Effects of Myocardial Hypoxia and lschemia on Myocardial Scintigraphy
NORMAN I. LEVENSON, MD* ROBERT J. ADOLPH, MD, FACC DONALD W. ROMHILT, MD MARJORIE GABEL VINCENT LEON
J. SODD,
S. AUGUST,
PhD PhD
Cincinnati, Ohio Washington. D. C.
From The Division of Cardiology, Department of Internal Medicine: Department of Radiology, Radioisotope Laboratory; Nuclear Medicine Laboratory, Bureau of Radiological Health, Food and Drug Administration, University of Cincinnati Medical Center, Cincinnati, Ohio, and the Cyclotron Branch, Naval Research Laboratory, Washington, D. C. This study was supported in part by Contract NIH NHLI 71 2489 under the Myocardial Infarction Program, from the National Heart and Lung Institute, National Institutes of Health, Bethesda, Md., by U. S. Public Health Service Grant HE-8307, and by the Southwestern Ohio Heart Association, Cincinnati, Ohio. *Supported by Veterans Administration Training Grant TR-200. Manuscript accepted July 24, 1974. Address for reprints: Donald W. Romhilt, MD, Cardiac Research Laboratory, H3, University of Cincinnati Medical Center, 234 Goodman St., Cincinnati, Ohio 45229.
The effect of regional myocardiai ischemia and hypoxia on myocardial scintigraphy was studied in patients and dogs after intravenous administration of cesium-129. Seven men with angiographically proved ischemic heart disease underwent exercise testing and 12gCs was given immediately when ischemia was manifested in the electrocardiogram. Defects were not evident in the scintigrams of any patient. Failure to visualize a defect might be related to delayed uptake of 12gCs by the myocardium (maximal uptake in 45 minutes). The ischemic state was dissipated before the disparity in uptake between normal and ischemic myocardium could be visualized. Cesium-129 is useful for identifying acute myocardiai infarcts but should not be used to visualize transient exercise-induced regional ischemia. Six dogs were given 12aCs afler induction of regional myocardial hypoxia by perfusion of the anterior descending coronary artery with venous blood. In each, scintigraphy revealed a defect that resolved after reperfusion with arterial blood. Two other dogs were given 12gCs before perfusion with hypoxemic blood; neither dog manifested a defect. Since perfusion was maintained by a pump these results suggest that the major cause of the scintigraphicaliy observed defect was inadequate cellular uptake of 12gCs rather than excessive cellular loss. Since regional myocardial hypoxia produced a reversible defect, scintigraphic studies might overestimate the size of an acute myocardial infarct in man by including the ischemic zone surrounding the infarct.
Myocardial scintigraphy performed with intravenously administered radionuclides can be used to detect areas of myocardial infarction or ischemia.1-4 The cyclotron-produced radionuclides potassium-43 and cesium-129 that have recently become available have more suitable gamma energies for deep tissue imaging than did earlier radionuelides. We have reported the effectiveness of i2eCs myocardial scintigraphy in the diagnosis of myocardial infarction.” Since the patient’s prognosis and likelihood of experiencing cardiogenic shock after myocardial infarction are related to the amount of myocardium that is infarcted, noninvasive techniques that will accurately quantify the size of an acute myocardial infarct are needed.5,fi Quantification is also needed to evaluate the efficacy of drugs and solutions in limiting the size of a myocardial infarct7 and to determine the possible effect of a periinfarction zone of ischemia upon the size of the defect observed in scintigrams after acute myocardial infarction. If ischemia contributes significantly to the observed defect, the size of a myocardial infarct could be overestimated by scintigraphy. Studies designed to elucidate the possible causes of the defect seen on myocardial scintigrams obtained with izgCs have not been reported. Zaret et al.2 using 43K myocardial scans attributed the defects observed to inadequate perfusion and to ischemia-induced efflux of potassium from the myocardium.
February 1975
The American Journal of CARDIOLOGY
Volume 35
251
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IN MYOCARDIAL
ISCHEMIA-LEVENSON
ET AL.
Pressure Tronsducen
ret%-,
FIGURE 1. Schematic diagram of the preparation used to produce regional myocardial hypoxemia in dogs. Ant. = anterior; Art. = artery; Lt. = left.
The purpose of this study was two-fold. In patients, we studied the efficacy of intravenously administered 12gCs as an agent for evaluating the effects of exercise-induced regional myocardial ischemia. In dogs, we attempted to clarify in part the several mechanisms by which ischemia may produce a defect on scintigrams obtained with 12gCs. Studies in dogs were designed to separate the effects of regional hypoxemia on cellular uptake of 12gCs from the more generalized effects of the regional ischemia observed in man. In ischemia, unlike hypoxemia, there is decreased coronary blood flow and perfusion pressure, decreased delivery of substrate and decreased removal of acid metabolites, all of which could contribute to a scintigraphic defect. Ischemia and hypoxemia have in common decreased oxygen tension (PO,). It was our intent to study only the effects of regional hypoxemia. Coronary perfusion with hypoxemic blood was preserved by controlling coronary blood flow and maintaining perfusion pressure with a roller pump. If we had produced ischemia by partial occlusion of the coronary artery, we would not have been able to separate the effects of decreased delivery of radionuclide to the myocardium and increased transit time across the membrane from the effects of hypoxia. In addition, with decreased perfusion pressure the dilution of ischemic blood by collateral blood flow and preferential shunting of oxygen and radionuclide from normally perfused surrounding myocar-
252
February 1975
The American Journal of CARDIOLOGY
dium could have confused tigrams.
interpretation
of the scin-
Methods Cesium-129 was produced at the Cyclotron Branch of the Naval Research Laboratory in Washington, D. C., The 12gCs was extracted by the method of Sodd et a1.8 of our nuclear medicine laboratory, resulting in carrier-free 12gCs. Scintigraphy was performed with a gamma scintillation camera and a coarse pinhole collimator with an energy setting of 360 kilo electron volts and a 35 percent window. Five to 10 minutes was required to obtain each, view, and 200,000 counts were collected per view. Seven men aged 38 to 57 years with known ischemic heart disease were studied. The diagnosis of ischemic heart disease was established in each patient by a history of angina pectoris, an ischemic response to a submaximal graded treadmill exercise test and coronary angiographic evidence of at least 50 percent obstruction in one or more of the major coronary arteries. One patient had clinical and electrocardiographic evidence of a prior myocardial infarction. A graded submaximal treadmill exercise test with continuous monitoring of the electrocardiogram was performed according to the protocol of Roitman et al.9 Patients performed exercise until the appearance of angina pectoris and/or 1 mm of horizontal S-T segment depression of 0.08 second’s duration in the monitored electrocardiogram. At this point, 4 mc of tzgCs was administered intravenously through a scalp-vein needle that had previously been placed in the antecubital vein. Exercise was then terminated. The patient was transported immediately by a physi-
Volume 35
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cian to the gamma camera with an accompanying portable electrocardiographic monitor and defibrillator. Scintigraphy was performed 10 minutes after administration of 1Ws. Five views were obtained in the following order: left lateral, left anterior oblique, anterior, left posterior oblique and right anterior oblique. Experimental studies: Using dogs, we designed a preparation to assess the effect of reduced oxygen delivery from obstructive coronary arterial lesions on 12gCs myocardial scintigrams. To ensure adequate delivery of isotope to the myocardium, flow in the anterior descending coronary artery was controlled and hypoxemia was produced by perfusion with venous blood having a low oxygen content. In eight mongrel dogs control scintigrams were obtained 1 week before the study. Anesthesia was induced with intravenously administered pentobarbital and the dogs were artifically ventilated with a Harvard respirator. The heart was exposed through a left lateral thoracotomy. Two epicardial electrodes were sewn on the anterior and lateral walls, respectively, of the left ventricular myocardium, and unipolar electrograms were recorded from the two locations simultaneously. The right femoral artery and both jugular veins were cannulated with large bore tubing. The venous return from the jugular veins and the femoral arterial return were joined by a Y cannula to a coronary arteri.a1 inflow catheter and tubing and passed through an occlusive Sarnes roller pump. A schematic diagram of the preparation is illustrated in Figure 1. Venous or arterial inflow was selected by clamping the respective inflow line. The pump was calibrated for flow rates of 10 to 50 cc/min using timed collections of blood. The proximal segment of the anterior descending branch of the left coronary artery was dissected free and cannulated with a plastic no. 5F catheter as close as possible to its origin from the main left coronary artery. Blood PO2 was mea-
Summary Case no.
IN MYOCARDIAL
ISCHEMIA-LEVENSON
ET AL.
sured with the Astrup method. The coronary artery initially was perfused by arterial blood with a PO2 of 80 to 120 mm Hg. Flow was maintained at a rate that produced a mean perfusion pressure equal to a simultaneously recorded mean aortic pressure. Pressures were measured using Statham P23 Db pressure transducers. Aortic pressure, perfusion pressure and the two epicardial electrograms were recorded simultaneously on a direct-writing Hewlett Packard physiologic recorder. Flow was not altered thereafter. Regional myocardial hypoxia was produced by perfusing the left anterior descending coronary artery by jugular venous blood with a PO2 of 25 to 35 mm Hg. Hypoxia was considered present when the S-T segment was elevated at least 5 to 6 mm above the control level and myoeardial cyanosis was observed in the distribution of the left anterior descending coronary artery. In six of the eight dogs studied, 6 mc of lzgCs was injected into the inferior vena cava after induction of hypoxemia. Hypoxemia was maintained until scintigrams in three views (anterior, left anterior oblique and left lateral) were obtained. Scintigraphy was started 15 to 20 minutes after administration of 12gCs, and 5 to 10 minutes was required to obtain each scintigram, Coronary perfusion with venous blood then was discontinued and femoral arterial perfusion was reinstituted. The hypoxic state was considered to have reverted to normal on disappearance of both S-T segment elevation and myocardial cyanosis, which occurred 5 to 15 minutes after arterial reperfusion. Serial scintigrams were obtained every 15 minutes for 180 minutes in the view in which the defect was most easily visualized. After this period repeat scintigrams in the other two views were obtained. The remaining two dogs were studied in a different manner to evaluate the possibility that the scintigraphically observed defect was related to excessive efflux of 12aCs from
of Results in Seven Patients Graded Exercise Test
Resting ECG
1
lschemic
No infarct
2
lschemic
No infarct
3
lschemic
4
lschemic
No infarct Inferior infarct
5
lschemic
6
lschemic
7
lschemic
No infarct No infarct No infarct
Coronary Stenosis on Angiogram
Left Ventriculogram
Exercise 1%~ Scintigram
LCA, 50%; LAD, 75%; LCX, 75%; RCA, 90% LAD, 70%; LCX, 35%; RCA, 55% RCA, 90%
Normal
No defect
Not performed
No defect
Normal
No defect
LAD, 60%; LCx; 70% RCA, 80%
No change in control defect
LCX, 100%
Generalized hypokinesia, akinesia of apex Not performed
LAD, 65%; RCA, 45% LAD, 65%
Generalized hypokinesia Normal
ECG = electrocardiogram; LAD = anterior descending branch of the left coronary circumflex branch of the left coronary artery; RCA = right coronary artery.
February 1975
artery;
No defect No defect No defect
LCA = left main coronary
The American Journal of CARDIOLOGY
artery;
LCx =
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the myocardial cells. In these two dogs the same preparation was utilized but izgCs was administered during the initial femoral arterial perfusion of the left anterior descending coronary artery and three control scintigrams were obtained. The left anterior descending coronary artery was then perfused with jugular venous blood for 180 minutes, and scintigrams were obtained in the anterior view every 15 minutes. After 180 minutes repeat scintigrams in all three views were obtained. The recordings were interpreted by
Clinical Findings
experienced
in interpreting
Results
The appearance of normal myocardial scintigrams obtained with use of intravenously administered 12gCs has previously been described in detail.:3 There is an even uptake of 12gCs by the myocardium, which
LAO
ANT.
L.Lat.
FIGURE 2. Case 5. Normal myocardial scintigram after exercise of a male patient without clinical or electrocardiographic evidence of myocardial infarction ANT. = anterior view; LAO = left anterior oblique view: L.Lat. = left lateral view: LPO = left posterior oblique view.
LPO
A N T.
LAO
FIGURE
3. Dog 2. Normal myocardial
254
February
1975
two independent investigators myocardial scintigrams.
scintigram
The American
obtained
before production
Journal of CARDIOLOGY
Volume
L.Lat. of hypoxemia
35
SCINTIGRAPHY
resembles a horseshoe or doughnut in the various views. Figures 2 and 3 are normal scintigrams from a patient (Case 5) and a dog, respectively. In the center of each scintigram there is a region of decreased to absent activity that represents the left ventricular cavity. The right ventricle is seen in some scintigrams as a thin wall that extends from the superior aspect of the interventricular septum. In one of the seven patients (Case 4) with documented coronary artery disease, an area of decreased activity in the myocardial scintigram taken after exercise was identical to that activity observed in the control scintigram taken at rest. The patient’s electrocardiogram revealed an old inferior wall myocardial infarction. Thus, none of our patients had areas of decreased activity in the myocardial scintigram that could be attributed to exercise-induced myocardial ischemia (Table I). Experimental Findings Each of the six dogs given 12gCs before production of regional myocardial hypoxemia had an area of decreased to absent activity in the myocardial scintigram during hypoxia. The defect was present in one or all of the views taken and involved the apex
A
CONTROL
IN MYOCARDIAL
ISCHEMIA-LEVENSON
ET AL.
and anterior wall of the left ventricle (Fig. 4). The defect in the scintigram corresponded to the area that was cyanotic when perfused with venous blood. Scintigrams in five of the six dogs demonstrated complete resolution of the defect 60 to 180 minutes after reinstitution of arterial perfusion. In the remaining dog partial resolution of the defect was observed in the lateral view but complete resolution in the left anterior oblique and anterior views. In contrast, the two dogs that received 12gCs before the production of hypoxia did not manifest scintigraphic defects after 180 minutes of perfusion with hypoxemic venous blood. Discussion Myocardial scintigraphy using 12gCs and a gamma camera has been shown to be a safe, simple and effective method for detecting an acute or old myocardial infarction.3 In previous studies a myocardial infarction appeared in the scintigram as a defect or area of decreased to absent scintillations interrupting the smooth horseshoe or doughnut-shaped contour of the left ventricle. This study revealed that hypoxemia causes identical defects in the scintigram, and Zaret et a1.2 have shown similar results in exercise-induced myocardial ischemia.
HYPOXIA
C
FIGURE 4. Dog 2. Sequential myocardial scintigrams in the anterior view. A, control scintigram. B, arrows outline the scintigraphic defect after 75 minutes of regional hypoxemia with venous blood. C, partial resolution of scintigraphic defect after 12 minutes of arterial reperfusion. D, complete resolution of scintigraphic defect after 180 minutes of arterial reperfusion.
February 1975
D
ARTERIAL REPERFUSION
ARTERIAL REPERFUSION
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Scintigraphic effect of hypoxia: A defect appearing in the scintigram could result from any or all of the following mechanisms in coronary artery disease: (1) inadequate perfusion, so that less radionuelide is presented to a portion of the myocardium than to surrounding regions that have a normal blood supply; (2) increased cellular permeability induced by hypoxia resulting in a net efflux of radionuclide from the myocardial cells; and (3) decreased cellular uptake of radionuclide secondary to damage of active transport mechanisms. We have demonstrated that in the presence of severe regional myocardial hypoxia with adequate perfusion of that region ensured by controlled flow, the concentration of 12eCs in the hypoxic region of the myocardium was decreased. A defect did not develop during 180 minutes of regional hypoxia in the two dogs that received 12gCs before the induction of hypoxia. The inability to produce defects in these two dogs suggests that the most important cause of scintigraphically observed defects during hypoxemia is not excessive efflux of 12gCs but decreased cellular uptake of 12gCs secondary to damage to the active transport system of the myocardial cellular membrane. Scintigraphic effect of exercise-induced ischemia: Each of the seven patients with an ischemic response to an exercise test and at least 50 percent narrowing of one major coronary artery demonstrated by coronary angiography had a normal exercise myocardial scintigram. This finding differs from the data of Zaret et a1.,2 who reported regions of decreased 4SK uptake with exercise in 16 of 19 patients with angina pectoris and positive coronary angiograms. PoelO reported that the myocardial uptake and clearance of potassium were more rapid and efficient than the uptake and clearance of cesium; however, the maximal myocardial concentration of the two radionuclides was the same. After intracoronary injection, potassium was more efficiently removed from the blood by the myocardium in a single passage than was cesium (71 percent versus 22 percent). Thus, 43K scanning can commence within 5 to 10 minutes after intravenous administration, whereas with use of cesium a delay of 30 to 90 minutes is required to attain maximal counting rates although adequate scintigrams may be obtained within 10 to 15 minutes. The difference between the effects of regional hypoxia in the dog model and exercise-induced regional ischemia in man probably resulted from the delayed myocardial uptake of 12gCs. The period of hypoxia in dogs was sufficiently prolonged to permit differentiation of 12gCs in normal and hypoxemic myocardium. After resolution of hypoxic injury to the myocardial cell
there was sufficient circulating 12gCs available for resolution of the scintigraphic defect. In exercising man, although 12gCs was given during the exerciseinduced ischemic episode and scintigrams were obtained within 10 minutes of intravenous injection and termination of exercise, the ischemic state was dissipated before significant amounts of 12sCs were cleared from the blood and concentrated by the myocardium. The rapid myocardial uptake and concentration of 43K make it the agent of choice for evaluation of transient regional myocardial ischemia during exercise in patients with ischemic heart disease. The effects of ischemia on the kinetics of potassium have been studied both experimentally in the dogll and in pacing-induced angina pectoris in man.12 We could find no previous reports relating to the kinetics of cesium during ischemia. Casell has shown that the efflux of potassium from the ischemic myocardium was dependent on the magnitude and duration of the &hernia. Ischemia differs from hypoxia in that, although reduced oxygen tension is common to both states, perfusion is inadequate in the former. Decreased substrate delivery or retention of anaerobic metabolites, or both, could affect membrane permeability adversely in the ischemic model. Therefore, our studies of regional myocardial hypoxemia in dogs are not entirely applicable to acute myocardial infarction, acute coronary insufficiency or exercise-induced angina pectoris in man. Nevertheless, we have shown that a major cause for a myocardial defect observed in scintigrams obtained with 12gCs is inadequate myocardial uptake by the hypoxic cell in the presence of adequate perfusion. In addition, the presence of a scintigraphically observed defect in both experimental myocardial hypoxia and in exercise-induced ischemia in studies using 4.1K2 suggests that the size of an acute myocardial infarct may be overestimated by myocardial scintigraphy. This discrepancy does not depend upon the physiologic mechanism that causes the scintigraphic defect. Ultimately the sensitivity of myocardial scintigraphy in quantitating the size of an acute myocardial infarct will require correlation with postmortem examination of the heart. Acknowledgment We are grateful for the support and assistance given by Dr. R. 0. Bondelid, Mr. R. B. Theus, Mr. G. E. Miller and the Operation Section of the Cyclotron Branch of the Naval Research Laboratory, Washington, DC., for the production of the rzgCs used in this project; by Richard Grant of the Nuclear Medicine Laboratory for the extraction and preparation of the 12sCs and by Jeannine Lewis and Tim Cahill of the Nuclear Medicine Laboratory for their assistance in obtaining the myocardial scans.
References 1. Carr EA, Gleason G, Shaw myocardial cesium-131.
256
J, et al: The direct diagnosis infarction by photoscanning after administration Am Heart J 68:627-636, 1964
February 1975
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of of
2. Zaret BL, Strauss HW, Martln ND, et al: Noninvasive regional myocardial perfusion with radioactive potassium. N Engl J Med 288:809-812, 1973
Volume 35
SCINTIGRAPHY
3.
4.
5.
6. 7.
Romhilt DW, Adolph RJ, Sodd VJ, et al: Cesium-129 myocardial scintigraphy to detect myocardial infarction. Circulation 48: 1242-1251, 1973 McGowan RL, Nell MD, Zaret BL, et al: Rubidium-81, a new agent for myocardial perfusion scans at rest and exercise, and comparison with potassium-43 (abstr). Am J Cardiol 33:154, 1974 Page DL, Caulfield JB, Kastor JA, et al: Myocardial changes associated with cardiogenic shock. N Engl J Med 285:133-137, 1971 Alonso DR, Scheidt S, Post M, et al: Pathophysiology of cardiogenic shock. Circulation 48:588-596. 1973 Marbko PR, Braunwald E: Modification of myocardiil infarction size after coronary occlusion. Ann Intern Med 79:720-733 1973
IN MYOCARDIAL
ISCHEMIA-LEVENSON
ET AL.
8. Sodd VJ, Blue JW, Scholz KL: lzgCs production via the 127l (LY, 2n) lzgCs reaction and its preparation as a radiopharmaceutical. Phys Med Biol 16:587-598, 1971 9. Roitman D, Jones WB, Sheffield LT: Comparison of submaximal exercise ECG test with coronary cineangiocardiogram. Ann Intern Med 72:641-647, 1970 10. Poe ND: Comparative myocardial uptake and clearance characteristics of potassium and cesium. J Nucl Med 13:557-560 1972 11. Case RB: Ion alterations during myocardial ischemia. Cardiology 56:245-262. 1971/72 12. Parker JO, Chlong MA, West RO, et al: The effect of ischemia and alterations of heart rate on myocardial potassium balance in man. Circulation 42:205-217, 1970
February 1975
The American Journal of CARDIOLOGY
Volume 35
257
NORMAN I. LEVENSON, MD* ROBERT J. ADOLPH, MD, FACC DONALD W. ROMHILT, MD MARJORIE GABEL VINCENT LEON
J. SODD,
S. AUGUST,
PhD PhD
Cincinnati, Ohio Washington. D. C.
From The Division of Cardiology, Department of Internal Medicine: Department of Radiology, Radioisotope Laboratory; Nuclear Medicine Laboratory, Bureau of Radiological Health, Food and Drug Administration, University of Cincinnati Medical Center, Cincinnati, Ohio, and the Cyclotron Branch, Naval Research Laboratory, Washington, D. C. This study was supported in part by Contract NIH NHLI 71 2489 under the Myocardial Infarction Program, from the National Heart and Lung Institute, National Institutes of Health, Bethesda, Md., by U. S. Public Health Service Grant HE-8307, and by the Southwestern Ohio Heart Association, Cincinnati, Ohio. *Supported by Veterans Administration Training Grant TR-200. Manuscript accepted July 24, 1974. Address for reprints: Donald W. Romhilt, MD, Cardiac Research Laboratory, H3, University of Cincinnati Medical Center, 234 Goodman St., Cincinnati, Ohio 45229.
The effect of regional myocardiai ischemia and hypoxia on myocardial scintigraphy was studied in patients and dogs after intravenous administration of cesium-129. Seven men with angiographically proved ischemic heart disease underwent exercise testing and 12gCs was given immediately when ischemia was manifested in the electrocardiogram. Defects were not evident in the scintigrams of any patient. Failure to visualize a defect might be related to delayed uptake of 12gCs by the myocardium (maximal uptake in 45 minutes). The ischemic state was dissipated before the disparity in uptake between normal and ischemic myocardium could be visualized. Cesium-129 is useful for identifying acute myocardiai infarcts but should not be used to visualize transient exercise-induced regional ischemia. Six dogs were given 12aCs afler induction of regional myocardial hypoxia by perfusion of the anterior descending coronary artery with venous blood. In each, scintigraphy revealed a defect that resolved after reperfusion with arterial blood. Two other dogs were given 12gCs before perfusion with hypoxemic blood; neither dog manifested a defect. Since perfusion was maintained by a pump these results suggest that the major cause of the scintigraphicaliy observed defect was inadequate cellular uptake of 12gCs rather than excessive cellular loss. Since regional myocardial hypoxia produced a reversible defect, scintigraphic studies might overestimate the size of an acute myocardial infarct in man by including the ischemic zone surrounding the infarct.
Myocardial scintigraphy performed with intravenously administered radionuclides can be used to detect areas of myocardial infarction or ischemia.1-4 The cyclotron-produced radionuclides potassium-43 and cesium-129 that have recently become available have more suitable gamma energies for deep tissue imaging than did earlier radionuelides. We have reported the effectiveness of i2eCs myocardial scintigraphy in the diagnosis of myocardial infarction.” Since the patient’s prognosis and likelihood of experiencing cardiogenic shock after myocardial infarction are related to the amount of myocardium that is infarcted, noninvasive techniques that will accurately quantify the size of an acute myocardial infarct are needed.5,fi Quantification is also needed to evaluate the efficacy of drugs and solutions in limiting the size of a myocardial infarct7 and to determine the possible effect of a periinfarction zone of ischemia upon the size of the defect observed in scintigrams after acute myocardial infarction. If ischemia contributes significantly to the observed defect, the size of a myocardial infarct could be overestimated by scintigraphy. Studies designed to elucidate the possible causes of the defect seen on myocardial scintigrams obtained with izgCs have not been reported. Zaret et al.2 using 43K myocardial scans attributed the defects observed to inadequate perfusion and to ischemia-induced efflux of potassium from the myocardium.
February 1975
The American Journal of CARDIOLOGY
Volume 35
251
SCINTIGRAPHY
IN MYOCARDIAL
ISCHEMIA-LEVENSON
ET AL.
Pressure Tronsducen
ret%-,
FIGURE 1. Schematic diagram of the preparation used to produce regional myocardial hypoxemia in dogs. Ant. = anterior; Art. = artery; Lt. = left.
The purpose of this study was two-fold. In patients, we studied the efficacy of intravenously administered 12gCs as an agent for evaluating the effects of exercise-induced regional myocardial ischemia. In dogs, we attempted to clarify in part the several mechanisms by which ischemia may produce a defect on scintigrams obtained with 12gCs. Studies in dogs were designed to separate the effects of regional hypoxemia on cellular uptake of 12gCs from the more generalized effects of the regional ischemia observed in man. In ischemia, unlike hypoxemia, there is decreased coronary blood flow and perfusion pressure, decreased delivery of substrate and decreased removal of acid metabolites, all of which could contribute to a scintigraphic defect. Ischemia and hypoxemia have in common decreased oxygen tension (PO,). It was our intent to study only the effects of regional hypoxemia. Coronary perfusion with hypoxemic blood was preserved by controlling coronary blood flow and maintaining perfusion pressure with a roller pump. If we had produced ischemia by partial occlusion of the coronary artery, we would not have been able to separate the effects of decreased delivery of radionuclide to the myocardium and increased transit time across the membrane from the effects of hypoxia. In addition, with decreased perfusion pressure the dilution of ischemic blood by collateral blood flow and preferential shunting of oxygen and radionuclide from normally perfused surrounding myocar-
252
February 1975
The American Journal of CARDIOLOGY
dium could have confused tigrams.
interpretation
of the scin-
Methods Cesium-129 was produced at the Cyclotron Branch of the Naval Research Laboratory in Washington, D. C., The 12gCs was extracted by the method of Sodd et a1.8 of our nuclear medicine laboratory, resulting in carrier-free 12gCs. Scintigraphy was performed with a gamma scintillation camera and a coarse pinhole collimator with an energy setting of 360 kilo electron volts and a 35 percent window. Five to 10 minutes was required to obtain each, view, and 200,000 counts were collected per view. Seven men aged 38 to 57 years with known ischemic heart disease were studied. The diagnosis of ischemic heart disease was established in each patient by a history of angina pectoris, an ischemic response to a submaximal graded treadmill exercise test and coronary angiographic evidence of at least 50 percent obstruction in one or more of the major coronary arteries. One patient had clinical and electrocardiographic evidence of a prior myocardial infarction. A graded submaximal treadmill exercise test with continuous monitoring of the electrocardiogram was performed according to the protocol of Roitman et al.9 Patients performed exercise until the appearance of angina pectoris and/or 1 mm of horizontal S-T segment depression of 0.08 second’s duration in the monitored electrocardiogram. At this point, 4 mc of tzgCs was administered intravenously through a scalp-vein needle that had previously been placed in the antecubital vein. Exercise was then terminated. The patient was transported immediately by a physi-
Volume 35
SCINTIGRAPHY
cian to the gamma camera with an accompanying portable electrocardiographic monitor and defibrillator. Scintigraphy was performed 10 minutes after administration of 1Ws. Five views were obtained in the following order: left lateral, left anterior oblique, anterior, left posterior oblique and right anterior oblique. Experimental studies: Using dogs, we designed a preparation to assess the effect of reduced oxygen delivery from obstructive coronary arterial lesions on 12gCs myocardial scintigrams. To ensure adequate delivery of isotope to the myocardium, flow in the anterior descending coronary artery was controlled and hypoxemia was produced by perfusion with venous blood having a low oxygen content. In eight mongrel dogs control scintigrams were obtained 1 week before the study. Anesthesia was induced with intravenously administered pentobarbital and the dogs were artifically ventilated with a Harvard respirator. The heart was exposed through a left lateral thoracotomy. Two epicardial electrodes were sewn on the anterior and lateral walls, respectively, of the left ventricular myocardium, and unipolar electrograms were recorded from the two locations simultaneously. The right femoral artery and both jugular veins were cannulated with large bore tubing. The venous return from the jugular veins and the femoral arterial return were joined by a Y cannula to a coronary arteri.a1 inflow catheter and tubing and passed through an occlusive Sarnes roller pump. A schematic diagram of the preparation is illustrated in Figure 1. Venous or arterial inflow was selected by clamping the respective inflow line. The pump was calibrated for flow rates of 10 to 50 cc/min using timed collections of blood. The proximal segment of the anterior descending branch of the left coronary artery was dissected free and cannulated with a plastic no. 5F catheter as close as possible to its origin from the main left coronary artery. Blood PO2 was mea-
Summary Case no.
IN MYOCARDIAL
ISCHEMIA-LEVENSON
ET AL.
sured with the Astrup method. The coronary artery initially was perfused by arterial blood with a PO2 of 80 to 120 mm Hg. Flow was maintained at a rate that produced a mean perfusion pressure equal to a simultaneously recorded mean aortic pressure. Pressures were measured using Statham P23 Db pressure transducers. Aortic pressure, perfusion pressure and the two epicardial electrograms were recorded simultaneously on a direct-writing Hewlett Packard physiologic recorder. Flow was not altered thereafter. Regional myocardial hypoxia was produced by perfusing the left anterior descending coronary artery by jugular venous blood with a PO2 of 25 to 35 mm Hg. Hypoxia was considered present when the S-T segment was elevated at least 5 to 6 mm above the control level and myoeardial cyanosis was observed in the distribution of the left anterior descending coronary artery. In six of the eight dogs studied, 6 mc of lzgCs was injected into the inferior vena cava after induction of hypoxemia. Hypoxemia was maintained until scintigrams in three views (anterior, left anterior oblique and left lateral) were obtained. Scintigraphy was started 15 to 20 minutes after administration of 12gCs, and 5 to 10 minutes was required to obtain each scintigram, Coronary perfusion with venous blood then was discontinued and femoral arterial perfusion was reinstituted. The hypoxic state was considered to have reverted to normal on disappearance of both S-T segment elevation and myocardial cyanosis, which occurred 5 to 15 minutes after arterial reperfusion. Serial scintigrams were obtained every 15 minutes for 180 minutes in the view in which the defect was most easily visualized. After this period repeat scintigrams in the other two views were obtained. The remaining two dogs were studied in a different manner to evaluate the possibility that the scintigraphically observed defect was related to excessive efflux of 12aCs from
of Results in Seven Patients Graded Exercise Test
Resting ECG
1
lschemic
No infarct
2
lschemic
No infarct
3
lschemic
4
lschemic
No infarct Inferior infarct
5
lschemic
6
lschemic
7
lschemic
No infarct No infarct No infarct
Coronary Stenosis on Angiogram
Left Ventriculogram
Exercise 1%~ Scintigram
LCA, 50%; LAD, 75%; LCX, 75%; RCA, 90% LAD, 70%; LCX, 35%; RCA, 55% RCA, 90%
Normal
No defect
Not performed
No defect
Normal
No defect
LAD, 60%; LCx; 70% RCA, 80%
No change in control defect
LCX, 100%
Generalized hypokinesia, akinesia of apex Not performed
LAD, 65%; RCA, 45% LAD, 65%
Generalized hypokinesia Normal
ECG = electrocardiogram; LAD = anterior descending branch of the left coronary circumflex branch of the left coronary artery; RCA = right coronary artery.
February 1975
artery;
No defect No defect No defect
LCA = left main coronary
The American Journal of CARDIOLOGY
artery;
LCx =
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ET AL.
the myocardial cells. In these two dogs the same preparation was utilized but izgCs was administered during the initial femoral arterial perfusion of the left anterior descending coronary artery and three control scintigrams were obtained. The left anterior descending coronary artery was then perfused with jugular venous blood for 180 minutes, and scintigrams were obtained in the anterior view every 15 minutes. After 180 minutes repeat scintigrams in all three views were obtained. The recordings were interpreted by
Clinical Findings
experienced
in interpreting
Results
The appearance of normal myocardial scintigrams obtained with use of intravenously administered 12gCs has previously been described in detail.:3 There is an even uptake of 12gCs by the myocardium, which
LAO
ANT.
L.Lat.
FIGURE 2. Case 5. Normal myocardial scintigram after exercise of a male patient without clinical or electrocardiographic evidence of myocardial infarction ANT. = anterior view; LAO = left anterior oblique view: L.Lat. = left lateral view: LPO = left posterior oblique view.
LPO
A N T.
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FIGURE
3. Dog 2. Normal myocardial
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resembles a horseshoe or doughnut in the various views. Figures 2 and 3 are normal scintigrams from a patient (Case 5) and a dog, respectively. In the center of each scintigram there is a region of decreased to absent activity that represents the left ventricular cavity. The right ventricle is seen in some scintigrams as a thin wall that extends from the superior aspect of the interventricular septum. In one of the seven patients (Case 4) with documented coronary artery disease, an area of decreased activity in the myocardial scintigram taken after exercise was identical to that activity observed in the control scintigram taken at rest. The patient’s electrocardiogram revealed an old inferior wall myocardial infarction. Thus, none of our patients had areas of decreased activity in the myocardial scintigram that could be attributed to exercise-induced myocardial ischemia (Table I). Experimental Findings Each of the six dogs given 12gCs before production of regional myocardial hypoxemia had an area of decreased to absent activity in the myocardial scintigram during hypoxia. The defect was present in one or all of the views taken and involved the apex
A
CONTROL
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and anterior wall of the left ventricle (Fig. 4). The defect in the scintigram corresponded to the area that was cyanotic when perfused with venous blood. Scintigrams in five of the six dogs demonstrated complete resolution of the defect 60 to 180 minutes after reinstitution of arterial perfusion. In the remaining dog partial resolution of the defect was observed in the lateral view but complete resolution in the left anterior oblique and anterior views. In contrast, the two dogs that received 12gCs before the production of hypoxia did not manifest scintigraphic defects after 180 minutes of perfusion with hypoxemic venous blood. Discussion Myocardial scintigraphy using 12gCs and a gamma camera has been shown to be a safe, simple and effective method for detecting an acute or old myocardial infarction.3 In previous studies a myocardial infarction appeared in the scintigram as a defect or area of decreased to absent scintillations interrupting the smooth horseshoe or doughnut-shaped contour of the left ventricle. This study revealed that hypoxemia causes identical defects in the scintigram, and Zaret et a1.2 have shown similar results in exercise-induced myocardial ischemia.
HYPOXIA
C
FIGURE 4. Dog 2. Sequential myocardial scintigrams in the anterior view. A, control scintigram. B, arrows outline the scintigraphic defect after 75 minutes of regional hypoxemia with venous blood. C, partial resolution of scintigraphic defect after 12 minutes of arterial reperfusion. D, complete resolution of scintigraphic defect after 180 minutes of arterial reperfusion.
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Scintigraphic effect of hypoxia: A defect appearing in the scintigram could result from any or all of the following mechanisms in coronary artery disease: (1) inadequate perfusion, so that less radionuelide is presented to a portion of the myocardium than to surrounding regions that have a normal blood supply; (2) increased cellular permeability induced by hypoxia resulting in a net efflux of radionuclide from the myocardial cells; and (3) decreased cellular uptake of radionuclide secondary to damage of active transport mechanisms. We have demonstrated that in the presence of severe regional myocardial hypoxia with adequate perfusion of that region ensured by controlled flow, the concentration of 12eCs in the hypoxic region of the myocardium was decreased. A defect did not develop during 180 minutes of regional hypoxia in the two dogs that received 12gCs before the induction of hypoxia. The inability to produce defects in these two dogs suggests that the most important cause of scintigraphically observed defects during hypoxemia is not excessive efflux of 12gCs but decreased cellular uptake of 12gCs secondary to damage to the active transport system of the myocardial cellular membrane. Scintigraphic effect of exercise-induced ischemia: Each of the seven patients with an ischemic response to an exercise test and at least 50 percent narrowing of one major coronary artery demonstrated by coronary angiography had a normal exercise myocardial scintigram. This finding differs from the data of Zaret et a1.,2 who reported regions of decreased 4SK uptake with exercise in 16 of 19 patients with angina pectoris and positive coronary angiograms. PoelO reported that the myocardial uptake and clearance of potassium were more rapid and efficient than the uptake and clearance of cesium; however, the maximal myocardial concentration of the two radionuclides was the same. After intracoronary injection, potassium was more efficiently removed from the blood by the myocardium in a single passage than was cesium (71 percent versus 22 percent). Thus, 43K scanning can commence within 5 to 10 minutes after intravenous administration, whereas with use of cesium a delay of 30 to 90 minutes is required to attain maximal counting rates although adequate scintigrams may be obtained within 10 to 15 minutes. The difference between the effects of regional hypoxia in the dog model and exercise-induced regional ischemia in man probably resulted from the delayed myocardial uptake of 12gCs. The period of hypoxia in dogs was sufficiently prolonged to permit differentiation of 12gCs in normal and hypoxemic myocardium. After resolution of hypoxic injury to the myocardial cell
there was sufficient circulating 12gCs available for resolution of the scintigraphic defect. In exercising man, although 12gCs was given during the exerciseinduced ischemic episode and scintigrams were obtained within 10 minutes of intravenous injection and termination of exercise, the ischemic state was dissipated before significant amounts of 12sCs were cleared from the blood and concentrated by the myocardium. The rapid myocardial uptake and concentration of 43K make it the agent of choice for evaluation of transient regional myocardial ischemia during exercise in patients with ischemic heart disease. The effects of ischemia on the kinetics of potassium have been studied both experimentally in the dogll and in pacing-induced angina pectoris in man.12 We could find no previous reports relating to the kinetics of cesium during ischemia. Casell has shown that the efflux of potassium from the ischemic myocardium was dependent on the magnitude and duration of the &hernia. Ischemia differs from hypoxia in that, although reduced oxygen tension is common to both states, perfusion is inadequate in the former. Decreased substrate delivery or retention of anaerobic metabolites, or both, could affect membrane permeability adversely in the ischemic model. Therefore, our studies of regional myocardial hypoxemia in dogs are not entirely applicable to acute myocardial infarction, acute coronary insufficiency or exercise-induced angina pectoris in man. Nevertheless, we have shown that a major cause for a myocardial defect observed in scintigrams obtained with 12gCs is inadequate myocardial uptake by the hypoxic cell in the presence of adequate perfusion. In addition, the presence of a scintigraphically observed defect in both experimental myocardial hypoxia and in exercise-induced ischemia in studies using 4.1K2 suggests that the size of an acute myocardial infarct may be overestimated by myocardial scintigraphy. This discrepancy does not depend upon the physiologic mechanism that causes the scintigraphic defect. Ultimately the sensitivity of myocardial scintigraphy in quantitating the size of an acute myocardial infarct will require correlation with postmortem examination of the heart. Acknowledgment We are grateful for the support and assistance given by Dr. R. 0. Bondelid, Mr. R. B. Theus, Mr. G. E. Miller and the Operation Section of the Cyclotron Branch of the Naval Research Laboratory, Washington, DC., for the production of the rzgCs used in this project; by Richard Grant of the Nuclear Medicine Laboratory for the extraction and preparation of the 12sCs and by Jeannine Lewis and Tim Cahill of the Nuclear Medicine Laboratory for their assistance in obtaining the myocardial scans.
References 1. Carr EA, Gleason G, Shaw myocardial cesium-131.
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J, et al: The direct diagnosis infarction by photoscanning after administration Am Heart J 68:627-636, 1964
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2. Zaret BL, Strauss HW, Martln ND, et al: Noninvasive regional myocardial perfusion with radioactive potassium. N Engl J Med 288:809-812, 1973
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3.
4.
5.
6. 7.
Romhilt DW, Adolph RJ, Sodd VJ, et al: Cesium-129 myocardial scintigraphy to detect myocardial infarction. Circulation 48: 1242-1251, 1973 McGowan RL, Nell MD, Zaret BL, et al: Rubidium-81, a new agent for myocardial perfusion scans at rest and exercise, and comparison with potassium-43 (abstr). Am J Cardiol 33:154, 1974 Page DL, Caulfield JB, Kastor JA, et al: Myocardial changes associated with cardiogenic shock. N Engl J Med 285:133-137, 1971 Alonso DR, Scheidt S, Post M, et al: Pathophysiology of cardiogenic shock. Circulation 48:588-596. 1973 Marbko PR, Braunwald E: Modification of myocardiil infarction size after coronary occlusion. Ann Intern Med 79:720-733 1973
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8. Sodd VJ, Blue JW, Scholz KL: lzgCs production via the 127l (LY, 2n) lzgCs reaction and its preparation as a radiopharmaceutical. Phys Med Biol 16:587-598, 1971 9. Roitman D, Jones WB, Sheffield LT: Comparison of submaximal exercise ECG test with coronary cineangiocardiogram. Ann Intern Med 72:641-647, 1970 10. Poe ND: Comparative myocardial uptake and clearance characteristics of potassium and cesium. J Nucl Med 13:557-560 1972 11. Case RB: Ion alterations during myocardial ischemia. Cardiology 56:245-262. 1971/72 12. Parker JO, Chlong MA, West RO, et al: The effect of ischemia and alterations of heart rate on myocardial potassium balance in man. Circulation 42:205-217, 1970
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