PET Editorial Series

Positron Emission Tomography of the Heart: Mapping Flow and Metabolism In Vivo

Positron emission tomography (PET) offers the unique opportunity to view myocardial perfusion, metabolism, and function in vivo. The imaging technology is necessarily complex and multidisci-plinary; it capitalizes on recent advances in nuclear physics, radiochemistry, and electronics to permit the construction of slice images of the heart that depict physiologic processes rather than anatomic structures.

In contrast to x-ray imaging (absorptive imaging), conventional procedures in nuclear cardiology are examples of emission imaging in which photon (which has physical properties identical to x-ray) is pro-duced by a radionuclide injected into the patient and the detector is a scintillation crystal positioned over the heart rather than x-ray film. The low-energy photons produced by natural decay of 201T1 or 99mTc in the myocardium or cardiac blood pool are subject to the same absorption and scattering processes by tis-sue ("attenuation") as are x-rays. In fact, the only physical difference between an x-ray and a γ ray or photon produced by radioactive decay is the site of origin in the source atoms—x-rays originate in the orbital electron cloud, whereas γ rays are typically produced in the nucleus.

Although in diagnostic radiology the process of at-tenuation is exploited to produce an absorptive im-age, in nuclear medicine the tissue attenuation leads to a loss of information and degradation of the emis-sion image. Because many photons emanating from the heart are scattered or absorbed, they either never escape from the body or are deflected away from the detector.

Thus, tissue attenuation is one of the main limita-tions of single photon emission scans such as the "thallium stress test," the multigated ventriculogram or "MUGA," and the 99mTc-pyrophosphate infarct scan. In contrast, when a positron emitter decays,

Address reprint requests to Dr. M. E. Merhige at his current address: Buffalo Cardiology and Pulmonary Associates, 5305 Main Street, Buffalo, NY 14211.

two high-energy photons are produced simulta-neously through an "annihilation" reaction between the positron and a nearby orbital electron, and these travel away from each other at approximately 180 degrees from the site of origin. Each such photon has more than 6 times the energy of the single thal-lium photon and almost 4 times the energy of a γ ray from 99mTc. Because of the high energy (511 keV) of annihilation photons, tissue attenuation losses (ab-sorption and scatter) are substantially less in PET than in single photon imaging. Furthermore, be-cause two photons are produced simultaneously, detectors can be placed on opposite sides of the heart and electronically "gated" so that only counts that arrive almost simultaneously are counted and dis-played in the emission image. In addition, a "trans-mission" image can be constructed in PET by using an external positron source placed in a ring around the patient, before injection of the radiotracer; thus, a map of the varied tissue densities in the thorax is produced. This absorptive image resembles a low-resolution x-ray image in appearance and can be used to correct the final emission image for attenu-ation losses. In contrast, no attenuation correction procedure is available for conventional scans pro-duced with single photon emitters (including single photon emission computed tomography [SPECT]). The physical properties of positron decay, coupled with sophisticated electronic instrumentation, allow accurate recovery of the amount of radioactivity in a given region of the heart.

UC, 150, 13N, and 18F, all positron emitters pro-duced in the cyclotron, can be incorporated into or-ganic molecules for study of myocardial metabolism. In addition to their favorable physical properties, these radionuclides have much shorter half-lives than thallium or technetium; thus, the radiation dose to the patient is generally lower than in conventional studies, and serial studies can be performed. 82Rb, a positron emitter with an ultrashort half-life (78 sec-onds), has chemical properties similar to those of thallium. As a potassium analogue, it is useful for imaging myocardial perfusion and has the impor-tant advantage of being produced in a desktop gen-erator, without the need of a cyclotron.

Uptake of any radiotracer in the myocardium de-pends on two factors: the amount of tracer presented to the tissue and the fraction of tracer that is then extracted and retained by the tissue. Potassium

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analogues such as 201T1 and 82Rb are highly extracted by myocardial cells and are retained in the intracel-lular space long enough to allow acquisition of an image. Therefore, the regional distribution of up-take in the image reflects primarily the amount delivered. Thus, myocardial segments with high perfusion have proportionately more activity than do segments with reduced perfusion. A 2:1 ratio of maximal flow in a normal to stenotic coronary artery bed must be present before defects appear in planar myocardial perfusion images obtained with thallium.1

Therefore, the sensitivity of a perfusion imaging tech-nique for the diagnosis of coronary stenosis depends in large measure on the adequacy of the stimulus for inducing high coronary flows in the normally per-fused tissue so that defects can be recognized.

By coupling the imaging advantages of PET using 82Rb (or [13N]NH3, another highly extracted tracer that is useful for perfusion imaging) with an effec-tive stimulus for inducing maximal coronary vasodi-lation such as intravenously administered dipyrida-mole, even mild coronary stenoses can be detected before they are severe enough to produce clinical symptoms or a defect on conventional exercise scinti-grams. PET images are obtained with the patient at rest 1 minute after injection of 30 to 40 mCi of 82Rb. This procedure is then repeated after intravenous infusion of dipyridamole (0.56 mg/kg) during low-level handgrip exercise (which offsets the mild hypo-tensive effect of the drug). Tomographie images ob-tained with the patient at rest and during dipyrida-mole "stress" handgrip exercise can be compared after reconstruction into short-axis, vertical and horizontal long-axis, and "bull's-eye" displays. When the results of the dipyridamole stress test were re-lated to results of quantitative coronary arteriogra-phy in 50 patients studied at the University of Texas Health Science Center at Houston, a sensitivity of 95% and specificity of 100% were reported in detect-ing hemodynamically significant coronary disease.2

With the current extension of this analysis to 193 patients, the sensitivity and specificity remain high (95 to 98%) (Gould KL: Personal communication). This high sensitivity and specificity of PET imaging for the detection of coronary artery disease have been confirmed by several other groups, which have reported sensitivities ranging from 95 to 97% and specificities at 100%.3"6 In contrast, conventional exercise SPECT imaging for the diagnosis of coro-nary disease is associated with a 90% sensitivity and 85% specificity, and both these values are reduced to 80% when planar thallium imaging is used.7

Because positron emitters (such as n C , 1 50, 13N, and 18F) can be incorporated into organic molecules, PET is unique among imaging modalities in its abil-ity to create maps of regional myocardial metabo-lism. Thus, living tissue can be distinguished from dead tissue on the basis of whether metabolic activ-ity is present or absent.

In the heart, regions of low flow can be recognized as defects on perfusion images made with [13N]NH3 or 82Rb. Uptake of the glucose analogue [18F]fluoro-deoxyglucose (FDG) into such ischemic myocardial segments has been used to detect viable myocardial tissue within regions that were thought to be ne-crotic, on the basis of the presence of Q waves on the surface electrocardiogram or severe regional wall motion abnormalities. Although the normal heart is a metabolic omnivore capable of consuming free fatty acids, glucose, lactate, amino acids, or ketone bodies as fuel, under hypoxic conditions the preferred sub-strate of the heart is glucose because it can be me-tabolized anaerobically through the glycolytic path-way.8 Although the energy produced by this process (10 to 15% of normal energy requirements in the beating heart) may be sufficient to support cellular viability, it is insufficient to accommodate myocar-dial contraction. Thus, after an ischemic coronary event, viable cardiac tissue may be present even in an area of frank dyskinesia, a phenomenon that has been referred to as "stunning" of the myocardium.9

It is of obvious paramount clinical importance to recognize the presence of viable tissue in a dyssyner-gic myocardial segment during or after myocardial infarction, inasmuch as revascularization may re-store wall motion and substantially improve overall left ventricular function. PET studies of patients who have sustained myocardial infarction often dem-onstrate preserved FDG uptake, an indication of persistent metabolic activity and presumably pre-served viability, in patients with "Q-wave infarcts" and regional dyskinesia.

Schelbert and colleagues,10 at the University of California in Los Angeles, studied the ability of meta-bolic imaging with PET to predict recovery of re-gional wall motion in 17 patients with coronary dis-ease and resting regional wall motion abnormalities who had been referred for coronary artery bypass grafting. Three patterns of [13N]NH3 and [18F]FDG uptake were observed in 73 abnormally contracting left ventricular segments: preoperative wall motion abnormalities were predicted to be reversible if FDG uptake was preserved in the presence of normal or of decreased [13N]NH3 uptake and to be irreversible if

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uptake of both FDG and NH3 was decreased. Revas-cularization was adequate in 41 of 46 regions with abnormalities predicted to be reversibly ischemic, and wall motion improved postoperatively in 85% of these. In contrast, postoperative improvement was evident in only 8% of those regional segments with abnormalities predicted by PET to be irreversibly injured. Importantly, the presence of pathologic Q waves in a region of abnormal wall motion correctly predicted irreversibility only 43% of the time.

Thus, PET imaging of myocardial perfusion and metabolism may accurately identify patients with coronary disease in whom successful revasculariza-tion is likely to lead to improvement in left ventricu-lar function.

Carbon monoxide can be labeled with UC or 150 and is then taken up by erythrocytes after inhalation or intravenous injection; this technique provides a simple way of imaging the right and left ventricular blood pools with PET. Global and regional wall motion analysis and also tomographic measurement of right and left ventricular ejection fraction are possible when acquisition of the nuclear ventriculo-gram is gated to the eletrocardiographic signal. If gated perfusion imaging with [13N]NH3 or 82Rb is also performed, complementary information about myo-cardial thickening in segments adjacent to ventricu-lographic wall motion abnormalities can be obtained, which may improve specificity in the diagnosis of coronary artery disease.

Perhaps the greatest obstacle to the widespread use of PET cardiac imaging at the community hospi-tal level is the cost. PET cameras, which are cur-rently constructed commercially by several compa-nies, range in price from $1 to $2.5 million.6 It is hoped that simplified instruments suitable for the clinical setting, as well as the economic advantages of mass production, will decrease this cost in the near future. The cyclotron and radiochemistry labo-ratory necessary for clinical radiopharmaceutical pro-duction used in the performance of metabolic and blood pool imaging also cost $1 to $2 million; hence, the shared use of PET tracers produced in a regional cyclotron is encouraged. The 82Sr-82Rb generator, which obviates the need for the cyclotron for perfu-sion imaging, costs from $15,000 to $20,000 and produces 82Rb for about a month. Annual operating costs for a PET center are estimated to be $400,000 to $1 million, the amount depending on the sophisti-cation of the facility. Experts have projected that 6 to 12 clinical studies could be performed daily, for

which technical charges would range from $600 to $1,500 per patient.

To explore further clinical applications of PET imaging, we have conducted metabolic imaging stud-ies in dogs. In usual clinical practice, during acute myocardial infarction complicated by cardiogenic shock the blood pressure is supported with a cat-echolamine infusion—most commonly, dopamine. If we are to recognize reversibly ischemic, viable, and hence potentially salvageable myocardium in patients under these clinical circumstances, with use of the uptake of radiolabeled FDG out of proportion to re-duced coronary flow as demonstrated noninvasively with PET, we must know the effect of dopamine infusion on myocardial FDG uptake. To test the hypothesis that dopamine infusion prevents myocar-dial [18F]FDG uptake, we sedated dogs and performed myocardial [18F]FDG imaging under three experi-mental conditions. After administration of a glucose load to ensure substrate availability, each animal was studied in random sequential order during infu-sion of either insulin or dopamine, or during infusion of both insulin and dopamine, while cardiac work was monitored. Myocardial FDG uptake was mea-sured from the PET images as the ratio of myocar-dial to blood pool activity. In each dog, the highest cardiac FDG uptake occurred during insulin infu-sion. In contrast, myocardial FDG uptake substan-tially decreased during dopamine infusion, declining to levels comparable to the intravascular activity in the left ventricular blood pool. When insulin was added to the dopamine infusion, myocardial FDG uptake was enhanced.11 The depression of myocar-dial FDG uptake by dopamine seems to be indepen-dent of effects on cardiac work12 and, based on pre-liminary data, may be reversible by ß blockade. Plasma substrate levels were measured during each infusion; dopamine infusion leads to increased plasma levels of both free fatty acids and glucose, but the glucose is not appreciably extracted by the myocar-dium in the absence of exogenous insulin. These data suggest that dopamine infusion induces a glu-cose-intolerant state similar to the diabetic state, in which free fatty acids, which are in abundance, com-pete successfully against glucose as the major fuel for the heart.13 Of paramount clinical importance is whether dopamine depresses myocardial glucose uptake under ischemic conditions as well.

Another laboratory study has been focused on demonstrating whether the mass of myocardium rendered reversibly ischemic during coronary occlu-

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sion can be quantitated noninvasively by using meta-bolic and flow imaging with PET. If successful, this would be the only currently available technique ca-pable of objectively measuring myocardial salvage in vivo in humans.

As a first step, we have compared the mass of ischemic myocardium measured by PET with con-comitant measurements made with radiolabeled microspheres in vitro in an open-chest canine model of acute coronary occlusion. Eight dogs underwent ligation of the left anterior descending coronary ar-tery, followed by PET imaging of perfusion with [13N]NH3. During the imaging procedure, 15-μπι radiolabeled microspheres were injected into the left atrium. The microspheres are distributed in the myocardium in proportion to flow, inasmuch as they are trapped subsequently in the microcirculation during their first pass through the myocardium. The heart was removed, and the fraction of myocardial tissue with flows less than 50% of control values was measured from the microsphere analysis. Because investigators have shown that a 50% reduction in flow is accompanied by a 50% reduction in fractional shortening of the myocardial fibers,14 such tissue is clearly ischemic. The fraction of myocardium with flow less than 50% of control was then determined directly from the PET images. In terms of the frac-tion of left ventricular myocardium at ischemic risk, the PET measurements demonstrated a close linear correlation with the microsphere analysis (r = 0.94).15

With the potential for PET perfusion imaging to measure the ischemic zone at risk in vivo, the amount of myocardium within this zone that is still viable can be determined through metabolic imaging. PET imaging will then be useful for objectively measur-ing myocardial salvage in patients with acute myo-cardial infarction treated with various pharmaco-logic or invasive modalities.

PET represents a natural but "giant" step in the evolution of nuclear cardiac imaging toward a new quantitative capability that allows measurement of coronary flow, metabolic substrate flux, ventricular function, and cellular viability—all noninvasively— with minimal radiation exposure to the patient.

Michael E. Merhige, M.D. Dahlia Garza, M.D. Section of Nuclear Cardiology Positron Diagnostic and Research Center University of Texas Health Science Center Houston, Texas

REFERENCES 1. Gould KL: Noninvasive assessment of coronary stenoses by

myocardial perfusion imaging during pharmacologic coro-nary vasodilatation. I. Physiologic basis and experimental validation. Am J Cardiol 41:267-278, 1978

2. Gould KL, Goldstein RA, Mullani NA, Kirkeeide RL, Wong W-H, Tewson TJ, Berridge MS, Bolomey LA, Hartz RK, Smalling RW, Fuentes F, Nishikawa A: Noninvasive as-sessment of coronary stenoses by myocardial perfusion imaging during pharmacologic coronary vasodilation. VIII. Clinical feasibility of positron cardiac imaging without a cyclotron using generator-produced rubidium-82. J Am Coll Cardiol 7:775-789, 1986

3. Schelbert HR, Wisenberg G, Phelps ME, Gould KL, Henze E, Hoffman EJ, Gomes A, Kuhl DE: Noninvasive assess-ment of coronary stenoses by myocardial imaging during pharmacologic coronary vasodilation. VI. Detection of coronary artery disease in human beings with intravenous N-13 ammonia and positron computed tomography. Am J Cardiol 49:1197-1207, 1982

4. Tamaki N, Yonekura Y, Senda M, Kureshi SA, Saji H, Kodama S, Konishi Y, Ban T, Kambara H, Kawai C, Torizuka K: Myocardial positron computed tomography with 13N-ammonia at rest and during exercise. Eur J Nucl Med 11:246-251, 1985

5. Yonekura Y, Tamaki N, Senda M, Nohara R, Kambara H, Konishi Y, Koide H, Kureshi SA, Saji H, Ban T, Kawai C, Torizuka K: Detection of coronary artery disease with 13N-ammonia and high-resolution positron-emission computed tomography. Am Heart J 113:645-654,1987

6. ACNP/SNM Task Force on Clinical PET: Positron emission tomography: clinical s tatus in the United States in 1987. J Nucl Med 29:1136-1143, 1988

7. Gill JB, Ritchie JL: Single photon emission computerized tomography. In Clinical Cardiac Imaging. Edited by DD Miller. New York, McGraw-Hill Book Company, 1988, pp 53-66

8. Taegtmeyer H: Cardiovascular imaging: the biochemical basis. Hosp Prac [Off] 19:137-141; 147-155, June 1984

9. Braunwald E, Kloner RA: The stunned myocardium: pro-longed, postischemic ventricular dysfunction. Circulation 66:1146-1149, 1982

10. Tillisch J , Brunken R, Marshall R, Schwaiger M, Mandel-kern M, Phelps M, Schelbert H: Reversibility of cardiac wall-motion abnormalities predicted by positron tomogra-phy. N Engl J Med 314:884-888, 1986

11. Merhige ME, Ekas R, Mossberg K, Taegtmeyer H, Gould KL: Catecholamine stimulation, substrate competition, and myocardial glucose uptake in conscious dogs assessed with positron emission tomography. Circ Res 61 (Suppl): II124-II129, 1987

12. Merhige ME, Garza D, Mossberg KA, Taegtmeyer H, Gould KL: Catechol suppression of myocardial glucose uptake In Vivo: a metabolic effect independent of cardiac work (ab-stract). Circulation 76 (Suppl):IV-116, 1987

13. Merhige ME, Garza D, Sease D, Marani S, Taegtmeyer H, Gould KL: Catecholamine suppression of myocardial glu-cose uptake in vivo: a metabolic effect mediated by sub-strate availability. J Am Coll Cardiol 11 (Suppl):llA, 1988

14. Vatner SF: Correlation between acute reductions in myo-cardial blood flow and function in conscious dogs. Circ Res 47:201-207, 1980

15. Merhige ME, Garza D, Sease D, Rowe RW, McLean M, Gould K: Quantitation of critically ischemic myocardial mass during acute coronary occlusion in vivo by positron emission tomography (abstract). J Nucl Med 30(Suppl):866, 1989