Nuclear cardiology: New developments and future directions

Nuclear cardiology: future directions

New developments

and

Ami E. Iskandrian, MD, and Jamshid Mackiahi, MD New developments in the field of nuclear cardiology include attenuation, scatter and depth resolution correction, newly designed gamma cameras, newer tracers, and newer stress agents. These developments, together with many new applications, are likely to continue to place nuclear cardiology in the mainstream of management of cardiac patients. (J Nucl Cardiol1997; 4:S189-92.) Key Words: single-photon emission computed tomography * radionuclide angiography metabolic tracers * infarct-avid imaging

In the past 20 years many developments have occurred in nuclear cardiology: approval by the Food and Drug Administration (FDA) of 99mTc-labeled sestamibi, 99”Tc-labeled tetrofosmin, ” ‘In-labeled antimyosin, dipyridamole, and adenosine; shift from planar to singlephoton emission computed tomographic (SPECT) imaging; increasing use of multihead detectors for SPECT imaging; use of gated perfusion imaging, positron emission tomographic (PET) imaging with SPECT cameras, and SPECT radionuclide angiography. There has also been a greater emphasis on risk assessment, outcome and cost-effectiveness, and assessment of myocardial viability. These advances, as important as they are, may be only the beginning. It is almost certain that further developments are on the way.‘.lo In this chapter we will touch briefly on some of these areas (Table 1). Attenuation/Scatter

Compensation

Scattered photons change direction and lose energy on interaction within the patient. If detected within the photon peak window, they are likely to be mispositioned and lead to reduced image contrast and reduced lesion detection.‘a2 On the other hand, if photons are not detected because they are absorbed by soft tissue, they reduce the image contrast nonuniformly. The probability of absorption decreases as the photon energy increases, and for this reason attenuation is more severe with thallium- than with technetium-labeled tracers. The first system used for attenuation correction on a triple-detecFrom the Cardiovascular Research Center, Allegheny University of the Health Sciences, Philadelphia, Pa., and the Division of Nuclear Medicine and Biophysics, Department of Molecular and Medical Pharmacology, University of California at Los Angeles School of Medicine, Los Angeles, Calif. Reprint requests: Ami E. Iskandrian, MD, Cardiovascular Research Center, Allegheny University of the Health Sciences, Broad & Vine, Mail Stop 471, Philadelphia, PA 19102-l 192. Copyright 0 1997 by American Society of Nuclear Cardiology. 1071-3581/97/$5.00 + 0 4310179770

tor SPECT camera was based on a line source coupled with a long focal fan beam collimator to acquire a transmission scan simultaneously with the standard emission scan. With a dual 90-degree detector SPECT system, attenuation/scatter compensation is based on a scanning line source approach with conventional parallel-hole collimators and highly collimated line sources that scan the entire field of view of the camera simultaneously with emission acquisition. Only the portion of the detector directly across from the line source accepts photons from the transmission source. The remainder of the detector surface acquires the emission scan in the usual manner. A third method for obtaining transmission images requires that one detector be dedicated to the transmission scan. ls3Gd is the popular tracer for the transmission line source scans. It has a long half-life (242 days) and approximately 100 KeV photon emissions. The current trends in scatter correction take advantage of the multienergy sampling capabilities of the new digital detectors that acquire data from different regions of energy simultaneously. Multiple techniques differ from each other primarily by the location and width of the energy windows used, sampling regions to integrate the scatter data, and algorithms to predict and correct the data. Image reconstruction is done with iterative algorithms, which work by modeling the SPECT acquisition with mathematic representation of the image formation process and initial estimate of the tracer distribution and attenuation map. Iterative algorithms yield successful, more accurate approximation of the two-tracer distribution by including additional information affecting the image process such as attention and scatter. Such algorithms can be categorized as statistical or analytic. In the future, it may be important to add depth resolution compensation to allow for differences in resolution as a function of the distance between the heart and the detector. Attenuation/scatter programs for myocardial SPECT imaging are now commercially available and initial results from multicenter trials are promising. They S189

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Table SPECT

1.

New

developments

acquisition/processing:

in nuclear

Journalof NuclearCardiology March/April1997,Part2 c4iolo.w

attenuation/scatter

compensation Raciionuclicieangiography; multiwire camera Newer

imaging

Myocardial

perfusion

Hypoxia

markers

Acute Fatty

infarction acid

Thrombus Sympathetic Stress

tracers

agents;

metabolism and

atherosclerosis innervation

adenosine AZ-receptor agonist; arbutamine

provide a significant achievement toward true quantitative SPECT imaging and improved diagnostic precision. Radionuclide

Angiography

Gated SPECT radionuclide angiographic studies can now be acquired in 10 to 15 minutes and processed in 5 to 10 minutes.‘B3 These are significant improvements since the first description of the method in 1980. The use of multiheaded cameras is an advantage to shorten acquisition time. The advantages of gated SPECT radionuclide angiography include increased precision in measuring left ventricular volume and ejection fraction and assessment of wall motion. The method has also been shown to be accurate for detection of atrioventricular nodal bypass tracks and quantification of mitral or aortic valve regurgitation. A new development in first-pass radionuclide angiographic studies is the use of the multiwire camera, which is based on the principles of the multiwire proportional counter. The inventor, a Swiss physicist named George Charpak, was awarded the Nobel prize for physics in 1993. Because the system does not use sodium iodide crystal and has no photon multiplier tubes, the detector is lightweight and compact, allowing it to be used as a portable device. The detector contains an aluminum entrance window and a drift region containing pressurized xenon. The major advantage of the multiwire gamma camera is its high sensitivity and improved resolution over the Anger gamma camera. This camera needs low-energy radionuclides such as 17’Ta, which has an energy level of 60 KeV and a half-life of 9.3 minutes. The short half-life limits the radiation exposure of the patient and allows serial studies. Newer Tracers Perfusion Tracers. 99”Tc-labeled furifosmin or 412, developed by Mallinckrodt Inc. (St. Louis, MO.),

has completed phase III clinical trials and is awaiting approval by the FDA. This agent, like sestamibi and tetrofosmin, is cationic and lipophilic and undergoes hepatobiliary excretion.4 Phase III clinical trials suggested that overall results were comparable to those of 201T1. “““‘Tc-labeled NOET . 99”Tc-labeled NOET is a tracer that is undergoing clinical trials in Europe. It has features intermediate between those of thallium and the other technetium-labeled tracers. For example, it has a high first-pass extraction that shows little plateauing at high flow rates; it is neutral and lipophilic but redistributes (not as fast as teboroxime but not as slow as thallium). The high extraction fraction and redistribution phenomena have potential advantages for use of this tracer for flow measurements and viability assessment. PET Tracers. Recently, “Rb has been approved by the FDA for myocardial perfusion imaging. “Rb is a generator-produced PET radiopharmaceutical and thus obviates the need for an on-site cyclotron for clinical use. Another significant development in clinical use of PET radiopharmaceuticals is the development of regional cyclotron facilities for production and delivery of “Ffluorodeoxyglucose (FDG), a positron-emitting glucose analog. FDG has been validated extensively for assessment of myocardial viability. The increased availability of FDG through regional cyclotron facilities combined with high-energy collimation or the newly developed coincidence imaging with SPECT cameras would make clinical PET more practical. Sympathetic

Innervation

‘231-metaiodobenzylguanidine is available in Japan and Europe but has not undergone multicenter clinical trials in the United States. It is a norepinephrine analog that is stored in the vesicles in the sympathetic nerve terminals.’ The myocardial uptake, washout, and myocardial/mediastinal ratio reflect sympathetic activity and tone, which have been shown to be important prognostic markers in patients with heart failure. A rapid myocardial washout and high mediastinal/myocardial ratio identify patients at high risk. This tracer appears to be well suited for the study of patients with heart failure and also in the study of patients with serious ventricular arrhythmia‘s. ‘231-Labeled

Fatty Acids

1231-labeled fatty acids have undergone many modifications since the initial report in 1965. Radiolabeled iodophenylpentadecanoic acid (IPPA) undergoes rapid P-oxidation in the mitochondria, and the presence of the phenyl group prevents nonspecific deiodination and the rapid release of free iodine.5 The addition of a methyl

Journal

Volume

of Nuclear 4, Number

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group to this long-chain fatty acid B-methyliodophenylpentadecanoic acid (BMIPP) slows the oxidation and results in prolonged myocardial retention. 1231-IPPA has completed phase III clinical trials in the United States and is awaiting approval by the FDA for detecting myocardial viability in patients with ischemic cardiomyopathy. In Japan and Europe, 1231-BMIPP is often combined with perfusion tracers such as “‘Tl to detect myocardial viability. Extensive literature indicates that a mismatch pattern (larger BMIPP defect than thallium defect) is a marker of patients at high risk and a marker of recovery of left ventricular function in patients with acute coronary syndromes. BMIPP appears to have a unique memory feature that is attributed to metabolic stunning such that an episode of myocardial ischemia can be detected by BMIPP imaging even hours after the ischemic episode has subsided and the perfusion pattern and wall motion abnormality have normalized. This feature may make it ideal for emergency room imaging in patients with chest pain syndromes. Infarct-Avid

Imaging

Although ‘“In-labeled antimyosin is highly sensitive and specific for diagnosing acute myocardial infarction, the lag time between its administration and imaging is a disadvantage for the immediate diagnosis of acute myocardial infarction.6 On the other hand, ggmTc-labeled glucurate can be used for hyperacute localization and visualization of acute myocardial infarction in both reperfused and nonreperfused hearts. Large areas of acute myocardial infarction are visualized earlier than small infarcts. Nevertheless, data suggest that even with small infarcts visualization is possible within 3 hours of the administration of the tracer in the absence of thrombolysis and earlier in the presence of thrombolysis. Positive scans with 9gmTc-labeled glucurate acid revert to normal in about 2 to 3 days; therefore there is the potential utility for both 99”Tc-labeled glucurate and “‘In-labeled antimyosin in tandem allowing the early and late detection of acute myocardial infarction. 99mT~labeled glucurate, however, has not yet been tested in large trials in the United States. Hypoxia Markers Radiopharmaceuticals that incorporate nitroimidazole moieties have been developed to detect regional tissue oxygen tension.7 In 1981 it was suggested that this class of compounds could be used for the direct visualization of tissue hypoxemia. Assessment of tissue oxygen tension may be the best indicator of the balance between myocardial blood flow and oxygen consumption. Several such compounds have been evaluated: the

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positron emitting radiotracer ‘aF-labeled misonidazole and 99”Tc-labeled nitroimidazole BMS- 18 1321. The nitroimidazole is believed to passively diffuse across the cell membrane and, once in the cytoplasm, nitroreduction occurs independently of oxygen tension. In the presence of normal oxygen tension, the radical anion (R-NO,) interacts with oxygen, yielding superoxide and noncharged misonidazole; the noncharged misonidazole then diffuses out of the cell. In the presence of low tissue oxygen tension, the misonidazole anion is reduced further, yielding nitroso compounds and hydroxylamines that have a lower permeability and are retained within the cells. Another compound BMS-194796 is a more hydrophilic nitroimidazole than BMS- 18 132 1 and has higher myocardial retention after transient ischemia and less retention in the liver. Thus the class of nitroimidazole compounds has a promise for positive imaging of ischemic myocardium. Thrombus

and Atherosclerotic

Plaque Imaging

Several blood components can be labeled for thrombus imaging. These include red blood cells, some of the clotting factors, fibrinogen, fibrin, and platelets8 The composition of arterial thrombus differs from that of venous thrombus; the arterial thrombus is platelet rich, whereas the venous thrombus is fibrin rich. Thus the selection of which imaging agent to use is determined to a great extent on the type of thrombus that is clinically suspected. Other factors that are important for thrombus imaging include the delivery rate of the radiolabeled agent to the thrombus site, the specificity of the binding site for active thrombosis, the number of binding sites, the affinity of radiolabeled compounds for binding sites, detachment rate, clearance of background activity, and the size of the agents. The ultimate goal is to be able to image the atherosclerotic plaque, especially the unstable plaque responsible for unstable angina pectoris, acute myocardial infarction, or sudden death. This field is rapidly advancing; for example, it is known that smooth muscle hyperplasia plays an important role in the formation of the atherosclerotic plaque. It is likely that in the process of plaque formation there is also transformation of these muscle cells from the contractile phenotype to the synthetic phenotype. This is associated with upregulation of the purine P, receptors. 99”Tc-labeled AP4A has been used to image these receptors in an animal model with atherosclerosis. Stress Agents Arbutamine is a newly developed synthetic catecholamine with B-agonist and mild o-agonist activity.9 Compared with dobutamine, the chronotropic and ino-

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tropic effects of arbutamine are more balanced, suggesting that, for a given level of inotropic stimulation, arbutamine produces greater chronotropic effect than dobutamine. Arbutamine is administered with a closedloop delivery system and has undergone phase III clinical trials with myocardial perfusion and echocardiography. The data suggest that the diagnostic accuracy of this stress is comparable to that of other currently available pharmacologic stressors. Arbutamine is awaiting approval by the FDA. There is a number of selective adenosine A,- and AZ-receptor agonists and antagonists that can be used in conjunction with or in lieu of either dipyridamole or adenosine as coronary vasodilators. Thus adenosine A,antagonist could be administered before dipyridamole or adenosine to block the A,-mediated side effects (such as chest pains and atrioventricular block). On the other hand, pure adenosine AZ-receptor agonist can be used to produce coronary vasodilation without the Ai-receptorrelated side effects.‘O In addition, adenosine triphosphate may also be used as a coronary vasodilator as is currently being done in Japan. References 1. Iskandrian AS, Verani MS. Nuclear cardiac imaging: principles and applications. 2nd ed. Philadelphia: FA Davis, 1995.

Journal of Nuclear Cardiology March/April 1997, Part 2

2. Cullom SJ, Galt JR. New approaches to SPECT imaging with scatter and attenuation compensation. In: Iskandrian AS, Verani MS, editors. New developments in nuclear cardiac imaging. New York: Futura Publishing. In press. 3. Verani MS, Iskandrian AS. New approaches with radionuclide angiography. In: Iskandrian AS, Verani MS, editors. New developments in nuclear cardiac imaging. New York: Futura Publishing. In press. 4. Hendel RC. Technetium 99m furifosmin (Q-12). In: Iskandrian AS, Verani MS, editors. New developments in nuclear cardiac imaging. New York: Futura Publishing. In press. 5. Corbett JR. Myocardial imaging with radiolabeled fatty acid. In: Iskandrian AS, Verani MS, editors. New developments in nuclear cardiac imaging. New York: Futura Publishing. In press. 6. Khaw BA. New approaches to infarct imaging. In: Iskandrian AS, Verani MS, editors. New developments in nuclear cardiac imaging. New York: Futura Publishing. In press. 7. Sinusas AI. New approaches to myocardial imaging with hypoxia markers. In: Iskandrian AS, Verani MS, editors. New developments in nuclear cardiac imaging. New York: Futura Publishing. In press. 8. Cerqueira MD. New approaches to thrombus and atherosclerotic plaque imaging. In: Iskandrian AS, Verani MS, editors. New developments in nuclear cardiac imaging. New York: Futura Publishing. In press. 9. Kiat H. New approaches to catecholamine imaging with albutamine. In: Iskandrian AS, Verani MS, editors. New developments in nuclear cardiac imaging. New York: Futura Publishing. In press. 110. Glover DK. New approaches to vasodilator imaging. In: Iskandrian AS, Verani MS, editors. New developments in nuclear cardiac imaging. New York: Futura Publishing. In press.