Imaging Techniques for Myocardial Inflammation

Transcription

1 ANNALS O F CLINICAL AND LABORATORY SCIEN CE, Vol. 16, No. 2 Copyright 1986, Institute for Clinical Science, Inc. Imaging Techniques for Myocardial Inflammation JO H N B. O CONNELL, M.D., ROBERT E. H EN K IN, M.D., and JOHN A. ROBINSON, M.D. Departments of Medicine and Radiology, Loyola University Medical Center, Maywood, IL ABSTRACT Dilated cardiomyopathy (DC) represents a heterogeneous group of disorders which results in m orbidity and m ortality in young individuals. Recent evidence suggests that a subset of these patients have histologic evidence of myocarditis which is potentially treatable with immunosuppression. The identification of myocardial inflam m ation may therefore lead to developm ent of therapeutic regim ens designed to treat the cause rather than the effect of the myocardial disease. Ultimately, this may result in improvement in the abysmal prognosis of DC. The currently accepted technique for identification of active myocardial inflammation is endomyocardial biopsy. This technique is not perfect, however, since pathologic standards for the diagnosis of myocarditis have not been established. Furtherm ore, focal inflammation may give rise to sampling error. The inflammation-avid radioisotope gallium-67 citrate has been used as an adjunct to biopsy improving the yield of myocarditis from 7 percent to 36 percent. Serial imaging correlates well to biopsy results. F u tu re studies are designed to study the applicability of lym phocyte labelling techniques to myocardial inflammatory disease. Introduction Idio p ath ic d ila te d cardiom yopathy (IDC) is an im portant cause of morbidity and mortality in the young adult population.30 Although the therapy of congestive heart failure, a common manifestation of IDC, has improved substantially over the past 15 years with the addition of vasodilators and intravenous inotropic agents, there has been no effect on long term survival. The c u rren t th erapies, therefore, are palliative at best because they are designed to treat the signs and sym ptom s (co n g estiv e h e a rt failu re, arrhythm ia, or throm boem bolic complications) and not the cause of this heart muscle disease. The only form of therapy proven to prolong life is cardiac transplantation /86/ $01.50 Institute for Clinical Science, Inc. Send rep rin t requests to John B. O Connell, M.D., Section of Cardiology, Loyola University Medical C enter, 2160 South First Avenue, Maywood, IL

2 IMAGING TECHNIQUES FOR MYOCARDIAL INFLAMMATION 147 The variable prognosis of ID C suggests that it is the end result of a heterog eneous g ro u p of c o n d itio n s. W h en Mason and colleagues dem onstrated that active myocardial inflammation could be identified histologically by using endom yocardial biopsy (EM B) in patients with advanced dilated cardiomyopathy, new hope for the developm ent of therapies designed to treat the cause rather than the effect of the cardiom yopathic process e m e rg e d.21 Since th e n th e ir o b s e r v a t i o n s h a v e b e e n c o n - firm ed2,3 4 6'7'11'12, ,41 45 and uncontrolled trials of im m unosuppressive th erapy suggest th at a subset of patients with clinical IDC and inflammation on myocardial biopsy may respond with clinical and hemodynamic improvem ent by the addition of prednisone and azathioprine.6 12'16,21 29 A large randomized controlled trial m ust be com pleted before the effect of these agents on the natural history of ID C can be d eterm ined.22 Although efficacy of immunosuppressive therapy in active myocarditis is not yet proven, identification of myocardial inflammation may be im portant to the clinician for o th er reasons. In anim al m odels, th e re is com pelling evidence that regular physical exercise results in m arked worsening of inflammation and subsequent necrosis and may be detrim ental to inflammatory heart diseases.40 C o n seq u en tly, re stric tin g activity in patients with active myocarditis may be th e r a p e u tic a lly b e n e f ic ia l. M u ra l throm bi may form in the inflamed endomyocardium even in the absence of akin etic segm ents on echocardiogram s, necessitating anticoagulant th erapy in individuals with active myocarditis.5 For th ese reasons, a reliab le tool for th e identification of myocardial inflammation is desirable if optimal care is to be provided. Finally, if a patient with proven m y o c a rd itis c lin ic a lly d e te rio ra te s, immunosuppression may be considered. Identification of myocardial inflammation Endom yocardial biopsy is the standard against which all other techniques of detection of myocardial inflammation are compared. This technique, although safe in experienced hands,31 is costly and may b e associated w ith m o rb id ity in inexperienced hands. Although widely available in tertiary care centers, it is not likely that endomyocardial biopsy will be a practical tool in sm aller com m unity hospitals, prim arily because experience w ith histopathologic in te rp retatio n of biopsy sam ples may be lim ited in that setting. Although interpretation of myocardial biopsy at face value seems relatively straightforward, in fact, m ultiple reports describing the incidence of histologic myocarditis from five percent to 63 p ercent in dilated cardiom yopathy is strong evidence there are significant discrepancies in pathologic in te rp re ta tion n.12.16,19,27,32,33,38,41,45 p or example: How many lymphocytes in the myocardial interstitium are necessary to establish a diagnosis of myocarditis?11 Is it im portant to quantitate lym phocytes since myocarditis may be only focal in a biopsy specim en? H ow im p o rtan t is dem onstrable myocyte necrosis and how does one dem onstrate myocyte necrosis? Does fibrosis alter the pathologic interpretation? Is im m unohistochem istry of value?4 And finally: Can one establish a diagnosis of active m yocarditis in the presence of myocyte abnormalities compatible w ith dilated cardiom yopathy? Before the specificity of endomyocardial biopsy can be ascertained, these questions need to be answered. It is also very difficult to quantitate the sensitivity of endom yocardial biopsy since the identification of a false negative population cannot be achieved. Th e re is, o n c e ag a in, c o n tro v e rs y reg ard in g th e p o te n tia l for sam pling error of endom yocardial biopsy. The

3 148 O'CONNELL, HENKIN, AND ROBINSON focality of significant m yocarditis was first brought to light on autopsy study of patients dying of varicella infection by H aeckel.14 H e showed that when routine histologic specimens of the myocardium w ere obtained at autopsy, the incidence of myocarditis was quite low. In addition, w hen careful histologic serial sections w ere perform ed, myocarditis was uniformly present in these hearts, suggesting that m ultiple sections m ust be obtained in order to minimize the sampling error even w hen the entire heart is available. Since most cardiologists in the United States who perform endomyocardial biopsy use the safest procedure, one that involves biopsy of the septal portion of the right ventricle,20 left ventricular su b e n d o c a rd iu m is n o t available for examination. Although four or five specim ens may b e o b tain ed from various areas of the septum, the patchy nature of m yocarditis m ay re su lt in significant sampling error. Proof of this can only be perform ed if the entire heart is available for histologic evaluation; however, these autopsy analyses re p re s e n t a skew ed p o p u la tio n, th a t is, p re su m p tiv e ly patients with m ore fulminant, end-stage forms of the disease die of their disease. Therefore, the sensitivity of endomyocardial biopsy will never be ascertained; however, one can assume that the specificity is far greater than the sensitivity. It was hoped that careful evaluation of clinical, hemodynamic, and non-invasive p a ra m e te rs in p a tie n ts w ith biopsyproven myocarditis would sort out clinical clues retrospectively that could be utilized in screening for individuals with a h ig h in c id e n c e o f m y o c a rd itis at biopsy. In fact, that has not been the case. In p atien ts w ith recen t onset of congestive h eart failure, th e re are no clinical, hemodynamic, or non-invasive param eters than can reliably help in the identification of a subset of patients with active myocarditis.2 3, ,33 43 Furthermore, since the autoim m une nature of this process is postulated to involve cellm ediated immune responses,44 the nonspecific indicators of inflammation, such as erythrocyte sedim entation rate and white blood cell count, has proven to be useless in identifying those patients with active myocarditis. Antiheart antibodies, although common in active myocarditis, have not been shown to be specific for that condition. In summary, the identification of active m yocarditis cu rren tly relies upon the use of endom yocardial biopsy, a technique which is potentially specific but lacks the necessary sensitivity to identify patchy myocardial inflammation. The use of clinical and laboratory tools to identify a population likely to have myocarditis on biopsy has been frustrating to date since no clear-cut differen ce has b e e n id en tified b etw een p a tien ts w ith active m yocarditis and those w ithout. T herefore, a safe, reliable, repro d u ceab le, highly sensitive technique is desirable as an adjunct to biopsy in the diagnosis of myocarditis. Imaging Techniques T e c h n e t iu m -9 9 m P y r o ph o sph a te (99mT c PYP) Investigators in Japan w ere the first to id en tify th a t this 99mTc PYP, com monly used as a hot spot imaging agent for myocardial infarction, may show diffuse uptake in m yopericarditis.25 This observation was verified with studies in the animal model of Coxsackie virus B3 m yocarditis in BALB/c m ice.17 W hen sequential studies of myocardial uptake w ere perform ed, the m yocardial 99mTc PYP uptake correlated with the extent of myocardial necrosis but decreased with the progression of cellular infiltration docum enting that, although an excellent m arker of myocardial damage, this imaging technique does not mark active myocardial inflam m ation.23 F u rth erm o re, other investigators have dem onstrated

4 IMAGING TECHNIQUES FOR MYOCARDIAL INFLAMMATION 149 sim ilar diffuse m yocardial u p take in patients with ID C who have no evidence of active m yocarditis su g g estin g th at many forms of myocardial damage may n o n -sp ecifically re s u lt in 99mTc PYP uptake.9,36 G allium -67-C itrate (67Ga) Initially developed as a bone scanning agent but later shown to be an excellent m arker for identification of extent of lymphoma and some selected soft tissue tumors, 67Ga was noted to be an excellent imaging agent for chronic inflammation.15 In fact, several autoim m une conditions such as sarcoidosis,1 interstitial pneum onitis,26 C rohn s disease,13 noninfectious interstitial nephritis,43 dermatomyositis,37 and rheum atoid arthritis,24 have all been imaged successfully with 67Ga. Initial interest in the use of 67Ga imaging in myocardial lesions was its use as a hot spot im aging agent in acute myocardial infarction;18 how ever, with th e d e v e lo p m e n t of 99mTc PYP, this in terest rapidly tap ered. T he p resent authors first became interested in studying th e role of 67Ga im aging in active myocarditis when a young woman p resented to our institution w ith a malignant thymoma and congestive heart failu r e. In an a t t e m p t to s ta g e h e r thym om a, a 67G a scan was perform ed which dem onstrated no uptake over the known pleural neoplasm b u t very dense uptake over the m yocardium. D espite aggressive therapy for h er lym phom a, she ex pired several m onths later; at autopsy, evidence of m yocarditis was identified. This stim ulated us to study 67Ga as a tool in im aging th e m yocardium for inflam m ation; how ever, th e available techniques for gallium scanning were not adequate to image the myocardium and modifications of that technique had to be made. C urrently, 67Ga h eart scans are perform ed 72 hours after intravenous injection of 5m Ci of 67Ga citrate. O ur patients are imaged in the anterior, left lateral, and 45 and 60 left a n te rio r oblique projections. It is tried to exclude all but the superior portion of the liver so that the 625,000 counts accum ulated will not be of hepatic origin. Images are perform ed w ith a latest generation large fie ld o f v ie w g a m m a c a m e ra w ith medium energy collimmator capable of detecting the 93, 185, and 300 kev 67Ga energy peaks. O ur images are processed in a nuclear m edicine com puter with a 256 X 256 matrix, enhanced less than 20 percent of the maximal pixel, and the scans are in te rp re ta te d by a n u clear m e d ic in e p h y s ic ia n (R E H ) w ho is b linded to th e clinical and pathologic data. Scans are interpreted as positive if their density is equal to or greater than that of the sternum and equivocal if the density is less than that of the sternum. Utilizing this technique, it was possible to identify gallium uptake (figure 1) over th e m yocardium in th re e individuals with ID C, two of whom w ere treated with im m unosuppressive therapy with encouraging results.35 Since m yocardial inflam m ation frequently occurs in the presence of pericardial inflammation, it was possible to identify active uptake over the pericardium in three patients with proven pericardial inflammation, one of whom had a thin pattern of uptake that was visually much different than those patients with m y o card ial in fla m m a tio n in I D C.28 T h irty -n in e u n se le c te d p atien ts w ith IDC w ere scanned. It was found that in 19 of those individuals there was active uptake over the m yocardium.29 W hen com paring clinical, hem odynam ic, and non-invasive param eters of myocardial dysfunction, those individuals with gallium uptake could not be separated from those who were gallium negative. W hen offered im m u n o su p p ressiv e th erap y, 15 of th e 19 67Ga p o sitiv e patients accepted and received predni

5 O'CONNELL, HENKIN, AND ROBINSON F igure 1. 67Ga scan in anterior projection showing no uptake (left) and dense diffuse myocardial uptake (right), (From O Connell, JB, et al: Modes of detection of inflammation in the cardiomyopathy heart. Myocar ditis: Precursor of Cardiomyopathy. Robinson J. A. & O Connell J. B., eds. Lexington, MA, D.C. Health & Co., 1983 pp Reproduced with permission.) sone and azathioprine for two years. Nine (60 percent) had persistently posi tive gallium scans despite immunosup pressive therapy and no clinical nor hemodynamic improvem ent as a result of this tre a tm e n t. Six (40 p ercen t) showed conversion of the gallium scan from po sitiv e to n eg ativ e by th re e months with substantial improvement in ejection fraction and no mortality in the follow-up period. These patients have been followed for seven years (five years after discontinuation of immunosuppres sion), and, to date, all of the patients remain alive and well. This prompted us to postulate that in the 60 percent of patients who received immunosuppres sion and whose gallium scan did not con vert to negative, perhaps the scan was positive for reasons other than inflamma tion because it was not possible to alter the process causing the m yocardial uptake with the potent immunosuppres sive regimen. It was our hope that the 40 percent of patients who responded and had gallium scan conversion to negative represented a population of patients with active m yocarditis who im proved on immunosuppressive therapy. Endomyo cardial biopsies were not available for that study and, therefore, these conclu sions were not firm. The 67Ga imaging was com pared to endom yocardial biopsy in patients in biopsy-proven myocarditis (figure 2).32 The overall incidence of myocarditis was seven percent in 68 patients with con gestive heart failure of recent onset. As previously noted, clinical or hem ody namic param eters could not differentiate those patients who had biopsy evidence of myocarditis from those who did not. Fourteen gallium scans were positive. Five of the six patients w ith biopsyproven myocarditis had a dense diffuse uptake of gallium. The single patient without gallium uptake had a probably hypersensitivity m yocarditis and had dense uptake of posterior m ediastinal lymph nodes which may have decreased our visual ability to detect myocardial uptake. Serial 67Ga imaging showed a direct correlation with resolution of his tologic evidence of m yocarditis. The

6 IMAGING TECHNIQUES FOR MYOCARDIAL INFLAMMATION 151 F igure 2. Paired (,'Ga scan in anterior projection showing dense diffuse myocardial uptake (s = sternum, L = liver, h = heart) in panel A and photomicrograph of endomyocardial biopsy specimen showing active myocarditis with lymphomononuclear cell infiltration and myoctye necrosis [ m = myocyte] in panel B Hematoxylin and eosin original magnification x 200. (From O Connell J. B., et al: Gallium-67 imaging in patients with dilated cardiomyopathy and biopsy-proven myocarditis. Circulation 70:58-62, Repro duced with permission.) incidence of biopsy-proven myocarditis rose five-fold (7 to 36 percent) if the gal lium scan was positive. True sensitivity and specificity of this technique cannot be calculated from these data because of the small patient numbers. W hen 67Ga imaging was performed for detecting inflammatory lesions in other organ systems, the sensitivity was found to be 90 percent with a specificity of 64 percent, which would compare favorably to our m yocardial d ata.10 Strain and others compared 67Ga imaging to myo cardial biopsy and found that the sensi tivity was quite low (44 percent) with a specificity of 100 percent.39 The rather m arked difference in results betw een their study and ours is perhaps reflective of difference in pathologic interpretation of endomyocardial biopsy. W hen 67Ga was compared to 99mTc PYP imaging in rabbit norepinephrine-induced myocar ditis, diffuse cardiac uptake of 67Ga was found in 13 of 15 rabbits. There was no uptake of 99mTc PYP in eight rabbits; yet, the histology of all 23 hearts showed sim ilar levels of myocarditis.34 Based on our current studies, it is felt that 67Ga imaging may, in fact, be a sen sitive m arker of active m yocarditis although lacking specificity. Its utility is dependent upon meticulous attention to the details of the technical aspects of imaging the heart with this isotope. This technique has been very useful in follow ing our patients w ith biopsy-proven myocarditis as a non-invasive marker of inflammation obviating the necessity of

7 152 O'CONNELL, HENKIN, AND ROBINSON m ultiple repetitive biopsies. The value of 67Ga as a screening tool for myocarditis will be evaluated in a large multicentered trial of im m unosuppression and biopsy-proven myocarditis. Future Prospects Although perhaps a sensitive marker of inflam m ation, 67Ga is not th e ideal im aging agent. A 72 hour delay from in je c tio n to im ag in g is re q u ire d to improve target to background ratios to enhance the ability to interpret the scans visually. This agent has an extrem ely long half life (96 hours); thus, serial scans require a m inim um of a th ree to four week separation betw een studies. F u r thermore, because this is a gamma em itter, safety in radiation dose dictates that no m ore than perhaps four scans be perform ed in any given year. T herefore, although promising, this 67Ga is not the ideal radioisotope. New approaches on the horizon for imaging the myocardium in myocarditis include cell labeling techniques utilizing indium or technetium-99m8 to label autologous lymphocytes in an eifort to follow their homing pattern into the myocardium indicating active inflammation. Summary Since active myocarditis is postulated as a cause of m orbidity and mortality as a result of congestive heart failure, techniques designed to identify active myocarditis non-invasively are im portant so that therapy designed to alter the inflammatory response may be attem tped. 67Ga may be a sensitive but non-specific indicator of active myocarditis which can be a useful adjunct in the diagnostic armam entarium of th e clinical cardiologist w hen c o u p le d w ith endom y o card ial biopsy. F u tu re studies are planned in which 67Ga imaging will be com pared to endomyocardial biopsy in a randomized m ulti-centered trial. Although less than an ideal isotope, because of its radiopharmaceutical properties, isotopic studies involving lymphocyte labelling may be valuable in future studies of non-invasive identification of active myocarditis. References 1. A l b e r t s, C., V an d e r S c iio o t, J. B., V an D a atselaar, J. J., B raat, M. C. P., and Roos, C. M.: 67Ga scintigraphy, serum lysozyme and angiotensin-converting enzyme in pulmonary sarcoidosis. Eur. J. Resp. Dis. 64:38-46, B a a n d r u p, U. and O l s e n, E. G. J.: Critical analysis of endomyocardial biopsies for patients suspected of having cardiomyopathy. I. Morphologic and morphometric aspects. Brit. Heart J. 45: , B o l t e, H.-D. and L u d w ig, B.: Viral myocarditis: Symptomatology, clinical diagnostics, and hemodynamics. Viral Heart Disease. Bolte, H.-D., ed. New York, S prin g er Verlag, 1983, pp C a s s l in g, R. S., L i n d e r, J., S e a r s, T. D., W a l l e r, B. F., R o g l e r, W. C., W il s o n, J. E., K u g l e r, J. D., D a y, D. H., D i l l o n, J. C., S l a c k, J. D., and M c M a n u s, B. M.: Quantitative evaluation of inflammation in biopsy specimens from idiopathically failing or irritable hearts: Experience in 80 pediatric and adult patients. Am. Heart J. 110: , D aly, K., M o n a g h a n, M., R ic h a r d s o n, P., J acks o n, G., and J e w it t, D.: Significant incidence of mural thrombi in acute myocarditis - Indication for early antiocoagulation. J. Am. Coll. Cardiol. 1:584, D a l y, K., R ic h a r d s o n, P. J., O l s e n, E. G. J., M o r g a n - C a p n e r, P., M c S o r l e y, C., J a c k s o n, G., and J e w it t, D. E.: Acute myocarditis. Role of histological and virological examination in the diagnosis and assessment of immunosuppressive therapy. Brit. Heart. J. 51:30-36, D e c, J r., G. W., P a l a c io s, I. F., F a l l o n, J. T., A r e t z, H. T., M il l s, J., L e e, D. C-S., and J o h n s o n, R. A.: Active myocarditis in the spectrum of acute dilated cardiomyopathies: Clinical features, histologic correlates, and clinical outcome. New Engl. J. Med. 312: , D o ly, A., F i.nat- D u c l o s, F., D o ly, M., V ey re, A., P l a g u e, R., and M e y n e il, G.: Study of cell changes induced by radiolabelling of human lymphocytes with 99m-technetium. Clin. Exp. Immunol. 52: , D uska, F., V iz d a, J., K u b ic e k, J., K a fka, P., N e s- vadba, Z., Z danoky, P., and B a stecley, J.: The sensitivity of scintigraphic myocardial imaging by the use of 99mTc-labelled pyrophosphate in the diagnosis of cardiomyopathy of various etiology. Eur. J. Nucl. Med. 4:87-90, E b r ig iit, J. R., S o in, J. A., a n d M a n o l i, R. S.:

8 IMAGING TECHNIQUES FOR MYOCARDIAL INFLAMMATION 153 Y., T akishita, A., and F ujim u, S.: Intense, persistent myocardial-avid technetium-99m-pyrophosphate scintigraphy in acute mvocarditis. Am. Heart J. i0i: , N i d e n, A. H., M is h k in, F. S., and K h u r a n a, M. M. L. : 67Gallium citrate lung scans in interstitial lung disease. Chest 69: , N o d a, S.: Histopathology of endomyocardial biopsies from patients with idiopathic cardiomyopathy: Quantitiative evaluation based on multivariate statistical analysis. Jpn. Cire. J. 44:95-116, O C o n n e l l, J. B., R o b in s o n, J. A., H e n k in, R. E., and G u n n a r, R. M.: Gallium-67 citrate scanning for noninvasive detection of inflammation in pericardial diseases. Am. J. Cardiol. 46: , O C o n n e l l, J. B., R o b in s o n, J. A., H e n k in, R. E., and G u n n a r, R. M.: Immunosuppressive therapy in patients with congestive cardiomyopathy and mvocardial uptake of gallium-67. Circulation 64: , O C o n n e l l, J. B. a n d G u n n a r, R. M.: Dilatedcongestive cardiomyopathy: Prognostic features and therapy. J. Heart Transplant 2:7-17, O C o n n e l l, J. B., S u b r a m a n ia n, R., R o b in s o n, J. A., and S c a n l o n, P. J.: Endom yocardial biopsy: Techniques and application in heart disease of unknown cause. J. H eart Transplant 3: , O C o n n e l l, J. B., H e n k in, R. E., R o b in s o n, J. A., S ubram anian, R., S c a n l o n, P. J., and G unnar, R. M.: Gallium-67 imaging in patients with dilated cardiomyopathy and biopsv-proven myocarditis. Circulation 70:58 62, Pa rillo, J. E., A re t z, H. T., Pa lacio s, I., F all o n, J. T., and B l o c k, P. C.: The results of transvenous endom yocardial biopsy can frequently be used to diagnose myocardial diseases in patients with idiopathic heart failure: Endomyocardial biopsies in 100 consecutive patients revealed a substantial incidence of myocarditis. Circulation 69:93-102, R e e v e s, W. C., J a c k s o n, G. L., F l ic k in g e r, F. W., K w e e, H. G., S c h w it e r, E. J., W e r n e r, J., W h it e s e l l, L., B id d l e, M. A., C open tia v er, G., S h a ik h, B. S., and Z e l is, R.: Radionuclide imaging of experimental mvocarditis. Circulation 63: , R o b in s o n, J. A., O C o n n e l l, J., H e n k in, R. E., and G u n n a r, R. M.: Gallium-67 imaging in cardiomyopathy. Ann. Intern. Med. 90: , S h ih, W.-J., D e L a n d, F. H., D o m s t a d, P. A., The gallium scan. Problems and misuse in examination of patients w ith suspected infection. Arch. Intern. Med. 142: , E d w a r d s, W. D., H o l m e s, D. R., J r., and R e e d e r, G. S.: Diagnosis of active lymphocytic myocarditis by endomyocardial biopsy. Quantitative criteria for light microscopy. Mayo Clin. Proc. 57: , F e n o g l io, J. J., J r., U r s e l l, P. C., K e l l o g g, C. F., D r u s in, R. E., and W e is s, M. D.: Diagnosis and classification of myocarditis by endomyocardial biopsy. New Engl. J. Med. 308:12-18, G o l d e n b e r g, D. J., R u s s e l l, C. D., M ik a s, A. A., D ubovsky, E. V., and L o g ic, J. R.: Value of gallium-67 citrate scanning in Crohn s disease: Concise communication. J. Nucl. Med. 20: , H a e c k e l, D. B.: Myocarditis in association with varicella. Am. J. Pathol. 29: , H e n k i n, R. E.: Gallium-67 in the diagnosis of inflam m atory disease. Gallium -67 Imaging. Hoffer, P. B., Beckman, C., and Henkin, R. E., eds. New York, John Wiley and Sons, 1978, pp H e s s, M. L., H a stil l o, A., and M o iia ntr y, P. K.: In flam m ato ry m yocard itis: In c id e n c e and response to T-lymphocyte depletion. J. Am. Coll. Cardiol. i:584, K a d o t a, K., M a t s u m o r i, A., K a m bara, H., and K a w a i, C.: Myocardial uptake of technetium - 99m stannous pyrophosphate in experim ental viral myocarditis. J. Nucl. Med. 20: , K r a m e r, R. J., G o l d s t e in, R. E., H ir s iif ie l d, J r., J. W., R o b e r t s, W. C., J o h n s t o n, G. S., and E p s t e in, S. E. : Accumulation of gallium-67 in regions of acute myocardial infarction. Am. J. Cardiol. 33: , K u n k e l, B., L a p p, H., K o b e r, G., and K a tten - ba ch, M.: Light-microscopic evaluation of myocardial biopsies. Cardiomyopathy and Myocardial Biopsy. Kattenbach, M., Loogen, F., and Olsen, E. G. J., eds. New York, Springer-Verlag, 1978, pp M aso n, J. W.: Techniques for right and left ventricular endomyocardial biopsy. Am. J. Cardiol. 41: , M a s o n, J. W., B il l in g iia m, M. E., and R ic c i, D. R.: Treatment of acute inflammatory myocarditis assisted by endomyocardial biopsy. Am. J. Cardiol. 45: , M a so n, J. W.: Endomydcardial biopsy: The balance of success and failure. Circulation 7/: 1S5 188, M a tsum ori, A., K a d o ta, K., and K aw ai, C.: Technetium-99m pyrophosphate uptake in experimental viral perimyocarditis. Sequential study of myocardial uptake and pathologic correlates. Circulation 6i: , M c C a l l, I. W., S h e p p a r d, H., H a dd a w a y, M., P a r k, W. M., and W a r d, D. J.: G allium -67 scanning in rheumatoid arthritis. Brit. J. Radiol. 56: , M itsuta ke, A., N akamura, M., I n o w, T., K ik u c h i, and S c h a c h t, R. A.: S eq u en tia l early and delayed myocardial 99mTc pyrophosphate scans: Evaluation of diffuse myocardial uptake. Eur. J. Nucl. Med. 8: , S m ith, W. P., R o b in s o n, R. G., and G o b u ty, A. H.: Positive whole-body 67Ga scintigraphy in dermatomyositis. Am. J. Roentgenol. J?33: , S t r a in, J. E., G r o s e, R. M., H ir s c ii, C. L., K r a m e r, D. C., Ciio, S., and F a c t o r, S. M.:

9 154 O CONNELL, HENKIN, AND ROBINSON Atypical presentations of myocarditis. Circulation 68:111-27, S train, J. E., F in e, E. J., G rose, R. M., K ramer, D. C., C h o, S., and F a cto r, S. M.: Comparison of myocardial biopsy and gallium-67 imaging for diagnosing myocarditis. Circulation 68: , T il l e s, J. C., E l s o n, S. H., S h a k a, J. A., A b e l - m a n n, W. H., L e r n e r, A. M., and F in l a n d, M.: Effects of exercise on Coxsackie A 9 myocarditis in ad u lt m ice. Proc. Soc. Exp. Biol. M ed. 117: , U n v e r f e r t h, D. V., F e t t e r s, J. K., U n v e r f e r t h, B. J., L e i e r, C. V., M a c o r ie n, R. D., A r n, A. R., and B a k e r, P. B.: Human myocardial histologic characteristics in congestive heart failure. Circulation 68: , W a n g, T. S. T., O l u w o l e, S., F a w w a z, R. A., W o l f f, M., K u r o m o t o, N., S atake, K., H ardy, M. A., and A n d e r s o n, P. O.: Cellular basis for accumulation of In-lll-labelled leukocytes and platelets in rejecting cardiac allografts: concise com m unication. J. Nucl. M ed. 23: , W o o d, B. C., S h a w a, J. N., G e r m a n n, D. R., W o o d, W. G., and C r o u c h, T. T.: G allium citrate Ga67 imaging in noninfectious interstitial nephritis. Arch. Intern. Med. 738: , W o o d r u f f, J. F., a n d W o o d r u f f, J. J. : Involvem ent of T lymphocytes in the pathogenesis of coxcackie virus B3 heart disease. J. Immunol. 113: , Z e e - C h e n g, Z.- C., T sai, C. C., P a l m e r, D. D., C o d d, J. E., P e n n in g t o n, D. G., and W il l ia m s, G. A.: High incidence of myocarditis by endomyocardial biopsy in patients with idiopathic congestive cardiomyopathy. J. Am. Coll. Cardiol. 3:63-70, 1984.