Limited Clinical Diagnostic Specificity of Technetium-99m Stannous Pyrophosphate Myocardial Imaging In Acute Myocardial Infarction

MASOOD. AHMAD, MD, FRCP (C) JERZY P. DUBIEL, MD, FACC K. WILLIAM LOGAN, PhD THOMAS A. VERDON, MD RICHARD H. MARTIN, MD, FACC

Columbia, Missouri

To test the sensitivity and specificity of techneUum-99m stannous pyro- phosphate myocardial imaging in the diagnosis of acute myocardial in- farcUon, myocardial scintigrams were performed in 115 patients. Positive scintigrams were found in all 48 patients with acute myocardial infarction; uptake was localized in 29 patients with transmural infarction and diffuse in 2 patients with transmural infarction and in the remaining 17 patients with subendocardial myocardial infarction. Positive scintigrams were also found in 31 of 67 patients without clinical evidence of acute myocardial infarction. Diffusely positive scinUgrams were found in 3 of 3 patients with unstable angina pectoris, 7 of 30 patients with stable angina pectoris, 4 of 13 patients who had undergone aortocoronary bypass surgery, 4 of 4 patients with congestive cardiomyopathy and 1 patient studied 1 day after direct current cardioversion. Localized uptake of 9SmTc-pyrophosphate was found in 9 of 10 patients with left ventricular aneurysm and in 3 of 13 patients after aortocoronary bypass surgery. All four patients with atypical chest pain and two patients with pericarditis had normal scintigrams.

Our data confirm the previously reported sensitivity of sgrnTc-py- rophosphate imaging in detection of acute myocardial infarction but in- dicate that positive scinUgrams are not specific for this entity.

From The Division of Cardiology, Department of Medicine, University of Missouri Medical Center and Harry S Truman Memorial Veterans Admin- istration Hospital, Columbia, Mo. 65201. Manu- script received June 7, 1976; revised manuscript received July 12, 1976, accepted July 14, 1976.

Address for reprints: Masood Ahmad, MD, Di- vision of Cardiology, University of Missouri Medical Center, Columbia, Mo. 65201.

Several recent reports 1-7 have suggested tha t 99mTc-pyrophosphate myocardial imaging is a highly sensitive technique in detect ing acute myocardial infarction, bu t positive scintigrams have also been repor ted in pat ients wi thout infarction. 3,~,6 This communica t ion reports our ex- perience with this technique in pat ients with and wi thout myocardial infarction and describes several clinical situations in which false positive 99mTc-pyrophosphate myocardial scintigrams may be found.

Material and Methods

Technetium-99m stannous pyrophosphate myocardial scintigrams were ob- tained with a gamma camera (Searle Radiographics model H.P.) utilizing a 15,000 hole low energy all-purpose collimator (LEAP--parallel). Myocardial imaging was performed in the anterior, lateral and left anterior oblique positions 45 to 60 minutes after the intravenous injection of 15 mCi of 99mTc-pyrophosphate tagged to 5 mg of stannous pyrophosphate. The average duration of imaging in each patient was 20 minutes. Repeat scintigrams were obtained 2 hours after injection of 99mTc-pyrophosphate in 10 patients.

Positive scintigrams were classified "diffuse" when the uptake was generalized and "localized" when radioactive uptake was limited to one discrete region of the left ventricle. Intensity of uptake was graded 0 to 4+ according to the scheme devised by Parkey et al. ] Scintigrams with 0 and 1+ uptake were considered negative. The scintigrams of all patients in this study were evaluated by two independent observers who had no prior knowledge of the clinical status of the patient. There was no disagreement in interpretation of negative scintigrams or positive scintigrams with localized activity. Three scintigrams interpreted as 1+ diffuse by one observer and 2+ diffuse by the second observer were con- sidered negative.

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eSmTc-PYROPHOSPHATE MYOCARDIAL IMAGING--AHMAD ET AL.

Patients with acute myocardial infarction: Forty-eight patients with acute myocardial infarction were admitted to the coronary care unit and studied in the nuclear medicine laboratory on the 2nd or 3rd day of hospitalization. Serum enzymes, creatine phosphokinase (CPK), serum glutamic oxaloacetic transaminase (SGOT), lactic dehydrogenase (LDH) and serial electrocardiograms were obtained during the first 3 days of hospitalization. Thirty-one patients dem- onstrated characteristic electrocardiographic changes of transmural myocardial infarction (anterior location in 19, inferior in 10 and posterior in 2 patients). Seventeen patients without significant new Q waves in the electrocardiogram were considered to have nontransmural or subendocardial infarc- tion (on the basis of typical elevation of serum enzyme values). Follow-up scintigrams were obtained in seven patients with transmural infarction up to 2 months after the initial study.

Patients without acute myocardial infarction: Sixty- seven patients without clinical evidence of acute myocardial infarction were selected from patients admitted to the hospital for various cardiac disorders as well as from the cardiac out- patient clinic and classified into eight subgroups.

Group I: 30 patients with stable angina pectoris, 11 having angiographically confirmed coronary artery disease and all having normal serum enzyme values. Electrocardiograms in this group showed no changes suggestive of acute myocar- dial infarction. Serial scintigrams were obtained in three pa- tients 1 and 2 hours after injection of 99r"Tc-pyrophosphate. Three of these patients also had myocardial scintigrams ob- tained before and after a maximal bicycle ergometer exercise stress test. After obtaining a control myocardial scintigram 3 days before the stress test, these patients experienced angina and significant ischemic S-T segment depression at the ter- mination of exercise. Repeat injections of 99mTc-pyro-

phosphate were performed and scintigrams obtained 1 hour later.

Group II: Three patients with unstable angina pectoris manifested by prolonged episodes of angina somewhat re- fractory to large doses of nitrates and propranolol. The angina subsided with continued bed rest, and none of these patients manifested electrocardiographic or enzymatic evidence of acute myocardial infarction. Subsequent coronary angiogra- phy demonstrated significant coronary artery disease in two of these patients; the third patient did not return for follow-up study.

Group III: Four patients with atypical chest pain, normal electrocardiograms and cardiac enzymes. Coronary angio- grams obtained in two of the four were normal.

Group IV: Ten patients with left ventricular aneurysm documented by left ventriculography. Three of these 10 pa- tients had stable angina pectoris with normal serum enzyme values and stable electrocardiogram at the time of study. Se- rial scintigrams were obtained in four patients 1 and 2 hours after injection of 99mTc-pyrophosphate. Follow-up scintigrams were obtained in five patients 2 to 8 weeks later.

Group V: Thirteen patients who had undergone aortocor- onary bypass graft surgery 30 4- 8 (mean 4- standard error) months previously. Five of these patients had stable angina pectoris without evidence of acute myocardial infarction at the time of study. Repeat scintigrams were obtained in three patients 2 hours after injection of 99mTc-pyrophosphate.

Group VI: Four patients with primary cardiomyopathy and congestive cardiac failure.

Group VII: Two patients with acute pericarditis. Group VIII: One patient with vague chest pains and atrial

fibrillation who had myocardial scintigrams performed before and after attempted cardioversion utilizing two synchronized direct current shocks of 100 and 200 joules.

T A B L E I

Scintigraphic Data in Patients With and Without Acute Myocardial Infarction

Scintigraphic Findings

Localized 99mTc-PYP Diffuse 99mTc-PYP Uptake Uptake

Patients Mean Age-+ SE Total no. Mean Time of Patient Group (no.) (yr) Positive 2+ 3+ 4+ 2+ 3+ 4+ Imaging

A. Patients With Acute Myocardial Infarct ion

Transmural MI 31 60 -+ 6.2 31 1 10 18 0 1 1 3.7 -+ 0.4 days after MI

Subendocardial MI 17 57 -+ 2.1 17 0 .0 0 2 11 4 4.2 -+ 0.6 days after MI

B. Patients Wi thout Acute Myocardial Infarct ion

I. Stable angina 30 51 + 1.8 7 0 0 0 2 5 0 . . . . pectoris

I1. Unstable angina 3 57 -+ 1.4 3 0 0 0 0 3 0 . . . pectoris

I I I . A typ ica l chest 4 55 + 2.4 0 0 0 0 0 0 0 . . . pain

IV. Left ventr icular 10 51.2 +- 2.8 9 0 6 3 0 0 0 32.1 -+ 9.8 mo aneurysm post infarct ion

V. Postaortocoronary 13 60.0 + 3.2 7 1 2 0 2 2 0 30.1 -+ 8 mo bypass surgery postoperative

VI . Congestive 4 45 + 1.2 4 0 0 0 1 3 0 . . . ca rd iomyopa thy

V I I . Acute 2 48 0 0 0 0 0 0 0 . . . pericardit is

VIII. Postcardioversion 1 57 1 0 0 0 0 1 0 1 day postcardio- version

MI = acute myocardial in farct ion; PYP = pyrophosphate; SE = standard error.

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9SmTc-PYROPHOSPHATE MYOCARDIAL IMAGING----AHMAD ET AL.

Results

Patients with acute myocardial infarction (Table IA): Twenty-nine of 31 patients with acute transmural myocardial infarction had radioactivity in the myo- cardial scintigram localized to one discrete region of the left ventricle corresponding closely to the electrocar- diographic site of myocardial infarction. For the group, the mean time of imaging after acute myocardial in- farction was 3.7 ± 0.4 days. Two patients with transmural myocardial infarction had diffuse uptake; the scintigrams in these patients were obtained 7 to 10 days after the onset of symptoms. Follow-up scintigrams were obtained in seven patients; two of these with pre- viously localized scintigrams demonstrated diffuse uptake up to 2 months after myocardial infarction. One of these patients was subsequently found to have a left ventricular aneurysm by left ventriculography. A typical myocardial scintigram with a "doughnut pattern" in a patient with transmural acute anterolateral myocardial infarction with persistence of activity 3 weeks later is shown in Figure 1.

All 17 patients with subendocardial myocardial in- farction had generalized diffuse uptake. Figure 2 shows a typical scintigram from this group.

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Pat ients wi thout acute myocardial infarction (Table IB): Seven of 30 patients with stable angina pectoris (Group I) and all 3 patients with unstable an- gina pectoris (Group II) had diffuse uptake of 99~Tc- pyrophosphate. Persistent scintigraphic activity was noted in three patients from Group I whose scintigrams were obtained 2 hours after injection of 99mTc-py- rophosphate. There was no clinical difference between patients in Group I with and without positive scinti- grams. Three patients with stable angina pectoris and negative scintigrams underwent bicycle ergometer stress testing to self-determined maximal exertion. Angina and ischemic S-T segment depression in the electro- cardiogram developed in all three patients, but repeat scintigrams remained negative. All four patients with atypical chest pain and normal serum enzyme values and electrocardiogram (Group III) had negative scin- tigrams.

Nine of 10 patients with angiographically doc- umented left ventricular aneurysm (Group IV) had 99mTc-pyrophosphate uptake localized to the site of the wall motion abnormality. Follow-up scintigrams ob- tained in five patients 2 to 8 weeks later gave similar results. A detailed analysis of results in this group of patients has recently been reported. 5

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FIGURE 1. Upper panel, "doughnut pattern" positive scintigram in anterior (A), 45 ° left anterior oblique (O) and lateral (L) views from a patient with extensive acute transmural anterolat- eral myocardial infarction. Solid arrows show the area of infarction and open arrows the sternum (A and O) and spine (L). Lower panel, scintigram in the same views obtained 3 weeks later.

FIGURE 2. Positive scintigram in an- terior (A), 45 ° left anterior oblique (O) and lateral (L) views from a patient with acute subendocardial myocardial in- farction. Solid arrows show the area of infarction and open arrows the sternum (A and O) and spine (L),

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Seven of 13 patients studied 30.1 + 8 months after aortocoronary bypass surgery (Group V) had positive scintigrams revealing localized activity in three patients and diffuse uptake in four. Of the three patients with scintigrams showing localized activity, two had left ventricular dyskinesia and visible myocardial calcifi- cation. Repeat scintigrams obtained in these three pa- tients 2 hours after injection of 99mTc-pyrophosphate remained positive. Stable angina pectoris was present in four patients with diffusely positive scintigrams and in one patient with localized activity. Five patients in this group had electrocardiographic changes of acute transmural myocardial infarction in the immediate postoperative phase. Figure 3 shows a positive scinti- gram from this group.

All four patients with primary cardiomyopathy and congestive cardiac failure (Group VI) had diffusely positive scintigrams. One of these four patients had abnormal serum enzyme values (mildly elevated CPK, SGOT and LDH levels in a single determination) at the time of study whereas the electrocardiogram was stable and unchanged in all.

Two patients with acute pericarditis (Group VII) had negative scintigrams. The single patient in Group VIII who was admitted with vague chest pains and atrial fi-

brillation had no electrocardiographic or enzymatic evidence of myocardial infarction before or after direct current cardioversion, but diffuse scintigraphic uptake appeared after cardioversion (Fig. 4).

Discussion

99mTc-pyrophosphate myocardial imaging is being used increasingly as a noninvasive radionuclide tech- nique to assist in the diagnosis of acute myocardial in- farction. Previous studies have demonstrated that this technique is highly sensitive in detecting acute myo- cardial infarction in both experimental animals and in patients. 1-7 Characteristic patterns of localized uptake in transmural myocardial infarction and diffuse uptake in subendocardial myocardial infarction have been described. 1-7 Our data confirm these findings. However, positive scintigrams may be obtained in patients with no evidence of acute myocardial infarction. 5

Mechanisms of positive scintigrams: A 99mWc- pyrophosphate scintigram presumably becomes positive because of uptake by calcium deposited in and around the infarcted zone. 8-1° Studies in experimental animals have demonstrated that maximal 99mTc-pyrophosphate uptake is flow-dependent, with maximal concentration in the ischemic zone surrounding the infarcted area. H,12

FIGURE 3. Positive scintigram in anterior (A), 45 ° left anterior oblique (O) and lateral (L) views obtained from a patient 2 months after aortocoronary bypass graft surgery. Solid arrows show the area of uptake and open arrows the sternum (A and O) and spine (L).

FIGURE 4. Upper panel, negative scintigram in anterior (A), 45 ° left anterior oblique (O) and lateral (L) views from the patient with atrial fi- brillation before cardioversion. Open arrows show the sternum (A and O) and spine (L). Lower panel, positive scintigram in the same views obtained 1 day after cardioversion. Solid arrows show the area of uptake.

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99mTc-PYROPHOSPHATE MYOCARDIAL IMAGING~AHMAD ET AL.

Thus, the development of the characteristic "doughnut pattern" in the scintigrams of some patients with transmural myocardial infarction may represent la- beling of the ischemic zone along the margins of the infarcted area. In contrast to previous findings, 11,12 Botvinick et al. 13 were not able to find a central necrotic zone with low 99mTc-pyrophosphate content in post- mortem examination of experimentally produced myocardial infarction with a "doughnut-shaped" scintigraphic pattern in vivo.

Positive scintigrams become negative approximately 2 weeks after infarction in experimental animals ~ ~ and approximately 1 week after acute myocardial infarction in most patients1,3; however, some patients retain scintigraphic activity for longer periods. 3 One of our patients with persistently positive scintigrams also had persistent S-T segment elevation. Left ventricular cineangiography subsequently demonstrated a left ventricular aneurysm. This observation suggests the possibility that persistence of a positive scintigram after myocardial infarction may be an early sign of the de- velopment of left ventricular aneurysm.

Positive scintigrams in all 3 patients with unstable angina pectoris and in 7 of the 30 patients with stable angina pectoris may indicate that the 99mTc-py- rophosphate technique is more sensitive than electro- cardiographic and enzymatic methods in detecting myocardial necrosis. 3 However, this question cannot be answered in the absence of definite postmortem histo- logic data. It does not seem likely that diffuse uptake in these patients without myocardial infarction is due to scintillation of intracardiac blood pool because per- sistent scintigraphic activity was observed in patients who had repeat scintigrams performed 2 hours after injection of 99mTc-pyrophosphate. Our finding that there is no radioactive uptake in patients with angina

after a maximal exercise stress test suggests that 99mTc-pyrophosphate myocardial imaging does not detect reversible ischemia. Diffusely positive scinti- grams in patients with primary cardiomyopathy and congestive heart failure have been described previous- ly. 6. The cause of the uptake of 99mTc-pyrophosphate in these patients is not known.

We have recently reported positive scintigrams in patients with left ventricular aneurysm with uptake localized to the angiographically visualized site of the wall motion abnormality and have proposed that the uptake may result from presence of myocardial calcium deposits in and around the area of the aneurysm. 5 The possibility cannot be excluded that focally positive 99mTc-pyrophosphate scintigrams in patients with previous coronary artery bypass graft surgery may be due to uptake in the area of the ventriculotomy scar resulting from sump tube insertion. 14 Deposition of calcium in the left ventricular myocardium after car- diovascular surgery has been reported. 15,16

Development of positive scintigrams after cardio- version may result from myocardial damage caused

• by the electric current. Zaret 17 reported marked gen- eralized epicardial uptake of 99mTc-pyrophosphate after direct precordial countershock in dogs. This finding suggests caution in interpreting positive scintigrams after cardiopulmonary resuscitation or defibrillation, because these measures themselves may result in 99mTc-pyrophosphate uptake in the absence of infarc- tion.

Clinical implication: The finding of myocardial uptake of 99mTc-pyrophosphate in the various clinical situations described in patients without enzymatic or electrocardiographic evidence of acute myocardial in- farction indicates the need for caution in interpreting such positive myocardial scintigrams.

References

1. Parkey RW, Bonte FJ, Meyer SL, et ah A new method of radio- nuclide imaging of acute myocardial infarction in humans. Circu- lation 50:540-546, 1974

2. Bonte FJ, Parkey RW, Graham KD, et ah A new method of ra- dionuclide imaging of acute myocardial infarcts. Radiology 110: 473-474, 1974

3. Willerson JT, Parkey RW, Bonte FJ, et ah Technetium stannous pyrophosphate myocardial scintigrams in patients with chest pain of varying etiology. Circulation 51:1046-1052, 1975

4. Willerson JT, Parkey RW, Bonte FJ, et ah Acute subendocardial myocardial infarction in patients. Its detection by technetium-99m stannous pyrophosphate myocardial scintigrams. Circulation 51:436-441, 1975

5. Ahmad M, Dublel JP, Verdon TA, et ah Technetiurn-99m stannous pyrophosphate myocardial imaging in patients with and without left ventricular aneurysm. Circulation 53:833-838, 1976

6. Gould LA, Perez LA, Hayt DB, et ah Clinical experience: 99mTC polyphosphate for myocardial imaging (abstr). Circulation 49, 50:Supp1111:111-4, 1974

7. McLaughlin P, Coates G, Wood D, el al: Detection of acute myo- cardial infarction by technetium-99m polyphosphate. Am J Cardiol 35:390-396, 1975

8. D'Agostlno AN: An elecVon microscopic study of cardiac necrosis produced by 9 alpha-fluorocortisol and sodium phosphate. Am J Pathol 45:633-644, 1964

9. D'AgosUno AN, Chiga M: Mitochondrial mineralization in human myocardium. Am J Clin Pathol 53:820-824, 1970

10. Shen AC, Jennings RB: Kinetics of calcium accumulation in acute myocardial ischemic injury. Am J Pathol 67:441-452, 1972

11. BuJa LM, Parkey RW, Dees JH, et ah Morphologic correlates of technetium-99m stannous pyrophosphate imaging of acute myo- cardial infarction in dogs. Circulation 52:596-607, 1975

12. Zaret BL, Dicola CV, Donatredlan RK, et ah Dual radionuclide study of myocardial infarction: relationships between myocardial uptake of potassium-63, technetium-99m stannous pyrophosphate, re- gional myocardial blood flow and creatine phosphokinase deple- tion. Circulation 53:422-428, 1976

13. Botvinick EH, Shames D, Harris L, et ah Noninvasive quantitation of myocardial infarction with technetium-99m pyrophosphate. Circulation 52:909-915, 1975

14. Ahmad M, Dublel J, Verdon T, et al: Myocardial uptake of tech- netium-99m stannous pyrophosphate in patients with previous coronary artery bypass graft surgery (abstr). Circulation 52:Suppl Ih11-148, 1975

15. Hermann G, Haupt GJ, Blrkhead NC: Rapid myocardial calcifi- cation after cardiac surgery. JAMA 186:260-261, 1963

16. Reichenbach DD, Benditt EP: Myofibrillar degeneration: a response of the myocardial cell to injury. Arch Pathol 85:189-199, 1968

17. Zaret BL: Radionuclide imaging of myocardial ischemia and in- farction. Circulation 53:Suppl 1:1-126-1-128, 1976

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