- Email: [email protected]
Accuracy of dobutamine tetrofosmin myocardial perfusion imaging for the noninvasive diagnosis of transplant coronary artery stenosis
ALLOGRAFT VASCULOPATHY
Accuracy of Dobutamine Tetrofosmin Myocardial Perfusion Imaging for the Noninvasive Diagnosis of Transplant Coronary Artery Stenosis Abdou Elhendy, MD, PhD, Fabiola B. Sozzi, MD, Ron T. van Domburg, PhD, Pascal Vantrimpont, MD, Roelf Valkema, MD, PhD, Eric P. Krenning, MD, PhD, Jos RTC Roelandt, MD, PhD, Lex P.W.M. Maat, MD, and Aggie HMM Balk, Background: Exercise stress myocardial perfusion scintigraphy has been used for the diagnosis of transplant coronary artery stenosis (TCAS) in cardiac allograft recipients. However, the role of pharmacologic stress myocardial perfusion imaging has not been evaluated. Aim of the study is to assess the accuracy of dobutamine stress 99m technetium tetrofosmin myocardial perfusion imaging for the diagnosis of TCAS in heart transplant recipients. Patients and methods: We studied 50 patients (age 56 ⫾ 8 year, 45 men) at a mean of 6.4 ⫾ 2.8 years after cardiac transplant with dobutamine (up to 40 `g/kg/min) ı stress 99m technetium tetrofosmin SPECT. Resting images were acquired 24 hours after the stress study. Significant TCAS was defined as ⱖ50% luminal diameter stenosis by coronary angiography. Results: Significant TCAS was detected in 30 patients (60%). Myocardial perfusion abnormalities (reversible and/or fixed defects) were detected in 27 of the 30 patients with and in 9 of the 20 patients without significant TCAS (sensitivity ⫽ 90%, CI 82-98, specificity ⫽ 55% CI 41-69, positive predictive value ⫽ 75%, CI 6387, negative predictive value ⫽ 79%, CI 67-90 and accuracy ⫽ 76%, CI 64-88). Patients with multivessel TCAS had a larger stress perfusion defect score (5.6 ⫾ 3.1 vs 3.2 ⫾ 2.4, p ⬍ 0.05) compared to patients with single vessel TCAS. Among patients with abnormal perfusion who had no significant TCAS, 2 had lesions ⬍50%, 2 had luminal irregularities and 5 had no abnormalities at angiography.
From the Thoraxcenter and the Department of Nuclear Medicine,a University Hospital, Rotterdam, the Netherlands, and the Department of Cardiovascular Disease and Internal Medicine,b Mayo Clinic, Rochester, MN, USA Submitted January 7, 2000; accepted January 7, 2000. Reprint requests: Abdou Elhendy, MD, PhD, 200 1st Street SW, Rochester, MN 55905, Tel: 507 2849470. Fax: 507 2840164.
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E-mail: [email protected]. Copyright © 2000 by the International Society for Heart and Lung Transplantation. 1053-2498/00/$–see front matter PII S1053-2498(00)00068-1 This study was supported in part by the Department of Cardiology, Cairo University Hospital, Cairo, Egypt.
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Therefore specificity was 62% (8/13) in patients without any detectable angiographic abnormalities. Conclusions: Dobutamine stress tetrofosmin myocardial perfusion imaging is a highly sensitive method for the detection of TCAS in recipients of cardiac allografts. The high negative predictive value of the test indicates that patients who demonstrate normal perfusion by this method may be excluded from further invasive studies. J Heart Lung Transplant 2000;19:360–366.
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ardiac allograft vasculopathy is a major cause of morbidity and mortality in cardiac allograft recipients.1 Previous studies have reported conflicting data regarding the accuracy of current available stress testing modalities for the diagnosis of cardiac allograft vasculopathy.1–3 Exercise stress myocardial perfusion scintigraphy is a feasible method for that purpose.2– 4 However, the sensitivity of the test may be reduced in patients with sub-maximal exercise test. Although cardiac transplantation results in a dramatic improvement of quality of life, exercise tolerance in allograft recipients remains impaired in comparison with normal subjects.5 Pharmacologic stress myocardial perfusion imaging is an alternative method in patients with limited exercise capacity. Only one study6 assessed the role of dipyridamole perfusion scintigraphy for the diagnosis of transplant coronary artery stenosis (TCAS) and the reported sensitivity was poor (22%). Dobutamine stress testing is increasingly used for evaluation of coronary artery disease (CAD) in patients with limited exercise capacity. Echocardiographic evaluation of wall motion abnormalities at rest and at high dose dobutamine was shown as a useful tool in the diagnosis and prognostic stratification of patients after cardiac transplantation, although the sensitivity of the test has been low in some studies.7–10 Stress myocardial perfusion imaging is an alternative to stress echocardiography particularly in centers without expertise in echocardiographic imaging and in patients with a poor echocardiographic window.11 Although, the accuracy of myocardial perfusion imaging for the diagnosis of CAD has been demonstrated in various clinical settings,12 the utility of dobutamine myocardial perfusion imaging in recipients of cardiac allografts has not been evaluated. The aim of this study is to assess the accuracy of dobutamine stress 99m technetium tetrofosmin myocardial perfusion imaging for the diagnosis of significant TCAS in cardiac allograft recipients.
METHODS Patient selection The study population consisted of 50 recipients of cardiac allograft who underwent dobutamine stress 99m technetium tetrofosmin SPECT at a mean of 6.4 ⫾ 2.8 (range 2–14) years after the transplantation and coronary angiography within 3 months from the dobutamine stress test. Mean age was 56 ⫾ 8 years. There were 45 men and 5 women. Two patients had atypical chest pain. Risk factors for CAD were hypertension in 32 (64%) patients, diabetes mellitus in 5 (10%) patients, smoking in 6 (12%) patients and hypercholesterolemia in 26 (52%) patients. At the day of the test, 4 patients (8%) were receiving beta-blockers. Other medications included calcium channel blockers in 30 patients (60%), angiotensin converting enzyme inhibitors in 7 (14%) patients and diuretics in 11 (22%) patients. Immunosuppressive therapy included prednisone and cyclosporine in all patients with the addition of azathioprine in 22 (44%) patients and mycophenolate mofetil in 4 patients (8%).
Dobutamine stress test Dobutamine was infused through an antecubital vein starting at a dose of 5 followed by 10 g/kg/min (3 minutes stages), increasing by 10 g/kg/min every 3 minutes to a maximum of 40 g/kg/min. Atropine (up to 1 mg) was given in patients not achieving 85% of age-predicted maximal heart rate and dobutamine infusion was continued. The electrocardiogram was continuously monitored and was recorded each minute. Cuff blood pressure was measured at rest and every 3 minutes during stress. The test was interrupted if severe chest pain, ST-segment depression ⬎2 mm, significant ventricular or supraventricular arrhythmia, hypertension (blood pressure ⱖ240/120), systolic blood pressure fall ⬎40 mm Hg or any intolerable side effect regarded as being due to dobutamine occurred during the test. Metoprolol (1-5 mg) was used intravenously to reverse the
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effects of dobutamine if they did not revert quickly. Ischemia at the electrocardiogram was defined as ⱖ0.1 mV horizontal or downsloping ST-segment depression or ⱖ0.1 mV ST-segment elevation measured 80 mS from the J point compared to baseline.
SPECT imaging Approximately 1 minute before the termination of the stress test, an intravenous dose of 370 MBq of 99m technetium tetrofosmin was administered.11 For resting studies 370 MBq of tetrofosmin were injected 24 hours after the stress study. Image acquisition was performed with a triple head gamma camera system (Picker Prism 3000 XP, Cleveland, Ohio). For each study 6 oblique (short axis) slices from the apex to the base and 3 sagittal (vertical long axis) slices from the septum to the lateral wall were defined.11 Each of the 6 short axis slices was divided into 8 equal segments. The interpretation of the scan was semi-quantitatively performed by visual analysis assisted by the circumferential profiles analysis. Stress and rest tomographic views were reviewed side by side by an experienced observer who was unaware of the patients’ clinical or angiographic data. A reversible perfusion defect was defined as a perfusion defect on stress images that partially or completely resolved at rest in ⱖ2 contiguous segments or slices. A fixed perfusion defect was defined as a perfusion defect on stress images in 2 or more contiguous segments or slices which persists on rest images. To assess the severity of perfusion abnormalities, the left ventricular myocardium was divided into 6 segments: anterior, inferior, septal anterior, septal posterior, posterolateral and apical. Each of the 6 major left ventricular segments was scored using a 4 grade score method (0 ⫽ normal, 1 ⫽ slightly reduced, 2 ⫽ moderately reduced, 3 ⫽ severely reduced or absent uptake). Perfusion defect score was derived by the summation of the score of the 6 myocardial segments.11
Coronary angiography Coronary angiography was performed within 3 months from the dobutamine stress test. Significant TCAS was defined as a diameter stenosis ⱖ50% in ⱖ1 major epicardial artery.13 The anterior, apical, septal and anteroseptal segments were assigned to the left anterior descending coronary artery (LAD). The posterior and lateral segments were assigned to the left circumflex (LCX). The inferior and basal septal segments were assigned to the right coronary artery (RCA). The apical lateral segment was considered as an overlap segment between the LAD
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and the LCX. The apical inferior segment was considered an overlap segment between the LAD and the RCA. Overlap segments were assigned to the regions with concomitant abnormalities. Statistical analysis: Unless specified, data are presented as mean values ⫾ SD. The chi-square test was used to compare differences between proportions. The Student’s t-test was used for analysis of continuous data. P value ⬍0.05 was considered statistically significant. Sensitivity, specificity and accuracy were derived according to the standard definitions and were represented with the 95% confidence intervals (95% CI).
RESULTS Dobutamine stress test There was a significant increase of heart rate (93 ⫾ 11 vs 142 ⫾ 9 beats/minute, p ⬍ 0.0001), systolic blood pressure (144 ⫾ 19 vs 151 ⫾ 28 mm Hg, p ⬍ 0.01) and rate pressure product (13516 ⫾ 3026 vs 21365 ⫾ 4114, p ⬍ 0.0001) from rest to peak stress respectively. Two patients developed atypical and one patient developed typical chest pain during stress. The target heart rate (ⱖ85% of the maximal exercise heart rate predicted for age) was reached in 41 patients (82%). Minor side effects were nausea and flushing in 2 patients (4%) and headache in 4 patients (8%). Atropine was administered in 5 patients. An increase of heart rate of ⬎10 beats occurred in 2 patients.
Coronary angiography Significant TCAS was detected in 30 patients (60%). Thirteen patients (26%) had single vessel TCAS, 10 (20%) had 2 vessel TCAS and 7 (14%) had 3 vessel TCAS. Significant stenoses involved the LAD in 24 patients (48%), the LCX in 18 patients (36%) and in the RCA in 12 patients (24%). Four patients had ⬍50% TCAS, 3 patients had luminal irregularities without stenosis whereas 13 patients had no abnormalities detected by angiography.
Prediction of CAD by electrocardiographic changes Ischemic electrocardiographic changes occurred in 12 of 30 patients with and in 2 of 20 patients without TCAS (sensitivity ⫽ 40%, CI 26-54, specificity ⫽ 90% CI 82-98, accuracy ⫽ 60%, CI 46-74). One of the 2 patients with a false positive electrocardiographic changes had concomitant perfusion abnormalities.
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FIGURE 1 Sensitivity (SENS), specificity (SPEC) and accuracy (ACC) of dobutamine stress 99m technetium tetrofosmin SPECT for the regional diagnosis of transplant coronary artery stenosis. LAD ⫽ left anterior descending, LCX ⫽ left circumflex, RCA ⫽ right coronary artery.
Tetrofosmin SPECT Myocardial perfusion abnormalities (reversible and/or fixed defects) were detected in 27 of the 30 patients with and in 9 of the 20 patients without significant TCAS (sensitivity ⫽ 90%, CI 82-98, specificity ⫽ 55% CI 41-69, positive predictive value ⫽ 75%, CI 63-87, negative predictive value ⫽ 79%, CI 67-90 and accuracy ⫽ 76%, CI 64-88). The sensitivity was 85% in patients with single vessel TCAS (11/13), 90% in patients with 2 vessel TCAS (9/10) and 100% in patients with 3 vessel TCAS (7/7). In patients with TCAS and perfusion abnormalities, perfusion defects were reversible in 17 patients whereas 10 patients had fixed perfusion abnormalities.
Abnormal perfusion in multivessel distribution Perfusion defects in 2 different vascular territories, suggestive of multivessel TCAS occurred in 10 of the 17 patients with and in 5 of 33 patients without multivessel TCAS (sensitivity ⫽ 59%, CI 45-72, specificity ⫽ 85% CI 75-95, accuracy ⫽ 76%, CI 64-88). Among the 5 patients with multivessel pattern of perfusion abnormalities in absence of multivessel TCAS at angiography, 3 patients had single vessel TCAS, one patient had ⬍50% LAD lesion and one patient had no abnormalities at angiography. Patients with multivessel TCAS had a larger
stress perfusion defect score (5.6 ⫾ 3.1 vs 3.2 ⫾ 2.4, p ⬍ 0.05) compared to patients with single vessel TCAS, respectively. The accuracy for the detection of significant stenosis of individual coronary arteries is shown in Figure 1. No significant difference was found regarding sensitivity, specificity or accuracy in the 3 vascular regions.
Patients with perfusion abnormalities without significant TCAS Myocardial perfusion abnormalities were detected in 9 out of the 20 patients without significant TCAS by angiography (5 had reversible and 4 had fixed perfusion abnormalities). Among patients with abnormal perfusion, 2 had coronary lesions ⬍50%, 2 had luminal irregularities and 5 had no abnormalities at angiography. Distal pruning was detected in 2 patients (one with concomitant luminal irregularities and the other with a lesion ⬍50%). Therefore specificity was 62% (8/13) in patients without any detectable angiographic abnormalities.
DISCUSSION This is the first study, which evaluates the accuracy of dobutamine myocardial perfusion imaging for the non-invasive diagnosis of TCAS. Our data showed that dobutamine tetrofosmin myocardial perfusion SPECT imaging is a highly sensitive methods for the
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diagnosis of significant TCAS in patients studied 6.4 ⫾ 2.8 (range 2–14) years after heart transplantation. Myocardial perfusion abnormalities were detected in 90% of patients with TCAS. The high sensitivity was shown in patients with single vessel TCAS (85%) as well as in patients with multivessel TCAS (94%). Myocardial perfusion abnormalities in ⱖ2 vascular regions were highly specific for multivessel TCAS, although this pattern occurred only in 59% of these patients. Patients with multivessel TCAS demonstrated a larger myocardial perfusion defect score compared to patients with single vessel TCAS denoting the ability of the technique in evaluation of the extent of TCAS. No significant difference was detected regarding the accuracy for the diagnosis of individual coronary artery stenoses. The similar sensitivity in the 3 vascular regions reflects the advantage of SPECT technique in the detection and localization of perfusion abnormalities. The similar specificity may be explained by the better target background ratio for the inferior wall achieved by the use of technetium-labelled agents.14 The use of 99mtechnetium tetrofosmin was previously demonstrated to improve imaging quality of exercise myocardial perfusion scintigraphy compared to 201thallium.15
Patients with abnormal perfusion and no significant TCAS The occurrence of myocardial perfusion abnormalities in 45% of patients without ⱖ50% stenosis of epicardial coronary arteries may be explained in part by the complex nature of graft vasculopathy. Histologic studies and intravascular ultrasonography have demonstrated intimal thickness, vascular sclerosis and occlusion of small distal vessels which may lead to ischemia or microvascular infarction despite normal angiographic findings in the early course of the disease.16 –19 Other factors that may contribute to the occurrence of perfusion abnormalities in association with normal angiographic findings include impairment of endothelial function and vasodilator reserve.18,19 Therefore, it should be emphasized that coronary angiography may lack sensitivity for the detection of early transplant CAD as it depicts the silhouette of the lumen of coronary arteries and has a limited ability in the evaluation of small vessel disease. Other imaging techniques have been introduced to avoid this limitation. Intravascular ultrasound was shown to detect early disease of the arterial wall that can not be detected by angiography. However, this technique can not be consid-
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ered as a gold standard for the diagnosis of transplant coronary artery disease because of the inability to study the distal lesions.17,20 In our study 4 of the 9 patients who demonstrated perfusion abnormalities in absence of stenotic lesions with ⱖ50% luminal diameter stenosis had less severe lesions, luminal irregularities or distal pruning which may indicate an association with a distal lesion with impairment of vasodilator reserve. Although, the occurrence of imaging artifacts is known to reduce the specificity of myocardial perfusion imaging, a significant proportion of myocardial perfusion abnormalities in absence of ⱖ50% TCAS in this study may represent true impairment of myocardial perfusion at rest or during stress. This is due to the presence of small vessel disease, microinfarctions and impairment of vasodilator reserve because these findings are known to occur in patients with transplant vasculopathy and may precede significant narrowing of the coronary arterial lumen.17 Nevertheless, coronary angiography remains a widely used technique for evaluation and prognostic stratification of cardiac transplant recipients. This study showed a high sensitivity of dobutamine terofosmin SPECT imaging for the detection of TCAS. Despite the low specificity of the technique when angiography was used as the gold standard, the high sensitivity and negative predictive accuracy indicates that the probability of TCAS is low if the patient demonstrates normal perfusion. Therefore, invasive evaluation of coronary arteries in patients with a negative test might not be required.
Comparison with previous studies There are conflicting data regarding the sensitivity and specificity of exercise myocardial perfusion imaging among previous studies. Sensitivity ranged between 22% and 100%.1– 4,6,21 Ciliberto et al4 studied 50 heart transplant patients. Exercise thallium scintigraphy was negative in all of the 35 patients with normal coronary arteries (100% specificity), and abnormal in 10 of 15 patients with CAD (67% sensitivity). Rodney et al3 studied the value of thallium-201 and technetium 99m sestamibi for the detection of TCAS in 25 heart transplant recipient. Ten of 13 patients with TCAS had abnormal thallium-201 scans (sensitivity ⫽ 77%). Sensitivity of MIBI was not significantly different from that of thallium. There were no false-positive scans in the 12 patients without TCAS (specificity ⫽ 100%). The sensitivity and specificity of dipyridamole perfusion imaging were 21% and 88%, respectively, as reported by Smart et al.6 Flow up studies of the same
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population with exercise thallium revealed a sensitivity of 21%. In contrast with the studies reporting high specificity of myocardial perfusion scintigraphy, Puskas et al20 reported that in 43 patients with normal coronary angiography studied early after cardiac transplant by exercise thallium SPECT, pathologic results defined as fixed defects, redistribution or reverse redistribution were detected in 40% of segments. Scintigraphic results did not correlate with intimal thickness of epicardial coronary arteries accessible to intravascular ultrasonography. The score of inhomogeneity of myocardial perfusion was progressive indicating the possibility of small vessel alteration as suggested by the authors. McKillop et al22 reported that 4 patients without TCAS had fixed defects on planar thallium scintigraphy. Howarth et al21 reported a sensitivity of 78% and specificity of 33% among 7 patients who underwent 13 stress thallium SPECT studies.
tant clue regarding the possibility of further intervention as revascularization or retransplantation. The results of the scans were available to the treating physicians. Therefore, possible referral bias for coronary angiography might have had an effect on the results of the study. Finally, this study did not assess the prognostic significance of myocardial perfusion abnormalities and therefore, further studies are needed to expand the role of dobutamine myocardial perfusion scintigraphy in cardiac transplant recipients.
Studies of dobutamine stress echocardiography
REFERENCES
The role of dobutamine stress echocardiography in the diagnosis of TCAS and prognostic stratification of transplant recipient has been recently evaluated. Sensitivity for the diagnosis of TCAS ranged between 79% and 95% and specificity ranged between 55% and 95%.7–10,23 Severe inducible wall motion abnormalities were associated with a higher probability of future cardiac events.8 Our study demonstrated that dobutamine myocardial perfusion scintigraphy is a sensitive method for the diagnosis of TCAS and therefore this method can provide an alternative imaging modality particularly in patients with poor echocardiographic window and in centers with less expertise in stress echocardiographic imaging.
Limitations of the study The correlation between myocardial perfusion and angiographic abnormalities is limited by the low sensitivity of angiographic techniques for the detection of transplant CAD. It is possible that some of the perfusion abnormalities identified as false positive in this study represent true abnormalities consequent to a disease behind the angiographic resolution capacity. However, despite that intravascular ultrasonography has a higher sensitivity for early detection of coronary artery pathologies, the value of this technique is still limited to the large epicardial arteries. Although the gold standard for the early detection of transplant CAD is not well defined, identification of a significant epicardial coronary artery stenosis remains an important task because such abnormalities provide impor-
Clinical implications and conclusions Dobutamine stress tetrofosmin myocardial perfusion imaging is a highly sensitive method for the detection of TCAS in recipients of cardiac allograft transplant. The high negative predictive value of the test indicates that patients who demonstrate normal perfusion by this method may be excluded from further invasive studies.
1. Fang JC, Rocco T, Jarcho J, Ganz P, Mudge GH. Noninvasive assessment of transplant-associated arteriosclerosis. Am Heart J 1998;135:980 –7. 2. Rodney RA, Johnson LL. Myocardial perfusion scintigraphy to assess heart transplant vasculopathy. J Heart Lung Transplant 1992;11:S74 – 8. 3. Rodney RA, Johnson LL, Blood DK, Barr ML. Myocardial perfusion scintigraphy in heart transplant recipients with and without allograft atherosclerosis: a comparison of thallium201 and technetium 99m sestamibi. J Heart Lung Transplant 1994;13:173– 80. 4. Ciliberto GR, Mangiavacchi M, Banfi F, et al. Coronary artery disease after heart transplantation: non-invasive evaluation with exercise thallium scintigraphy. Eur Heart J 1993;14:226 –9. 5. Mandak JS, Aaronson KD, Mancini DM. Serial assessment of exercise capacity after heart transplantation. J Heart Lung Transplant 1995;14:468 –78. 6. Smart FW, Ballantyne CM, Cocanougher B, et al. Insensitivity of noninvasive tests to detect coronary artery vasculopathy after heart transplant. Am J Cardiol 1991;67:243–7. 7. Akosah KO, Mohanty PK. Role of dobutamine stress echocardiography in heart transplant patients. Chest 1998;113:809 –15. 8. Lewis JF, Selman SB, Murphy JD, Mills RM Jr, Geiser EA, Conti CR. Dobutamine echocardiography for prediction of ischemic events in heart transplant recipients. J Heart Lung Transplant 1997;16:390 –3. 9. Akosah KO, Olsovsky M, Kirchberg D, Salter D, Mohanty PK. Dobutamine stress echocardiography predicts cardiac events in heart transplant patients. Circulation 1996;94(9 Suppl):II283– 8. 10. Akosah KO, Mohanty PK, Funai JT, et al. Noninvasive detection of transplant coronary artery disease by dobutamine stress echocardiography. J Heart Lung Transplant 1994;13:1024 –38. 11. Elhendy A, Valkema R, van Domburg RT, et al. Safety of dobutamine-atropine stress myocardial perfusion scintigraphy. J Nucl Med 1998;39:1662– 6.
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12. Pennell DJ, Underwood SR, Swanton RH, Walker JM, Ell PJ. Dobutamine thallium myocardial perfusion tomography. J Am Coll Cardiol 1991;18:1471–9. 13. Baptista J, Arnese M, Roelandt JRTC, et al. Quantitative coronary angiography in the estimation of the functional significance of coronary stenosis: Correlation with dobutamine-atropine stress test. J Am Coll Cardiol 1994;23: 1434 –9. 14. Zaret BL, Rigo P, Wackers FJ, et al. Myocardial perfusion imaging with 99mTc tetrofosmin. Comparison to 201T1 imaging and coronary angiography in a phase III multicenter trial. Tetrofosmin International Trial Study Group. Circulation 1995;91:313–9. 15. Khattar RS, Hendel RC, Crawley JC, et al. Improved diagnostic accuracy of planar imaging with technetium 99mlabelled tetrofosmin compared with thallium-201 for the detection of coronary artery disease. J Nucl Cardiol 1997;4: 291–7. 16. Billingham ME. Histopathology of graft coronary disease. J Heart Lung Transplant 1992;11:S38 – 44. 17. Spes CH, Klauss V, Rieber J, et al. Functional and morphological findings in heart transplant recipients with a normal coronary angiogram: an analysis by dobutamine stress echocardiography, intracoronary Doppler and intravascular ultrasound. J Heart Lung Transplant 1999;18:391– 8.
The Journal of Heart and Lung Transplantation April 2000 18. Mullins PA, Chauhan A, Sharples L, et al. Impairment of coronary flow reserve in orthotopic cardiac transplant recipients with minor coronary occlusive disease. Br Heart J 1992;68:266 –71. 19. Billingham ME. The pathologic changes in long-term heart and lung transplant survivors. J Heart Lung Transplant 1992;11:S38 – 44. 20. Puskas C, Kosch M, Kerber S, et al. Progressive heterogeneity of myocardial perfusion in heart transplant recipients detected by thallium-201 myocardial SPECT. J Nucl Med 1997;38:760 –5. 21. Howarth DM, Forstrom LA, Samudrala V, Sinak LJ, McGregor CG, Rodeheffer RJ. Evaluation of 201T1 SPET myocardial perfusion imaging in the detection of coronary artery disease after orthotopic heart transplantation. Nucl Med Commun 1996;17:105–13. 22. McKillop JH, Goris ML. Thallium-201 myocardial imaging in patients with previous cardiac transplantation. Clin Radiol 1981;32:447–9. 23. Mairesse GH, Marwick TH, Melin JA, et al. Use of exercise electrocardiography, technetium-99m-MIBI perfusion tomography, and two-dimensional echocardiography for coronary disease surveillance in a low-prevalence population of heart transplant recipients. J Heart Lung Transplant 1995; 14:222–9.
Accuracy of Dobutamine Tetrofosmin Myocardial Perfusion Imaging for the Noninvasive Diagnosis of Transplant Coronary Artery Stenosis Abdou Elhendy, MD, PhD, Fabiola B. Sozzi, MD, Ron T. van Domburg, PhD, Pascal Vantrimpont, MD, Roelf Valkema, MD, PhD, Eric P. Krenning, MD, PhD, Jos RTC Roelandt, MD, PhD, Lex P.W.M. Maat, MD, and Aggie HMM Balk, Background: Exercise stress myocardial perfusion scintigraphy has been used for the diagnosis of transplant coronary artery stenosis (TCAS) in cardiac allograft recipients. However, the role of pharmacologic stress myocardial perfusion imaging has not been evaluated. Aim of the study is to assess the accuracy of dobutamine stress 99m technetium tetrofosmin myocardial perfusion imaging for the diagnosis of TCAS in heart transplant recipients. Patients and methods: We studied 50 patients (age 56 ⫾ 8 year, 45 men) at a mean of 6.4 ⫾ 2.8 years after cardiac transplant with dobutamine (up to 40 `g/kg/min) ı stress 99m technetium tetrofosmin SPECT. Resting images were acquired 24 hours after the stress study. Significant TCAS was defined as ⱖ50% luminal diameter stenosis by coronary angiography. Results: Significant TCAS was detected in 30 patients (60%). Myocardial perfusion abnormalities (reversible and/or fixed defects) were detected in 27 of the 30 patients with and in 9 of the 20 patients without significant TCAS (sensitivity ⫽ 90%, CI 82-98, specificity ⫽ 55% CI 41-69, positive predictive value ⫽ 75%, CI 6387, negative predictive value ⫽ 79%, CI 67-90 and accuracy ⫽ 76%, CI 64-88). Patients with multivessel TCAS had a larger stress perfusion defect score (5.6 ⫾ 3.1 vs 3.2 ⫾ 2.4, p ⬍ 0.05) compared to patients with single vessel TCAS. Among patients with abnormal perfusion who had no significant TCAS, 2 had lesions ⬍50%, 2 had luminal irregularities and 5 had no abnormalities at angiography.
From the Thoraxcenter and the Department of Nuclear Medicine,a University Hospital, Rotterdam, the Netherlands, and the Department of Cardiovascular Disease and Internal Medicine,b Mayo Clinic, Rochester, MN, USA Submitted January 7, 2000; accepted January 7, 2000. Reprint requests: Abdou Elhendy, MD, PhD, 200 1st Street SW, Rochester, MN 55905, Tel: 507 2849470. Fax: 507 2840164.
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E-mail: [email protected]. Copyright © 2000 by the International Society for Heart and Lung Transplantation. 1053-2498/00/$–see front matter PII S1053-2498(00)00068-1 This study was supported in part by the Department of Cardiology, Cairo University Hospital, Cairo, Egypt.
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Therefore specificity was 62% (8/13) in patients without any detectable angiographic abnormalities. Conclusions: Dobutamine stress tetrofosmin myocardial perfusion imaging is a highly sensitive method for the detection of TCAS in recipients of cardiac allografts. The high negative predictive value of the test indicates that patients who demonstrate normal perfusion by this method may be excluded from further invasive studies. J Heart Lung Transplant 2000;19:360–366.
C
ardiac allograft vasculopathy is a major cause of morbidity and mortality in cardiac allograft recipients.1 Previous studies have reported conflicting data regarding the accuracy of current available stress testing modalities for the diagnosis of cardiac allograft vasculopathy.1–3 Exercise stress myocardial perfusion scintigraphy is a feasible method for that purpose.2– 4 However, the sensitivity of the test may be reduced in patients with sub-maximal exercise test. Although cardiac transplantation results in a dramatic improvement of quality of life, exercise tolerance in allograft recipients remains impaired in comparison with normal subjects.5 Pharmacologic stress myocardial perfusion imaging is an alternative method in patients with limited exercise capacity. Only one study6 assessed the role of dipyridamole perfusion scintigraphy for the diagnosis of transplant coronary artery stenosis (TCAS) and the reported sensitivity was poor (22%). Dobutamine stress testing is increasingly used for evaluation of coronary artery disease (CAD) in patients with limited exercise capacity. Echocardiographic evaluation of wall motion abnormalities at rest and at high dose dobutamine was shown as a useful tool in the diagnosis and prognostic stratification of patients after cardiac transplantation, although the sensitivity of the test has been low in some studies.7–10 Stress myocardial perfusion imaging is an alternative to stress echocardiography particularly in centers without expertise in echocardiographic imaging and in patients with a poor echocardiographic window.11 Although, the accuracy of myocardial perfusion imaging for the diagnosis of CAD has been demonstrated in various clinical settings,12 the utility of dobutamine myocardial perfusion imaging in recipients of cardiac allografts has not been evaluated. The aim of this study is to assess the accuracy of dobutamine stress 99m technetium tetrofosmin myocardial perfusion imaging for the diagnosis of significant TCAS in cardiac allograft recipients.
METHODS Patient selection The study population consisted of 50 recipients of cardiac allograft who underwent dobutamine stress 99m technetium tetrofosmin SPECT at a mean of 6.4 ⫾ 2.8 (range 2–14) years after the transplantation and coronary angiography within 3 months from the dobutamine stress test. Mean age was 56 ⫾ 8 years. There were 45 men and 5 women. Two patients had atypical chest pain. Risk factors for CAD were hypertension in 32 (64%) patients, diabetes mellitus in 5 (10%) patients, smoking in 6 (12%) patients and hypercholesterolemia in 26 (52%) patients. At the day of the test, 4 patients (8%) were receiving beta-blockers. Other medications included calcium channel blockers in 30 patients (60%), angiotensin converting enzyme inhibitors in 7 (14%) patients and diuretics in 11 (22%) patients. Immunosuppressive therapy included prednisone and cyclosporine in all patients with the addition of azathioprine in 22 (44%) patients and mycophenolate mofetil in 4 patients (8%).
Dobutamine stress test Dobutamine was infused through an antecubital vein starting at a dose of 5 followed by 10 g/kg/min (3 minutes stages), increasing by 10 g/kg/min every 3 minutes to a maximum of 40 g/kg/min. Atropine (up to 1 mg) was given in patients not achieving 85% of age-predicted maximal heart rate and dobutamine infusion was continued. The electrocardiogram was continuously monitored and was recorded each minute. Cuff blood pressure was measured at rest and every 3 minutes during stress. The test was interrupted if severe chest pain, ST-segment depression ⬎2 mm, significant ventricular or supraventricular arrhythmia, hypertension (blood pressure ⱖ240/120), systolic blood pressure fall ⬎40 mm Hg or any intolerable side effect regarded as being due to dobutamine occurred during the test. Metoprolol (1-5 mg) was used intravenously to reverse the
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effects of dobutamine if they did not revert quickly. Ischemia at the electrocardiogram was defined as ⱖ0.1 mV horizontal or downsloping ST-segment depression or ⱖ0.1 mV ST-segment elevation measured 80 mS from the J point compared to baseline.
SPECT imaging Approximately 1 minute before the termination of the stress test, an intravenous dose of 370 MBq of 99m technetium tetrofosmin was administered.11 For resting studies 370 MBq of tetrofosmin were injected 24 hours after the stress study. Image acquisition was performed with a triple head gamma camera system (Picker Prism 3000 XP, Cleveland, Ohio). For each study 6 oblique (short axis) slices from the apex to the base and 3 sagittal (vertical long axis) slices from the septum to the lateral wall were defined.11 Each of the 6 short axis slices was divided into 8 equal segments. The interpretation of the scan was semi-quantitatively performed by visual analysis assisted by the circumferential profiles analysis. Stress and rest tomographic views were reviewed side by side by an experienced observer who was unaware of the patients’ clinical or angiographic data. A reversible perfusion defect was defined as a perfusion defect on stress images that partially or completely resolved at rest in ⱖ2 contiguous segments or slices. A fixed perfusion defect was defined as a perfusion defect on stress images in 2 or more contiguous segments or slices which persists on rest images. To assess the severity of perfusion abnormalities, the left ventricular myocardium was divided into 6 segments: anterior, inferior, septal anterior, septal posterior, posterolateral and apical. Each of the 6 major left ventricular segments was scored using a 4 grade score method (0 ⫽ normal, 1 ⫽ slightly reduced, 2 ⫽ moderately reduced, 3 ⫽ severely reduced or absent uptake). Perfusion defect score was derived by the summation of the score of the 6 myocardial segments.11
Coronary angiography Coronary angiography was performed within 3 months from the dobutamine stress test. Significant TCAS was defined as a diameter stenosis ⱖ50% in ⱖ1 major epicardial artery.13 The anterior, apical, septal and anteroseptal segments were assigned to the left anterior descending coronary artery (LAD). The posterior and lateral segments were assigned to the left circumflex (LCX). The inferior and basal septal segments were assigned to the right coronary artery (RCA). The apical lateral segment was considered as an overlap segment between the LAD
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and the LCX. The apical inferior segment was considered an overlap segment between the LAD and the RCA. Overlap segments were assigned to the regions with concomitant abnormalities. Statistical analysis: Unless specified, data are presented as mean values ⫾ SD. The chi-square test was used to compare differences between proportions. The Student’s t-test was used for analysis of continuous data. P value ⬍0.05 was considered statistically significant. Sensitivity, specificity and accuracy were derived according to the standard definitions and were represented with the 95% confidence intervals (95% CI).
RESULTS Dobutamine stress test There was a significant increase of heart rate (93 ⫾ 11 vs 142 ⫾ 9 beats/minute, p ⬍ 0.0001), systolic blood pressure (144 ⫾ 19 vs 151 ⫾ 28 mm Hg, p ⬍ 0.01) and rate pressure product (13516 ⫾ 3026 vs 21365 ⫾ 4114, p ⬍ 0.0001) from rest to peak stress respectively. Two patients developed atypical and one patient developed typical chest pain during stress. The target heart rate (ⱖ85% of the maximal exercise heart rate predicted for age) was reached in 41 patients (82%). Minor side effects were nausea and flushing in 2 patients (4%) and headache in 4 patients (8%). Atropine was administered in 5 patients. An increase of heart rate of ⬎10 beats occurred in 2 patients.
Coronary angiography Significant TCAS was detected in 30 patients (60%). Thirteen patients (26%) had single vessel TCAS, 10 (20%) had 2 vessel TCAS and 7 (14%) had 3 vessel TCAS. Significant stenoses involved the LAD in 24 patients (48%), the LCX in 18 patients (36%) and in the RCA in 12 patients (24%). Four patients had ⬍50% TCAS, 3 patients had luminal irregularities without stenosis whereas 13 patients had no abnormalities detected by angiography.
Prediction of CAD by electrocardiographic changes Ischemic electrocardiographic changes occurred in 12 of 30 patients with and in 2 of 20 patients without TCAS (sensitivity ⫽ 40%, CI 26-54, specificity ⫽ 90% CI 82-98, accuracy ⫽ 60%, CI 46-74). One of the 2 patients with a false positive electrocardiographic changes had concomitant perfusion abnormalities.
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FIGURE 1 Sensitivity (SENS), specificity (SPEC) and accuracy (ACC) of dobutamine stress 99m technetium tetrofosmin SPECT for the regional diagnosis of transplant coronary artery stenosis. LAD ⫽ left anterior descending, LCX ⫽ left circumflex, RCA ⫽ right coronary artery.
Tetrofosmin SPECT Myocardial perfusion abnormalities (reversible and/or fixed defects) were detected in 27 of the 30 patients with and in 9 of the 20 patients without significant TCAS (sensitivity ⫽ 90%, CI 82-98, specificity ⫽ 55% CI 41-69, positive predictive value ⫽ 75%, CI 63-87, negative predictive value ⫽ 79%, CI 67-90 and accuracy ⫽ 76%, CI 64-88). The sensitivity was 85% in patients with single vessel TCAS (11/13), 90% in patients with 2 vessel TCAS (9/10) and 100% in patients with 3 vessel TCAS (7/7). In patients with TCAS and perfusion abnormalities, perfusion defects were reversible in 17 patients whereas 10 patients had fixed perfusion abnormalities.
Abnormal perfusion in multivessel distribution Perfusion defects in 2 different vascular territories, suggestive of multivessel TCAS occurred in 10 of the 17 patients with and in 5 of 33 patients without multivessel TCAS (sensitivity ⫽ 59%, CI 45-72, specificity ⫽ 85% CI 75-95, accuracy ⫽ 76%, CI 64-88). Among the 5 patients with multivessel pattern of perfusion abnormalities in absence of multivessel TCAS at angiography, 3 patients had single vessel TCAS, one patient had ⬍50% LAD lesion and one patient had no abnormalities at angiography. Patients with multivessel TCAS had a larger
stress perfusion defect score (5.6 ⫾ 3.1 vs 3.2 ⫾ 2.4, p ⬍ 0.05) compared to patients with single vessel TCAS, respectively. The accuracy for the detection of significant stenosis of individual coronary arteries is shown in Figure 1. No significant difference was found regarding sensitivity, specificity or accuracy in the 3 vascular regions.
Patients with perfusion abnormalities without significant TCAS Myocardial perfusion abnormalities were detected in 9 out of the 20 patients without significant TCAS by angiography (5 had reversible and 4 had fixed perfusion abnormalities). Among patients with abnormal perfusion, 2 had coronary lesions ⬍50%, 2 had luminal irregularities and 5 had no abnormalities at angiography. Distal pruning was detected in 2 patients (one with concomitant luminal irregularities and the other with a lesion ⬍50%). Therefore specificity was 62% (8/13) in patients without any detectable angiographic abnormalities.
DISCUSSION This is the first study, which evaluates the accuracy of dobutamine myocardial perfusion imaging for the non-invasive diagnosis of TCAS. Our data showed that dobutamine tetrofosmin myocardial perfusion SPECT imaging is a highly sensitive methods for the
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diagnosis of significant TCAS in patients studied 6.4 ⫾ 2.8 (range 2–14) years after heart transplantation. Myocardial perfusion abnormalities were detected in 90% of patients with TCAS. The high sensitivity was shown in patients with single vessel TCAS (85%) as well as in patients with multivessel TCAS (94%). Myocardial perfusion abnormalities in ⱖ2 vascular regions were highly specific for multivessel TCAS, although this pattern occurred only in 59% of these patients. Patients with multivessel TCAS demonstrated a larger myocardial perfusion defect score compared to patients with single vessel TCAS denoting the ability of the technique in evaluation of the extent of TCAS. No significant difference was detected regarding the accuracy for the diagnosis of individual coronary artery stenoses. The similar sensitivity in the 3 vascular regions reflects the advantage of SPECT technique in the detection and localization of perfusion abnormalities. The similar specificity may be explained by the better target background ratio for the inferior wall achieved by the use of technetium-labelled agents.14 The use of 99mtechnetium tetrofosmin was previously demonstrated to improve imaging quality of exercise myocardial perfusion scintigraphy compared to 201thallium.15
Patients with abnormal perfusion and no significant TCAS The occurrence of myocardial perfusion abnormalities in 45% of patients without ⱖ50% stenosis of epicardial coronary arteries may be explained in part by the complex nature of graft vasculopathy. Histologic studies and intravascular ultrasonography have demonstrated intimal thickness, vascular sclerosis and occlusion of small distal vessels which may lead to ischemia or microvascular infarction despite normal angiographic findings in the early course of the disease.16 –19 Other factors that may contribute to the occurrence of perfusion abnormalities in association with normal angiographic findings include impairment of endothelial function and vasodilator reserve.18,19 Therefore, it should be emphasized that coronary angiography may lack sensitivity for the detection of early transplant CAD as it depicts the silhouette of the lumen of coronary arteries and has a limited ability in the evaluation of small vessel disease. Other imaging techniques have been introduced to avoid this limitation. Intravascular ultrasound was shown to detect early disease of the arterial wall that can not be detected by angiography. However, this technique can not be consid-
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ered as a gold standard for the diagnosis of transplant coronary artery disease because of the inability to study the distal lesions.17,20 In our study 4 of the 9 patients who demonstrated perfusion abnormalities in absence of stenotic lesions with ⱖ50% luminal diameter stenosis had less severe lesions, luminal irregularities or distal pruning which may indicate an association with a distal lesion with impairment of vasodilator reserve. Although, the occurrence of imaging artifacts is known to reduce the specificity of myocardial perfusion imaging, a significant proportion of myocardial perfusion abnormalities in absence of ⱖ50% TCAS in this study may represent true impairment of myocardial perfusion at rest or during stress. This is due to the presence of small vessel disease, microinfarctions and impairment of vasodilator reserve because these findings are known to occur in patients with transplant vasculopathy and may precede significant narrowing of the coronary arterial lumen.17 Nevertheless, coronary angiography remains a widely used technique for evaluation and prognostic stratification of cardiac transplant recipients. This study showed a high sensitivity of dobutamine terofosmin SPECT imaging for the detection of TCAS. Despite the low specificity of the technique when angiography was used as the gold standard, the high sensitivity and negative predictive accuracy indicates that the probability of TCAS is low if the patient demonstrates normal perfusion. Therefore, invasive evaluation of coronary arteries in patients with a negative test might not be required.
Comparison with previous studies There are conflicting data regarding the sensitivity and specificity of exercise myocardial perfusion imaging among previous studies. Sensitivity ranged between 22% and 100%.1– 4,6,21 Ciliberto et al4 studied 50 heart transplant patients. Exercise thallium scintigraphy was negative in all of the 35 patients with normal coronary arteries (100% specificity), and abnormal in 10 of 15 patients with CAD (67% sensitivity). Rodney et al3 studied the value of thallium-201 and technetium 99m sestamibi for the detection of TCAS in 25 heart transplant recipient. Ten of 13 patients with TCAS had abnormal thallium-201 scans (sensitivity ⫽ 77%). Sensitivity of MIBI was not significantly different from that of thallium. There were no false-positive scans in the 12 patients without TCAS (specificity ⫽ 100%). The sensitivity and specificity of dipyridamole perfusion imaging were 21% and 88%, respectively, as reported by Smart et al.6 Flow up studies of the same
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population with exercise thallium revealed a sensitivity of 21%. In contrast with the studies reporting high specificity of myocardial perfusion scintigraphy, Puskas et al20 reported that in 43 patients with normal coronary angiography studied early after cardiac transplant by exercise thallium SPECT, pathologic results defined as fixed defects, redistribution or reverse redistribution were detected in 40% of segments. Scintigraphic results did not correlate with intimal thickness of epicardial coronary arteries accessible to intravascular ultrasonography. The score of inhomogeneity of myocardial perfusion was progressive indicating the possibility of small vessel alteration as suggested by the authors. McKillop et al22 reported that 4 patients without TCAS had fixed defects on planar thallium scintigraphy. Howarth et al21 reported a sensitivity of 78% and specificity of 33% among 7 patients who underwent 13 stress thallium SPECT studies.
tant clue regarding the possibility of further intervention as revascularization or retransplantation. The results of the scans were available to the treating physicians. Therefore, possible referral bias for coronary angiography might have had an effect on the results of the study. Finally, this study did not assess the prognostic significance of myocardial perfusion abnormalities and therefore, further studies are needed to expand the role of dobutamine myocardial perfusion scintigraphy in cardiac transplant recipients.
Studies of dobutamine stress echocardiography
REFERENCES
The role of dobutamine stress echocardiography in the diagnosis of TCAS and prognostic stratification of transplant recipient has been recently evaluated. Sensitivity for the diagnosis of TCAS ranged between 79% and 95% and specificity ranged between 55% and 95%.7–10,23 Severe inducible wall motion abnormalities were associated with a higher probability of future cardiac events.8 Our study demonstrated that dobutamine myocardial perfusion scintigraphy is a sensitive method for the diagnosis of TCAS and therefore this method can provide an alternative imaging modality particularly in patients with poor echocardiographic window and in centers with less expertise in stress echocardiographic imaging.
Limitations of the study The correlation between myocardial perfusion and angiographic abnormalities is limited by the low sensitivity of angiographic techniques for the detection of transplant CAD. It is possible that some of the perfusion abnormalities identified as false positive in this study represent true abnormalities consequent to a disease behind the angiographic resolution capacity. However, despite that intravascular ultrasonography has a higher sensitivity for early detection of coronary artery pathologies, the value of this technique is still limited to the large epicardial arteries. Although the gold standard for the early detection of transplant CAD is not well defined, identification of a significant epicardial coronary artery stenosis remains an important task because such abnormalities provide impor-
Clinical implications and conclusions Dobutamine stress tetrofosmin myocardial perfusion imaging is a highly sensitive method for the detection of TCAS in recipients of cardiac allograft transplant. The high negative predictive value of the test indicates that patients who demonstrate normal perfusion by this method may be excluded from further invasive studies.
1. Fang JC, Rocco T, Jarcho J, Ganz P, Mudge GH. Noninvasive assessment of transplant-associated arteriosclerosis. Am Heart J 1998;135:980 –7. 2. Rodney RA, Johnson LL. Myocardial perfusion scintigraphy to assess heart transplant vasculopathy. J Heart Lung Transplant 1992;11:S74 – 8. 3. Rodney RA, Johnson LL, Blood DK, Barr ML. Myocardial perfusion scintigraphy in heart transplant recipients with and without allograft atherosclerosis: a comparison of thallium201 and technetium 99m sestamibi. J Heart Lung Transplant 1994;13:173– 80. 4. Ciliberto GR, Mangiavacchi M, Banfi F, et al. Coronary artery disease after heart transplantation: non-invasive evaluation with exercise thallium scintigraphy. Eur Heart J 1993;14:226 –9. 5. Mandak JS, Aaronson KD, Mancini DM. Serial assessment of exercise capacity after heart transplantation. J Heart Lung Transplant 1995;14:468 –78. 6. Smart FW, Ballantyne CM, Cocanougher B, et al. Insensitivity of noninvasive tests to detect coronary artery vasculopathy after heart transplant. Am J Cardiol 1991;67:243–7. 7. Akosah KO, Mohanty PK. Role of dobutamine stress echocardiography in heart transplant patients. Chest 1998;113:809 –15. 8. Lewis JF, Selman SB, Murphy JD, Mills RM Jr, Geiser EA, Conti CR. Dobutamine echocardiography for prediction of ischemic events in heart transplant recipients. J Heart Lung Transplant 1997;16:390 –3. 9. Akosah KO, Olsovsky M, Kirchberg D, Salter D, Mohanty PK. Dobutamine stress echocardiography predicts cardiac events in heart transplant patients. Circulation 1996;94(9 Suppl):II283– 8. 10. Akosah KO, Mohanty PK, Funai JT, et al. Noninvasive detection of transplant coronary artery disease by dobutamine stress echocardiography. J Heart Lung Transplant 1994;13:1024 –38. 11. Elhendy A, Valkema R, van Domburg RT, et al. Safety of dobutamine-atropine stress myocardial perfusion scintigraphy. J Nucl Med 1998;39:1662– 6.
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12. Pennell DJ, Underwood SR, Swanton RH, Walker JM, Ell PJ. Dobutamine thallium myocardial perfusion tomography. J Am Coll Cardiol 1991;18:1471–9. 13. Baptista J, Arnese M, Roelandt JRTC, et al. Quantitative coronary angiography in the estimation of the functional significance of coronary stenosis: Correlation with dobutamine-atropine stress test. J Am Coll Cardiol 1994;23: 1434 –9. 14. Zaret BL, Rigo P, Wackers FJ, et al. Myocardial perfusion imaging with 99mTc tetrofosmin. Comparison to 201T1 imaging and coronary angiography in a phase III multicenter trial. Tetrofosmin International Trial Study Group. Circulation 1995;91:313–9. 15. Khattar RS, Hendel RC, Crawley JC, et al. Improved diagnostic accuracy of planar imaging with technetium 99mlabelled tetrofosmin compared with thallium-201 for the detection of coronary artery disease. J Nucl Cardiol 1997;4: 291–7. 16. Billingham ME. Histopathology of graft coronary disease. J Heart Lung Transplant 1992;11:S38 – 44. 17. Spes CH, Klauss V, Rieber J, et al. Functional and morphological findings in heart transplant recipients with a normal coronary angiogram: an analysis by dobutamine stress echocardiography, intracoronary Doppler and intravascular ultrasound. J Heart Lung Transplant 1999;18:391– 8.
The Journal of Heart and Lung Transplantation April 2000 18. Mullins PA, Chauhan A, Sharples L, et al. Impairment of coronary flow reserve in orthotopic cardiac transplant recipients with minor coronary occlusive disease. Br Heart J 1992;68:266 –71. 19. Billingham ME. The pathologic changes in long-term heart and lung transplant survivors. J Heart Lung Transplant 1992;11:S38 – 44. 20. Puskas C, Kosch M, Kerber S, et al. Progressive heterogeneity of myocardial perfusion in heart transplant recipients detected by thallium-201 myocardial SPECT. J Nucl Med 1997;38:760 –5. 21. Howarth DM, Forstrom LA, Samudrala V, Sinak LJ, McGregor CG, Rodeheffer RJ. Evaluation of 201T1 SPET myocardial perfusion imaging in the detection of coronary artery disease after orthotopic heart transplantation. Nucl Med Commun 1996;17:105–13. 22. McKillop JH, Goris ML. Thallium-201 myocardial imaging in patients with previous cardiac transplantation. Clin Radiol 1981;32:447–9. 23. Mairesse GH, Marwick TH, Melin JA, et al. Use of exercise electrocardiography, technetium-99m-MIBI perfusion tomography, and two-dimensional echocardiography for coronary disease surveillance in a low-prevalence population of heart transplant recipients. J Heart Lung Transplant 1995; 14:222–9.