After a general introduction, the classification systems for cardiomyopathy are discussed. The main clinical types are discussed together with their variants. Hypertrophic, dilated, restrictive, non-compaction, mitochondrial and arrhythmogenic cardiomyopathy are all detailed and illustrated. Tables list the many genes associated with development of these cardiomyopathies. Rarer forms such as histiocytoid cardiomyopathy and mitogenic cardiomyopathy are also illustrated.
Cardiomyopathy has been defined as “a myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality” .
Cardiomyopathy in children is a cause of significant morbidity and mortality. It is a cause of sudden unexpected death in this age range and is the commonest indication for paediatric heart transplant. Heart muscle disease associated heart failure in children in the United Kingdom and Ireland has an incidence of 0.87/100 000 of the population less than 16 years of age, with a median age of presentation of 1 year . Although showing a similar spectrum of abnormalities to that found in adults, cardiomyopathy in children presents its own peculiarities. Some forms of cardiomyopathy are found exclusively in children, while others, common in adults, are scarcely seen in this population.
Clinically and pathologically, cardiomyopathies have traditionally been classified into three basic types according to their pathophysiology:
1. Dilated cardiomyopathy in which the left, or sometimes both, ventricles are dilated and show decreased systolic function as measured by decreased shortening fraction (normal greater than 30%) or decreased ejection fraction (normal greater than 55%) on echocardiography (Figure 7.1A).
2. Hypertrophic cardiomyopathy in which there is abnormal thickening of (principally) the left ventricular myocardium. There may be associated left ventricular outflow tract obstruction. There is disturbed systolic and diastolic myocardial function (Figure 7.1B).
3. Restrictive cardiomyopathy in which there is decreased diastolic ventricular filling often with atrial enlargement. There is abnormal relaxation of the ventricular myocardium with decreased ventricular compliance and consequent restriction of ventricular filling. This causes raised end diastolic pressure with secondary increase in atrial pressure and consequent atrial dilatation (Figure 7.1C).
(B) and restrictive
(C) phenotypes. Hypertrophic cardiomyopathy in its classical form shows marked increase in thickness in the left ventricular myocardium, sometimes with outlet obstruction. Dilated cardiomyopathy, while also showing increased muscle mass, is characterised by ventricular dilatation and frequently by ventricular endocardial fibroelastosis. The characteristic morphological feature of restrictive cardiomyopathy is the disproportionate dilatation of the atria.
There are currently two major clinical systems of classifying cardiomyopathy that, while agreeing on broad categories, differ in their details, most notably the inclusion or exclusion of ion channelopathies. These are the 2006 American Heart Association Classification  (Table 7.1) and the 2007 European Society of Cardiology classification (Table 7.2) . Both classifications recognise the traditional divisions and also take into account genetic (or familial) occurrence .
|Arrhythmogenic right ventricular cardiomyopathy|
|Left ventricular non-compaction|
|Conduction system disease|
|Stress provoked (takotsubo)|
|Infants of insulin-dependent diabetic mothers|
|Consequence of cancer therapy|
|Arrhythmogenic right ventricular cardiomyopathy|
|Unclassified Non-compacted myocardium|
|The categories are subdivided into familial (genetic) and non-familial types|
From the point of view of the pathologist, the morphology of the main types of cardiomyopathy tends to be distinctive, at least in their fully established forms, but there are areas of overlap; some forms of hypertrophic cardiomyopathy may, in their course, develop a dilated phenotype and most forms of dilated and restrictive cardiomyopathy show increased heart weight and histological evidence of myocyte hypertrophy. The aetiology of some cardiomyopathies is known, for example cardiomyopathy due to metabolic disorder or in association with muscular dystrophy or other skeletal muscle disease. Many forms of cardiomyopathy have a genetic or familial basis, but some forms of heart muscle disease are undoubtedly acquired as a result of exposure of susceptible individuals to infectious agents or toxins. There may be no factor to which the heart muscle disease is as yet attributable – so-called primary or idiopathic cardiomyopathy.
The European Society of Cardiology classification abandoned the distinction between primary and secondary cardiomyopathy and based their classification on groupings of specific morphological and functional phenotypes rather than putative pathophysiological mechanisms, which may be more suited to research purposes than to everyday practice, and did not include rhythm disturbance in their classification . They further subclassified their groups into familial and non-familial forms so as to raise awareness of genetic determinants of cardiomyopathies and to orient diagnostic tests. This classification is given in Table 7.2.
7.2 Hypertrophic Cardiomyopathy
This refers to disease of the heart muscle where the primary pathology is hypertrophy of the ventricular myocardium in the absence of a predisposing factor such as systemic hypertension or valvar heart disease. Often displaying asymmetrical involvement of the interventricular septum, this form of cardiomyopathy is sometimes associated with obstruction of the left ventricular outflow .
Grossly, the heart is enlarged, and the heart weight increased. There is hypertrophy of the ventricular myocardium. This may be confined to the septum but usually involves all of the left ventricle (Figure 7.2). Whorling of the hypertrophied myocardium may be evident macroscopically, as may fibrosis (Figure 7.3). An impact lesion of the left ventricular outflow endocardium, representing an area of white fibrous thickening of the septal endocardium corresponding to the shape of the anterior mitral valve leaflet and caused by abnormal impact of this leaflet on the hypertrophied septum, is commonly seen in adults (Figure 7.4), but is distinctly unusual in children. The septal thickening may cause obstruction to the left ventricular outflow (Figure 7.5). The histological hallmark of hypertrophic cardiomyopathy is myocyte disarray. Disarray consists of disorganised hypertrophied myocytes that have a splayed appearance. They lack the normal fascicular arrangement and run in various directions, often overlap and may have a whorled appearance (Figure 7.6). Fibrosis is a usual accompaniment (Figure 7.7). There are frequently dysplastic changes in the intramyocardial arteries (Figure 7.8). The disease was originally described in adolescents and was associated with a high frequency of sudden death. It can occur in neonates and even in utero. In paediatric practice it is an uncommon cause of death.
Figure 7.2 Hypertrophic cardiomyopathy. Adolescent male who died suddenly. The heart weighed 570 g. A section at mid-ventricular level through the ventricles shows concentric thickening of the left ventricular wall, most prominent in the interventricular septum. Streaks of pale fibrosis are seen in the anterior septum.
Figure 7.3 Hypertrophic cardiomyopathy. A close-up view of the anterior interventricular septum showing whorling of the muscle bundles. There is a focal increase in pale interstitial fibrous tissue. The endocardium is not thickened.
Figure 7.4 Hypertrophic cardiomyopathy. An adult male with hypertrophic cardiomyopathy. The left ventricular outflow tract has been opened to display the septum. On the septum, immediately beneath the aortic valve, is a triangular area of endocardial fibrosis, the apex of the triangle pointing towards the cardiac apex. The shape of this so-called impact lesion corresponds to that of the anterior leaflet of the mitral valve, which has been retracted to the right in this picture. This appearance is rarely, if ever, seen in children.
Figure 7.5 Hypertrophic cardiomyopathy outflow obstruction. A 12-year-old who died suddenly without any previous medical history of note. There is hypertrophic cardiomyopathy. This simulated long-axis view of the heart shows that there is disproportionate enlargement of the interventricular septum that bulges into the left ventricular outflow.
Figure 7.6 Hypertrophic cardiomyopathy – myocyte disarray. An area of myocyte disarray from the explanted heart of a 14-year-old girl who underwent heart transplant for hypertrophic cardiomyopathy. The myocytes are enlarged and splayed and run in multiple different directions imparting a swirling appearance. There is also an increase in interstitial tissue. Disarray is usually very prominent in hypertrophic cardiomyopathy and not difficult to discern.
Figure 7.7 Hypertrophic cardiomyopathy – fibrosis. Sudden death of a male age 23 years with MYBPC3 mutation positive hypertrophic cardiomyopathy. The heart showed hypertrophy, disarray and multiple foci of interstitial fibrosis. One such focus is illustrated. There are small scars in addition to fibrosis surrounding individual myocytes.
Figure 7.8 Hypertrophic cardiomyopathy – dysplastic intramyocardial artery. A myectomy specimen from obstructive cardiomyopathy stained with Masson’s trichrome stain. This small intramyocardial artery is dysplastic: its wall shows nodular proliferation of smooth muscle cells with fibrosis and the lumen is irregular in outline.
A family history of hypertrophic cardiomyopathy is present in about 60% of cases of childhood cardiomyopathy, and just over 50% show sarcomeric protein gene mutations . Most cases of idiopathic hypertrophic cardiomyopathy are now known to be caused by mutations in the genes encoding structural proteins of the contraction apparatus of the cardiac myocyte . To date, mutations in 26 genes coding principally for cardiac sarcomeric proteins have been claimed to cause hypertrophic cardiomyopathy [8–26], albeit the association for some of them is putative rather than confirmed (Table 7.3) . Of these, mutations in MYH7 and MYBPC3 account for 75% of cases with an identifiable pathogenic variant : the phenotype of mutations in both genes is indistinguishable . By no means have mutations in all these genes been demonstrated in cardiomyopathy in children. Among these genes are those encoding α- and β-myosin heavy chains, actin, tropomyosin and cardiac troponins T, C and I. It is also recognised that particular mutations may correlate with a particular phenotype and correspond with, for example, the degree of myocyte hypertrophy or the magnitude of the risk of sudden death . More recently, mutations in genes coding for proteins other than sarcomeric proteins have been identified. These genes code for proteins of the Z-disc, the sarcolemma or the sarcoplasmic reticulum [16–26].
|β-Myosin heavy chain||MYH7||14q12||8|
|α-Myosin heavy chain||MYH6||14q12||9|
|Cardiac α actin||ACTC1||15q14||10|
|Cardiac troponin C||TNNC1||3p21||12|
|Cardiac troponin I||TNNI3||19p13||13|
|Cardiac troponin T||TNNT2||1q32||11|
|Cardiac myosin binding protein C||MYBPC3||11p11||14|
|Regulatory myosin light chain||MYL2||12q23||15|
|Essential myosin light chain||MYL3||3p21||15|
|Cysteine and glycine-rich protein 3||CSRP3||11p15.1||16|
|Alpha actinin 2||ACTN2||1q43||17|
|LIM binding domain 3 protein||LDB3||10q23.2||17|
Although myocyte disarray is the defining histological hallmark of hypertrophic cardiomyopathy, it can occur in other settings. Myofibre disarray occurs in the normal heart at the junction of the free wall of the ventricles with the interventricular septum (Figure 7.9). The area involved is small, and disarray should not be seen in the normal heart in the interventricular septum or lateral ventricular walls. Myocyte disarray is present in the hypertrophy accompanying many forms of congenital heart disease, most notably hypoplastic left heart, where it is described in up to 80% of cases (Figure 4.42). Myocyte disarray may also be seen in restrictive cardiomyopathy. The muscle fibre hypertrophy with disarray in hypertrophic cardiomyopathy affects not just the ventricles but can also be found in the atrial myocardium (Figure 7.10). The identification of hypertrophic cardiomyopathy has important implications for other siblings and family members, and, where possible, genetic material should be obtained at autopsy to permit gene screening, as appropriate .
7.3 Other Cardiomyopathies with a Hypertrophic Phenotype
The hypertrophied left ventricular myocardium of hypertrophic cardiomyopathy is a phenotype, and diseases other than those caused by mutations in sarcomeric protein genes can present with a hypertrophic phenotype. A list of the commoner conditions is given in Table 7.4. Such diseases include Pompe disease (glycogen storage disease type II), mutations of the PRKAG2 gene, Danon disease and Anderson–Fabry disease. These conditions are treated at length in Chapter 10.
|Glycogen storage disease: Pompe, Danon PRKAG2|
|Infant of diabetic mother|
|Infant steroid administration|
7.3.1 Friedreich’s Ataxia
Friedreich’s ataxia is a rare autosomal recessive disorder characterised by spinocerebellar degeneration. It is caused by an unstable GAA trinucleotide repeat expansion (>120 repeats) in the first intron of both alleles of the frataxin gene on chromosome 9q13. Most cases that have cardiac involvement demonstrate concentric left ventricular hypertrophy, but dilated cardiomyopathy and electrical disturbance also occur . Pathologically there is myocyte hypertrophy with disarray and interstitial fibrosis, and deposition of calcium and iron in myocytes is described and there is focal inflammation . The condition tends to remain stable during childhood. The length of the trinucleotide repeats appears not to correlate with the severity of the cardiac disease .
7.3.2 Noonan’s Syndrome
Noonan’s syndrome is an autosomal dominant disease characterised by short stature, facial dysmorphism and cardiac defects. The most common cardiac defect is pulmonary stenosis occurring in about 50% of cases. Other cardiac defects include polyvalvar dysplasia . About 10% of patients have a hypertrophic cardiomyopathy . Germline mutations in the RAS mitogen-activated protein kinase (MAPK) pathway are involved in the pathogenesis of Noonan’s syndrome. About 45% of cases of Noonan’s syndrome are due to missense mutations in the PTPN11 gene on 12q24.1 . That gene encodes SHP-2, a protein tyrosine kinase that has multiple functions in signal transduction including signalling via the RAS MAPK pathway. Noonan’s syndrome-associated PTPN11 mutations are gain-of-function mutations that disrupt the activation–inactivation mechanism of SHP-2. Mutations in the genes encoding for other proteins in the RAS/MAPK pathway have been identified in those cases of Noonan’s syndrome that do not have PTPN11 mutations, namely SOS1, RAF1, MEK1 and KRAS. Hypertrophic cardiomyopathy is more frequently observed in patients with RAF1 mutations . Histologically there is myocyte disarray (Figure 7.11) .
(A) Infant aged 8 months with hypertrophic cardiomyopathy and polyvalvar dysplasia. The four-chamber view of the heart demonstrates the ventricular hypertrophy and the myxoid thickening of the atrioventricular valves. These appearances strongly suggest Noonan’s syndrome.
(B) A separate case – a section from the heart of one of twins with genetically proven Noonan’s syndrome. The myocardium shows hypertrophy and disarray.
Infants of diabetic mothers may develop myocardial hypertrophy identical to hypertrophic cardiomyopathy in the neonatal period . This cardiomyopathy is usually transient and resolves spontaneously. Hypertrophic cardiomyopathy is also described in infants who have received steroids for pulmonary immaturity or chronic lung disease ; again, this cardiomyopathy tends to be transitory but shows identical echocardiographic appearances and haemodynamics to idiopathic hypertrophic cardiomyopathy.
Mitochondrial cardiomyopathies in infancy frequently display a hypertrophic phenotype (Section 7.7).
7.4 Dilated Cardiomyopathy
This term denotes the phenotype of biventricular dilatation with atrial dilatation and reduced myocardial contractility. There may be associated conduction system disturbance, and in some cases there are extracardiac manifestations, most frequently skeletal myopathy, but also skin abnormalities, haematological disorders or hearing loss .
Pathologically, the histological features are not specific. There is histological evidence of myocardial hypertrophy and fibrosis . The heart is enlarged, sometimes markedly so (Figure 7.12), is dilated, has a globular shape (Figure 7.13) and the weight is increased. The muscular trabeculae, including the papillary muscles of the atrioventricular valves, appear stretched and thin. There is associated endocardial fibroelastosis of the left ventricle. The affected endocardium is opaque and white and may be up to several millimetres thick. The thickening affects the papillary muscles and extends into the inter-trabecular recesses (Figure 7.13). The right ventricle usually does not show significant endocardial fibrosis. There may be fibrosis of the myocardium – particularly the papillary muscles of the mitral valve. If there are multiple small foci of fibrosis scattered throughout the ventricles, especially in the younger child, the possibility of resolving myocarditis should be considered (Figure 7.14). The atria may show endocardial thickening. Mural thrombus may form in the atria or in the ventricles (Figure 7.15). If there has been treatment with a ventricular assist device there may be remodelling of the ventricle that may no longer be dilated and may even have normal dimensions: the endocardial fibrosis, however, persists (Figure 7.16). Histologically, the myocytes show nuclear enlargement and hyperchromasia and they are stretched, thin and wavy (Figure 7.17). Inflammatory cell infiltration is not usually a prominent feature, but scattered lymphocytes may be present. The presence of more than a few inflammatory cells suggests myocarditis, and appropriate samples need to be assessed for the presence of viruses (Figure 7.18). Mast cell numbers are increased in the interstitium  (Figure 7.19). The epicardium may show a chronic inflammatory cell infiltrate or fibrosis. Secondary degenerative changes are often present in the valves in the form of thickening of the leaflets. There is usually a considerable degree of interstitial myocardial fibrosis (Figure 7.17B). The intramyocardial vessels are usually normal, but in areas of dense scarring they may show intimal fibroelastic thickening. The endocardial fibroelastosis consists of dense laminar fibroelastic tissue that usually does not show increased vascularity or inflammatory cell infiltration (Figure 7.20). There may be smooth muscle hyperplasia in the endocardium.
Figure 7.13 Dilated cardiomyopathy. The same heart as in Figure 7.12, removed and opened showing the dilated left ventricular cavity with globular shape and the opaque, white thickening of the left ventricular endocardium.
(A) Three-month-old who underwent heart transplant for severe dilated cardiomyopathy post Enterovirus myocarditis and cardiac arrest. The four-chamber view shows a dilated left ventricle with extensive dystrophic calcification of the free wall of the left ventricle and upper interventricular septum. An incidental large blood cyst is present on the mitral valve leaflet.
(B) An 11-year-old with dilated cardiomyopathy. The explanted heart shows ventricular dilatation with thinning of the walls. The cut surface of the myocardium is blotchy caused by multiple scattered foci of fibrosis suggestive of healed myocarditis. No virus was recovered in this case.
Figure 7.15 Dilated cardiomyopathy – thrombus formation. Four-month old child who died of sepsis and cardiac failure after a prolonged hospital course. There is cardiomyopathy with bilateral ventricular dilatation and there is apical thrombus in both ventricles.
Figure 7.16 Dilated cardiomyopathy. Two-year-old child. Explanted heart with a cannula from a ventricular assist device in the left ventricular apex. The left ventricular cavity dimensions are near normal, but there is dense endocardial fibroelastic thickening. The heart weight was 165 g.
(A) Five-year-old with severe dilated cardiomyopathy. Biopsy shows muscle fibres that are elongated, wavy, stretched and thinned. There is considerable fine interstitial fibrosis. There is no significant inflammatory cell infiltrate.
(B) Masson-trichrome-stained section from the same case shows fibrotic thickening of the endocardium and fibrous tissue extending around individual atrophic myocytes.
Figure 7.18 Dilated cardiomyopathy post-myocarditis. Three-month-old who underwent heart transplant for dilated cardiomyopathy following Enterovirus myocarditis. A section from the left ventricular myocardium of the explanted heart shows foci of heavy lymphocytic infiltration. This degree of lymphocytic infiltration is not seen in idiopathic dilated cardiomyopathy and indicates an inflammatory aetiology for the cardiomyopathy.
Figure 7.19 Dilated cardiomyopathy: mast cells. Two-year-old boy with idiopathic dilated cardiomyopathy who underwent heart transplant. A section from the explanted heart showing interstitial fibrous tissue with at least three mast cells visible. Interstitial mast cell numbers are increased in dilated cardiomyopathy, in myocarditis and, indeed, in any condition leading to an increase in interstitial fibrous tissue.
Figure 7.20 Dilated cardiomyopathy. Explanted heart from a fifteen-year-old with idiopathic dilated cardiomyopathy. A high-power view of the thickened endocardium of the left ventricle. There is fibrous expansion of the tissue with numerous elastic fibres. In the centre there is a small nodule of smooth muscle cells. There is no inflammatory cell infiltration.
The dilated form of cardiomyopathy represents a phenotype and it has many causes . About one-third of patients with dilated cardiomyopathy have an affected first-degree relative . The most common mode of transmission of the familial forms is autosomal dominant, but recessive, X-linked and mitochondrial inheritance is also reported. There are more than 40 genes known to be mutated and they encode for proteins that have a wide range of unrelated functions including transcripts encoding sarcomeric contractile proteins, cytoskeletal proteins, nuclear membrane proteins and the dystrophin-associated glycoprotein complex . Table 7.5 lists genes, mutations in which have been associated with dilated cardiomyopathy [47–81]. It is intended to be indicative rather than definitively comprehensive.
|β-Myosin heavy chain||MYH7||14q12||50||Sarcomere|
|Cardiac ankyrin repeat protein (CARP)||ANKRD1||10q23||52||Intercalated disc|
|Cardiac LIM protein||CSRP3||11p15||47||Z-disc|
|Cardiac myosin binding protein C||MYBPC3||11p11||53||Sarcomere|
|Cardiac Na channel||SCN5A||3p22.2||54||Cell membrane|
|Cardiac troponin C||TNNC1||3p21||55||Sarcomere|
|Cardiac troponin I||TNNI3||19p13||56||Sarcomere|
|Cardiac troponin T||TNNT2||1q32||57||Sarcomere|
|Eyes absent homolog 4||EYA4||6q223||65||Nuclear|
|Laminin alpha 4||LAMA4||6q21||68|
|Muscle-restricted coiled coil||MURC||9q31.1||69|
|RNA-binding motif protein 20||RBM20||10q25.2||75, 76|
Mutations may occur in genes encoding sarcomeric proteins such as troponins T, C and I, actin, or β-myosin heavy chain . The mutations occur in regions affecting functionally different domains of the molecules from those occurring in hypertrophic cardiomyopathy.
Mutations may also occur in the myocyte cytoskeleton that connects the sarcomere to the sarcolemma. Such genes include those coding for δ-sarcoglycan , desmin , dystrophin , lamin , vinculin , Cypher/ZASP , cardiac LIM protein  and desmoplakin . Such mutations compromise the transmission of contractile force from the sarcomere to the extracellular matrix or impair the normal response of the sarcomere to stretching. Viral myocarditis may progress to dilated cardiomyopathy, and some forms of dilated cardiomyopathy yield virus on culture or polymerise chain reaction (PCR). It has been shown that enterovirus proteases cleave dystrophin in vitro . Mutations are described also in genes regulating transcription such as EYA4 . Mutations in the phospholamban gene are thought to cause dilated cardiomyopathy by inhibition of calcium uptake in the sarcoplasmic reticulum .
Rbm20-deficient rats and humans with RBM20 missense mutations share cardiomyopathy with fibrosis and arrhythmia with sudden death . Mutations in RBM20 cause a clinically aggressive form of dilated cardiomyopathy (DCM), with an increased risk of malignant ventricular arrhythmias (Figure 7.21) .
A specific form of infantile dilated cardiomyopathy has been described fairly recently, the defining feature of which is the presence of numerous myocyte mitotic figures. The condition has been termed mitogenic cardiomyopathy . The condition is as yet not fully characterised. The initial report lists five infants, all females, including two pairs of siblings, all of whom died in early infancy. They had no specific birth or neonatal problems and presented with general lethargy, decreased feeding, respiratory distress and cyanosis with signs of congestive cardiac failure. At post-mortem, the hearts were enlarged and heavy with dilated chambers, ventricles more so than atria, and mild to moderate endocardial fibroelastosis in all. Histologically there was prominent hypertrophic myofibre changes with elongated, enlarged and hyperchromatic nuclei, and increased mitotic activity with up to four mitotic figures per single high-power field (Figure 7.22A and B). Scattered atypical mitotic figures were present. There was a proliferation index of up to 20% (normal age matched less than 1%). Mutation in the Alstrom gene is described in at least some cases .
(A) One of a pair of siblings who died of dilated cardiomyopathy. The heart showed features of dilated cardiomyopathy including prominent endocardial fibroelastosis. There are at least three mitotic figures within this single high-power field of the myocardium.
(B) Her sister died some years later of dilated cardiomyopathy. A section of her myocardium shows at least four mitotic figures in this field.
The significance of these changes is not yet fully apparent, although mitotic figures should not be seen in the myocardium post-natally. The implication is that there is failure of the normal switching off of myocardial cell mitosis that should occur around the time of birth. I have seen approximately 10 cases of mitotic figures in the post-natal myocardium, many associated with cardiomyopathy, but at least one occurring in the setting of viral myocarditis.
Infants of exclusively breast-fed mothers may suffer vitamin D deficiency with development of rickets and may present with dilated cardiomyopathy, which, rarely, may be fatal (Figure 7.23). The condition resolves on administration of vitamin D [86–89]. In infants, hypocalcaemia is usually due to maternal vitamin D deficiency and is accompanied by compensatory hyperparathyroidism. In contrast, in adult patients, hypocalcaemic cardiomyopathy is usually a result of hypoparathyroidism, with or without concomitant vitamin D deficiency .