Pathology of cardiomyopathies in childhood

Pathology of Cardiomyopathies in Childhood MEREDITH M. SILVER, M.B., B.S., M.Sc. MALCOLM D. SILVER, M.D., Ph.D. Departments of Pathology The Hospital for Sick Children and The Toronto Hospital University of Toronto Ontario Canada

Put simply, a cardiomyopathy is a clinical condition characterized by impaired myocardial function. Using this definition, the term has wide application. An example in infancy would be the dilated cardiomyopathy associated with left ventricular ischemia caused by anomalous origin of a left coronary artery from the pulmonary trunk. We use the term in a more restricted sense. By a convention shared by clinicians and pathologists, a diagnosis of cardiomyopathy is made only after excluding myocardial disease caused by hypertension, coronary artery disease, valvular, or congenital heart disease; only the last is common in childhood. When a child dies of heart disease but without a cardiologic diagnosis (and such patients often die suddenly), a pathologist must exclude heart diseases in the four categories indicated above before diagnosing a cardiomyopathy. In seeking to clarify the definition of cardiomyopathy, the WHO Expert Committee in 1984 unwittingly created a communication problem between pathologists and clinicians.* The committee recommended using the term “cardiomyopathy” for “intrinsic heart disease of unknown cause” and created a second category called “specific heart muscle dis-

Address correspondence to Dr. Meredith M. Silver, Department of Pathology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.

ease” for the numerous cases of cardiomyopathy with a known cause, e.g., alcohol abuse. To a pathologist, “specific” designates a diagnostic morphologic finding whereas most heart muscle diseases associated with a known cause (e.g., alcohol abuse) have nonspecific morphology. Thus, a cardiomyopathy may have a known or unknown cause and, as a result of either, have either”specific” (diagnostic) or “nonspecific” (nondiagnostic) morphologic findings. We will use these words in the diagnostic sense. Frequency

of Cardiomyopathies

in Infancy

and Childhood

Cardiomyopathies are uncommon at any age and are less frequent in children than adults. Mortality statistics in the United States show that death from cardiomyopathy is more common in early infancy than in children aged from 1 to 14 years, but deaths in adults are far more common.’ In children, mortality rates do not vary much for sex or race.2 In our autopsy service, 50 cases of cardiac malformation are seen for every case of cardiomyopathy. Some kinds of cardiomyopathy with a specific morphology, such as amyloidosis, are common in adults but unknown in childhood. Others, like sarcoidosis, are very rare.3 Such cardiomyopathies will not be mentioned further in this article. Conversely, several specific cardiomyopathies, such as endocardial fibroelastosis, Pompe’s disease, and Prog Pediatr Curdiol 1992; I(S):&39 Copyright 0 1992 by Andover Medical

Pathology of Cardiomyopathies

oncocytic cardiomyopathy, the young.

are manifest only in

Tissues Available for Morphologic Study An endomyocardial biopsy may be done to diagnose the cause of heart failure, heart enlargement, dysrhythmia, and so on. In that circumstance, cardiologic workup would be extensive and, if the recovered tissue is both representative and abnormal, a diagnosis is possible. However, the tissue samples derived from an endomyocardial bioptome are very small and may not be representative. Alternatively, histopathologic findings may not be specific. Even so, those nonspecific findings may be compatible with those of longstanding heart failure and so help diagnosis by exclusion. In our experience, a biopsy from a cardiomyopathic heart is rarely diagnostic except in a variety of rare diseases with specific morphology. Many of these are peculiar to childhood and are discussed here. In the majority of cases with nonspecific morphology, only a descriptive diagnosis is possible. We use most of a biopsy sample for morphologic studies but other special studies may be planned. We agree with the opinion that tissue from an endomyocardial biopsy should also be used for subcellular and molecular investigations on the etiopathogenesis of myocardial diseases.4 The second tissue sample received by a pathologist is an explanted heart. Indeed, heart transplants are done more often in children with cardiomyopathy (frequently the familial dilated variety) than for any other diagnosis.5 Examining an explanted heart may allow the pathologist to (1) arrive at the correct pathologic diagnosis, (2) relate recorded functional abnormalities and structural changes in the heart, and (3) obtain tissue for special studies designed to investigate etiopathogenesis. However, the evolution of chronic heart muscle disease is slow and morphology of end-stage organs is often nonspecific; in this, the heart does not differ from other vital organs. A chronic disease that alters cardiac function will lead to structural changes that will be discernable on gross examination. In many such cases, microscopic examination may add little to the diagnosis. Recognition of a pattern of disease, at whatever level of investigation, is the key to understanding pathogenesis. Research-oriented investigations on tissue derived from explanted hearts will depend on local interests and technological ex-

in Childhood

9

pertise. The pathologist is in a key position, not only to collect, store, and distribute tissues, but, based on morphologic findings, to initiate research along lines most likely to be productive. Third, tissue may be derived from autopsy. That material often shows an advanced morphologic stage of a cardiomyopathy, even in cases of sudden death. This is, perhaps, more likely in children than adults, because children often do not recognize that they are ill. When they present clinically or at autopsy, they may show normal growth for age despite longstanding heart muscle disease. Not infrequently, such children are active at sports and may die suddenly while engaged in exercise, a complication well known in hypertrophic cardiomyopathy6z7and right ventricular cardiomyopathy.8,9 but also seen in dilated cardiomyopathy.10~‘2 Other children present in a preterminal state of congestive heart failure. We have seen cases of children with dilated or restrictive cardiomyopathy who apparently became symptomatic with advanced cardiac failure only a week or two before death. Thus, examining a cardiomyopathic heart at autopsy may have the disadvantage of a long delay between onset of disease and death. Nevertheless, all four heart chambers are available for gross, microscopic, and ultrastructural study and provide a great advantage over a sample obtained by biopsy. Having the entire heart to examine, albeit with some degree of autolysis, gives every opportunity for anatomic diagnosis and clinicopathological correlation. If fresher tissue is needed for special studies, it may be obtained by heart biopsy immediately after death or at the start of the autopsy. What the pathologist sees on gross examination is very similar to what the cardiologist viewed, using special techniques, a short time before the patient’s death. Thus, opportunities for exact clinicopathological correlation are enormous. Knowing the clinical findings before an autopsy allows a pathologist to plan gross cardiac dissection, photography, and sampling for histopathology and special studies that might identify the cause. Familial Cardiomyopathies Because heritable diseases loom large as a cause of childhood cardiomyopathies, a diagnosis of cardiomyopathy, whether dilated or nondilated, may have important implications for the family of an index case. A pathologist performing perinatal au-

10

Progress in Pediatric Cardiology

topsies recognizes fetal and congenital cardiomyopathies and will certainly need to consider the possibility of familial disease. Cardiologic screening of relatives of an index case may uncover new cases, thus providing the opportunity to offer effective therapy or timely intervention, as has occurred in families with hypertrophic and dilated cardiomyopathy and right ventricular cardiomyopathy.‘3-‘6 Classification

of Cardiomyopathies

A clinician classifies cardiomyopathies on the basis of altered function into dilated, hypertrophic, and restrictive cardiomyopathies. A pathologist uses the same classification. In cases not investigated during life, one may infer the alteration of function from the pathologic finding. Although dilated cardiomyopathy is by far the most common pattern in adults, this may not be true in children, in whom hypertrophic cardiomyopathy is relatively common. “Dilated” identifies the main and earliest anatomic finding, namely, left ventricular dilation greater than expected for the degree of hypertrophy. This judgment is based on both gross (heart weight, ventricular wall thickness, chamber size) and microscopic findings (degree of hypertrophy in nucleus and attenuation in myocyte sarcoplasm). In a subset of dilated cardiomyopathy patients, ventricular dilation is mild. In other cases, clinical features may overlap with those of restrictive cardiomyopathy. In hypertrophic cardiomyopathy, the left ventricle is hypertrophied (often with accentuation in the interventricular septum) and the chamber is reduced in size, reflecting the clinical finding of impaired diastolic filling. Pathologic diagnosis is based not only on gross findings but on a characteristic microscopic pattern in the zone of myocardial hypertrophy. Both at our center and clinically, hypertrophic cardiomyopathy in childhood is more common than the dilated type. Especially in the young, it may evolve into a dilated end stage, or share a clinical overlap with restrictive cardiomyopathy. Many conditions mimic the gross findings in hypertrophic cardiomyopathy; we call them pseudohypertrophic cardiomyopathies. As in adults, restrictive cardiomyopathy (restrictive obliterative, nondilated, infiltrative) is much rarer than either dilated or hypertrophic types in childhood; the main clinical finding is reduced diastolic compliance. Pathologists sometimes use de-

scriptive terminology such as “nondilated nonhypertrophic” if microscopic study does not reveal specific morphologic findings that explain the functional abnormality.

MORPHOLOGIC FINDINGS Morphologic data in this paper are based on (1) personal observations in perinatal, infantile, and childhood cases of cardiomyopathy; (2) reports in the English literature pertaining to cases who died when <2O years of age; and (3) reports on singlegene diseases that affect the myocardium, whether they present in childhood or adult life. Dilated

Cardiomyopathy

Dilated cardiomyopathy (DC) develops as a result of many different genetic and acquired causes that work either singly or synergistically.17 In infants and children, genetic causes of DC are especially important. For example, familial DC was observed in multiple kindreds containing cases in several generations.18 A Stanford study of relatives of subjects who received heart transplants for DC showed a 10% incidence of familial DC in that population.19 Again, a “mildly dilated” subset -56% of 20 patients aged 16 to 65 years showed an unusually high familial incidence.” In an Italian study of familial DC cases, echocardiographic diagnosis of DC was made in 19 of 45 relatives, including both symptomatic and apparently healthy subjects.21 Michels et a1.15 also investigated relatives of DC index cases and found that over 20% had familial disease. A genetic substrate may underlie many of the known environmental causes of DC (e.g., cardiotoxins, drugs). Many drugs induce a hypersensitivity myocarditis. 22 An acute myocarditis (whether caused by infective, immune-mediated, or drugrelated mechanisms) may heal with replacement fibrosis of cardiac myocytes. In some cases, this leads to DC. Whether this happens (instead of a patient dying or recovering) might depend on the patient’s genetic makeup. Many diseases associated with dilated cardiomyopathy have been tabulated.23 Gross Pathology. The heart in DC is heavier than normal and globally dilated (Figure 1).24,25 (Control heart weights in infants and children are better related to body weight and length than to age.26*27)At this hospital, heart weight at autopsy in infantile and childhood cases of DC is on average

Pathology

of Cardiomyopathies

El FIGURE 1. 7-year-old

left ventricle

heart failure.

(1.8 times more

thrombi

heart shows

thick.

fibrous

despite tissue.

where

related

to the enlarged,

rowheads). pm.)

sarcoplasm,

(Hematoxylin-eosin

this

with ob-

and increased are re-

particularly

pleomorphic,

myocytes

from

myocytes

attenuation,

by granular some

were

the compact

section

The myofilaments

focally

nuclei:

dilation,

cardiac

placed

chromatic

history

was 780 g

and all chambers

(J3) Histologic

left ventricular

hypertrophy,

tract of a

in the right atria1 append-

the left ventricular

layer was l-cm

interstitial

Heart weight

than expected)

with mural

age. Despite

vious

and outflow

boy who died after a three-month

of congestive dilated,

(A) The dilated

Dilated cardiomyopathy.

and hypertrophied

hyper-

are binucleate stain, scale

(ar-

= 100

in Childhood

11

1.5 to 2 times greater than the expected weight for body size. This hypertrophy is of postnatal onset, because fetal and newborn cases of familial DC have heart weights that are normal for gestational age. In six cases of DC aged 14 to 20 years and examined by Maron et a1.2s the heart weighed >500 g. One presumes that, at least in older children with DC, longer survival after onset of congestive heart failure would be associated with relatively greater heart weight; this is true in adults.” All four heart chambers are dilated in children with DC. When assessed by inspection or heart weight, the degree of ventricular dilation is more obvious than the degree of hypertrophy.28 Nevertheless, myocardial trabeculae are always thickened. The subendocardial zone and papillary muscles of the left ventricle may appear pale due to diffuse interstitial fibrosis.28,30 Rarely in children, small myocardial scars may be seen scattered in the subendocardial zone of the left ventricle.28 We have seen a 500-g heart in a 13-year-old boy in which the ventricular muscle was hypertrophied and severely scarred but with no necrosis or inflammation (Figure 2A); he was asymptomatic until two weeks before death. Endocardial thickening is common, especially in the left ventricular apical region. Mural thrombi are common in the same region and may be a source of thromboemboli.24,2” Such thrombi may, by organization, evolve into endocardial plaques and/or calcify. Both atria and the right ventricle are dilated and hypertrophied, in keeping with the degree and duration of congestive heart failure. They, too, may contain mural thrombi or endocardial plaques; myocardial scarring may be visible in the wall of the right ventricle. Histopathology. No special histologic features are seen in most cases of DC in childhood, as is also true in DC in adults. Also, the morphology found in familial DC cases appears identical to that in sporadic cases. l5 By light microscopy, cardiac myocytes appear hypertrophied but may be attenuated so that sarcoplasmic profiles appear relatively narrow for age and body size. Nuclei are enlarged and hyperchromatic, with square ends or lobated profiles, and may appear pyknotic (Figure 1B); increased nuclear-sarcoplasmic ratio was emphasized in one study. 31The sarcoplasm is often vacuolated due to increased glycogen or lipid, confirmed by special stains or electron microscopy. Cardiac myo-

12

Progress in Pediatric Cardiology

B FIGURE 2. Dilated cardiomyopathy and chronic myocarditis. (A) Dilated cardiomyopathy. Histology of the left ventricular myocardium from the 500-g globally dilated heart of a l&year-old boy who died with ventricular fibrillation only two weeks after becoming symptomatic; congestive heart failure was evident for only one week before death. Extensive viral cultures and serology were negative. Cardiac myocytes show hypertrophy and attenuation. As well as diffuse interstitial fibrosis, the myocardium showed patchy replacement by mature fibrous tissue, but no inflammation. @,I Chronic myocarditis. Left ventricular myocardium from a lo-year-old boy who died after an illness diagnosed clinically as “pericarditis and possible myocarditis” that commenced with an influenzalike illness five weeks before death. Heart weight at autopsy was 308 g (2.4 times more than expected) but included extensive mural thrombi in both ventricles and the right atrium. The myocardium in all heart chambers showed inflammation in the subacute to chronic stage with extensive replacement by fibrous tissue containing mature collagen. Inflammatory cells

cyte steatosis has no specificity but, in a child, should raise the possibility of a carnitine deficiency (discussed below). Similarly, a diffusely granular sarcoplasm could indicate a mitochondrial myopathy (see below). Other nonspecific cytoplasmic degenerative features include cloudy swelling, edema, increased lipofuchsin pigment, and loss of cross striations and myofilaments (Figure 1B). In addition to nuclear pyknosis, cardiac myocytes may show sarcoplasmic necrosis with cavitation of their cytoplasm (myocytolysis) and invasion by macrophages. Foci of necrotic cardiac myocytes may be grouped at the edge of a scar, and myocytes isolated in scar tissue may be either hypertrophic or atrophic. Fibrosis, whether between or replacing myocytes, affects the myocardium of the left ventricle more than any other heart chamber, but both interstitial and perivascular fibrous tissues are increased in all four chambers.” The pattern of interstitial fibrosis is the same in DC as in hypertrophic cardiomyopathy,32 but, morphometrically, relatively more fibrosis is present in DC. 33There, it is most marked in the subendocardial zone, producing histologic findings consistent with ischemic damage.28,30,31 Fresh or organizing thrombi are commonly seen on the mural endocardium of the left or right ventricle. Endocardial plaques are caused either by fibrosis of mural thrombi or fibroelastosis and are sometimes continuous with myocardial scars. Calcification may be present in such scars, especially in the very young, and be extensive in radiographs.34 Interstitial fibrosis is described in endomyocardial biopsies of DC in childhood35 but was absent in another series, except in one case presumed to be healed myocarditis.” The presence of acute or subacute inflammation (edema, focal myocyte necrosis, an infiltrate of polymorphonuclear leukocytes, granulation tissue, and giant cells) supports a diagnosis of active myocarditis rather than DC, Nevertheless, one accepts the presence of occasional small collections of mononuclear leukocytes in some cases of DC. In two small series of endomyocardial biopsies done

were mainly lymphocytes and plasma cells with occasional granulocytes. Remaining cardiac myocytes were hyperplastic with large bizarre nuclei, some of which contained bodies suggestive of viral inclusions. The latter could not be found in electron microscopy studies. (A,B, Mason trichrome stain, scale = 100 pm.)

Pathology of Cardiomyopathies

to diagnose congestive heart failure in childhood (24 infants and children), no active myocarditis was In another series of endomyofound in any case. 35~36 cardial biopsies in infants and children with congestive heart failure, 18 cases (2 of whom had historical evidence of viral myocarditis) showed no active myocarditis.37 One of the 2 cases came to autopsy a month after biopsy; postmortem myocardial sections showed scattered round cell infiltration interpreted as consistent with myocarditis.37 Leatherbury et al. 38 found, by endomyocardial biopsy, 5 cases of myocarditis among 20 infants and children; 4 of the 5 myocarditis cases had been clinically diagnosed with DC. In series of endomyocardial biopsies in adults, the morphologic distinction between rapidly progressive cardiomyopathy and chronic active myocarditis was difficult and somewhat arbitrary.39,40 O’Connell40 reviewed the incidences of myocarditis reported in endomyocardial biopsies in reported series and found that they varied from 1% to 67%. Patient selection, a varying morphological threshold among pathologists in making a diagnosis of myocarditis,41 and sampling problems inherent in obtaining endomyocardial biopsies may explain the disparity. Serial biopsies in patients with myocarditis sometimes show a progressive decrease in acute inflammation and an increase in myocyte hypertrophy together with fibrosis.42 A lo-year-old boy who apparently had no symptoms until two weeks before death showed healing acute myocarditis at autopsy (Figure 2B) with a mature scar throughout the myocardium that contained residual hypertrophied cardiac myocytes as well as marked but patchy chronic inflammation and granulation tissue, This kind of case suggests that a proportion of DC cases evolve from myocarditis. Ultrastnrcturul Features. By electron microscopy, nonspecific features of both myocyte hypertrophy and degeneration are seen, including mitochondrial hyperplasia (with decreased size, abnormal cristae, dense inclusions), abnormal Z bands (widened, split, streaming, clumped), dilated and disorganized sarcoplasmic and transverse tubular systems, loss of myofibrils, increased lipid droplets, myelin figures, increased phagolysosomes (lipofuchsin, dense bodies), and increased glycogen (cytoplasmic, nuclear, and intramitochondrial).24,37~43-45 Five pairs of twins (mean age, 16) with familial DC had abnormal mitochondria with circular and stacked (“thumbmint”) cristae in cardiac mvocvtes but had

in Childhood

13

no loss of contractile filaments.45 In the same study, 62 cases of nonfamilial DC showed enlarged irregular nuclei, partial to total loss of myofilaments, and mitochondria that were smaller than normal.45 In a group of 20 DC cases classed as showing only mild dilation, loss of myofibrils was less than in usual DC cases.” The relative sparing of myofibrils in these subjects, mainly adult women with familial DC, did not correlate with a better prognosis.” Hypertrophic

Cardiomyopathy

Hypertrophic cardiomyopathy (HC), a familial disease transmitted by an autosomal dominant gene, may also occur sporadically.46 It is of interest that in the French Canadian family reported by Pare et al.47 in 1961, a linkage to chromosome 14, where the genes coding for the two heavy myosin chains are also located, has recently been demonstrated.48 Molecular methods of diagnosing HC may soon have application. 49Clinically, the diagnosis is now usually made by echocardiography. However, a pathologist may be skeptical of a diagnosis of hypertrophic cardiomyopathy that is not confirmed histologically. Asymmetric septal hypertrophy (ASH) may be caused by one of numerous conditions and imitate HCz3; these cases are the so called “pseudohypertrophic” cardiomyopathies. Although HC is seen ultrasonographically in the fetus” and in both infancy and childhood,28~51~52 most cases present after the pubertal growth spurt.53 Boys are affected twice as often as girls after puberty, but no sex difference is reported in younger subjects. It is a common cause of sudden death in young adults such as male athletes in their second or third decade.6,7,54 Children with HC may have no symptoms or present with symptoms due to left ventricular outflow obstruction. They may have severe hypertrophy and obstruction yet be asymptomatic.” In the newborn, clinical features are often atypical. Sudden death is rare in infants and young children,53 who present with cyanosis and congestive heart failure; the right ventricular outflow may be obstructed rather than the left.28,52Figure 3 shows the anatomic equivalent of biventricular outflow tract obstruction in the heart of a 4-month-old boy who died in 1964 of “idiopathic cardiomegaly.” This heart was recovered from storage and sectioned in the coronal plane for this photograph; extensive microscopic sections confirmed the diagnosis of HC. Gross Pathology. Infantile and childhood cases

14

Progress in Pediatric Cardiology

FIGURE 3. Hypertrophic cardiomyopathy in early infancy. (A) Photograph of the heart of a 4-month-old boy who died in 1964. The specimen was recently bisected in the long axis for this view, revealing marked left ventricular hypertrophy with accenfuafion in the distal septum (1.6-cm wide, see line). The heart weighed 91 g (four times more than expected). The septum burged into the outflow tracts of both ventricles (arrowheads on right outflow tract, mirror image). The infant had cyanotic heart failure from birth and infundibular pulmonic stenosis from 3 months (diagnosed at a second cardiac catheterization). Autopsy diagnosis in 1957 was “idiopathic myocardial hypertrophy, malnutrition, and Staphylococcal pneumonia”; multiple transverse ventricular sections taken recently showed the characteristic microscopic findings of hypertrophic cardiomyopathy. (B) Control heart from a 4-month-old male victim of sudden infant death syndrome, bisected in the long axis. Width of the basal septum was 0.4 cm. Cut surfaces ure complete (unlike A) because no sectioning or sampling was done until after this photograph was taken. Heart weight was 34 g {normal for body size). (Courtesy of Dr. D. G. Perrin, Toronto.)

at this center had hearts consistently weighing three times more than expected for body size. In adults and older adolescents, heart weight is increased (>SOO g and sometimes >lOOO g),24 correlating with the most extreme left ventricular hypertrophy 56 The septal and parietal echocardiographically. bands in the right ventricle are very prominent and may give a pathologist opening a heart the first clue about the diagnosis. Left ventricular thickness is increased with thickened trabeculae and massive papillary muscles, reducing the left ventricular cavity to a slit. The heart usually shows marked concentric left ventricular hypertrophy, often with a disproportionate thickening of the subaortic interventricular septum, so that the smooth-surfaced septum bulges into the left ventricular outflow tract. A ratio of 3:2 (1.5) between the thickened septum and the left ventricular free wall is consistent with a clinical diagnosis of ASH.51,57 In infantile HC cases, the ratio exceeds 1.3 by 2 years of age.52 Severest degrees of hypertrophy and septal thickening are more common in younger (postadolescent) subjects than in older cases.58,59 Severe outflow tract obstruction during life may correlate best with a postero-basal free left ventricular wall as thick as the septum. 51*56In some HC families, affected subjects show either concentric left ventricular hypertrophy or ASH.53,60 In cases with marked ASH, sclerosis of the aortic surface of the anterior mitral valve leaflet may be seen together with a mirror-image patch of endocardial thickening on the bulging septal muscle (Figure 4). Also, the chordae and adjacent head of the anterior papillary muscle may be involved in this sclerotic patch, which is a very specific gross marker of HC. The sclerosis is due to forcible contact of the outflow surface of the anterior mitral leaflet with the smooth septum during systolic ejection of blood from the ventricle, induced by a Venturi effect.61 Such sclerotic plaques are seen in the majority of adult cases and may also be present in children.= Systolic anterior motion of the mitral valve also causes mitral regurgitation, which may be associated with endocardial thickening in the left atrium caused by the abnormal jet of regurgitant blood. True organic obstruction, as distinct from functional obstructionconnected withventuri forces, is said to be present especially in those cases with local hypertrophy affecting midseptum or distal septum, the so-called apical hypertrophy first de-

Pathology

FIGURE

4. Hypertrophic

cardiomyopathy.

ventricular

outflow

old woman

with hypertrophic

died suddenly

while running; marked

The sclerotic

patch

cusp mirrors

the shape

This finding stenosis”

below

who

the heart weighed septal

aortic

mitral leaflet.

of the “muscular

and is due to functional

420 g

hypertrophy.

the right coronary

of the anterior

is a hallmark

a 20-year-

cardiomyopathy

asymmetric

outflow

15

in Childhood

The left

tract in the heart from

and showed

of Cardiomyopathies

subaortic tract ob-

struction.

FIGURE

5. Hypertrophic

restrictive

Left ventricle

mimicking and outflow

tract in the heart from

an II-year-old

sented

heart only 10 days before

with congestive

death and who died from diac catheterization

thy. The heart weighed expected) cardial

338 g (three

and moderately

thickening

times more

in the outflow

hypertrophied, Microscopic

sections

dium

septum

pertrophic

cardiomyopathy. of pathologists

ventricular

section

den deaths, apparent

because

in standard

tion regions

tract. Both showed

extending

in cardiac sections

a complete

deaths,

the diagnostic

or longitudinal

into of hy-

This case underlines retaining

particularly

morphology

of atrioventricular sections

a

myocar-

this led to the final diagnosis

importance

hy-

and lined by endo-

and disarrayed

in the interventricular

than

with mild endo-

large zone of hypertrophied both free walls;

Car-

cardiomyopa-

was concentrically

dilated,

especially

cardial fibroelastosis.

fibrillation.

restrictive

and the left ventricle

pertrophied

boy who pre-

ventricular

showed

atria were dilated,

scribed in Japan. 59r62We have not seen this pattern in childhood cases of HC. With the increased resistance of the hypertrophied left ventricle to diastolic filling, the mitral ring and the left atrium become relatively dilated. At a later stage, right heart chambers may be dilated, consistent with left heart failure. The left ventricle may dilate late in the natural history of the disease, probably because the hypertrophied and disarrayed left ventricular myocardium becomes scarred. Such HC cases may develop clinical features of DC or even restrictive cardiomyopathy. Figure 5 shows the dilated left ventricle of an llyear-old boy with HC who died only 10 days after onset of symptoms and in whom cardiologic investigations revealed typical features of a restrictive cardiomyopathy. Indeed, in children with HC, including those who die suddenly with no previous symptoms of heart disease, it is not uncommon to find a heart that has the gross morphology of a case of DC, with endocardial thickening and subendocardial pallor but with no distinctive gross bulging of the septal wall. In such cases, the diagnosis of HC is made by

cardiomyopathy

cardiomyopathy.

the transsudis not junc-

of papillary

muscles.

microscopic examination of transverse sections of the interventricular septum and may come as a surprise. It is important in such cases to retain sufficient cardiac muscle for microscopic assessment of myocardial disarray; at least an entire transventricular slice should be kept in addition to the usual samples from all four chambers. As indicated above, subvalvular outflow tract obstruction of the right ventricle may occur also, usually in infants and children.28,52 It appears to be due to distal septal hypertrophy encroaching on and distorting the infundibulum. Right outflow

16

Progress in Pediatric

tract obstruction (Figure 3) may be as great as or greater than left-sided obstruction in early infancy. 53,63This is in keeping with right ventricular dominance in the normal fetal heart.64 (The ratio of septal thickness to free wall thickness in a normal fetal heart may be as high as 2 at midgestation, and declines gradually to 1.5 by the time of birth.@) Mirror-image sclerosis of the right ventricular septal wall and outflow surface of the anterior tricuspid leaflet is extremely rare in our experience. Histopathology. The microscopic feature that appears characteristic for the disease is extensive disarray or disorganization of cardiac myocytes.65-b7 Because some cases of familial HC show disarray but not left ventricular hypertrophy,@,69 one must infer that the microscopic abnormality is the cardinal diagnostic feature of HC. Figure 6 shows myocardial disarray in a transverse section of the interventricular septum from the hypertrophied heart with ASH of a 12-year-old boy who died suddenly while riding a bicycle. Disarray is seen in the same distribution as hypertrophy, being most evident in the middle circularly running layers of the interventricular septum. That the HC gene defect is expressed in the developing heart is evidenced by disarray observed in newborn cases.28,52 Hence, disarray represents disordered histogenesis and is, therefore, a dysplasia; this term was first applied in 1961.47 The term “hamartoma” has also been applied to the abnormal myocardial organization seen in HC.54 Pathologists using those terms clearly recognized the large, well-demarcated zone of hypertrophied and disorganized myocardium that has since been mapped and quantitated in numerous cases. Microscopically, cardiac myocyte hypertrophy and disarray are present in a well-defined zone located centrally in the interventricular septum in infants dying of HC (Figure 7), demonstrating that the gene defect acts on the developing heart, at least in some cases. 28,52In considering the pathogenesis of HC, the opinion that ASH represents a failure of regression of a normal fetal pattern overlooks the fact that only minor volumes of fetal myocardium in the normally developing septum are disarrayed. It is possible that, as well as being disorganized and hypertrophied, the zone of abnormal myocardium is also hyperplastic, as suggested by studies of cell counts across the septum.70,n Hyperplasia of heart muscle cells implies onset during fetal life because

Cardiology

FIGURE 6. Hypertrophic cardiomyopathy. Microscopic section (oriented transversely) of the interventricular septum in a case of hypertrophic cardiomyopathy shows disorganized hypertrophied cardiac myocytes (disarray) with a whorled pattern. Note fascicles cut in transverse section above and below admixed with longitudinally cut fuscicles centrally. The heart weighed 380 g (three times more than expected) and showed asymmetric septal hypertrophy. This 12year-old boy died suddenly while riding a bicycle; a brother had died suddenly at the same age. (Hematoxylin-eosin stain, scale = 100 pm.)

cardiac myocyte proliferation normally ceases at birth.71 The disordered or disorganized myocardial architecture demonstrates loss of the normal parallel arrangement, increased side branching, and frequent side-to-side junctions (Figure 6). The disarrayed fascicles are located centrally within the septum, where >50% of the myocytes may be affected; they often extend into the middle layers of the left ventricular free wall, particularly the anterior wall. Myocyte disarray is associated with interstitial fibrosis and is much less obvious in longitudinal than in transverse ventricular sections67,72; it seems emphasized in connective tissue stains. Also, it is more obvious in thick than thin sections.” Transverse sections are vital if disarray is to be discerned, mapped, and quantitated (Figures 6 and 7). Several different patterns of disarray are described,” with some of these variations possibly due to patchy replacement fibrosis. Because of its distribution, disarrayed myocardium may not be sampled in an endomyocardial biopsy. It is easy to recognize dis-

Pathology of Cardiomyopathies

B FIGURE 7. Hypertrophic cardiomyopathy in early infancy. (A) Transverse section of the posterior interventricular septum (posterior descending coronary artery, above left; intertrabecular sinuses of right ventricle, above right) shows marked myocardial hypertrophy and disarray as well as enlarged intramyocardial coronary arteries (arrowheads). This 4month-old girl died of congestive heart failure present since birth. At 1 month, echocardiography showed asymmetric septal hypertrophy; the septum was l-cm thick. At autopsy, the heart weighed 80 g (four times more than expected). (B) Control heart section, in the same orientation as A, from the heart of a I-monthold boy who died of ventricular fibrillation. A chaotic atria1 rhythm had been present since birth and an endomyocardial biopsy was done four weeks before death; its scar is identified (arrow). At autopsy the heart weighed 50 g (two times more than expected) because of concentric left ventricular hypertrophy. Myocardial fascicles are normally arranged; compare with A, in which all of the myocardium except at the

in Childhood

17

array when the pattern is florid, but less easy, in hematoxylin-eosin-stained sections, if not as florid, Such sections stained by connective tissue stains are usefu1 in defining the latter cases. Although not unique to HC, the pattern and extent of disarrayed myocardium found in that condition is so characteristic it is virtually pathognomonic. 65-b7Disarray is seen in both obstructive and nonobstructive forms of the disease.66 If quantitative studies are done, the volume of disarrayed myocardium is likely to exceed 30 % , compared to a maximum of 5 % seen in various kinds of abnormal hearts.65 Maron and RobertP emphasize that a nonparallel arrangement of cardiac myocytes should not be considered as disarray if they are found in areas where cells normally converge at an acute angle, for example, at or near the junction of interventricular septum with the left and right ventricular free walls, within trabeculae, within or at the edges of scarred areas, at points of convergence of major muscle fascicles, or adjacent to interstitial spaces containing blood vessels. Foci of disorganized cardiac myocytes showing disarray are also found occasionally in both developing and adult hearts, and more frequently in hypertrophied hearts.65,74 Also, such changes occur in hearts with a variety of congenital cardiac malformations.65,74 Degenerating muscle cells may be seen in sections from hearts with HC and are sometimes associated with focal collections of mononuclear inflammatory cells. Contraction band necrosis is noted occasionally.30 Dilated lymphatic channels are also prominent in the myocardium. Intramural coronary arteries are increased in size and number and have thickened walls and narrowed lumens.75,76Abnormally thick-walled intramyocardial arteries are also present in infantile HC cases.25*75The vascular changes may reflect poor coronary bIood flow during diastole. On the other hand, they may represent a vascular response to myocardial hypertrophy. Because intramyocardial coronary arteries are enlarged in the hypertrophied zone of disarrayed myocardium even in infantile cases of HC (Figure 7A), we believe that the vascular changes are reactive. The clinical observation of progression to left

top shows marked disorganization of the fascicles. (A,B, hematoxylin-eosin stain, scale = 1000 am)

18

Progress in Pediatric Cardiology

ventricular dilation and congestive heart failure in some HC cases correlates with subendocardial ischemit scarring. 76,77The clinical progression of HC to DC has also been noted in childhood cases.78 Ultrastructural Features. By transmission electron microscopy, affected cardiac myocytes are much hypertrophied, with a commensurate increase in the contractile apparatus (sarcomeres), energy-producing organelles (mitochondria), and energy stores (glycogen, lipid) .24*43,79 Myofibrils and myofilaments within individual cells are disorganized, with markedly thickened and disarrayed Z bands; large irregular intercalated discs are readily found. The pattern of hypertrophied sarcomeres is disarrayed, with abrupt splitting, transverse bridging, and incorporation into the contractile apparatus of adjacent cells. In addition, features of hypertrophy and nonspecific degeneration are common. By scanning electron microscopy, the myocytes are disarrayed in three dimensions. Instead of streaming in parallel fascicles and connecting to adjacent cells at each end, they connect at sides and form loops and ring forms.80 Morphology after Myomecromy. If medical treatment fails or a severe subaortic pressure gradient is demonstrated, patients are often treated surgically by ventricular myomectomy.55~s9~81The resection necessarily damages branches of the left bundle of His and may produce a ventricular septal defect as an acute complication. We have received myomectomy specimens in surgical pathology that include a healed scar from a previous myomectomy. At autopsy, a healed myomectomy site is seen as a saucer-shaped depression lined by scarred endomyocardium in the smooth septum. The resected specimen shows cardiac myocyte hypertrophy and fibrosis but may not show myocardial disarray. The surgical procedure effectively relieves the outflow tract obstruction and usually cures the related mitral regurgitation. However, it does not prevent progressive fibrosis from developing in the myocardium nor subsequent sudden death. Conditions That Simulate Hypertrophic Cardiomyopathy. ASH, demonstrated by echocardiography, may occur in many conditions that cause left ventricular hypertrophy. The association has been mistaken for HC and the findings have erroneously been used to explain the pathogenesis of HC. Such cases of “pseudohypertrophic cardiomyopathy” occur at any age. Some are prevalent in in-

fancy and childhood. For example, ASH is seen by ultrasound examination of the fetus of a diabetic mother.*2 It may also be present, usually transiently, in the somatically overgrown infant born to a diabetic mother. 83,&4 Fetuses with Rh hemolytic disease may develop ASH,& while ACTH therapy for infantile seizures86,87and steroid therapySB also induce it. ASH is described in infants with an islet cell adenoma of the pancreas,89 with BeckwithWiedermann syndrome, QO and with diozoxide therapy for hyperinsulinemic hypoglycemia.” The condition may develop in older children and adults with endocrine diseases.92-95 Some inborn metabolic errors induce ASH, with or without left ventricular outflow obstruction.96 They include Pompe’s disease,97,9s Fabry’s disease,99 and mitochondrial myopathies.‘OOJO’ We note in some reports of greatly enlarged hearts with or without ASH caused by inborn metabolic errors that the myocardium is hypocontractile. We note, too, that the authors of those studies do not interpret the hearts as showing HC.‘oz,‘03 ASH may be the predominant cardiac finding in Friedreich’s ataxia,lo4J05 the multiple Lentiginoses (Leopard) syndrome,‘06J07 and in Noonan’s syndrome.‘D8-“0 In a study of 12 children, 6 had HC and 6 (Pompe, Noonan, Friedreich, and Lentiginoses cases) had “secondary hypertrophic cardiomyopathy .“*l* ASH or “hypertrophic cardiomyopathy” is described in cases of neurofibromatosis,“2 Marfan syndrome,‘13 myotonic dystrophy,“4 and Swyer syndrome.l15 Not surprisingly, ASH is observed with cardiac malformations and tumors.“6-‘39 We emphasize that, histologically, disarrayed myocardium is not present in the hearts of subjects with pseudohypertrophic cardiomyopathy that come to autopsy, apart from small zones normally seen at any age.65-67This means that adequate morphological studies must be done to document the extent of disarray and correlate it with gross findings before anyone accepts that heart diseases associated with ASH are truly caused by HC. Regrettably, this has not been done for the majority of conditions claimed to be associated with this disease; in fact, many reports do not include adequate, or indeed any, histopathology. Restrictive

Cardiomyopathy

Restrictive cardiomyopathy (RC), also called nondilated or infiltrative cardiomyopathy, affects both

Pathology

of Cardiomyopathies

sexes and all ages. It is less common than either DC or HC. Familial cases of RC are reported rarely.‘20,‘21 The defect in compliance in this form of cardiomyopathy resembles that seen in HC, but the heart shows no significant left ventricular hypertrophy. Some cases with RC have clinical features that overlap with either DC or HC. Cardiological investigations may demonstrate a reduced ventricular chamber size due to endomyocardial scarring or mural thrombosis. Indeed, the apical chamber is reduced or lost in the most common variety, endomyocardial fibrosis (see below), accounting for the term “restrictive-obliterative” cardiomyopathy. Pathology. The morphologic correlate of a reduced diastolic compliance is a gross or microscopic finding that explains stiffening of the myocardium. The latter may be induced by a splinting effect of endocardial or endomyocardial scarring (e .g . , due to endocardial fibroelastosis or endomyocardial fibrosis) that may be obvious on gross examination, or by a myocardial infiltrate (whether benign or malignant) that splints individual cardiac myocytes and may only be demonstrable histologically. Such interstitial and intracellular infiltrates have in common the property of constraining the motion of cardiac myocytes. Nonneoplastic infiltrates may be intercellular (e.g., fibrosis, amyloid, glycosaminoglycans) or intracellular (e.g., siderosis, stored metabolites). Of the three types of cardiomyopathy, RC is the most likely to be caused by diseases that have a specific morphology and so be defined by endomyocardial biopsy or at autopsy. However, many cases are associated with degrees of interstitial fibrosis, producing a nonspecific pattern as described in childhood cases.122r123Some patients diagnosed with RC during life prove, at biopsy or autopsy, to have only myocyte hypertrophy and interstitial fibrosis. 122Congenitally hypoplastic and dysplastic ventricular myocardium is also reported to cause RC.1Z4,125In some autopsy cases, microscopy of transverse sections of the interventricular septum identifies HC (Figure 5).

MORPHOLOGIC FEATURES OF CARDIOMYOPATHIES ASSOCIATED WITH INDIVIDUAL DISORDERS Dysrhythmias Dysrhythmias are a common complication and often a presenting feature in many types of cardiomy-

in Childhood

19

opathy, particularly those of familial variety (e.g., Kugelberg-Welander syndrome,‘26 ectodermal dysplasia127). Myotonic dystrophy (see below) is a prime example of a familial muscular dystrophy with an abnormal cardiac conduction. Cardiac conduction appears more important than cardiac muscle problems in some families with familial heart muscle disease.‘28 Conditions associated with heart block leading to DC include the prolonged QT syndrome129,‘30 and mitochondrial myopathy with ragged red fibers (chronic progressive external ophthalmoplegia or Kearns-Sayre disease).‘31,‘32 One must remember that dysrhythmias cause sudden death in DC, HC, and right ventricular cardiomyopathies. 6-*2 Dysrhythmias may also be a cause of de novo congestive heart failure, with recovery from failure once the abnormal rhythm reverts to normal.*33-137 Chronic supraventricular tachycardia in infants and children is sometimes investigated by endomyocardial biopsy.‘35**37 Figure 7B shows scarring at the site of a right ventricular endomyocardial biopsy (done four weeks before death) because of a chaotic atria1 rhythm present since birth in a 4-month-old infant with heart failure. The left ventricle showed marked concentric hypertrophy, with a heart weight 1.9 times greater than expected for body size. A clinical diagnosis of HC, based on echocardiographic finding of ASH, had been made at 3 weeks of age, but microscopic examination of the interventricular septum did not show any disarrayed myocardium (Figure 7B), thus disproving the clinical diagnosis. Infective Agents Associated With Dilated Cardiomyopathy Serial biopsies have shown, in a single subject, evolution from an acute myocarditis to DC.*’ This suggests that some cases of DC start with an acute inflammation; it does not prove that this progression was caused by a viral infection. Similarly, a healing myocarditis found at autopsy (Figure 2B) suggests that some cases of DC evolve from an acute myocarditis. Viruslike particles are sometimes observed in endomyocardial biopsies from children37 but have not been proven as virions, as is now feasible by either immunoelectron microscopy or in situ hybridization techniques. Some studies have failed to identify viruslike particles in either DC or myocarditis.31 Others, using polymerase chain reaction technology,

20

Progress in Pediatric Cardiology

have identified coxsackie B viral DNA in some studies of patients with either DC or active or healed myocarditis, but other studies have been negative.‘38-‘43 Thus the relationship between viral myocarditis and DC is not clear cut. A DC occurs in acquired immunodeficiency syndrome (AIDS) cases144-147and HIV has been identiHowever, it is not yet fied in cardiac myocytes. 148,149 certain whether the DC in AIDS is due to HIV, the numerous other pathogens that may infect the heart in AIDS, or the drugs used in its treatment.15’*151 Lyme disease is thought to cause DC by an autoimmune mechanism similar to that postulated in Chagas myocarditis.‘52 The borrelia that causes Lyme disease have been seen in silver-stained sections of heart muscle.‘53 Nutritional Deficiencies Associated With Dilated Cardiomyopathy Nutritional deficiencies, such as thiamine or selenium deficiency, are associated with DC that has no specific morphologic features. Wet (shoshin) beriberi occurs in teenage children in Japan who eat only “junk” food. 154Beriberi may also develop in children on chronic hemodialysis or extreme dietary restrictions imposed to treat a metabolic error. Selenium deficiency is thought responsible for Keshan cardiomyopathy, common in northeast China.155 This cardiomyopathy also occurs occasionally in children fed parenterally.‘56 We saw a grossly hypertrophied and dilated heart in a 3-year-old child with prolidase deficiency whose diet for many weeks before death consisted solely of carbohydrates; retrospective analyses after death revealed both thiamine and selenium deficiencies in life.

Drugs and Cardiotoxins Associated With DC The chemotherapeutic agents used to treat cancer in children include some that separately or synergistically cause a “toxic” cardiomyopathy that leads to a DC. For example, the anthracyclines are enzyme poisons with dose-dependent toxic effects; they may cause death in congestive heart failure.‘57-1S9 Doxorubicin is the archetypical agent that damages the heart in this fashion. Cardiac myocyte degeneration, death, and replacement by fibrosis are attended by myocardial hypertrophy.22,159 However, in endomyocardial biopsies from two leukemic children studied four years after anthracyclineinduced congestive heart failure, myocardial hy-

pertrophy was present without any interstitial fitherapy alone can brosis. 160 Cyclophosphamide also induce cardiomyopathy; it also appears to accentuate anthracycline-induced cardiac damage.161 Radiation, too, acts synergistically with antineoplastic drugs to damage the heart, probably by damaging intramyocardial blood vessels and so causing ischemia.‘57,162T’“3 Catecholamines appear to induce “stress cardiomyopathy” seen in cases of sudden death’& and also in DC, as is evident from cases reported in young patients with pheochromocytoma.165 Contraction band necrosis is a direct result of drug/hormone overdose166; the associated cardiomyopathy presumably results from myocardial damage and subsequent healing. Chloroquine, used to treat collagen vascular diseases and malaria, causes DC. By electron microscopy, characteristic zebra bodies have been seen in myocytes in this condition.‘67,‘68 Familial Neurological, Neuromuscular, and Skeletal Muscle Diseases Many familial neurological, neuromuscular, and myopathic diseases affect the heart. Some, such as myotonic dystrophy, particularly affect the conduction system. Most are associated with DC but some, notably Friedreich’s ataxia, may imitate HC. A kindred with familial DC is reported also to have weakness of proximal skeletal muscles.169 Morphologic abnormalities in biopsied skeletal muscles are described in cardiomyopathy cases.‘70f1n Friedreich’s ataxia may present with either diffuse (concentric) hypertrophy or asymmetric septal hypertrophy resembling HC.‘“,lo5 The microscopic findings are nonspecific, however, with degeneration, fibrosis, and fatty replacement.172,173 Some cases of Friedreich’s ataxia present with DC.‘74,‘75 Abetalipoproteinemia (Bassen-Kornweig disease) resembles Friedreich’s ataxia in its neurological lesions. It is also associated with myocardial fibrosis and congestive heart failure.176 Refsum disease, an inborn disease of phytanic acid metabolism, is associated with marked cardiac hypertrophy and a tendency to sudden death. Morphologically, enlarged cardiac myocytes appear empty, with loss of cross striations; Purkinje cells appear to be especially affected.‘77,17* Subepicardial scars may affect the postero-basal wall of the left ventricle in Duchenne’s muscular

Pathology

of Cardiomyopathies

dystrophy.*79 Such scars correlate well with the distinctive electrocardiogram seen in Duchenne’s dystrophy patients and female carriers.180,18* Cardiac biopsies from four Duchenne cases, done before cardiac disease was apparent clinically, showed multiple ultrastructural abnormalities including mitochondrial hyperplasia and increased residual bodies.“’ In our experience in a few childhood cases of DC in Duchenne’s or limb-girdle muscular dystrophy, patchy diffuse fibrosis but no localized scarring was present in the left ventricle. Figure 8 shows the heart from a 7-year-old boy with limb-girdle dystrophy who developed severe congestive heart failure (left ventricular ejection fraction 36%) four months after diagnosis of the muscular dystrophy. A cardiac biopsy showed myocardial fibrosis but no inflammation. This was confirmed at autopsy two months later, when the heart weighed 1.7 times the expected heart weight for body size. Myotonic dystrophy is prominently associated with conduction defects with or without DC; patients may die suddenly of a dysrhythmia.‘79J83-1e6 Severe myocardial dysfunction is rare and morphological findings are nonspecific, with increased interstitial fibrous tissue, fatty infiltration, and myofibrillar degeneration.‘85,‘87 Familial myopathies such as centronuclear,‘88 multicore, and nemaline rod myopathy1W,‘91 may affect the myocardium but are usually predominant in skeletal muscle. Patients with a nemaline rod myopathy whose skeletal muscle disease is subclinical occasionally present with a DC.‘92 Other cases of cardiomyopathy are associated with myopathy and neurologic abnormalities. They are often lethal in newborns and affect multiple siblings. They are difficult to classify.‘93-‘95 Mitochondrial myopathies (or enzymopathies) are presumably transmitted via maternal mitochondrial DNA and often affect the myocardium, causing an enlarged heart with poor contractility. Cardiac myocytes are diffusely swollen and granular, and their sarcomeres are dispersed, but not replaced, by granular sarcoplasm. Mitochondrial hyperplasia may also be a reactive change in cardiac myocytes, as is appreciated in cases of DC studied ultrastructurally.44,45 Many different enzyme defects are known in the mitochondrial membrane respiratory chain. Any one may cause failures of oxidative metabolism and contractility. Mitochondrial enzymopathies can af-

in Childhood

21

A

FIGURE

8. Dilated cardiomyopathy

muscular

dystrophy.

right ventricles limb-girdle before

death)

dystrophy

and dilated before

endocardial

Subendocardial

fibroelastosis

subendocardial

and patchy

pallor

together

myocardium.

were

in the left

to a thin layer of with diffuse

microscopic

scarring

Focal mural

the septal wall of the right ventricle nized thrombi.

(diagnosed

are seen in the right

was due microscopically

stitial fibrosis

boy with

six months

All heart chambers

thrombi

with

left and

(diagnosed

cardiomyopathy

death).

and organizing

atria1 appendage. ventricle

associated

of the opened

of the heart of a 7-year-old

muscular

two months dilated

Views

interin the

plaques

on

were due to orga-

22

Progress in Pediatric Cardiology

feet the myocardium predominantly (rather than skeletal muscle and liver), causing a marked hypertrophy that simulates HC196-199;some cases with these enzymopathies also have congenital cataracts.100,101*197,19 Cardiac myocyte mitochondria in such conditions may show ultrastructural abnormalities such as ring shapes.196”m Hyperglycinemia syndrome, a defect in isoleucine metabolism, may be associated with DC because of mitochondrial enzyme dysfunction.201 Systemic carnitine deficiency (lipid storage myopathy) may affect only skeletal muscle or occur as a systemic disease when it also affects myocardium and liver.202-205Morphologically, affected tissues merely show parenchymal fatty change, a nonspecific finding. Endocardial fibroelastosis in a stillborn, newborn, or young child may be due to camitine deficiency causing a DC.206*207The condition is diagnosed by biochemical assay of carnitine in serum and skeletal muscle. A secondary deficiency of carnitine may develop in genetic diseases of fatty acid oxidation because of defects in long- or medium-chain acyl coenzyme-A dehydrogenases. Such enzyme defects are associated with sudden death in infants, resembling either sudden infant death syndrome or Reye’s syndrome.208 Excessive fat droplets are present in the myocardium at autopsy and some cases have an associated DC.2w*210

CARDIOMYOPATHIES WITH A SPECIFIC MORPHOLOGY Endomyocardial Fibrosis Worldwide, endomyocardial fibrosis is the most common cause of RC. In the tropics, it affects adolescents and young adults who at some stage in their clinical course have an eosinophilia, presumably due to a parasitic infestation.211*212Young subjects of both sexes characteristically present with episodic heart failure progressing to death within months or years. 211~213-215 Children in Brazil are also affected by endomyocardial fibrosis; there the disease may be confused with Chagas’ myocarditis.216 The thick, white, plaquelike left ventricular endomyocardial scarring is confined to the inflow tract and is demarcated at the junction with the normal outflow tract by a ridge that may be calcified.211*213,214 The anterior mitral leaflet is not affected, but endomyocardial plaque involves the posterior mitral leaflet tethering it and causing mitral insufficiency.’ In the

right ventricle, endomyocardial scarring is more patchy, but the right ventricular apex is often obliterated and the outflow tract dilated.214 Both atria tend to be hugely dilated. Microscopically, the thickened endocardium shows hyaline scar and myxoid connective tissue, with organizing fibrin on its luminal surface.211,213 Focal necrosis of endocardial collagen is seen in the early stages, and is followed by scarring.217 Calcification and even ossification may be found in the endomyocardial scar. 218If any are present, eosinophils occur in the granulation tissue layer that replaces the necrotic collagen. Superficial to this, endocardium is thickened by stellate mesenchymal cells set in a ground substance most abundant in the earliest cases. It evolves gradually into dense white scar tissue containing variable amounts of elastin.211 Stellate zones of subendocardial myocardial necrosis are seen in early cases,211 and scarring extends irregularly into the superficial myocardium to about a third of its depth. The scarring is related to vessels that communicate with the ventricular chamber but not to intramyocardial coronary vessels.217 Such fibrous septae may reach the epicardium focally.’ Elastosis may develop in the thickened endocardium in the outflow tracts of either ventricle, secondary to jetstream blood flow. Endomyocardial Fibrosis with Eosinophilia Endomyocardial fibrosis with eosinophilia is rare in western countries and may have or depend on a similar pathogenesis as the tropical disease.219,220 Like endomyocardial fibrosis, it causes RC. It usually occurs in older subjects, affecting males more often than females,’ but some cases are reported in childhood.221 Subjects usually have a disease marked by eosinophilia. This may be reactive to a parasitic infestationz4 or be neoplastic, for example, eosinophilic or myeloblastic leukemia.222 The pathology of endomyocardial fibrosis in North American subjects closely resembles that in the more common tropical disease. Nevertheless, mural endocardium may be more diffusely involved, with spread to heart valves and a higher risk of embolization, a rare complication in the tropical disease. Roberts and Ferrans24 described the hearts of eight North American males aged 13 to 52, all of whom had eosinophilia; five had eosinophilic leukemia. Hearts were mildly hypertrophied and dilated, with dense fibrous endomyocardial scars devoid of elas-

Pathology of Cardiomyopathies

FIGURE 9. Endocardial fibroelastosis due to global ischemia. A thick layer of endocardial fibroelastosis lines the left ventricle in the heart of an II-month-old girl with anomalous origin of the left coronary artery from the pulmonary trunk. Note that black-stained elastic fibers are also present in myocardial scars, separated from the endocardium by a zone of cardiac myocytes that show vacuolar degeneration. The cause of ventricular dilation in such cases is global ischemia due to a “run off” of oxygenated blood from the right coronary artery, via collaterals to the left and then to the pulmonary artery. (Movat pentachrome stain, scale = 100pm.j

tic tissue and, in some instances, covered by mural thrombus. Infective endocarditis was a frequent complication. Only a few eosinophils were seen in the thickened endocardium. In the same study, hearts from 24 subjects from Uganda with endomyocardial fibrosis showed very similar gross and microscopic features. Eosinophils or their degradation products are believed to cause both endomyocardial fibrosis and granulomatous myocardial necrosis (“eosinophilic abscesses”).223~224 Endocardial

Fibroelastosis

Endocardial fibroelastosis (EFE) is seen in the very young, especially the fetus and newborn, and has a very characteristic gross appearance. The affected heart chamber is diffusely lined by a “sugar icing” that coats trabeculae and occludes the openings of intertrabecular sinuses.‘78 Microscopically, the endocardium is thickened by fibrous tissue containing elastin fibers (Figure 9). Whether the elastin is produced by fibroblasts or smooth muscle cells, or

in Childhood

23

both, is not known, but a layer of smooth muscle is present throughout the normal endocardium and is clearly visible in EFE (Figure 1OC). The elastin fibers are much thicker in congenital than in postnatally acquired cases.225 The clinical pattern associated with EFE is usually a DC but may be a RC. Presumably, the difference in clinical manifestations is related to the thickness of fibroelastosis and the degree of ventricular dilation. Most cases of diffuse EFE in newborn hearts (in the absence of a cardiac malformation such as hypoplastic left heart syndrome) are associated with left ventricular dilation, but the ventricle may be contracted in rare cases. Evolution of a contracted-form EFE was observed by ultrasonography in a fetus with a stenotic bicuspid aortic valve; the left ventricle appeared dilated at midgestation and became contracted during the 20 weeks before delivery.226 We agree with Lurie227 that EFE is not a unique disease. Lurie suggests it is “a reaction to stress”; we prefer the term “stretch” to “stress” because EFE appears to represent a nonspecific reaction to increased ventricular wall tension in a growing heart, a reaction that is far more marked in the very young perhaps because young tissues produce more abundant elastic tissue. Alternatively, it might reflect reaction to a DC that is more rapid and severe because it affects a growing heart. The most extreme cases of EFE are seen in the fetus, whether caused by a DC or aortic atresia in hypoplastic left heart syndrome. In infancy, global ischemic damage due to anomalous origin of the left coronary artery from the pulmonary trunk causes severe EFE.228Figure 9 shows such a case, an infant with an anterolateral myocardial infarct as well as a dilated left ventricle with diffuse EFE. Not only is elastin laid down in the stretched endocardium, but it occurs in myocardial interstitial fibrosis.229 EFE is observed echocardiographically in the fetus with DCz30 It is less common in childhood DC but may be seen at any age.231*232We have seen diffuse left ventricular EFE in the hearts, examined at autopsy, of two brothers with familial DC, both of whom died in the sixth decade. In the literature, familial cases of EFE occur in subjects with familial DC.233-235Consanguinity of parents and the condition occurring in monozygous twins suggest a pattern of autosomal recessive inheritance.2” In some familial DC sibships, only the younger members

24

Progress in Pediatric Cardiology

FIGURE 10. Familial dilated cardiomyopathy with endocardial fibroelastosis. (A) The heart of a Is-month-old boy with this condition. The ventricles are transected in their short axis to show marked endocardial fibroelastosis in the dilated left ventricle, best appreciated between the papillary muscles (right side). A similar change in the right ventricle is barely visible but is microscopically (C). A brother died at 4 months with a cardioiogic diagnosis of congenital endocardial fibroelastosis but no autopsy was done; the parents are first cousins. (B) An endomyocardial biopsy done at 3 months of age showed interstitial fibrosis but no inflammation or endocardial fibroelastosis. (Masson trichrome stain, scale = 100 urn.) (C) At autopsy (one year after biopsy) the right ventricle showed a thin layer of endocardial fibroelastosis histologically, as well as myocyte hypertrophy and interstitial fibrosis. Note the layer of smooth muscle (arrowhead) in the endocardium, with delicate elastic fibrils within the yellow-stained endocardium. (Resorchin/fuchsin-hematoxylin/phloxine/saffron stain, scale = 100 urn.)

show EFE,236and then sometimes only microscopically.u7 Figure 10 shows familial DC with EFE in the heart of an infant boy, the product of a consanguinous marriage. Many different gene defects cause familial DC and induce EFE during intrauterine life. An inborn metabolic error with this capability, systemic carnitine deficiency, is known. 206*207 Also, an infant with a familial mitochondrial myopathy had EFE on en-

domyocardial biopsy. 36 EFE is also observed in hearts affected by storage diseases such as glycogenosisu8 and mucopolysaccharidosis, Type I (Hurler type) .239*240 In a retrospective morphologic study of autopsy cases, acute myocarditis was frequently associated with childhood EFE, suggesting that myocarditis (presumably viral) was the cause of ventricular dilatation with consequent EFE.“’ Parvovirus (the

Pathology of Cardiomyopathies

in Childhood

25

FIGURE 11. Dilated cardiomyopathy associated with iron storage. (A, B) Myocardial siderosis in the heart of a 1%year-old boy with /I-thalassemia treated with numerous transfusions. The boy died of cardiac arrest after chronic congestive heart failure. The heart was markedly enlarged, with all chambers dilated; the myocardium was the characteristic rusty brown produced by siderosis. Microscopically, golden hemosiderin pigment is seen in cardiac myocytes and in scar macrophages, the latter seen best just above the scale bar in A. In longitudinal section @), the pigment within myocytes lies at the nuclear poles. The left ventricle showed extensive interstitial and replacement fibrosis. (Hematoxylin/ phloxine/saffron stain, scale = 100 pm.) (C) Pseudohypertrophic cardiomyopathy in a case of Pompe’s disease. Marked concentric left ventricular thickening in this heart from a case of Pompe’s disease (male, 5 months old) is due to marked glycogen storage within cardiac myocytes. The heart weighed 157g (4.2 times more than expected). In this form of glycogenosis (type Ila) the storage glycogen is, ultrastructurally, of B type occuring free in the sarcoplasm. Cardiac involvement in Pompe’s diseases leads to death in early infancy. (See Figure 12A.)

fifth exanthem, erythema infectiosum) was thought to have caused fatal chronic myocarditis with associated EFE in an infant,242 and may also cause a similar disease in puppies.243 In the only case of parvovirus B19 infection we studied, the macerated hydropic fetus had the characteristic pink nuclear inclusion bodies in circulating erythroblasts within intramyocardial blood vessels but had no myocarditis (or EFE). Hydrops in such cases may be due to extreme anemia rather than myocarditis. We have seen biventricular EFE in the congenital prolonged QT syndrome; this has been recorded previously. 244Heart block underlies EFE in some

heart block metabolic myopathies. 207 Congenital due to destruction of the fetal conduction system by anti-R0 and/or anti-La IgG antibodies from the mother in cases of maternal collagen vascular disease such as lupus erythematosus is also associated with congenital EFE. 245-249We believe that, in all dysrhythmia-associated congenital EFE cases, ventricular dilation (stretch) provokes EFE. Cardiomyopathy Copper

Storage

Associated

With Iron or

in the Myocardium

Siderosis, seen in the myocardium in congenital anemias and hereditary hemochromatosis treated

Progress in Pediatric Cardiology

26

A

B

C

FIGURE 12. Miscellaneous cardiomyopathies. (A) In Pompe’s disease in this 9month-old boy, the cardiac myocytes are uniformly enlarged and their myofilaments are displaced peripherally by clear zones of sarcoplasm. The clear zones correspond with positiuity in periodic acid-Schifi stain (diastase sensitive) and, ultrastructurally, with sarcoplasmic /3 glycogen. (J3) Oncocytic cardiomyopathy in a 15month-old girl shows focal transformation of cardiac myocytes into oncocytes (pale rounded cells). Ultrastructurally, the granularity is due to mitochondrial hyperplasia; sarcomeres are absent in affected cells. This change is thought to be hamartomatous in type, analogous to cardiac rhabdomyomatosis, and is associated with lethal dysrhythmias. (C) In mitochondrial cardiomyopathy in a l-year-old girl, cardiac myocytes are uniformly enlarged and diffusely granular because of mitochondrial hyperplasia. Many different defects of respiratory chain enzymes may cause mitochondrial cardiomyopathy. It must be differentiated from the mitochondrial hyperplasia seen as a nonspecific reaction in dilated cardiomyopathy and the focal transformation of cardiac myocytes seen in oncocytic cardiomyopathy. (A, 8, C, hematoxylin-eosin stain, scale = 100 urn.)

with blood transfusions, is associated with dilated cardiomyopathy in both childhood and adult life.250-252In congenital anemias, reticuloendothelial iron storage precedes myocardial siderosis. Cardiac myocyte dysfunction develops early in congenital anemias treated with blood transfusion and in juvenile cases of hemochromatosis.251 As in hereditary hemochromatosis,253-256 excessive iron storage in cardiac myocytes eventually leads to DCz5* or, rarely, to RC .255,256 In severe cardiac siderosis, the heart is rusty brown. Microscopically, hemosiderin accumulation in cardiac myocytes, particularly in the perinuclear region, is associated with varying degrees of cellular degeneration and replacement fibrosis (Figure llA, B). Ultrastructurally, cardiac myocytes contain abundant siderosomes mainly in the peri-

nuclear region. The degree of siderosis is greater in ventricles than atria and in working myocardium than in the conduction system.253,254Although cardiac involvement may be overshadowed by iron storage in other organs, severe cardiac siderosis causes intractable heart failure.253 If thalassemia, sickle cell anemia or other hemoglobinopathies, or a congenital or acquired hemolytic anemia underlies the cardiac siderosis, the anemia will potentiate ischemic myocardial damage. Abnormal red cells (e.g., sickle or target cells, spherocytes, or acanthocytes) may be observed in microscopic sections of the heart. In all iron storage conditions, the cardiomyopathy may resolve if iron is leached by venesection or chelator therapy. Copper storage is seen in cardiac myocytes in Wilson’s disease and the heart may show interstitial

Pathology of Cardiomyopathies in Childhood

or replacement fibrosis. Congestive heart failure and sudden death occur in this disease, but cardiac morphological changes do not correlate well with tissue levels of copper.257,258 Specific Cardiomyopathies due to Inborn Errors of Metabolism Many storage diseases affect the myocardium.259 Abnormal metabolite deposits in cardiac myocytes may be accompanied by storage in endocardium and/or cardiac connective tissue. Depending on the metabolite, the site, and amount stored, an affected subject may manifest cardiac problems caused by valvular and/or myocardial storage. As is usual with inborn errors, infantile onset tends to be fatal in early life because of generalized involvement and particularly neurological involvement. The morphology of the stored metabolite is specific, but diagnosis is usually made without need to examine myocardium microscopically or ultrastructurally. Pompe’s disease (Type IIa glycogenosis), an autosomal recessive disease with infantile onset, presents a pseudohypertrophic pattern (Figures llC, 12A).96,97 Other glycogenoses sometimes affect the Gaucher’s disease, an autosomyocardium. 238~26(F263 ma1 recessive disease with infantile, childhood, and adult onset subtypes, may present with RC.264 Cases of GM1 gangliosidosis, mucopolysaccharidosis, and mucolipidosis are also reported with storage in cardiac myocytes.102~‘03~240~258~265~266 Fabry’s disease, a sex-linked storage disease, presents in adult life; myocardial involvement may be an isolated phenomenon in some cases.267.268 Oncocytic Cardiomyopathy Oncocytic cardiomyopathy is a rare condition that is possibly hamartomatous. It is usually seen in infant girls with tachyarrhythmia and/or sudden death (Figure 12B). Autopsy cases reported in the literature had extensive multifocal lesions composed of granular eosinophilic polygonal cardiac myocytes that lacked sarcomeres.269,270 Several reports confuse it with mitochondrial cardiomyopathies.198,271s2nThe morphology is distinctive, however, because oncocytic change in cardiac myocytes is always focal or multifocal, whereas mitochondrial cardiomyopathy demonstrates a diffuse mitochondrial hyperplasia (Figure 12C). The oncocytes replace the conduction system as well as working myocardium.2”~270In addition to dysrhythmia (most

27

often, a supraventricular tachycardia), subjects commonly show Wolff-Parkinson-White syndrome.273 Accessory atrioventricular connections composed of oncocytic cells have been demonstrated histologically. 273~274 Three subjects survived over three years following surgical treatment of arrhythmogenic foci in infancy.z75 Myocardial Hamartomatous, Dysplastic, and Cytomegalic Lesions These are mentioned because lesions may be multifocal, associated with dysrhythmia, and cause outflow tract obstruction. Such lesions may be found in endomyocardial biopsies. Cardiac rhabdomyomas (congenital glycogen tumors) are commonly multifocal and associated with tuberous sclerosis; other cases, including patients with large intracavitary lesions obstructing blood flow, do not have skin lesions of tuberous sclerosis.276 Affected myocytes are enormously enlarged because of glycogen in the cytoplasm, giving the characteristic “spider cell” appearance seen by light microscopy. The lesions appear grossly as tumors or may affect the myocardium diffusely. They are most prevalent in the very young but are also seen in older children.276,277Whether single or multiple, they may be an incidental finding or present as a mass obstructing a ventricular outflow tract.“8.119.276 Cardiac fibroma, which is more often a solitary than multifocal lesion, is also thought to be hamartomatous. It, too, may present as an obstructive mass but is also associated with arrhythmias.“78 The myocardium of one or both ventricles may be hyperplastic, hypertrophied (with or without reduced chamber size), and/or dysplastic (disorganized cardiac myocytes), reminiscent of the embryonic spongy myocardium.‘24,‘25,279 Focal cardiac myocyte hypertrophy or cytomegaly is a rare change seen in newborn hearts, sometimes associated with Beckwith-Wiedemann syndrome and/or dysrhythmia.2s0~282

RIGHT VENTRICULAR CARDIOMYOPATHIES It is likely that arrhythmogenic right ventricular cardiomyopathy (“dysplasia”) and parchment right ventricle (see below) are manifestations of a single disease spectrum. Possibly, they represent autosoma1 dominant and recessive forms of the same familial disease.9,28J Parchment right ventricle affects

28

Progress in Pediatric Cardiology

multiple siblings in some families284-285but is not reported in succeeding generations. Thus, an autosomal recessive transmission seems most likely. The majority of familial cases of arrhythmogenic right ventricular cardiomyopathy appear to be of autosomal dominant transmission,1b*286,287 but 14 familial (probable autosomal recessive) cases had clinical and morphological features similar to those of parchment right ventricle.283 Arrhythmogenic right ventricular cardiomyopathy may also be related to familial DC. Two siblings with arrhythmogenic right ventricular cardiomyopathy were identified clinically among the relatives of 12 probands with familial DC.288 An association of ectodermal dysplasia with both arrhythmogenic right ventricular cardiomyopathy and DC has been described.289 Arrhythmogenic

Right Ventricular

Cardiomyopathy

This condition, with a dilated hypokinetic right ventricle associated with dysrhythmias, especially ventricular tachycardia, was called “dysplasia” in early reports.290 It is characterized morphologically by either partial or total atrophy and fibro-fatty replacement of the right ventricular myocardium. The source of the dysrhythmias (and with it a tendency to sudden death) is in the junctional areas between normal and “dysplastic” right ventricular myocardium. The latter is now thought to be an acquired progressive atrophy with fatty replacement of myocardium rather than a congenitally disorganized tissue pattern.8,16,291 Cases within a family show either fibrous or fatty right ventricular myocardium. Although rare, the condition appears to be much more common than parchment right ventricle (see below). Young subjects (boys three times more often than girls) present with palpitations, tachycardia, syncope, or sudden death.8r9,290-293 Three childhood cases were found in a review of children presenting with ventricular tachycardia.294 The heart shows atrophy and fatty or fibrous replacement of myocardium of the right ventricle, especially in the middle and outer layers of the wall. Such lesions are best demonstrated grossly by transilluminating the heart. Figure 13 shows fatty replacement of the myocardium in the right ventricular free wall from a lbyear-old boy who died suddenly while exercising; his uncle had also died

FIGURE 13. Right ventricular cardiomyopathy. A section of the free wall of the right ventricle of a 16year-old boy who died while playing tennis; an uncle had also died suddenly. The myocardium is extensively replaced by fat, with some preserved cardiac myocytes in the subendocardial zone (right) showing hypertrophy and surrounding fibrosis. Intertrabecular spaces are dilated, in keeping with marked dilation of the right ventricle; the scale overlies an intertrabecular sinus. A few subepicardial myocytes are preserved deep to the epicardial fat (left). (Hematoxylin-eosin stain, scale = 1000 am.) (Courtesy of Dr. Z. Maniowski, Mississauga, Ontario.)

suddenly. Residual subendocardial myocytes are least affected and may be hypertrophied. Although the entire free wall may be affected, the lesion is more often segmental, with aneurysm formation in the pulmonary infundibulum at the apex or in the proximal inferior wall; the interventricular septum is usually spared. The left ventricular free wall may be partially affected in some cases.295 Focal degeneration and necrosis of residual

Pathology of Cardiomyopathies

cardiac myocytes are seen together with a chronic inflammatory cell infiltrate in some cases, raising the possibility

of healing myocarditis.296J97

Parchment Right Ventricle Parchment right ventricle has been reported in approximately 20 cases since first described in the 1950~.‘~~,~~ It is much rarer than the recently described arrhythmogenic right ventricular cardiomyopathy. An alternate name is Uhl’s anomaly,300 but the literature contains reports of cases of a blighted right ventricle due to a cardiac malformation (e.g., pulmonary atresia with intact septum) called Uhl’s anomaly, so we prefer to use Osler’s original name of parchment right ventricle.298 In infants and young children, the condition is invariably associated with severe congestive heart failure and early death.301 The heart shows segmental or total absence of the right ventricular myocardium and, in reports that include histopathologic description and illustrations,301,302 the morphology appears identical to arrhythmogenic right ventricular cardiomyopathy. In some cases, parchment change also involves the left ventricular free wa11.2W,301 Histologically, thickened endocardial fibrous tissue containing endocardial smooth muscle cells (which may be hypertrophied) and epicardial fatty connective tissue are covered by visceral pericardium. A residual layer of hypertrophied myocytes may persist on the subendocardial side of the ventricular wall, and mural thrombi occur on the endocardium.N1 Parchment right ventricle must not be confused with an Ebstein malformation (atrialization of right ventricle) or with the blighted right ventricle seen in hypoplastic right heart syndrome.

ACKNOWLEDGMENT Mike Starr (Department of Pathology, The Hospital for Sick Children, Toronto) prepared the illustrations.

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