stenosis was defined as ⱖ75% narrowing of the reference lumen diameter. Thrombolysis In Myocardial Infarction (TIMI) flow grade was assessed visually.18 Statistical analysis: Data are presented as mean ⫾ SD. Agreement between observers was assessed with statistics.19 Inter- and intraobserver variabilities for the estimation of the myocardial blood flow (A*) were obtained by double-blinded observers by repeating analysis of 20 representative myocardial contrast echocardiograms. Repeated measures analysis of variance with Bonferroni’s adjustment for multiple comparisons was used to compare wall motion and perfusion parameters. Temporal changes in perfusion defect size were compared with ejection fraction changes using linear regression analysis. Statistical significance of differences in diagnostic value was evaluated by McNemar’s chi-square MAY 1, 2005
plete occlusion of the infarct-related artery (left circumflex coronary artery in 2 patients and right coronary artery in 1 patient), resulting in TIMI flow grade 0 before angioplasty. All 32 patients underwent successful mechanical reperfusion, including stent placement, achieving TIMI grade flow 3 and ⬍50% residual stenosis. TIMI flow before angioplasty was not significantly related to initial perfusion defect size by MCE, to peak creatine kinase values, or to follow-up ejection fraction (r2 ⬍0.1, p ⫽ NS). Twenty of 32 patients had high levels of troponin T on admission (0.14 ⫾ 0.26 g/L), and all patients had high levels of troponin T at follow-up (0.87 ⫾ 1.2 g/L at 96 hours after admission). Clinical, biochemical, and angiographic data are listed in Table 1. No effects of SonoVue were noted on rhythm and blood pressure, and no allergic reactions were observed during and 30 minutes after contrast agent administration. Temporal course of myocardial perfusion and wall motion: Wall mo-
tion analysis was feasible in 496 of 512 segments (97%), and abnormal wall motion was detected initially in 128 of 496 segments (26%), including 83 hypokinetic and 45 akinetic and dyskinetic segments. Wall motion score improved initially at 4 days after angioplasty and showed further improvement at 4-week folFIGURE 1. (A) Wall motion started to improve at 4-day follow-up in segments that low-up (Figure 1). Similarly, global showed tissue reperfusion. (B) Similarly, global ejection fraction initially occurred 4 ejection fraction started to recover at days after angioplasty. (C) Improvement of myocardial perfusion occurred sooner, at 4 days and further improved at 24 hours, and improved more at 4-day and 4-week follow-up. *p <0.05, initially 4-week follow-up (Figure 1). Conversus 24 hours; #p <0.05, 24 hours versus 4 days; ‡p <0.05, 4 days versus 4 weeks. PCI ⴝ percutaneous coronary intervention. versely, perfusion score improved in segments with functional recovery at 24 hours and showed a further intest.11,12,15 Differences were considered significant at a p crease at 4 days and at 4-week follow-up (Figure 1). Thus, recovery of wall motion at rest followed myovalue ⬍0.05. cardial tissue reperfusion. Improved perfusion and lack of wall motion recovery, a condition suggestive of myocardial “stunning,” was seen in 62 of 128 RESULTS Clinical, angiographic, and safety data: Forty con- initially dysfunctional segments (48%) at 24-hour folsecutive patients fulfilled the inclusion criteria, but 8 low-up and in 52 of 128 segments (41%) at 4-day were excluded from analysis for the following reasons: 4 follow-up (Table 2). Visual assessment of perfusion was feasible in 476 patients were scheduled for urgent coronary artery bypass grafting so that serial myocardial contrast echocar- of 512 segments (93%), and quantification was feasidiograms were missed, and perfusion defects could not ble in 449 segments (87%). Estimation of myocardial be detected by MCE in 4 patients, including 2 who had blood flow showed similar temporal patterns with the extremely poor echocardiographic windows. Of the 32 visually assessed perfusion score. Thus, A* signifiremaining patients who serially underwent myocardial cantly increased at 24 hours and showed further imcontrast echocardiographic studies, 19 showed high- provement at 4-day and 4-week follow-up, reaching grade flow-limiting stenotic lesions (TIMI flow 1 or 2) values similar to those of segments with normal wall and 10 showed non–flow-limiting stenotic lesions motion (Figure 2). Conversely, A* remained un(ⱖ75%) before angioplasty. Three patients showed com- changed in segments without functional recovery. CORONARY ARTERY DISEASE/MCE IN NON–ST-ELEVATION MYOCARDIAL INFARCTION
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TABLE 2 Temporal Course of Myocardial Wall Motion and Perfusion in 128 Initially Dysfunctional Segments by Visual Myocardial Contrast Echocardiography After PCI
24 Hours
4 Days
4 Weeks
4 0 4
68 6 62
82 30 52
107 96
Improved myocardial perfusion Improved myocardial WM Improved perfusion but lack WM recovery (stunning) WM ⫽ wall motion. Other abbreviation as in Table 1.
TABLE 3 Detection of Functional Recovery by Real-time Myocardial Contrast Echocardiography
MCE at 24 hours MCE at 4 days
Sensitivity
Specificity
PPV
NPV
Accuracy
60% 81%*
69% 88%
85% 95%
37% 61%*
63% 83%*
*p ⬍0.05 for MCE at 24 hours versus 4 days. NPV ⫽ negative predictive value; PPV ⫽ positive predictive value.
(83% vs 63%, p ⬍0.05) for prediction of functional recovery compared with MCE at 24 hours (Table 3). Figure 3 shows a patient whose reperfusion spontaneously occurred 24 hours to 4 days after angioplasty. Thus, correct prediction of functional recovery was achieved by MCE at 4-day follow-up. Analysis by patients: Change of perfusion defect area at 4 days correlated closely (r2 ⫽ 0.76, p ⬍0.0001) with changes in ejection fraction after 4 weeks (Figure 4). Twenty-four patients showed an increased ejection fraction of ⱖ8% at 4 weeks (42 ⫾ 5% initially vs 58 ⫾ 8% at 4 weeks, p ⬍0.001). In these patients, perfusion defect size significantly decreased at 24 hours and showed further decreases at 4 days and at 4 weeks (Figure 2). In patients who did not show increased ejection fraction (n ⫽ 8), perfusion defect size remained unchanged. Inter- and intraobserver variabilities: Agreements between observers were 92% ( ⫽ 0.81) for interpreting myocardial contrast echocardiograms and 89% ( ⫽ 0.78) for interpreting wall motion. Intra- and interobserver variabilities were 13% and 17%, respectively, for assessment of A* and 12% and 7%, respectively, for planimetric quantification of the perfusion defect area.
FIGURE 2. (A) Myocardial blood flow significantly increased at 24 hours and showed a further improvement at 4 days and at 4 weeks in segments that showed functional recovery. (B) Similarly, perfusion defect area significantly decreased at 24 hours and showed a further decrease at 4 days and at 4 weeks in patients who showed improvement of global ejection fraction (>8%) at 4-week follow-up. *p <0.05, initially versus 24 hours; # p <0.05, 24 hours versus 4 days; ‡p <0.05, 4 days versus 4 weeks. Abbreviation as in Figure 1.
Prediction of regional functional recovery: Because myocardial tissue reperfusion occurred continuously, expanding over the first 24 hours, MCE at 4 days was more sensitive (81% vs 60%, p ⬍0.05) and accurate 1036 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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DISCUSSION This study demonstrates that impaired microvascular integrity is present in patients who have NSTEMI and that its extent and temporal course are related to recovery of wall motion. Real-time MCE can accurately predict functional recovery in these patients. Temporal course of myocardial reperfusion in NSTEMI:
Most patients (60% to 80%) who present with acute coronary syndromes in the emergency department show no ST elevation on their electrocardiogram.20 In this study, we have described for the first time the temporal course of myocardial reperfusion in patients who have NSTEMI and undergo successful angioplasty. Myocardial reperfusion is a complex phenomenon that expands over the first 24 hours after revasMAY 1, 2005
stable ischemic heart disease.12 In this study, MCE demonstrated good accuracy for prediction of functional recovery in patients who have acute NSTEMI. The phenomenon of myocardial stunning, defined as the presence of postischemic dysfunction without necrosis, is well established in the setting of acute infarction.5,6 In this study, a considerable number of segments (41% to 48%) demonstrated improved perfusion but abnormal wall motion at 24-hour and 4-day follow-up, a condition compatible with stunning. On a patient level, contractile function started improving after 4 days, whereas myocardial tissue reperfusion was seen 24 hours after angioplasty. Thus, these data prove the principle of myocardial stunning in patients who have NSTEMI and suggest that MCE can accurately identify stunned tissue with high probability for functional recovery. Previous studies that investigated myocardial reperfusion after myocardial infarction focused on prediction of functional recovery on a segmental level.5,6,24 However, because residual left ventricular function after infarction is a primary determinant of long-term survival, prediction of global improvement is more important for patient risk stratificaFIGURE 3. Myocardial reperfusion of the apex occurred spontaneously in a pation. In this study, we have shown tient who had acute anterior NSTEMI 24 hours to 4 days after revascularization for the first time that temporal of the left anterior descending artery. Assessment of myocardial perfusion 4 days after revascularization correctly predicted functional recovery at 4-week followchanges of myocardial reperfusion in up. patients who have NSTEMI can be assessed quantitatively by real-time MCE and are closely related to excularization, and its temporal patterns are closely tent of improvement in global ejection fraction. related to functional recovery. Galiuto et al21 and Study limitations: The number of patients studied Bronchet et al22 reported that reperfusion can sponta- was relative small. Because most patients studied neously occur between 24 hours and 6 to 9 days after showed functional recovery at 4-week follow-up, the STEMI. In accord with these results, in the present sensitivity of MCE may have been overestimated. study, myocardial perfusion improved spontaneously However, the aim of this study was to investigate in 30% of dysfunctional segments between 24 hours functional recovery, which is more probable in paand 4 weeks. Quantitative estimation of myocardial tients who have NSTEMI than in those who have blood flow confirmed visual findings, showing imSTEMI. We used slow bolus injections for adminisprovement (1.5-fold to 2-fold) after 24 hours and a further increase (3-fold) after 4 days. These findings tration of contrast agent, where delivery of micromay be explained by coronary spasm of the infarct- bubbles is not constant and may confound calculations related artery or through microvascular embolization of the peak rate of increase in contrast intensity. The after successful angioplasty that resolves in later use of continuous infusion may have provided more stages of reperfusion.23 Because myocardial tissue accurate results for estimation of myocardial blood reperfusion was not limited to the first 24 hours, flow. However, we and others have shown that calcuprediction of functional recovery was more accurate lation of replenishment kinetics is still feasible by by performance of MCE at 4-day follow-up. We pre- slow bolus injections during optimal myocardial viously reported that myocardial perfusion imaging opacification,12,15,25 which may, therefore, represent a can detect myocardial viability in patients who have more practical approach in routine clinical settings. CORONARY ARTERY DISEASE/MCE IN NON–ST-ELEVATION MYOCARDIAL INFARCTION
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FIGURE 4. (B) Decrease in perfusion defect area at 4 days correlated strongly with improvement of global ejection fraction at 4-week follow-up (r2 ⴝ 0.76, p <0.001). (A) A weaker correlation (r2 ⴝ 0.22, p <0.01) was found at 24-hour follow-up.
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MAY 1, 2005