Cardiomyopathy in Myotonic Dystrophy. A Light and Electron Microscopic Study of the Myocardium

Transcription

1 Cardiomyopathy in Myotonic Dystrophy A Light and Electron Microscopic Study of the Myocardium Nobuyuki TANAKA, M.D., Hiromitsu TANAKA, M.D., Motohiko TAKEDA, M.D., Tatsuru NIIMURA, M.D., Takuya KANEHISA, M.D., and Shin-ichi TERASHI, M.D.* SUMMARY A case of 31-year-old woman with myotonic dystrophy who developed only slight cardiac symptoms has been reported. Light and electron microscopic study was performed on myocardium obtained with endomyocardial biopsy. Light microscopy revealed a considerable degree of fatty infiltration in the myocardium, slight interstitial fibrosis and degenerated myocardial cells. On electron microscopy, marked mitochondriosis and a small number of vacuoles consisting of single limiting membrane and indefinite content low in electron density were observed. Peculiar intranuclear structure and myofibrils showing partial over-contraction and indistinct Z band were also present, and these findings were discussed comparing with the previous reports. Endomyocardial biopsy seemed to be very useful to detect the myocardial changes even in the early stage of this disease, and the electron microscopic examination of the myocardium may provide the finding which is pathognomonic for the development of the cardiomyopathy in myotonic dystrophy. Additional Indexing Words: Myotonic dystrophy Cardiomyopathy Endomyocardial biopsy Fatty infiltration Electron micrograph of myocardium Mitochondriosis Sarcoplasmic reticulum YOTONIC dystrophy is a heredo-familial disorder characterized by myotonia, atrophy of the muscles, dysfunction in different endocrine glands and dystrophic signs in other tissues including baldness and cataracts. Griffith1) was the first to focus attention on the heart in myotonic dystrophy. In 1911, he described a patient with pulse rate of 30 to 46 per minute. Since that time an increasing number of reports have appeared describing From the First Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Kagoshima. * First Department of Pathology, Faculty of Medicine, Kagoshima University, Kagoshima. Received for publication February 13,

2 Vol.14 No.3 CARDIOMYOPATHY IN MYOTONIC DYSTROPHY 203 cardiac abnormalities in myotonic dystrophy, such as electrocardiographic changes3),4),7) and hypotension.6) Few histopathological studies of the heart, however, have been reported and only 2 cases were examined for heart ante mortem. In 1964, Petkovich, Dunn and Reed8) described the light microscopic findings of the myocardium provided at the time of long-term pacemaker implantation. Besides, the electron microscopic examination of the myocardium in myotonic dystrophy was first reported by Bulloch et al9) in In 1962, Konno and Sakakibara10) devised a special form of endomyocardial bioptome, and the endomyocardial biopsy using this bioptome has been reported to be safe and dependable.11) Recently, we had the opportunity to observe a 31-year-old woman of myotonic dystrophy who exhibited slight exertional dyspnea and monofocal ventricular premature beats. This report deals with light and electron microscopic findings of the myocardium obtained with endomyocardial biopsy of the right ventricle. CASE REPORT A 31-year-old woman was admitted to Kagoshima University Hospitl with the complaints of slight exertional palpitation and dyspnea on September 4, In 1945, at the age of 6, she developed grasping myotonia. Her menstruation has been very irregular from the time of menarche at the age of 14. She married at the age of 27 and had 2 pregnancies which resulted in spontaneous abortion at 3 and 4 months' gestation, respectively. Palpitation and slight dyspnea on exertion appeared in 1952, at the age of 13. In 1968, about 1 year before admission she noticed bilateral cataracts. She has had cold intolerance and caught a cold frequently. Family pedigree is shown in Fig. 1. Her father has myotonia, cataracts, muscular atrophy and baldness. One of her brother developed myotonia and muscular atrophy. She has 2 paternal uncles who have frontal baldness. One of her paternal cousins has myotonia and baldness. On physical examination, she appeared almost healthy except for bilateral cataracts and slight muscular atrophy in the neck. Pulse rate was 66 per minute and occasional premature beats were present. Blood pressure was 106/80mmHg in the upper limbs. The heart and the lung were clear on percussion and auscultation. Hepato-splenomegaly, abdominal mass and pretibial edema were not observed. Grasping myotonia was apparently present. The percussion myotonia was clearly demonstrated in the hand and the tongue. Muscular atrophy and weekness were dominant in sternomastoids and in the muscles of the forearm. Other neurological examinations remained normal. The peripheral blood counts, urinalysis, serum electrolytes, serum creatine and creatinine, s-got and -GPT, serum CPK, total and fractional proteins, blood sugar and immunoglobulin analysis were all within normal limits. The serum cholesterol was 319mg/ml. Triosorb test was 30% and the basal metabolic rate

3 204 TANAKA, ET AL. Jap. Heart J. May, 1973 shown Fig. 1. The family pedigree. The patient reported in this paper is by arrow. Fig. 2. Chest X-ray photogram.

4 Vol.14 CARDIOMYOPATHY IN MYOTONIC DYSTROPHY 205 No.3 Fig. 3. Electrocardiogram showing occasional monofocal ventricular premature beats and increased R/S ratio in V1. was -21%. The 24-hour 131I-uptake was 14% and wasn't increased by TSH administration. Urinary excretion of 17-OHCS and 17-KS were 2.1mg/day and 2.2 to 5.8mg/day, respectively. The corticotropin response test disclosed 35% decrease of eosinophiles, however, urinary 17-OHCS level remained unchanged. The basal body temperature curve was low and flat and the administration of gonadotropin revealed no response. But the menstruation had occurred after the administration of estrogen and progesterone. The heart silhouette was slightly hyposthenic and languid as shown in Fig. 2 but the cardio-thoracic ratio was just within normal limit. The electrocardiogram represented in Fig. 3 revealed normal sinus rhythm and occasional monofocal ventricular premature beats. In all leads, P waves were low and PQ interval was 0.18sec. Master's two step test was negative. Right heart catheterization revealed mean pulmonary wedge pressure of 4.0mmHg, pulmonary arterial pressure of 14/9mmHg, and right ventricular pressure of 11/0mmHg. The cardiac output calculated with Fick's method was 5,500ml/min and the stroke volume was 68.7ml. Electromyographic study disclosed typical myotonic pattern and "diver-bomber" effect characteristic of myotonic dystrophy. MATERIALS AND METHODS Endomyocardial Biopsy: Endomyocardial biopsy was performed according to the Konno's technique.10),11) The endomyocardial bioptome was inserted into the right ventricle via the right saphenous vein and the specimen was obtained without any side effects. Electron Microscopy: The myocardial tissues obtained were cut into smaller pieces on ice and fixed with 2% osmium tetroxide in 0.1M phosphate buffer (ph 7.4) for 1 hour. After rapid dehydration with increasing concentrations of ethanol, the tissues were subjected to Epon embedding. Porter-Blum ultramicrotome, Ivan S arvall Inc, was used for cutting the blocks and the sections were stained with uranyl acetate and lead acetate. Electron micrographs were taken with JEM type-7 electron microscope. Light Microscopy: Light microscopic examination of the skeletal muscle and the heart muscle was carried out after staining with hematoxylin-eosin and Mal - lory-azan stains according to the usual method.

5 206 TANAKA, ET AL. Jap. Heart J. May, 1973 RESULTS Light Microscopy of the Skeletal Muscle: Biopsy specimen of the right quadriceps femoris muscle shown in Fig. 4 represented a small number of atrophic muscle fibers and central migration of nuclei. The quantity of interstitial connective tissues and sarcolemmal nuclei remained normal. Necro- ~160). Fig. 4. Light micrograph of the skeletal muscle (Hematoxylin and eosin, Fig. 5. Light micrograph of the myocardium showing marked fatty infiltration and degenerative myocardial cells with granular sarcoplasma and small vacuolation (Hematoxylin and eosin, ~100).

6 Vol.14 No.3 CARDIOMYOPATHY IN MYOTONIC DYSTROPHY 207 tic muscle debris, fatty infiltration and ring fibers were not present. Light Microscopy of the Myocardium: Marked fatty infiltration and slight interstitial fibrosis were present in the myocardium, and the remaining myocardial fibers differed in size as shown in Fig. 5. Adjoining the fatty infiltration, there were degenerated myocytes having granular sarcoplasma and small vacuolation. The endocardial and subendocardial tissues appeared to be normal. Myocardial necrosis, lipofuscin deposit and cellular infiltration were not observed. Electron Microscopy of the Myocardium: With increased number of mitochondria, a small number of vacuoles which were bounded with single limiting membrane resembling the findings described by Bulloch et al and contained indefinite substance which was low in electron density were present as shown in Fig. 6. It was, however, difficult to ascertain the original structure of the vacuoles from which they derived. Marked mitochondriosis was present in places, especially in the circumferences of nuclei as shown in Fig. 7, Fig. 6. Electron micrograph of the myocardium showing increased num - ber of mitochondria and a small number of vacuoles (V) consist of single limiting membrane and indefinite content which is low in electron density.

7 208 TANAKA, ET AL. Jap. Heart J. May, 1973 Fig. 7. Long section of myocardium showing perinuclear proliferation of mitochondria. The intercalated discs, end-to-end junction (EJ) seems to be bound tightly but side-to-side junction (SJ) is apparently distended. still the gross structure of each mitochondria seemed to retain its normal configuration. The basic structure of myofibrils appeared to be normal except for partial over-contraction of the myofibrils and few indistinct Z lines as represented in Figs. 6 and 8. A peculiar intranuclear figure and perinuclear proliferation of electron dense lysosome were observed as shown in Fig. 9. DISCUSSION Some histopathological studies on the heart in myotonic dystrophy have appeared in the literature. Berthold12) reviewed the literature on pathological anatomy of 45 patients with myotonic dystrophy. Of 29 cases examined on heart histologically, 14 cases had normal hearts or only slight changes in the hearts. Fifteen cases, on the other hand, revealed pathological findings in the hearts including myocardial atrophy, proliferation of interstitial connective tissues and perinuclear pigments. Orndahl et al7) reported 4 autopsy cases

8 Vol.14 CARDIOMYOPATHY IN MYOTONIC DYSTROPHY 209 No.3 Fig. 8. Long section of myocardium. Partially over-contracted myofibrils are seen. aged 39, 47, 53, and 62. They stated that the histological changes might be well correlated to the degree of atherosclerosis in the coronary arteries. However, a 60-year-old patient with myotonic dystrophy described by Cannon13) had minimally atherosclerotic coronary vessels and histologically normal bilateral ventricles. De Wind and Jones,5) reviewing 98 cases of myotonic dystrophy, excluded the atherosclerois as the prime cause of cardiomyopathy in this disease. Payne and Greenfield, 4) and Fisch and Evans2) also reached the similar conclusion. In our case, a 31-year-old woman, the myocardial lesion could not be attributed to atherosclerosis. The fatty infiltration and fibrosis of the myocardium seem to be the most common histopathological findings described by many authors as summarized in Table I. Some of the authors reported additional findings such as vacuolar degeneration and splitting of the myocardial fibers,14) interstitial edema and fibrosis,12) cell infiltration in the stroma8) and variation in size of the myocardial fibers. Consequently, in the patients of myotonic dystrophy, the myocardial involvements, when present, are one of or the combination of the dif-

9 210 TANAKA, ET AL. Jap. Heart J. M ay, 1973 Fig. 9. A peculiar intranuclear structure (P) and electron dense lysosomes (L) are represented. Table I. Histopathological Findings on Myocardium in Myotonic Dystrophy Previously Reported

10 Vol.14 No.3 CARDIOMYOPATHY IN MYOTONIC DYSTROPHY 211 ferent histological changes as described avobe. However, these histological findings were considered to be not pathognomonic but nonspecific for cardiomyopathy in myotonic dystrophy. In this case, the myocardial specimen obtained with endomyocardial biopsy disclosed similar histological changes such as fatty infiltration and myocardial degeneration, and these findings seemed to be sufficient to understand the cardiac symptoms including exertional palpitation and ventricular premature beats. It is noteworthy that a considerable degree of myocardial involvements were present in the patient who had only slight skeletal muscle lesion. However, Petkovich4) and Thomson15) considered that the similar pathological process which involved the skeletal muscle might be responsible for the development of the cardiomyopathy in myotonic dystrophy. Bulloch et al9) reported the first and the only 1 case of myotonic dystrophy whose myocardium was examined by electron microscopy as well as light microscopy. They stated that the sarcoplasmic reticulum might be the site of early pathological change in myocardium, and that myocardial biopsy in the early stage of this disease would be of great interest in attempting to identify an early structural lesion. The endomyocardial biopsy afforded us a chance to examine the heart muscle exhibiting only slight cardiac symptoms. The presence of vacuolation and indistinct Z lines resembled the findings described by Bulloch et al. The structure of the vacuoles in our case did'nt indicate double limiting membranes and lamellated electron dense rings (myeline figures) as described by them, but consisted of single limiting membrane and dim content low in electron density. It is difficult to identify the primary structure of the vacuoles, however, we considered that the dilated tubules of the endoplasmic reticulum might be the primary structure of the vacuoles as seen from the location of the vacuoles and their single limiting membrane. Proliferation of mitochondria and peculiar intranuclear figure observed in our case were not reported by Bulloch et al. In spite of marked mitochondriosis, the mitochondrial structure was well maintained and the mitochondrial ghosts and sarcoplasmic debris were not observed in our case. In order to verify the primary site and nature of cardiomyopathy in myotonic dystrophy, it is necessary to accumulate many electron microscopic examinations on myocardium in an early stage of the disease with the aid of endomyocardial biopsy. Furthermore, it is well known fact that the myotonic dystrophy is frequently complicated by dysfunctions in different endocrine glands as reported in this paper. Therefore, to understand the exact pathological process of the development of cardiomyopathy in this disease, it also seems to be important to deliberate on the effects of the hormonal disorders on myocardium.16)-18)

11 212 TANAKA, ET AL. Jap. Heart J. May, 1973 ACKNOWLEDGEMENTS We wish to thank Dr. K. Kawamura, the Third Department of Internal Medicine, Faculty of Medicine, University of Kyoto, for his kind criticism on electron microscopic findings on myocardium. REFERENCES 1. Griffith TW: Quart J Med 5: 229, Fisch C, Evans PV : New Eng J Med 251: 527, Fisch C: Am Heart J 41: 525, Payne CA, Greenfield JC: Am Heart J 65: 436, De Wind LT, Jones RJ: JAMA 144: 229, Spillane JD: Brit Heart J 13: 343, Orndahl G: Acta Med Scand 176: 479, Petkovich NJ, Dunn M, Reed W: Am Heart J 68: 391, Bulloch RT, Davis, JL, Hara M: Arch Path 84: 130, Sakakibara S, Konno S: Jap Heart J 3: 537, Konno S, Sakakibara S: Bulletin of the Heart Institute, 1, Berthold H: Deutsch Zeitschr Nervenheilkunde 178: 374, Cannon PJ: Am J Med 32: 765, Hozumi T: Naika 27: 178, 1971 (in Japanese) 15. Thomson AMP: J Path Bact 96: 285, Douglass RC, Jacobson SD: J Clin Endocrin 17: 1354, Goodof II: J Clin Endocrin 4: 30, McFadden PM, Berenson GS: Circulation 45: 808, 1972