Applied Radiology

Josef Machac, MD, The Mount Sinai School of Medicine of New York University, New York, NY

EDITOR'S NOTE

Myocardial PET perfusion imaging has been used clinically for over a decade. During this time, both SPECT and PET imaging technology and expertise have improved. However, significant problems with cardiac SPECT accuracy remain, particularly in women and the increasing proportion of obese patients. PET perfusion imaging offers high specificity in these and other difficult patients. Improvements in modern PET gamma cameras allow gating of Rb-82 images, offering the possibility of wall motion acquisition, routinely performed with cardiac SPECT imaging. In addition, there is a need for implementation of practical blood flow quantification to provide valuable information not available by other means, including quality control for pharmacological stress imaging, the evaluation of small vessel disease and endothelial dysfunction, detection of "balanced ischemia," and the detection of coronary collaterals.

This article discusses how these changes offer an opportunity to apply the full power of cardiac PET imaging. The shift of the clinical paradigm from disease detection to prognostic risk stratification dictate an update in clinical cardiac PET imaging outcome studies. These will serve to define the role of myocardial PET perfusion imaging in the next decade.­­ Josef Machac, MD

Myocardial PET Perfusion Imaging: The Next Generation

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 recognition of its value in myocardial perfusion and viability imaging. ^1,2 However, its limitation to a few PET centers has retarded its clinical development. The recent rapid growth of PET imaging systems offers a new opportunity for cardiac PET imaging. It is also a challenge for clinical cardiac imaging to take a quantum leap to a new level of functional imaging capability.

Principles of PET Imaging

PET imaging utilizes a class of radionuclide tracers that decay with positron emission. This leads to the production of two 511 kev photons travelling in opposite directions. A PET camera is 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, high resolution, high speed, and larger fields of view.

For cardiac imaging, high resolution is not currently a major concern. Myocardial contraction results in smearing of the image, unless one performs ECG gating, where high count sensitivity, rather than resolution, is critical for good image quality. Moreover, for clinical myocardial imaging, only an appreciable mass of myocardium that is hypoperfused or dysfunctional is of diagnostic or prognostic significance. ³

Image uniformity is by far the most important property of cardiac PET perfusion imaging. Figure 1 shows SPECT images of a cardiac phantom, showing progressive attenuation from the apex toward the base. Experienced readers are familiar with this pattern and learn to distinguish it from real defects. ⁴ Sometimes, this is difficult to do. On the other hand, a real perfusion defect can be hidden within an area of apparent attenuation. PET imaging corrects this problem.

The effectiveness of cardiac SPECT imaging has been greatly augmented by ECG gating. Gating provides added information about global and regional left ventricular and right ventricular function, enhancing its prognostic value, ³ and helps to differentiate real defects from attenuation artifacts. ⁵ However, further improvement is needed.

Among the tracers used for PET perfusion imaging, N-13 ammonia allows high quality static and gated imaging, ⁶ as well as myocardial blood flow quantification at rest and stress. ⁷ However, the requirement for an on-site cyclotron for its production limit its clinical use. Even in PET centers with a cyclotron, the current lack of reimbursement imposes additional limits.

O-15 water allows reliable quantification of blood flow. ⁸ However, poor image quality and the requirement for on-site cyclotron production just before each use preclude its routine application.

Rubidium-82 (Rb-82) is a potassium analogue that, 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. The short half-life of Rb-82 allows repeated acquisitions every 10 minutes. Its round-the-clock availability makes rubidium-82 the most practical PET perfusion imaging agent. 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. It requires a high-sensitivity, high-speed PET scanner, which is able to handle the high injected dose (50 to 60 mCi). ^9,10

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. One obtains an 8-frame gated myocardial wall motion/perfusion study for wall motion evaluation and quantification similar to gated SPECT imaging. The resting imaging is followed by a 10-minute transmission imaging, performed with a rod source of activity (Germanium-68), housed inside the scanner cabinet, which circles the body. The transmission images provide information for attenuation correction, which is a crucial component of cardiac PET imaging.

The final step is pharmacological stress imaging. The most common stressors are dipyridamole or adenosine, which increase blood flow three- to four-fold in normal regions. ¹¹ Dobutamine or arbutamine can be used in patients with asthma who cannot tolerate dipyridamole or adenosine. At peak stress level, another intravenous Rb-82 infusion is delivered, followed by stress imaging for 6 minutes. The stress images can also be gated, with resultant wall motion information during stress. Other stressors can be used, including mental stress, smoking, handgrip, and the ice-pressor test for special applications.

Figure 2 presents a normal PET perfusion study and the end diastolic and end-systolic frames from the gated resting study. Figure 3 shows PET perfusion images of a patient with multiple perfusion abnormalities at stress and rest, LV dilatation, and regional and global LV dysfunction.

Indications

With a reported high sensitivity (92% to 95%) and specificity (95%) of disease detection by PET myocardial perfusion imaging, one can argue that all patients should have myocardial perfusion imaging studies with PET, if available. Analysis by Patterson et al ¹² revealed that, despite higher cost per study, PET imaging is cost-effective by decreasing the utilization of more costly angiography and intervention procedures. This was supported by utilization outcome studies by Merhige et al. ¹³ On the other hand, this conclusion was challenged by analysis using a different model and assumptions. ¹⁴

A conservative approach selects patients with a high likelihood that PET imaging will yield added value compared with SPECT or other noninvasive tests. This includes obese individuals and women with large breasts, in whom SPECT imaging is less effective. ¹⁵ 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. Patients with equivocal or conflicting test results also benefit from PET imaging.

Figure 4 illustrates a stress SPECT Tc-99m sestamibi study performed for pre-operative risk stratification in a 370-lb man with an abnormal ECG and multiple risk factors for CAD. It shows a moderate to severe inferoposterior defect, and a possible moderate anterobasal defect that were not corrected the by SPECT attenuation correction. They were considered to be likely due to attenuation artifact, but real disease could not be dismissed. The Rb-82 PET study in the same patient showed no evidence of the inferoposterior or anterobasal defects, at rest or stress. This patient would have been incorrectly assigned to a high-risk category, but instead belonged to a low-risk category. The problem of accurate diagnostic and prognostic imaging in moderately and markedly obese individuals is likely to grow, in view of the increasing average weight in the developed world each year. ¹⁶

Diagnostic accuracy of noninvasive imaging in women has been problematic. The added value of PET imaging in women compared with SPECT imaging has been documented. ^17,18 Figure 5 presents an example of a 52-year-old woman with evidence of anterior wall ischemia on a SPECT Tc-99m sestamibi study and a normal Rb-82 PET study, suggesting an attenuation artifact.

Flow Reserve Measurement

PET imaging offers the potential for quantification of myocardial blood flow at rest and stress with Rb-82. Without flow quantification, one may underestimate or even miss extensive or diffuse disease, and the so-called "balanced ischemia." ^9,10,19 Alternately, one may fail to produce sufficient vasodilation during stress, leading to a false-negative study.

Formal quantification of blood flow requires a multi-frame dynamic acquisition. Myocardial and blood-pool activity curves must be generated and corrected for decay, the partial volume effect, tissue cross-talk, and dead-time. A compartmental model is used to solve for multiple unknowns, including blood flow.

This approach is difficult for routine use. Simpler alternatives, even if less rigorous, can still be useful. The simplest one uses the ratio of Rb-82 uptake during stress and rest. ²⁰ Their ratio reflects the true flow reserve, but ignores the effects of cardiac output increase during stress on Rb-82 blood pool activity, and the decreasing extraction fraction of Rb-82 as coronary flow increases. Thus, the uptake ratio underestimates the true flow reserve fraction. Nevertheless, the Rb-82 uptake ratio has been used successfully as an index of the flow response to stress and to detect the coronary steal syndrome. ^21,22

A compromise alternative uses modified equations for the trapping of microspheres in tissues. ²³ It corrects myocardial Rb-82 uptake by the summed blood pool activity and by the relation between flow and extraction fraction obtained from animal studies.

A global failure to achieve a normal flow reserve ratio greater than 2.0 to 2.5 ^9,10 suggests a failure in vasodilator efficacy; small-vessel disease in such situations as diabetes, hypertension, or endothelial dysfunction; or extensive epicardial disease, the so-called "balanced ischemia." Studies show improvement in flow reserve with interventions. Endothelial dysfunction has been studied noninvasively using the cold-pressor test. ^24,25 Physiological interventions can easily be performed with Rb-82 PET imaging.

A 70-year-old man with risk factors for CAD and a positive exercise ECG stress test was evaluated in our laboratory for severity of CAD. The PET images showed only a small apical defect, which improved at rest (Figure 6), indicating only mild disease. However, the measured flow reserve was very low (1.2). 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 three-vessel disease. This extent of disease would have been missed, since cavity dilatation or a positive ECG response with dipyridamole that make one suspicious were absent.

The accelerated atherosclerosis following heart transplantation tends to be diffuse and involves both epicardial and small vessels diffusely. ²⁶ Such patients are ideal candidates for follow-up with flow reserve quantification by PET. ²⁷ Reliance on regional heterogeneity alone may underestimate the extent and severity of disease.

Quantification of blood flow also can reveal the presence of collaterals to diseased regions. Myocardium supplied by significantly diseased arteries does not increase blood flow to the same degree as normal regions. In multivessel disease and the presence of collaterals, blood flow with stress may actually decrease, demonstrating the "coronary steal syndrome," which can be detected by quantification of regional blood flow. ^21,22,28 The PET imaging study in Figure 7 is of a man who presented with recurrent chest pains showed severe extensive periapical and lateral defects, with essentially normal resting perfusion. While the flow reserve in the septum is nearly normal, the lateral wall showed a 30% fall in flow with stress, an example of coronary steal. On angiography, the patient had three-vessel disease, with collaterals.

Viability Imaging

Routine rest and stress PET imaging with Rb-82 provides useful relevant information on myocardial viability, similar to that of Tl-201 imaging and Tc-99m sestamibi SPECT imaging. Combined with wall motion information, the PET myocardial perfusion study can be expected to answer the clinical question in most patients. ^29,30 There are, nevertheless, regions with demonstrable viability that show deficient uptake of Rb-82, an example of hibernating myocardium. ³¹ Patients with poor LV function are best performed with combined rest and stress Rb-82 imaging and F-18 FDG imaging. HCFA has recently endorsed reimbursement for FDG PET imaging for myocardial viability.

Conclusion

In spite of enhanced diagnostic and prognostic capabilities with the use of gated SPECT, significant limitations to SPECT imaging still exist. Early clinical experience with Rb-82 PET perfusion imaging has demonstrated a consistently high accuracy for CAD detection. This makes PET perfusion imaging a compelling first choice in an identifiable subgroup of the clinical population, those who are difficult to diagnose by other means. The implementation of routine gating with PET myocardial perfusion imaging and the development of practical flow reserve quantification promise to augment the already considerable added value of myocardial PET imaging.

The current proliferation of dedicated PET cameras is an opportunity and a challenge to make PET more widely available for cardiac imaging. In PET centers overburdened with oncology work, the expansion of PET services to cardiac imaging could provide a reason for the acquisition of an additional PET camera. Centers that 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 (2 to 3 per day) to pay for a rubidium-82 generator and contribute to the PET camera overhead. The same reasoning could be applied to mobile PET systems.

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 10 years ago. Since both SPECT and PET imaging methods have continued to evolve, these studies need to be updated.

Outcome studies have amply documented the added value of SPECT radionuclide imaging in prognostic stratification. The literature on PET prognostic risk stratification in areas other than in viability imaging largely still remains to be written. Given the robustness of PET imaging in assessing the severity of CAD, it is expected that PET imaging will meet this challenge successfully. In spite of the impressive past accomplishments of cardiac radionuclide imaging, the pressures for continued improvements in performance is attested to by current efforts being made with alternate imaging modalities.