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MEDICINE REVIEW ARTICLE Myocardial Perfusion SPECT: Current Concepts Oliver Lindner, Herbert Rusche, Michael Schäfers, Otmar Schober, Wolfgang Burchert SUMMARY Introduction: Myocardial perfusion SPECT has made considerable progress in recent years, both in terms of methodology and of clinical applications. Methods: Selective literature review. Results: In patients with suspected or known CAD prognostic studies support the use of myocardial perfusion imaging in stratifying patients by prognosis and management approaches. The number and severity of perfusion disturbances on scintigraphy relate closely to the frequency of cardiac death and nonfatal myocardial infarction. The use of a stepwise diagnostic algorithm for CAD allows individualized stratification by risk and prognosis. In addition, the scintigraphic result can be integrated into decision making around risk factor management, medical therapy and revascularization. Discussion: In patients with suspected to advanced coronary artery disease myocardial perfusion SPECT allows reliable identification of low and high risk patients. Normal perfusion scans with no perfusion disturbances are in general associated with a low cardiac event rate. Dtsch Arztebl 2007; 104(14): A 952–8. Key words: myocardial perfusion szintigraphy, coronary artery disease, cardiological diagnosis, SPECT, revascularization C ardiovascular diseases are the most common cause of death in Western industrialized countries. Timely diagnosis of coronary artery disease (CAD) is the decisive factor influencing the course of the illness and its prognosis. It is, therefore, important to identify patients with CAD and to initiate effective treatment (risk factor modification, pharmacotherapy, interventional or operative myocardial revascularization) based on prognosisoriented decision processes. Stress electrocardiography (ECG) is the most important initial component of the diagnostic algorithm for patients suspected of having CAD (1, 2). Depending on the ECG findings, imaging studies may be performed afterward. The type of imaging study that is most commonly used is myocardial perfusion scintigraphy (MPS). In Germany, in the year 2003, MPS was performed 194,084 times and stress ECG was performed 173,031 times within the framework of care reimbursed by the governmentally mandated health insurance companies (3). This article will discuss the current diagnostic and prognostic value of MPS and explain how its findings can be integrated into the therapeutic decision-making process. Myocardial perfusion scintigraphy: principles MPS reveals the effect of arterial stenoses on myocardial perfusion and thereby indicates the presence of hemodynamically relevant coronary artery stenoses. It employs radiopharmaceuticals that are taken up by myocardial tissue in an amount depending on the state of tissue perfusion. If coronary stenosis is present, stress testing reveals less uptake of the radiopharmaceutical in the myocardial wall supplied by the stenotic vessel than in other, normally perfused myocardial segments. Testing at rest, in contrast, reveals no regional differences in tracer uptake, because the stenosis does not impair perfusion at rest. The related imaging study employs a tomographic technique (as in CT or MRI) and is called myocardial SPECT ("single photon emission computerized tomography"). MPS is performed either with 201Tl (thallium) or with 99mTc (technetium) tracers (Sestamibi or Tetrofosmin). The various tracer substances used do not differ fundamentally Herz- und Diabeteszentrum NRW, Universitätsklinik der Ruhr-Universität Bochum, Institut für Radiologie, Nuklearmedizin und Molekulare Bildgebung, Bad Oeynhausen: Dr. med. Lindner, Prof. Dr. med. Burchert; Universitätsklinik der Ruhr-Universität Bochum, Abteilung für Allgemeinmedizin: Prof. Dr. med. Rusche, Westfälische Wilhelms-Universität, Münster,Klinik und Poliklinik für Nuklearmedizin: Prof. Dr. med. Dr. rer. nat. Schober, Prof. Dr. med. Schäfers Dtsch Arztebl 2007; 104(14): A 952–8 ⏐ www.aerzteblatt.de 1 MEDICINE TABLE The diagnostic accuracy of non-invasive studies for the demonstration of CHD Studies (number) Patients (number) Sensitivity % Specificity % 147 24,074 68 (23–100) 77 (17–100) Ergometric 33 4,480 87 (71–97) 73 (47–100) Pharmacological 17 2,465 89 (72–93) 75 (28–100) Stress ECG1 (e2) Myocardial scintigraphy2 (12) Stress echocardiography2 (e3) Ergometric 33 3,480 86 (71–97) 81 (64–100) Pharmacological (dobutamine) 37 3,280 82 (54–98) 84 (44–100) Myocardial perfusion MRI2 (e4) 11 254 80 (65–92) 85 (75–100) 1 According to the most recent metaanalysis, cf. Refs. (2, 12, 13); 2 Pooled data; sensitivity and specificity as weighted averages, confidence range in parentheses. The reference in each case was the demonstration of a >50% stenosis by coronary angiography. The studies included no correction for referral bias and thus presumably overestimated sensitivity and underestimated specificity, because an abnormal test often leads to referral for performance of coronary angiography, while a normal test only rarely does (e5). in their clinical utility (4, 5). The radiation exposure to a patient undergoing MPS with 99mTc perfusion tracers in a single-day protocol is 8.5 mSv (assuming that the patient weighs 70 kg and that the applied amount of radioactivity is 250 MBq for stress testing and 750 MBq for testing at rest); this quantity can be reduced to 4.3 mSv with the use of a 2-day protocol (70-kg patient, applied radioactivity 250 MBq both for stress testing and for testing at rest) (6, 7). For comparison, the annual natural radiation exposure in Germany is 2 to 4 mSv, and the effective radiation dose from a chest CT is 6 to 10 mSv (8). Stress testing Stress testing in myocardial perfusion can be performed either ergometrically or pharmacologically. In ergometric testing, the oxygen consumption of the myocardium is increased, and an increase in perfusion results; this increase is found to be deficient if a 50% to 75% coronary artery stenosis is present (diminished coronary reserve). In order to demonstrate hemodynamically relevant stenoses reliably, the patient should be at least submaximally stressed so that the heart rate equals or exceeds 0.85 × (220 - age in years). If this is not possible, myocardial perfusion can also be increased directly, i.e., independently of the patient's cooperation, with the coronary vasodilator adenosine. Adenosine produces coronary vasodilatation, which is followed by a reflex increase of the heart rate by ca. 10% and a slight drop in blood pressure. It has a plasma half-life of less than two seconds; thus, its effect is short-lived and easily controlled. Alternatively, the β1-agonist dobutamine can also be used to increase myocardial perfusion. This drug is a catecholamine derivative and may therefore cause supraventricular and ventricular arrhythmias. Stress testing with dobutamine is used in patients who cannot be stressed ergometrically and in whom adenosine is contraindicated (e.g., because of manifest obstructive pulmonary disease, theophylline use, or second-degree atrioventricular block) (4). Serious side effects such as high-grade arrhythmias, infarction or death are rare in ergometric or pharmacological stress tests, with a frequency of ca. 1 in 10,000 patients (9). With the use of these different procedures, an adequate increase of myocardial perfusion can be achieved in nearly every patient undergoing testing. Even patients who are in poor physical condition, obese patients, and those who cannot be mobilized because of concomitant orthopedic, neurological, or other diseases can be adequately tested with myocardial scintigraphy, even when they are physically incapable of being stressed to the degree that would otherwise be required. Functional analysis – "gated SPECT" Gated SPECT is an extension of myocardial SPECT using a technique that can be thought of as analogous to a "flip-book": each heartbeat is divided into 8 intervals on the basis of the Dtsch Arztebl 2007; 104(14): A 952–8 ⏐ www.aerzteblatt.de 2 MEDICINE DIAGRAM 1 Left: summed stress score (SSS) and summed rest score (SRS) in a high-risk MPS with ischemia in the anterior wall, the cardiac apex, and the septum. The summed difference score (SDS) is 31 (SSS minus SRS). Right: representative sections. ECG wave. Each interval is pictorially displayed and analyzed. Gated SPECT thus yields information not only on overall perfusion, but also on left-ventricular functional parameters such as end-diastolic and end-systolic volume and left ventricular ejection fraction (LVEF). These measurements are made during testing at rest and also after stress testing. There is normally no difference between resting LVEF and post-stress LVEF, because both measurements are made with a gamma camera while the patient is at rest. If ischemia is present, however, the post-stress LVEF may be lower than resting LVEF because of "myocardial stunning": at the time of data acquisition, the myocardium has not yet recovered from the ischemia that it suffered during stress testing, and ischemic ventricular dysfunction is still present. Thus, a greater than 5% difference between resting LVEF and post-stress LVEF provides further evidence of ischemia (10). Diagnostic accuracy of myocardial scintigraphy Coronary angiography is usually taken as a standard of reference for the characterization of imaging techniques for the diagnosis of CAD; thus, the results of functional tests are generally compared with coronary morphology as revealed by angiography. Stress echocardiography and myocardial perfusion scintigraphy are established procedures whose sensitivity and specificity for the diagnosis of CAD are considered to be equivalent (table); beyond these techniques, there are also newer ones such as dobutamine stress MRI and myocardial perfusion MRI with adenosine or dipyridamole. The sensitivities and specificities of the currently available non-invasive techniques, as compared to invasive coronary angiography, are listed in the table. There have not been any studies to date in which these techniques were directly compared with one another. Sensitivity and specificity are not fully adequate parameters to characterize the quality (usefulness) of a diagnostic test. The nature of patient recruitment ("referral bias") leads to an overestimation of sensitivity and an underestimation of specificity. The so-called Dtsch Arztebl 2007; 104(14): A 952–8 ⏐ www.aerzteblatt.de 3 MEDICINE "normalcy rate" is a further parameter characterizing the reliability of MPS in a normal collective of individuals and thus no longer places it in a head-to-head comparison with coronary angiography (11). The normalcy rate is defined as the percentage of patients with a low probability of coronary heart disease (i.e., no more than 10%) whose MPS is normal; it was found to be 91% (12). Indications for MPS and other procedures The German national care guidelines (nationale Versorgungsleitlinie, NVL) for chronic CAD recommend the use of an ergometric or pharmacological stress test with imaging (MPS, stress echocardiography, or cardiac MRI) in the following situations (1, 2): > if chronic CAD is suspected with an intermediate pre-test probability: – if the ST segments cannot be reliably judged on the resting ECG because of left ventricular hypertrophy, Wolff-Parkinson-White syndrome, digitalis use, left bundle branch block, or a pacemaker ECG, – in patients who cannot be adequately stressed so that relevant findings can be obtained on a stress ECG (i.e., patients whose heart rate cannot be raised to 85% of the agerelated maximum), or – if ergometry does not yield conclusive findings. > in known CAD (in addition to the indications described above): – if the patient's symptoms and physical findings have changed but the patient cannot be adequately stressed to yield relevant findings on a stress ECG, or – as an alternative to a stress ECG in patients who, despite treatment, become symptomatic again after an asymptomatic interval, and in whom the localization of ischemia and the functional relevance of a stenosis and/or myocardial vitality is of clinical importance. The NVL state that MPS is indicated above all other tests if the patient has an intermediate pre-test probability of CAD (10% to 90%) as well as a pacemaker ECG or left bundle branch block. In all of the other situations mentioned, no particular type of imaging study is preferred over the others (1, 2). Interpretation of findings and prognosis If the pre-test probability of CAD is in the intermediate range (10% to 90%), a pathological finding on an imaging study confirms the suspicion of CAD, while a normal finding largely excludes functionally relevant CAD. Moreover, nuclear medical tests yield important prognostic information. Data on the prognostic value of stress echocardiography and MRI are limited (1). If non-invasive imaging yields abnormal findings, the German national care guidelines, like the American guidelines, recommend that diagnostic coronary angiography be performed (1, 2, 13). In cardiac imaging as elsewhere in medicine, however, the transition from normal DIAGRAM 2 Dtsch Arztebl 2007; 104(14): A 952–8 ⏐ www.aerzteblatt.de The frequency of cardiac events depending on the degree of hypoperfusion, after (14); SSS, summed stress score; MPS, myocardial perfusion scintigraphy. From: Circulation 1999; 98:190, with the kind permission of Lippincott, Williams and Wilkins. 4 MEDICINE to pathological findings is fluid. In the case of myocardial perfusion scintigraphy, the diagnostic terms "normal," "borderline pathological," and "pathological" were defined in past years by extensive studies, with cardiac risk as the underlying conceptual basis. Cardiac risk is said to be low if the cardiac mortality is less than 1% per year (a comparable risk to that of the general population), and high if it exceeds 3% per year (12, 13). Quantitative perfusion scores derived from myocardial perfusion scintigraphy can be used to create a pictorial representation of cardiac risks and prognosis. The left ventricular myocardium is represented on a circular disk (polar tomogram) (diagram 1). This procedure may be compared to pressing the petals of a flower. The myocardial apex is found in the center of the polar tomogram, while the basal myocardial segments occupy its periphery. The upper quarter of the tomogram represents the anterior wall, its right quarter the lateral wall, its lower quarter the posterior wall, and its left quarter the septum. A score is calculated by dividing the myocardium into 20 segments, grading the tracer uptake in each segment on a scale of 0 (normal) to 4 (markedly reduced), and adding up the scores from all segments (diagram 1). The value obtained during stress testing is called the summed stress score (SSS), while that obtained during testing at rest is called the summed rest score (SRS). The SRS is a measure of already infarcted myocardium, while the SSS reflects reduced perfusion of either reversible (ischemic) or irreversible cause (already infarcted myocardium). The difference between the two, called the summed difference score (SDS), is thus a measure of reversible (ischemic) hypoperfusion. Diagram 2 shows the frequency of cardiac events (cardiac death and nonfatal myocardial infarction) as a function of the SSS calculated from MPS, as well as the resulting estimation of risks in 5,183 patients with suspected or known CAD over a period of observation of ca. 2 years (14). The following may be observed: > a normal finding (SSS < 4) on stress MPS is associated with a low rate of cardiac events, i.e., a rate that is comparable to that of the normal population; > as the SSS increases, the frequency of cardiac events increases; DIAGRAM 3 Risk stratification with myocardial perfusion scintigraphy (MPS) depending on the pre-test estimation of cardiac risk and the stage of CAD. Independently of the pre-test risk, MPS with significant hypoperfusion ("high-risk MPS," red diamonds) is associated with a higher frequency of cardiac events than MPS with mild or no hypoperfusion ("low-risk MPS," blue squares). Patients can be segregated in this way into high- and low-risk groups. For example, a patient with advanced CAD and a pre-test expected frequency of cardiac events (cardiac death or nonfatal myocardial infarction) of 4% per year who is then found to have a high-risk MPS can be assigned an event probability of ca. 5% per year; the same patient, if found to have a low-risk MPS, can be assigned an event probability of 2% per year (11). From: J Nucl Cardiol 2004; 11: 171–85, with the kind permission of Elsevier. Dtsch Arztebl 2007; 104(14): A 952–8 ⏐ www.aerzteblatt.de 5 MEDICINE > the stress MPS reveals mild hypoperfusion (borderline findings with 4 SSS < 9), then nonfatal infarctions will occur more frequently than fatal cardiac events. A metaanalysis of 39 studies involving a total of 69,655 patients revealed that a normal MPS (low-risk MPS, SSS < 4) is associated with a rate of cardiac events (cardiac death and nonfatal infarction) of 0.85% per year, while a pathological MPS (high-risk MPS, SSS 9) is associated with a rate of cardiac events of 5.9% per year. If one stratifies the currently available study data by the degree of severity of CAD, and thus by the varying probability of cardiac events (diagram 3), one finds that: > MPS is able to distinguish high- from low-risk patients over the entire spectrum of CAD; > the rate of cardiac events in persons with a pathological (high-risk) MPS increases with increasing severity of CAD; > the frequency of cardiac events in persons with a normal (low-risk) MPS is nearly always below 2% per year, regardless of the stage of CAD that is present, i.e., even in patients with three-vessel disease (11, 12, 15). In summary, the number and extent of disturbances of perfusion that are revealed by MPS provide a good means of estimating the risk of future cardiac events (2). If the results of functional analysis (gated SPECT), with LVEF as the most important parameter, are considered in addition, then still more refined prognostic statements can be made. The LVEF value used here is the one obtained by post-stress measurement, i.e., ca. 60 minutes after ergometric or pharmacological stress. A longitudinal study with a follow-up interval of 1.5 years showed that patients with an LVEF of 45% or more had an annual mortality below 1% regardless of the presence or absence of hypoperfusion, while those with an LVEF below 45% had a markedly higher mortality. LVEF was found to be the best predictor of cardiac death, while hypoperfusion was found to be the best predictor of nonfatal myocardial infarction (16, 17). Myocardial infarction is mainly due to the rupture of atherosclerotic plaques that, before rupture, caused less than 50% stenosis of the vessel in which they were located, and were thus hemodynamically insignificant (18, 19). MPS is generally able to detect only hemodynamically significant stenoses; thus, one may well ask why a normal MPS is associated with a low rate of myocardial infarction and a pathological MPS with a higher rate of myocardial infarction. The answer is that hemodynamically significant stenoses cannot be considered in isolation but are rather the "tip of the iceberg," i.e., they represent only one aspect of the overall pathological condition of the cardiovascular system. Hypoperfusion detected by MPS is an indicator of coronary artery disease. Moreover, even if angiographically demonstrable coronary artery stenosis is absent, MPS may nevertheless demonstrate stress-related hypoperfusion on the basis of endothelial dysfunction, providing a further indication of a diseased coronary arterial system (20, 21). The valid fundamental principle is as follows: MPS is a safe way to identify patients at risk. The lesion that leads to infarction cannot, however, be detected with the current non-invasive techniques (12). Evaluation of findings On the basis of the concept described above, the findings of MPS can be used for further diagnostic and therapeutic decision-making. It should be remembered that the mortality rates for cardiovascular procedures such as percutaneous transluminal catheter angioplasty (PTCA) or coronary artery bypass grafting (CABG) are 1% (12, 22, 23). The current state of scientific evidence justifies using the degree of cardiac risk predicted by the MPS (low, middle, or high) in the following ways as an aid to decision-making in a stratified diagnostic scheme: > If the MPS is normal (low-risk), then the rate of cardiac events is less than 1% per year and is thus comparable both to the cardiac risk of the general population and lower than the risk of an invasive cardiovascular procedure. Thus, if the MPS is normal, the recommended clinical intervention is optimal management of all cardiovascular risk factors that are present. Further diagnostic studies are not required (13). > If the MPS reveals mild hypoperfusion (intermediate cardiac risk), then the risk of cardiac death is still under 1%, but the risk of a nonfatal infarction is relatively high. In this group of patients, the risk of death from a cardiovascular intervention is still higher than the cardiac mortality, so the proper therapeutic approach is, once again, optimal Dtsch Arztebl 2007; 104(14): A 952–8 ⏐ www.aerzteblatt.de 6 MEDICINE DIAGRAM 4 Estimation of the risk of cardiac death after medical treatment or revascularization in relation to the extent of myocardial hypoperfusion, measured as SDS (the "summed difference score"). If the SDS is higher than 8 (to 10), then revascularization procedures confer a more favorable prognosis than medical treatment alone (25). From: Circulation 2003; 1007: 2900–7, with the kind permission of Lippincott, Williams and Wilkins. medical management with minimization of all risk factors. An analysis of 10,627 patients reveals that this strategy is to be recommended for patients with an SDS up to 8 (diagram 4). If angina pectoris is a prominent complaint, however, a coronary intervention may be indicated; in such cases, the prognostic aspect (with reference to death or myocardial infarction) is not the primary concern (25, e1). > If the MPS reveals moderate or severe hypoperfusion (high cardiac risk), then the risk of cardiac death is high. In such cases, the MPS is considered unequivocally pathological. As recommended by the German national guidelines, the patient should undergo diagnostic coronary angiography with the goal of revascularization. In this situation, the prognostic utility of revascularization is greater than that of medical treatment (diagram 4). The same is true if the LVEF is below 45%, even if the associated hypoperfusion is only mild (14, 16, 25). Summary MPS is clearly superior to competing non-invasive techniques with respect to the level of scientific evidence available from current studies on the prognosis and treatment of coronary heart disease (2). This explains why MPS has been a well-established technique in the English-speaking countries for many years. It is widely used as part of a guidelineoriented, stratified diagnostic algorithm after a stress ECG has been performed, or if the ECG cannot be properly interpreted, whenever the presence of coronary heart disease is known or suspected. A further advantage of MPS is that myocardial perfusion scintigraphy with pharmacologically induced myocardial stress can be performed even in patients who cannot be ergometrically stressed to the extent required for adequate diagnostic information to be obtained. Conflict of Interest Statement Dr. Lindner has received honoraria and/or reimbursement of travel costs from Bristol Myers Squibb, Phillips, and Aventis. He was temporarily employed by GE Healthcare and collaborated on a multicenter study by GE Healthcare. Prof. Burchert participated in multicenter studies by GE Healthcare and has received reimbursement of travel costs and lecture honoraria from this company. He has received reimbursement of travel costs and/or honoraria from Bristol Myers Squibb, Siemens, Phillips, and SanofiSynthelabo. Prof. Rusche, Prof. Schäfers, and Prof. Schober state that they have no conflict of interest as defined by the Guidelines of the International Committee of Medical Journal Editors. Manuscript received on 12 October 2005; final version accepted on 18 September 2006. Translated from the original German by Ethan Taub, M.D. REFERENCES For e-references please refer to the additional references listed below. 1. Bundesärztekammer, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, Kassenärztliche Bundesvereinigung: Nationale Versorgungs-Leitlinie Chronische KHK (Kurzfassung). 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Dtsch Arztebl 2007; 104(14): A 952–8 ⏐ www.aerzteblatt.de 8 MEDICINE e3. Cheitlin MD, Armstrong WF, Aurigemma GP et al.: ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2003; American College of Cardiology www.acc.org/clinical/guide lines/echo/index_clean.pdf e4. Wilke NM, Jerosch-Herold M, Zenovich A, Stillman AE: Magnetic resonance first-pass myocardial perfusion imaging: clinical validation and future applications. J Magn Reson Imaging 1999; 10: 676–5. e5. Lindner O, Fricke E, Preuss R et al.: Nicht-invasive Diagnostik der KHK bei Diabetes mellitus. Diabetes, Stoffwechsel und Herz 2006; 15: 33–43. Corresponding author Dr. med. Oliver Lindner Institute for Radiology, Nuclear Medicine, and Molecular Imaging Heart and Diabetes Center NRW University Clinic of the Ruhr - University of Bochum Georgstr. 11 D-32545 Bad Oeynhausen, Germany [email protected] Dtsch Arztebl 2007; 104(14): A 952–8 ⏐ www.aerzteblatt.de 9