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A plea for early, open mitral commissurotomy
Fundamentals Radionuclides infarction
of clinical in the assessment
cardiology of myocardial
Milton S. Klein, M.D. Robert Roberts, M.D. R. Edward Coleman, M.D.* St. Louis, MO.
Radionuclides in Cardiology have been used mainly for detection of myocardial infarction’ and assessment of left ventricular function.2 The need for improved detection of myocardial infarction is related to the lack of sensitivity and specificity of the ECG or plasma enzymes in certain clinical conditions.“, a Diagnosis of infarction after cardiac surgery is particularly troublesome since even creatine phosphokinase isoenzymes, specific for myocardial damage, are consistently elevated as a result of the iatrogenic injury., The recent interest in protection of ischemic myocardium6 requires measurement of infarct size and several studies suggest that quantification of infarct images may be possible,‘, 8 which has intensified the search for more appropriate radionuclidesg Four categories of radionuclides have been utilized to identify zones of &hernia or infarction as areas of decreased activity or “cold spots”: (1) Potassium analogs (*3K, tzsC~, “‘Rb, and more recently 201T1)10-1*;(2) metabolic substrates (labeled free fatty acids, 13NH,15; (3) inert gases (s5Kr, *%e)l6,1’; and (4) labeled microspheres or radionuclides macroaggregates.18, I9 However, which accumulate in areas of infarction (“hot From the Cardiovascular Division, Wa&ington Univezsity School of Medicine, St. Louis, MO., and the Department of Radiology, The ikinckrodt Institute of Radiology, Washington University School of Medicine. This study was supported in part by SCOR in Ischemic Heart Disease Grant P17 HL-17646 from the National Heart and Lung Institute, National Institutes of Health. Received for publication March 29, 1977. Reprint requests: Robert Roberts, M.D., Director, Cardiac Care Unit, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO. 63110. *Department of Radiology, Univemity of Utah Medical Center, Salt Lake City, Utah.
0002-8703/78/0595-0859$00.90/O
o 1978 The
C. V. Mosby
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sp~t..s”),~~ offer some advantages over those which localize in normal tissue (“cold spots”). To date, radiopharmaceuticals which produce “cold spots” cannot distinguish acute myocardial infarction from scar tissue, old infarction, or ischemia.“-‘* Accordingly, this review will deal primarily with those agents which are taken up in the area of infarction. Historically, the first studies to delineate myocardial infarction by a radionuclide accumulating in necrotic tissue utilized mercurial compounds.1o Poor resolution and radiation risks precluded their extensive use clinically.21 Subsequently, the serendipitous discovery that bone seeking radionuclides accumulate m myocardial infarcts initiated the widespread use of technetium-labeled compounds for infarct imaging.22 The basis of a positive image is dependent on several factors: (1) the ratio of radioactivity in infarcted compared to normal myocardium which should generally be at least 4:l; (2) the ratio of radioactivity in myocardium to that of surrounding structures (ribs, liver, etc.); (3) the size of the infarct; and (4) the distribution and density of cell death (although the same number of myocardial cells may be necrotic in subendocardial as in transmural infarctions, the latter is more easily visualized scintigraphically because of the localization of counts in one area). Mercurial
compounds
Mercurochrome has long been known to stain necrotic tissue and fluoresce under ultraviolet light.zs Much of the early work in myocardial infarct imaging was performed using compounds labeled with radioactive mercury because of their stability and accumulation in necrotic tissue.‘O The first attempts to demonstrate radionuchde
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Klein, Roberts, and Coleman accumulation in experimental myocardial infarcts in vivo were performed in 1962 using 203Hgchlormerodrin.10 Fifteen of 16 dogs with coronary occlusions were shown to have abnormal scintigrams with a preponderance of counts in ischemic and necrotic myocardium compared with normal myocardium by direct counting of histologic specimens. Imaging of myocardial infarcts in vitro in pigs also demonstrated accumulation of 20”Hgchlormerodrin as early as 12 to 24 hours after infarction, but with optimal results at three to five days after infarction. Images were normal by 9 to 12 days. 24 Of even greater interest was the finding that coronary reperfusion was not necessary for accumulation of mercurial compounds in infarcts.25 Studies in patients, however, have been disappointing.26 Only three of 13 patients with myocardial infarctions were successfully imaged with 203Hg-chlormerodrin four to eight days postinfarction. In dogs it was necessary to administer 700 @i but the 47 day half-life of zo3Hg and high radiation exposure to the liver and kidney precluded the use of high doses in humans. Thus, the amount of activity accumulated in the myocardial infarcts was suboptimal for image production. Other mercurial compounds, however, have been shown to accumulate more avidly in myocardial infarcts.*1 For example, *03Hghydroxy mercury-45 dibromofluorescein has a ratio of activity in infarcts compared to normal myocardium of 1OO:l while Z03Hg-chlormerodrin has a ratio of only 6:l. Although other radiopharmaceuticals have more recently taken the place of mercurial compounds in clinical use, these radionuclides were instrumental in establishing that: (1) tracers do accumulate in myocardial infarcts, (2) they can be detected externally, and (3) accumulation occurs despite total occlusion of a coronary artery. lodinated
compounds
Some early studies reported the accumulation of 13*1 in myocardial infarcts.Z8 One study of 23 patients with acute myocardial infarction reported a 20 per cent greater number of counts localized over the left side of the chest when compared to the right side after oral administration of 50 to 200 /&i of NaX31. Seven days after infarction, however, postmortem data revealed a ratio of radioactivity in infarcts compared to normal myocardium of only l.7:l.28 Subsequent studies demonstrated that the left precordial
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activity probably represented Ia11 concentration in gastric secretions persisting in the stomach due to delayed gastric emptying seen in patients with recent myocardial infarctions.29 Gallium
citrate
After it was recognized that mercurial radionuelides would not be beneficial in the clinical setting of infarct imaging, investigators turned to agents such as gallium citrate. “‘Gallium citrate is a radiopharmaceutical which accumulates in areas of inflammation and in certain tumors.“o Since this radiopharmaceutical accumulates in white blood cells which are known to migrate to the periphery of acute infarctions, it seemed likely that “‘Gallium citrate would accumulate in regions of myocardial necrosis. When 3 to 4 mCi of “‘Gallium citrate were administered intravenously two days after transient occlusion of the left anterior descending coronary artery, accumulation of the radionuclide was noted in dogs with infarction (prolonged occlusion), but not with transient &hernia (less than 20 minute occlusions). Furthermore, in vivo and in vitro studies demonstrated a good correlation between the intensity of “‘Gallium uptake and the number of leukocytes seen histologically in the infarct zone as well as with the extent of myocardial CPK depletion.“’ However, g7Gallium myocardial imaging has not been shown to be useful clinically. Since the ratio of radioactivity in infarcts compared to normal myocardium is relatively small compared to other radionuclides, one would expect rather poor sensitivity.32 In one study, only five of eight patients with myocardial infarction demonstrated an abnormal image. It should be emphasized that “‘Gallium detects areas of inflammation, and is, therefore, not specific for infarction. Hence, other disorders such as pericarditis might also be associated with an abnormal image. Accumulation of gallium by the liver makes recognition of diaphragmatic infarctions difficult. In addition, images do not become abnormal for several days, precluding early detection of infarction. Furthermore, since images remain abnormal for at least three weeks, serial imaging is impossible.“’ lndium
labeled
leukocytes
Further attempts to take advantage of the migration of leukocytes into infarcts for the purposes of myocardial imaging employed the
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labeling of leukocytes with “‘In-Shydroxyquinoline.33 This was accomplished without alterations in white blood cell viability or function. When labeled leukocytes are administered to animals with experimental infarction, images of the infarct can be obtained in dogs 24 hours after coronary occlusion. Forty-eight hours after infarction an increased number of counts were detected in the infarct zone compared to the normal myocardium. Ratios of radioactivity of infarct compared to normal myocardium were 23:l. Tetracycline
Since the mercurial compounds produce infarct images with poor resolution, and since radiopharmaceuticals which accumulate in infarcts as a result of inflammation lack specificity, investigators initiated studies with technetium-labeled tetracycline designed to improve sensitivity and specificity. Like the mercurial compounds, tetracycline fluoresces and accumulates in myocardial tissue undergoing necrosis3’ Immediately after intravenous administration, tetracycline produces a yellow fluorescence in normal heart muscle, but not in necrotic tissue. However, within the next three hours, the intensity of fluorescence increases around the infarct border and is absent from normal tissue. The mechanism of accumulation of 99mTc(Sn) tetracycline is thought to be related to binding of the tracer to protein in nucleic acids in necrotic myocardial cells. Its accumulation appears to be influenced by free calcium accumulation in necrotic myocardium-a mechanism postulated for other radiopharmaceuticals as well.“” After three to four days, fluorescence is seen only in the margin of the infarct, and by seven days clumps of tracer are noted throughout the infarct. With administration of 10 to 15 mCi of 99mTc(Sn) tetracycline intravenously 4 to 24 hours after acute myocardial infarction, accumulation is primarily in the liver, kidneys, and gall bladder. Four hours after infarction only one of four dogs had a scintigraphically demonstrable infarct. By 24 hours, however, ratios of radioactivity in infarcts compared to normal myocardium ranged from 5.9 to 8.4:l. Hemorrhagic infarcts were more readily demonstrable by labeled tetracycline.35 Early studies in patients7 demonstrated that each of 14 patients with acute myocardial infarction had positive 99mTc(Sn) tetracycline images if
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in assessing MI
injected 24 hours after infarction and imaged 24 hours after injection. All nine patients without acute infarction had negative images, including several patients with old infarction. Localization of infarction determined scintigraphically was concordant with electrocardiographic localization. Also, the correlation of infarct size (measured by peak total CPK) with images categorized as having large, moderate, or small infarcts scintigraphically was good (r = 0.84). The sensitivity and specificity of 99mTc(Sn) tetracycline myocardial imaging is less impressive in other studies.36 Only 12 of 25 true positive, and six of 11 true negative images were reported in one study.36 Other difficulties precluding the widespread clinical utility of 99mTc(Sn) tetracycline myocardial imaging include the following: (1) the 24 hour delay from infarct to image precludes early infarct diagnosis; (2) uptake of the tracer by the liver makes the accurate diagnosis of diaphragmatic infarction difficult; (3) relatively small ratios of activity in infarcts compared to normal myocardium account for poor delineation of the infarct zone. Hence, 99mTc(Sn) tetracycline has not become a frequently used method of infarct imaging. *smTechnetium
glucoheptonate
A major difficulty with most imaging agents in diagnosing acute myocardial infarction has been the delay in the production of an abnormal image. Circumventing this problem by finding a radionuelide designed to permit early imaging would be of great importance. One agent that appears to offer promise in detecting infarction sooner is g9”Tc-glucoheptonate. When this radionuclide was administered to nine dogs four hours after coronary occlusion, the ratio of activity in infarcts compared to normal myocardium was 2O:l. Concentration of the radionuclide in infarcts was somewhat dependent on blood flow since the greatest number of counts occurred when perfusion was 20 to 40 per cent of normal. Early imaging was not significantly encumbered by overlay of radioactivity in skeletal structures or cardiac blood pool, and ratios of radioactivity in infarcts compared to normal tissue were better than those seen with 9gmTc(Sn) tetracycline, but similar to those observed with 99mTc(Sn) pyrophosphate.32, 37 In one study of 27 patients with chest pain, 99mTc-glucoheptonate was administered two to 48
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hours after chest pain, and 12 of 15 patients with acute infarction exhibited abnormal images. Several false positive images were reported. Scintigraphically estimated infarct size correlated well with peak total CPK (r = 0.77).3* In another study, ggmTc-glucoheptonate detected only three of 13 true positives and two of two true negatives.36 Thus, despite some encouraging experimental results, drawbacks of poor resolution, and poor sensitivity make g9mTc-glucoheptonate infarct imaging less beneficial than other tracers presently in use. Bone-seeking
radionuclides
Introduction. Bone-seeking tracers were noted to accumulate in zones of acute myocardial infarction during routine bone scans.2o Subsequently, phosphate compounds labeled with technetium were found to be excellent indicators of acute myocardial necrosis, and are presently used extensively in many Coronary Care Units. 99mTc(Sn) pyrophosphate. Some of the earliest studies utilizing bone-seeking radionuclides were performed in dogs with experimental infarction given g9mTc(Sn) pyrophosphate.‘* This tracer is a commonly used bone-scanning agent. Technetium-99m with its 140 keV gamma rays and its short half-life is well suited for nuclear medicine instrumentation. The mechanism of accumulation of YYmTc(Sn) pyrophosphate in acute infarction has not been unequivocally established. Electron dense deposits of calcium hydroxyapatite like crystals have been demonstrated in mitochondria of cardiac tissue which has undergone necrosis.33 Administration of labeled calcium chloride showed deposition of the calcium in mitochondria within the infarct if coronary occlusion was prolonged and followed by a period of reperfusion.40 Thus, accumulation of these crystals appears to be specific for infarction, and is dependent on perfusion as well as necrosis. The presence of calcium hydroxyapatite deposits in mitochondria from myocardial infarct zones similar to those found in bone suggests a possible mode by which boneseeking radionuclides accumulate in (and thus, identify) regions of acute infarction. A donut-like rim of increased radioactivity is seen frequently in experimental acute transmural infarctions and appears to correlate well with localization of calcium hydroxyapatite deposits in greatest concentrations.41 Of 19 dogs with acute coronary
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occlusion, all exhibited abnormal images at 24 to 48 hours after infarction. A progressive decline in radioactivity was noted when injections were performed from two to 13 days after infarction. Similarly, diminution in the calcium concentration in mitochondria from areas of infarction corresponded to the decreasing accumulation of s9mTc(Sn) pyrophosphate as a function of time after infarction. Within two weeks after infarction, the major proportion of calcium deposits were replaced by granulation tissue. This finding suggests a relationship between the binding of gsmTc( Sn) pyrophosphate and deposition of calcium deposits in mitochondria; however, it is probably not the sole mechanism by which 9smTc(Sn) pyrophosphate accumulates in myocardial infarcts, since the per cent of injected dose of 9smTc(Sn) pyrophosphate and 3*P-labeled pyrophosphate was only ten to twentyfold greater in the mitochondria from infarct zones compared to normal areas. However, a two hundred to six hundredfold increase in counts from homogenates of whole myocardial infarcts compared to homogenates of mitochondria from the infarct suggested that substantial deposition of the radionuclide occurs in subcellular loci other than mitochondria.4Z Since the pattern of accumulation of the tracer in transmural infarction corresponds to the location of densest migration of leukocytes to the periphery of the infarct, an alternative mechanism might be that phagocytosis of the radionuelide is responsible for the production of an abnormal image. However, administration of cyclophosphamide to dogs with acute infarction did not preclude the production of positive images despite marked leukopenia. Thus, phagocytosis of YYmTc(Sn) pyrophosphate is an unlikely mechanism of accumulation.“2 The specificity of gYmTc(Sn) pyrophosphate for the detection of acute infarction has been studied by transient occlusion of the left coronary artery in dogs. In this model, ischemia in the absence of infarction was not associated with a positive image.” In patients, injection of g”mTc(Sn) pyrophosphate as early as 12 to 16 hours after infarction was associated with a positive image. Optimal images are obtained one to three days postinfarction, but remain positive consistently for seven days, and are usually normal after two weeks. In one study of 23 patients, the sensitivity
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and specificity of 9gmTc(Sn) pyrophosphate in detecting acute myocardial infarction were excellent unless images were obtained more than seven days after infarction.2o Localization of infarction by imaging compared with electrocardiograms was very good.‘“, 43 One large study of 101 patients with myocardial infarction demonstrated 96 abnormal images. The five patients with “false negative images” were all scanned more than seven days after infarction. Ninety-two of 101 patients without infarction had negative images. Of the remaining nine positive images, seven patients were thought to have unstable angina .44A second study of 165 patients showed that 85 per cent with infarction based on electrocardiograms and elevated plasma MB CPK activity had positive images. There was a 7 per cent false positive rate, some of whom represented patients arriving in the Coronary Care Unit several days after infarction at a time when cardiac enzymes had returned to baseline but when images were still abnormal.” In other studies, 49mTc(Sn) pyrophosphate detected 17 of 17 true positives and seven of 10 true negatives. This tracer appears to display the greatest sensitivity and specificity, and the highest quality images when compared to other technetiumlabeled compounds.“G gYmTc(Sn) pyrophosphate images are also capable of detecting acute subendocardial infarction. Each of 17 patients with subendocardial infarction diagnosed by conventional diagnostic criteria had abnormal images which were either localized or faint, diffuse abnormalities. This latter type of abnormality has been noted to be characteristic of non-transmural infarctions.‘” Despite experimental data showing that transient coronary occlusions do not produce abnormal images,42 and that the location of accumulation of 99mTc(Sn) pyrophosphate corresponds to the location of greatest calcium deposition (known to occur only in necrotic myocardium),al the specificity of this radionuclide for detection of infarction remains controversial. Patients with unstable angina in the absence of injury appear to exhibit abnormal images.” Evidence suggesting that ischemia per se is not associated with abnormal images is mounting. Fetal mouse hearts which were reversibly damaged by perfusion with solutions containing no glucose or oxygen for 24 hours at 37” C exhibited very little YYmTc(Sn) pyrophosphate accumulation. In contrast, irre-
American
Heart
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MI
versible damage with hypoxia and hypoglycemia at 42” C was associated with 152 per cent greater activity at 24 hours compared with that noted after one hour.*” Furthermore, patients undergoing maximal exercise stress tests do not exhibit abnormal 99mTc(Sn) pyrophosphate images.” Thus, these images appear to be specific for infarction in this setting. In studies in our own laboratory (unpublished data) in patients with unstable angina in whom infarction is excluded by normal plasma MB CPK, abnormal images were generally not seen even if the tracer was injected at the time of chest ,pain or 24 hours later. These data suggest that many of the patients with positive images and a history of unstable angina actually have subendocardial infarctions. Numerous causes of false positive “VmTc(Sn) pyrophosphate images have been reported including left ventricular aneurysms,‘* ventriculotomy scars from sump drains,‘Y and calcified heart valves.50 Whether or not images are abnormal in the presence of calcified valves may be related to the rate of calcium turnover, degree of calcium deposition, or blood supply to paravalvular tissue. Closed chest massage,51 and direct countershock in animals? and in patient@ have been shown to be associated with abnormal images. This may be related to cardiac trauma or deposition of the radionuclide in necrotic chest wall muscles. As previously mentioned, diffusely positive ggmTc(Sn) pyrophosphate images have been reported primarily in patients with unstable angina’” or subendocardial infarction..‘5 However, the specificity of the diffusely positive image has been questioned. In preliminary studies diffusely abnormal images were observed in some normal subjects.5’ Subsequent data from normal subjects given YYmTc(Sn) pyrophosphate intravenously revealed that a delay in clearance of the tracer from the cardiac blood pool in some patients was responsible for production of a diffusely positive image. These findings emphasize the need for delayed images (two hours) after injection of the tracer before a diffuse image is considered abnormal.” Diagnosis of acute myocardial infarction at the time of cardiac surgery is frequently difficult. The conventional indices of infarction (history, cardiac enzymes, and electrocardiograms) may lack the usual specificity in the setting of recent surgery.js, j6 In a study of 50 patients undergoing
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coronary artery bypass surgery,5 there was a 16 per cent incidence of perioperative myocardial infarction judged by development of new Qwaves, and associated in each case with an abnormal 9gmTc(Sn) pyrophosphate image. This group included some patients with pre-surgical or perioperative bundle branch block, and underscored the fact that not all new bundle branch blocks should be interpreted as resulting from a fresh infarction. All patients with or without infarction exhibited elevated MB CPK activity. Thus, plasma enzyme elevations could not be used to detect infarction and ischemic injury in patients with operative trauma to the heart. Since the electrocardiogram in this setting may also occasionally be equivocal, infarct imaging may be particularly useful as a specific index for the diagnosis of infarction. Potential clinical uses for YYmTc(Sn) pyrophosphate myocardial imaging include the diagnosis of: (1) subendocardial infarction, (2) infarction in the presence of ventricular conduction disturbances, (3) recent infarction at a time when cardiac enzymes have returned to baseline, and (4) perioperative infarction (especially after coronary artery bypass surgery). Quantification of myocardial infarct size with radionuclides is being actively pursued experimentally and clinically but results at present are inconclusive. Good correlations have been obtained when anterior wall infarcts in dogs were imaged with a gamma camera grid and computer interface 48 hours after infarction and images were compared with gross infarct weight at postwere mortem (r = 0.87). The best correlations obtained with the left anterior oblique view grid uiuo and infarct weight computations in infarct image area and (r = 0.92).8 Planimetering correlating results with peak total CPKjf in or infarct weight estimated from patients, morphology in dogs (r = 0.914) has been quite successfu1.58Myocardial CPK depletion in experimental infarction also correlates with tissue 9YmTc(Sn) pyrophosphate activity (r = 0.89)” Studies of patients have been less impressive, however;58 use of 99mTc(Sn) pyrophosphate images in patients to categorize infarcts into large, medium, or small groups, failed to provide good correlations with peak total CPK or enzymatically estimated infarct size.43 Of 27 patients with myocardial infarction, 99mTc(Sn) pyrophosphate image areas correlated poorly with maxi-
664
ma1 precordial ST segment elevation (r = 0.39), or with the sum ST segment elevation (r = 0.47). In general, infarct size is difficult to quantify in locations other than anterior. Since the ratio of 99mTc(Sn) pyrophosphate activity in infarcts compared to normal myocardium was related to both the extent of necrosis and the degree of perfusion (as judged by injections of labeled microspheres in dogs with infarcts), merely measuring the number of counts in an area of infarct may not reflect infarct size alone.5!’ Hence, the markedly decreased flow to the necrotic center of an infarct is associated with only modest sequestration of 99mTc(Sn) pyrophosphate. Also, problems related to overlap of bone, resolution, and sizing of three dimensional stuctures with a two dimensional system, all make infarct sizing less than optimal. Other
bone-scanning
radiopharmaceuticals
9YmTc(Sn) polyphosphate has similar physicochemical properties to those of 99mTc(Sn) pyrophosphate.60 g9mTc-polyphosphate has been shown to accurately detect both transmural and subendocardial infarction in patients three to 20 days after infarction.“’ As with s9mTc(Sn) pyrophosphate, correlations of scintigraphic localization of infarction with electrocardiographic localization is quite good. Understanding some of the physico-chemical properties of the tracer affords some insight into potential causes of false positive or false negative results. Molecular weights of “““Tc-polyphosphate between 4,900 and 6,090 daltons are optimal for imaging.60 Weights greater than 8,000 confer colloidal properties associated with localization of the tracer in the reticuloendothelial system. Weights less than 3,000 promote rapid renal clearance and little bone deposition. Since Y9mTc(Sn) polyphosphate (like other technetium compounds) are made by reduction of 99mTc-pertechnetate to 4emTc by SnCl, 2 H,O, ideal ratios of polyphosphate to tin have been established. Ratios of 25:l are optimal since leas tin produces inefficient labeling and excess tin confers colloidal properties. Also, the solid state of tin promotes greater complex stability since polyphosphate degrades at pH > 1.0.60 A comparison of s”“Tc-polyphosphate with 9QmTc(Sn) pyrophosphate in dogs with infarcts demonstrated ratios of radioactivity in infarcts compared to normal myocardium that were similar.6” ‘*Fluorine, another bone-scanning agent, l
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1978, Vol. 95, No. 5
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has nearly a thirtyfold greater ratio of activity in bone compared to infarct when compared to that observed with 9QmTc-polyphosphate. Thus, ‘*Fluerine is not likely to be a useful tracer because of problems of resolution related to its avidity for bone.62 Kinetic studiese3 of 99mTc-polyphosphate and ‘“Fluorine demonstrate that both radionuelides are cleared from the blood pool in a biexponential manner. The frrst portion of the curve is thought to be due to rapid uptake by bone, and the second portion is due to renal clearance. 18Fluorine clears faster from both portions of the curve since ssmTc compounds bind to red blood cells and plasma a-2 globulins (80 per cent of plasma radioactivity with 9QmTc is protein bound compared to 15 per cent with ‘*Fluorine. Finally, a comparison of the resolution and sensitivity of the images showed Q9mTc-polyphosphate to be a superior radionuclide.“” Considerations
2.
3.
4.
5.
6. 7.
8.
for the future
Each of the radiopharmaceuticals mentioned have drawbacks. The ideal infarct imaging tracer would have the following properties: 1. High sensitivity and specificity for the diagnosis of acute infarction; 2. Short half-life permitting serial imaging; 3. High infarct compared to normal tissue ratios of activity, with little background activity; 4. Early clearance from the blood pool; 5. Early detection of acute infarction; 6. Accurate estimation of infarct size; 7. Non-invasive administration (not requiring coronary injections); 8. Safety; of the tracer; 9. Easy production 10. Low cost. At present, radiopharmaceuticals are being utilized primarily for the detection, sizing, and localization of acute myocardial infarction. Perhaps a more detailed understanding of their mechanisms of accumulation will permit in-depth study of the pathophysiology of the disease states and mechanisms of action of pharmacologic agents. The authors wish to thank Mr. Donald Bemier for his technical assistance and Ms. Karen Patrick and Ms. Carole Goodell for the preparation of the manuscript. REFERENCES
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during early myocardial &hernia in an animal model, Circulation 53115, 1976. Zaret, B. L., Strauss, H. W., Hurley, P. J., Natarajian, T. K., and Pitt, B.: A non-invasive scintiphotographic method for detecting regional ventricular dysfunction in man, N. Engl. J. Med. 284:1165, 1971. Gunnar, R. M., Pietras, R. J., Blackaller, J., Dadmun, S. E., Szanto, P. B., and Tobin, J. R., Jr.: Correlation of vectorcardiogxaphic criteria for myocardial infarction with autopsy findings, Circulation 35:158, 1967. Dixon, S. H., Jr., Fuchs, J. C. A., and Ebert, P. A.: Changes in serum creatine phosphokinase activity,_ Arch. Surg.10366, 1971. Klein. M. S.. Coleman. R. E.. Weldon. C. S.. Sobel. B. E.. and Roberta, R.: Concordance of electrocardiographic and scintigraphic criteria of myocardial injury after cardiac surgery, J. Thorac. Cardiovasc. Surg. 71:934, 1976. Braunwald, E.: Protection of the ischemic myocardium, Circulation 53 (Suppl. I):March, 1976. Hohnan, B. L., Leach, M., Zweiman, F. G., Tempte, J., Lown, B., and Gorlin, R.: Detection and sizing of acute myocardial infarcts with sSmTc(Sn) tetracycline, N. Engl. J. Med. 291:159, 1974. Botvinick, E. H., Shames, D., Lappin, H., Tyberg, J. V., Townsend, R., and Parmley, W. W.: Non-invasive quantitation of myocardial infarction with technetium 99m pyrophcephate, Circulation 52909, 1975. Holman, B. L.: Selective uptake of radiopharmaceuticals by acutely infarcted myocardium, in:- Cardiovascular nuclear medicine. Strauss. H. W.. Pitt. B.. and James. A. E., Jr., eds., St. Louis, 1974, The C’V. Mosby Corn: pany, p. 226. Carr. E. A.. Jr.. Beierwaltes. W. H.. Patno. M. E.. Bartlett, J. ‘D., ‘and Weget, A. V.: The detection of experimental myocardial infarcts by photoscanning, AM. I
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and
Coleman
macroaggregated albumin. New procedures for identification of stress-induced regional ischemia, Am. J. Cardiol. 35:380, 1975. Parkey, R. W., Bonte, F. J., Meyer, S. L., Atkins, J. M., Curry, G. L., Stokely, E. M., and Willerson, J. T.: A new method for radionuclide imaging of acute myocardial infarction in humans, Circulation 50:540, 1974. Malek, P., Vavrejn, B., Ratusky, J., Kronrad, L., and Kolc, J.: Detection of myocardial infarction by in vivo scanning, Cardiology 51~22, 1967. Bonte. F. J.. Parkev. R. W.. Graham. K. D.. Moore. R. T.. and Stokely, M.: A few method for radionuclide imaging of myocardial infarcts, Radiology 110:473, 1974. Hubner, P. J. B.: Radioisotopic detection of experimental myocardial infarction using mercury derivatives of fluorescein, Cardiovasc. Res. 4509, 1970. Gorten, R. J., Hardy, L. B., McCrow, B. H., Stokes, J. R., and Lumb, G. D.: The selective uptake of Hg*“,‘-chlormerodrin in experimentally produced myocardial infarcts, AM. HEART J. 72:71, 1966. Ramanathan, P., Ganatra, T., Daulatram, K., Sen, P. K., and Blau, M.: Uptake of Z03Hg-hydroxy-mercury-fluorescein in myocardial infarcts, i l&l. Med. 12:&l, 1971. Carr. E. A.. Cafrunv. E. J.. and Bartlett. J. D.: Evaluation of H@ chlormerodrin in the demonstration of human myocardial infarcts by scanning, Univ. Michigan Med, Bull. 29:27, 1963. Malek, P., Ratusky, J., Vavrejn, B., Kronrad, L., and Kolc, 3.: Ischaemia detecting radioactive substances for scanning cardiac and skeletal muscle, Nature (London) 214:1130, 1967. Dreyfus, F., Ben-Porath, M., and Menczel, J.: Radioiodine uptake by the infarcted heart, Am. J. Cardiol. 6~237, 1960. Mason, D. T., Frye, R. L., and Wagner, H. N.: Radioisotope scanning of the precordial distribution of iodide in patients with myocardial infarction, Circulation 24: 1338, 1961. Edwards, C. L., and Hayes, R. L.: Tumor scanning with “‘Gallium citrate, J. Nucl. Med. 10:103, 1969. Kramer, R. J., Goldstein, R. E., Hirshfeld, J. W., Roberts, W. C., Johnston, G. S., and Epstein, S. E.: Accumulation of gallium-67 in regions of acute myocardial infarction, Am. J. Cardiol. 33:861, 1974. Zweiman, F. G., Hohnan, B. L., O’Keefe, A., and Idoine, J.: Selective uptake of *YmTc complexes and 6’G3 in acutely infarcted myocardium, J. Nucl. Med. 16:975, 1975. Ahmed, S. A., Weiss, E. S., Thacker, M., Welch, M. J., Coleman, R. E., Ter-Pogossian, M. M., and Sobel, B. E.: Externally monitored leukocytic infiltration in myocardial infarcts (Abstract), Am. J. Cardiol. 37:116, 1976. Malek, P., Kolc, J., Zastava, V. L., Zac, F., and Peleska, B.: Fluorescence of tetracycline analogues fixed in myocardial infarction, Cardiology 42:303, 1963. Holman, B. L., Dewanjee, M. K., Idoine, J., Fliegel, C. P., Davis, M. A., Treves, S., and Eldh, P.: Detection and localization of experimental myocardial infarction with !‘YmTc-tetracycline, J. Nucl. Med. 14:595, 1973. Iesch, M., Tanaka, T., and Holman, B. L.: Comparative accuracy of “““Tc-pyrophosphate, ygmTc-tetracycline and “H’“Tc-glucoheptonate for the scintigraphic diagnosis of acute myocardial infarction (Abstract), Circulation 51 and 52 (Suppl. 11)53, 1975. Rossman, D. J., Strauss, H. W., Siegel, M. E., and Pitt, B.: Accumulation of y”mTc-glucoheptonate in acutely infarcted myocardium, J. Nucl. Med. 16:875, 1975. Rossman, D. J., Rouleau, J., Strauss, H. W., and Pitt, B.: Detection and size estimation of acute myocardial infarcI
I
I
I
39.
40.
41. I
42.
tion using “““Tc-glucoheptonate, J. Nucl. Med. 16:980, 1975. D’Agostino, A. N.: An electron microscopic study of cardiac necrosis produced by 9-a-ffuorocortisol and sodium phosphate, Am. J. Pathol. 45633, 1964. Shen, A. C. and Jennings, R. B.: Kinetics of calcium accumulation in acute myocardial ischemic injury, Am. J. Pathol. 67:441, 1972. Buja, L. M., Parkey, R. W., Dees, J. H., Stokely, E. M., Harris, R. A., Bonte, F. J., and Willerson, J. T.: Morphologic correlates of technetium99m stannous pyrophosphate imaging of acute myocardial infarcts in dogs, Circulation 52:596, 1975. Klein, M. S., Coleman, R. E., Ahmed, S. A., Weiss, E. S., Roberts, R., and Sobel. B. E.: “*“Tc(Sn) uvrouhosnhate scintigraphy: sensitivity, specificity and mechanisms (Abstract), Circulation 51 and 52 (Suppl. 11):52, 1975. Coleman, R. E., Klein, M. S., Roberts, R., and Sobel, B. E.: Improved detection of myocardial infarction with “HmTc(Sn) pyrophosphate and serum MB CPK, Am. J. Cardiol. 37:732, 1976. Willerson, J. T., Parkey, R. W., Bonte, F. J., Meyer, S. L., Atkins, J. M., and Stokely, E. M.: Technetium stannous pyrophosphate myocardial scintigrams in patients with chest pain of varying etiology, Circulation 51:1946, 1975. Willerson, J. T., Parkey, R. W., Bonte, F. J., Meyer, S. L., and Stokelv, E. M.: Acute subendocardial mvocardial infarction in patients-its detection by techne&m-99m stannous pyrophosphate myocardial s&t&rams, Circulation 51:436, 1975. Schelberg, H., Ingwall, J., Sybers, H., and Ashburn, W.: Infarct imaging agents in fetal mouse hearts after reversible and irreversible injury (Abstract), Circulation 51 and 52 (Suppl. 11):70, 1975. Klein, M. S., Coleman, R. E., Roberts, R., and Weiss, A. N.: Tc-99m (Sn) pyrophosphate scintigrams in exercise-induced angina and calcified valves (Abstract), Am. J. Cardiol. 37:149, 1976. Ahmad, M., Dubiel, J. P., Vernon, T. A., and Martin, R.: Technetium99m stannous pyrophosphate myocardial imaging in patients with and without left ventricular aneurysm, Circulation 53:833, 1976. Ahmad, M., Dubiel, J. P., Logan, K., Verdon, T., and Martin, R.: Myocardial uptake of technetium99m stannous pyrophosphate in patients with previous coronary artery bypass graft surgery (Abstract), Circulation 51 and 52 (Suppl. 11):148, 1975. O’Rourke, R., Righetti, A., Schelbert, H., Daily, P., Ashbum, W., and Ross, J., Jr.: Usefulness of pre and post-operative Tc-99m-pyrophosphate scans in -cardiac surgical patients (Abstract), Am. J. Cardiol. 37:161, 1976. Mayorga-Cortes, A., Campeau, R. J., Sheps, D., Gottlieb, S., Miale, A., Jr., and Mverburg, R. J.: Value and limitations of YYmTechnetium stannous pyrophosphate myocardial imaging in acute subendocardial infarction (Abstract), Circulation 51 and 52 (Suppl. 11):214, 1975. DiCola, V. K., Freedman, G. S., and Zaret, B. L.: Effect of direct current countershock upon myocardial technetium-99m stannous pyrophosphate uptake (Abstract), Am. J. Cardiol. 37:131, 1976. Pugh, B. R., Parkey, R. W., Bonte, F. J., Poliner, L., Buia, L. M.. and Willerson. J. T.: Cardiovemion and its potential role in the production of “false-positive” technetium-99m stannous pyrophosphate myocardial scintigrams (Abstract), Am. J. Cardiol. 37:163, 1976. Klein, M. S., Coleman, R. E., Weiss, A. N., and Roberts, ..”
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
.
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55.
56. 57.
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R.: False positive myocardial infarct images due to delayed removal of y9mTc(Sn) pyrophosphate from the blood pool (Abstract), Clin. Res. 24:224A, 1976. Alderman, E. L., Matloff, H. J., Shumway, N. E., and Harrison, D. C.: Evaluation of enzyme testing for the detection of myocardial infarction following direct coronary surgery, Circulation 48:135, 1973. Bassan, M. M., Oatfield, R., Hoffman, I., Matloff, J., and Swan, H. J. C.: New Q waves after aortocoronary bypass surgery, N. Engl. J. Med. 290:349, 1974. Harris, R. A., Parkey, R. W., Bonte, F. J., Stokely, E. M., Buja, L. M., and Willerson, J. T.: Sizing acute myocardial infarction in patients utilizing technetium stannous pyrophosphate myocardial scintigrams (Abstract), Clin. Res. 1:3A, 1975. Willerson, J. T., Parkey, R. W., Buja, L. M., Harris, R. A., Stokelv. E. M.. Blomavist. G.. and Bonte. F. J.: Sizine acute myocardial infarction utilizing technetium stannous pyrophosphate myocardial scintigrams in dogs and man (Abstract), Circulation 51 and 52 (Suppl. II):lOS, 1975. Tomanek, R. J., Marcus, M. L., Ehrhardt, J. C., Kerber, I,
59.
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_
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R. E., and Brown, D. D.: Technetium pyrophosphate uptake in infarcted cardiac muscle and relative importance of extent of necrosis and myocardial perfusion (Abstract). Am. J. Cardiol. 37:177, 1976. 60.’ Dewanjeey M. K., Fletcher, J. W., and Davis, M. A.: Chemical properties and biologic distribution of technetium-tin-polyphosphates (Abstract), N. Nucl. Med. 13:427, 1972. 61. McLaughlin, P., Coates, G., Wood, D., Cradduck, T., and March, J.: Detection of acute myocardial infarction by technetium99m polyphosphate, Am. J. Cardiol. 35:39O, 1975. 62. Bonte, F. J., Parkey, R. W., Graham, K. D., and Moore, J. G.: Distributions of several agents useful in imaging myocardial infarcts, J. Nucl. Med. 16:132, 1975. 63. Krishnamurthy, G. T., Thomas, P. B., Tubis, M., Endow, J. S., Pritchard, J. H., and Blahd, W. H.: Comparison of Y”mTc-polyphosphate and ‘“F. I. Kinetics, J. Nucl. Med. 16:832, 1974. 64. Kriahnamurthy, G. T., Walsh, C. F., Shoop, L. E., Berger, H. G., and Blahd, W. H.: Comparison of 4PnTc-polyphosphate and ‘“F. II. Imaging, J. Nucl. Med. 15:837, 1974.
667
of clinical in the assessment
cardiology of myocardial
Milton S. Klein, M.D. Robert Roberts, M.D. R. Edward Coleman, M.D.* St. Louis, MO.
Radionuclides in Cardiology have been used mainly for detection of myocardial infarction’ and assessment of left ventricular function.2 The need for improved detection of myocardial infarction is related to the lack of sensitivity and specificity of the ECG or plasma enzymes in certain clinical conditions.“, a Diagnosis of infarction after cardiac surgery is particularly troublesome since even creatine phosphokinase isoenzymes, specific for myocardial damage, are consistently elevated as a result of the iatrogenic injury., The recent interest in protection of ischemic myocardium6 requires measurement of infarct size and several studies suggest that quantification of infarct images may be possible,‘, 8 which has intensified the search for more appropriate radionuclidesg Four categories of radionuclides have been utilized to identify zones of &hernia or infarction as areas of decreased activity or “cold spots”: (1) Potassium analogs (*3K, tzsC~, “‘Rb, and more recently 201T1)10-1*;(2) metabolic substrates (labeled free fatty acids, 13NH,15; (3) inert gases (s5Kr, *%e)l6,1’; and (4) labeled microspheres or radionuclides macroaggregates.18, I9 However, which accumulate in areas of infarction (“hot From the Cardiovascular Division, Wa&ington Univezsity School of Medicine, St. Louis, MO., and the Department of Radiology, The ikinckrodt Institute of Radiology, Washington University School of Medicine. This study was supported in part by SCOR in Ischemic Heart Disease Grant P17 HL-17646 from the National Heart and Lung Institute, National Institutes of Health. Received for publication March 29, 1977. Reprint requests: Robert Roberts, M.D., Director, Cardiac Care Unit, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO. 63110. *Department of Radiology, Univemity of Utah Medical Center, Salt Lake City, Utah.
0002-8703/78/0595-0859$00.90/O
o 1978 The
C. V. Mosby
Co.
sp~t..s”),~~ offer some advantages over those which localize in normal tissue (“cold spots”). To date, radiopharmaceuticals which produce “cold spots” cannot distinguish acute myocardial infarction from scar tissue, old infarction, or ischemia.“-‘* Accordingly, this review will deal primarily with those agents which are taken up in the area of infarction. Historically, the first studies to delineate myocardial infarction by a radionuclide accumulating in necrotic tissue utilized mercurial compounds.1o Poor resolution and radiation risks precluded their extensive use clinically.21 Subsequently, the serendipitous discovery that bone seeking radionuclides accumulate m myocardial infarcts initiated the widespread use of technetium-labeled compounds for infarct imaging.22 The basis of a positive image is dependent on several factors: (1) the ratio of radioactivity in infarcted compared to normal myocardium which should generally be at least 4:l; (2) the ratio of radioactivity in myocardium to that of surrounding structures (ribs, liver, etc.); (3) the size of the infarct; and (4) the distribution and density of cell death (although the same number of myocardial cells may be necrotic in subendocardial as in transmural infarctions, the latter is more easily visualized scintigraphically because of the localization of counts in one area). Mercurial
compounds
Mercurochrome has long been known to stain necrotic tissue and fluoresce under ultraviolet light.zs Much of the early work in myocardial infarct imaging was performed using compounds labeled with radioactive mercury because of their stability and accumulation in necrotic tissue.‘O The first attempts to demonstrate radionuchde
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Klein, Roberts, and Coleman accumulation in experimental myocardial infarcts in vivo were performed in 1962 using 203Hgchlormerodrin.10 Fifteen of 16 dogs with coronary occlusions were shown to have abnormal scintigrams with a preponderance of counts in ischemic and necrotic myocardium compared with normal myocardium by direct counting of histologic specimens. Imaging of myocardial infarcts in vitro in pigs also demonstrated accumulation of 20”Hgchlormerodrin as early as 12 to 24 hours after infarction, but with optimal results at three to five days after infarction. Images were normal by 9 to 12 days. 24 Of even greater interest was the finding that coronary reperfusion was not necessary for accumulation of mercurial compounds in infarcts.25 Studies in patients, however, have been disappointing.26 Only three of 13 patients with myocardial infarctions were successfully imaged with 203Hg-chlormerodrin four to eight days postinfarction. In dogs it was necessary to administer 700 @i but the 47 day half-life of zo3Hg and high radiation exposure to the liver and kidney precluded the use of high doses in humans. Thus, the amount of activity accumulated in the myocardial infarcts was suboptimal for image production. Other mercurial compounds, however, have been shown to accumulate more avidly in myocardial infarcts.*1 For example, *03Hghydroxy mercury-45 dibromofluorescein has a ratio of activity in infarcts compared to normal myocardium of 1OO:l while Z03Hg-chlormerodrin has a ratio of only 6:l. Although other radiopharmaceuticals have more recently taken the place of mercurial compounds in clinical use, these radionuclides were instrumental in establishing that: (1) tracers do accumulate in myocardial infarcts, (2) they can be detected externally, and (3) accumulation occurs despite total occlusion of a coronary artery. lodinated
compounds
Some early studies reported the accumulation of 13*1 in myocardial infarcts.Z8 One study of 23 patients with acute myocardial infarction reported a 20 per cent greater number of counts localized over the left side of the chest when compared to the right side after oral administration of 50 to 200 /&i of NaX31. Seven days after infarction, however, postmortem data revealed a ratio of radioactivity in infarcts compared to normal myocardium of only l.7:l.28 Subsequent studies demonstrated that the left precordial
660
activity probably represented Ia11 concentration in gastric secretions persisting in the stomach due to delayed gastric emptying seen in patients with recent myocardial infarctions.29 Gallium
citrate
After it was recognized that mercurial radionuelides would not be beneficial in the clinical setting of infarct imaging, investigators turned to agents such as gallium citrate. “‘Gallium citrate is a radiopharmaceutical which accumulates in areas of inflammation and in certain tumors.“o Since this radiopharmaceutical accumulates in white blood cells which are known to migrate to the periphery of acute infarctions, it seemed likely that “‘Gallium citrate would accumulate in regions of myocardial necrosis. When 3 to 4 mCi of “‘Gallium citrate were administered intravenously two days after transient occlusion of the left anterior descending coronary artery, accumulation of the radionuclide was noted in dogs with infarction (prolonged occlusion), but not with transient &hernia (less than 20 minute occlusions). Furthermore, in vivo and in vitro studies demonstrated a good correlation between the intensity of “‘Gallium uptake and the number of leukocytes seen histologically in the infarct zone as well as with the extent of myocardial CPK depletion.“’ However, g7Gallium myocardial imaging has not been shown to be useful clinically. Since the ratio of radioactivity in infarcts compared to normal myocardium is relatively small compared to other radionuclides, one would expect rather poor sensitivity.32 In one study, only five of eight patients with myocardial infarction demonstrated an abnormal image. It should be emphasized that “‘Gallium detects areas of inflammation, and is, therefore, not specific for infarction. Hence, other disorders such as pericarditis might also be associated with an abnormal image. Accumulation of gallium by the liver makes recognition of diaphragmatic infarctions difficult. In addition, images do not become abnormal for several days, precluding early detection of infarction. Furthermore, since images remain abnormal for at least three weeks, serial imaging is impossible.“’ lndium
labeled
leukocytes
Further attempts to take advantage of the migration of leukocytes into infarcts for the purposes of myocardial imaging employed the
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labeling of leukocytes with “‘In-Shydroxyquinoline.33 This was accomplished without alterations in white blood cell viability or function. When labeled leukocytes are administered to animals with experimental infarction, images of the infarct can be obtained in dogs 24 hours after coronary occlusion. Forty-eight hours after infarction an increased number of counts were detected in the infarct zone compared to the normal myocardium. Ratios of radioactivity of infarct compared to normal myocardium were 23:l. Tetracycline
Since the mercurial compounds produce infarct images with poor resolution, and since radiopharmaceuticals which accumulate in infarcts as a result of inflammation lack specificity, investigators initiated studies with technetium-labeled tetracycline designed to improve sensitivity and specificity. Like the mercurial compounds, tetracycline fluoresces and accumulates in myocardial tissue undergoing necrosis3’ Immediately after intravenous administration, tetracycline produces a yellow fluorescence in normal heart muscle, but not in necrotic tissue. However, within the next three hours, the intensity of fluorescence increases around the infarct border and is absent from normal tissue. The mechanism of accumulation of 99mTc(Sn) tetracycline is thought to be related to binding of the tracer to protein in nucleic acids in necrotic myocardial cells. Its accumulation appears to be influenced by free calcium accumulation in necrotic myocardium-a mechanism postulated for other radiopharmaceuticals as well.“” After three to four days, fluorescence is seen only in the margin of the infarct, and by seven days clumps of tracer are noted throughout the infarct. With administration of 10 to 15 mCi of 99mTc(Sn) tetracycline intravenously 4 to 24 hours after acute myocardial infarction, accumulation is primarily in the liver, kidneys, and gall bladder. Four hours after infarction only one of four dogs had a scintigraphically demonstrable infarct. By 24 hours, however, ratios of radioactivity in infarcts compared to normal myocardium ranged from 5.9 to 8.4:l. Hemorrhagic infarcts were more readily demonstrable by labeled tetracycline.35 Early studies in patients7 demonstrated that each of 14 patients with acute myocardial infarction had positive 99mTc(Sn) tetracycline images if
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injected 24 hours after infarction and imaged 24 hours after injection. All nine patients without acute infarction had negative images, including several patients with old infarction. Localization of infarction determined scintigraphically was concordant with electrocardiographic localization. Also, the correlation of infarct size (measured by peak total CPK) with images categorized as having large, moderate, or small infarcts scintigraphically was good (r = 0.84). The sensitivity and specificity of 99mTc(Sn) tetracycline myocardial imaging is less impressive in other studies.36 Only 12 of 25 true positive, and six of 11 true negative images were reported in one study.36 Other difficulties precluding the widespread clinical utility of 99mTc(Sn) tetracycline myocardial imaging include the following: (1) the 24 hour delay from infarct to image precludes early infarct diagnosis; (2) uptake of the tracer by the liver makes the accurate diagnosis of diaphragmatic infarction difficult; (3) relatively small ratios of activity in infarcts compared to normal myocardium account for poor delineation of the infarct zone. Hence, 99mTc(Sn) tetracycline has not become a frequently used method of infarct imaging. *smTechnetium
glucoheptonate
A major difficulty with most imaging agents in diagnosing acute myocardial infarction has been the delay in the production of an abnormal image. Circumventing this problem by finding a radionuelide designed to permit early imaging would be of great importance. One agent that appears to offer promise in detecting infarction sooner is g9”Tc-glucoheptonate. When this radionuclide was administered to nine dogs four hours after coronary occlusion, the ratio of activity in infarcts compared to normal myocardium was 2O:l. Concentration of the radionuclide in infarcts was somewhat dependent on blood flow since the greatest number of counts occurred when perfusion was 20 to 40 per cent of normal. Early imaging was not significantly encumbered by overlay of radioactivity in skeletal structures or cardiac blood pool, and ratios of radioactivity in infarcts compared to normal tissue were better than those seen with 9gmTc(Sn) tetracycline, but similar to those observed with 99mTc(Sn) pyrophosphate.32, 37 In one study of 27 patients with chest pain, 99mTc-glucoheptonate was administered two to 48
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hours after chest pain, and 12 of 15 patients with acute infarction exhibited abnormal images. Several false positive images were reported. Scintigraphically estimated infarct size correlated well with peak total CPK (r = 0.77).3* In another study, ggmTc-glucoheptonate detected only three of 13 true positives and two of two true negatives.36 Thus, despite some encouraging experimental results, drawbacks of poor resolution, and poor sensitivity make g9mTc-glucoheptonate infarct imaging less beneficial than other tracers presently in use. Bone-seeking
radionuclides
Introduction. Bone-seeking tracers were noted to accumulate in zones of acute myocardial infarction during routine bone scans.2o Subsequently, phosphate compounds labeled with technetium were found to be excellent indicators of acute myocardial necrosis, and are presently used extensively in many Coronary Care Units. 99mTc(Sn) pyrophosphate. Some of the earliest studies utilizing bone-seeking radionuclides were performed in dogs with experimental infarction given g9mTc(Sn) pyrophosphate.‘* This tracer is a commonly used bone-scanning agent. Technetium-99m with its 140 keV gamma rays and its short half-life is well suited for nuclear medicine instrumentation. The mechanism of accumulation of YYmTc(Sn) pyrophosphate in acute infarction has not been unequivocally established. Electron dense deposits of calcium hydroxyapatite like crystals have been demonstrated in mitochondria of cardiac tissue which has undergone necrosis.33 Administration of labeled calcium chloride showed deposition of the calcium in mitochondria within the infarct if coronary occlusion was prolonged and followed by a period of reperfusion.40 Thus, accumulation of these crystals appears to be specific for infarction, and is dependent on perfusion as well as necrosis. The presence of calcium hydroxyapatite deposits in mitochondria from myocardial infarct zones similar to those found in bone suggests a possible mode by which boneseeking radionuclides accumulate in (and thus, identify) regions of acute infarction. A donut-like rim of increased radioactivity is seen frequently in experimental acute transmural infarctions and appears to correlate well with localization of calcium hydroxyapatite deposits in greatest concentrations.41 Of 19 dogs with acute coronary
662
occlusion, all exhibited abnormal images at 24 to 48 hours after infarction. A progressive decline in radioactivity was noted when injections were performed from two to 13 days after infarction. Similarly, diminution in the calcium concentration in mitochondria from areas of infarction corresponded to the decreasing accumulation of s9mTc(Sn) pyrophosphate as a function of time after infarction. Within two weeks after infarction, the major proportion of calcium deposits were replaced by granulation tissue. This finding suggests a relationship between the binding of gsmTc( Sn) pyrophosphate and deposition of calcium deposits in mitochondria; however, it is probably not the sole mechanism by which 9smTc(Sn) pyrophosphate accumulates in myocardial infarcts, since the per cent of injected dose of 9smTc(Sn) pyrophosphate and 3*P-labeled pyrophosphate was only ten to twentyfold greater in the mitochondria from infarct zones compared to normal areas. However, a two hundred to six hundredfold increase in counts from homogenates of whole myocardial infarcts compared to homogenates of mitochondria from the infarct suggested that substantial deposition of the radionuclide occurs in subcellular loci other than mitochondria.4Z Since the pattern of accumulation of the tracer in transmural infarction corresponds to the location of densest migration of leukocytes to the periphery of the infarct, an alternative mechanism might be that phagocytosis of the radionuelide is responsible for the production of an abnormal image. However, administration of cyclophosphamide to dogs with acute infarction did not preclude the production of positive images despite marked leukopenia. Thus, phagocytosis of YYmTc(Sn) pyrophosphate is an unlikely mechanism of accumulation.“2 The specificity of gYmTc(Sn) pyrophosphate for the detection of acute infarction has been studied by transient occlusion of the left coronary artery in dogs. In this model, ischemia in the absence of infarction was not associated with a positive image.” In patients, injection of g”mTc(Sn) pyrophosphate as early as 12 to 16 hours after infarction was associated with a positive image. Optimal images are obtained one to three days postinfarction, but remain positive consistently for seven days, and are usually normal after two weeks. In one study of 23 patients, the sensitivity
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and specificity of 9gmTc(Sn) pyrophosphate in detecting acute myocardial infarction were excellent unless images were obtained more than seven days after infarction.2o Localization of infarction by imaging compared with electrocardiograms was very good.‘“, 43 One large study of 101 patients with myocardial infarction demonstrated 96 abnormal images. The five patients with “false negative images” were all scanned more than seven days after infarction. Ninety-two of 101 patients without infarction had negative images. Of the remaining nine positive images, seven patients were thought to have unstable angina .44A second study of 165 patients showed that 85 per cent with infarction based on electrocardiograms and elevated plasma MB CPK activity had positive images. There was a 7 per cent false positive rate, some of whom represented patients arriving in the Coronary Care Unit several days after infarction at a time when cardiac enzymes had returned to baseline but when images were still abnormal.” In other studies, 49mTc(Sn) pyrophosphate detected 17 of 17 true positives and seven of 10 true negatives. This tracer appears to display the greatest sensitivity and specificity, and the highest quality images when compared to other technetiumlabeled compounds.“G gYmTc(Sn) pyrophosphate images are also capable of detecting acute subendocardial infarction. Each of 17 patients with subendocardial infarction diagnosed by conventional diagnostic criteria had abnormal images which were either localized or faint, diffuse abnormalities. This latter type of abnormality has been noted to be characteristic of non-transmural infarctions.‘” Despite experimental data showing that transient coronary occlusions do not produce abnormal images,42 and that the location of accumulation of 99mTc(Sn) pyrophosphate corresponds to the location of greatest calcium deposition (known to occur only in necrotic myocardium),al the specificity of this radionuclide for detection of infarction remains controversial. Patients with unstable angina in the absence of injury appear to exhibit abnormal images.” Evidence suggesting that ischemia per se is not associated with abnormal images is mounting. Fetal mouse hearts which were reversibly damaged by perfusion with solutions containing no glucose or oxygen for 24 hours at 37” C exhibited very little YYmTc(Sn) pyrophosphate accumulation. In contrast, irre-
American
Heart
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in assessing
MI
versible damage with hypoxia and hypoglycemia at 42” C was associated with 152 per cent greater activity at 24 hours compared with that noted after one hour.*” Furthermore, patients undergoing maximal exercise stress tests do not exhibit abnormal 99mTc(Sn) pyrophosphate images.” Thus, these images appear to be specific for infarction in this setting. In studies in our own laboratory (unpublished data) in patients with unstable angina in whom infarction is excluded by normal plasma MB CPK, abnormal images were generally not seen even if the tracer was injected at the time of chest ,pain or 24 hours later. These data suggest that many of the patients with positive images and a history of unstable angina actually have subendocardial infarctions. Numerous causes of false positive “VmTc(Sn) pyrophosphate images have been reported including left ventricular aneurysms,‘* ventriculotomy scars from sump drains,‘Y and calcified heart valves.50 Whether or not images are abnormal in the presence of calcified valves may be related to the rate of calcium turnover, degree of calcium deposition, or blood supply to paravalvular tissue. Closed chest massage,51 and direct countershock in animals? and in patient@ have been shown to be associated with abnormal images. This may be related to cardiac trauma or deposition of the radionuclide in necrotic chest wall muscles. As previously mentioned, diffusely positive ggmTc(Sn) pyrophosphate images have been reported primarily in patients with unstable angina’” or subendocardial infarction..‘5 However, the specificity of the diffusely positive image has been questioned. In preliminary studies diffusely abnormal images were observed in some normal subjects.5’ Subsequent data from normal subjects given YYmTc(Sn) pyrophosphate intravenously revealed that a delay in clearance of the tracer from the cardiac blood pool in some patients was responsible for production of a diffusely positive image. These findings emphasize the need for delayed images (two hours) after injection of the tracer before a diffuse image is considered abnormal.” Diagnosis of acute myocardial infarction at the time of cardiac surgery is frequently difficult. The conventional indices of infarction (history, cardiac enzymes, and electrocardiograms) may lack the usual specificity in the setting of recent surgery.js, j6 In a study of 50 patients undergoing
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Klein, Robe&~,
and Coleman
coronary artery bypass surgery,5 there was a 16 per cent incidence of perioperative myocardial infarction judged by development of new Qwaves, and associated in each case with an abnormal 9gmTc(Sn) pyrophosphate image. This group included some patients with pre-surgical or perioperative bundle branch block, and underscored the fact that not all new bundle branch blocks should be interpreted as resulting from a fresh infarction. All patients with or without infarction exhibited elevated MB CPK activity. Thus, plasma enzyme elevations could not be used to detect infarction and ischemic injury in patients with operative trauma to the heart. Since the electrocardiogram in this setting may also occasionally be equivocal, infarct imaging may be particularly useful as a specific index for the diagnosis of infarction. Potential clinical uses for YYmTc(Sn) pyrophosphate myocardial imaging include the diagnosis of: (1) subendocardial infarction, (2) infarction in the presence of ventricular conduction disturbances, (3) recent infarction at a time when cardiac enzymes have returned to baseline, and (4) perioperative infarction (especially after coronary artery bypass surgery). Quantification of myocardial infarct size with radionuclides is being actively pursued experimentally and clinically but results at present are inconclusive. Good correlations have been obtained when anterior wall infarcts in dogs were imaged with a gamma camera grid and computer interface 48 hours after infarction and images were compared with gross infarct weight at postwere mortem (r = 0.87). The best correlations obtained with the left anterior oblique view grid uiuo and infarct weight computations in infarct image area and (r = 0.92).8 Planimetering correlating results with peak total CPKjf in or infarct weight estimated from patients, morphology in dogs (r = 0.914) has been quite successfu1.58Myocardial CPK depletion in experimental infarction also correlates with tissue 9YmTc(Sn) pyrophosphate activity (r = 0.89)” Studies of patients have been less impressive, however;58 use of 99mTc(Sn) pyrophosphate images in patients to categorize infarcts into large, medium, or small groups, failed to provide good correlations with peak total CPK or enzymatically estimated infarct size.43 Of 27 patients with myocardial infarction, 99mTc(Sn) pyrophosphate image areas correlated poorly with maxi-
664
ma1 precordial ST segment elevation (r = 0.39), or with the sum ST segment elevation (r = 0.47). In general, infarct size is difficult to quantify in locations other than anterior. Since the ratio of 99mTc(Sn) pyrophosphate activity in infarcts compared to normal myocardium was related to both the extent of necrosis and the degree of perfusion (as judged by injections of labeled microspheres in dogs with infarcts), merely measuring the number of counts in an area of infarct may not reflect infarct size alone.5!’ Hence, the markedly decreased flow to the necrotic center of an infarct is associated with only modest sequestration of 99mTc(Sn) pyrophosphate. Also, problems related to overlap of bone, resolution, and sizing of three dimensional stuctures with a two dimensional system, all make infarct sizing less than optimal. Other
bone-scanning
radiopharmaceuticals
9YmTc(Sn) polyphosphate has similar physicochemical properties to those of 99mTc(Sn) pyrophosphate.60 g9mTc-polyphosphate has been shown to accurately detect both transmural and subendocardial infarction in patients three to 20 days after infarction.“’ As with s9mTc(Sn) pyrophosphate, correlations of scintigraphic localization of infarction with electrocardiographic localization is quite good. Understanding some of the physico-chemical properties of the tracer affords some insight into potential causes of false positive or false negative results. Molecular weights of “““Tc-polyphosphate between 4,900 and 6,090 daltons are optimal for imaging.60 Weights greater than 8,000 confer colloidal properties associated with localization of the tracer in the reticuloendothelial system. Weights less than 3,000 promote rapid renal clearance and little bone deposition. Since Y9mTc(Sn) polyphosphate (like other technetium compounds) are made by reduction of 99mTc-pertechnetate to 4emTc by SnCl, 2 H,O, ideal ratios of polyphosphate to tin have been established. Ratios of 25:l are optimal since leas tin produces inefficient labeling and excess tin confers colloidal properties. Also, the solid state of tin promotes greater complex stability since polyphosphate degrades at pH > 1.0.60 A comparison of s”“Tc-polyphosphate with 9QmTc(Sn) pyrophosphate in dogs with infarcts demonstrated ratios of radioactivity in infarcts compared to normal myocardium that were similar.6” ‘*Fluorine, another bone-scanning agent, l
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Radionuclides
has nearly a thirtyfold greater ratio of activity in bone compared to infarct when compared to that observed with 9QmTc-polyphosphate. Thus, ‘*Fluerine is not likely to be a useful tracer because of problems of resolution related to its avidity for bone.62 Kinetic studiese3 of 99mTc-polyphosphate and ‘“Fluorine demonstrate that both radionuelides are cleared from the blood pool in a biexponential manner. The frrst portion of the curve is thought to be due to rapid uptake by bone, and the second portion is due to renal clearance. 18Fluorine clears faster from both portions of the curve since ssmTc compounds bind to red blood cells and plasma a-2 globulins (80 per cent of plasma radioactivity with 9QmTc is protein bound compared to 15 per cent with ‘*Fluorine. Finally, a comparison of the resolution and sensitivity of the images showed Q9mTc-polyphosphate to be a superior radionuclide.“” Considerations
2.
3.
4.
5.
6. 7.
8.
for the future
Each of the radiopharmaceuticals mentioned have drawbacks. The ideal infarct imaging tracer would have the following properties: 1. High sensitivity and specificity for the diagnosis of acute infarction; 2. Short half-life permitting serial imaging; 3. High infarct compared to normal tissue ratios of activity, with little background activity; 4. Early clearance from the blood pool; 5. Early detection of acute infarction; 6. Accurate estimation of infarct size; 7. Non-invasive administration (not requiring coronary injections); 8. Safety; of the tracer; 9. Easy production 10. Low cost. At present, radiopharmaceuticals are being utilized primarily for the detection, sizing, and localization of acute myocardial infarction. Perhaps a more detailed understanding of their mechanisms of accumulation will permit in-depth study of the pathophysiology of the disease states and mechanisms of action of pharmacologic agents. The authors wish to thank Mr. Donald Bemier for his technical assistance and Ms. Karen Patrick and Ms. Carole Goodell for the preparation of the manuscript. REFERENCES
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