Radionuclides in acute myocardial infarction Jan Lessem Heart section, Dept. of Medicine, General Hospital, MALMU, SWEDEN
The history of cardiovascular nuclear medicine is intimately related to the development of nuclear medicine and to the desire of cardiologists to find procedures less traumatic than catheterizations (4, 39). These factors combined with difficulties of diagnosing ischaemic heart diseases in some pa-
tients, due to previous pathological ECG and equivocal enzyme response, led to the use of radionuclide methods in this group of patients. Most patients with suspected acute myocardial infarction are usually immobile during the first phase of their disease and are monitored in a coronary care unit.
Fig. 1. A mobile gammacamera - Portacamera I ! c (General Electric). Bedside examination i s shown.
27
Radionuclide methods were not available to the cardiologist, despite the development of better radiopharmaceuticals, until the recent development of the mobile gamma camera (fig. 1). This brought bedside nuclear medicine into the coronary care unit (45). The employment of radionuclide methods in the diagnosis and evaluation of patients with acute myocardial infarction followed mainly three directions (Table I):
Table I Methods used In cardlovascular nuclear medlclne I . Positive infarct scintigraphy - substances accumulating in necrotic myocardium: 203Hg- Mercurascan 67Ga 99mTc-pyrophosphate WmTc-tetracycline WmTc-glucoheptonate 2. Negative infarct scintigraphy - substances accumulating in normal myocardium 43K 86Rb 131cs
129cs
zolTl
+
13NH4
54Mn llC-Palmitic acid 3. Radiocardiography - hernodynamic assesments WmTc-human serum albumin WmTc-erythrocytes 1) “Positive” infarct scintigraphy, with sub-
stances accumulating in infarcted myocardium. Among the first substances described were mercury isotopes, such as 203Hgtagged to hydroxymercuryfluorescein (33) which gave satisfactory results in dogs with induced acute infarct (18, 25, 42); these never succeeded clinically. Recently, a different group of substances, mainly phosphates labelled with WmTc, were shown to be clinically applicable in the diagnosis of acute myocardial infarction. Bonte and coworkers (6)
28
showed that a pyrophosphate labelleled with 99mTc accumulated in acutely infarcted myocardium. Later others verified this (16, 28, 35, 56). 9 9 m T c pyrophosphate proved exrrcmely useful in diagnosing peri- and postoperative myocardial infarctions (32, 41); in this clinical setting, enzymes and ECG cannot be used after cardiac surgery. 99mTc, obtained as a daughter product of WMo, has a half-life of 6 hours and gamma ray energy of 147 keV. Thus it is suitable for the low energy mobile gamma cameras. The mechanism behind the pyrophosphate uptake is obscure, but it has been postulated that pyrophosphate has an affinity to hydroxyapatite crystals formed in the mitochondria when the myocardial cells undergo necrosis (8, 49, 50). Several groups (12, 20, 48) recently presented evidence that pyrophosphate is taken up mainly by irreversibly damaged myocardial cells. These might still have some perfusion left (55) thus enabling pyrophosphate to reach them. Simultaneously with the development of 99mTc-pyrophosphate, other agents, such as WmTc-tetracycline (23, 24) and later WmTc-glucoheptonate (26), were introduced as infarct labelling agents. However, both these substances have largely been abandoned, as the interval between injection of the radionuclide and the imaging procedure was too long, allowing other parameters to provide the diagnosis. ”Negative” infarct scintigraphy using substances accumulating in normal myocardium. These radionuclides are believed to reflect regional myocardial perfusion, and when the perfusion is decreased, a perfusion defect appears in the scintigram. The substances in this group are potassium-43 (57) and its analogues. Several have been used, such as 86Rb (11), I3lCs (4, 12), and lZ9Cs (44). All of them had a gamma energy level more suitable for the rectilinear scanner than for the gamma camera; thus their clini-
cal applicability was limited. Recently, another potassium analogue, 201T1, was introduced (27) and proved to be a very useful tool in the diagnosis of acute myocardial infarction (19, 52, 54). I t has two energy levels, (80 and 167 keV), both being ideal for the low energy mobile gamma cameras. The long half-life (about 72 hours) eliminates the disadvantage of being a cyclotron produced product. The potassium analogues reflect the function of the sodium-potassium pump within the myocardial cells. When the myocardium is perfused, a significant amount of potassium is withheld intracellularly. If the perfusion is decreased, the amount of available potassium is also decreased; thus a perfusion defect in the scintigram will appear. From this, it is apparent that no differentiation of the age of the perfusion defect is possible with these radionuclides.
720
-
640
-
576
-
504
-
432
-
360
-
288
-
216
-
144
72
Maseri and coworkers (34) showed that potassium or its analogues are largely extracted by the myocardium during the first circulatory pass, and when evenly mixed with the blood, are distributed proportionally to the cardiac output (46). 3) Radiocardiography, where the left ventricular function and wall motion are studied. Ventricular function can be measured non-invasively by two methods: First by recording the initial passage of a bolus injected blood pool tracer through the heart, first Fass study, which Ashburn and Schelbert utilized (47). The first pass method utilizes a recording of the time-activity curve over the left ventricle that has peaks and valleys corresponding to end-diastole and end-systole (Fig. 2). Second by data recording after the tracer has equilibrated. An ECG-gate and the scintillation camera is used so that images
-
0
Fig. 2. A first passage curve is exemplified. The ejection fraction in this patient was calculated to be 4 1 010.
29
Several studies, independent (17) of each other, have shown (17, 51) correlation coefficients of 0.9 or better for ejection fractions obtained with radionuclide methods and angiography (37). Impaired left ventricular function can then be diagnosed. Left ventricular wall motion is best studied with gated blood pool studies, where diagnosis of akinetic a n d dyskinetic areas can easily be made. Both methods have the advantage of accumolating data over a relatively short time. This allows them to be used rather easily in the coronary care unit. They can very easily be repeated several times during the patient’s stay in the ward, and thereby yield information of his day to day heniodynamic situation. It seems as though both methods, properly utilized, can predict left ventricular failure early (15, 51) and also estimate the effect of treatment. The indications for using radionuclide methods in cardiology are several and have been demonstrated by several reports. The following seem to be the major indications: 2) Differentiation of origin of chest pain (47) b) Previous pathological ECG, e.g., bundle Fig. 3. After injection of 15 mCi 99~nTc-human branch block, remaining ST-T changes serum albumin, a gated study was performed in after previous infarcts in combination this patient. The upper panel illustrates endwith chest pain postoperatively systole and the bottom panel illustrates endc) Differentiation bctween new and old indiastole. N o akinetic area can be recognized. farcts (54) d) No adequate enzyme response, e.g., alare recorded during end-systole and endcoholism, liver pathology, postoperatidiastole (40, 43) (Fig. 3). Gated studies vely have the advantage of being able to use several views after a single tracer injection, e) Hemodynamic assebsement of the working capacity of the right and left venand are therefore more like regular angiotricles during several phases of the ingraphy. Both methods can be used to calfarct culate the left ventricular ejection fraction, according to the following formula: Besides these, several reports by Botvinick and coworkers have shown that sizing of LVEF = EDV - ESV/EDV - BKG, infarcted myocardium can be performed where with WmTc-pyrophosphate (7). Holman and LVEF = left ventricular ejection coworkers recently confirmed these findings fraction (22). These results suggest that in the future E D V = end-diastole volume it will be possible to judge the efficiency of ESV = end-systolic volume decreasing the size of a necrotic area b y BKG = background pharmacological o r surgical interventions.
30
These techniques make possible early diagnosis of acute myocardial infarction (29). Willerson and coworkers found positive pyrophosphate scintigrams already 12 hours after the onset of symptoms; Wackers et a1 found that perfusion defects with 20*T1could be diagnosed as early as 6 hours after the cnset of symptoms. In Wackers’ series all patients examined before 6 hours after the onset had developed perfusion defects in areas later corresponding to ECGlocalization of the infarct (54).
Cllnlcal study All these methods were used in patients admitted to the coronary care unit of the Malmo General hospital with primary clinical suspicion of acute myocardial infarction due to severe chest pain, pulmonary oedema, dysrythmias, and dyspnea. The clinical diagnosis of acute myocardial infarction was based on any of the following criteria: Subjective symptoms in combination with typical QRST-changes in the ECG Subjective symptoms in combination with two elevated enzyme values (SASAT, S-LD) Typical QRST-changes in the ECG in combination with two elevated enzyme values Autopsy data (21, 28). In contrast, the diagnosis of unstable angina pectoris was based on a combination of the following criteria: Previous stable angina, or angina of recent onset with progresive increase in severity of symptoms Angina at rest with recurrent episodes lasting more than 20 minutes and poorly relieved by nitrates No elevation of serum enzymes Transient ST-T changes that frequently return to normal after the attack (10, 4). All 350 patients were examined with 10 mCi NmTc-pyrophosphate (Byk-Mallincrodt, USA, Solcoscint, Kabi-Diagnostica,
Diagnostics inc., USA); 125 patients were also investigated with 1.5 mCi 201Tl (Philips Duphar, the Netherlands). In 48 patients, different hemodynamic evaluations were also made. A mobile gamma camera, Portacamera I1 B or C (General Electric, USA) was used with a standard low-energy parallel hole colimator. The scintigrams were obtained in anterior - posterior, left 30” anterior oblique and left lateral positions. All were evaluated for presence, absence, size, localization, and intensity of an uptake or a defect. When radiocardiography was performed, the left ventricular ejection fraction was counted; if a gated study was undertaken, the wall motion was estimated.
Results
Of the 350 pyrophosphate examinations, 264 showed positive uptakes (Table 11). I n the group of 188 patients with acute transmural infarction, 180 showed radionuclide accumulation and well localized intense uptakes in 90 per cent. (Fig. 4). The correla-
Fig. 4 . Myocardial rcintigram with 99mTc-pyrophosphate, recorded 90 minutes after injection, in LAO 30’ position. An anterior grade 3 intense uptake was recorded in the patient with a transmural anterior infarct. The recording was made with the Portacamera II c.
31
tion between the uptake localization and ECG localization of the infarct was excellent. All 5 patients with left bundle branch block, but who fulfilled the criteria for acute myocardial infarcion also exhibited well localized and intense pyrophosphate uptakes. The earliest uptake was registered in 10 patients examined 4 hours after the onset of symptoms. Of the patients diagnosed as unstable angina pectoris, 73 per cent showed an uptake; but this was distinctly different lrom the uptake in transmural infarcts, which also Abr'ulla and coworkers found ( I ) . These patients had low graded, diffusely spread uptakes (Fig. 5 ) . Fig, 6 . A huge antero-lateral uptake with the intensity graded 3. The patient suffered f r o m Chagas disease. The scintigram mimicked the pattern of transmural myocardial infarction.
Fig. I. A 42-year old male with a diffuse low intense pyrophosphate uptake seen in combination with unstable angina pectoris.
Positive uptakes were found in five patients with other cardiac diseases. One had Chagas disease (30) (Fig. 6 ) , and one, Prinzmetal variant angina. Two were found in patients with old infarcts and ventricular aneurysms, which al.so Ahmad (2) observed. The final positive pyrophosphate scintigrams were registered in a patient who developed an acute myocardial infarction after defibrillation (Fig. 7), a finding previously reported by diCola and coworkers (14).
32
Fig. 7 . A pyrophosphate uptake recorded in a patient after transthoracic counter current schock.
125 patients were also examined with
Zo1T1. A very good correlation existed between a thallium defect and a pyrophosphate uptake (Fig. 8). However, seven TIscintigrams showed perfusion defects where no new infarct could be verified in patients who had previously sustained infarcts.
separate them from those with acute myocardial infarction. A similar finding was recently reported by Wackers and coworkers (53). No false negative has been reported with 201Tl-scintigraphy. Gated thallium studies have also been performed with a pin hole collimator (focusing on the septum) which has been utilized when septal infarcts o r conduction disorders were present (Fig. 10).
Fig. 8. An LAO
4 1 O recording with 201T1, in a pctient with an inferior transmural infarct. In the apical area a large perfusion defect is seen. The recording was made with Portacamera 11 c 20 minutes after injection.
In six of them the pyrophosphate examination remained negative and in one it was questionably positive, probably owing to a ventricular aneurysm. Five patients with unstable angina pectoris had perfusion defects (Fig. 9) thus making it impossible to
Fig. 10. A gated 2olTl-study performed with a pin hole collimator in a patient with a left bundle branch block. The upper panel illustrates end-systole and the lower end-diastole. In the lower panel, a perfusion defect is seen in the septal region.
Conslusions Fig. 9. The LAO 4 j 0 recording with 201T1, in a patient with unstable angina. Note the decreased perfusion in the antero-spetal region.
I t can be concluded that both 99mTc-pyrophosphate and 201T1 are useful aids in the diagnosis of acute myocardial infarction, as Parkey and several others have shown (29, 38, 5). Both methods have a high degree of
33
sensitivity and specificity and rarely show false negative results. False positives appear in patients with unstable angina pectoris or with old infarcts, and this applies for both radionuclides. The decision about which radionuclide method or combination is most useful in the evaluation of a specific patient with chest pain largely depends on the clinical situation and the questions being asked. If an acute diagnosis is looked for, 99mTcpyrophosphate seems to be the isotope of choice, judging by the evidence in the literature (53, 56). In a patient where all clinical evidence supports the diagnosis of myocardial infarction, but where any of the laboratory parameters fail, 201T1 seems to be the ideal isotope for the subacute situations. Several authors (54) recommend 20*TI when it is a question of silent and old infarction.
Any combination with radiocardiography seems to be feasible when the left ventricular function should be studied in a patient with or without an cstablished acute myocardial infarction. If any method, either positive or negative infarct scintigraphy, yields a positive result, che probability that the patient has an acute infarction is more than 85 per cent. This at least equals the sensitivity of the otherwise routinely used clinical methods (20, 22). The possibility of differentiating between unstable angina pectoris and myocardial infarction (29, 56) adds another important dimension to these methods. Combined with radiocardiography and determination of left ventricular function it adds a new important, and powerful tool in the evaluation of patients with acute myocardial infarction.
Table II: Summary of the result wlth WmTc-pyrophosphate Number of patients
188
5
Diagnosis
Transmural AM1 Left Bundle Branch block with AM1
Positive pyrophosphate scintigrams
Negative p y rophosphate scintigrams
180
8
5
0
22
Subendocardial AM1
22
10
75
Unstable angina pectoris
52
23
29
Other cardiac disorders
5
24
(I Chagas, 1 Prinzmetal, 2 ventricular aneurysms, 1 post defibrillation) 21
34
Non-cardiac disorders
0
21
References 1. Abdulla, A., Canedo, M., Cortez, B., Mc Ginnis, K.. Wilhelm, S.: Detection of unstable angina by WmTc-pyrophosphate myocardial scintigraphy. Chest 69: 168, 1976. 2. Ahmad, M., Dubiel, J., Verdon, T., Martin, R.: Technetium Wm-stannous pyrophosphate myocardial imaging in patients with and without left ventricular aneurysm. Circulation 53: 833,
11. Carr, E., Beierwaltes, W., Wegst, A., Banlett, J. D.: Myocardial scanning with rubidium -86. J. Nucl. Med. 3: _.
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Peterson, K., Sobel, B.: Left ventricular volume and ejection fraction determination by radionuclide angiography. Semin. Nucl. Med. 3: 165, 1973. Berger, H., Freedman, G., Zaret, B.: Non invasive radionuclide imaging in the patient with cardiovascular disease. Connecticut Medicine 40: 511, 1976. Berger, H., Gottschalk, A., Zaret, B.: Radionuclide imaging of myocardial infarction in man. J. Nucl. Med. 18: 594, 1977. Bonte, F., Parkey, R., Graham, K., Stokley, E., Moore, J.: A new method for radionuclide imaging of myocardial infarcts. Radiology 110: 473, 1974. Botvinick, E., Shames, D., Lappin, A., Tyberg, J., Townsend, R., Parmley, W.: Non invasive quantification of myocardial infarction with Technetium99m pyrophosphate. Circulation 52: 909, 1975. Buja, M., Parkey, R., D e e , J., Stokley, E., Harris, R., Bonte, F., Willerson, J.: Morphologic correlates of technetium -99m stannous pyrophosphate imaging of acute myocardial infarcts in dogs. Circulation 52: 596, 1975. Cabasson, J., Septfonds, J., Artus, J., Miro, L., Soucon, H.: Skmkiologie scintigraphique de infarctus du myocarde. J. de med. de Montpell. 10: 3, 1975. Cairns, J., Fantus, I., Klassen, G.: Unstable angina pectoris. Amer. Heart J. 92: 373, 1976.
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B.: Direct diagnosis of myocardial infarction by photoscanning after administration of cesium - 131. Amer. Heart J. 68: 627, 1964. Coleman, E., Klein, M., Ahmed, A., Weiss, E., Buchholz, W., Sobel, B.: Mechanisms contributing ;o myocardial accumulation of Technetium -99m Stannous pyrophosphate after coronary occlusion. Amer. J. Card. 39: 55, 1977. DiCola, V., Freedman, G., Downing, E., Zaret, B., Myocardial uptake of technetium 99m Stannous pyrophosphate following direct current transthoracic Counterschock. Circulation 54: 980, 1976. Duncan, B., Fulton, M., Morrison, SC., Lutz, W., Donald, K., Kerr, F., Kirby, J., Julian, O., Oliver, M.: Prognosis of new and worsening angina pectoris. Brit. Med. J. 1: 981, 1976. Ennis, J., Walsh, M., Mahon, J.: Value of Infarctspecific Isotope (SmTclabelled stannous pyrophosphate) in myocardial scanning. Brit. Med. J. 11 : 517, 1975. Folland, E., Ritchie, J., Hamilton, G., Kennedy, J.: First pass and blood pool radioisotope angiography as methods of determining left ventricular ejection fraction. J. Nucl. Med. 18: 600, 1977. Gorten, R., Hardy, L., McCraw, B., Stokes, J., Lumb G.: The selective uptake of Hg203-chlormerodrin in experimentally produced myocardial infarcts. Amer. Heart J. 72: 71, 1966. Hamilton, G., Trobaugh, G., Ritchie, J., Williams, D., Weaver, D., Gould, L.: Myocardial imaging with intravenously injected Thallium-201 in patients with suspected coronary artery diseasc. Amer. J. Card. 39: 347, 1977. Henning, H., Schelbert, H., Ashburn, W., Kalliner, J.: Relation between left
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ventricular performance assessed by scintigraphic and enzymatic methods. J. Nucl. 18: 681, 1977. Henning, R., Lundman, T.: Swedish cooperative CCU-study. Acta Med. Scand., suppl. 586, 1975. Holman, L., Chisholm, R., Braunwald, E.: The prognostic implication of acute myocardial infarct scintigraphy. J. Nucl. Med. 18: 61 1, 1977. Holman, B., Davis, M., Hanson, R.: Myocardial infarct imaging with Technetium-labelled complexes. Sem. Nucl. Med. 7: 29, 1977. Holman, L., Lesch, M., Zweiman, F., Temte, J., Lown, B., Gorlin, R.: Detection and sizing of acute myocardial infarcts with SmTc-tetracycline. New Engl. J. of Med. 291: 159, 1974. Hubner, P.: Radioisotopic detection of experimental myocardial infarction using mercury derivates of flourescein. Cardiovasc. Res. 4: 509, 1970. Jacobstein, J., Alonso, D., Roberts, A., Cipriano, P., Combes, J., Post, M.: Early diagnosis of myocardial infarction in the dog with SmTc-Glucoheptonate J. Nucl. Med. 18: 413, 1977. Leibowitz, A., Greene, M., Fairchild, R., Bradley-Moore, P., Atkins, H., Ansori, A., Richards, P., Belgrave, E.: Thallium 201 for medical use. J. Nucl. Med. 16: 151, 1975. Lessem, J., Johansson, B. W., Nosslin, B.: Myocardial scintigraphy in 150 coronary care unit patients. European J. Cardiol, 4: 453, 1976. Lessem, J., Johansson, B. W., Nosslin, B., Thorell, J.: Clinical analysis of myocardial scintigraphy with SmTcpyrophosphate. Medical Radionuclide i,maging, Proceedings of a symposia vol 11: 231, 1977, IAEA, Vienna. Lessem, J., Persson, B.: Myocardial scintigraphy in Chages disease. Lancet, in press, 1977. Lessem, J., Polimeni, P., Page, E., Resnekov, L., Harper, P.: Tc-99m pyro-
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phosphate image of rat ventricular infarcts, correlation of time course with microscopic pathology. Amer. J. Card. 39: 279, 1977. Lyons, K., Olson, H., Kupers, J., Aronow, W., Stemmer., E.: Preoperative, postoperative and late follow-up Tc99m pyrophosphate myocardial scintigraphy and coronary by pass surgery. J. Nucl. Med. 18: 612, 1977. Malek, P., Vavrejn, B., Ratsky, J., Konrad, L., Kolc, J.: Detection of myocardial infarction by in vivo scanning. Cardiologia 51: 22, 1967. Maseri, A., Parodi, O., Severi, S., Desola, A.: Transient transmural reduction of myocardial blood flow, demonstrated by Thallium 201-scintigraphy as a cause of variant angina. Circulation 54: 280, 1976. Mc Laughlin, P., Coates, G., Wood, D., Cradduck, T., Morch, J.: Detection of acute myocardial infarction by Technetium-99m polyphosphate. Amer. J. Cardiol. 35: 390, 1975. Oldendorf, W.: Evaluation of a simple technique for abrupt intravenous injection of radioisotope. J. Nucl. Med. 6: 205, 1965. Parisi, A., Tow, O., Sasakala, A.: Clinical appraisal of current nuclear and other noninvasive cardiac techniques. Am. J. Card. 38: 722, 1976. Parkey, R., Bonte, F., Stokely, E., Lewis, S., Graham, K., Buja, M., Willerson, J.: Acute Myocardial Infarction imaged with 99mTc-stannous pyrophosphate and 201Tl a clinical evaluation. J. Nucl. Med. 17: 776, 1976.
39. Pitt, B., Strauss, W.: Myocardial imaging in the Noninvasive evaluation of Patients with suspected ischemic heart Disease. Amer. J. Cardiol. 37: 797, 1976. 40. Pitt, B., Strauss, W.: Myocardial Per-
fusion Imaging and gated cardiac blood pool scanning. Amer. J., Card. 38: 739, 1976.
41. Platt, M., Mills, L., Parkey, R., Willerson, J., Bonte, F., Shapiro, W., Slugg, W.: Perioperative myocardial infarction diagnosed by Technetium-99m stannous pyrophosphate myocardial scintigrams. Circulation 54: suppl I11 -24, 1976. 42. Ramanathan, P., Ganatra, R., Daulatram, K., Sen, P., Blau, M.: Uptake of 203Hg-hydroxy-mercury-fluoresceinin Myocardial infarcts. J. Nucl. Med. 12: 641, 1971. 43. Rigo, P., Strauss, W., Taylor, D., Kelly, D., Weisfeldt, M., Pitt, B.: Left ventricular function in acute myocardial infarction evaluated gated scintiphotography. Circulation 50: 678, 1974. 44. Romhilt, D., Adolph, R., Sodd, V., Levenson, N., August, L., Nishiayama, A., Betke, R.: Cesium-129 myocardial scintigraphy to detect myocardial infarction. Circulation 48: 1242, 1973. 45. Rose, L.: Portability in nuclear medicine Applied Radiology Nov, Dec: 210, 1976. 46. Sapirstein, L.: Regional blood flow by fractional distribution of indicators. Amer. J. Physiol. 193: 161, 1958. 47. Schelbert, H., Henning, H., Ashburn, W., Verba, J., Karliner, J., O’Rourke, R.: Serial measurements of left ventricular ejection fraction by radionuclide angiography early and late after myocardial infarction. Amer. J. Card. 38: 407, 1976. 48. Schelbert, H., Ingwall, J., Sybers, H., Ashburn, W.: Uptake of infarct-imaging agents in reversibly and irreversibly injured myocardium in cultured fetal mouse heart. Circ. Res. 39: 860, 1976. 49. Shen, A., Jennings, R.: Myocardial calcium and magnesium in acute ischemic injury. Amer. J. Pathol. 67: 417, 1972.
50. Shen, A., Jennings, R.: Kinetics of calcium accumulation in acute myocardial ischemic injury. Amer. J. Path. 67: 441, 1972. 51. Strauss, W., Pitt, B.: Common procedures for noninvasive determination of regional myocardial perfusion, evaluation of regional wall motion and detection of acute infarction. Am. J. Card. 38: 731, 1976. 52. Strauss, W., Pitt, B.: Thallium-201 as a myocardial imaging agent. Sem. Nucl. Med. 7: 49, 1977. 53. Wackers, F., Koen, L., Sokole, E., Samson, G., v.d. Schoot, J., Wellens, A., Durrer, D.: Thallium-201 scintigraphy in unstable angina. J. Nucl. Med. 18: 594, 1977. 54. Wackers, F., Sokole, E., Samson, G., v.d. Schott, J., Wellens, H.: Myocardial imaging in coronary heart disease with radionuclides with emphasis on Thallium-201. Eur. J. Cardiol. 4: 273, 1976. 55. Walsh, W., Schwartz, J., Bautovich, G., Booth, A., Harper, P., Al-Sadir, J., Resnekov, L.: Localization patterns of 99m Technetium-diphosphonate in experimental myocardial infarction. Clin. Res. 23: 213, 1975. 56. Willerson, J., Parkey, R., Bonte, F., Meyer, S., Atkins, J., Stokley, E.: Technetium stannous pyrophosphate myocardial scintigrams in patients with chest pain of varying etiology. Circulation 51: 1046, 1975. 57. Zaret, B., Vlay, S., Freedman, G., Wollson, S., Cohen, L.: Quantitative relationship between Potassium-43 imaging and left ventricular cineangiography following myocardial infarction in man. Circulation 52: 1076, 1975.
37
The history of cardiovascular nuclear medicine is intimately related to the development of nuclear medicine and to the desire of cardiologists to find procedures less traumatic than catheterizations (4, 39). These factors combined with difficulties of diagnosing ischaemic heart diseases in some pa-
tients, due to previous pathological ECG and equivocal enzyme response, led to the use of radionuclide methods in this group of patients. Most patients with suspected acute myocardial infarction are usually immobile during the first phase of their disease and are monitored in a coronary care unit.
Fig. 1. A mobile gammacamera - Portacamera I ! c (General Electric). Bedside examination i s shown.
27
Radionuclide methods were not available to the cardiologist, despite the development of better radiopharmaceuticals, until the recent development of the mobile gamma camera (fig. 1). This brought bedside nuclear medicine into the coronary care unit (45). The employment of radionuclide methods in the diagnosis and evaluation of patients with acute myocardial infarction followed mainly three directions (Table I):
Table I Methods used In cardlovascular nuclear medlclne I . Positive infarct scintigraphy - substances accumulating in necrotic myocardium: 203Hg- Mercurascan 67Ga 99mTc-pyrophosphate WmTc-tetracycline WmTc-glucoheptonate 2. Negative infarct scintigraphy - substances accumulating in normal myocardium 43K 86Rb 131cs
129cs
zolTl
+
13NH4
54Mn llC-Palmitic acid 3. Radiocardiography - hernodynamic assesments WmTc-human serum albumin WmTc-erythrocytes 1) “Positive” infarct scintigraphy, with sub-
stances accumulating in infarcted myocardium. Among the first substances described were mercury isotopes, such as 203Hgtagged to hydroxymercuryfluorescein (33) which gave satisfactory results in dogs with induced acute infarct (18, 25, 42); these never succeeded clinically. Recently, a different group of substances, mainly phosphates labelled with WmTc, were shown to be clinically applicable in the diagnosis of acute myocardial infarction. Bonte and coworkers (6)
28
showed that a pyrophosphate labelleled with 99mTc accumulated in acutely infarcted myocardium. Later others verified this (16, 28, 35, 56). 9 9 m T c pyrophosphate proved exrrcmely useful in diagnosing peri- and postoperative myocardial infarctions (32, 41); in this clinical setting, enzymes and ECG cannot be used after cardiac surgery. 99mTc, obtained as a daughter product of WMo, has a half-life of 6 hours and gamma ray energy of 147 keV. Thus it is suitable for the low energy mobile gamma cameras. The mechanism behind the pyrophosphate uptake is obscure, but it has been postulated that pyrophosphate has an affinity to hydroxyapatite crystals formed in the mitochondria when the myocardial cells undergo necrosis (8, 49, 50). Several groups (12, 20, 48) recently presented evidence that pyrophosphate is taken up mainly by irreversibly damaged myocardial cells. These might still have some perfusion left (55) thus enabling pyrophosphate to reach them. Simultaneously with the development of 99mTc-pyrophosphate, other agents, such as WmTc-tetracycline (23, 24) and later WmTc-glucoheptonate (26), were introduced as infarct labelling agents. However, both these substances have largely been abandoned, as the interval between injection of the radionuclide and the imaging procedure was too long, allowing other parameters to provide the diagnosis. ”Negative” infarct scintigraphy using substances accumulating in normal myocardium. These radionuclides are believed to reflect regional myocardial perfusion, and when the perfusion is decreased, a perfusion defect appears in the scintigram. The substances in this group are potassium-43 (57) and its analogues. Several have been used, such as 86Rb (11), I3lCs (4, 12), and lZ9Cs (44). All of them had a gamma energy level more suitable for the rectilinear scanner than for the gamma camera; thus their clini-
cal applicability was limited. Recently, another potassium analogue, 201T1, was introduced (27) and proved to be a very useful tool in the diagnosis of acute myocardial infarction (19, 52, 54). I t has two energy levels, (80 and 167 keV), both being ideal for the low energy mobile gamma cameras. The long half-life (about 72 hours) eliminates the disadvantage of being a cyclotron produced product. The potassium analogues reflect the function of the sodium-potassium pump within the myocardial cells. When the myocardium is perfused, a significant amount of potassium is withheld intracellularly. If the perfusion is decreased, the amount of available potassium is also decreased; thus a perfusion defect in the scintigram will appear. From this, it is apparent that no differentiation of the age of the perfusion defect is possible with these radionuclides.
720
-
640
-
576
-
504
-
432
-
360
-
288
-
216
-
144
72
Maseri and coworkers (34) showed that potassium or its analogues are largely extracted by the myocardium during the first circulatory pass, and when evenly mixed with the blood, are distributed proportionally to the cardiac output (46). 3) Radiocardiography, where the left ventricular function and wall motion are studied. Ventricular function can be measured non-invasively by two methods: First by recording the initial passage of a bolus injected blood pool tracer through the heart, first Fass study, which Ashburn and Schelbert utilized (47). The first pass method utilizes a recording of the time-activity curve over the left ventricle that has peaks and valleys corresponding to end-diastole and end-systole (Fig. 2). Second by data recording after the tracer has equilibrated. An ECG-gate and the scintillation camera is used so that images
-
0
Fig. 2. A first passage curve is exemplified. The ejection fraction in this patient was calculated to be 4 1 010.
29
Several studies, independent (17) of each other, have shown (17, 51) correlation coefficients of 0.9 or better for ejection fractions obtained with radionuclide methods and angiography (37). Impaired left ventricular function can then be diagnosed. Left ventricular wall motion is best studied with gated blood pool studies, where diagnosis of akinetic a n d dyskinetic areas can easily be made. Both methods have the advantage of accumolating data over a relatively short time. This allows them to be used rather easily in the coronary care unit. They can very easily be repeated several times during the patient’s stay in the ward, and thereby yield information of his day to day heniodynamic situation. It seems as though both methods, properly utilized, can predict left ventricular failure early (15, 51) and also estimate the effect of treatment. The indications for using radionuclide methods in cardiology are several and have been demonstrated by several reports. The following seem to be the major indications: 2) Differentiation of origin of chest pain (47) b) Previous pathological ECG, e.g., bundle Fig. 3. After injection of 15 mCi 99~nTc-human branch block, remaining ST-T changes serum albumin, a gated study was performed in after previous infarcts in combination this patient. The upper panel illustrates endwith chest pain postoperatively systole and the bottom panel illustrates endc) Differentiation bctween new and old indiastole. N o akinetic area can be recognized. farcts (54) d) No adequate enzyme response, e.g., alare recorded during end-systole and endcoholism, liver pathology, postoperatidiastole (40, 43) (Fig. 3). Gated studies vely have the advantage of being able to use several views after a single tracer injection, e) Hemodynamic assebsement of the working capacity of the right and left venand are therefore more like regular angiotricles during several phases of the ingraphy. Both methods can be used to calfarct culate the left ventricular ejection fraction, according to the following formula: Besides these, several reports by Botvinick and coworkers have shown that sizing of LVEF = EDV - ESV/EDV - BKG, infarcted myocardium can be performed where with WmTc-pyrophosphate (7). Holman and LVEF = left ventricular ejection coworkers recently confirmed these findings fraction (22). These results suggest that in the future E D V = end-diastole volume it will be possible to judge the efficiency of ESV = end-systolic volume decreasing the size of a necrotic area b y BKG = background pharmacological o r surgical interventions.
30
These techniques make possible early diagnosis of acute myocardial infarction (29). Willerson and coworkers found positive pyrophosphate scintigrams already 12 hours after the onset of symptoms; Wackers et a1 found that perfusion defects with 20*T1could be diagnosed as early as 6 hours after the cnset of symptoms. In Wackers’ series all patients examined before 6 hours after the onset had developed perfusion defects in areas later corresponding to ECGlocalization of the infarct (54).
Cllnlcal study All these methods were used in patients admitted to the coronary care unit of the Malmo General hospital with primary clinical suspicion of acute myocardial infarction due to severe chest pain, pulmonary oedema, dysrythmias, and dyspnea. The clinical diagnosis of acute myocardial infarction was based on any of the following criteria: Subjective symptoms in combination with typical QRST-changes in the ECG Subjective symptoms in combination with two elevated enzyme values (SASAT, S-LD) Typical QRST-changes in the ECG in combination with two elevated enzyme values Autopsy data (21, 28). In contrast, the diagnosis of unstable angina pectoris was based on a combination of the following criteria: Previous stable angina, or angina of recent onset with progresive increase in severity of symptoms Angina at rest with recurrent episodes lasting more than 20 minutes and poorly relieved by nitrates No elevation of serum enzymes Transient ST-T changes that frequently return to normal after the attack (10, 4). All 350 patients were examined with 10 mCi NmTc-pyrophosphate (Byk-Mallincrodt, USA, Solcoscint, Kabi-Diagnostica,
Diagnostics inc., USA); 125 patients were also investigated with 1.5 mCi 201Tl (Philips Duphar, the Netherlands). In 48 patients, different hemodynamic evaluations were also made. A mobile gamma camera, Portacamera I1 B or C (General Electric, USA) was used with a standard low-energy parallel hole colimator. The scintigrams were obtained in anterior - posterior, left 30” anterior oblique and left lateral positions. All were evaluated for presence, absence, size, localization, and intensity of an uptake or a defect. When radiocardiography was performed, the left ventricular ejection fraction was counted; if a gated study was undertaken, the wall motion was estimated.
Results
Of the 350 pyrophosphate examinations, 264 showed positive uptakes (Table 11). I n the group of 188 patients with acute transmural infarction, 180 showed radionuclide accumulation and well localized intense uptakes in 90 per cent. (Fig. 4). The correla-
Fig. 4 . Myocardial rcintigram with 99mTc-pyrophosphate, recorded 90 minutes after injection, in LAO 30’ position. An anterior grade 3 intense uptake was recorded in the patient with a transmural anterior infarct. The recording was made with the Portacamera II c.
31
tion between the uptake localization and ECG localization of the infarct was excellent. All 5 patients with left bundle branch block, but who fulfilled the criteria for acute myocardial infarcion also exhibited well localized and intense pyrophosphate uptakes. The earliest uptake was registered in 10 patients examined 4 hours after the onset of symptoms. Of the patients diagnosed as unstable angina pectoris, 73 per cent showed an uptake; but this was distinctly different lrom the uptake in transmural infarcts, which also Abr'ulla and coworkers found ( I ) . These patients had low graded, diffusely spread uptakes (Fig. 5 ) . Fig, 6 . A huge antero-lateral uptake with the intensity graded 3. The patient suffered f r o m Chagas disease. The scintigram mimicked the pattern of transmural myocardial infarction.
Fig. I. A 42-year old male with a diffuse low intense pyrophosphate uptake seen in combination with unstable angina pectoris.
Positive uptakes were found in five patients with other cardiac diseases. One had Chagas disease (30) (Fig. 6 ) , and one, Prinzmetal variant angina. Two were found in patients with old infarcts and ventricular aneurysms, which al.so Ahmad (2) observed. The final positive pyrophosphate scintigrams were registered in a patient who developed an acute myocardial infarction after defibrillation (Fig. 7), a finding previously reported by diCola and coworkers (14).
32
Fig. 7 . A pyrophosphate uptake recorded in a patient after transthoracic counter current schock.
125 patients were also examined with
Zo1T1. A very good correlation existed between a thallium defect and a pyrophosphate uptake (Fig. 8). However, seven TIscintigrams showed perfusion defects where no new infarct could be verified in patients who had previously sustained infarcts.
separate them from those with acute myocardial infarction. A similar finding was recently reported by Wackers and coworkers (53). No false negative has been reported with 201Tl-scintigraphy. Gated thallium studies have also been performed with a pin hole collimator (focusing on the septum) which has been utilized when septal infarcts o r conduction disorders were present (Fig. 10).
Fig. 8. An LAO
4 1 O recording with 201T1, in a pctient with an inferior transmural infarct. In the apical area a large perfusion defect is seen. The recording was made with Portacamera 11 c 20 minutes after injection.
In six of them the pyrophosphate examination remained negative and in one it was questionably positive, probably owing to a ventricular aneurysm. Five patients with unstable angina pectoris had perfusion defects (Fig. 9) thus making it impossible to
Fig. 10. A gated 2olTl-study performed with a pin hole collimator in a patient with a left bundle branch block. The upper panel illustrates end-systole and the lower end-diastole. In the lower panel, a perfusion defect is seen in the septal region.
Conslusions Fig. 9. The LAO 4 j 0 recording with 201T1, in a patient with unstable angina. Note the decreased perfusion in the antero-spetal region.
I t can be concluded that both 99mTc-pyrophosphate and 201T1 are useful aids in the diagnosis of acute myocardial infarction, as Parkey and several others have shown (29, 38, 5). Both methods have a high degree of
33
sensitivity and specificity and rarely show false negative results. False positives appear in patients with unstable angina pectoris or with old infarcts, and this applies for both radionuclides. The decision about which radionuclide method or combination is most useful in the evaluation of a specific patient with chest pain largely depends on the clinical situation and the questions being asked. If an acute diagnosis is looked for, 99mTcpyrophosphate seems to be the isotope of choice, judging by the evidence in the literature (53, 56). In a patient where all clinical evidence supports the diagnosis of myocardial infarction, but where any of the laboratory parameters fail, 201T1 seems to be the ideal isotope for the subacute situations. Several authors (54) recommend 20*TI when it is a question of silent and old infarction.
Any combination with radiocardiography seems to be feasible when the left ventricular function should be studied in a patient with or without an cstablished acute myocardial infarction. If any method, either positive or negative infarct scintigraphy, yields a positive result, che probability that the patient has an acute infarction is more than 85 per cent. This at least equals the sensitivity of the otherwise routinely used clinical methods (20, 22). The possibility of differentiating between unstable angina pectoris and myocardial infarction (29, 56) adds another important dimension to these methods. Combined with radiocardiography and determination of left ventricular function it adds a new important, and powerful tool in the evaluation of patients with acute myocardial infarction.
Table II: Summary of the result wlth WmTc-pyrophosphate Number of patients
188
5
Diagnosis
Transmural AM1 Left Bundle Branch block with AM1
Positive pyrophosphate scintigrams
Negative p y rophosphate scintigrams
180
8
5
0
22
Subendocardial AM1
22
10
75
Unstable angina pectoris
52
23
29
Other cardiac disorders
5
24
(I Chagas, 1 Prinzmetal, 2 ventricular aneurysms, 1 post defibrillation) 21
34
Non-cardiac disorders
0
21
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37
