Prognostic significance of fixed perfusion abnormalities on stress technetium-99m sestamibi single-photon emission computed tomography in patients without known coronary artery disease

Prognostic Significance of Fixed Perfusion Abnormalities on Stress Technetium-99m Sestamibi SinglePhoton Emission Computed Tomography in Patients Without Known Coronary Artery Disease Abdou Elhendy, MD, PhD, Arend F.L. Schinkel, MD, Ron T. van Domburg, Jeroen J. Bax, MD, PhD, and Don Poldermans, MD, PhD

PhD,

Fixed perfusion abnormalities in patients with known coronary artery disease (CAD) are associated with myocardial damage and adverse outcomes. However, the significance of these abnormalities in patients without known CAD is unclear. The aim of this study was to assess the prognostic significance of fixed versus reversible perfusion abnormalities in patients without known CAD. We studied 327 patients (58 ⴞ 11 years of age; 215 men) with no history of myocardial infarction or revascularization, who demonstrated myocardial perfusion abnormalities on stress (exercise or dobutamine) sestamibi tomographic imaging. Follow-up end points were all-cause mortality and hard cardiac events (cardiac death and nonfatal myocardial infarction). Myocardial perfusion abnormalities were reversible in 226 patients (69%) and fixed in 101 patients (31%). During a mean follow-up of 7 years, 72 patients (22%) died (cardiac death in 30) and 15 patients had nonfatal myocar-

dial infarctions. The annual mortality rate was higher in patients with fixed abnormalities than in those with reversible abnormalities (4.4% vs 2.7%, p <0.01), whereas the annual hard cardiac event rate was not significantly different between the 2 groups (2.5% vs 2%). In a multivariate analysis model, the summed stress score was an independent predictor of hard cardiac events (risk ratio 1.7, 95% confidence interval 1.3 to 5.4). The presence of a fixed perfusion abnormality was independently associated with an increased risk of death after adjustment for clinical and stress test data and the summed stress score (risk ratio 2.5, 95% confidence interval 1.3 to 3.7). In patients with suspected, but no history of CAD, fixed perfusion abnormalities were associated with a higher risk of death compared with reversible perfusion abnormalities. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;92:1165–1170)

he diagnosis of myocardial ischemia with stress myocardial perfusion imaging is based on the deT tection of reversible perfusion abnormalities. In pa-

due to its shorter half-life compared with thallium201.9 Fixed perfusion abnormalities on stress technetium-99m sestamibi/dual isotope imaging have been associated with increased risk of cardiac events in an unselected patient population as well as in patients with previous myocardial infarction.4,5,10 –14 However, the significance of these abnormalities in patients without previous myocardial infarction is unknown. The aim of this study was to compare the outcome of patients with reversible abnormalities versus patients with fixed perfusion abnormalities on stress technetium-99m sestamibi single-photon emission computed tomography (SPECT) in a population with suspected but no proved CAD.

1,2

tients with previous myocardial infarction, fixed perfusion abnormalities often represent subendocardial or transmural scarring.3,4 The prognosis of these patients is shown to be dependent on the extent of defects and reversible myocardial perfusion abnormalities.5 Fixed perfusion abnormalities may be detected in patients without a history of myocardial infarction or coronary artery disease (CAD).6 – 8 The significance of these abnormalities is not clearly understood. The use of technetium-99m labeled agents provides the advantages of improved imaging quality, increased consistency of image analysis, and a larger injectable dose

METHODS

From the Department of Cardiology, Thoraxcenter, Rotterdam, The Netherlands; Leiden University Hospital, Leiden, The Netherlands; and the Department of Internal Medicine, Section of Cardiology, University of Nebraska Medical Center, Omaha, Nebraska. Manuscript received April 14, 2003; revised manuscript received and accepted July 23, 2003. Address for reprints: Abdou Elhendy, MD, PhD, 982265 Nebraska Medical Center, Omaha, Nebraska 68198-2265. E-mail: [email protected]. ©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 92 November 15, 2003

Patient selection: The study population consisted of consecutive patients with suspected CAD who had a perfusion abnormality on stress technetium-99m sestamibi myocardial perfusion SPECT in our laboratory between 1990 and 1995. Exclusion criteria were history of myocardial infarction, previous myocardial revascularization, angiographically documented CAD, known cardiomyopathy, heart failure, significant val0002-9149/03/$–see front matter doi:10.1016/j.amjcard.2003.07.024

1165

mm Hg or intake of antihypertensive medication. Diabetes mellitus was defined as a fasting glucose level of Fixed Defects Reversible Defects ⱖ7.8 mmol/L or the need for insulin Parameters (n ⫽ 101) (n ⫽ 226) p Value or oral hypoglycemic agents. HyperAge (yrs) 57 ⫾ 13 59 ⫾ 10 NS cholesterolemia was defined as a toMen 71 (71%) 144 (64%) 0.04 tal cholesterol of ⱖ6.4 mmol/L or Angina before stress test 18 (18%) 82 (35%) 0.0005 treatment with lipid-lowering mediAtypical chest pain 33 (33%) 79 (34%) NS cation. The pretest probability of Hypertension 48 (48%) 69 (43%) NS Diabetes mellitus 8 (8%) 20 (9%) NS CAD was determined using the criSmoking 27 (27%) 64 (28%) NS teria of Diamond and Forrester.15 Hypercholesterolemia 15 (15%) 67 (30%) 0.0001 Exercise protocol: Exercise stress ST–T-wave abnormalities at rest 21 (21%) 36 (16%) 0.06 was performed in 189 patients using a ␤ blockers 25 (25%) 80 (35%) 0.02 symptom-limited upright bicycle erACE inhibitors 20 (20%) 36 (16%) NS Pretest probability of CAD 0.01 gometry test with step-wise increLow 11 (11%) 18 (8%) ments of 20 W every minute as Intermediate 66 (66%) 119 (53%) previously described.16 Three elecHigh 24 (24%) 89 (39%) trocardiographic leads were continExercise/dobutamine stress (patients) 64/37 125/101 NS Stress systolic blood pressure (mm Hg) 171 ⫾ 35 171 ⫾ 32 NS uously monitored. Cuff blood presStress heart rate (beats/min) 142 ⫾ 24 135 ⫾ 20 0.01 sure measurements and 12-lead Stress rate–pressure product 24,413 ⫾ 7,182 23,164 ⫾ 6,019 NS electrocardiography were recorded Workload (Wt) 148 ⫾ 37 148 ⫾ 36 NS at rest and every minute during exST-segment depression 7 (7%) 36 (16%) 0.01 ercise and recovery. Angina during stress 10 (10%) 67 (30%) 0.0001 Dobutamine stress protocol: DoACE ⫽ angiotensin-converting enzyme. butamine/atropine stress testing was performed in 138 patients as previously described.17 Dobutamine was injected intravenously, first at a dose TABLE 2 Scintigraphic and Outcome Data of the Study Patients According to the of 10 ␮g/kg/min for 3 minutes and Type of Perfusion Abnormality then increased by 10 ␮g/kg/min evFixed Reversible ery 3 minutes, up to a maximum dose Parameters (n ⫽ 101) (n ⫽ 226) p Value of 40 ␮g/kg/min. If the test end point Summed stress score 4.3 ⫾ 1.7 4.8 ⫾ 2.2 NS was not reached at a dobutamine Summed rest score 4.3 ⫾ 1.7 1.2 ⫾ 1.2 0.001 dose of 40 ␮g/kg/min, atropine (up Localization of abnormality to 1 mg) was given intravenously. Anterior 23 (23%) 67 (30%) NS Blood pressure, heart rate, and elecPostero-lateral 9 (9%) 24 (11%) NS Inferior 69 (69%) 131 (58%) 0.08 trocardiography were continuously Septal anterior 17 (17%) 37 (16%) NS monitored. Test end points were Septal posterior 19 (19%) 47 (21%) NS achievement of target heart rate Apical 26 (26%) 77 (34%) NS (85% of maximum age-predicted Men with inferior defect 59/71 (83%) 102/144 (71%) 0.08 heart rate), horizontal or downslopWomen with anterior defect 13/30 (43%) 35/82 (43%) NS Events ing ST-segment depression ⬎2 mm Overall deaths 33 (33%) 39 (17%) 0.0001 at 80 ms after the J-point compared Cardiac death 11 (11%) 19 (8%) 0.1 with baseline, severe angina, a deNonfatal myocardial infarction 3 (3%) 12 (6%) 0.1 crease in systolic blood pressure of Myocardial revascularization 19 (19%) 63 (28%) 0.02 Unstable angina 17 (17%) 43 (19%) NS ⬎40 mm Hg, blood pressure ⬎240/ 120 mm Hg, or significant cardiac arrhythmia. Metoprolol was availvular heart disease, cardiac pacer and 12-lead electro- able to reverse the (side) effects of dobutamine and/or cardiographic findings of left bundle branch block, atropine if these did not revert spontaneously after pathologic Q waves, or left ventricular hypertrophy. termination of dobutamine infusion. The level of the Inclusion criteria were fulfilled in 329 patients. The ST segment was calculated by averaging the signals choice of stress test was based on ability to exercise. using a computerized system (Cardiovet, CSG/12, Patients with limited exercise capacity underwent a Schiller, Baar, Switzerland) with both stress tests. dobutamine stress test. Follow-up was successful in Significant ST-segment depression was defined as a 327 patients (99%). The data of these patients are ⱖ1 mm horizontal or downsloping ST-segment dereported. All patients gave informed consent before pression that occurred at 80 ms after the J point. the test and the hospital ethics committee approved the Technetium-99m sestamibi SPECT imaging: An intraprotocol. A structured interview and clinical history venous dose of 370 MBq of technetium-99m sestawere acquired and cardiac risk factors were assessed mibi (Cardiolite, Dupont, Wilmington, Delaware) was before nuclear testing. Hypertension was defined as administered approximately 1 minute before terminarepeated blood pressure measurements of ⬎140/90 tion of the dobutamine or exercise test.17 For studies at TABLE 1 Clinical and Stress Test Data of Study Patients According to the Type of Perfusion Abnormality

1166 THE AMERICAN JOURNAL OF CARDIOLOGY姞

VOL. 92

NOVEMBER 15, 2003

perfusion defect on the exercise images that partially or completely resolved at rest in ⱖ2 contiguous segments or slices in the 47-segment model. A fixed perfusion defect was defined as a perfusion defect on exercise images in ⱖ2 contiguous segments or slices that persisted on images at rest in the 47-segment model. 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 venFIGURE 1. Kaplan-Meier survival curves (all-cause mortality) in patients with reversible tricular segments was scored using abnormalities and in patients with fixed perfusion abnormalities on stress sestamibi SPECT. a 4-point scoring method (0 ⫽ normal, 1 ⫽ slightly reduced, 2 ⫽ moderately reduced, 3 ⫽ severely reduced or absent uptake). The summed stress score was calculated to estimate the extent and severity of perfusion defects at rest and with stress. Follow-up: Follow-up data collection was performed by contacting patients’ general practitioners and by review of hospital records. Outcome events were overall death, cardiac death, and nonfatal myocardial infarction. Cardiac death was defined as death caused by acute myocardial infarction, significant cardiac arrhythmias, or refractory congestive heart failure. FIGURE 2. Kaplan-Meier survival curves (end points of cardiac death and nonfatal myoSudden death occurring without cardial infarction) in patients with reversible abnormalities and in those with fixed peranother explanation was included fusion abnormalities on stress sestamibi SPECT. as cardiac death. Nonfatal myocardial infarction was defined by carrest, 370 MBq of sestamibi was injected ⱖ24 hours diac enzyme levels and electrocardiographic changes. after the exercise study. Image acquisition was per- Hard cardiac events were defined as cardiac death and formed with a Siemens Gammasonics single-head nonfatal myocardial infarction. Myocardial revascuRota Camera (Orbiter; Siemens Corp., Iselin, New larization procedures and unstable angina were also Jersey). Thirty-two projections were obtained, from noted during follow-up. the left posterior oblique to the right anterior oblique Statistical analysis: Continuous data were expressed over 180°. For each study, 6 oblique (short-axis) slices as mean value ⫾ SD. The Student’s t test was used to from the apex to the base and 3 sagittal (vertical analyze continuous data. Differences between proporlong-axis) slices from the septum to the lateral wall tions were compared using the chi-square test. Univariwere defined. Each of the 6 short-axis slices was ate and multivariate Cox proportional hazard regression divided into 8 equal segments. The septal part of the 2 models (BMDP Statistical Software Inc., Los Angeles, basal slices was excluded from analysis because this California) were used to identify predictors of death and region corresponds to the fibrous portion of the inter- hard cardiac events. Variables were selected in a stepventricular septum and normally exhibits reduced up- wise forward selection manner with entry and retention take. Consequently, a total of 47 segments were iden- set at a significance level of 0.05. The risk of a variable tified (3 long axis and 44 short axis).17 The was expressed as a hazard ratio with a corresponding interpretation of the scan was semi-quantitatively per- 95% confidence interval. Variables considered for mulformed by visual analysis assisted by the circumfer- tivariate analysis were those that were significant in the ential profiles analysis. Stress and resting tomographic univariate analysis. The probability of survival was calviews were reviewed side-by-side by an experienced culated using the Kaplan-Meier method, and survival observer who was unaware of the patients’ clinical curves were compared between patients with fixed and data. A reversible perfusion defect was defined as a patients with reversible perfusion abnormalities using the CORONARY ARTERY DISEASE/RISK ASSESSMENT WITH SESTAMIBI IMAGING

1167

of perfusion abnormalities are presented in Table 2. There was no sigUnivariate Multivariate nificant difference between both groups with regard to the summed Parameters RR (CI) Parameters RR (CI) stress score or regional prevalence of Hard cardiac events perfusion abnormalities. However, Age 1.1 (1.08–1.2) Age 1.05 (1.02–1.08) there was a trend to a higher prevaStress systolic blood pressure 1.2 (1.1–1.6) Summed stress score 1.7 (1.3–5.4) lence of fixed perfusion abnormaliSummed stress score 1.8 (1.2–6.5) Total mortality ties in the inferior wall. Age 1.1 (1.02–1.2) Age 1.06 (1.03–1.08) Follow-up data: During a mean Male gender 2.2 (1.2–4) Male gender 1.3 (1.5–1.9) follow-up period of 7 ⫾ 2.4 years, 72 Diabetes mellitus 2.8 (1.3–4.5) Diabetes mellitus 2.3 (1.2–4.6) patients (22%) died, 30 of whom Hypertension 1.8 (1.1–3.0) Fixed defects 2.5 (1.3–3.7) Fixed perfusion defects 2.9 (1.4–4.5) (42%) died due to cardiac causes. Summed stress score 1.4 (1.1–2.9) Nonfatal myocardial infarction occurred in 15 patients (5%), and 82 CI ⫽ 95% confidence intervals; RR ⫽ risk ratio. patients (25%) underwent coronary revascularization, which occurred early (within 60 days from the stress log-rank test. A p value ⬍0.05 was considered statisti- test) in 40 patients. Incidence of follow-up events in cally significant. both groups is provided in Table 2. Survival curves in both groups are shown in Figures 1 (hard cardiac events) and 2 (all-cause mortality). The annual morRESULTS Clinical data: Mean age was 58 ⫾ 11 years, and tality rate was higher in patients with fixed than in there were 215 men (66%) in the study. Symptoms patients with reversible abnormalities (4.4% vs 2.7%, before the stress test were typical angina in 100 pa- p ⬍0.01), whereas the annual hard cardiac event rate tients (31%) and atypical chest pain in 112 patients was not significantly different between both groups (34%). Risk factors for CAD were hypertension in (2.5% vs 2%; Figure 2). A larger proportion of pa117 patients (36%), diabetes mellitus in 28 patients tients with reversible abnormalities underwent subse(9%), hypercholesterolemia in 82 patients (25%) and quent myocardial revascularization (Table 2). smoking in 91 patients (28%). Predictive value of clinical data and SPECT results: TaStress data: There was a significant increase in ble 3 presents the univariate and multivariate predicheart rate (79 ⫾ 19 vs 138 ⫾ 23 beats/min) and tors of both end points. Independent predictors of hard systolic blood pressure (140 ⫾ 21 vs 171 ⫾ 35 mm cardiac events were age and summed stress score. Hg) from resting to peak stress (both p ⬍0.001). The Independent predictors of all-cause mortality were mean achieved workload with exercise was 148 ⫾ 37 age, male gender, diabetes mellitus, and the presence W. The mean maximal dobutamine dose was 37 ⫾ 8 of fixed perfusion abnormalities. The presence of in␮g/kg/min. Atropine was administered to 79 patients ferior wall abnormalities in men or anterior wall ab(57%). No patient experienced a myocardial infarction normalities in women did not have significant interor sustained ventricular tachycardia. Short runs of action effects on the association of fixed abnormalities ventricular tachycardia occurred in 10 patients (3%) with risk of death (p ⫽ NS). and short runs of supraventricular tachycardia occurred in 5 patients (1.5%). Angina occurred in 77 DISCUSSION patients (24%) and ST-segment depression occurred We studied the prognostic significance of fixed in 43 patients (13%) during stress. compared with reversible perfusion abnormalities in SPECT results: Stress myocardial perfusion abnor- 327 patients without a history of myocardial infarction malities were fixed in 101 patients (31%) and revers- or known CAD who demonstrated perfusion abnorible in 226 patients (69%). In patients with reversible malities on stress sestamibi SPECT. Perfusion abnorabnormalities, the defects were partially reversible in malities were reversible in 69% of patients and fixed 80 patients. Clinical data of the patients, according to in 31% of patients. During a long-term mean folthe type of perfusion abnormality, are shown in Table low-up of 7 years, there were 72 deaths and 15 non1. Patients with reversible perfusion abnormalities had fatal myocardial infarctions. Patients with fixed pera higher incidence of hypercholesterolemia and his- fusion abnormalities had a double-fold greater risk of tory of angina and were more likely to have had a high overall death compared with patients with reversible pretest probability of CAD and to receive ␤ blockers abnormalities (overall incidence of death 33% vs 17% before the stress test compared with patients with and an annual death rate of 4.4% vs 2.7%, respecreversible abnormalities. There was no significant dif- tively). Patients with fixed perfusion abnormalities ference between both groups with regard to age, prev- had an annual hard cardiac event rate similar to paalence of diabetes, and hypertension. A larger propor- tients with reversible abnormalities. Separate analysis tion of patients with fixed abnormalities were men. of hard cardiac events showed a trend to a higher ST-segment depression and angina were more fre- incidence of cardiac death with fixed defects (11% vs quently induced during stress in patients with revers- 8%) and a higher incidence of nonfatal myocardial ible abnormalities. Perfusion scores and localization infarction with reversible defects (6% vs 3%). The TABLE 3 Predictors of Follow-up Events by Cox Models

1168 THE AMERICAN JOURNAL OF CARDIOLOGY姞

VOL. 92

NOVEMBER 15, 2003

summed stress score independently predicted hard cardiac events. Fixed perfusion abnormalities were independently predictive of overall death after adjustment for clinical and stress test data and the summed stress score. Mechanism of fixed perfusion abnormalities: The underlying mechanisms of occurrence of fixed perfusion abnormalities in patients without history of CAD cannot be definitely ascertained. In this study, we excluded patients with clinical conditions known to be associated with perfusion abnormalities in the absence of CAD, such as cardiomyopathy, heart failure, valvular heart disease, and electrocardiographic findings of left ventricular hypertrophy or left bundle branch block.1 Many mechanisms may be postulated to explain the presence of fixed perfusion abnormalities in this study. One mechanism may be the occurrence of silent non–Q-wave myocardial infarction before the stress study. Lumley et al8 found that 32% of abnormal stress sestamibi scans in patients without history or electrocardiographic evidence of myocardial infarction showed fixed perfusion abnormalities. It was postulated that these abnormalities represented undiagnosed myocardial infarction. Another mechanism may be myocardial stunning that persists during imaging at rest with a perfusion defect reflecting a partial volume effect.18 A third mechanism could be severe CAD with impairment of perfusion at rest that does not worsen during stress. Another mechanism could be the recurrence of spontaneous myocardial ischemia during the study at rest, which makes the stress perfusion abnormality appear as fixed. The ischemic theory is supported as 1 of possible mechanisms because 10% of these patients demonstrated angina during stress, 22% subsequently underwent myocardial revascularization or had a myocardial infarction, and 17% had unstable angina during follow-up. Hypertensive heart disease and left ventricular hypertrophy without electrocardiographic changes may also be a mechanism of fixed perfusion abnormalities as well as occult or early cardiomyopathy. All these conditions have been associated with increased risk of cardiovascular and overall mortality. Failure to demonstrate reversibility of the defects in patients with fixed abnormalities cannot be attributed to low stress levels, because heart rates during stress were higher in patients with fixed abnormalities, reflecting the lower frequency of ␤-blocker treatment before the test and the lower incidence of angina during stress compared with patients with reversible abnormalities. The trend to a higher incidence of cardiac death in patients with fixed defects compared with those with reversible defects may be explained by an association of fixed defects with left ventricular dysfunction and a propensity to arrhythmias. In contrast, patients with reversible abnormalities were more likely to experience ischemia-related events, such as nonfatal myocardial infarction and myocardial revascularization. This may be explained by the presence of an active coronary lesion subtending jeopardized myocardium in patients with reversible abnormalities. Previous studies have shown that most myocardial infarctions

in patients with previously abnormal stress perfusion studies occur in vascular territories that demonstrate reversible perfusion abnormalities.19 Some of the fixed perfusion abnormalities in patients without previous myocardial infarction may represent artifacts. It has been recognized that artifacts occur in the inferior wall in men due to diaphragmatic attenuation and in the anterior wall in women due to breast attenuation.6 Gated studies have been useful in differentiating a true perfusion abnormality from an artifact. However, this distinction was not verified using a gold standard, such as coronary angiography. In our study, there was a trend to a higher prevalence of inferior wall perfusion abnormalities in patients with fixed abnormalities compared with those with reversible abnormalities, whereas the prevalence of anterior wall abnormalities in women was similar in both groups. One possible explanation of this finding is the tendency of clinically unrecognized myocardial infarction to occur in the inferior wall, as reported by Cabin and Roberts.20 There was no interaction between the localization of abnormalities to these regions and the outcome end points. However, any possible interaction may have been confounded by the presence of perfusion abnormalities in ⬎1 region in the same patient. Although it is quite possible that some of these abnormalities are artifacts, it is unlikely that this had a major impact on the findings of our study, in view of the striking difference in mortality between patients with fixed abnormalities and those with reversible perfusion abnormalities. Association of fixed perfusion abnormalities with increased mortality: The association of fixed perfusion

abnormalities with a greater risk of overall death compared with reversible perfusion abnormalities is difficult to explain. It is possible that these patients were treated less aggressively during follow-up because they failed to demonstrate a standard sign of ischemia. Failure to recognize a fixed perfusion abnormality as a sign of CAD and or undiagnosed myocardial infarction may have led to inadequate treatment with medications that have been shown to improve survival, such as aspirin, ␤ blockers, and angiotensin-converting enzyme inhibitors. Some of the cardiac deaths may have been misclassified as noncardiac, considering the practical difficulties in the definite determination of the cause of death as indicated by Lauer et al.21 Another explanation is the higher proportion of men in the group with fixed abnormalities, which a demonstrated higher mortality rate in men. Finally, fixed perfusion abnormalities may be a manifestation of target organ damage associated with hypertension and diabetes mellitus.22 Both conditions were associated with increased risk of mortality in this study. Study limitations: Although this study demonstrated the prognostic significance of fixed perfusion abnormalities, their pathophysiologic mechanism could not be investigated. A gated study would have been useful to correlate these abnormalities with regional function.6,7 Further studies are required to elucidate the functional and angiographic correlates of fixed perfusion abnormalities, and consequently, to determine the

CORONARY ARTERY DISEASE/RISK ASSESSMENT WITH SESTAMIBI IMAGING

1169

appropriate intervention that may reduce the risk of mortality and cardiac events in these particular patients. Clinical implications: Fixed perfusion abnormalities on stress myocardial perfusion imaging are not uncommon findings in patients with suspected CAD and who have no history of myocardial infarction or previous revascularization. These abnormalities are associated with a greater risk of death compared with the risk associated with reversible perfusion abnormalities. Therefore, these patients should be managed at least as aggressively as patients with reversible abnormalities. The pathophysiologic mechanism of fixed perfusion abnormalities and the appropriate strategies to reduce the death rate in these patients remain to be determined. 1. Ritchie JL, Bateman TM, Bonow RO, Crawford MH, Gibbons RJ, Hall RJ, O’Rourke RA, Parisi AF, Verani MS. Guidelines for clinical use of cardiac radionuclide imaging. Report of the American College of Cardiology/American Heart Association Task Force on assessment of diagnostic and therapeutic cardiovascular procedures (Committee on Radionuclide Imaging), developed in collaboration with the American Society of Nuclear Cardiology. J Am Coll Cardiol 1995;25:521–547. 2. Beller GA, Zaret BL. Contributions of nuclear cardiology to diagnosis and prognosis of patients with coronary artery disease. Circulation 2000;101:1465– 1478. 3. Baer FM, Smolarz K, Theissen P, Voth E, Schicha H, Sechtem U. Regional 99mTc-methoxyisobutyl-isonitrile-uptake at rest in patients with myocardial infarcts: comparison with morphological and functional parameters obtained from gradient-echo magnetic resonance imaging. Eur Heart J 1994;15:97–107. 4. Kang X, Germano G, Berman DS. Risk stratification in patients with remote prior myocardial infarction using rest-stress myocardial perfusion SPECT: prognostic value and impact on referral to early catheterization. J Nucl Cardiol 2002;9:23–32. 5. Aboul-Enein FA, Berman DS, Hayes SW, Schisterman E, Friedman J, Germano G. Do nonreversible defects affect risk of cardiac death in chronic coronary artery disease? (abstr). J Am Coll Cardiol 2002;39(suppl 2):343. 6. DePuey EG, Rozanski A. Using gated technetium-99m-sestamibi SPECT to characterize fixed myocardial defects as infarct or artifact. J Nucl Med 1995;36: 952–955. 7. Yao SS, Nichols K, DePuey EG, Rozanski A. Detection of occult left ventricular dysfunction in patients without prior clinical history of myocardial infarction by technetium-99m sestamibi myocardial perfusion gated single-photon emission computed tomography. Clin Cardiol 2002;25:429 –435. 8. Lumley MA, Torosian T, Rowland LL, Ketterer MW, Pickard SD. Correlates

1170 THE AMERICAN JOURNAL OF CARDIOLOGY姞

VOL. 92

of unrecognized acute myocardial infarction detected via perfusion imaging. Am J Cardiol 1997;79:1170 –1173. 9. Hendel RC, Parker MA, Wackers FJ, Rigo P, Lahiri A, Zaret BL. Reduced variability of interpretation and improved image quality with a technetium 99m-labelled tetrofosmin. J Nucl Cardiol 1994;1:509 –514. 10. Brown KA. Prognostic value of myocardial perfusion imaging: state of the art and new developments. J Nucl Cardiol 1996;3:516 –537. 11. Iskander S, Iskandrian AE. Risk assessment using single-photon emission computed tomographic technetium-99m sestamibi imaging. J Am Coll Cardiol 1998;32:57–62. 12. Geleijnse ML, Elhendy A, van Domburg RT, Cornel JH, Reijs AE, Roelandt JR, Krenning EP, Fioretti PM. Prognostic value of dobutamine-atropine stress technetium-99m sestamibi perfusion scintigraphy in patients with chest pain. J Am Coll Cardiol 1996;28:447–454. 13. Berman DS, Hachamovitch R, Kiat H, Cohen I, Cabico JA, Wang FP, Friedman JD, Germano G, Van Train K, Diamond GA. Incremental value of prognostic testing in patients with known or suspected ischemic heart disease: a basis for optimal utilization of exercise technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography. J Am Coll Cardiol 1995;26:639 –647. 14. Calnon DA, McGrath PD, Doss AL, Harrell FE, Watson DD, Beller GA. Prognostic value of dobutamine stress technetium-99m-sestamibi single-photon emission computed tomography myocardial perfusion imaging: stratification of a high-risk population. J Am Coll Cardiol 2001;38:1511–1517. 15. Diamond GA, Forrester JS. Analysis of probability as an aid in the clinical diagnosis of coronary-artery disease. N Engl J Med 1979;300:1350 –1358. 16. Elhendy A, van Domburg RT, Sozzi FB, Poldermans D, Bax JJ, Roelandt JR. Impact of hypertension on the accuracy of exercise stress myocardial perfusion imaging for the diagnosis of coronary artery disease. Heart 2001;85:655–661. 17. Elhendy A, Valkema R, van Domburg RT, Bax JJ, Nierop PR, Cornel JH, Geleijnse ML, Reijs AE, Krenning EP, Roelandt JR. Safety of dobutamineatropine stress myocardial perfusion scintigraphy. J Nucl Med 1998;39:1662– 1666. 18. Santiago JF, Heiba SI, Jana S, Mirzaitehrane M, Dede F, Abdel-Dayem HM. Transient ischemic stunning of the myocardium in stress thallium-201 gated SPECT myocardial perfusion imaging: segmental analysis of myocardial perfusion, wall motion and wall thickening changes. Eur J Nucl Med Mol Imaging 2002;29:979 –983. 19. Miller GL, Herman SD, Heller GV, Kalla S, Levin WA, Stillwell KM, Travin MI. Relation between perfusion defects on stress technetium-99m sestamibi SPECT scintigraphy and the location of a subsequent acute myocardial infarction. Am J Cardiol 1996;78:26 –30. 20. Cabin HS, Roberts WC. Quantitative comparison of extent of coronary narrowing and size of healed myocardial infarct in 33 necropsy patients with clinically recognized and in 28 with clinically unrecognized (“silent”) previous acute myocardial infarction. Am J Cardiol 1982;50:677–681. 21. Lauer MS, Blackstone EH, Young JB, Topol EJ. Cause of death in clinical research: time for a reassessment? J Am Coll Cardiol 1999;34:618 –620. 22. De Lorenzo A, Lima RS, Siqueira-Filho AG, Pantoja MR. Prevalence and prognostic value of perfusion defects detected by stress technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography in asymptomatic patients with diabetes mellitus and no known coronary artery disease. Am J Cardiol 2002;90:827–832.

NOVEMBER 15, 2003