Familial Cardiomegaly by G

J Clin Pathol: first published as 10.1136/jcp.12.4.355 on 1 July 1959. Downloaded from J. clin. Path. (1959), 12, 355.

FAMILIAL CARDIOMEGALY BY G. GARRETT,* W. J. HAY, AND A. G. RICKARDS From the Royal Lancaster Infirmary, Lancaster

(RECEIVED FOR PUBLICATION SEPTEMBER 18, 1957)

In 1949 William Evans gave the name of these criteria and include eight necropsy studies. familial cardiomegaly to what he believed to be a Only these cases are included in Table I and the "distinct syndrome having a definite clinical, subsequent discussion. cardiographic, and pathological pattern." The The purpose of this paper is to present a further essential features were the familial incidence example of a family with cardiomegaly, the three of cardiomegaly without obvious cause and a affected members of which died suddenly. Post- marked tendency to arrhythmia and heart block mortem studies were made in all three cases with associated palpitation, giddiness, and although in one details of the necropsy findings syncope. Death may be sudden or rapid due to are no longer available. the development of left ventricular failure. In the electrocardiogram the QRS complexes are often Case Histories exceptionally wide and the T waves inverted. Case 1.-G. D., a man aged 30 years at death, came Conspicuous myocardial fibrosis and hypertrophy home from work one evening in April, 1956, in his of the remaining muscle fibres are the striking usual good health, and while playing with his children copyright. pathological findings. Both the degree of in the garden suddenly collapsed and died. There conduction defect and the prognosis seem to was no history of rheumatic fever or other serious depend on the extent of myocardial fibrosis and illness in the past. Eight months before his death he cardiac sustained a slight injury to the right groin with enlargement. haematoma formation in the spermatic cord. His Evans referred to two previous accounts of wife thought that he was slow to pick up after that obscure cardiomegaly occurring in members of accident, but he eventually recovered, and his mother, http://jcp.bmj.com/ the same family published in the case records of who was with him on the day before he died, the Massachusetts General Hospital in 1942 and remarked that she thought he was in excellent health. by Addarii (1943) and Addarii, Martini, Mahaim, At no time was he heard to complain of dyspnoea, and Winston (1946). Subsequently cases have chest pain, faintness, or palpitation. been published by Davies (1952), Parsons (1952), Necropsy performed by one of us (A. G. R.) on the De Matteis and Ozzano (1954), Campbell and instructions of the coroner 21 hours after death revealed the following abnormalities. Turner-Warwick (1956), Gaunt and Lecutier was that of a well-built male with The body young on September 25, 2021 by guest. Protected (1956), and Paulley, Jones, Green, and Kane a previous appendicectomy scar; significant macro- (1956). Among these, however, are included cases scopic findings were confined to the thoracic cavity. of cardiomegaly with no supporting family The heart was markedly enlarged (weight 500 g.), the history and others where there is good reason hypertrophy mostly affecting the left ventricle, which to believe that the cardiac hypertrophy was in parts was nearly 2 cm. thick and appeared at first secondary to acquired valvular disease, congenital sight to be of the usual hypertensive type. On closer cardiac malformations, or toxoplasmosis. In our inspection it was seen that the outer part of the view the diagnosis of familial cardiomegaly myocardium consisted of pale fibrous tissue almost giving the impression of an outer shell surrounding should only be made when other causes of cardiac the inner layer (Fig. 1). Strands of fibrous tissue enlargement have been excluded and when there could be seen penetrating the deeper aspects of the is a clear supporting family history. Moreover, myocardium, but the predominantly peripheral in the present state of knowledge, it seems wise distribution was striking. The compact outer rim was only to include those cases where the diagnosis well demarcated from the rest of the myocardium has been established by necropsy study in at least except in the region of the interventricular septum one affected member of the family. The reports where its discrete pattern became replaced by diffuse of seven affected families (15 cases) comply with fibrotic mottling. The trabeculae carnae, papillary and chordae tendineae showed no evidence *Present address: Department of Clinical Pathology, Manchester muscles, Royal Infirmary. of fibrosis. The right ventricle and both auricles J Clin Pathol: first published as 10.1136/jcp.12.4.355 on 1 July 1959. Downloaded from

356 G. GARRETT, W. J. HAY, anid A. G. RICKARDS

TABLE I MAIN CLINICAL FEATURES

Age Length of Author's () History Necropsy No. Author Case Age Sex Family from No. at Relationship Symptoms Arrhythmias Heart Block Onset of IFindings Death Symptoms

2 Case records----A_ , I1l i (21)X4|l, M Brother with...:,t- con- Dyspnoea, Complete A-V 6 months Yes of M.G. gestive failure. fatigue, block Hosp. Sister with car- congestive (1942) diomegaly A-V failure UIU6CK anaI conl- gestive failure 2 Addarrii et al. I (?) M Brother of Case 3 Dyspnoea, Auricular Complete A-V 9 ,. (t943) syncope fibrillation block, brancli bundle block 3 Addarii et al. I (21) M Brother of Case 2. Dyspnoea, Auricular fibril- Complete A-V 15 years ,, ((1946) Mother died fatigue, lation, parox- block, branch C.C.F. and syn- syncope, ysmal tachy- bundle block cope congestive cardia failure 4 Evans (1949) I (18) M Son of Case 6. Giddiness. Paroxysmal Branch bundle 2 tooiths Brother of Case paroxysmal tachycardia, block 5 tachycardia extrasystoles 5 2 20 M Son of Case 6. Giddiness Auricular fibril- 6 ,, Brother of Case lation, parox- 4 ysmal auricular tachycardia 6 3 43 F Mother of4 and 5. Syncope Auricular fibril- 12 years Three of her sib- lation, extra- lings believed systoles affected - 7 8 (16) M Son of Case 8 Sinus brady- 412 *s Yes cardia 8 App. 42 F Mother of Case 7 Paroxysmal, Paroxysmal Prolonged P-R 2 months tachycardia tachycardia interval, with occa- branch bundle

sional block copyright. syncope 9 Gaunt and I (51) M Brother of Case I I Dyspnoea, Auricular Comple:e A-V 20 Yes Lecutier syncope fibrillation block (1956) 10 2 23 F' Daughter of Case Arthralgia, 3 ,, 1t1 slight 1,* . dyspnoea 11 3 (531) F Mother of Case 10. Syncope, Complete A-V 4 years - Sister of Case 9 dyspnoea block, branclh bundle block 12 Campbell and (23) M Son of Case 13 Syncope, Paroxysmal Prolonged P-R, 3 years Yes http://jcp.bmj.com/ Turner- palpitation, tachycardia, branch bundle Warwick dyspnoea, ventricular block (1956) severe chest extrasystoles pain 13 ,. ..1 2 (29) F Mother of Case 12l Dyspnoea, Branch bundle I year Eight of her 12 congestive block siblings died of failure, heart disease syncope under 40 years 14 3 (36) M Son of Case 15 Syncope Sinus and nodal Varying degrees 6 months Yes bradycardia, of A-V block, nodal or ven- branch bundle on September 25, 2021 by guest. Protected tricular extra- block systoles 15 4 66 F Mother of Case 14. Faintness, Paroxysmal Branch bundle 40 years Her sister, fatigue, auricular block mother, three dyspnoea flutter, aunts, and grand- sinus mother died of bradycardia heart disease

appeared unaffected, and the pericardium and myocardium distributed peripherally and correspond- endocardium were also macroscopically normal. The ing to the area seen with the naked eye. The fibrous aorta merely showed slight atheroma of its first part, strands tended to separate the muscle fibres into and there was no evidence of coarctation. The lungs bundles (Fig. 2) and many of these isolated lobules of were engorged and the trachea and bronchi contained muscle showed degenerative changes similar to those a large amount of mucus; all the other organs, seen in early cell death following ischaemia (Fig. 3); including the brain and spinal cord, appeared normal slight infiltration with lymphocytes was seen in to the naked eye. occasional areas of fibrosis (Fig. 4). The right Microscopic examination of the left ventricle ventricle showed a similar pattern of interstitial showed marked hypertrophy of individual muscle fibrosis, although of lesser extent, and its distribution fibres associated with gross fibrosis of the was more irregular and was not confined to the J Clin Pathol: first published as 10.1136/jcp.12.4.355 on 1 July 1959. Downloaded from FAMILIAL CARDIOMEGALY 357

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FIG. I.-Cross section of left ventricular wall showing peripheral ~~~~~~~~~~~~~~~~ w fibrotic mottling in Case 1.

tFG. FIG. 2.-Trabeculated fibrosis of the left ventricle in Case 1. Haema- toxylin and eosin, x 60.

FIG. 3.-Degenerative change in muscle fibres surrounded by fibrous tissue in Case 1. Haematoxylin and eosin, x 150. J Clin Pathol: first published as 10.1136/jcp.12.4.355 on 1 July 1959. Downloaded from

358 G. GARRETT, W. J. HAY, and A. G. RICKARDS

papillary tips," but unfortunately the myocardium was not examined histologically. The coronary arteries were recorded as being normal. Various organs were examined for a wide variety of chemical poisons with negative results, death being eventually attributed to " acute pulmonary oedema precipitated by streptococcal pneumonia." From the description of the lungs and heart 41 it seems clear that in fact death was due to ... .. left ventricular failure. Case 3.-P. D., the sister of Cases 1 and 2, also died suddenly at the age of 18 years ...... * on December 26, 1939, exactly seven years before the death of her sister. In this case also there was no history of previous ill- = ; health. She was dancing without distress until after midnight, when she returned home and retired to bed. A few minutes later her parents went in to see her and found her . dead. Her case was also the subject of a t coroner's inquiry, but copies of the post- mortem findings are no longer available although it appears from the records that the 17INK precise cause of death was never established X>* Other Relatives.-The antecedents of these

three cases (Table II) on both male andcopyright. ¶! < e:^ xv female sides have in general been long-lived, but, of the exceptions, their mother's only - brother died at the age of 11 years from pneumonia, and her mother died at the age >>}R

toxylin and eosin, x 80. to be physically well. Their mother is an http://jcp.bmj.com/ obese, arthritic woman, with a blood peripheral areas; the left auricle was normal, tbut pressure of 170/100 mm. Hg, slight dyspnoea on slight fibrotic changes were present in the wall of the exertion, and occasional swelling of the ankles. right chamber. There was no histological eviderice Radiographs of the chest showed no cardiac of amyloidosis and stains for amyloid were negative. enlargement and an electrocardiogram was normal. The endocardium was normal and the coronairy The surviving siblings and all the nine members of arteries and arterioles showed no evidence of diseaLse. the next generation, with the exception of one young Histological examination of the thyroid, testtes, man in the Navy, have been examined clinically and kidneys, thymus, pancreas, liver, adrenal glanids, radiologically without finding any evidence of on September 25, 2021 by guest. Protected pituitary, spleen, brain, spinal cord, and voluntairy cardiomegaly. Electrocardiograms have been taken muscle revealed no significant abnormality. T'he of five members of the family and show no lungs showed basal venous engorgement and tthe abnormality. aorta some soft atheroma. Discussion Case 2.-K. D., the sister of Case 1, died sudder at the age of 18 years on December 26, 1946. Th4 nlrye Study of the pathological appearances of the was no history of previous ill-health. The day befcDre heart in these cases and in the eight previous her death was spent working, as usual, as a necropsy reports referred to in Table I reveals no telephonist at the Post Office. Next morning she fFelt uniform pattern and indeed the variability of the off-colour, became pale and faint, and complainled post-mortem findings suggests that the cases listed that her legs were numb. She developed increasing here as examples of familial cardiomegaly may shortness of breath with frothy sputum, white at first have had more than one cause. For descriptive but later tinged with pink. She died shortly bef( ire midnight. purposes they may be separated into those in Her death was the subject of a coroner's inquiry, which the muscle hypertrophy was the main or and the necropsy report gave as the main findirngs only abnormal finding and those in which cardiac enlargement and pulmonary oedema. T'he hypertrophy was accompanied by widespread heart was said to show "a little fibrosis of tthe interstitial fibrosis. J Clin Pathol: first published as 10.1136/jcp.12.4.355 on 1 July 1959. Downloaded from

FAMILIAL CARDIOMEGALY 359 TABLE II FAMILY TREE

(11)4

3 9 6 21 12 20 6 8 5 copyright. 4 t Affected ( ) Age at death

Only two cases fall into the first category, appearance of the auricles. In no case has there namely, Cases 1 and 14 (Table I). In the former been found any macroscopic or microscopic case the heart weighed 600 g. and was grossly evidence of disease of the coronary arteries. dilated, being described by Dr. Tracy Mallory as Occasional focal collections of chronic inflam- http://jcp.bmj.com/ "one of the largest hearts from the point of matory cells have been noted in two cases (Cases view of capacity that we have ever seen." All 12 and 3) similar to the occasional foci present in the chambers shared in the hypertrophy, but the first case described here; Case 3 also showed there was no other microscopic abnormality of patchy necrosis of muscle fibres similar to that the myocardium. In Campbell and Turner- occurring in our Case 1. Two of the cases in this Warwick's case the heart weighed 1,050 g., chiefly fibrotic group (4 and 9) have shown unusually due to hypertrophy of the left ventricle which marked deposits of glycogen within the muscle on September 25, 2021 by guest. Protected measured up to 25 mm. in thickness. Histologic- fibres, although similar in other respects to the ally there was simple hypertrophy of muscle remainder of the group. fibres some of which showed central vacuolation; Consideration of these pathological types the nature of the vacuolar material was not suggests a fundamental difference between those established, but stains for fat and glycogen were showing extensive myocardial fibrosis and those negative. in which the pathological picture is one of simple The remaining cases belong to the second hypertrophy. Despite the not dissimilar clinical fibrotic group (Cases 2, 3, 4, 7, 9, and 12 in Table features it seems unlikely that these are different I and our own Case 1). Moderate or marked stages of the same disease process or indeed that cardiac hypertrophy was present in all, the lowest they have any aetiological relationship. The two heart weight recorded being 737 g. (Case 9) types have not been found in the same family. and the highest 1,134 g. (Case 4). Extensive The picture of the fibrotic type appears to be myocardial fibrosis was present in all cases that of replacement fibrosis and survival hyper- although the precise distribution of the fibrous trophy. Previous episodes of myocarditis which tissue is not always recorded. In most the fibrosis might account for this picture have naturally been affected both right and left ventricular walls, but sought in case histories. Rheumatic infection is in few was there any reference to the histological recorded in only three cases (11, 12, and 13), in J Clin Pathol: first published as 10.1136/jcp.12.4.355 on 1 July 1959. Downloaded from

360 G. GARRETT, W. J. HA Y, and A. G. RICKARDS two of which the diagnosis was doubtful; Aschoff for the diagnosis of glycogen disease. In the light nodes were not found in the only case which came of our present knowledge it seems more reason- to necropsy. In the remaining cases there is no able to regard the deposits as a non-specific history of illness suggesting Fiedler's or other infiltration which may complicate the pathological non-rheumatic myocarditis. pattern of the fibrotic form of familial Paulley, Jones, Green, and Kane (1956) have, cardiomegaly. however, described several cases of fibrotic A further possible aetiological factor is the cardiomegaly which they attributed, on the basis curious association between cardiomegaly and of positive serological reactions, to toxoplasmosis. two familial neurological conditions, Friedreich's In one family, at least three of the four cases ataxia and progressive muscular dystrophy. The coming to necropsy showed a fibrotic cardio- association of myocarditis with Friedreich's ataxia megaly similar to that described above, although was first recorded by Pitt (1886-7). Several atypical in that the left ventricle was not reports later appeared in the Continental predominantly affected and mural thrombus and literature and in 1946 Russell reported four embolism was a marked feature. Moreover, two examples of the condition with post-mortem of the four cases had enlarged firm spleens. details; not infrequently the neurological lesion Clinically their cases bore less resemblance to is accompanied by a chronic progressive familial cardiomegaly, the absence of syncope myocarditis of fibrotic type which closely being particularly noteworthy. Paulley et al. resembles that found in the fibrotic form of (1956) were unable to demonstrate toxoplasma familial cardiomegaly. It was Russell's opinion bodies in the myocardium of their cases and that the heart muscle is destroyed through a focal, positive serological reactions cannot be considered piecemeal, coagulative necrosis as a result of as conclusive evidence of active toxoplasma which the fibres are ultimately replaced by bodies from a case of obscure myocarditis in collagenous tissue, the surviving muscle under-

which evidence of generalized toxoplasmosis was going a compensatory hypertrophy. This copyright. lacking, but toxoplasma infection may well have description could well be applied to the been the aetiological factor in the cases of Paulley histological appearances in the cases of familial et al. In view of their findings we obtained cardiomegaly now described, although, as Evans samples of serum for toxoplasma antibody (1949) comments, " the relation of this condition titration from a brother, son, and wife of our to Friedreich's disease would be more definitely Case 1 and in no instance was a significant established if instances of each were met with in antibody titre recorded. one family." Roth (1948) described a family http://jcp.bmj.com/ The finding of glycogen deposits in the muscle affected by Friedreich's disease and peroneal fibres in Cases 4 and 9 raises the question as to muscular dystrophy in which there was a high whether some cases of familial cardiomegaly may incidence of heart disease, but there was no be due to a disorder of glycogen metabolism. In evidence to suggest that they were cases of a few cases of Von Gierke's disease, glycogen familial cardiomegaly. Some 30 cases of cardiac infiltration has been confined to the heart, so- involvement have been reported in progressive called "cardiomegalia glycogenica," but di muscular dystrophy and the subject has recently on September 25, 2021 by guest. Protected Sant'Agnese, Andersen, and Mason (1950), who been reviewed by Bevans (1945) and Storstein and have recently reviewed this subject, consider that a Austarheim (1955). The post-mortem appear- fatal termination within the first year of life is ances of the heart in these cases seem to show a invariable in this condition, and, moreover, those very variable picture; sometimes the hearts are cases of glycogen storage disease in which the atrophic and in other cases marked hypertrophy heart is involved do not progress to myocardial is found. Macroscopically fatty infiltration and fibrosis. Russell (1948), in trying to assess the intracellular vacuolation of the fibres has been significance of the presence of muscle glycogen described; in several cases a patchy fibrosis, deposits in post-mortem tissue, examined often maximal in the outer myocardium, has been specimens of muscle from 11 necropsy cases taken present. This association of hereditary neuro- at varying intervals after death; although she was pathies and fibrotic cardiomegaly has suggested able to demonstrate glycogen in the muscle fibres to some that the cardiopathies in the familial and the infiltration was scanty compared with that neuropathic varieties may have a common found in the first case described by Evans (1949). aetiology which may lie in an as yet undetected The exact significance of these glycogen deposits inborn error of metabolism. Support for this is obscure, but the mere presence of glycogen " chemical theory " of diffuse cardiac fibrosis is within the myocardium does not provide a basis reinforced by the knowledge that diffuse J Clin Pathol: first published as 10.1136/jcp.12.4.355 on 1 July 1959. Downloaded from FAMILIAL CARDIOMEGALY 361

myocarditis may follow the ingestion of a variety Our thanks are due to Mr. L. G. Powell, H.M. of chemical compounds including arsenicals, Coroner for South Westmorland, for making sulphur, and sulphonamides (Elster, Horn, and available previous post-mortem reports. Tuchman, 1955), and recently McAllen (1955) has observed severe myocardial changes, including REFERENCES widespread fibrosis, supervene in two cases in Addarii, F. (1943). Boll. Sci. med., 21, 41. which there was prolonged depletion in potassium Martini, L., Mahaim, I., and Winston, M. (1946). Cardiologia (Basel), 11, 36. absorption. These human lesions were strikingly Bevans, M. (1945). Arch. Path. (Chicago), 40, 225. similar to the cardiac lesions found in potassium- Campbell, M., and Turner-Warwick, M. (1956). Brit. Heart J., 18, deficient animals. 393. Case Records of Massachusetts General Hospital (1942). New Engl. In conclusion it must be admitted that in spite J. Med., 226, 158. Davies, L. G. (1952). Brit. Heart J., 14, 206. of the numerous theories of origin, the aetiology De Matteis, F., and Ozzano, T. (1954). Minerva med. (Torino), 45, of familial cardiomegaly still remains obscure. (1), 1549. di Sant'Agnese, P. A., Andersen, D. H., and Mason, H. H. (1950). Pediatrics, 6, 607. Summary Elster, S. K., Horn, H., and Tuchman, L. R. (1955). Amer. J. Med., 18,900. A family with cardiomegaly is described in Evans, W. (1949). Brit. Heart J., 11, 68. which the three affected members died suddenly Gaunt, R. T., and Lecutier, M. A. (1956). Ibid., 18, 251. health and were McAllen, P. M. (1955). Ibid., 17, 5. when apparently in good Parsons, P. J. (1952). Med. J. Aust., 2, 435. submitted to necropsy. Paulley, J. W., Jones, R., Green, W. P. D., and Kane, E. P. (1956). Brit. Heart J., 18, 55. The clinical and pathological features of these Pitt, G. N. (1887). Guy's Hosp. Rep., 44, 369. and previously published cases of familial Roth, M. (1948). Brain, 71, 416. Russell, D. S. (1946). J. Path. Bact., 58, 739. cardiomegaly are discussed and the possible - (1948). Quoted by Evans (1949). aetiology of the condition considered. Storstein, O., and Austarheim, K. (1955). Acta med. scand., 150,431. copyright. http://jcp.bmj.com/ on September 25, 2021 by guest. Protected