Three Autopsied Cases of Postmyocarditic Cardiomegaly

Comparison with Dilated Cardiomyopathy

Sachio KAWAI, M.D., Hideki KASUYA, M.D., Mitsuru SHIMIZU, M.D., Ryozo OKADA, M.D., Toshiaki YAMAUCHI, M.D.,* Kazuo URUGA, M.D.,* Shigeru YAMAMOTO, M.D.,** and Tadashi KOBAYASHI, M.D.**

SUMMARY Three patients with clinically proven myocarditis who later developed dilated cardiomyopathy (DCM)-like features were studied pathologically at necropsy and compared with 42 other cases with DCM. The patients were an 18 year old female, a 20 year old male and a 28 year old male. They all had an upper respiratory tract infection as a prodromal symptom and then developed dyspnea on effort, electrocardiographic changes and cardiomegaly. In case 1, the antibody titers for Coxsackie B2 virus were elevated. In cases 1 and 3, myocardial biopsies revealed a mononuclear cell infiltrate. All 3 died of congestive heart failure. Histologically, layer-unit depletion of the myocardium (the myocardial damage and its sequelae (loss or minimal fibrosis) are restricted to certain layers), infiltration of mononuclear cells and moderate fibrosis were noted. In case 3, fibrosis and layer-unit depletion of the myocardium were mild. In our 42 DCM cases, the mean area of fibrosis was 40% in the fibrosis type, 15% in the nonfibrosis type and 30% in chronic myocarditis. In postmyocarditic cardiomegaly (PMC), the areas of fibrosis were 21.6%, 21.7% and 13.1% for the 3 cases. Mean cellularity indexes were 3.9% in PMC, 5.1% in the fibrosis type of DCM, 19.4% in the chronic myocarditis cases and 27% in the nonfibrosis type of DCM. With respect to fibrosis and interstitial cellularity, PMC most resembles the nonfibrosis type of DCM.

Additional Indexing Words: Dilated cardiomyopathy Myocarditis Postmyocarditis Coxsackie virus Myocardial fibrosis

From the Research Laboratory for Cardiovascular Pathology, Department of Internal Medicine, Juntendo University, Tokyo, the Iwaki Kyoritsu General Hospital, Fukushima,* and the Third De- partment of Internal Medicine, Aichi Medical University, Aichi,** Japan. Address for reprints: Sachio Kawai, M.D., Research Laboratory for Cardiovascular Pathology, Department of Internal Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. Received for publication May 14, 1987. Accepted April 22, 1988. 809 Jpn. Heart J. 810 KAWAI, ET AL. November 1988 YOCARDIAL pathology in patients with dilated cardiomyopathy (DCM) can vary widely.1), 2) Therefore, some authors think that DCM may be a multifactorial disease, reflecting a postmyocarditic state.3)-6) The following data support this assumption: the residual cell infiltrate in the myocardium of patients with DCM, the irregular patchy fibrosis suggesting the sequelae of myocarditis and the data of experimental myocarditis.7), 8) However, there have been only a few cases reported9)-13) that had clinical evidence of myocarditis, later developed DCM-like features (postmyocarditic cardiomegaly; PMC) and were later confirmed by histological findings at autopsy. We studied 3 autopsied patients with PMC histologically and compared their histological findings with those of 42 cases with DCM.

SUBJECTS AND METHODS

From the cooperative study of the Idiopathic Cardiomyopathy Research

Committee sponsored by the Ministry of Health and Welfare in Japan, 3 cases that had clinically proven myocarditis and later developed DCM-like features, and 42 cases with clinically diagnosed DCM were collected from many institutes and hospitals in Japan. Ten cases without valvular disease, diabetes mellitus and significant coronary artery stenosis were selected from the autopsy series at Juntendo University and used as controls.

Hearts fixed in 10% formalin were used for investigation. The weight of the heart and the gross internal and external aspects of the heart were examined. On the transverse section of the midportion of the ventricle, the wall thickness of the left ventricle was measured by calipers at the compact layer. The mean thickness of the wall was calculated as the mathematical average of the anterior and posterior wall thicknesses. For histological investigation, horizontal sections of both ventricles were embedded using routine methods, cut into 6 micron sections, stained with hematoxylin and eosin, azan and Elastica-van Gieson's method, and examined under a light microscope.

The areas of fibrosis in the compact layer of the left ventricle were estimated as a percentage of the whole by the point-count method using a 25-point eye-piece (Integrating eye-piece I of Zeiss).13) The number of myocardial cells in the left ventricular wall (Nf) was determined by a modification of

Suwa's method using sampling lines.13) The diameter of the average myocyte was measured by IBAS-I (Zeiss).13) Interstitial small round cells (lym- phocytes, plasma cells and macrophages) were counted under a light microscope with a magnification of 400 (field area=10.2•~104ƒÊm2) by scanning along the eight sampling lines which were drawn perpendicular to the com- Vol.29 No.6 POSTMYOCARDITIC CARDIOMEGALY 811 pact layer of the left ventricle from the outer to inner layer. Determinations were carried out at four sites: the anterior, lateral and posterior walls of the left ventricle and the interventricular septum. Their mean was used as the cellularity index. Classification: Forty two patients with clinically diagnosed DCM were histologically divided into 3 groups. Cases with marked cell infiltration were classified as chronic myocarditis (CM). Cases with severe diffuse fibrosis (over 25% of the area) in the compact layer of the left ventricle were classified as the fibrosis type of DCM. Other cases with DCM were classified as the nonfibrosis type of DCM. Statistical analysis: Analysis of variance and Student's t-test were employed for comparison of the variables between each group.

RESULTS Case 1 was an 18 year old female. Until December, 1979 she had been a good player on her high school table tennis club. She caught an upper respiratory tract infection and developed shortness of breath and palpitations in spite of her family doctor's intensive care. The doctor's diagnosis was common cold and hypotension. On March 26, 1980, she was diagnosed as having myocarditis on the basis of electrocardiographic changes (Fig.1a), and was admitted to the Iwaki Kyoritsu General Hospital. On examination, she was of small build and afebrile. Cardiac examination revealed a gallop rhythm and no murmur. Her pulse was regular at 100bpm. Her blood pressure was 110/76mmHg. The cardiothoracic ratio on chest X-ray (GTR) was 64% (up from 44% on a January 1979 film). Soon after admission, she developed right hemiparesis and aphasia due to embolization in the branching portion of the left middle cerebral artery. The hemiparesis disappeared after the use of urokinase, low-molecular weight dextran sulfate and coumarin. The symptoms of congestive heart failure continued; her heart rate was regular at 110bpm, the CTR was 55%, and the left ventricular ejection fraction on echocardiogram was 0.2. Digitalis intoxication (on digoxin 0.125mg per day) developed frequently. The first endomyocardial biopsy (April 30) showed a moderate infiltrate of small round cells and myocardial disarrange- ment (Fig.1b). Cardiac catheterization revealed a mean pulmonary wedge pressure of 30mmHg, left ventricular end-diastolic pressure (LVEDP) of 38 mmHg, cardiac output of 3.1L/min, ejection fraction (EF) of 0.29, and grade II mitral regurgitation (MR). Antibody titers for Coxsackie B2 virus de- 812 KAWAI, ET AL. Jpn. Heart J. November 1988

Fig.1. ECG, biopsy and necropsy findings in patient 1.

a: Electrocardiogram on admission (March 26, 1980). b: Histology of the first biopsy specimen (April 30, 1980). Mild infiltration of small round cells and mild disarray are noted. Hematoxylin and eosin stain, •~400. c: Histology of the second biopsy specimen (July 30, 1980). Mild to moderate interstitial fibrosis and disarray are shown. The residual cell infiltration is decreased. Azan stain, •~200. d: Inner aspect of the left ventricular outflow tract. Mural thrombi are

present. e: Panoramic view of the azan-stained transverse sections of the ventricle. f: Low power view of the lateral wall of the left ventricle. Marked depletion of midcircular layer and outer layer of the myocardium associated with fibrosis can be observed. Patchy type fibrosis is seen in the outer layer of both ventricles, but fibrosis in the middle layer is minimal. Azan stain, •~3. creased from 64x on March 28 to 32x on May 27. The second biopsy (July 30) revealed mild perivascular fibrosis and a decrease in the interstitial cell infiltrate (Fig.1c). A second catheterization showed a LVEDP of 44mmHg, ol.29 No.6 POSTMYOCARDITIC CARDIOMEGALY 813

EF of 0.6 and grade I MR. She was discharged on September 18. On November 1, she was readmitted because of anorexia and general malaise. Chest X-ray showed a pneumonia-like shadow in the right lower lung field. Antibiotics were not effective. Corticosteroids were given. On December 20, she died from congestive heart and respiratory failure. On autopsy, the heart weighed 370gm, and showed mild dilatation of the left ventricle (LV), thinning of the left ventricular wall and mural thrombi in both ventricles (Fig.1d). On the panoramic view of both ventricles (Fig. 1e), there was myocardial cell depletion and minimal replacement-type fibrosis in the midcircular layer of the anteroseptolateral wall of the LV and the outer layer of the posterior wall of the LV (Fig.1f). The inner and trabec- ular layers were relatively well-preserved. Histologically, a residual mono- cytic infiltrate in the myocardium and a few elastic fibers in the fibrotic foci were observed. Morphometrical data are summarized in Table I. Case 2 was a 20 year old male. His uncle was diagnosed as having idiopathic cardiomegaly and died suddenly at the age of 21. On March 20, 1974, the patient caught an upper respiratory virus-like infection and had pyrexia. After 5 days, he developed chest pain and nausea. An electrocardiogram showed abnormal Q waves in leads II, III, aVF, V3 and V4 (Fig. 2a). Laboratory data included the following: serum GOT, 74 to 239U; GPT, 23 to 42U; LDH, 1470U; CPK, 41U; CRP, 3+. He was given 2mg of dexamethasone per day for presumed acute myocarditis. The symptoms disappeared within a few days and the enzyme levels normalized. The antibody titers of Coxsackie B, Adeno, Echo, Influenza and Herpes viruses were not elevated. However, the CTR increased from 46% on March 25, 1974 to 62% on April 26, 1977. He was admitted to the Aichi Medical University Hospital. On examination, he was a well-built boy 11 years of age. An echocardiogram revealed a left ventricular end-diastolic dimension of 49mm, EF of 0.44, and his blood tests showed hypogammaglobulinemia. On the electrocardiogram, the voltage of the R wave in V1 was decreased to

Table I. Clinical and Pathological Data in Patients with Postmyocarditic Cardiomegaly

F=female; M=male; (m)=months; HW=heart weight; % FIB=area of fibrosis in the left ventricle (%); Nf =number of myocardial fibers in the left ventricular wall, Jpn. Heart J. 814 KAWAI, ET AL. November 1988

Fig.2. ECG, chest X-ray and necropsy findings in patient 2.

a: Electrocardiogram (May 28, 1983).

b: Chest X-rays on March, 1974 and July, 1983. c: Frontal view of the heart. An aneurysmal change is present in the right

pulmonary conus. Wall thinning and retractions are present in the anterior wall of the left ventricle. d: Panoramic view of the azan-stained transverse sections of the ventricles. e: Low power view of the interventricular septum and trabeculation of the

right ventricle. Marked layer-unit depletion of the myocardium (*) is

present in the septum. Hematoxylin and eosin stain, •~3. f: Residual inflammatory cell infiltration in the left ventricle. Hematoxylin and eosin stain, •~40. almost a QR pattern, the Q waves in II, III and aVF had widened, and the T waves in the right chest leads had inverted. After his entrance to a university (May, 1981), he began to feel dyspnea on effort. The CTR increased to 78% and cerebral infarction occurred on Feb- Vol.29 No.6 POSTMYOCARDITIC CARDIOMEGALY 815 ruary 3, 1983 (Fig.2b). On July 27, 1983, in spite of aggressive therapy, he died at the age of 20.

On autopsy, the heart weighed 420gm and had dilatation of both ventricles and fibrosis in the posterior wall of the left ventricle. The wall thickness of the right ventricular conus was decreased focally and a 5•~5cm sized aneurysm was observed (Fig.2c). Total depletion of the myocardium in the free wall of the right ventricle and a large amount of layer-unit depletion in the left ventricle were noted on the panoramic view as shown (Fig.2d, e).

Histologically, a small number of mononuclear cells had accumulated in the fibrotic foci and on the border of the intact myocardium (Fig.2f).

Case 3 was a 28 year old shop assistant. A heart murmur was noted when he was 10 years old, but he had no cardiac symptoms. He received no medical treatment. He caught a cold in March, 1971, and developed dyspnea and anasarca. He was admitted to Juntendo Hospital on March 29, 1971.

On examination, he was normally built (146cm, 52kg) and afebrile. Car- diac examination revealed an increased S2, S4 gallop, pansystolic Levine grade 3/6 murmur at the left sternal border in the third intercostal space and

Fig.3. Chest X-ray, ventriculogram and ECG in patient 3. a: Chest X-ray on admission (March 30, 1971). b: Chest X-ray on July 20, 1971. The cardiothoracic ratio is markedly reduced. c: Left ventriculogram (end-systole) (April 27, 1971). d: Left ventriculogram (end-diastole). e: Electrocardiograms (April 9, 1971 and September 12, 1977). 816 KAWAI, ET AL. NovemberJpn. Heart 1988 J. no thrill. His pulse was 96 and regular. Blood pressure was 108/74mmHg.

He had rales in both lungs, and hepatomegaly palpated 3cm below the costal margin. Diuretics and digoxin were administered. Cardiac catheterization revealed a ventricular septal defect (type 2) with a left to right shunt ratio of 41% (Fig.3c, d). Examination of the chromosomes, amino- proteoglycan metabolism and viral antibodies were all negative. After treatment of the heart failure, direct closure of the ventricular septal defect was performed surgically with success. A myocardial biopsy during surgery showed histological findings compatible with subacute myocarditis (Fig.4c). Administration of corticosteroid hormones reduced his symptoms of heart failure and the CTR improved from 68% to 53% (Fig.

3a, b). One year after surgery, severe congestive heart failure recurred. In

September 1977, he died of heart failure.

At autopsy, the heart weighed 660gm, and showed dilatation of both atria and ventricles (Fig.4a), a healed surgical closure of the VSD (14•~

15mm) and secondary endocardial fibroelastosis of the LV (Fig.4b). On a panoramic view of the azan-stained sections, moderate thinning of the ventricular wall and mild fibrosis were seen. Histologically, a relatively small amount of fibrosis and small round cells were observed (Fig.4d, e).

Comparison with DCM:

Clinical and morphometrical data of the 3 patients with PMC and 42 patients with clinically diagnosed DCM are listed in Table II. In the patients with PMC, the heart weights were heavier than normal (370-660gm) and the left ventricular wall was thin. There was a large amount of fibrosis in the left ventricles of patients 1 and 2. The Nf was decreased in patient 1, but not in patient 3. The myocytes were large in patient 2 (Table I).

In comparison with other types of DCM, the total clinical course, the heart weight and the wall thickness of the left ventricle did not differ significantly. The area of fibrosis in PMC was significantly smaller than that of CM and the fibrosis type of DCM, but was not different from that of the nonfibrosis-type of DCM. The cellularity index and the myocyte size of

PMC were significantly larger than those of the controls, but not different from those seen in CM, fibrosis-type DCM or nonfibrosis-type DCM (Table

II).

DISCUSSION

These 3 patients with PMC developed cardiac symptoms after respiratory tract infections. Although data for the acute phase are scanty for case 1, they also presented with cardiomegaly, electrocardiographic changes and impair- Vol.29 No.6, POSTMYOCARDITIC CARDIOMEGALY 817

Fig.4. Histopathological findings in patient 3.

a: Transverse sections of the left ventricle. Upper: mid portion. Dilata- tion of the left ventricle and minimal fibrosis in the anterior septum. Lower: lower third. Moderate fibrosis can be observed in the anteroseptal wall. b: Left ventricular aspect of the surgically closed ventricular septal defect

(arrow). The endocardium shows fibrous thickening. c: Histopathological findings of the biopsy specimen taken during surgery. Moderate infiltration of small round cells and proliferation of small vessels in the necrotic focus are visible. Hematoxylin and eosin stain, •~200. d: Histologic findings of the necropsy specimen. A residual infiltration of small round cells can be observed in the fibrotic focus. Hematoxylin and eosin stain, •~100. e: Low power view of the anterior wall of the left ventricle (lower third). Layer-unit depletion of the myocardium and replacement fibrosis can be seen (*). Azan stain, •~3.

ment of ventricular contraction. In cases 1 and 3, the biopsy showed myocarditis. In case 2, elevation of serum enzymes was confirmed. Thus, all patients were diagnosed clinically as definite cases of myocarditis. 818 KAWAI, ET AL. NovemberJpn. Heart 1988 J.

Table II. Comparisons of the Clinical and Pathological Data in Patients and Nonfibrosis-

NS=not significant. *p<0.05, **p<0.01, ***p<0.001.

Table III. Postmyocarditic Cardiomegaly (Necropsy

NP=not particular; Y=years; M=months; CTR=cardiothoracic ratio; LV=left ventricle; Cox

Layer-unit depletion in the compact layer of the myocardium, moderate fibrosis and residual infiltration of inflammatory cells were observed in all cases. Although because of the effect of the surgical procedure for VSD, Vol.29 POSTMYOCARDITIC CARDIOMEGALY 819 No.6 with Postmyocarditic Cardiomegaly, Chronic Myocarditis, Fibrosis-type DCM type DCM

All values are mean values. Abbreviations are same as in Table I.

Cases): A Summary of the Literature

B=Coxsackie B viral titers; of=atrial fibrillation.

strict comparison of cases 1 and 2 is difficult, mild fibrosis and residual cell infiltration were also shown in case 3. In all patients, moderate or mild interstitial fibrosis and a minimal cell infiltrate were found. 820 KAWAI, ET AL. NovemberJon. Heart 1988 J.

In Table III, 9 necropsied cases with PMC are listed from the litera-

ture.8)-12) They all had prodromal symptoms. Six cases had an elevated

antibody titer against Coxsackie B virus. The mean clinical course was

20.1•}18.6 months. The heart weights were increased for their age. Ven-

tricular dilatation or wall thinning was recorded in 8 cases, and cell infiltra-

tion and myocardial fibrosis of varying degrees were observed. The mor-

phological findings in the patients with PMC resembled our 3 cases with respect to ventricular dilatation, myocardial fibrosis and the residual inter-

stitial cell infiltrate. However, layer-unit depletion of the myocardium was

not reported in these articles.

On the basis of the pathologic analysis of a group of patients with idiopathic cardiomyopathy, we14) proposed that the irregular patchy fibrosis, minimal interstitial infiltrate of small round cells in the myocardium and proliferation of small vessels might be sequelae of myocarditis, and that cases with these histological findings and cardiomegaly should be differentiated from other cases of cardiomyopathy by the diagnosis of postmyocarditic cardiomegaly. Differentiation of PMC from chronic myocarditis is made on the basis of the number of interstitial cells. The myocardium of patients with chronic myocarditis is rich in interstitial cells.

The cause of the residual cell infiltrate is unclear. Possible mechanisms include a nonspecific reaction to fibrous tissue, a late immune reaction to a viral infection or a persistent viral infection.15)

The morphometrical data of PMC and DCM are listed in Table II.

The mean area of fibrosis (in percent) in PMC was between that of fibrosis type DCM or chronic myocarditis and that of nonfibrosis type DCM. The cellularity index of the patients with PMC resembled that of the patients with nonfibrosis type DCM and was significantly higher than that of the controls.

The Nf in PMC was significantly lower than that of the controls but was not different among the patient groups. On a morphometrical basis, PMC resembled the nonfibrous type DCM.

(This study was supported by a Research Grant for Idiopathic Cardio- myopathy provided by the Ministry of Health and Welfare of Japan.)

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