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PET Myocardial Perfusion Imaging Josef Machac, MD Nuclear Medicine, The Mount Sinai School of Medicine of New York University, New York, NY, USA INTRODUCTION Clinical positron emission tomography (PET) imaging is experiencing rapid expansion due to the recognition by the clinical community of its value in decision making in oncology. Cardiac PET imaging had an early head start in myocardial perfusion imaging and imaging of myocardial viability (1,2 ). However, its "limitation to a few PET centers" has retarded its clinical development. The recent rapid growth of dedicated PET imaging systems offers a new opportunity for a re-examination of cardiac PET imaging. It is also a challenge for clinical cardiac imaging to take a quantum leap beyond the now ubiquitous SPECT imaging to a new level of functional imaging capability. PRINCIPLES OF PET IMAGING PET imaging utilizes a class of radionuclide tracers which decay with the emission of a positron. The positron interacts with an electron. Their combined mass is converted into the energy of two 511 kev photons traveling in opposite directions. A PET camera contains an array of detectors which are able to detect the two gamma rays in coincidence. The last decade has seen the development of high performance dedicated PET cameras featuring high sensitivity (efficiency of detection) about 10-20 times higher than SPECT, high resolution, of 4-5 mm in air and about 7 mm in water vs 20-25mm for SPECT, high speed, and larger fields of view, 15 cm vs 10-11 cm previously (3,4 ). For cardiac imaging, high resolution is not currently a major concern. Myocardial contraction results in smearing of the information in static acquisition. This can be overcome by gating, but then high count sensitivity is critical for good image quality. The need for noise filtering sacrifices resolution in favor of image smoothness. Moreover, for clinical myocardial imaging, only an appreciable mass of myocardium that is hypoperfused or dysfunctional is of diagnostic or prognostic significance (5). Image uniformity is by far the most important property of PET imaging for cardiac imaging. Coincidence detection allows more effective correction for non-uniform attenuation than for SPECT imaging (6,7,8). Non-uniform attenuation in the chest results in multiple different patterns of SPECT images attenuation, depending on body habitus and position of the heart (9,10,11). Current attenuation correction hardware and software algorithms for SPECT imaging have come a long way in improved effectiveness but offer only a partial correction of the problem, and sometimes result in greater error (12,13,14,15 ). Furthermore, most SPECT cardiac acquisition is performed over 180 degrees over the chest, which results in additional spatial distortion and non-uniformity (16,17 ). Fig 1 shows images of a cardiac phantom, filled with either Tl-201, Tc-99m, acquired with a SPECT imaging system, or F-18 FDG acquired with a PET scanner, immersed in a water bath, containing defects of varying sizes. In the SPECT images, we see progressive attenuation toward the base. Experienced readers are familiar with this pattern and learn to distinguish this pattern from a real defect (18), also seen in the image. Sometimes, due to non-uniform attenuation, this is difficult to do. A real perfusion defect may be exaggerated in size and severity. On the other hand, a real perfusion defect can be hidden within an area of apparent attenuation. PET imaging, utilizing a transmission scan in addition to the emission scan, corrects this problem, as seen in Fig 1 .

Fig 1. A realistic heart phantom with defects of varying sizes, encased in a nonuniform attenuation medium, was imaged in SPECT mode when filled with either Tl-201 or Tc99m, and in PET mode when filled with F-18 FDG. The SPECT images show progressive attenuation from the apex toward the base. Superimposed perfusion defects may be either exaggerated or hidden within the attenuation pattern. The PET images show uniform correction of attenuation.

The effectiveness of SPECT imaging has been greatly augmented by gating. Gating not only provides added information about global and regional left ventricular and right ventricular function (19,20,21), enhancing its prognostic value, but also helps to differentiate real defects from attenuation artifacts (22). However, there is room for further improvement. The accurate interpretation of cardiac SPECT images requires a high level of training and skill to recognize artifacts and pitfalls, normal variants, and disease patterns. PET imaging offers a paradigm that simplifies the task significantly. Table 1 lists radionuclide tracers used for PET perfusion imaging. N-13 ammonia features a sufficiently long half life to allow high quality imaging, including gated imaging (23,24,25,26), as well as myocardial blood flow quantification at rest and stress (27,28). Indeed, much of the early pioneering work on PET perfusion imaging was done with N-13 ammonia. This tracer continues to be a major tool in studies using quantification of myocardial perfusion (see below). However, the requirement for an on-site cyclotron for its production and current lack of reimbursement limit its clinical use even in PET centers with a cyclotron.

O-15 water features a very short-lived tracer, whose rapid diffusion across capillaries and plasma membranes after injection allow for reliable quantification of blood flow (29). However, poor contrast between blood pool and myocardium and the requirement for on-site cyclotron production just before each use preclude its routine application. Rubidium-82 is a potassium analogue which, like thallium-201, is extracted by all living cells. It is produced from a commercially available, FDA approved strontium-82 containing generator, which must be replenished 13 times a year. Its round-the clock availability makes rubidium-82 the most practical PET perfusion imaging agent. Its short half-life allows rapid back to back repeated acquisitions every 10 minutes. The rubidium-82 generator is computer controlled and delivers a measured bolus of activity when activated. The short half-life of Rb-82, however, imposes a limit on the available imaging time for each injection, and a limit on the obtainable image counts, thus requiring a high sensitivity multicrystal PET scanner, which is able, at the same time, to handle the high amount of activity (50-60 mCi) injected without running into deadtime problems (30). Modern multicrystal PET camera designs allow high sensitivity of detection, as well as negligible losses from dead-time. Solid crystal coincidence gamma cameras, however, are limited in their ability to achieve satisfactory images with Rb-82 due to the upper limit on the amount of activity that can be handled without distortion (31). Rubidium-82 PET imaging is limited by the high cost of the Rb-82 generator, which together with the high fixed cost of a PET camera, necessitates a minimum of 2-3 reimbursed studies per day to be economically feasible. IMAGING PROCEDURE: Clinical myocardial perfusion PET imaging with Rb-82 consists of positioning, transmission imaging, and resting and stress imaging. The resting acquisition takes 6 minutes. It can be performed with ECG gating. With appropriate filtering, one obtains an 8-frame gated myocardial wall motion/perfusion study with a potential for wall motion evaluation and quantification similar to SPECT imaging. The resting imaging is usually followed by 10 minute transmission imaging, performed with a rod source of activity (Germanium-68) housed inside the scanner cabinet, which circles the body. The resulting transmission images, analogous to a CT scan, provide information for attenuation correction, which is a crucial component of cardiac PET imaging. New designs combining PET and CT scans in one instrument unit promise to reduce the transmission scan time to less than a minute. The final step is pharmacological stress imaging. The most common stressors are dipyridamole or adenosine, which increase blood flow 3-4 fold in normal regions (32,33 ). Regions supplied by coronary arteries with hemodynamically significant lesions or endothelial dysfunction do not demonstrate increased blood flow to the same degree as in normal regions. Thus uptake with stress is decreased relative to other regions. In multivessel disease with the presence of collaterals, or severe hypotension, blood flow with stress may actually decrease, demonstrating the so-called coronary steal syndrome, which can be detected by quantification of regional blood flow (34,35,36). Dobutamine or arbutamine with or without the use atropine, can be used in those patients that cannot tolerate dipyridamole or adenosine. At peak stress level, another Rb-82 infusion is delivered, followed by stress imaging for 6 minutes. The stress images can be also be gated, with resultant wall motion information during stress, simultaneously with the perfusion information. Other stressors can be used, including mental stress, smoking, handgrip and the ice-pressor test for special applications (37,38,39). Fig 2a shows stress and rest images of a normal study. Fig 2b shows the end diastolic and end-systolic

frames from the gated resting study. Fig 3a shows stress and images in a patient with stress-inducible ischemia. Notable is the marked LV dilation during stress. The resting images in diastole and systole in Fig 3b show normal wall motion. Fig 4a shows an example of stress and rest images of a patient with multiple perfusion abnormalities both with stress and rest, and the corresponding gated images in Fig 4b showing regional and global dysfunction and LV dilatation.

Fig 2a. Stress and rest images of a normal Rb-82 PET study.

Fig 2b. End-diastolic (ED) and end-systolic (ES) frames at rest with good wall thickening and wall motion. VLA = vertical long axis cuts, HLA = horizontal long-axis cuts, SA= short axis cuts.

Fig 3a. Stress and rest Rb -82 PET images in a patient with dipyridamole stress-inducible lateral wall and apical ischemia. Notable is the marked LV dilation during stress.

Fig 3b. The resting images in diastole and systole show normal resting wall motion except for decreased lateral wall thickening.Fig

4a. Rb-82 PET perfusion images of a patient with LV dilatation and multiple perfusion abnormalities both with stress and rest.

Fig 4b.The corresponding gated ED and ES images show extensive regional and global dysfunction and LV dilatation.

INDICATIONS With the reported high accuracy of disease detection of PET myocardial perfusion imaging (90-95% sensitivity and 95% specificity) (40,41,42,43,44,45), one can argue that all patients should have

myocardial perfusion imaging studied with PET. Cost-effectiveness modeling by Patterson et al (46) showed that despite higher per/study cost of PET imaging, PET imaging is cost-effective by decreasing the utilization of angiography and intervention procedures, thus saving money overall. This was supported in clinical practice by utilization outcome studies by Merhige et al (47,48). On the other hand, this conclusion was challenged by the analysis of Huyting et al (49), by using a different model and assumptions. A conservative approach would select patients with a high likelihood that PET imaging will yield greater added value compared to SPECT or other noninvasive tests. Patients in whom stress imaging with exercise is neither required nor feasible, and in patients with a high likelihood of false positive or false negative studies by SPECT are likely to benefit from PET imaging. This includes obese individuals, and women with large breasts, where SPECT imaging is less effective due to attenuation artifacts (50,51,52 ). Many patients with end-stage renal and liver disease have edema, ascites, and high elevated diaphragms, sometimes with pericardial effusions, which may lead to nonuniform attenuation abnormalities (53). Patients with equivocal results with other noninvasive tests or conflicting results can benefit from PET imaging. Fig 5a shows a stress SPECT Tc-99m sestamibi study performed in a 370 lb male with an abnormal ECG and multiple risk factors for CAD, referred for screening for pre-operative risk stratification. It shows a moderate to severe inferoposterior defect, and a possible moderate anterobasal defect. SPECT attenuation correction did not correct the defects. These abnormalities were considered to be likely due to attenuation artifact but real disease could not be dismissed, in view of the patient's risk. Fig 5b shows the stress-rest Rb-PET study, which was performed shortly after. The PET perfusion images showed no evidence of the inferoposterior or anterobasal defects, at rest or stress. Thus, the patient that would have been incorrectly assigned to a high risk category, belonged instead to a low risk category. On the other hand, it may have been difficult to detect real ischemia in the inferoposterior wall, had it been present. The problem of accurate diagnostic and prognostic imaging in moderately and markedly obese individuals is likely to grow, in view of the increasing weight in the developed world with each passing year.

Fig 5a. Stress SPECT Tc -99m sestamibi study performed in a 370 lb male showing a moderate to severe inferoposterior defect, and a possible moderate anterobasal defect. SPECT attenuation correction (AC) did not correct the defects.

Fig 5b. Stress-rest Rb-82 PET imaging study in the same patient performed a few days later. It showed no evidence of the inferoposterior or anterobasal defects. Only a mild reversible apical and apicoseptal defect was notable. The large body mass did result in noisier SPECT and PET images.

Diagnostic imaging in women has been evaluated by others in the past (54,55,56,57 ). The added value of PET imaging in women compared to SPECT imaging has been documented (58,59). Fig 6a, 6b shows anterior wall ischemia in a SPECT study in a 52 yr woman. Fig 6c showed a normal Rb-82 PET study.

Fig 6a. Evidence of anterior wall ischemia on a SPECT Tc-99m sestamibi study in a 52 yr woman.

Fig 6b. SPECT attenuation correction did not result in a substantial improvement.

Fig 6c. Normal Rb-82 PET study in the same patient.

FLOW RESERVE MEASUREMENT

PET imaging offers the potential for quantification of blood flow at rest and stress with tracers like Rb82. For routine interpretation, one compares relative flow distribution. In the absence of flow quantification, one may underestimate or even miss extensive or diffuse disease, or the so-called "balanced ischemia" (60,61). Alternately, one may fail to produce sufficient vasodilation during stress (62), leading to a false-negative study, and not know it. Formal quantification of blood flow by PET imaging usually involves a multi-frame dynamic acquisition, in which both myocardial and blood pool activity is sampled. The resultant myocardial and blood pool input function curves are corrected for decay, the partial volume effect, tissue cross-talk, and are used in a compartmental model. This requires solving for multiple unknowns, including blood flow, the partition coefficient, distribution volumes, or their equivalents (63,64). Such an approach, however, is difficult for routine use. Simpler alternatives, even if less rigorous, would still be useful. The simplest approach is to use the uptake of Rb-82 during stress and during rest, after one corrects for injected dose (65). Their ratio reflects the true flow reserve, but ignores the effects of postinjection Rb-82 blood pool activity, which drops as the cardiac output increases during stress (66). Also, decreasing extraction fraction occurs as coronary flow increases (67). Thus the uptake ratio underestimates the true flow reserve fraction. Nevertheless the Rb-82 uptake ratio has been successfully used (68,69) to detect such phenomena as coronary steal syndrome, and as an index of the flow response to stress. A compromise approach is a modification of the equations for the trapping of microspheres in tissues, as proposed by the University of Texas group (70). It corrects myocardial Rb-82 uptake by the summed blood pool activity, and by the relation between flow and extraction fraction, measured in animal studies. This approach was found to function in animal validation studies. In what situations can flow reserve measurement be useful? Failure to achieve a normal flow reserve ratio of 2.0-2.5 (71) might suggest a failure in vasodilator efficacy, or possible diffuse disease. Diffuse disease might consist of small vessel disease, whether through fixed small vessel disease, extensive epicardial disease, so called "balanced ischemia", in such situations as diabetes, or hypertension, or endothelial dysfunction (72,73). Numbers of studies have shown an improvement in the flow reserve with interventions. Endothelial dysfunction, demonstrated invasively through intracoronary infusion of acetylcholine, has been studied non-invasively with the cold-pressor test (74,75). Sequential interventions can easily be performed with Rb-82 PET imaging in such patients. Fig 7 shows the PET stress and rest images of a man with risk factors for CAD and a positive exercise

ECG stress test was evaluated for severity of CAD. The PET images showed only a small apical defect, which improved at rest, indicating only mild disease. However, the measured flow reserve of 1.2 was very low. On the suspicion that the low flow reserve was due to inadequate stress stimulus, small vessel disease, or 'balanced ischemia" the patient underwent angiography, which showed 3-vessel disease. In the absence of quantification, this disease severity would have been missed, although in other patients, clues such as cavity dilatation or a positive ECG response with dipyridamole might tip one off that one is dealing with severe diffuse disease.

Fig 7. Rb-82 PET stress and rest images in a show only a small apical defect and a minimal inferolateral defect, which improved at rest, indicating only mild disease. The measured global flow reserve was 1.2 (normal is greater than 2.0-2.5).

The accelerated atherosclerosis after heart transplantation tends to be diffuse, and involve both epicardial and small vessels diffusely (76). Patients with diffuse disease, like those after heart transplantation, are ideal candidates for follow-up with flow reserve quantification (77). Reliance on heterogeneity in perfusion images may underestimate the extent and severity of flow. Quantification of blood flow also can be used to reveal the presence of collateral blood supply to diseased regions, through the "coronary steal" phenomenon. Fig 8 shows the stress-rest images in a man who was presenting with chest pains. His stress images show severe extensive periapical and lateral defects, with essentially noral resting perfusion. While the flow reserve of 1.9 is nearly normal in the septum, the lateral wall showed a 30% fall in flow with stress, demonstrating an example of coronary steal. On angiography, the patient had 3 vessel disease, with collaterals. This has been observed in studies using either quantification with the compartmental model (78,79), as well as with Rb-82 uptake ratios (80).

Fig 8. Rb-82 PET stress -rest images in a 70 year old man show severe extensive periapical and lateral defects, with essentially normal resting perfusion. While the flow reserve of in the septum is nearly normal (1.9), the lateral wall showed a 30% fall in flow with stress, an example of coronary steal. On angiography, the patient had 3 vessel disease, with collaterals.

VIABILITY IMAGING Routine rest and stress MPI with Rb-82 provides useful relevant information on myocardial viability, similar to that of Tl-201 imaging and Tc-99m sestamibi SPECT imaging regarding stress-induced ischemia, and preserved uptake of Rb-82 at rest. Combined with wall motion information from other wall motion studies or with gated Rb-82 images, the PET myocardial perfusion study can be expected to answer the clinical question in most patients. Preserved perfusion and wall motion signifies normal myocardium. Stress induced ischemia in myocardial segments with preserved wall motion at rest indicates jeopardized myocardium. Stress-induced ischemia in hypo-functioning myocardium suggests a region susceptible to repetitive stunning (81). There is evidence that Rb-82, like thallium-201, shows preserved uptake in viable myocardium (82), and has been shown to accurately map infarct size and viable myocardium (83). The resting Rb-82 PET imaging study is analogous to a resting re-injection Tl-201 study, which has been shown to enhance viability detection in some patients. The short half-life of Rb-82, however, precludes the ability to demonstrate 624 hour delayed uptake of the tracer in hibernating myocardium, as has been shown to be useful in Tl-201 imaging. It has been suggested that the rate of Rb-82 washout or retention over a 6 minute dynamic acquisition can differentiate viable from nonviable myocardium(84y), but this needs to be verified further. There are, nevertheless, regions with demonstrable viability and preserved uptake of FDG, that show deficient uptake of Rb-82, like Tl-201. In such situations of poor LV function combined rest-stress Rb-82 imaging, whenever possible, are best combined with FDG imaging for optimal evaluation of myocardial viability. The indication for the combination is poor LV function, and the need to decide on the value of a revascularization intervention. In the US, a newly promulgated HCFA reimbursement is available for FDG PET imaging that follows a nondiagnostic SPECT perfusion study for myocardial viability, 15 years after the

pioneering work of Tillisch et al demonstrated its usefulness (85). CONCLUSION Early clinical experience with Rb-82 PET perfusion imaging almost a decade ago has demonstrated a consistently high accuracy of CAD detection. In spite of the increasing use of Tc-99m labeled perfusion agents and the enhanced diagnostic and prognostic capability through the use of gated SPECT, significant limitations to SPECT imaging still exist. This makes PET perfusion imaging a compelling first choice in an identifiable subgroup of the clinical population. Unless measured attenuation correction in SPECT imaging is brought to an effectiveness similar to that in PET imaging, the use of PET for myocardial perfusion imaging will earn its value. The implementation of routine gating with PET myocardial perfusion imaging, and commercial development of processing, quantification and display for gated PET imaging, plus the development of practical software for flow reserve quantification, promises to augment the already considerable added value of myocardial PET imaging. The current proliferation of dedicated PET cameras for oncology is an opportunity and a challenge to make PET available more widely for cardiac imaging, too. This may be difficult in PET centers already busy with oncology work, unless the expansion of PET services to cardiac imaging were to provide a good reason for the acquisition of an additional PET camera. At the opposite end of the spectrum, centers which are hesitant to acquire a dedicated PET scanner, because of an insufficient number of anticipated oncology imaging studies, could have a sufficient number of cardiac studies, to pay for the rubidium-82 generator and contribute to the overhead of the PET camera. The same reasoning could be applied to mobile PET systems. Some locations could make combined oncology and cardiac mobile PET imaging, with a rubidium generator on board, a clinically and economically sound choice. At the same time, important challenges lie ahead for cardiac myocardial PET imaging. Most of validation studies of Rb-82 PET perfusion imaging were conducted ten years ago. Both SPECT and PET imaging have continued to evolve. Therefore, these studies need to be updated. The steady growth of cardiac radionuclide SPECT imaging over the past 15 years is a testimony to the demonstrable usefulness of SPECT imaging in clinical management of heart disease. Of importance to clinical noninvasive imaging was the change of the diagnostic paradigm from the diagnosis of CAD to prognostic risk stratification in clinical decision making. Outcome studies have amply documented the added value of SPECT radionuclide imaging in prognostic stratification in the general population with suspected CAD, following an acute myocardial infarction, acute chest pain, and prior to non-cardiac surgery. Outcome studies in women with SPECT imaging have been conducted, but studies with SPECT imaging in obese individuals is lacking. The literature on PET imaging in prognostic stratification in areas other than in viability imaging has remained sparse. Given the diagnostic robustness of PET imaging, it is to be expected that PET imaging for prognostic risk stratification will meet this challenge successfully, especially as the number of centers with capability for cardiac PET imaging expands. In spite of the higher cost per study for PET imaging, experience with other diagnostic settings has repeatedly shown, that if greater diagnostic power is clearly demonstrable at key decision -making points, the greater accuracy prevails. In spite of the impressive past accomplishments of cardiac radionuclide SPECT imaging, the pressures for greater performance is attested to by current efforts being made to develop other imaging modalities, including ultrasound, cardiac CT, and cardiac MRI imaging. REFERENCES 1. Schelbert HR, Phelps ME, Hoffman EJ, et al. Regional myocardial perfusion assessed with N-13 laeled ammonia and positron emission computerized axial tomography. Am J Cardiol 43: 209-218, 1979 2. Tillisch J, Brunken R, Marshall R, et al. Reversibility of cardiac wall motion abnormalities predcted by positron emission tomography. N Engl J Med 314: 884-8, 1986

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2nd Virtual Congress of Cardiology Dr. Florencio Garófalo

Dr. Raúl Bretal

Dr. Armando Pacher

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