Congenital Heart Disease Associated with Hypertrophic Cardiomyopathy

Br Heart J: first published as 10.1136/hrt.40.9.1034 on 1 September 1978. Downloaded from

British Heart Journal, 1978, 40, 1034-1039

Congenital heart disease associated with hypertrophic cardiomyopathy

JANE SOMERVILLE AND LUIS BECIO From the Paediatric and Adolescent Unit, National Heart Hospital, London; and Department of Pathology, Hospital de Ninos, Buenos Aires, Argentina suMMARY Experience has shown that clinical hypertrophic cardiomyopathy (HOCM, ASH) occurs in some patients with congenital heart disease, particularly simple lesions with a good natural prognosis. Its presence should be suspected when the clinical course is atypical for the basic congenital lesion or when there is unexpected cardiomegaly, an associated left sided lesion or left ventricular hypertrophy in abnormalities which primarily affect the right side ofthe heart, or an atypical electrocardiogram showing QS patterns, left anterior hemiblock, deeply inverted septal T inversion, or unusual ST-T changes over the left ventricle. Histopathologically, 'myocardial dysplasia', indistinguishable on light microscopy from HOCM, is common in many hearts with congenital cardiac lesions, particularly in the ventricular septum. It varies in extent, distribution, and site. Its presence may account for certain unpredictable changes in congenital heart disease. The influence of 'dysplasia' on the clinical state in both isolated myopathy and when combined with congenital heart lesions depends on its extent and on the occurrence of secondary postnatal haemodynamic and biochemical disturbances. Myocardial dysplasia is probably congenital and common and it may be asymptomatic; pathologist and clinician should be aware of and search for it. http://heart.bmj.com/ Progress in the management of congenital heart also affect the heart muscle, major conducting disease has been concerned with early diagnosis of arteries, and even coronary arteries, and as such are mechanical abnormalities and the successful surgical examples of 'congenital cardiovascular disease' treatment carried out increasingly earlier in child- (Becu et al., 1976). hood. Attention has been directed to the obvious Hypertrophic cardiomyopathy in its various structural deformity and the resultant circulatory forms is obviously a congenital abnormality, often disturbances. This approach has been rewarding transmitted as a Mendelian dominant (Emanuel but has probably delayed the recognition of co- et al., 1971), and is a peculiar and bizarre abnorma- on October 2, 2021 by guest. Protected copyright. existent congenital myocardial disease in some lity of the heart muscle. The association of this patients. When present, this not only can modify mysterious disease with structural congenital heart the clinical features but also may influence the abnormalities now requires reappraisal in the light course after successful surgical correction of the of current knowledge. defect. Now faced with a new medical community, Definition: hypertrophic cardiomyopathy namely the survivors of successful treatment for and dysplasia congenital heart lesions, we are seeing that there is more abnormality in the cardiovascular system than Damage to the myocardium in fetal life causes can be treated by the surgeon's skill. There is various histological changes in the hearts examined accumulating evidence (Somerville and Becu, 1977b) after birth, such as fibrosis, infarction, hypertrophy, that in patients with structural cardiac malfor- necrosis, fibroelastosis, and 'dysplasia' in one or mations the congenital abnormality is not always both ventricles. confined to valves, septa, and connections but may The term 'dysplasia' is used to describe the histological appearance of the myocardium where Received for publication 31 October 1977 the muscle fibres are malaligned, disordered, 1034 Br Heart J: first published as 10.1136/hrt.40.9.1034 on 1 September 1978. Downloaded from

Congenital heart disease associated with hypertrophic cardiomyopathy 1035 truncated, and 'whorled', associated with perinu- past 15 years in the National Heart Hospital. This clear vacuolisation, with such changes located most suggests that the association is rare, below 1 per severely in the ventricular septum. These altera- cent of congenital cardiac lesions seen, and that it tions in myocardial morphology are indistinguish- might be a coincidence. able from those found in the different clinical forms Although pathologists have occasionally drawn of hypertrophic cardiomyopathy (Ferrans et al., attention to the abnormal myocardium in congenital 1972). heart disease (Berry, 1967; Franciosi and Blanc, Further adaptive pathological changes may 1968), myocardial dysfunction which cannot be develop in the heart during the years after birth explained by the obvious mechanical lesion tends to as a response to altered function, growth, or as a be ignored or is attributed to damage at the time of reparative process. Such changes may result in operation or to ischaemia in relation to chronic low restoration to, or maintenance of, normal myo- cardiac output. We believe that if the possibility cardial function or be associated with varying types of congenital abnormalities of heart muscle, parti- of clinical ventricular dysfunction. The mani- cularly dysplasia, were more frequently considered, festations of disordered myocardial pathology in the the incidence of congenital heart disease with living patient must depend upon whether hyper- hypertrophic cardiomyopathy might be higher. trophy, fibrosis, or new muscle formation occurs Recognition depends on criteria for diagnosis as and in what combination, amount, and site. well as awareness of the possibility. Mild cases may In living patients, hypertrophic cardiomyopathy be missed particularly if unaware clinicians and presents in different ways, variously described as pathologists do not search. 'functional obstruction of the left ventricle' (Brock, 1957), asymmetrical septal hypertrophy (ASH) Types of congenital cardiac defects (Teare, 1958), idiopathic hypertrophic subaortic associated with hypertrophic stenosis (IHSS) (Morrow and Braunwald, 1959), cardiomyopathy hypertrophic obstructive cardiomyopathy (HOCM) (Goodwin et al., 1960), and more recently mid- When congenital heart disease and hypertrophic ventricular HOCM (Falicov and Resnekov, 1977). cardiomyopathy occur together, the structural In all these clinical syndromes the same basic lesions reported are usually simple ones, such as myocardial disorder, namely severe 'dysplasia', secundum atrial septal defect, small ventricular is present on histological examination, but this septal defect, persistent ductus, pulmonary valve varies in extent, distribution, andseverity,accounting stenosis, aortic valve stenosis, and

coarctation of the http://heart.bmj.com/ for the different clinical presentations. It is interest- aorta. All these as 'isolated' lesions may have a ing that Pare et al. (1961) referred to the condition reasonable prognosis which means there may be as 'hereditary cardiovascular dysplasia' which to us time for adaptive or reactive myocardial changes now appears to be a most appropriate name, to develop. showing a correct understanding of the disease. Hypertrophic cardiomyopathy unassociated with Here the term 'hypertrophic cardiomyopathy' structural abnormalities in the architecture of the describes the whole group who have the same basic heart can cause death in stillborns, newborns, and histological disorder of the myocardium, namely infants, but clinical manifestations usually appear 'dysplasia'. later after survival has permitted secondary changes on October 2, 2021 by guest. Protected copyright. to occur in the myocardium. The same appears to Incidence be true when hypertrophic cardiomyopathy and congenital heart disease appear in the same patient. Structural congenital heart disease occurs in about Most of the completely documented reports are in 1:100 births if stillborns are included (Mitchell children over 5 years and more particularly in et al., 1971). The incidence of 'isolated' hyper- adolescents and adults. It must be said that know- trophic cardiomyopathy in the general population ledge of myocardial abnormalities particularly is unknown. The coexistence of clinically obvious 'dysplasia' in infants with complex congenital hypertrophic cardiomyopathy and congenital car- anomalies is deficient. Observers' eyes are fixed on diac malformations (Somerville and McDonald, the gross disorder of cardiac architecture and not 1968; Shem-Tov et al., 1971) appears to be un- on the myocardium. Perhaps study of the myo- common. When both are recognised in the same cardium in stillborns and newborns dying with patient the myocardial disorder has to be severe to congenital heart disease might reveal interesting be noticed in the presence of congenital defects information on this. In our experience infarction, which influence the physical signs. Only 19 patients fibrosis, and 'dysplasia' do occur in the hearts of with both conditions have been identified during the infants who die with truncus arteriosus, trans- Br Heart J: first published as 10.1136/hrt.40.9.1034 on 1 September 1978. Downloaded from

103616ane Somerville and Luis Becu position, and common atrioventricular canal. The of the ventricular septum in congenital heart disease clinical contribution of such pathological processes we do not know what its contribution is to clinical is not yet defined. disease and dysfunction in the living. We doubt if a little dysplasia in the ventricular septum is of im- Diagnosis of hypertrophic cardiomyopathy portance. Dysplasia perhaps has the potential to in congenital heart disease influence the haemodynamics and natural history when present in critical amounts or if certain Recognition of cardiomyopathy influencing the stresses occur. Though dysplastic muscle is also natural history of congenital heart disease is vital as present in the right ventricle in isolated clinical its presence may spoil the results of surgical treat- hypertrophic cardiomyopathy this is a disease which ment as well as leaving an important clinical resi- mainly affects the left ventricle. duum. When there is added cardiomyopathy of In order to examine the problem of dysplasia importance the clinical picture does not perfectly and hypertrophic cardiomyopathy in congenital fit the textbook description of the basic congenital heart disease, the hearts and clinical features of cardiac anomaly. For example, there may be un- patients with 'isolated' or simple pulmonary valve pected dyspnoea, heart failure, or cardiomegaly in stenosis were studied since only the right ventricle infancy which improves, or the finding of mitral should be affected by mechanical stresses. Careful regurgitation or subaortic stenosis in basically sectioning of both ventricles, septa, aorta, and right-sided lesions such as tetralogy of Fallot, coronary arteries in 25 specimens mainly from atrial septal defect, or pulmonary stenosis provides infants under the age of 2 years showed that there important clues. were large areas of 'dysplastic' myocardium indis- An atypical electrocardiogram appears to be the tinguishable from HOCM, not only in right best guide to the presence of serious additional ventricular muscle but also in the left ventricle and myocardial disease. Such findings as left anterior septum, in 25 per cent (Becui et al., 1976). In 5 hemiblock in a lesion not usually associated with it patients there was obvious severe macroscopical or extensive and unexpected steep T wave inversion abnormality of the left ventricle and ventricular over the left ventricle particularly over septal leads, septum yet no structural valve lesion was present to and QS patterns or the absence of predicted hyper- account for such changes. Retrospective review of trophy patterns should suggest extensive myocardial the clinical course of dead patients showed that the dysplasia. gross pathological changes in left ventricular myo- Angiocardiography shows bizarre appearances of cardium clearly had had clinical effects. The the left and sometimes the right ventricular cavity. extensive dysplasia in the myocardium must have http://heart.bmj.com/ It is mandatory that in right-sided lesions with any been congenital since it was also present in some of these unusual features the diagnosis of clinical newborns. In another series of living patients cardiomyopathy is suspected before invasive in- treated by pulmonary valvotomy, 15 per cent had vestigations are done so that the correct tests and suggestive clinical evidence of left ventricular angiocardiograms are performed. dysfunction and even pulmonary oedema was seen Final confirmation of the diagnosis of hyper- after operation for no obvious reason. One of these trophic cardiomyopathy has tended to rely pre- patients reinvestigated 8 years later had clinical and dominantly upon gross macroscopical appearances angiographic features of hypertrophic myopathy on October 2, 2021 by guest. Protected copyright. at necropsy and the allegedly characteristic histo- affecting the left ventricle. Routine angiocardio- logical features of HOCM and ASH. However, we graphic investigation of left ventricular function believe that histology and electron microscopy are in 39 patients with simple pulmonary valve stenosis of value only if the clinical and haemodynamic has also shown that the left ventricular ejection findings are consistent with the gross appearance of fraction is unusually high in about 20 per cent and the heart. Indeed, microscopy may be misleading if unusually low in 8 out of 10 children under 2 years the more obvious evidence is lacking since 'dysplasia' at the time of operation (Sa'e Melo and Somerville, may be found frequently in congenital heart disease 1977, unpublished observations). as well as occasionally in the heart muscle in It is interesting that left ventricular studies in rheumatic heart disease (Dingemans and Becker, simple pulmonary valve stenosis have been used to 1977). establish the normal values for left ventricular function in children (Miller and Swan, 1964). We Problems now believe that this was an unwise choice for normal standards. However, our major difficulty in Although our studies have shown that dysplastic relating myocardial function to pathological changes muscle is common particularly in the cephalad part is that we do not know the extent ofthese changes in Br Heart J: first published as 10.1136/hrt.40.9.1034 on 1 September 1978. Downloaded from

Congenital heart disease associated with hypertrophic cardiomyopathy 1037 the ventricular muscle in the living, though study also gross 'higgledy piggledy' changes throughout of myocardial biopsy material from the infundibular the aorta (Somerville and Ross, 1977), might be septum has shown severe dysplasia to be most related to the presence of too much dysplastic obvious in those who retain large infundibular myocardium. Could the presence of unusual gradients after valvotomy. amounts of dysplastic myocardium explain left The aortic media in hearts with pulmonary valve ventricular dysfunction with secondary mitral cusp stenosis also showed severe disorientation of the prolapse in simple atrial septal defect or the strange muscular and elastic fibres ofthe media described as septal T inversion which can persist in adolescents 'higgledy piggledy' arteriopathy and there were with simple congenital heart disease? Perhaps of frequently lesions in the coronary arteries not related greater interest is that it might explain the develop- to the severity of myocardial or aortic changes. Such ment of subpulmonary obstruction in classic trans- findings surely support the concept of congenital position of the great arteries (Somerville and Becu', cardiovascular disease which may be present in 1977b) as well as the persistence of infundibular pulmonary valve stenosis. Indeed, the same aortic gradients after pulmonary valvotomy for severe changes have also been found in infants and pulmonary valve stenosis. children presenting with systemic hypertension Corroborative evidence, but not proof, comes without other congenital heart disease (Becu' and from the finding of extensive areas of myocardial Gallo, 1974), in the various congenital syndromes dysplasia in the appropriate part of the heart in all manifesting as supra-aortic stenosis (Somerville and these situations. We believe that the disturbed Becu', 1977a), in association with other congenital circulatory mechanics resulting from the structural valve abnormalities including 'thick semilunar lesions stimulates secondary changes in the form and valve stenoses' (Somerville and Ross, 1977), and function of the dysplastic muscle so that it in turn occasionally in patients with isolated hypertrophic influences the mechanical disturbance. Once ob- cardiomyopathy. It is of note that systolic hyper- struction in a muscular outflow begins, turbulence tension may occur with all these lesions, and might occurs, fibrous tissue is laid down, and a vicious be related to conduction of the pulse wave down the circle of effects upon the myocardium may be abnormal central arteries. initiated which is only partly checked by removal As already stated, the clinical effects of the con- of the fixed part of the obstruction. If the primary genital dysplasia both in the muscle of the heart and abnormality is really in the myocardium the in the media of the conducting arteries are really clinical state even after good surgery may evolve unknown. For the myocardium, the answer probably unfavourably as is shown by the natural history of depends upon the severity and extent of the myo- fixed subaortic stenosis (Somerville and Montoyo, http://heart.bmj.com/ cardial dysplasia, necrosis, and fibrosis, and what 1971; Somerville and Becu', 1977b). These clinical secondary factors are added. These secondary states share not only the pathological features but changes must be influenced by many factors such as also many of the haemodynamic features of the stimuli to secondary hypertrophy from a valve diseases embraced by the term hypertrophic cardio- obstruction or hypertension, athletic way of life, or myopathy. How the dysplastic myocardium actually altered catecholamine excretion, and all of the above influences the electrocardiogram also needs clari- may influence the outcome but are difficult to fication. quantify. Just as in patients with 'isolated' hyper- on October 2, 2021 by guest. Protected copyright. trophic cardiomyopathy the clinical effects are many Aetiological factors and different, so are the effects of myocardial dysplasia in congenital heart disease. Myocardial dysplasia like the abnormal 'higgledy Since we now know that many congenitally piggledy' pathology in the aorta with which it is abnormal hearts contain large areas of dysplastic commonly but not constantly associated results from myocardium, it is justifiable to speculate that this several known different noxious agents which may explain some of the unusual clinical features affect the fetus and its cardiovascular system. For of survivors with congenital heart disease. instance, both are common in the hearts and vessels For instance, the large left ventricle in small or of children affected by rubella, and are constant in spontaneously closed ventricular septal defects and supra-aortic stenosis of varying causes including the HOCM-like response and disproportionate vitamin D or vitamin E intoxication, anticonvulsant septal size which may occur with mild bicuspid and other drugs, familial, and even those where aortic valve stenosis and with classic congenital there is no obvious cause. Dysplasia or disorganised aortic valve stenosis in the young, and which is a alignment in cardiovascular tissue probably is the constant feature of the variant form of aortic valve result of incomplete 'healing' or development after stenosis with poorly formed lumpy aortic valves and intrauterine damage and is probably as non- Br Heart J: first published as 10.1136/hrt.40.9.1034 on 1 September 1978. Downloaded from

103817ane Somerville and Luis Becui specific as scar tissue in skin which tells nothing fetal cardiovascular system. about the original injury. If the concept is true that There is more congenital abnormality in these myocardial dysplasia is frequently present in con- hearts than the obvious hole, valve abnormality, genital heart disease as part of diffuse congenital or disorder of connections, and such hearts should cardiovascular damage caused in utero, then it should be correctly diagnosed as 'congenital cardiovascular also be found in other examples of fetal (or congeni- disease'. Both myocardial and arterial disease may tal) syndromes without obvious structural con- affect the survivors with both simple and complex genital heart disease. In fact, clinically manifest cardiac malformations. hypertrophic cardiomyopathy is frequent in Understanding of this problem may also throw Noonan's syndrome (Ehlers et al., 1972), lenti- light on the mysterious group of diseases classified ginosis (Somerville and Bonham-Carter, 1972), as 'hypertrophic cardiomyopathy' which the patho- Friedreich's ataxia (Thoren, 1977), fetal alcohol logist can diagnose with apparent certainty when the syndrome (Loser et al., 1977), the children of clinical and macroscopical features are obvious. Our diabetic mothers (Gutgesell et al., 1976), and other studies suggest that the diagnostic myocardial named syndromes (Stocker et al., 1977). It is dysplasia is common in congenital heart disease and predicted that the association will be described in may sometimes, depending on the intensity of one's more congenital syndromes. search, be associated with clinical myocardial dysfunction such as is found in hypertrophic Conclusions cardiomyopathy. Perhaps there is a parallel between the presence of When hypertrophic cardiomyopathy and congenital myocardial dysplasia and that of malignant cells. heart disease coexist the myocardial abnormality Many hearts contain myocardial dysplasia, parti- must be severe to be recognised. It is likely that the cularly those with structural congenital heart disease importance and incidence ofthe association has been since it is a congenital disorder. Similarly, many underestimated because unaware pathologists and people have malignant cells but it requires certain clinicians do not look for it. In the few well- secondary factors, predispositions, and critical documented cases of the two conditions occurring numbers for them to become a clinical problem. together the structural congenital cardiac lesion What makes myocardial dysplasia become clinical would have had a relatively good prognosis if it had hypertrophic cardiomyopathy or influence dynamics occurred in isolation. This allows time for the post- in congenital heart disease requires more study. The natal adaptive changes in the abnormal myocardium preoccupation with the non-specific histological end to occur and influence the clinical presentation. The point should now be redefined http://heart.bmj.com/ finding of histological changes called myocardial 'dysplasia', which are indistinguishable from HOCM or ASH, is common in congenital heart defects of all References types and may be associated with macroscopical ventricular myocardial abnormalities which cannot Becui, L., and Gallo, A. (1974). Arteriosclerosis in infancy. European Journal of Cardiology, 1, 508. be explained by the mechanical disturbance. What Becu, L., Somerville, J., and Gallo, A. (1976). Isolated determines whether myocardial dysplasia will pulmonary valve stenosis as part of more widespread influence the clinical picture is unknown but we cardiovascular disease. British Heart Journal, 38, 472-482. on October 2, 2021 by guest. 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Congenital heart disease associated with hypertrophic cardiomyopathy 1039 Ferrans, V. J., Morrow, A. G., and Roberts, W. C. (1972). Somerville, J., and Becii, L. (1977a). Ascending aortic patho- Myocardial ultrastructure in idiopathic hypertrophic sub- logy in supra-aortic stenosis and 'isolated' congenital aortic stenosis. A study of operatively excised left ventri- cardiac malformations (abstract). European journal of cular outflow tract muscle in 14 patients. Circulation, 45, Cardiology, 5, 301. 769-792. Somerville, J., and Becd, L. (1977b). Congenital heart disease Franciosi, R. A., and Blanc, W. A. (1968). Myocardial in- associated with hypertrophic cardiomyopathy. Johns farcts in infants and children. I. A necropsy study in con- Hopkins MedicalJournal, 140, 151-162. genital heart disease. Journal of Pediatrics, 73, 309-319. Somerville, J., and Bonham-Carter, R. E. (1972). The heart in Goodwin, J. F., Hollman, A., Cleland, W. P., and Teare, D. lentiginosis. British HeartyJournal, 34, 58-66. (1960). Obstructive cardiomyopathy simulating aortic Somerville, J., and McDonald, L. (1968). Congenital ano- stenosis. British Heart Journal, 22, 403-414. malies in the heart with hypertrophic cardiomyopathy. Gutgesell, H. P., Mullins, C. E., Gillette, P. C., Speer, M. British Heart3Journal, 30, 713-722. Rudolph, A. J., and McNamara, D. G. (1976). Transient Somerville, J., and Montoyo, J. (1971). Fate of fixed mem- hypertrophic subaortic stenosis in infants of diabetic branous subaortic stenosis after resection (abstract). mothers. Journal of Pediatrics, 89, 120-125. British HeartJournal, 33, 143. Loser, H., Apitz, J., and Majewski, F. (1977). Cardiovascular Somerville, J., and Ross, D. N. (1977). Atypical aortic valve malformations in embryofetal alcohol syndrome (abstract). stenosis-a diffuse congenital cardiovascular disease. European Journal of Cardiology, 5, 303-304. Recognition and surgical management. Communication, Miller, G. A. H., and Swan, H. J. C. (1964). Effect of chronic British Cardiac Society, 56th A.G.M. Leeds. pressure and volume overload on left heart volumes in Stocker, F. P., Weber, J. W., Egger, K., Tonz, O., Vassella, subjects with congenital heart disease. Circulation, 30, F., Locher, G. W., and Kraus-Ruppert, R. (1977). Cardio- 205-216. myopathy in subacute infantile necrotizing encephalomye- Mitchell, S. C., Krones, S. B., and Berendes, H. W. (1971). lopathy (abstract). European J'ournal of Cardiology, 5, 283. Congenital heart disease in 56,109 births: incidence and Teare, D. (1958). Asymmetrical hypertrophy of the heart in natural history. Circulation, 43, 323-332. young adults. British Heart journal, 20, 1-8. Morrow, A. G., and Braunwald, E. (1959). Functional aortic Thordn, C. (1977). Cardiomyopathy in Friedreich's ataxia stenosis. A malformation characterized by resistance to left (follow-up study of E.C.G. and effect of beta-receptor ventricular outflow without anatomic obstruction. Circu- blockade). European Journal of Cardiology, 5, 282. lation, 20, 181-189. Pare, J. A. P., Fraser, R. G., Pirozynski, W. J., Shanks, J. A., and Stubington, D. (1961). Hereditary cardiovascular dysplasia. A form of familial cardiomyopathy. AmericanJournal Requests for reprints to Dr Jane Somerville, of Medicine, 31, 37-62. Shem-Tov, A., Deutsch, V., Yahini, J. H., and Neufeld, H. N. Paediatric and Adolescent Unit, National Heart (1971). Cardiomyopathy associated with congenital heart Hospital, Westmoreland Street, London WlM disease. British HeartJournal, 33, 782-793. 8BA. http://heart.bmj.com/ on October 2, 2021 by guest. Protected copyright.