Postgraduate Medical Journal (December 1972) 48, 732-737.

Pathology of primary cardiomyopathiesECKHARDT G. J. OLSEN

I WOULD like to discuss the pathological aspects ofprimary cardiomyopathies, with emphasis on diag-nosis, in the following order:

(1) Congestive cardiomyopathy (systolic pumpfailure).

(2) Hypertrophic cardiomyopathy, with or withoutobstruction (diastolic compliance failure).

(3) Obliterative cardiomyopathy.Congestive cardiomyopathyThe hearts are usually hypertrophic and all

chambers are dilated, often to a severe degree.Conventional measurements of ventricular wallthickness may fall within the normal range, due todilatation masking the severe degree of hypertrophywhich may be present. Endocardial thickening maybe widespread and is of a non-specific variety,consisting of fibro-elastic tissue. Thrombus may besuperimposed which can reduce the ventricularcavity size.

Careful examination of the left ventricular wallwill frequently show some fibrous replacement ofmyocardial muscle limited to the inner third of themyocardium. These changes are best seen in the leftventricle, but they may also be observed in the rightventricle where they are less severe (Fig. 1).

HistologyLight microscopic examination shows a uniform

picture. The normal architecture is preserved.The myocardial fibres from either ventricleor atrium, although hypertrophied, are usuallyattenuated as a result of dilatation, and measure-ments of the myocardial fibre diameters fallwithin normal range (5 - 12 ,.m). The myocardialfibres which show the greatest attenuation lie closeto the endocardium; towards the epicardium thefibres are usually thicker. The nuclear changes ofhypertrophy are present which. if thinning ofmyocardial fibres is evident, suggests that hyper-trophy is present (Fig. 2a).

Fine fibrous replacement of only part of myo-cardial fibres is occasionally present, and two tothree fibres may run into small foci of fibrosis. Thisis frequently seen in cases suffering from congestivecardiomyopathy, but it is by no means pathogno-monic. This fine fibrous replacement may bescattered throughout the myocardium and differs indegree from the larger areas of fibrous replacementconfined to the inner third of the myocardium,

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FIG. 1. Cross-section of a heart of a patient suffering fromcongestive cardiomyopathy. Note the dilatation of bothventricles and some patchy fibrous replacement partic-ularly in the inner third of the left ventricle. In the lowersection thrombus can be seen overlying the apex.

which can easily be seen macroscopically. Foci ofchronic inflammatory cells may sometimes be seen.The small myocardial blood vessels have beennormal in all the material personally examined.

Extensive histochemical examination has beenundertaken in collaboration with my colleaguesSusan Van Noorden and A. G. E. Pearse. Nospecific features have been found and the increasedactivity of the various enzyme systems which hasbeen observed reflects hypertrophy of the myocardialfibres.

Ultrastructural changes also show the appearanceof ordinary hypertrophy with an increase in mito-chondria. The cristae in some of these subjects showalteration of the normal arrangement and occasionalmitochondrial 'ghosts' are seen. There is a moderateincrease of lipofuscin granules and accumulationof glycogen.

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Pathology ofprimary cardiomyopathies 733

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FIG. 2. Photomicrograph to compare hypertrophy of myocardial fibres. (a) Congestivecardiomyopathy. Note the long runs of attenuated myocardial fibres and the nuclearchanges of hypertrophy. (b) Myocardial hypertrophy due to aortic valve stenosis. Notethe long runs of regular, hypertrophied fibres and the absence of a perinuclear halo.(c) Hypertrophic cardiomyopathy with obstruction. Note the extreme hypertrophy, bizarre-shaped nuclei, a perinuclear halo surrounding one of the nuclei, dystrophic myocardialfibrils and apparent interruption of myocardial fibres by fibrous tissue. All sections weretaken from the interventricular septum at the same magnification. H & E, x 330.

AetiologyThe aetiology of congestive cardiomyopathy,

which enjoys a large number of synonyms(Cockshott, thorpe & Ikeme, 1967), is unknown.Various theories have been proposed.

(1) Viral theory. A variety of viruses have beenidentified but definite proof is still lacking (Gardneret al., 1967; Fletcher & Wenger, 1968).

(2) A deficiency in succinic dehydrogenase hasbeen suggested (Kobernick et al., 1963). In ourown experience an increase has been consistentlyobserved.

(3) Arteriopathy of the small vessels has beenproposed (James, 1964).

(4) An infective agent has been suggested(Baimbridge et al., 1967) but appearances observedby these workers have been variously explained asbeing due to toxic effects or artefact (Grist, 1967;Van Noorden et al., 1971).

Hypertrophic cardiomyopathy with or withoutobstruction (diastolic compliance failure)When patients with this disease come to necropsy,

the striking abnormality in the heart is the asym-

metric hypertrophy of the interventricular septum.Attention was drawn to this asymmetric hypertrophyby Professor Donald Teare (1958). An abnormallyplaced anterior mitral valve leaflet has been described(Bjork et al., 1961; Bjork, 1964) but in our experiencethis has not been observed (Fig. 3), although theanterior leaflet and, to a certain extent, the posteriorleaflet, is occasionally thickened. This is a non-specific feature, collagen being superimposed on tothe 'deformed face' of the mitral valve cusps. Thisis secondary to mitral incompetence which isfrequently present.The extent of the abnormal fibres can be assessed

by studying numerous longitudinal sections of theheart. They usually extend from the region of theapex to the aortic valve (Fig. 4). The abnormalfibres may involve the posterior or anterior surfacesof the left ventricular cavity to a variable extent.On cross-section, the tremendous asymmetrichypertrophy of the ventricular septum is usuallystriking when one compares it with the thickness ofthe free wall of the left ventricle. The left ventricularcavity is usually small and the right cavity may bea narrow slit. Fibrous tissue, often arranged in

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734 Eckhardt G. J. Olsen

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FIG. 3. Hypertrophic cardiomyopathy with obstruction.The left ventricle has been opened to show the asym-metric hypertrophy seen at the interventricular septum.Note the slight thickening of the anterior mitral valvecusp (secondary to mitral insufficiency). (With per-mission of the editors and publishers of CardiovascularClinics.)

whorls, can be seen in the thickened interventricularseptum. The muscle most commonly involved isthe deep bulbospiral muscle, and the overlyingsuperficial bulbospiral and deep sinospiral musclemay become so thin that the abnormal muscleapparently extends to the ventricular cavities. Veryoccasionally the deep sinospiral muscle may bethe only part involved.

HistologyThe histological features are striking and in my

opinion pathognomonic. In cases of hypertrophiccardiomyopathy with obstruction, the regulararrangement of the long runs of parallel musclefibres is totally lost in the affected areas and thefibres run in all directions. In addition to this, onefinds tremendous hypertrophy of individual myo-(4rdial fibres and values of 60-90 ,um are common.The nuclei are extremely large and often bizarrein shape, containing large clumps of chromatin.The nuclei are often surrounded by a clear peri-nuclear halo. This must be distinguished fromoedema of myocardial cells which may occasionallybe responsible for the perinuclear spaces. Themyocardial fibrils adjacent to these haloes disappearand have a moth-eaten appearance. There is alsoan increase in collagen tissue which surroundsindividual myocardial fibres, and gives the appear-ance that these fibres are of a rather short length.Another feature, which we have found useful froma diagnostic point of view, is the so called whorlformation (Fig. 5). Marked fibrous replacementcan occur in the affected areas but we have been

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FIG. 4. Diagrammatic representation of the extent ofabnormal fibres; the stippled effect has been employedto convey a three-dimensional picture.

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FIG. 5. From a patient with hypertrophic obstructivecardiomyopathy showing a small whorl of hypertrophiedmyocardial fibres. H & E, x 330.

unable to relate these appearances to length ofhistory. Quantitative estimation of collagen hasnever been more than 2% of the whole myocardialmass (Gvozdjak, personal communication).The histological appearances of congestive cardio-

myopathy and hypertrophic cardiomyopathy withobstruction are summarized in Fig. 2, and comparedwith left ventricular hypertrophy due to aortic valvestenosis. The bundle of His in all these cases showedno abnormality. It has been suggested that theremight be some abnormal connections or displace-ment of the left bundle fasciculi (Lunel, personalcommunication 1972).

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Pathology ofprimary cardiomyopathies 735

Hypertrophic cardiomyopathy without obstructionWhen the patients with obstruction lose the

obstructive element clinically before death in themajority of cases, the 'bulge' is still observed atnecropsy. Very occasionally the interventricularasymmetry may completely disappear. It is thereforeessential that clinical information is available, asotherwise the pathologist may fail to look in theright area and a diagnosis may never be reached.Multiple cross-sections allow reconstruction of thearrangement of these abnormal fibres. They are inexactly the same position as in the cases whichshow the asymmetric hypertrophy prominently.The aetiology is unknown. It has been suggested

that the asymmetric hypertrophy may represent arhabdomyoma or hamartoma. A congenital growthderangement was suggested by Schmincke as earlyas 1907. Noradrenosis has been suggested (Pearse,1964) but subsequent work has shown that thisfluorescence may not be specific for noradrenosisand may also occur in collagen tissue. It has alsobeen suggested that the primary disorder might beone of myocardial muscle metabolism (Lannigan,1965).

Professor Pearse, Miss Van Noorden and I haveexamined two groups of patients (Table 1). Fromeach of the patients (who suffered from a varietyof heart conditions in which myocardial hypertrophymay occur), biopsy material was obtained and wascompared with biopsy material from twenty patients

TABLE 1. Patients used as controls and patients withhypertrophic cardiomyopathy with obstruction.

Clinical diagnosis No. ofpatients

Group INormal 5Congestive cardiomyopathy 4Cardiomyopathy of unknown type 4Infective endocarditis IHypertension (essential) 4Tetralogy of Fallot 4Ventricular septal defect 2Mitral stenosis 3Subaortic stenosis 13Aortic valve stenosis 7

Total 47

Group IIHypertrophic cardiomyopathy with obstruction 20

Total number of patients' hearts examined 67

(With permission of the editors and publishers ofCardiovascular Clinics.)

suffering from hypertrophic cardiomyopathy withobstruction. The biopsy material was obtained atsurgical operation which formed part of the patients'treatment. The material was examined histologically,histochemically and electron-microscopically. Histo-grams have been constructed to assess the diagnosticvalue of the various criteria which have been des-cribed above, and fibrosis, short interrupted fibres,large bizarre nuclei, perinuclear haloes, whorls andaverage fibre diameter, have been examined (Fig. 6).

HISTOLOGICAL No. HISTOLOGCAL +of +++I+ + 0 + 0FEATURE of ++ + FEATUREcases

80

60 PACE'F I BROS IS ROUND

INTERRUPTED DIRECTIONALLY

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FIG. 6. Closed columns, patients suffering from hypertrophic obstructive cardiomyopathy;diagonally hatched columns, patients suffering from left ventricle hypertrophy due toorganic obstruction.

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736 Eckhardt G. J. Olsen

Histochemical investigation has also been carriedout and many enzyme systems have been examined.We found only glycogen of real diagnostic import-ance; there is a marked increase of glycogen,particularly in the perinuclear area and also to acertain extent between the fibrils.

Electron-microscopic examination was not helpfulfrom a diagnostic point of view as the distributionof abnormal fibrils was patchy and no criterionwas pathognomonic. Generally speaking, the changesseen ultrastructurally can be observed at lightmicroscopic level.We have also attempted to show the diagnostic

appearances by a quantitative method and haveawarded points to each biopsy according to theseverity of the criteria present. In histologicalexamination five criteria were used, in histochemicalexamination four criteria, and ultrastructurallyseven criteria were used. The findings in a smallnumber of patients show that a diagnosis at histo-chemical level can be made with a high degree ofaccuracy, but that at histochemical and ultra-structural level considerable overlap exists (Fig. 7).When we examined the histological criteria forthe larger number of patients we found thateven at histological level there was considerableoverlap between the two groups of patients, and afew of these patients clinically diagnosed ashypertrophic cardiomyopathy with obstructionfall well below the 50% mark. The reason for thislow index is commonly insufficient material orperhaps that a non-diseased area was sampled.

Obliterative cardiomyopathyThe most common example of obliterative

cardiomyopathy is endomyocardial fibrosis (EMF).J. N. P. Davies in 1948 was among the first todraw attention to this disease. At macroscopiclevel this consists of extreme endocardial thickeninginvolving the inflow tracts of the ventricles inparticular, and in the case of the left ventricle,the posterior mitral valve cusp, chordae tendineae,and posterior papillary muscle may all be involvedin this process. As the outflow tract is approached,the endocardial thickening may end abruptly in athick, rolled edge (Davies, 1968). Fibrous septaextend from the thickened endocardium into theunderlying myocardium. Thrombus may be super-imposed on the abnormal endocardium in whichcalcification may also occur.

HistologyThe thickened endocardium, in contrast to

non-specific endocardial thickening, is arranged inzones. The superficial zone consists of hyalinized

collagen tissue in which foci of calcification mayoccur. The middle zone is composed of loose fibroustissue and the deepest zone (nearest the myocardiuin)the so-called granulation tissue zone, consists ofdilated vascular channels and inflammatory cellsmade up predominantly of lymphocytes or plasmacells. Eosinophils may also be seen in these areas(Fig. 8).

ConclusionThe diagnosis of congestive cardiomyopathy can

only be made by exclusion of all other possiblecauses and there is no characteristic pathologicalappearance.

Hypertrophic cardiomyopathy with or withoutobstruction, has a characteristic histological appear-ance and can be diagnosed with a high degree ofaccuracy. Histochemical and ultrastructural investig-ations (with the exception ofstainingforglycogen) arenot helpful in making the diagnosis. The patchy dis-tribution within the affected myocardium makesinterpretation of needle biopsy material very difficult.

Histological Histochemica Ultrastructuralindex index index

100-A A

608 AA

70A AA AAA

30 A

',O-&

A AAA

20 AA0 A A

The total for each case is expressed above as a percentageof the possible maximum. Five histological, four histo-chemical, and seven ultrastructural criteria were used.A, Patients suffering from hypertrophic obstructivecardiomyopathy; A, patients suffering from left ventri-cular hypertrophy due to organic obstruction.

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Pathology ofprimary cardiomyopathies 737

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FIG. 8. Photomicrograph from a case of endomyocardialfibrosis. At the top recent thrombus can be seen above alayer of collagenous tissue. The zone above the myo-cardium shows the granulation tissue layer with inflam-matory cells and dilated vessels. H & E, x 33. (Withpermission of the editors and publishers of Cardiovas-cular Clinics.)

ReferencesBAIMBRIDGE, M.V., DARRACOTT, SALLY, CHAYEN, J., BITEN-

SKY, LUCILLE & POULTER L.W. (1967) Possibility ofanewinfective aetiological agent in congestive cardiomyopathy.Lancet, i, 171.

BJORK, V.O., HULTQUIST, G. & LODIN, H. (1961) Subaorticstenosis produced by an abnormally placed anterior mitralvalve leaflet. Journal of Thoracic Cardiovascular Surgery,41, 659.

BJORK, V.O. (1964) In: Cardiomyopathies, p. 127, Ciba Foun-dation Symposium. Churchill, London.

COCKSHOTT, W.P., THORPE, G.J. & IKEME, A.C. (1967)Radiological aspect of heart muscle disease in Nigerianadults. Circulation, 36,460.

DAVIES, J.N.P. (1948) Endocardial fibrosis in Africans. EastAfrican Medical Journal, 25, 10.

DAVIES, J.N.P. (1968) The ridge in endomyocardial fibrosis.Lancet, i, 631.

FLETCHER, G.F. & WENGER, N.K. (1968) Auto-immunestudies in patients with primary myocardial disease.Circulation, 37, 1032.

GARDNER, M.B., LEE, P.V., NORRIS, J.C., PHILLIPS, E. &CAPONEGRO, P. (1967) Virus-like particles in cardiac biopsy.Lancet, ii, 95.

GRIST, N.R. (1967) Aetiology of congestive cardiomyopathy.Lancet, ii, 395.

JAMES, T.N. (1964) An etiologic concept concerning theobscure myocardiopathies. Progress in CardicvascularDiseases, 7, 43.

KOBERNICK, S.D., MANDELL, G.M., FIRKIN, R.M. & HASHI-MOTO, Y. (1963) Succinic dehydrogenase deficiency inidiopathic cardiomegaly. American Journal of Pathology,43, 661.

LANNIGAN, R. (1965) Hypertrophic subaortic stenosis withmyocardial fibre degeneration, 1965. British Heart Journal,27, 772.

NOORDEN, VAN, SUSAN, OLSEN, E.G.J. & PEARSE, A.G.E.(1971) Hypertrophic obstructive cardiomyopathy, a histo-logical, histochemical and ultrastructural study of biopsymaterial. Cardiovascular Research, 5, 118.

PEARSE, A.G.E. (1964) The histochemistry and electron-microscopy of obstructive cardiomyopathies In: Cardio-myopathies, p. 132, Ciba Foundation Symposium. Chur-chill, London.

SCHMINCKE, A. (1907) Ueber linksseitige muskulose conus-stenosen. Deutsche medizinische Wochenschrift, 33, 2082.

TEARE, D. (1958) Asymmetrical hypertrophy of the heart inyoung adults. British Heart Journal, 20, 1.

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