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Antimyosin Scintigraphy for Detection of Myocarditis
Antimyosin Scintigraphy for Detection of Myocarditis* Scintigraphic Follow-up john Lekakis, M.D.; john Nanas, M.D.; Athanassia Moustafellou, M.D.; lbnos Kostamis, M .D.; and Spyridon Moulopou.los, M.D. To examine the value of antimyosin-indium 111 imaging in relation to endomyocardial biopsy in patients with suspected myocarditis, as weD as the natural evolution of abnormal 6oclings on the antimyosin scan, 1! patients with suspected myocarditis underwent endomyocardial biopsy and antimyosin scan. The heart-to-lung ratio (WL) was used to quantify the antimyosin scan. All 1! patients had abnormal results on the scan (WL, 1.7 to 2.9; mean, 2.1±0.3); 8 of the 1! patients also had a diagnostic endomyocardial biopsy. In four patients with abnormal 6ndings on antimyosin scan and normal 6ndings on biopsy, the WL ratio did not differ from eight patients with abnormal 6ndings on antimyosin scan and a diagnostic biopsy; also, the ejection fraction did not differ between the two groups. One patient died, and 8 patients had a repeat antimyosin scan within ! months after
Monoclonal antimyosin antibodies labeled with indium 111 (lllln) have been useful for detecting active myocyte damage; these antibodies have been shown to bind specifically to cardiac myocytes that have lost membrane integrity and exposed myosin to the extracellular space. 1 Because myocardial necrosis is an obligatory component of myocarditis, 2 lllln monoclonal antimyosin antibody imaging has been used to diagnose myocarditis;3-15 although the sensitivity of the method appears to be high, specificity is only moderate compared to endomyocardial biopsy. The cause of abnormal results on antimyosin imaging associated with a nondiagnostic endomyocardial biopsy is unresolved and may represent either a falsepositive scan or a false-negative biopsy. It has been reported that the sensitivity ofbiopsy is limited; Chow et al6 showed that despite 17.2 biopsies per patient, only 79 percent of the cases could be diagnosed; also Hauck et al7 reported that the frequency of falsenegative results of biopsy was 37 percent even when 10 biopsies per case were obtained. The evolution of the antimyosin scan in cases of suspected myocarditis, in relation to left ventricular function, could be helpful in clarifying the issue of a false-positive antimyosin scan or a false-negative biopsy. The natural evolution of the antimyosin scan has been studied only in a murine myocarditis model. 8 The present study examined the value of lllln anti•From the Departments of Clinical Therapeutics and Nuclear Medicine, Alexandra University Hospital, Athens, Greece. Manuscript received December 3, 1992; revision accepted April 24, 1993.
the initial study. The HIL ratio returned to normal in two out of three patients with normal results on biopsy and in three out of five patients with a diagnostic biopsy; the ejection fraction improved by 8 percent or more in one out of three patients with a nondiagnostic biopsy and in two out of five patients with a biopsy diagnostic for myocarditis. We conclude that the antimyosin scan is more frequently diagnostic than biopsy in suspected myocarditis. Patients with abnormal results on antimyosin scan and a nondiagnostic biopsy, as well as those with abnormal results on antimyosin scan and a diagnostic biopsy, tend to return to normal results on scan within ! months and improve their ejection fraction. (Chat 1993; 104:1421-30)
I
HIL ratio=heart-to-lung ratio
I
myosin antibody cardiac imaging in a group of patients strongly suspected of having myocarditis, as well as the natural evolution of the ejection fraction and the antimyosin scan. MATERIAL AND METHODS
Twelve patients suspected of having acute myocarditis were studied; 2 were women and 10 were men, with a mean age of 36± 13 years (range, 18 to 58 years). Eleven patients had experienced the recent onset of congestive heart failure, and one had chest pain and malignant ventricular arrhythmias. The ejection fraction by radionuclide ventriculography was abnormal in 10 patients and normal (>50 percent) in 2 (Table 1). The average ejection fraction was 34 ± 12 percent (range, 11 to 57 percent). Four patients had a definite febrile illness before the onset of cardiac symptoms. Eight patients underwent left cardiac catheterization and coronary arteriography; normal coronary anatomy was demonstrated in all eight patients. In four patients aged 18 to 28 years, coronary arteriography was not performed. Five patients with a low probability of myocarditis formed a control group; 1 was a female patient, and 4 were men, with a mean age of 32 ± 15 years (range, 15 to 54 years). One of the patients had a long-standing history of congestive heart failure, and endomyocardial biopsy was nondiagnostic for myocarditis; one had a congenital complete heart block, one patient was treated for atrial Butter, one had a sinus tachycardia without symptoms of congestive heart failure, and one patient had a coronary artery fistula. All subjects underwent myosin-specific monoclonal antibody imaging. Antimyosin antibody (Myoscint; Centocor Inc.) was supplied as a sterile nonpyrogenic solution containing 0.5 mg ofRUD10 Fab DTPA, which is a mouse monoclonal antibody fragment that binds specifically to myosin. Antimyosin is radiolabeled by the addition of sterile 111 In chloride. Two millicuries of'"In were diluted to 10 ml of volume and administered intravenously by slow injection. Planar imaging was performed 48 h later using a gamma camera (General Electric Maxi Camera 400). Three views were obtained (anterior, 45° left anterior oblique, and 7<1' left anterior oblique) using a 128 X 128 matrix for 10 min per view. Both photopeaks of CHEST I 104 I 5 I NOVEMBER, 1993
1427
Table 1-Ruulta of Antimyoain Scintigraphy, lfight Ventricular Endomgocardiol Bioply, and Left Ventricular Ejection FrGCiion
Initial Group and No. Patients 1 2 3 4 5 6 7 8 9 10 11 12 Control subjects 1 2 3 4 5
At 2 mo*
At 1 mo*
Age (yr), Sex
HIL
EFt
34,M 18, M 44, M 52, F 45, M 25, M 42, M 28, M 45, F 19, M 22, M 58, M
2.1 2.9 1.9 2.4 1.9 1.8 2.1 2.0 1.9 1.7 1.9 2.5
28 33 57 35 29 21 55 35 32 30 11
25, M 21, F 54,M 15, M 48, M
1.5 1.3 1.4 1.2 1.3
20 60 58 65 60
Biopsy
45
+ + + + + + + +
HIL 1.5 2.2 1.9 2.0 1.8 1.5 1.4 1.8
EFt
HIL
EFt
1.5 1.6
76 34
43 36
35 63 32 31 23 64
*Time after admission. tEF, ejection fraction in percent. "'In (173 keV and 247 keV) were used with 20 percent energy windows. Images were evaluated for the presence or absence of tracer uptake; a heart-to-lung {HIL) ratio was used to quantify tracer uptake;' the unprocessed anterior projection was used to adjust a region of interest in the myocardium and a region of interest in each lung. Average counts per pixel in the myocardium were divided by the average counts per pixel in each lung to obtain the H1L ratio. An H1L ratio greater than 1.6 was considered abnormal.• Right ventricular endomyocardial biopsy was performed in all patients with suspected myocarditis and in one patient from the control group. A Stanford bioptome was used, and three samples were obtained by means of the right internal jugular vein. All samples for biopsy were interpreted according to Dallas criteria• without knowledge of the results of antimyosin scan.
From the group of patients with suspected myocarditis, one patient died; in eight patients the antimyosin scan was repeated in 1 month; two patients had a third antimyosin scan in 2 months (Table 1). Within I week of antimyosin scan, a new radionuclide ventriculography was performed to assess global left ventricular function. All group data were expressed as mean values± SD.
FiGURE l. Scan from patient with acute myocarditis (anterior view). Diffuse uptake of tracer is seen in myocardium .
9 F1 . lilt - · can (ldt anteri<>r ohliqu • 4 1 ' ' ) rrnm me pali ·nl as Figure l. Diffuse activity is evident in cardiac region.
1428
RESULTS
Antimyosin antibody was administered without adverse reactions in all patients and control subjects; no reactions were detected in patients with repeated injections. In the control group, all 5 subjects had normal results on antimyosin study (Table 1); the HIL
Anllmyoain Scintigraphy for Detection of Myocarditis (Le/calcis et a/)
ratio ranged from 1.2 to 1.5 (mean, 1.3±0.1). In the group of patients with suspected myocarditis, the results of antimyosin scanning were diagnostic (Fig 1 and 2); the HIL ratio ranged from l. 7 to 2.9 (mean, 2.1 ± 0.3), and it was significantly higher than that observed in the control group (p
Indium Ill-labeled antimyosin antibodies have been shown to bind specifically to areas of myocardial necrosis;9 a close correlation between antibody uptake and the mass of necrotic myocardium has been found , in both animals and humans. 10•11 Since myocardial necrosis, in association with inflammation, is an essential component of myocarditis, a few studies tried to clarify the usefulness of antimyosin scanning in the detection of myocarditis. The feasibility of imaging myocarditis has been demonstrated in experimental murine studies. 8 •12 In humans, Yasuda et al3 investigated 28 patients with suspected acute myocarditis; 17 patients had a diagnostic scan and 11 had nondiagnostic scans. Eight of the patients with diagnostic scans did not show histologic evidence of myocarditis. The high sensitivity and negative predictive value was also reported by Carrio et al;4 in 13 patients suspected of having myocarditis, the antimyosin scan was diagnostic for myocarditis in 11, but biopsy-proven myocarditis was found in only 4. Similar findings were reported by Dec et al; 5 in 82 patients with clinically suspected myocarditis, the sensitivity of the antimyosin scan was 83 percent and the specificity 53 percent when compared to endomyocardial biopsy. All of those findings are in accord with our observations; all
patients with biopsy-proven myocarditis had abnormal results on scanning, but four patients with a nondiagnostic biopsy also had abnormal results on scanning. A diagnostic antimyosin scan associated with a nondiagnostic endomyocardial biopsy may represent either a false-positive scan or a false-negative biopsy. The sensitivity of right ventricular biopsy in myocarditis is questionable; myocarditis usually is a multifocal process, and specimens from biopsy may be obtained from unaffected areas of myocardium. Probably samples from biopsy of the right ventricle cannot be considered representative of the entire myocardium. In 14 hearts with histologically proven myocarditis studied ex vivo, Chow et al6 required 17.2 samples per case (an unrealistic number) to diagnose 79 percent (11) of 14 cases; with 4 to 5 samples per case, the chanee of a successful diagnosis was 50 percent; thus, right ventricular endomyocardial biopsy demonstrates relatively low levels of diagnostic sensitivity. On the other hand, antimyosin imaging appears to be a very specific method; on postmortem imaging, uptake of tracer matched the triphenyltetrazolium chloride staining, confirming that myosin-specific antibody binds specifically to irreversibly damaged myocardial cells.9 •11 Although we did not use tomography in our study, nonspecific myocardial uptake is unlikely, since persistent blood pool activity is rare at 48-h planar images. 5 In our study the fact that patients with diagnostic or nondiagnostic endomyocardial biopsy have a similar HIL ratio on the antimyosin scan, as well as a similar ejection fraction, indicates that these two groups represent a unique entity. Also the behavior of these two groups during the 2-month follow-up is similar; two out of three patients with a diagnostic scan and a nondiagnostic biopsy developed normal HIL ratios, while the same normalization was observed in three out of five patients with a diagnostic scan and a diagnostic biopsy. Since uptake of antimyosin has the same evolution in both groups, uptake in patients with a nondiagnostic biopsy probably represents a true uptake and not a false-positive scan. The natural evolution of the antimyosin scan has been studied only in a murine model of myocarditis;8 uptake was intense on day 10 (in all mice) and slight on day 20 (in 20 percent of the mice). Pathologic findings correlated well with the uptake of antimyosin. These results in animals are in accord with our findings in humans; a reduction of antimyosin uptake was observed in most patients during follow-up, regardless of a diagnostic or nondiagnostic biopsy. Dec et al5 reported a repeat antimyosin scan in 17 patients with an initial diagnostic antimyosin scan; 8 of the 17 patients had a follow-up antimyosin scan that no longer demonstrated uptake of tracer; 3 of these 8 patients had biopsy-verified myocarditis, and 5 did not. In that study, 5 quantitative CHEST I 104 I 5 I NOIIEMBER, 1993
1429
analysis of the intensity of the image was not performed, and many patients with a diagnostic biopsy received immunosuppressive therapy. The ejection fraction improved more than 8 percent in one out of three patients with a diagnostic scan and a nondiagnostic biopsy and in two out of five patients with a diagnostic scan and a diagnostic biopsy. Dec et al5 reported similar results in their study; 7 of 10 patients with a diagnostic scan and a diagnostic biopsy had an improved ejection fraction by more than 10 percent at 6 months; also 7 of 16 patients with a diagnostic scan and a nondiagnostic biopsy had an improved ejection fraction. In our study, none of the patients received immunosuppression, and thus these findings represent the natural evolution of myocarditis in these patients. In experimental studies, Kishimoto et al8 also showed an increase in the ejection fraction by more than 10 percent between days 10 and 150 in mice with myocarditis without any therapy. In conclusion, the findings of this study indicate that in patients with suspected myocarditis, the antimyosin scan is more frequently diagnostic than the endomyocardial biopsy. Many patients with initially diagnostic antimyosin scans demonstrate no tracer uptake at repeat antimyosin imaging at 2 months. Larger series will be needed to determine the role of serial antimyosin imaging in assessing the progress of the disease in patients with myocarditis. REFERENCES
1 Khaw BA, Strauss HW, Moore R, Fallon Jf, Yasuda T, Gold HK, et al. Myocardial damage delineated by indium-HI antimyosin Fab and technetium-99m pyrophosphate. J Nucl Med 1987; 28:76-82 2 Aretz HT. Billingham ME. Edwards WD. Factor SM, Fallon Jf, Fenoglio JJ, et al. Myocarditis: ahistopathological definition and classification. Am J Cardiovasc Patholl987; 1:3-14
1430
3 Yasuda T, Palacios IF, Dec GW, Fallon Jf, Gold HK, Leinbach RC, et al. Indium-Ill monoclonal antimyosin antibody imaging in the diagnosis of acute myocarditis. Circulation 1987; 76:306-
11 4 Carrio I, Bema L, Ballester M, Estorch M, Obrador D , Cladellas M, et al. Indium-Ill antimyosin scintigraphy to assess myocardial damage in patients with suspected myocarditis and cardiac rejection. J Nucl Med 1988; 29:1893-1900 5 Dec GW, Palacios IF, Yasuda T, Fallon JT, Khaw BA, Strauss HW, et al. Antimyosin antibody cardiac imaging: its role in the diagnosis of myocarditis. JAm Coli Cardioll990; 16:97-104 6 Chow LE, Radio SJ, Sears TD, McManus BM. Insensitivity of right ventricular endomyocardial biopsy in the diagnosis of myocarditis. JAm Coli Cardioll989; 14:915-20 7 Hauck AJ, Kearney DL, Edwards WD. Quantitative evaluation of postmortem endomyocardial biposy specimens (EMB) from 38 hearts of patients with autopsy-proved lymphocytic myocarditis: implications for the role of sampling error in the evaluation of myocarditis by EMB in living patients [abstract]. In: PrOceedings of the International Symposium ofln8ammatory Heart Disease: a multidisciplinary approach to myocarditis and heart allograft rejection. Omaha, Neb: Center for Continuing Education, University of Nebraska Medical Center, 1988; 165 8 Kishimoto C, Hung GL, Ishibashi M, Khaw BA, Kolodny GM , Abelmann WH, et al. Natural evolution of cardiac function, cardiac pathology and antimyosin scan in a murine myocarditis model. JAm Coli Cardioll991; 17:821-27 9 Khaw BA, Fallon Jf, Beller GA, Haber E . Specificity of the localization of myosin specific antibody fragments in experimental myocardial infarction: histologic, histochemical, autoradiographic and scintigraphic studies. Circulation 1979; 60:1527-31 10 Khaw BA, Scott J, Fallon Jf, Cahill SL, Haber E, Homey C. Myocardial injury: quantification by cell sorting initiated with antimyosin fluorescent spheres. Science 1982; 217:1050-53 11 Jain D, Lahiri A, Crawley JCW, Raftery EB. In 111-antimyosin imaging in a patient with acute myocardial infarction: postmortem correlation between histopathologic and autoradiographic extent of myocardial necrosis. Am J Card lmag 1988; 2:158-61 12 Matsumori A, Ohkusho T, Matoba Y, Okada I, Yamada T, Kawai C, et al. Myocardial uptake of antimyosin monoclonal antibody in a murine model of viral myocarditis. Circulation 1989; 79:400-
05
Monoclonal antimyosin antibodies labeled with indium 111 (lllln) have been useful for detecting active myocyte damage; these antibodies have been shown to bind specifically to cardiac myocytes that have lost membrane integrity and exposed myosin to the extracellular space. 1 Because myocardial necrosis is an obligatory component of myocarditis, 2 lllln monoclonal antimyosin antibody imaging has been used to diagnose myocarditis;3-15 although the sensitivity of the method appears to be high, specificity is only moderate compared to endomyocardial biopsy. The cause of abnormal results on antimyosin imaging associated with a nondiagnostic endomyocardial biopsy is unresolved and may represent either a falsepositive scan or a false-negative biopsy. It has been reported that the sensitivity ofbiopsy is limited; Chow et al6 showed that despite 17.2 biopsies per patient, only 79 percent of the cases could be diagnosed; also Hauck et al7 reported that the frequency of falsenegative results of biopsy was 37 percent even when 10 biopsies per case were obtained. The evolution of the antimyosin scan in cases of suspected myocarditis, in relation to left ventricular function, could be helpful in clarifying the issue of a false-positive antimyosin scan or a false-negative biopsy. The natural evolution of the antimyosin scan has been studied only in a murine myocarditis model. 8 The present study examined the value of lllln anti•From the Departments of Clinical Therapeutics and Nuclear Medicine, Alexandra University Hospital, Athens, Greece. Manuscript received December 3, 1992; revision accepted April 24, 1993.
the initial study. The HIL ratio returned to normal in two out of three patients with normal results on biopsy and in three out of five patients with a diagnostic biopsy; the ejection fraction improved by 8 percent or more in one out of three patients with a nondiagnostic biopsy and in two out of five patients with a biopsy diagnostic for myocarditis. We conclude that the antimyosin scan is more frequently diagnostic than biopsy in suspected myocarditis. Patients with abnormal results on antimyosin scan and a nondiagnostic biopsy, as well as those with abnormal results on antimyosin scan and a diagnostic biopsy, tend to return to normal results on scan within ! months and improve their ejection fraction. (Chat 1993; 104:1421-30)
I
HIL ratio=heart-to-lung ratio
I
myosin antibody cardiac imaging in a group of patients strongly suspected of having myocarditis, as well as the natural evolution of the ejection fraction and the antimyosin scan. MATERIAL AND METHODS
Twelve patients suspected of having acute myocarditis were studied; 2 were women and 10 were men, with a mean age of 36± 13 years (range, 18 to 58 years). Eleven patients had experienced the recent onset of congestive heart failure, and one had chest pain and malignant ventricular arrhythmias. The ejection fraction by radionuclide ventriculography was abnormal in 10 patients and normal (>50 percent) in 2 (Table 1). The average ejection fraction was 34 ± 12 percent (range, 11 to 57 percent). Four patients had a definite febrile illness before the onset of cardiac symptoms. Eight patients underwent left cardiac catheterization and coronary arteriography; normal coronary anatomy was demonstrated in all eight patients. In four patients aged 18 to 28 years, coronary arteriography was not performed. Five patients with a low probability of myocarditis formed a control group; 1 was a female patient, and 4 were men, with a mean age of 32 ± 15 years (range, 15 to 54 years). One of the patients had a long-standing history of congestive heart failure, and endomyocardial biopsy was nondiagnostic for myocarditis; one had a congenital complete heart block, one patient was treated for atrial Butter, one had a sinus tachycardia without symptoms of congestive heart failure, and one patient had a coronary artery fistula. All subjects underwent myosin-specific monoclonal antibody imaging. Antimyosin antibody (Myoscint; Centocor Inc.) was supplied as a sterile nonpyrogenic solution containing 0.5 mg ofRUD10 Fab DTPA, which is a mouse monoclonal antibody fragment that binds specifically to myosin. Antimyosin is radiolabeled by the addition of sterile 111 In chloride. Two millicuries of'"In were diluted to 10 ml of volume and administered intravenously by slow injection. Planar imaging was performed 48 h later using a gamma camera (General Electric Maxi Camera 400). Three views were obtained (anterior, 45° left anterior oblique, and 7<1' left anterior oblique) using a 128 X 128 matrix for 10 min per view. Both photopeaks of CHEST I 104 I 5 I NOVEMBER, 1993
1427
Table 1-Ruulta of Antimyoain Scintigraphy, lfight Ventricular Endomgocardiol Bioply, and Left Ventricular Ejection FrGCiion
Initial Group and No. Patients 1 2 3 4 5 6 7 8 9 10 11 12 Control subjects 1 2 3 4 5
At 2 mo*
At 1 mo*
Age (yr), Sex
HIL
EFt
34,M 18, M 44, M 52, F 45, M 25, M 42, M 28, M 45, F 19, M 22, M 58, M
2.1 2.9 1.9 2.4 1.9 1.8 2.1 2.0 1.9 1.7 1.9 2.5
28 33 57 35 29 21 55 35 32 30 11
25, M 21, F 54,M 15, M 48, M
1.5 1.3 1.4 1.2 1.3
20 60 58 65 60
Biopsy
45
+ + + + + + + +
HIL 1.5 2.2 1.9 2.0 1.8 1.5 1.4 1.8
EFt
HIL
EFt
1.5 1.6
76 34
43 36
35 63 32 31 23 64
*Time after admission. tEF, ejection fraction in percent. "'In (173 keV and 247 keV) were used with 20 percent energy windows. Images were evaluated for the presence or absence of tracer uptake; a heart-to-lung {HIL) ratio was used to quantify tracer uptake;' the unprocessed anterior projection was used to adjust a region of interest in the myocardium and a region of interest in each lung. Average counts per pixel in the myocardium were divided by the average counts per pixel in each lung to obtain the H1L ratio. An H1L ratio greater than 1.6 was considered abnormal.• Right ventricular endomyocardial biopsy was performed in all patients with suspected myocarditis and in one patient from the control group. A Stanford bioptome was used, and three samples were obtained by means of the right internal jugular vein. All samples for biopsy were interpreted according to Dallas criteria• without knowledge of the results of antimyosin scan.
From the group of patients with suspected myocarditis, one patient died; in eight patients the antimyosin scan was repeated in 1 month; two patients had a third antimyosin scan in 2 months (Table 1). Within I week of antimyosin scan, a new radionuclide ventriculography was performed to assess global left ventricular function. All group data were expressed as mean values± SD.
FiGURE l. Scan from patient with acute myocarditis (anterior view). Diffuse uptake of tracer is seen in myocardium .
9 F1 . lilt - · can (ldt anteri<>r ohliqu • 4 1 ' ' ) rrnm me pali ·nl as Figure l. Diffuse activity is evident in cardiac region.
1428
RESULTS
Antimyosin antibody was administered without adverse reactions in all patients and control subjects; no reactions were detected in patients with repeated injections. In the control group, all 5 subjects had normal results on antimyosin study (Table 1); the HIL
Anllmyoain Scintigraphy for Detection of Myocarditis (Le/calcis et a/)
ratio ranged from 1.2 to 1.5 (mean, 1.3±0.1). In the group of patients with suspected myocarditis, the results of antimyosin scanning were diagnostic (Fig 1 and 2); the HIL ratio ranged from l. 7 to 2.9 (mean, 2.1 ± 0.3), and it was significantly higher than that observed in the control group (p
Indium Ill-labeled antimyosin antibodies have been shown to bind specifically to areas of myocardial necrosis;9 a close correlation between antibody uptake and the mass of necrotic myocardium has been found , in both animals and humans. 10•11 Since myocardial necrosis, in association with inflammation, is an essential component of myocarditis, a few studies tried to clarify the usefulness of antimyosin scanning in the detection of myocarditis. The feasibility of imaging myocarditis has been demonstrated in experimental murine studies. 8 •12 In humans, Yasuda et al3 investigated 28 patients with suspected acute myocarditis; 17 patients had a diagnostic scan and 11 had nondiagnostic scans. Eight of the patients with diagnostic scans did not show histologic evidence of myocarditis. The high sensitivity and negative predictive value was also reported by Carrio et al;4 in 13 patients suspected of having myocarditis, the antimyosin scan was diagnostic for myocarditis in 11, but biopsy-proven myocarditis was found in only 4. Similar findings were reported by Dec et al; 5 in 82 patients with clinically suspected myocarditis, the sensitivity of the antimyosin scan was 83 percent and the specificity 53 percent when compared to endomyocardial biopsy. All of those findings are in accord with our observations; all
patients with biopsy-proven myocarditis had abnormal results on scanning, but four patients with a nondiagnostic biopsy also had abnormal results on scanning. A diagnostic antimyosin scan associated with a nondiagnostic endomyocardial biopsy may represent either a false-positive scan or a false-negative biopsy. The sensitivity of right ventricular biopsy in myocarditis is questionable; myocarditis usually is a multifocal process, and specimens from biopsy may be obtained from unaffected areas of myocardium. Probably samples from biopsy of the right ventricle cannot be considered representative of the entire myocardium. In 14 hearts with histologically proven myocarditis studied ex vivo, Chow et al6 required 17.2 samples per case (an unrealistic number) to diagnose 79 percent (11) of 14 cases; with 4 to 5 samples per case, the chanee of a successful diagnosis was 50 percent; thus, right ventricular endomyocardial biopsy demonstrates relatively low levels of diagnostic sensitivity. On the other hand, antimyosin imaging appears to be a very specific method; on postmortem imaging, uptake of tracer matched the triphenyltetrazolium chloride staining, confirming that myosin-specific antibody binds specifically to irreversibly damaged myocardial cells.9 •11 Although we did not use tomography in our study, nonspecific myocardial uptake is unlikely, since persistent blood pool activity is rare at 48-h planar images. 5 In our study the fact that patients with diagnostic or nondiagnostic endomyocardial biopsy have a similar HIL ratio on the antimyosin scan, as well as a similar ejection fraction, indicates that these two groups represent a unique entity. Also the behavior of these two groups during the 2-month follow-up is similar; two out of three patients with a diagnostic scan and a nondiagnostic biopsy developed normal HIL ratios, while the same normalization was observed in three out of five patients with a diagnostic scan and a diagnostic biopsy. Since uptake of antimyosin has the same evolution in both groups, uptake in patients with a nondiagnostic biopsy probably represents a true uptake and not a false-positive scan. The natural evolution of the antimyosin scan has been studied only in a murine model of myocarditis;8 uptake was intense on day 10 (in all mice) and slight on day 20 (in 20 percent of the mice). Pathologic findings correlated well with the uptake of antimyosin. These results in animals are in accord with our findings in humans; a reduction of antimyosin uptake was observed in most patients during follow-up, regardless of a diagnostic or nondiagnostic biopsy. Dec et al5 reported a repeat antimyosin scan in 17 patients with an initial diagnostic antimyosin scan; 8 of the 17 patients had a follow-up antimyosin scan that no longer demonstrated uptake of tracer; 3 of these 8 patients had biopsy-verified myocarditis, and 5 did not. In that study, 5 quantitative CHEST I 104 I 5 I NOIIEMBER, 1993
1429
analysis of the intensity of the image was not performed, and many patients with a diagnostic biopsy received immunosuppressive therapy. The ejection fraction improved more than 8 percent in one out of three patients with a diagnostic scan and a nondiagnostic biopsy and in two out of five patients with a diagnostic scan and a diagnostic biopsy. Dec et al5 reported similar results in their study; 7 of 10 patients with a diagnostic scan and a diagnostic biopsy had an improved ejection fraction by more than 10 percent at 6 months; also 7 of 16 patients with a diagnostic scan and a nondiagnostic biopsy had an improved ejection fraction. In our study, none of the patients received immunosuppression, and thus these findings represent the natural evolution of myocarditis in these patients. In experimental studies, Kishimoto et al8 also showed an increase in the ejection fraction by more than 10 percent between days 10 and 150 in mice with myocarditis without any therapy. In conclusion, the findings of this study indicate that in patients with suspected myocarditis, the antimyosin scan is more frequently diagnostic than the endomyocardial biopsy. Many patients with initially diagnostic antimyosin scans demonstrate no tracer uptake at repeat antimyosin imaging at 2 months. Larger series will be needed to determine the role of serial antimyosin imaging in assessing the progress of the disease in patients with myocarditis. REFERENCES
1 Khaw BA, Strauss HW, Moore R, Fallon Jf, Yasuda T, Gold HK, et al. Myocardial damage delineated by indium-HI antimyosin Fab and technetium-99m pyrophosphate. J Nucl Med 1987; 28:76-82 2 Aretz HT. Billingham ME. Edwards WD. Factor SM, Fallon Jf, Fenoglio JJ, et al. Myocarditis: ahistopathological definition and classification. Am J Cardiovasc Patholl987; 1:3-14
1430
3 Yasuda T, Palacios IF, Dec GW, Fallon Jf, Gold HK, Leinbach RC, et al. Indium-Ill monoclonal antimyosin antibody imaging in the diagnosis of acute myocarditis. Circulation 1987; 76:306-
11 4 Carrio I, Bema L, Ballester M, Estorch M, Obrador D , Cladellas M, et al. Indium-Ill antimyosin scintigraphy to assess myocardial damage in patients with suspected myocarditis and cardiac rejection. J Nucl Med 1988; 29:1893-1900 5 Dec GW, Palacios IF, Yasuda T, Fallon JT, Khaw BA, Strauss HW, et al. Antimyosin antibody cardiac imaging: its role in the diagnosis of myocarditis. JAm Coli Cardioll990; 16:97-104 6 Chow LE, Radio SJ, Sears TD, McManus BM. Insensitivity of right ventricular endomyocardial biopsy in the diagnosis of myocarditis. JAm Coli Cardioll989; 14:915-20 7 Hauck AJ, Kearney DL, Edwards WD. Quantitative evaluation of postmortem endomyocardial biposy specimens (EMB) from 38 hearts of patients with autopsy-proved lymphocytic myocarditis: implications for the role of sampling error in the evaluation of myocarditis by EMB in living patients [abstract]. In: PrOceedings of the International Symposium ofln8ammatory Heart Disease: a multidisciplinary approach to myocarditis and heart allograft rejection. Omaha, Neb: Center for Continuing Education, University of Nebraska Medical Center, 1988; 165 8 Kishimoto C, Hung GL, Ishibashi M, Khaw BA, Kolodny GM , Abelmann WH, et al. Natural evolution of cardiac function, cardiac pathology and antimyosin scan in a murine myocarditis model. JAm Coli Cardioll991; 17:821-27 9 Khaw BA, Fallon Jf, Beller GA, Haber E . Specificity of the localization of myosin specific antibody fragments in experimental myocardial infarction: histologic, histochemical, autoradiographic and scintigraphic studies. Circulation 1979; 60:1527-31 10 Khaw BA, Scott J, Fallon Jf, Cahill SL, Haber E, Homey C. Myocardial injury: quantification by cell sorting initiated with antimyosin fluorescent spheres. Science 1982; 217:1050-53 11 Jain D, Lahiri A, Crawley JCW, Raftery EB. In 111-antimyosin imaging in a patient with acute myocardial infarction: postmortem correlation between histopathologic and autoradiographic extent of myocardial necrosis. Am J Card lmag 1988; 2:158-61 12 Matsumori A, Ohkusho T, Matoba Y, Okada I, Yamada T, Kawai C, et al. Myocardial uptake of antimyosin monoclonal antibody in a murine model of viral myocarditis. Circulation 1989; 79:400-
05