Treadmill Exercise Produces Larger Perfusion Defects Than Dipyridamole Stress N-13 Ammonia Positron Emission Tomography

Transcription

1 Journal of the American College of Cardiology Vol. 47, No. 2, by the American College of Cardiology Foundation ISSN /06/$32.00 Published by Elsevier Inc. doi: /j.jacc Treadmill Exercise Produces Larger Perfusion Defects Than Dipyridamole N-13 Ammonia Positron Emission Tomography Cardiac Imaging Benjamin J. W. Chow, MD, FRCPC, FACC,* Rob S. Beanlands, MD, FRCPC, FACC,* Andrea Lee,* Jean N. DaSilva, PHD,* Robert A. dekemp, PHD,* Abdulkareem Alkahtani, MD,* Terrence D. Ruddy, MD, FRCPC, FACC* Ottawa, Ontario, Canada OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS The aim of this study was to compare treadmill exercise (TEX) and dipyridamole stress on the uptake and retention of N-13 ammonia. Size and severity of stress-induced myocardial perfusion defects are clinically important. Because ammonia uptake and retention seems to be related to perfusion, viability, and metabolism, exercise stress might induce larger perfusion defects than dipyridamole stress. Twenty-six patients underwent TEX and dipyridamole stress N-13 ammonia positron emission tomography (PET). Images were assessed with a 17-segment model and a five-point score. Summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) were calculated. Left ventricular (LV) defect sizes were measured quantitatively with a 70% threshold for abnormal perfusion. Compared with dipyridamole stress, TEX yielded larger SSS ( vs ; p 0.01), SDS ( vs ; p 0.02), and percentage of LV stress defect ( % vs %; p 0.02). In patients achieving adequate exercise, TEX N-13 ammonia PET myocardial perfusion imaging (MPI) yields larger stress perfusion defects than dipyridamole stress and might reflect the true myocardial ischemic burden. Treadmill exercise might be the preferred method of stress for routine N-13 ammonia PET MPI. (J Am Coll Cardiol 2006;47: 411 6) 2006 by the American College of Cardiology Foundation Size and severity of stress-induced myocardial perfusion defects are clinically important. Differences in perfusion defects with various stressors might have prognostic implications (1,2). Positron emission tomography (PET) is traditionally performed with vasodilator stress, and the evaluation of treadmill exercise (TEX) PET myocardial perfusion imaging (MPI) is limited. A previous study comparing TEX versus dipyridamole stress rubidium-82 PET showed that defect size and severity were similar (3). Because ammonia uptake and retention seems to be related to perfusion, viability, and metabolism (glutamine pathway), exercise stress might induce larger perfusion defects than with dipyridamole stress (4 7). The objective of this study was to compare TEX and dipyridamole stress on the uptake and retention of N-13 ammonia in patients able to perform adequate exercise stress. From the *Division of Cardiology, University of Ottawa Heart Institute, and the Division of Nuclear Medicine, Ottawa Hospital, Ottawa, Ontario, Canada. Dr. Beanlands was supported by the Canadian Institute of Health Research and the Ontario Premier s Research Excellence Award. This research was supported in part by the Ontario Research and Development Challenge Fund (#00-May-0710) for the Ontario Consortium of Cardiac Imaging. Manuscript received April 5, 2005; revised manuscript received August 30, 2005, accepted September 8, METHODS Patients. Between August 2003 and September 2004, 31 patients, able to perform adequate exercise stress, were prospectively referred to this single-center, randomized, single-blinded study. All patients had documented coronary artery disease (CAD) or an intermediate-to-high pre-test probability for CAD (3). Patients lacking informed consent, age 18 years, unable to exercise, or with a contraindication to dipyridamole or radiation were excluded. This study was approved by the University of Ottawa Heart Institute Human Research Ethics Board. The order of stress was randomized (dipyridamole vs. TEX). Dipyridamole and TEX stress N-13 ammonia PET were performed on different days, and each was preceded by rest imaging. Patients abstained from caffeine, xanthine derivatives, and atrioventricular nodal blocking drugs 12 h and fasted (except for medications) 6 h before each study. PET imaging. The PET images were acquired with an ECAT ART scanner (Siemens/CTI, Knoxville, Tennessee). A 4-min Cesium-137 singles transmission scan was acquired to confirm proper patient positioning and for attenuation correction (8). Ten millicuries (370 MBq) of N-13 ammonia was injected at rest and with stress. Static images were created by summing 17 min of emission data.

2 412 Chow et al. JACC Vol. 47, No. 2, 2006 Exercise Versus Dipyridamole N-13 Ammonia PET January 17, 2006:411 6 Abbreviations and Acronyms CAD coronary artery disease LV left ventricle/ventricular MPI myocardial perfusion imaging PET positron emission tomography SDS summed difference score SPECT single-photon emission tomography SRS summed rest score SSS summed stress score TEX treadmill exercise An 8-min transmission scan was acquired post-stress for attenuation correction (Fig. 1). Dipyridamole stress. The dipyridamole stress protocol has been previously described (3); N-13 ammonia was administered over 30 s, and static uptake images were created by summing 17 min of emission data. TEX stress. Symptom-limited Bruce protocol was performed. During the last 1.5 min of peak exercise, N-13 ammonia was administered. Patients were immediately repositioned in the PET camera, and a 17-min emission scan was acquired and used to create static images. Electrocardiography and image analysis. Electrocardiography analysis has been previously described (3). The PET images were assessed with a 17-segment model and a five-point grading system by two expert observers blinded to stress (2). Summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) were calculated. Images were also analyzed by a sectored analysis approach with a 70% threshold cutoff for abnormal perfusion (3). Image quality was assessed visually and quantitatively on the basis of myocardial count density (Bq/cc) and target/ background ratios (3). Statistical analysis. With SPSS version 11.5 (Chicago, Illinois), paired and independent samples of continuous variables were evaluated with the paired or unpaired t test and non-continuous variables with the McNemar test. The concordance of the observer grading of the exercise Table 1. Patient Demographics Demographics, n 26 Age (yrs) Gender (men) 23 (89) BMI (kg/m 2 ) Hypertension 20 (78) Diabetes 3 (12) Dyslipidemia 24 (92) Smoker 14 (54) Family history of CAD 8 (31) Cardiac history Myocardial infarction 11 (42) Percutaneous coronary intervention 9 (35) Coronary artery bypass surgery 4 (15) Medications Anti-platelet 23 (88) Beta-blocker 20 (78) Statin 21 (81) ACE-I or ARB 17 (65) Values are n (%) or mean SD. ACE-I angiotensin-converting enzyme inhibitor; ARB angiotensin receptor blocker; BMI body mass index; CAD coronary artery disease. and dipyridamole stress scans was evaluated with Kappa scores. Perfusion defects (summed scores and percentage of left ventricular [LV] defect) were correlated with a Pearson correlation coefficient and Bland-Altman plot analyses. RESULTS Patient population. Thirty-one patients were referred to our study. Four patients were excluded because of left bundle branch block (n 1), uncontrolled atrial tachyarrhythmia (n 2), and insufficient dose of N-13 ammonia (n 1). One patient was withdrawn from the study because of extensive severe ischemia with TEX N-13 ammonia PET. The remaining 26 patients underwent both TEX and dipyridamole stress N-13 ammonia PET MPI (Table 1). Treadmill test. The mean time interval between TEX and dipyridamole stress PET was days (Table 2). Peak stress heart rate and blood pressure were significantly higher Figure 1. Rest and stress N-13 ammonia positron emission tomography protocol.

3 JACC Vol. 47, No. 2, 2006 January 17, 2006:411 6 Chow et al. Exercise Versus Dipyridamole N-13 Ammonia PET 413 Table 2. Response to Treadmill Exercise and Dipyridamole (n 26) Exercise Dipyridamole p Value Duration of exercise (min) Age-predicted maximum HR (%) Patients achieving 85% APMHR 24 (92.3) Resting heart rate NS Peak stress HR Resting systolic blood pressure NS Resting diastolic blood pressure NS systolic blood pressure diastolic blood pressure Rate-pressure product 29,799 7,108 13,256 2, ST-segment depression 17 (65) 5 (19) Chest pain 4 (15) 14 (54) 0.01 Values are n (%) or mean SD. APMHR age-predicted maximal heart rate; HR heart rate. with exercise than dipyridamole stress. Chest pain was more common with dipyridamole, and ST-segment depression was more common with TEX. All five patients with dipyridamole-induced ST-segment depression had abnormal N-13 PET MPI. Mean time interval from onset of N-13 ammonia infusion to initiation of emission data acquisition was min. MPI. There was good correlation between dipyridamole and TEX stress N-13 PET (Fig. 2). defect sizes (percentage of LV) with a 70% threshold for abnormal had fair correlation between stressors (Table 3). Rest defect sizes (percentage of LV) before exercise and dipyridamole stress also had fair correlation. Treadmill exercise stress produced larger and more severe induced stress (SSS) and ischemic perfusion defects (SDS) compared with dipyridamole stress. Bland Altman analysis demonstrated a bias toward larger and more severe SSS and SDS with TEX than with dipyridamole stress (Fig. 3). The 17 patients with exercise-induced ischemic STsegment depression had larger perfusion defects (SSS) with exercise than with dipyridamole ( and , respectively; p 0.03) with good correlation (r 0.81). In the remaining nine patients without exercise-induced STsegment depression, there was a trend toward greater exercise SSS than dipyridamole SSS ( and , respectively; p 0.08). Furthermore, a similar trend was noted when patients with and without exercise-induced ST-segment depression were compared ( and , respectively; p 0.09). The interobserver variability of SSS showed good agreement with Kappa scores of 0.71 for exercise SSS (normal [SSS 4] or abnormal [SSS 4]) and 0.74 for dipyridamole SSS. Patients were categorized as having disease in the left anterior descending artery, left circumflex, and/or right coronary artery territories. Kappa analysis demonstrated fair correlation between exercise and dipyridamole stress in each territory (left anterior descending artery 0.57, left circumflex artery 0.69, and right coronary artery 0.54; p 0.01). Patients were also categorized as normal or singlevessel versus multivessel disease. Four of the 12 (33%) patients initially categorized as having normal or singlevessel disease with dipyridamole stress had multivessel disease with TEX N-13 ammonia PET. Furthermore, patients were categorized into normal to mildly abnormal SSS ( 8) and moderate to severely abnormal SSS ( 8). Five of the 18 (28%) patients with dipyridamole-induced normal or mildly abnormal SSS had moderate to severely abnormal SSS with TEX. Figure 2. (A) Correlation of exercise and dipyridamole summed stress score (SSS). (B) Correlation of exercise and dipyridamole summed rest score (SRS). (C) Correlation of exercise and dipyridamole summed difference score (SDS).

4 414 Chow et al. JACC Vol. 47, No. 2, 2006 Exercise Versus Dipyridamole N-13 Ammonia PET January 17, 2006:411 6 Table 3. Semi-Quantitative and Quantitative Analysis of N-13 PET Myocardial Perfusion Images Exercise Dipyridamole p Value Correlation Significance of Correlation Summed stress score Summed rest score NS Summed difference score LV defect size (stress) (%) LV defect size (rest) (%) NS Values are mean SD. LV left ventricle; PET positron emission tomography. Image quality. The TEX images demonstrated less infradiaphragmatic activity in 24 of the 26 patients (Fig. 4). Myocardial uptake count density was significantly lower with exercise than with dipyridamole (Table 4). DISCUSSION Most exercise stress PET MPI studies have focused on supine bicycle (9 11). Though TEX has been successfully Figure 3. (A) Bland Altman SSS (treadmill exercise [TEX] vs. dipyridamole). (B) Bland Altman SRS (TEX vs. dipyridamole). (C) Bland Altman SDS (TEX vs. dipyridamole). SD standard deviation; other abbreviations as in Figure 2. Figure 4. Larger stress defect with treadmill exercise than with dipyridamole stress. A mild (magenta) perfusion defect is present in the inferolateral wall and apex with dipyridamole stress. The size and severity (blue) of the defect is greater after exercise stress.

5 JACC Vol. 47, No. 2, 2006 January 17, 2006:411 6 Chow et al. Exercise Versus Dipyridamole N-13 Ammonia PET 415 Table 4. Image Quality of N-13 Ammonia PET Myocardial Perfusion Images (Exercise vs. Dipyridamole) Exercise Dipyridamole p Value N-13 ammonia dose, rest (MBq) NS N-13 ammonia dose, stress (MBq) Rest myocardial uptake (Bq/cc) 20,272 7,846 18,578 7,510 NS myocardial uptake (Bq/cc) 19,271 10,278 26,224 10, Myocardium/lung rest Myocardium/lung stress NS Myocardium/gut rest NS Myocardium/gut stress NS Myocardium/liver rest NS Myocardium/liver stress NS Myocardium/blood pool rest NS Myocardium/blood pool stress NS Values are mean SD. PET positron emission tomography. performed with rubidium-82 and FDG PET MPI (3,12), this is the first study to combine TEX with N-13 ammonia PET. In patients who achieve adequate exercise, TEX N-13 ammonia PET seems to induce larger and more severe stress and ischemic perfusion defects than dipyridamole stress. Retention of N-13 ammonia is adenosine triphosphatedependant and requires the metabolism of ammonia to glutamine (13). Thus, uptake and retention might be altered by changes in metabolic state (14,15). Exercise-induced ischemia might cause metabolic stunning, reduce the metabolism of ammonia to glutamine, and attenuate N-13 ammonia retention in areas of ischemia. Exercise MPI has been compared with various vasodilator stressors (4,16 18) Comparing exercise, dipyridamole, and adenosine stress Tc-99m single-photon emission tomography (SPECT), exercise resulted in greater defect extent, severity, and reversibility than dipyridamole but no differences in defect size between exercise and adenosine (17). Treadmill exercise SPECT stress defects were larger than with dipyridamole in 45% of patients (16). Larger exercise stress defects were typically observed in patients with higher heart rates (16). Nishimura et al. (19) showed that adenosine stress induced larger defect sizes than exercise Tl-201 SPECT. Abe et al. (4) compared adenosine and TEX Tl-201 MPI and found no difference in patients who were able to perform adequate exercise. Though our study demonstrated that TEX provoked larger and more severe perfusion defects than dipyridamole stress, this was more apparent in patients with mild to moderate SSS and SDS with dipyridamole stress. This finding might be explained by: the high level of exercise achieved in our patients, which might have resulted in more ischemia; the superior accuracy of N-13 ammonia PET that might have enabled the detection of differences between exercise and dipyridamole; and the rapid return of flow to normal after exercise compared with a dipyridamoleaminophylline protocol, which might delay N-13 ammonia washout from normal tissue compared with ischemic tissue, thus amplifying the defect size. Five patients having normal to mildly abnormal SSS with dipyridamole were reclassified as having moderate to severely abnormal SSS with TEX. Similarly, four patients classified as normal or single-vessel disease with dipyridamole stress had evidence of multivessel disease with TEX N-13 ammonia PET. These differences in exercise and dipyridamole stress SSS, SDS, and defect size might be clinically relevant and might influence patient management. Although TEX does not permit the benefits of dynamic acquisition for the quantification of blood flow, it does provide information about exercise tolerance and is preferred by most patients (3). Resting myocardial/lung ratio was significantly different before exercise and dipyridamole stress. Because resting target/background ratios should not differ in the same patient, we believe that this finding likely occurred by chance. The successful performance of the TEX stress N-13 ammonia PET required the coordination of the cyclotron laboratory and the imaging team. The completion of N-13 ammonia synthesis and its delivery occurred simultaneously with the initiation of TEX. A surplus of N-13 ammonia was manufactured (2.5 times the injected dose) to ensure that an adequate quantity of radiotracer was available at peak exercise. Study limitations. Our patient population was predominantly male, and our small sample size is prone to patientrelated systematic errors and was not powered to detect significant differences in the subgroup analysis. Coronary angiography was not routinely performed to validate the accuracy of TEX versus dipyridamole N-13 ammonia PET and warrants further investigation. Conclusions. In patients achieving adequate exercise, TEX N-13 ammonia PET MPI yields larger and more severe defects than dipyridamole stress. Images acquired after TEX might reflect the true ischemic burden. Treadmill exercise

6 416 Chow et al. JACC Vol. 47, No. 2, 2006 Exercise Versus Dipyridamole N-13 Ammonia PET January 17, 2006:411 6 might be the preferred method of stress for routine N-13 ammonia PET MPI. Acknowledgments The authors extend their gratitude to the staff at the National Cardiac PET Centre for their technical expertise. Reprint requests and correspondence: Dr. Benjamin J. W. Chow, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada, K1Y 4W7. bchow@ottawaheart.ca. REFERENCES 1. Marwick TH, Shan K, Patel S, Go RT, Lauer MS. Incremental value of rubidium-82 positron emission tomography for prognostic assessment of known or suspected coronary artery disease. Am J Cardiol 1997;80: Hachamovitch R, Berman DS, Shaw LJ, et al. Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction. Circulation 1998;97: Chow BJW, Ananthasubramaniam K, dekemp RA, Dalipaj MM, Beanlands RSB, Ruddy TD. Comparison of treadmill exercise versus dipyridamole stress as an adjunct to myocardial perfusion imaging with 82Rb positron emission tomography. J Am Coll Cardiol 2005;45: Abe S, Takeishi Y, Chiba J, Ikeda K, Tomoike H. Comparison of adenosine and treadmill exercise thallium-201 stress tests for the detection of coronary artery disease. Jpn Circ J 1993;57: Schelbert HR, Phelps ME, Huang SC, et al. N-13 ammonia as an indicator of myocardial blood flow. Circulation 1981;63: Schwaiger M, Muzik O. Assessment of myocardial perfusion by positron emission tomography. Am J Cardiol 1991;67:35D 43D. 7. Rosenspire KC, Schwaiger M, Mangner TJ, Hutchins GD, Sutorik A, Kuhl DE. Metabolic fate of [13N]ammonia in human and canine blood. J Nucl Med 1990;31: Townsend DW, Beyer T, Jerin J, et al. The ECAT ART Scanner for positron emission tomography. 1. Improvements in performance characteristics. Clin Positron Imaging 1999;2: Krivokapich J, Smith GT, Huang SC, et al. 13N ammonia myocardial imaging at rest and with exercise in normal volunteers. Quantification of absolute myocardial perfusion with dynamic positron emission tomography. Circulation 1989;80: Camici P, Araujo LI, Spinks T, et al. Increased uptake of 18Ffluorodeoxyglucose in postischemic myocardium of patients with exercise-induced angina. Circulation 1986;74: Tamaki N, Yonekura Y, Senda M, et al. Myocardial positron computed tomography with 13N-ammonia at rest and during exercise. Eur J Nucl Med 1985;11: Marwick TH, MacIntyre WJ, Salcedo EE, Go RT, Saha G, Beachler A. Identification of ischemic and hibernating myocardium: feasibility of post-exercise F-18 deoxyglucose positron emission tomography. Cathet Cardiovasc Diagn 1991;22: DeGrado TR, Bergmann SR, Ng CK, Raffel DM. Tracer kinetic modeling in nuclear cardiology. J Nucl Cardiol 2000;7: Rauch B, Helus F, Grunze M, et al. Kinetics of 13N-ammonia uptake in myocardial single cells indicating potential limitations in its applicability as a marker of myocardial blood flow. Circulation 1985;71: Bergmann SR, Hack S, Tewson T, Welch MJ, Sobel BE. The dependence of accumulation of 13NH3 by myocardium on metabolic factors and its implications for quantitative assessment of perfusion. Circulation 1980;61: David N, Marie PY, Angioi M, et al. Dipyridamole and exercise SPET provide different estimates of myocardial ischaemic areas: role of the severity of coronary stenoses and of the increase in heart rate during exercise. Eur J Nucl Med 2000;27: Levine MG, Ahlberg AW, Mann A, et al. Comparison of exercise, dipyridamole, adenosine, and dobutamine stress with the use of Tc-99m tetrofosmin tomographic imaging. J Nucl Cardiol 1999;6: Iskandrian AS. Single-photon emission computed tomographic thallium imaging with adenosine, dipyridamole, and exercise. Am Heart J 1991;122: Nishimura S, Mahmarian JJ, Boyce TM, Verani MS. Equivalence between adenosine and exercise thallium-201 myocardial tomography: a multicenter, prospective, crossover trial. J Am Coll Cardiol 1992;20: