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

1989; Elsevier BV; Volume: 64; Issue: 6 Linguagem: Inglês

10.1016/s0025-6196(12)65354-3

1942-5546

Michael E. Merhige, Dahlia Garza,

Cardiovascular Function and Risk Factors

Positron emission tomography (PET) offers the unique opportunity to view myocardial perfusion, metabolism, and function in vivo. The imaging technology is necessarily complex and multidisciplinary; 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 produced 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 tissue (“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 attenuation is exploited to produce an absorptive image, in nuclear medicine the tissue attenuation leads to a loss of information and degradation of the emission 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 limitations 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, two high-energy photons are produced simultaneously 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 thallium 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 (absorption and scatter) are substantially less in PET than in single photon imaging. Furthermore, because 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 displayed in the emission image. In addition, a “transmission” 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 attenuation losses. In contrast, no attenuation correction procedure is available for conventional scans produced 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. 11C, 15O, 13N, and 18F, all positron emitters produced in the cyclotron, can be incorporated into organic 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 seconds), has chemical properties similar to those of thallium. As a potassium analogue, it is useful for imaging myocardial perfusion and has the important advantage of being produced in a desktop generator, without the need of a cyclotron. Uptake of any radiotracer in the myocardium depends 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 analogues such as 201T1 and 82Rb are highly extracted by myocardial cells and are retained in the intracellular space long enough to allow acquisition of an image. Therefore, the regional distribution of uptake 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.1Gould KL Noninvasive assessment of coronary stenoses by myocardial perfusion imaging during pharmacologic coronary vasodilatation. I. Physiologic basis and experimental validation.Am J Cardiol. 1978; 41: 267-278Abstract Full Text PDF PubMed Scopus (365) Google Scholar Therefore, the sensitivity of a perfusion imaging technique for the diagnosis of coronary stenosis depends in large measure on the adequacy of the stimulus for inducing high coronary flows in the normally perfused 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 effective stimulus for inducing maximal coronary vasodilation such as intravenously administered dipyridamole, even mild coronary stenoses can be detected before they are severe enough to produce clinical symptoms or a defect on conventional exercise scintigrams. 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 hypotensive effect of the drug). Tomographic images obtained with the patient at rest and during dipyridamole “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 related to results of quantitative coronary arteriography 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 detecting hemodynamically significant coronary disease.2Gould 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 assessment 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. 1986; 7: 775-789Abstract Full Text PDF PubMed Scopus (208) Google Scholar 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%.3Schelbert HR Wisenberg G Phelps ME Gould KL Henze E Hoffman EJ Gomes A Kuhl DE Noninvasive assessment 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. 1982; 49: 1197-1207Abstract Full Text PDF PubMed Scopus (170) Google Scholar, 4Tamaki 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. 1985; 11: 246-251Crossref PubMed Scopus (53) Google Scholar, 5Yonekura 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. 1987; 113: 645-654Abstract Full Text PDF PubMed Scopus (68) Google Scholar, 6ACNP/SNM Task Force on Clinical PET Positron emission tomography: clinical status in the United States in 1987.J Nucl Med. 1988; 29: 1136-1143PubMed Google Scholar In contrast, conventional exercise SPECT imaging for the diagnosis of coronary disease is associated with a 90% sensitivity and 85% specificity, and both these values are reduced to 80% when planar thallium imaging is used.7Gill JB Ritchie JL Single photon emission computerized tomography.in: Miller DD Clinical Cardiac Imaging. McGraw-Hill Book Company, New York1988: 53-66Google Scholar Because positron emitters (such as 11C, 15O, 13N, and 18F) can be incorporated into organic molecules, PET is unique among imaging modalities in its ability to create maps of regional myocardial metabolism. Thus, living tissue can be distinguished from dead tissue on the basis of whether metabolic activity 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]fluorodeoxyglucose (FDG) into such ischemic myocardial segments has been used to detect viable myocardial tissue within regions that were thought to be necrotic, 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 substrate of the heart is glucose because it can be metabolized anaerobically through the glycolytic pathway.8Taegtmeyer H Cardiovascular imaging: the biochemical basis.Hosp Prac [Off]. June 1984; 19 (147–155): 137-141PubMed Google Scholar 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 myocardial 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.9Braunwald E Kloner RA The stunned myocardium: prolonged, postischemic ventricular dysfunction.Circulation. 1982; 66: 1146-1149Crossref PubMed Scopus (2391) Google Scholar It is of obvious paramount clinical importance to recognize the presence of viable tissue in a dyssynergic myocardial segment during or after myocardial infarction, inasmuch as revascularization may restore wall motion and substantially improve overall left ventricular function. PET studies of patients who have sustained myocardial infarction often demonstrate preserved FDG uptake, an indication of persistent metabolic activity and presumably preserved viability, in patients with “Q-wave infarcts” and regional dyskinesia. Schelbert and colleagues,10Tillisch J Brunken R Marshall R Schwaiger M Mandelkern M Phelps M Schelbert H Reversibility of cardiac wall-motion abnormalities predicted by positron tomography.N Engl J Med. 1986; 314: 884-888Crossref PubMed Scopus (1117) Google Scholar at the University of California in Los Angeles, studied the ability of metabolic imaging with PET to predict recovery of regional wall motion in 17 patients with coronary disease 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 uptake of both FDG and NH3 was decreased. Revascularization 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 revascularization is likely to lead to improvement in left ventricular function. Carbon monoxide can be labeled with 11C or 15O 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 ventriculogram is gated to the eletrocardiographic signal. If gated perfusion imaging with [13N]NH3 or 82Rb is also performed, complementary information about myocardial thickening in segments adjacent to ventriculographic 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 hospital level is the cost. PET cameras, which are currently constructed commercially by several companies, range in price from $1 to $2.5 million.6ACNP/SNM Task Force on Clinical PET Positron emission tomography: clinical status in the United States in 1987.J Nucl Med. 1988; 29: 1136-1143PubMed Google Scholar 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 laboratory necessary for clinical radiopharmaceutical production 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 perfusion 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 sophistication 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 studies in dogs. In usual clinical practice, during acute myocardial infarction complicated by cardiogenic shock the blood pressure is supported with a catecholamine 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 reduced 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 myocardial [18F]FDG uptake, we sedated dogs and performed myocardial [18F]FDG imaging under three experimental conditions. After administration of a glucose load to ensure substrate availability, each animal was studied in random sequential order during infusion of either insulin or dopamine, or during infusion of both insulin and dopamine, while cardiac work was monitored. Myocardial FDG uptake was measured from the PET images as the ratio of myocardial to blood pool activity. In each dog, the highest cardiac FDG uptake occurred during insulin infusion. In contrast, myocardial FDG uptake substantially 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.11Merhige 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. 1987; 1: II124-II129Google Scholar The depression of myocardial FDG uptake by dopamine seems to be independent of effects on cardiac work12Merhige ME Garza D Mossberg KA Taegtmeyer H Gould KL Catechol suppression of myocardial glucose uptake In Vivo: a metabolic effect independent of cardiac work (abstract).Circulation. 1987; 76: IV-116Google Scholar and, based on preliminary data, may be reversible by β 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 myocardium in the absence of exogenous insulin. These data suggest that dopamine infusion induces a glucose-intolerant state similar to the diabetic state, in which free fatty acids, which are in abundance, compete successfully against glucose as the major fuel for the heart.13Merhige ME Garza D Sease D Marani S Taegtmeyer H Gould KL Catecholamine suppression of myocardial glucose uptake in vivo: a metabolic effect mediated by substrate availability.J Am Coll Cardiol. 1988; 1: 11AGoogle Scholar 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 occlusion can be quantitated noninvasively by using metabolic and flow imaging with PET. If successful, this would be the only currently available technique capable 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 concomitant 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 artery, followed by PET imaging of perfusion with [13N]NH3. During the imaging procedure, 15-μm 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,14Vatner SF Correlation between acute reductions in myocardial blood flow and function in conscious dogs.Circ Res. 1980; 47: 201-207Crossref PubMed Scopus (280) Google Scholar 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 fraction of left ventricular myocardium at ischemic risk, the PET measurements demonstrated a close linear correlation with the microsphere analysis (r = 0.94).15Merhige 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. 1989; 30: 866Google Scholar 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 measuring myocardial salvage in patients with acute myocardial infarction treated with various pharmacologic 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.