Antimyosin uptake and myofibrillarlysis in dilated cardiomyopathy

ORIGINAL ARTICLES

Antimyosin uptake and myofibrillarlysis in dilated cardiomyopathy l a g a t Narula, M D , PhD, J a m e s F. S o u t h e r n , M D , PhD, G. William D e c , M D , Igor F. P a l a c i o s , M D , J o h n B. N e w e U , BA, J o h n T. Fallon, M D , PhD, H. William S t r a u s s , M D , B a n - A n Khaw, PhD, a n d T s u n e h i r o Y a s u d a , M D Background. Although antimyosin scintigraphy detects myocyte necrosis associated with myocarditis, it has also been reported to yield positive results in a large number of patients with clinical dilated cardiomyopathy without histologic evidence of myocarditis. The question to be resolved is whether this discordance represents false-positive results of antimyosin scans or whether antimyosin scintigraphy more accurately identifies the presence of myocyte necrosis than does endomyocardial biopsy testing. Methods and Results. Forty patients with the acute onset of dilated cardiomyopathy (left ventricular ejection fraction < 45%; mean 27% _ 11%) but no endomyocardial biopsy evidence of myocarditis, were identified from a consecutive series of 50 patients who had undergone indium 111 antimyosin antibody scintigraphy and endomyocardial biopsy for suspected myocarditis. The endomyocardial biopsy specimens were analyzed to identify features correlating with antimyosin uptake or improvement in left ventricular ejection fraction (LVEF) over time. Twenty-five patients showed left ventricular myocardial uptake of radiolabeled antimyosin antibody by both planar and tomographic imaging. The remaining 15 patients had no antimyosin uptake. Of the 25, 22 (88%) patients with positive findings on antimyosin scans had degenerated, myofibrillarlytic myocytes in their biopsy specimens. Of the 15 patients with negative findings on antimyosin scans, only 6 (40%) had similar myofibrillarlytic myocytes (~z = 8.13; p < 0.0047). No other histological feature correlated with the antimyosin positivity. Stepwise multiple regression analysis was performed for identification of predictors of short-term improvement in LVEF. Patients with positive findings on antimyosin scans showed a trend toward improvement with time (F = 3.97; p > 0.05). None of the histologic features predicted improvement in the LVEF. However, the combination of positive findings on an antimyosin scan and myofibrillarlysis did correlate significantly with spontaneous improvement in ejection fraction (F = 4.53; 0.01;

From the Cardiac Unit, Division of Nuclear Medicine and the Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston. Submitted for publication Mar. 21, 1995; revision accepted Jun. 19, 1995. Reprint requests: Tsunehiro Yasuda, MD, Cardiac Unit and Division of Nuclear Medicine, Tilton 2, 32 Fruit St., Boston, MA 02114. Copyright 9 1995 by American Society of Nuclear Cardiology. 1071-3581/95/$5.00 + 0 43/1/67624 470

Antimyosin antibody binds specifically to myocardial cells that have lost their sarcolemmic integrity, allowing either the presence of myosin on the cell surface or the penetration of antimyosin antibody into the cell? Scintigraphic examination with these antibodies has been used to localize and quantify regions of myocardial necrosis in myocardial infarction. 2-s Myocarditis has recently been defined, for the pur-

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Figure 1. Positive antimyosin image (lefipanel); diffuse uptake in cardiac region is seen in planar images and tomographic reconstructions. Negative findings on antimyosin scan (rightpanel) does not show uptake in either planar or tomographic images.

Figure 2. Photomicrograph of right ventricular endomyocardial biopsy specimen showing myofibrillarlysis (arrow). (Hematoxylin & eosin x 313.) pose of cooperative clinical trials, as the presence of myocardial necrosis associated with an inflammatory infiltrate. 6 Because myocardial necrosis is an obligatory component of this definition, it has also been possible to use antimyosin antibody imaging to detect myocarditis in the setting of dilated cardiomyopathy. 7,8 Almost all patients with positive biopsy results for myocarditis have an abnormal antimyosin scan. Conversely, almost all normal antimyosin scans are associated with negative biopsy results. High sensitivity and a high predictive value of negative antimyosin scan results compared with endomyocardial biopsy results makes this technique a useful screening tool for the patients with suspected myocarditis. 8 However, a large group of patients test positive for the disease by antimyosin scintigraphy but test negative by biopsy. 7,8 A subgroup of patients with positive antimyosin scan results but negative biopsy results may have undetected myocarditis; this possibility has

been shown by a correlation between positive scan results and a high probability of a spontaneous improvement in left ventricular function. It is also possible that myocyte degeneration without accompanying mononuclear cell infiltration may be responsible for the clinical presentation and positive scan results. This report reviews the histopathologic abnormalities in the biopsy specimens from patients with dilated cardiomyopathy who lacked biopsy evidence of myocarditis but had positive results on antimyosin scan. METHODS Patient Population. Fifty consecutive patients with recent onset of clinical dilated cardiomyopathy who were examined for suspected myocarditis and followed up at our institution form the basis of this report. Ages ranged from 18 to 77 years. There were 29 men and 21 women. Diagnostic evaluation included right and left heart cath-

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Narula et al. Antimyosin uptake and myofibrillarlysis in dilated cardiomyopathy

Table I . H i s t o l o g i c c h a r a c t e r i s t i c s o f patients with positive and negative scan results for d i l a t e d c a r d i o m y o p a t h y w i t h n o b i o p s y evidence of myocarditis

Histopathologic features Myocyte necrosis alone Contraction bands Myofibrillarlysis Lymphocytic infiltration alone Myocyte hypertrophy Interstitial fibrosis

Patients with positive scan results (n = 25)

Patients with negative scan results (n = 15)

1 4 22" 4

0 1 6 0

16 16

7 6

*xz = 8.13, p < 0.0047. eterization, coronary arteriography, gated blood pool imaging, right ventricular endomyocardial biopsy, and noninvasive cardiac imaging by using monoclonal antimyosin antibodies radiolabeled with indium 111. Dilated cardiomyopathy was defined as left ventricular ejection fraction (LVEF) of 45% or less resulting from diffuse wall motion abnormalities, provided that the observation could not be accounted for by hypertensive, ischemic, or valvular heart disease. Ten patients had evidence of myocarditis on an endomyocardial biopsy specimen by the Dallas criteria. 6 A comparison of the histopathologic findings and the antimyosin scintigraphic findings was performed for the remaining 40 patients with apparent nonmyocarditic dilated cardiomyopathy. Of the 40 patients with negative biopsy results, 33 presented with congestive heart failure of less than a 12-month duration; 4 patients had chest pain mimicking myocardial infarction as the presenting symptom; and 3 patients were admitted with life-threatening ventricular tachyarrhythmias. The initial determination of left ventricular ejection fraction was performed after optimization of medical therapy for all patients with heart failure at presentation. All patients received digoxin and diuretics, and the majority also received an afterload reducing agent (captopril or prazosin). The mean initial LVEF was 27% _+ 11% (range 8% to 45%). A follow-up assessment of L V E F was performed in all patients after approximately 6 months by radionuclide ventriculography. Vasodilator therapy was not altered in any patient before a repeated assessment of ventricular function. Improvement in ventricular function was defined as an absolute increase in L V E F _>10% accompanied by either a decrease in symptomatic heart failure by one or more New York Heart Association functional classes, or a decrease in cardiothoracic ratio on the chest r0entgenogram, s Antimyosin Cardiac Scintigraphy. Monoclonal antimyosin R l l D 1 0 antibody Fab coupled to DTPA (Centocor, Malvern, Pa.) was radiolabeled with indium 111. After

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Table 2. C o r r e l a t i o n o f t h e c h a n g e in LVEF o v e r t i m e h i s t o l o g i c c h a r a c t e r i s t i c s a n d antimyosin uptake Correlation of AEF by stepwise regression analysis with Positive antimyosin scan (AMS) results Initial ejection fraction (EFI) Myofibrillarlysis (Mfl) Myocyte hypertrophy (MH) Interstitial fibrosis Lymphocytic infiltration Myocyte necrosis Contraction bands Perinuclear vacuolization AMS * Mfl AMS * Mfl * EF1 AMS * Mfl * EFI * MH AEF = 19(+_ 15) + 20(-+6) 12(-+6) Mfl * MH

F = 3.97 2.34 1.31 0.04 0.21 0.01 0.11 0.70

0.13 4.53 4.79 4.96 AMS * Mfl - 0.6(-+0.2)

EF1 -

informed consent was obtained, 500 Ixg of antibody labeled with 1.8 mCi of indium 111 was administered through a peripheral vein within 48 hours of endomyocardial biopsy. 7'8 Ungated planar and single photon emission computed tomographic (SPECT) images were obtained at 48 hours after administration of the radioactive agent as previously described. 7'8 The planar images were obtained in the anterior and 60- to 70-degree left anterior oblique views through a medium energy collimator. The pulse height analyzers were set at centerlines of 173 and 247 keV with a 20% window for each. For SPECT imaging, patients were positioned so that the smallest diameter circle could be inscribed by the detector of a rotating gamma camera (Technicare Gemini 700 or Omega, Solon, Ohio). A series of 60 images was collected at 6-degree increments of 20 seconds each into a 64 x 64 matrix and stored in a dedicated computer for subsequent analysis. The SPECT images were reconstructed with a filtered back projection algorithm into transverse, coronal, and sagittal projections with a thickness of 1 cm. Planar and tomographic antimyosin images were interpreted directly from the computer display without knowledge of the biopsy results. The antimyosin scan was interpreted as positive when focal or diffuse uptake of tracer was present in the planar image and in at least two of the three tomographic reconstructions. A scan was read as negative when no tracer uptake was seen in either planar or tomographic images, or when faint uptake was present in the planar images but not confirmed in the tomograms. Right Ventricular Endomyocardlal Biopsy and Pathologic Examination. Patients underwent right ven-

JOURNAL OF NUCLEAR CARDIOLOGY

Antimyosin-Positive,

Antimyosin uptake and myofibrillarlysisin dilated cardiomyopathy Myofibrillarlysis-Positive

Antimyosin-Negative and/or Myofibrillarlysis-Negative

80

80

70-

70-

60-

60-

~

50-

50-

~

40-

~u 40-

~

30-

30-

~"

20-

20-

~

10-

~--

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N a r u l a et al.

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r

i...

0

A

lOo

EF1

EF2

B

EF1

EF2

Figure 3. Change in LVEF over 6 months as compared between two groups of patients; (A) those with both scintigraphic evidence of antimyosin uptake and histologic evidence of myofibrillarlysis in their endomyocardial biopsy specimens; and (B) those who lacked either or both antimyosin uptake and myofibrillarlysis. EF1 and EF2 represent initial and follow-up LVEFs.

tricular endomyocardial biopsy from the right ventricular septum with either a Caves-Schultz~Stanford or Cordis bioptome through the right internal jugular vein. 9-11 Five to seven biopsy specimens averaging 2 mm in diameter were obtained and processed conventionally for light and electron microscopy. Histologic sections from the paraffinembedded specimens were stained with hematoxylin and eosin and Masson's trichrome and analyzed for inflammation, myocyte necrosis, myofibrillarlysis, hypertrophy, and fibrosis. Specimens defined as showing myocarditis contained a predominately lymphocytic inflammatory infiltrate surrounding or adjacent to necrotic myocytes.6 Borderline myocarditis specimens contained an increase in focal interstitial lymphocytes but lacked myocyte necrosis. 6,12 The presence of lymphocytes in the inflammatory infiltrates was confirmed by immunoperoxidase staining for leukocyte common antigen and T-cell surface antigen (UCHL-1, DAKO) according to standard methods. Myofibrillarlysis (often termed vacuolar degeneration or myocytolysis) 13'14 was defined as marked loss of myofibrils resulting in cytoplasmic clearing of at least 75% diameter of the myocytes on sections stained with hematoxylin and eosin or trichrome. Areas of clearing of this degree are easily recognizable as distinct abnormalities and not merely shrinkage artifact between the nucleus and the sarcoplasm. Perinuclear clearing that fulfilled these criteria was accepted as myofibrillarlysis. Persistent myofibrils crossing through presumptive areas of clearing were rejected as artifacts caused by contraction bands.

Table 3. Antimyosin uptake, myofibrillarlysis, and significant increased in LVEF over t i m e

Antimyosin-positive, and rnyofibrillarlysispositive Others

AEF >_10%

AEF <10%

10

12

3

15

* X z = 4 . 5 5 , p < 0.035.

Statistical Analyses of the Data. Hypotheses concerning determinants of improved ventricular function were tested by multiple stepwise regression analysis with the BMDP2R statistical software (BMDP, Berkeley, Calif.). 15 Change in ejection fraction was designated as the dependent variable, and initial ejection fraction, antimyosin scan, biopsy results, age, and sex were the independent variables. The binary antimyosin scan and biopsy results (myofibrillarlysis, perinuclear vacuolization, lymphocytic infiltration, myocyte necrosis, contraction bands, myocyte hypertrophy and interstitial fibrosis) were embodied in the regression analysis according to the method of dummy variables. 16 All first-order interactions of the independent variables were also included as potential predictors as products of the corresponding variables. The F statistic for entry of

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Narula et al. Antimyosin uptake and myofibrillarlysis in dilated cardiomyopathy

Myocyte Population

Cellular Morphology

Antimyosin Uptake

(Y

1. Normal

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Histologic Necrosis

Functional Reversibility

NA

2. Myofibrillarlytie 2B

3. Necrotic

.

/" ""

. (?)

"

Figure 4. Comparison of normal myocytes, myofibrillarlytic myocytes, and necrotic myocytes to propose correlation of myofibrillarlysis and antimyosin uptake, sarcolemma in normal myocytes (population 1) is intact and disrupted in necrotic cells (population 3). Myofibrillarlytic myocyte population is expected to be mixture of cells at different stages of injury. Myofibrillarlytic cells may either show intact sarcolemmaa~ (population 2A) or may be dead 22-24 with subclinical (not identifiable by light microscopy) sarcolemmal defects (population 2B). Population 2B is likely to be antimyosin-positive and damaged with irreversible injury. Population 2A should be antimyosin-negative and may represent reversible component of myofibrillarlytic cell population. Acute onset of myocardial injury should give rise to variable combination of populations 2A, 2B and 3. Antimyosin positivity (due to population 2B and 3) should be obvious manifestation of injury and antimyosin-negative myofibrillarlytic cells (population 2A) should recover to provide improvement in LVEF.2s Magnitude of improvement in function should theoretically be determined by preponderance of population 2A over populations 2B and 3. This concept assumes that antimyosin uptake identifies irreversible myocyte injury before histologic manifestation is recognized (compare populations 2B and 3). independent variables into the regression models was considered significant for the corresponding tail probability p < 0.05. Two-way associations between various variables were analyzed by the chi-square test with Pearson's continuity correction. 17

RESULTS Antimyosin Scan Versus Endumyucardial Biopsy Findings. Of the 40 patients with (presumably nonmyocarditic) dilated cardiomyopathy, 25 showed left ventricular antimyosin uptake (Figure 1) suggesting myocyte necrosis. However, histologic evidence of myocyte necrosis was observed in only one patient. Myofibrillarlysis was present on the endomyocardial biopsy specimen in 22 of these 25 (88%) patients with positive findings on scans (Figure 2). In addition to myofibrillarlysis, four (16%) patients had evidence of lymphocyte infiltration suggesting borderline myocarditis. Evidence of focal interstitial fibrosis and variable degrees of myocyte hypertrophy each were observed in 16 of 25 patients (64%).

The remaining 15 patients had negative findings on antimyosin scans. None of these patients had histologic evidence of myocyte necrosis or myocardial inflammation. Myofibrillarlysis was observed in 6 of the 15 (40%) patients with negative findings on scans. Variable amounts of interstitial fibrosis were observed in six patients (40%) and myocyte hypertrophy was seen in seven (46%)patients. Myofibrillarlysis was the only histopathologic variable that was closely related to antimyosin antibody uptake (X2 = 8.13, p < 0.0047; Table 1) and was the only significant independent predictor of antimyosin positivity. Myofibrillarlytic cells in the biopsy specimens were sparsely distributed. Of the 28 biopsy specimens that contained severely myofibrillarlytic cells, 25 showed only a few scattered involved cells per biopsy fragment. Only three biopsy specimens showed clusters of myofibrillarlytic cells, and, in two of these, the clusters were limited to one fragment. None of these myofibrillarlytic loci resembled the sheets of myofibrillarlytic lesions seen at the edges of myocardial infarcts.

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Figure 5. Schematic figure to propose that cell membrane lesions of damaged cells may permit entry to Fab fragments of antibody before histologically identifiable necrosis becomes manifestY Scanning electron micrographs (left panel) show actual erythrocyte (RBC) membrane holes induced by complement membrane attack complex (MAC, top) and cloned cytolytic T lymphocytes (CTL, bottom). Diameters of these holes were measured to be 100 and 160~, respectively,as Diagram in right panel is magnification of single cell membrane lesion, each caused by MAC (inner circle) and CTL (outer circle), respectively. Size of Fab fragment (65 x 35~k,27 as determined by x-ray diffraction studies) is shown in inner circle for comparison with MAC- and CTL-induced lesions. Structure of Fab fragment shows dark gray-colored heavy and white-colored light chains, z9 It is evident that antimyosin Fab molecule should detect tiny sarcolemmic breaches before osmotic lysis of cell occurs and myocyte necrosis becomes apparent at light microscopy. (Scanning electron micrographs are reproduced by permission of Journal of Cellular Biochemistry28 and x-ray diffraction model of Fab fragment by permission of American Association for the Advancement of Science.29)

Antimyosin Scan and Improvement in Left Ventricular Ejection Fraction. Improvement in ventricular function was assessed as change in resting LVEF (AEF) from the time of antimyosin scan (EF1) to 6 months later (EF2). Stepwise multiple regression analysis of the relationship between AEF and the biopsy variables, the result of the antimyosin scan, and EF1 revealed antirnyosin scan (AMS) positivity as the best independent predictor of change in LVEF on follow-up (F = 3.97, p = NS; Table 2). Initial ejection fraction (EF1; F = 2.34, p = NS) and presence of myofibrillarlysis (Mfi; F = 1.31, p = NS) were the next best predictors in step 0 of the regression model, but were not statistically significant. The multiplicative interaction of antimyosin scan and myofibrillarlysis proved to be the only significant predictor of improvement in ventricular function as assessed by AEF (F = 4.53; 0.05 > p > 0.01). Initial ejection fraction and the interaction of myofibrillarlysis with myocyte hypertrophy (MH) made a slightly negative contribution to the predictive value. These factors yielded the following regression equation:

AEF = 19 (+15) + 20 (-+6) AMS. Mfl - 0.6 (-+0.2) E F 1 - 12(--_6) Mfl. MH where AMS, Mfl, and M H are binary variables (0 = negative, 1 = positive) and EF1 is the initial ejection fraction expressed as a percentage. Thus a positive antimyosin scan and the presence of myofibrillarlysis predict an eventual additional improvement in ejection fraction of 20% (+_6.5%) above the improvement found among those patients who had negative antimyosin scan results or the absence of myofibrillarlysis in a given clinical situation where all other histologic variables were kept constant. For example, a patient with initial ejection fraction of 40% had •EF of - 5 % (an eventual loss in ejection fraction) in case of lack of antimyosin uptake or myofibrillarlysis (or both). However, a patient with positive antimyosin scan results and biopsy evidence of myofibrillarlysis had AEF of 15% (an eventual gain in ejection fraction). This example assumes that myocardial hypertrophy was not observed in the endomyocardial biopsy samples. Spontaneous improvement of LVEF > 10% was

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Narula et al. Antimyosin uptake and myofibrillarlysisin dilated cardiomyopathy

observed in 10 of 22 (45%) patients with positive antimyosin uptake and evidence of myofibrillarlysis on biopsy specimens. Only 3 of the 18 patients lacking one or both of these markers had a comparable improvement (X2 = 4.55, p = 0.035; Table 3). The mean ejection fraction of the 22 patients with positive results on antimyosin scans and positive myofibrillarlysis rose from 27% + 10% to 41% + 17% (AEF = 12% + 20%). The mean ejection fraction of the other 18 patients remained unchanged (from 24% +_ 10% to 25% +- 12%) (Figure 3).

DISCUSSION The entire study population had acute onset of dilated cardiomyopathy that initially was clinically suspected to be due to myocarditis. Although, the right ventricular endomyocardial biopsy did not provide histologic evidence of myocarditis by Dallas criteria, 25 patients (63%) had positive antimyosin scan results indicating the presence of myocyte necrosis within the left ventricle. It is likely that a subset of these patients with positive antimyosin scan results had true myocarditis that was not detected with a right ventricuiar biopsy because of the small amount of myocardium sampled and the focal or multifocal nature of myocarditis. However, the sampling error of endomyocardial biopsy cannot be the reason for the scan-biopsy discordance seen in all 25 patients. In the absence of histologically identifiable myocarditis and myocyte necrosis, myofibrillarlysis was the only biopsy finding observed frequently in patients with cardiomyopathy and positive scan resuits compared with negative scan results. The precise relationship between myofibrillarlysis observed in this study and myocardial uptake of antimyosin antibody is not clear. Antimyosin uptake has frequently been shown in adriamycin cardiotoxicityas wherein myocyte degeneration is the most common histologic alteration. 19 The myofibrillarlytic myocyte population (Figure 4, population 2) is expected to be a mixture of cells at various stages of injury and can comprise a wide spectrum between reversibly damaged 2~ (population 2A) and necrotic myocytes22-24(population 2B) on the basis of integrity of the sarcolemma. The necrotic myocytes in the myofibrillarlytic myocyte population are postulated as the source of antimyosin uptake (population 2B)? 5 Although myocyte necrosis was not identified by light microscopy, the antimyosin positivity provided the scintigraphic evidence of early rnyocyte necrosisY Sequential endomyocardial biopsies and antimyosin scans during the surveillance of cardiac transplant patients for rejection have convincingly shown that antimyosin scintigraphic evidence of myocyte necrosis can precede histologically verified myocyte necrosis. 26

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The presence of "borderline" myocarditis in four patients in this study would also favor such an assumption. Our initial study showing antimyosin uptake by the histologically necrotic myocytes had used antimyosin-coated polystyrene microspheres with diameters of 1 txm.a Myocytes permitting sarcolemmic entry to such large particles would be evidently disrupted. In the clinical studies, smaller Fab fragments of antimyosin antibody of an estimated size of 65 • 35 /~k27 w e r e used. Such myosin-avid fragments would seek myocytes that have been damaged by sarcolemmic breaches of at least this size (Figure 5). The membrane lesions induced on a target cell by cloned cytolytic T cells show an internal diameter of 160~. 28 The pores in plasma membranes created by complement membrane attack complex mediated injury have an internal diameter of 100/~.2s Such pores are too small to aIlow larger protein molecules to escape from cytoplasm; may permit exchange of small soluble molecules, ions, and water resulting in gradual osmotic lysis; and may escape detection by standard light microscopy. It appears that the myocyte necrosis detected by antimyosin scintigraphy (Figure 4, populations 2B and 3) is in turn a marker of the large population of reversibly damaged myofibrillarlytic myocytes (population 2A). 25 These myofibrillarlytic cells (population 2A) are likely to be antimyosin-negative, because they may have intact sarcolemma. Edwalds et al. 2~ reported preservation of intracellular CK-MB, LDH, and AST enzymes and myoglobin in myofibrillarlytic cells that would have washed out if the sarcolemma was not intact. Viability of myofibrillarlytic myocytes is also supported by the study of Flameng et al., 2z who analyzed intraoperative myocardial biopsy specimens from hypokinetic segments of left ventricle during coronary artery bypass surgery. Postoperative improvement in wall motion was not observed if the biopsy fragments showed extensive fibrosis; however, the segmental wall motion abnormalities normalized if fragments showed histologic evidence of myofibrillarlysis. They implicated the improvement in regional myocardial contractility to reversal of chronic ischemia histologically represented by myofibrillarlysis. In the current study the myofibriUarlytic cells are likely to be determinants of subsequent improvement seen in LVEF. Because an acute myocyte insult may result in variable degrees of histologic injury, it is hypothesized that the magnitude of improvement in function should be determined by the preponderance of population 2A over population 2B. Myofibrillarlysis has been frequently reported in end-stage dilated cardiomyopathy a3 and has been believed to be the result of subendocardial ischemia) 4 However, the evidence of antimyosin positivity in this study appears to indicate the acuteness of

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Narula et al. Antimyosin uptake and myofibrillarlysis in dilated cardiomyopathy

the pathologic process and may have a different prognostic connotation from the myofibrillarlysis of the end-stage cardiomyopathy. The improvement in ventricular function seen in the majority of patients with positive scan results and myofibrillarlysis supports the partially reversible nature of the myocyte injury. CONCLUSIONS This study identifies myofibrillarlysis as a common pathologic alteration in patients with syrhptoms and with recent onset of dilated cardiomyopathy and positive antimyosin scan results, who lack right ventricular biopsy evidence of either myocarditis or myocyte necrosis. Because myofibrillarlytic cell populations comprise a wide spectrum between reversibly damaged and necrotic myocytes, it is proposed that the antimyosin uptake detects necrotic myocytes within the myofibrillarlytic cell populations that are not identified by light microscopy (Figure 4, population 2B). This discordance between the scan and histology results can be explained theoretically by sarcolemmic breaches in myofibrillarlytic myocytes (population 2B), which are small enough to admit tiny antimyosin Fab molecules, but not large enough to result in histologically identifiable necrosis. References 1. Khaw BA, Scott J, Fallon JT, Haber E. Myocardial injury quantitation by cell sorting method with antimyosin fluorescent microspheres. Science 1982;217:1050-3. 2. Khaw BA, Gold HK, Yasuda T, et al. Scintigraphic quantification of myocardial necrosis in patients after intravenous injection of myosin-specific antibody. Circulation 1986;74: 501-8. 3. Khaw BA, Yasuda T, Gold HK, et al. Acute myocardial infarct imaging with indium-ll l-labeled monoclonal antimyosin Fab. J Nucl Med 1987;28:1671-8. 4. Narula J, Khaw BA, Dec GW, et al. Recognition of myocarditius masquerading as acute myocardial infarction. N Engl J Med 1993;328:100-4. 5. Strauss HW, Narula J, Khaw BA, eds. Monoclonal antibodies in cardiovascular diseases. Philadelphia: Lea & Febiger, 1994. 6. Aretz HT, Billingham ME, Edwards WD, et al. Myocarditis a histopathological definition and classification. Am J Cardiovasc Pathol 1987;1:3-14. 7. Yasuda T, Palacios IF, Dec GW, et al. Indium lll-monoclonal antimyosin antibody imaging in the diagnosis of acute myocarditis. Circulation 1987;76:306-11. 8. Dec GW, Palacios I, Yasuda T, et al. Antimyosin antibody cardiac imaging: its role in the diagnosis of myocarditis. J Am Coll Cardiol 1990;16:97-104. 9. Dec GW, Palacios IF, Fallon JT, et al. Active myocarditis in the spectrum of acute dilated cardiomyopathies: clinical features, histopathological correlates, and clinical outcome. N Engl J Med 1985;312:885-90. 10. Mason JW, Billingham ME, Ricci DR. Treatment of acute inflammatory myocarditis assisted by endomyocardial biopsy. Am J Cardiol 1980;45:1037-44.

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11. Parrillo JE, Aretz HT, Palacios IF, Fallon JT, Block PC. The results of transvenous endomyocardial 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 1984;69:93-101. 12. Dec GW, Fallon JT, Southern JF, Palacios IF. "Borderline" myocarditis: an indication for repeat endomyocardial biopsy. J Am Coll Cardiol 1990;15:283-9. 13. Dick MR, Unverferth DV, Baba N. The pattern of myocardial degeneration in non-ischemic congestive cardiomyopathy. Human Pathol 1982;13:740-4. 14. Unverferth DV, Magorien RD, Lewis RE Leier CV. The role of subendocardial ischemia in perpetuating myocardial failure in patients with non-ischemic cardiomyopathy. Am Heart J 1983;105:176-9. 15. Dixon WJ, Brown MB, Engelman L, Hill MA, Jennrich RI. BMDP statistical software manual. Vol. 2. Berkeley, California: University of California Press, 1988:1045. 16. Morrison DF. Multivariate statistical methods. New York: Mc-Graw-Hill, 1976:33-4. 17. Pearson K. On a criterion that a given system of deviations from the probable in the case of a correlated system of variables is such that it can be reasonably supposed to have arisen from random sampling. Philos Mag 1900;50:15775. 18. Carrio I, Pousa AL, Estorch M, et al. Detection of doxorubicin cardiotoxicity in patients with sarcomas by indium-ill antimyosin monoclonal antibody studies. J Nucl Med 1993;34: 1503-7. 19. Bristow MR, Mason JW, Billingham ME, Daniels JR. Doseeffect and structure-function relationship in doxorubicin cardiomyopathy. Am Heart J 1981;102:709-18. 20. Edwalds GM, Said JW, Block MI, Herscher LL, Siegel R J, Fishbein MC. Myocytolysis (vacoular degeneration) of myocardium: immunohistochemical evidence of viability. Human Pathol 1984;15:753-6. 21. Flameng W, Suy R, Schwarz F, et al. Ultrastructural correlates of left ventricular contraction abnormalities in patients with chronic ischemic heart disease: determinants of reversible segmental asynergy post-revascularization surgery. Am Heart J 1981;102:846-57. 22. Geer JC, Crago CA, Little WC, Gardner LL, Bishop SP. Subendocardial ischemic myocardial lesions associated with coronary atherosclerosis. Am J Pathol 1980;8:663-80. 23. Schlesinger M J, Reiner L. Focal myocytolysis of the heart. Am J Pathol 1955;31:443-59. 24. Schwartz CJ, Mitchell JRA. The relation between myocardial lesion and coronary artery disease: an unselected necropsy study. Br Heart J 1962;24:761-86. 25. Narula J, Strauss HW, Khaw BA. Antimyosin positivity in doxorubicin toxicity: earlier than the conventional evidence! J Nucl Med 1993;34:1507-9. 26. Ballester RM, Obrador MD, Carrio I, et al. Indium-ll monoclonal antimyosin antibody studies after the first year of heart transplantation: identification of the risk groups for developing rejection during long-term follow-up and clinical implications. Circulation 1992;82:2100-8. 27. Green NM. Electron microscopy of the immunoglobulins. Adv Immunol 1969;11:1-30. 28. Podack ER. Molecular mechanisms of cytolysis by complement and cytolytic lymphocytes. J Cell Biochem 1986;30:13370. 29. Amit AG, Mariuzza RA, Phillips SEV, Poljak RJ. Threedimensional structure of an antigen antibody complex at 2.8/~ resolution. Science 1986;233:747-53.