EDITORIAL The oft neglected rest study Mark I. Travin, MD

See related article on p. 762 When one is using stress radionuclide myocardial perfusion imaging (MPI) for prognostic purposes, the focus is mostly on findings seen on the stress images. Beginning as early as a key study by Ladenheim et al1 with planar imaging to more contemporary studies using single photon emission computed tomography (SPECT) imaging,2-6 it has been consistently shown that the occurrence of adverse cardiac events is predicted by the extent and severity of perfusion defects on the stress study, often depicted semiquantitatively as a summed stress score (SSS). More recently, it has been shown that patient management, particularly in terms of selecting patients who would benefit from a revascularization procedure, is best directed by the amount of myocardial ischemia indicated by image findings— either the summed difference score (SDS) (SDS ⫽ SSS ⫺ Summed rest score [SRS]) or an equivalent measure such as the percent myocardium that is ischemic.7,8 In determining the amount of ischemia, whereas rest image findings provide a numeric reference point, the result of the rest perfusion image itself does not factor into the analysis. Nevertheless, one would expect that the prognostic implications of both the SSS and the SDS, or their percent equivalents, could differ greatly depending on the baseline myocardial state; that is, for any particular amount of ischemia, patients with more baseline resting myocardial abnormalities should have a poorer prognosis. In one respect, the baseline myocardial state can be represented by left ventricular systolic function. The prognostic power of left ventricular ejection fraction (LVEF) derived from any imaging technique is well established, and several studies have shown that for stress MPI, LVEF assessed by electrocardiography-gated SPECT adds incremental prognostic value to the perfuFrom the Department of Nuclear Medicine, Montefiore Medical Center, and Albert Einstein College of Medicine, Bronx, New York. Reprint requests: Mark I. Travin, MD, Department of Nuclear Medicine, Montefiore Medical Center, 111 E 210th St, Bronx, NY 10467-2490; [email protected]. J Nucl Cardiol 2008;15:739-42. 1071-3581/$34.00 Copyright © 2008 by the American Society of Nuclear Cardiology. All rights reserved. doi:10.1016/j.nuclcard.2008.08.001

sion results, a strong predictor especially of cardiac death9-11 (although one must consider that for stress MPI, LVEF is most often measured from the poststress images that can be different from the resting ejection fraction).12 As the extent/severity of rest perfusion defects is related to global ventricular function,13 one would expect the extent/severity of rest defects to have prognostic implications similar to LVEF. However, the causes of rest perfusion defects are more complex and multifactorial. In one regard, the extent and severity of resting SPECT defects, often represented by the SRS, reflect left ventricular function, as resting defects often indicate myocardial damage or scar; a discrete rest perfusion defect often corresponds to a regional wall motion abnormality. Nevertheless, a resting defect can also indicate a coronary blood flow abnormality alone. Although in the absence of myocardial scar, even in the presence of coronary artery disease (CAD), blood flow autoregulation results in initial homogeneous myocardial tracer uptake and thus no rest perfusion defect,14 when about 90% of an epicardial arterial cross-sectional lumen area is obliterated, autoregulation is inadequate and results in resting blood flow heterogeneity, therefore a resting SPECT perfusion defect.15,16 Consequently, a “perfusion” defect on a rest SPECT image indicates one or both of two potentially high-risk conditions—myocardial scar from infarction or some other primary myocardial disease process and/or a critical coronary artery stenosis. At the same time, a small area of infarction, though possibly resulting in a perfusion defect, may be too small to affect LVEF. Thus one would expect that results of the resting SPECT perfusion scan might have prognostic data independent of LVEF, regional wall motion abnormalities, and the amount of myocardial ischemia seen on stress images. Combining both the rest image results and the amount of detected ischemia may provide the most complete picture of patient cardiac risk. To investigate these concepts further, in this issue of the Journal, Shaw et al17 explore in detail the prognostic contributions of rest SPECT image findings in a large patient cohort. From a database of 7849 patients who underwent stress MPI at 5 tertiary medical centers and who were followed up at yearly intervals (median, 1.6 years; interquartile range, 1.2-2.0 years), patients with CAD events (fatal or nonfatal myocardial infarction [MI], heart failure death, or sudden cardiac death) and 739

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cardiovascular (CV) events (prior event list plus fatal stroke or death related to peripheral vascular disease) were identified, and event occurrence was correlated with clinical and SPECT image findings. Consistent with previous literature, the percent myocardial ischemia was related to the occurrence of CAD events. Importantly, the percent rest defect was a strong correlate as well. Also in accord with previous literature, the CAD eventfree survival curves of patients worsened as the percent myocardial ischemia increased, but a key finding shown in Figure 4 of the article was that for any given percent ischemia, the event-free survival rate worsened as the percent rest defect increased. Whereas for patients with no (0%) rest perfusion abnormalities, the CAD death or nonfatal MI rates ranged from 1.2% to 10% depending on percent ischemia, for patients with 10% rest defects or greater, CAD death or nonfatal MI rates ranged from 7% to 44%, an approximately 4- to 6-fold event increase. Figure 5 of the article shows that for any percent ischemia, there can be a dramatic increase in predicted annual CAD death or MI rate as the percent rest defect increases, particularly for patients with more than 5% ischemia. At the same time, if the percent rest defect is high, a small increase in the percent ischemia can substantially increase the CAD death/MI rate. Finally, even in the absence of ischemia, the presence of a severe rest perfusion abnormality predicted an annual CV death or MI rate as high as 3% and a 2-year CV event rate as high as 50%. An important finding from the reported data is that not only was percent rest defect a strong and independent predictor of cardiac events, but it also added prognostic power to LVEF in the subset of patients (4575) who had electrocardiography-gated data, with the percent rest defect having a significantly higher C-index by receiver operating characteristic analysis. This finding supports a previous report by one of the study’s authors showing that both abnormal LVEF and SRS independently correlate with poor prognosis, with higher SRS values in the setting of normal LVEFs conveying a risk similar to that associated with low LVEFs.18 The major conclusion of the study under discussion is that a combination of resting perfusion abnormalities and the amount of ischemia should provide the most complete SPECT imaging picture and is a better method of risk stratifying patients than other variable combinations, including LVEF. Are all rest perfusion images the same? As discussed, “perfusion” defects on rest imaging, assuming they are not artifacts, are multifactorial in origin, depending on both coronary blood flow and tissue viability factors. Therefore the meaning of rest image findings depends on both the radiotracer used and, in some cases, the time of imaging in relation to tracer injection. In the

Journal of Nuclear Cardiology November/December 2008

study under discussion, for some patients, thallium 201 was used for the rest images, whereas for others, technetium 99m tetrofosmin was used. These radiotracers have different uptake characteristics and kinetics.19,20 For Tl-201, about 85% of the tracer is extracted on first pass as opposed to about 54% for Tc-99m tetrofosmin, with Tc-99m tetrofosmin extraction plateauing more at higher flow rates. The perfusion pattern of Tc-99m tetrofosmin is relatively fixed after injection; in contrast, for Tl-201, the pattern is dynamic, with the initial tracer distribution pattern largely a reflection of the myocardial blood flow state at the time of injection, whereas with time, the distribution pattern becomes governed by the regional potassium pool and reflects the amount of viable myocardium.21 These factors all have an effect on the resting perfusion pattern for any given disease state. Although the authors do acknowledge that the type of rest agent may have influenced their results, they were unable to detect any difference with the analytic strategies that they used. This issue therefore needs to be explored further, as the prognostic implications of rest image findings likely differ, at least to some degree, depending on the properties of the tracer used. One must also consider that the type of patient undergoing testing influences the prognostic utility of test results. Certainly, a rest perfusion defect in a patient without a prior history of coronary disease who presents for evaluation of chest pain, referred to by the authors as “de novo,” often has a different meaning from that in a patient with a known prior MI. Rest defects in the latter likely represent a larger component of myocardial damage and therefore possibly a worse prognosis, with the patient less likely to benefit from a revascularization procedure. In the article under discussion, for any degree of percent rest defect, patients with prior MI did have a poorer prognosis than the “de novo” patients. It would have been useful, though, to know whether LVEFs were lower in the prior MI patients and to what extent this contributed to the worsened prognosis versus percent rest defect in these patients. Thus, as has been shown in numerous other instances, the type of stress imaging test protocol used and the patient’s baseline clinical state can both affect the meaning of test results.22-24 Such factors must be taken into account when incorporating rest image results into the overall test interpretation. CLINICAL IMPLICATIONS A major goal for the further clinical development of noninvasive imaging has been to derive a model using a combination of clinical and image variables that can accurately predict patient prognosis.25 Such a prognostic score for predicting cardiac death was recently formu-

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lated by Hachamovitch et al26 for patients undergoing adenosine stress MPI. In this analysis, although percent rest defect was not one of the variables used in the analysis, percent myocardium fixed, a variable similar to and often identical to percent rest defect, was a significant component of the model, as was percent myocardial ischemia. Both of these SPECT image variables had larger prognostic weights than each of the independent clinical variables (diabetes mellitus, early revascularization, resting heart rate, peak heart rate, electrocardiogram score), except for patient age and presenting symptoms of dyspnea. These findings support the conclusion of the study under discussion, that both the baseline myocardial state and the response of myocardium to stress are essential variables for any prognostic model. At the same time, in the current era, using expensive diagnostic testing for diagnostic and prognostic purposes alone is often not sufficient. Test results must also help direct patient management and lead to a better outcome in terms of mortality rate and/or quality of life. For radionuclide MPI, the crucial question is often whether a patient would be expected to benefit from a revascularization procedure. Although in the study under discussion, the percent rest defect did identify high-risk patients with annual CAD event rates greater than 10%, those with lesser degrees of ischemia would not likely benefit from revascularization in terms of survival rate. At the same time, as in a recent publication by Hachamovitch et al,8 once a certain threshold of ischemia is crossed that yields a statistically significant survival benefit with revascularization, it is the patients with the worse baseline myocardial state who have the most absolute benefit in terms of the number of lives saved per 100 patients treated. In this latter study LVEF characterized the baseline state, but on the basis of the study discussed here, one would expect percent rest defect to serve a similar role. One must use all of the imaging information available. It is important that for any testing procedure, all of the imaging information available be considered and then combined with clinical variables to yield the most complete picture of the patient. As shown in the study by Shaw et al,17 for radionuclide MPI, one should carefully and fully evaluate not only the stress images but the rest images as well, as the combination provides the best risk stratification. With CAD, a patient’s outcome will depend very much on what the cumulative myocardial condition will be with the next ischemic episode. Acknowledgment The author has indicated he has no financial conflicts of interest.

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21. Berman DS, Kiat H, Friedman JD, Diamond G. Clinical applications of exercise nuclear cardiology studies in the era of healthcare reform. Am J Cardiol 1995;75:3D-13D. 22. 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;38:1511-7. 23. Hachamovitch R, Hayes S, Friedman JD, Cohen I, Shaw LJ, Germano G, et al. Determinants of risk and its temporal variation in patients with normal stress myocardial perfusion scans: What is the warranty period of a normal scan? J Am Coll Cardiol 2003; 41:1329-40. 24. Berman DS, Kang X, Hayes SW, Friedman JD, Cohen I, Abidov A, et al. Adenosine myocardial perfusion SPECT in women compared with men: Impact of diabetes mellitus on incremental prognostic value and effect on patient management. J Am Coll Cardiol 2003;41:1125-33. 25. Selker HP, Griffith JL, Beshansky JR, Schmid CH, Califf RM, D’Agostino RB, et al. Patient-specific predictions of outcomes in myocardial infarction for real-time emergency use: A thrombolytic predictive instrument. Ann Intern Med 1997;127:538-56. 26. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. A prognostic score for prediction of cardiac mortality risk after adenosine stress myocardial perfusion scintigraphy. J Am Coll Cardiol 2005;45:722-9.