Sudden Death

Sudden death occurs most commonly in adolescents and young adults. ²⁵ Whilst initial descriptions of the natural history reported annual rates of sudden death from 3% to 6%, recent studies in adults revealed rates of 1% or less per year. ^5,26 Similarly, early studies of highly selected populations of children reported rates of sudden death ranging from 2% to 8% per year, ^27–29 but recent population-based reports from Australia ³⁰ and the United States ³¹ report an overall annual rate of sudden death of 1% to 1.5% per year beyond infancy.

Cardiac Failure

Whilst many children and teenagers with hypertrophic cardiomyopathy have few if any symptoms, presentation in infancy can be associated with severe and intractable cardiac failure. ^32–35 Some studies have suggested that presentation in infancy itself constitutes an unfavourable prognosis, ^33,35 but this finding is not consistent. ³⁴ Progression to an end-stage, or burnt-out, phase is a well-recognised complication, ^36–49 with a reported prevalence in up to one-sixth of adults. ^41,45,47 This end-stage is characterised by progressive left ventricular dilation, mural thinning, and systolic impairment. ⁵⁰ It is associated with a poor prognosis, ⁴⁷ with an overall rate of death of up to 11% per year. ⁴¹ In children, progression to the burnt-out phase is extremely rare, with only isolated reports. ^36,51 Progression to left ventricular systolic dysfunction and dilation may occur in a minority of patients with mitochondrial cardiomyopathies. ⁵²

Sarcomeric Protein Disease

Most individuals with non-syndromic hypertrophic cardiomyopathy have familial disease, inherited in an autosomal dominant manner. Genetic studies have shown that up to three-fifths of adults with the disease have mutations in one of at least 11 genes that encode the proteins of the cardiac sarcomere. These are the MYH7 gene, encoding for β-myosin heavy chain, and carried on chromosome 14; MTBPC3 encoding for myosin-binding protein C and carried on chromosome 11, TNNT2 encoding for cardiac troponin T and carried on chromosome 1; TNNI3 encoding for cardiac troponin I and carried on chromosome 19; TMP1 encoding α-tropomyosin and carried on chromosome 15; ACTC encoding α-cardiac actin and carried on chromosome 15; MYL3 encoding for essential myosin light chain and carried on chromosome 3; MYL2 encoding for regulatory myosin light chain and present on chromosome 12; TNNC1 encoding for cardiac troponin C and carried on chromosome 3; MYH6 encoding for α-myosin heavy chain and carried on chromosome 14 ^53–56 ; and TTN encoding for titin and carried on chromosome 2. ⁵⁷ There is considerable genetic heterogeneity, with over 400 different mutations identified to date, as well as marked variation in penetrance of the disease, and hence clinical expression. ⁵⁸ The mechanisms through which mutations in the genes result in the characteristic pathophysiological features are incompletely understood. It has been speculated that the phenotype results from reduced contractile function, but studies of myocytic function in patients who harbour mutations in the genes are inconsistent, with some mutations appearing to depress contractility whereas others enhance sensitivity to calcium and contractility. ⁵⁹

The majority of mutations have a dominant negative effect on sarcomeric function; in other words, the mutant protein is incorporated into the sarcomere, but its interaction with the normal wild-type protein disrupts normal sarcomeric assembly and function. Allelic heterogeneity may be explained by the effect of different mutations on the structure and function of the complete peptide. β-Myosin heavy chain, for example, consists of a globular head, an α-helical rod, and a hinge region. The globular head contains binding sites for ATPase and actin, as well as sites for interaction with regulatory and essential light chains in the region of the head-rod. Most mutations in the β-myosin gene are missense DNA nucleotide substitutions that change a single amino acid in the polypeptide sequence. The majority of disease-causing β-myosin heavy chain mutations are found in one of four locations. These are the actin-binding site, the nucleotide-binding pocket, a region in the hinge region adjacent to the binding site for two reactive thiols, and the α-helix close to the essential light chain interaction site. Depending on the position of the mutation, therefore, changes might be expected in ATPase activity, actin-myosin interaction, and protein conformation during contraction.

There is substantial variation in the expression of identical mutations, indicating that other genetic and possibly environmental factors influence expression of the disease. The effect of age is perhaps the best characterised factor, most patients developing electrocardiographic and echocardiographic manifestations of the disease after puberty and before the age of 30. Other modifying factors include gender, polymorphism of the genes regulating the renin-angiotensin-aldosterone system, and the occurrence of homozygosity and compound heterozygotes.

The importance of genetic mutations in children with hypertrophic cardiomyopathy is unknown. The observation that the development of left ventricular hypertrophy in individuals with familial disease often occurs during the period of somatic growth in adolescence ⁶⁰ has led to the suggestion that sarcomeric protein disease in very young children is rare. ²⁴ There have been no systematic studies, however, evaluating the prevalence of genetic mutations in children with the disease.

Noonan’s and LEOPARD Syndromes

Noonan’s syndrome is characterised by short stature, dysmorphic facies, skeletal malformations, and a webbed neck. ^61–63 Cardiac involvement is present in up to nine-tenths of patients with Noonan’s syndrome, most commonly as pulmonary stenosis, frequently secondary to a dysplastic valve, and hypertrophic cardiomyopathy. ⁶⁴ Some children present with congestive cardiac failure in infancy, which may be associated with biventricular hypertrophy and bilateral obstruction of the ventricular outflow tracts. ⁶⁴ The histological findings are indistinguishable from idiopathic hypertrophic cardiomyopathy. ⁶⁵ The syndrome is usually inherited as an autosomal dominant trait with variable penetrance and expression. Recently, mutations in the PTPN11 gene, encoding the protein tyrosine phosphatase SHP-2, a protein with a critical role in RAS-ERK-mediated intracellular signal transduction pathways controlling diverse developmental processes, ⁶⁶ have been shown to cause the syndrome. ⁶⁷ To date, at least 39 different mutations have been identified, accounting for approximately half of the cases. ⁶¹

LEOPARD syndrome (an acronym representing lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of the genitalia, retardation of growth, and deafness) shares many phenotypic features with Noonan’s syndrome. Recent studies have shown that most patients with LEOPARD syndrome also have mutations in the PTPN11 gene. ⁶⁸ Importantly, only up to one-tenth of individuals with mutations in the PTPN11 gene have hypertrophic cardiomyopathy. ^69,70

Other genes implicated in Noonan’s syndrome include SOS1 ⁷¹ , encoding a RAS-specific guanine nucleotide exchange factor, which accounts for up to three-tenths of cases ^72,73 ; KRAS, which encodes a GTP-binding protein in the RAS-ERK pathway, in less than one-twentieth of cases ⁷⁴ ; and RAF1, a downstream effector of RAS. ^75,76

Danon Disease

This is a lysosomal storage disorder characterised clinically by cardiomyopathy, skeletal myopathy, and developmental delay. It is an X-linked disorder caused by mutations in the gene encoding the lysosome-associated membrane protein-2 ⁷⁷ that result in intracytoplasmic accumulation of autophagic material and glycogen within vacuoles in cardiac and skeletal myocytes. ⁷⁸ Female carriers usually develop hypertrophic and dilated cardiomyopathy during adulthood, whereas males develop symptoms during childhood and adolescence. ⁷⁹ The prognosis is generally poor, with most patients dying of cardiac failure. Sudden cardiac death is reported, even in female carriers. ⁷⁹ Other features, which may aid in differentiating the condition clinically from idiopathic hypertrophic cardiomyopathy, include Wolff-Parkinson-White syndrome, elevated levels of creatine kinase in the serum, and retinitis pigmentosa. ⁸⁰

Adenosine Monophosphate–activated Protein Kinase Mutations

Mutations in the gene encoding the γ ₂ subunit of the adenosine monophosphate–activated protein kinase ⁸¹ can cause a syndrome of hypertrophic cardiomyopathy, abnormalities in conduction, and Wolff-Parkinson-White syndrome. Histologically, there is accumulation of glycogen within cardiac myocytes and conduction tissue. Many affected individuals have a skeletal myopathy, and biopsy of the skeletal muscles shows excess mitochondria and ragged red fibres. ⁸² Patients develop progressive conduction disease and left ventricular hypertrophy, with complete electrocardiographic expression by the age of 18 years. ⁸² Atrial arrhythmias are common. Survival in one study was 91% at a mean follow-up of 12 years, with disease-related deaths occurring secondary to thromboembolic stroke related to atrial fibrillation and sudden death. ⁸² Recent studies suggest that mutations of this gene account for no more than 1% of cases of hypertrophic cardiomyopathy. ⁸²

Mitochondrial Cardiomyopathies

Primary mitochondrial disorders are caused by sporadic or inherited mutations in nuclear or mitochondrial DNA that may be transmitted as autosomal dominant, autosomal recessive, X-linked, or maternal traits. The most frequent abnormalities occur in genes that encode the respiratory chain protein complexes, leading to impaired utilisation of oxygen and reduced production of energy. The clinical presentation of mitochondrial disease is variable in age at onset, symptoms, and range and severity of involvement of the different organs. Numerous case reports and small series have described cardiovascular abnormalities in patients with primary mitochondrial dysfunction, but data on the prevalence of cardiac disease is sparse, and mostly derived from experience in children. Cardiac involvement is a feature in up to two-fifths of mitochondrial encephalomyopathies, ⁸³ and usually takes the form of a hypertrophic cardiomyopathy, ⁸⁴ although other cardiomyopathies, including dilated and left ventricular non-compaction, are reported. ⁸³ Children with mitochondrial disease and cardiac involvement present earlier than those with non-cardiac disease ^83,84 and have a much worse prognosis, with one study reporting survival of no more than one-fifth at 16 years, compared with 95% for those without cardiac involvement. ⁸³ The cardiac phenotype is usually concentric left ventricular hypertrophy without obstruction of the outflow tract, and rapid progression to left ventricular dilation, systolic impairment, and cardiac failure. ^83,84 Sudden arrhythmic death has also been reported. ^83,84 Kearns-Sayre syndrome is a mitochondrial disorder comprising the triad of chronic progressive external ophthalmoplegia, retinitis pigmentosa, and atrioventricular block. ⁸⁵ Cardiac manifestations occur in over half the patients, and include syncope, congestive cardiac failure, and cardiac arrest. ⁸⁶ The conduction system is frequently affected, with rapid progression to complete heart block associated with death in up to one-fifth. ⁸⁷

Friedreich’s Ataxia

Friedreich’s ataxia is an autosomal recessive condition caused by mutations in the frataxin gene. Cardiac involvement is very common, and is most commonly, but not exclusively, characterised by concentric left ventricular hypertrophy without obstruction to the left ventricular outflow tract. ⁸⁸ Patients are usually asymptomatic, although progression to left ventricular dilation and cardiac failure is described. ⁸⁹ Rarely, children with Friedreich’s ataxia can present with left ventricular hypertrophy several years before the development of neurological signs. ⁸⁸ Treatment with the antioxidant idebenone appears to reduce the degree of left ventricular hypertrophy, ⁹⁰ but further studies are needed to assess the long-term effects.

Anderson-Fabry Disease

Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. The resultant enzymic deficiency causes progressive accumulation of glycosphingolipid in the skin, nervous system, kidneys, and heart. ⁹¹ Cardiac manifestations include progressive left ventricular hypertrophy, valvar disease, and abnormalities of conduction, with supraventricular and ventricular arrhythmias appearing after adolescence in males and females. ^91–94 Treatment with recombinant α-galactosidase A improves renal and neurological manifestations, as well as quality of life, but its effect on the cardiac manifestations is still under investigation. ⁹¹

Pompe’s Disease

Pompe’s disease, or acid maltase deficiency or glycogen storage disease IIa, is an autosomal recessive disorder with infantile, juvenile, and adult variants that differ with respect to age of onset, rate of progression, and extent of involvement of the tissues. The infantile and childhood forms are characterised by deposition of myocardial glycogen, massive cardiac hypertrophy, and cardiac failure. The infantile form presents in the first few months of life with severe skeletal muscular hypotonia, progressive weakness, cardiomegaly, hepatomegaly, and macroglossia, and is usually fatal before 2 years of age owing to cardiorespiratory failure. Obstruction of the left ventricular outflow tract occurs in one-twentieth of patients. ⁹⁵ The electrocardiogram typically shows broad high-voltage QRS complexes and ventricular pre-excitation. In the variants presenting in juveniles and adults, disease is usually limited to skeletal muscle, with a slowly progressive proximal myopathy and weakness of the respiratory muscles. Replacement with recombinant enzymes appears to cause regression of left ventricular hypertrophy in those with presentation during childhood, and is associated with improved survival. ⁹⁶

Infants of Diabetic Mothers

Infants of diabetic mothers can develop transient asymptomatic left ventricular hypertrophy ⁹⁷ that affects both ventricles, and generally resolves within 3 to 6 months. Rare reports of fatal hypertrophic cardiomyopathy in infants of diabetic mothers are described. ⁹⁸ The aetiology is unknown, but may relate to increased levels of maternal insulin-like growth factor. ⁹⁹

Macroscopic Features

In the common form of autosomal dominant hypertrophic cardiomyopathy, myocardial hypertrophy is usually asymmetric, affecting the ventricular septum more than the posterior or lateral walls of the left ventricle. ^100,101 Other patterns also occur, including concentric ( Fig. 49-1 ), mid-ventricular, sometimes associated with a left ventricular apical diverticulum, ¹⁰² and apical hypertrophy. ^103–105 Co-existent right ventricular hypertrophy is present in up to one-fifth of cases. ¹⁰⁰ The papillary muscles are often displaced anteriorly, contributing in one-quarter to systolic anterior motion in the resting state of the aortic, and in one-tenth, the mural, leaflets of the mitral valve. There is often an area of endocardial fibrosis on the septum beneath the aortic valve, caused by repeated contact with the aortic leaflet. ^100,101 The mitral valve itself is often structurally abnormal, with elongation of the aortic leaflet, an increased number of scallops in the mural leaflet, and occasional direct insertion of the papillary muscle into the ventricular surface of the aortic leaflet. ¹⁰⁶ Myocardial bridging of the anterior interventricular coronary artery has been observed in adults and children with hypertrophic cardiomyopathy, and may cause myocardial ischaemia. ^107,108

The gross pathological specimen shows concentric left ventricular hypertrophy in an 8-week-old infant with mitochondrial disease. (Courtesy of Dr Michael Ashworth, Great Ormond Street Hospital, London, United Kingdom.)

Microscopic Features

The histological hallmarks of the familial variant are the triad of myocytic hypertrophy, myocytic disarray, and interstitial fibrosis ( Fig. 49-2 ). ^100,101 Myocytic disarray is characterised by architectural disorganisation of the myocardium, with adjacent myocytes aligned obliquely or perpendicular to each other in association with increased interstitial collagen. ^100,101 The myofibrillary architecture within the myocyte itself is also disorganised, with loss of the normal parallel arrangement of the myofibrils. Although disarray occurs in many pathologies, the presence of extensive disarray, more than one-tenth of the ventricular myocardium, is thought to be a highly specific marker for hypertrophic cardiomyopathy. ^100,101 Small intramural coronary arteries are often dysplastic and narrowed due to mural thickening by hyperplasia of the smooth muscle cells. ¹⁰⁹

Histopathological slide of hypertrophic cardiomyopathy showing myocyte disarray and interstitial fibrosis.

(Courtesy of Dr Michael Ashworth, Great Ormond Street Hospital, London, United Kingdom.)

Diastolic Function

The major pathophysiological consequence of left ventricular hypertrophy is impairment of left ventricular diastolic properties. Diastolic dysfunction results from abnormalities in both the active component of actin and myosin dissociation in the early filling phase, and the passive properties of the ventricle that affect compliance. ^16,110–113 Prolonged or incomplete left ventricular relaxation results in a reduced rate and magnitude of rapid filling. This in turn leads to reduced left ventricular diastolic volume, reduced stroke volume, and altered diastolic relationships of pressure and volume. The net result is elevation of left ventricular end-diastolic pressures and symptoms of reduced exercise tolerance, dyspnoea, and pulmonary oedema.

Systolic Dysfunction

Global measures of left ventricular systolic function are often normal, but progression to left ventricular dilation and systolic impairment is a recognised complication in a subgroup of patients. Predicting which patients are at risk of developing end-stage disease remains a challenge, and the subject of ongoing research. Several studies have identified a number of markers associated with progression to systolic impairment. These include syncope, non-sustained ventricular tachycardia, an abnormal response of the blood pressure to exercise, ⁴⁷ young age at diagnosis, ^37,41 and severe microvascular dysfunction, as assessed by positron emission tomography. ¹¹⁴ A family history of end-stage disease may also be a useful predictor of left ventricular remodelling. ⁴¹ Several studies have identified increased left ventricular mural thickness ^37,47,48 and cavity dimensions, particularly an increased end-systolic dimension, ^41,47 as predictors of progression to left ventricular dilation and systolic impairment, although the predictive value of these and other markers remains to be evaluated in large prospective studies. Although case reports of end-stage disease in children are documented, ^36,115 progression to this phase in childhood is extremely rare. Whether onset of hypertrophic cardiomyopathy in infancy or early childhood predisposes individuals to developing end-stage disease is unknown.

Obstruction of the Left Ventricular Outflow Tract

Approximately one-quarter of children and adults with hypertrophic cardiomyopathy have obstructed left ventricular outflow tracts at rest. ^16,29,116 The problem is caused by contact between the aortic leaflet, and occasionally the mural leaflet, of the mitral valve and the ventricular septum. The most widely accepted explanation for this phenomenon is that septal hypertrophy and narrowing of the left ventricular outflow tract produce a zone of high velocity anterior to the mitral valve that causes its aortic leaflet to be sucked against the septum by the Venturi effect. This hypothesis does not explain a number of features associated with systolic anterior motion, in particular, the fact that it begins prior to opening of the aortic valve, and that it can occur in patients with little or no septal hypertrophy. Experimental and observational data suggests that anterior displacement of the papillary muscles and submitral apparatus are necessary to create sufficient slack in the leaflets to permit them to move forward in systole. The effect of enhancing contractility in this model is to increase the drag forces on the leaflet, thereby driving rather than sucking it into the septum.

Many patients without obstruction at rest have gradients that can be provoked by physiological and pharmacological interventions that diminish left ventricular end-diastolic volume or increase left ventricular contractility. Labile obstruction refers to the spontaneous appearance and disappearance of obstruction, while latent obstruction describes those gradients that are present only with provocation. The most commonly used techniques used to provoke obstruction are inhalation of amyl nitrate, the Valsalva manoeuvre, and administration of intravenous inotropes. Increasingly, upright exercise is used to provoke gradients in patients with exertional symptoms. ¹¹⁷ Obstruction causes acute reductions in cardiac output, elevated left ventricular filling pressures, and myocardial ischaemia. Corresponding symptoms include chest pain, exertional dyspnoea, presyncope, and syncope.

Arrhythmia

All arrhythmias increase in frequency with advancing age. In adults, atrial fibrillation is the commonest sustained arrhythmia, with an incidence of approximately 2% per year. ¹¹⁸ During follow-up, as many as one-quarter of patients develop paroxysmal or chronic atrial fibrillation, which is associated with increased risk of thromboembolic stroke and death from cardiac failure, but not with sudden death. ^5,118 Atrial fibrillation is rare in children and young adults, although paroxysms of haemodynamically compromising atrial fibrillation have been documented in individuals as young as 15 years. ¹¹⁹ Factors that increase the likelihood of atrial fibrillation include older age, worsening functional class, and left atrial enlargement as a result of an obstructed left ventricular outflow tract or severe diastolic left ventricular dysfunction. ¹¹⁸

The characteristic features of myocytic disarray and interstitial fibrosis seen in hypertrophic cardiomyopathy represent a potent substrate for ventricular arrhythmia. Furthermore, the presence of microvascular and coronary arterial abnormalities identified in some patients, and the haemodynamic alterations caused by the obstructed outflow tract, predispose patients to myocardial ischaemia, ^120–122 which is in itself a potential trigger for ventricular arrhythmias. In keeping with this, sudden arrhythmic death is the commonest mode of death, including in children and adolescents. ²⁵ Despite this, ventricular arrhythmia is rarely identified in life in children. ¹¹⁹ Isolated uniform ventricular extrasystoles are documented in up to three-tenths of children and adolescents, multi-form ectopics in one-tenth, and ventricular couplets in another tenth. Frequent ventricular extrasystoles, greater than 100 in 24 hours, however, are exceedingly rare. Furthermore, non-sustained ventricular tachycardia occurs in less than one-tenth of children and adolescents. ¹¹⁹ If present, it is a particularly poor prognostic indicator. ^27,29,123 Greater maximal left ventricular mural thickness and left atrial size may be associated with the development of non-sustained ventricular tachycardia. ¹²³

Patients that have been successfully resuscitated from sustained ventricular arrhythmias such as ventricular tachycardia or ventricular fibrillation are at a high risk of further events. ¹²⁴ Interrogation of tracings from implantable cardioverter-defibrillators preceding appropriate discharges for sustained ventricular arrhythmias demonstrates that ventricular fibrillation is often preceded by sinus tachycardia, atrial arrhythmia, and ventricular tachycardia. ^124,125 The mechanisms by which other tachyarrhythmias trigger ventricular fibrillation have not been fully elucidated, but myocardial ischaemia and abnormal vascular responses may play a role. ¹²⁴

Symptoms

Most individuals with hypertrophic cardiomyopathy have few, if any, symptoms. The initial diagnosis is often made as a result of family screening, following the incidental detection of a heart murmur or an abnormal electrocardiogram. Presentation in infancy can be associated with symptoms of cardiac failure, such as breathlessness, poor feeding, excessive sweating, and failure to thrive. ^{33–35,126,127} These symptoms usually occur in the presence of apparently normal left ventricular systolic function and are attributable to an obstructed outflow tract or to diastolic dysfunction.

In older children, the most common symptoms are dyspnoea and chest pain. Chest pain is commonly exertional, but may be atypical, and can also occur at rest or following large meals. Typically, there is considerable day-to-day variation in the amount of activity required to produce symptoms. ^27,28 Syncope is a relatively common symptom, for which there are multiple mechanisms, including obstruction of the left ventricular outflow tract, abnormal vascular responses, and atrial and ventricular arrhythmias. ^16,128,129 Unexplained or exertional syncope is associated with increased risk of sudden death in children and adolescents.

Physical Examination

General physical examination may provide important diagnostic clues in patients with associated syndromes or metabolic disorders. Clinical examination of the cardiovascular system is often normal, but in patients with obstruction of the left ventricular outflow tract, a number of typical features may be identified. The arterial pulse has a rapid upstroke and downstroke, resulting from rapid ejection during the initial phase of systole, followed by a sudden decrease in cardiac output during mid-systole. This is, occasionally, followed by a palpable reflected wave, resulting in a bisferiens pulse. Examination of the jugular venous pulsation may reveal a prominent a wave, caused by reduced right ventricular compliance. Palpation of the precordium may reveal a sustained, or double, apex beat, reflecting a palpable atrial impulse followed by left ventricular contraction. An additional late systolic impulse may rarely result in a triple apical impulse.

On auscultation, patients with the obstructive variant of hypertrophic cardiomyopathy have an ejection systolic murmur that is heard loudest at the left sternal edge, and which radiates to the right upper sternal edge and apex, but usually not to the carotid arteries or axilla. This murmur may be associated with a palpable precordial thrill. As the obstruction in hypertrophic cardiomyopathy is a dynamic phenomenon, the intensity of the murmur is increased by manoeuvres that reduce the preload or afterload, such as standing from a squatting position and the Valsalva manoeuvre. Most patients with obstruction of the left ventricular outflow tract also have mitral regurgitation, resulting from failure of coaptation of the leaflets during systolic anterior motion of the valve. This causes a pansystolic, high-frequency murmur at the apex, radiating to the axilla.

Electrocardiography

The resting 12-lead electrocardiogram is abnormal in up to 95% of individuals. A variety of patterns are recognised ( Fig. 49-3 ). The most common abnormalities include repolarisation abnormalities, pathological Q waves, most frequently in the inferolateral leads, and left atrial enlargement. Common patterns of abnormal repolarisation include inverted T waves and changes in the ST segments in leads I, aVL, V5, and V6, in leads II, III, and aVF, or in leads V1 to V4. Left-axis deviation, with a mean frontal QRS axis between −15 degrees and −90 degrees is common. ¹⁰ Intraventricular conduction delay is not uncommon, but bundle branch block, usually involving the left bundle, is infrequent. Voltage criterions for left ventricular hypertrophy alone are not specific for hypertrophic cardiomyopathy, and are often seen in normal, healthy teenagers and young adults. In infants, right ventricular hypertrophy is commonly found. Other recognised patterns include the presence of giant negative T waves in the mid-precordial leads, which are characteristic of hypertrophic cardiomyopathy localised to the distal portion of the left ventricle. ¹³⁰ It is not uncommon for the corrected QT interval to be slightly prolonged. Some patients have a short PR interval not associated with the Wolff-Parkinson-White syndrome. Atrioventricular conduction delay, including first-degree block, is rare except in particular subtypes, such as in association with PRKAG2 mutations and mitochondrial disease. ^131,132

Electrocardiographic patterns in hypertrophic cardiomyopathy. A shows a 12-lead ECG from a 12-year-old child with asymmetric septal hypertrophy. Note the pathological Q waves in leads II, III, aVF, V5, and V6, and voltage criterions for biventricular hypertrophy. B is a 12-lead tracing from an 8-year-old with severe hypertrophic obstructive cardiomyopathy, showing left ventricular hypertrophy and T wave inversion and ST segment abnormalities in leads I, aVL, and V4-V6. C is another 12-lead tracing, but from a 14-year-old with concentric left ventricular hypertrophy. It shows T wave inversion extending from V1 to V5, and deep Q waves in leads III and aVF. D is a 12-lead tracing from a young adult with apical hypertrophic cardiomyopathy. It shows widespread T wave inversion, with deep inverted T waves, particularly in the septal leads.

Echocardiography

The presence on echocardiography of a left ventricular mural thickness greater than two standard deviations above the corrected mean relative to body surface area in any myocardial segment, in the absence of any other cardiac or systemic disease capable of producing a similar degree of hypertrophy, is sufficient for the diagnosis. ⁵ The focus of early studies using M-mode interrogation was on the detection of asymmetrical septal hypertrophy, using a ratio between the diastolic thickness of the anterior septum and the left ventricular posterior wall of 1.3 to 1 as a diagnostic criterion. ¹³³ Such an increased ratio, however, is commonly found in normal neonates, and in children with congenital cardiac disease. ¹³⁴ The advent of cross sectional interrogation showed that any pattern of left ventricular hypertrophy is consistent with the diagnosis, including concentric equal hypertrophy across all segments of the left ventricle, eccentric hypertrophy with the lateral and posterior walls more affected than the septum, distal hypertrophy with the distal segments more affected than basal segments, and apical hypertrophy confined to the left ventricular apex ( Fig. 49-4 ). ^{14,104,135,136}

Echocardiographic patterns of hypertrophic cardiomyopathy. A shows a parasternal long-axis view of a 13-year-old with severe asymmetrical septal hypertrophy. The parasternal short-axis view of the same patient is shown in B C shows the parasternal short-axis view from a 12-year-old with concentric left ventricular hypertrophy. D is a parasternal short-axis view from a 14-year-old with an eccentric distribution of left ventricular hypertrophy.

Dynamic obstruction in the left ventricular outflow tract is associated with mid-systolic closure of the aortic valve, often associated with coarse fluttering of the aortic valve ( Fig. 49-5A ) on M-mode echocardiography. Obstruction of the left ventricular outflow tract can be detected using colour flow Doppler, and quantified using continuous-wave Doppler (see Fig. 49-5B and C ). Due to the dynamic nature of the obstruction of the left ventricular outflow tract, serial measurements of maximal gradients may not provide an accurate reflection of progression or stability. Surrogate measures of severity, such as left atrial dilation, should be documented. In some patients, systolic obliteration of the ventricular cavity may produce a high-velocity gradient in the mid-ventricle. Obstruction of the right ventricular outflow tract may be seen in infants, and in older children and adults with cardiomyopathy associated with Noonan’s syndrome and some metabolic disorders.

Echocardiographic features of left ventricular outflow tract obstruction. A shows an M-mode tracing of the aortic valve from a 5-year-old with severe obstructive hypertrophic cardiomyopathy, showing coarse fluttering and mid-systolic closure of the leaflets. B is another M-mode recording, but of the mitral valve from a 12-year-old with hypertrophic obstructive cardiomyopathy showing complete systolic anterior motion of the aortic mitral valvar leaflet. C is a continuous wave Doppler from the same patient, showing the characteristic waveform of the obstructed left ventricular outflow tract, in this case with a maximal velocity of nearly 5 m/s.

Most patients with systolic anterior motion of the mitral valve and obstruction of the left ventricular outflow tract have mitral regurgitation with a posteriorly directed jet, which can be detected using colour Doppler imaging. The severity of regurgitation correlates with the degree of obstruction in individual patients, but varies considerably between patients with obstruction of similar severity. The presence of complex mitral regurgitant jets, such as those directed anteriorly or centrally, should trigger a search for other valvar abnormalities, such as prolapse of leaflets.

Left ventricular global systolic function, as assessed from change in ventricular volume during the cardiac cycle, is typically increased. Regional and long-axis function is often reduced, and responses of cardiac output during exercise may be impaired. ^137–139 A small proportion of adults develop progressive thinning of the myocardium, associated with left ventricular systolic impairment and cavity dilation, but progression to this end-stage disease is rare in children.

Diastolic function is commonly assessed using pulsed wave Doppler to interrogate the mitral inflow and pulmonary veins, along with tissue Doppler imaging ( Fig. 49-6 ). Patients may have evidence of impaired relaxation as shown by E/A wave reversal and increased E-wave deceleration time on the Doppler interrogation of the mitral inflow, with a ratio of the systolic to the diastolic waves of greater than 1 on pulmonary vein Doppler, and the duration of the atrial reversal wave seen in the pulmonary veins less than the duration of the mitral inflow A wave (see Fig. 49-6 ). With worsening diastolic function, a pseudo-normal pattern is seen, with normalisation of the mitral inflow E/A ratio and prolongation of the E wave deceleration time, decreased pulmonary venous systolic velocity, increased pulmonary venous diastolic and atrial reversal velocities, pulmonary venous atrial reversal wave duration greater than mitral inflow A wave duration, and decreased velocity of the propagation slope on colour M-mode (see Fig. 49-6 ). In some patients, a restrictive phenotype is present, characterised by an increased mitral inflow E/A ratio, reduced E wave deceleration time, and increased pulmonary vein A reversal wave velocity. ¹⁴⁰ The velocity of the pulmonary venous atrial reversal wave has been shown to correlate with left ventricular filling pressures. ¹⁴¹ Tissue Doppler imaging, and strain and strain rate imaging, can also be used to assess diastolic and systolic function. These techniques have the advantage of being less dependent on loading conditions. ^141–145 Characteristically, patients with diastolic left ventricular impairment demonstrate reduced early diastolic velocities in the mitral annulus and septum, and reversal of the ratio of early to late diastolic velocities. In addition, the ratio of mitral inflow E wave to annular early diastolic velocity can be used as a measure of left ventricular end-diastolic pressure, and predicts exercise capacity. ^142,143 Tissue Doppler imaging may be useful in detecting mild disease in otherwise phenotypically normal gene carriers. ^144,146

The panels show the echocardiographic features of left ventricular diastolic impairment. A is a pulsed wave Doppler tracing of the mitral inflow from a 7-year-old with hypertrophic cardiomyopathy. It shows E/A wave reversal and a prolonged E wave deceleration time, characteristic of impaired relaxation of the left ventricle. B is another pulsed wave Doppler recording of a 15-year-old, showing pseudo-normalisation of the pattern of mitral inflow, with a normal E/A ratio but prolonged E wave deceleration time. C is a pulsed wave Doppler recording in the right upper pulmonary vein in a 14-year-old with severe hypertrophic cardiomyopathy, showing impaired relaxation of the left ventricle, characterised by a reduced diastolic wave and increased atrial reversal wave. D is a pulsed wave tissue Doppler recording of the lateral mitral annulus in a 13-year-old with hypertrophic cardiomyopathy showing reduced systolic (Sa), early diastolic (Ea), and late diastolic (Aa) velocities.

Ambulatory Electrocardiography

The frequency of arrhythmias detected during ambulatory electrocardiographic monitoring is age related. ^{119,147–149} In adults, 48-hour monitoring reveals supraventricular arrhythmias in up to half the patients, and non-sustained ventricular tachycardia in one-quarter. Most episodes of the latter arrhythmia are relatively slow, asymptomatic, and occur during periods of increased vagal tone. Sustained ventricular tachycardia is uncommon, but may occur in association with apical aneurysms. ¹⁵⁰ As discussed above, the frequency of arrhythmia in childhood is much lower, but the presence of ventricular arrhythmia in particular is a marker of poor prognosis. ^27,29,119

Cardiopulmonary Exercise Testing

Individuals usually have a reduced peak consumption of oxygen compared with healthy age-matched controls, even when asymptomatic. ^151,152 In children, exercise capacity and peak consumption of oxygen correlate with diastolic impairment. ^143,153 Up to one-quarter of adults have an abnormal response of blood pressure to exercise, ^154,155 related to abnormal vasodilation of the non-exercising vascular beds, possibly triggered by inappropriate firing of left ventricular baroreceptors ¹²⁸ and an impaired response of cardiac output. ¹⁵⁶ An abnormal response to exercise is associated with an increased risk of sudden death in young adults. ¹⁵⁷ In children, the use of cardiopulmonary exercise testing as a tool for stratification of risk has not been evaluated, but there are several problems associated with the technique. Very young children, usually under the age of 7 or 8 years, cannot reliably perform exercise testing, and flat responses are normal in pre-adolescents. The technique, nevertheless, remains a useful tool for the evaluation of severity and response to treatment in older teenagers.

Cardiac Magnetic Resonance Imaging

Like echocardiography, cardiac magnetic resonance imaging can assess the distribution and severity of left ventricular hypertrophy and provide functional measurements of systolic and diastolic function. The technique is particularly useful in the evaluation of patients with hypertrophy of the lateral wall, an area that can be difficult to visualise adequately using cross sectional echocardiography. In addition, magnetic resonance imaging can be used to assess myocardial tissue characteristics during life using gadolinium contrast agents ( Fig. 49-7 ). As many as four-fifths of adults have areas of patchy hyper-enhancement, the extent of which appears to correlate with risk factors for sudden death and with progressive left ventricular remodelling. ^158,159

Cardiac magnetic resonance imaging in hypertrophic cardiomyopathy. A shows black-blood HASTE imaging of a child with apical hypertrophic cardiomyopathy. B shows late gadolinium enhancement of the apical region in the same patient.

(Courtesy of Dr Marina Hughes, Great Ormond Street Hospital, London, United Kingdom.)

Other Imaging Modalities

Cardiac catheterisation and angiography are no longer used routinely in the assessment of children, as structural and haemodynamic data is easily obtained using non-invasive techniques. Coronary arteriography may demonstrate myocardial bridging and systolic compression of the epicardial and intramural coronary arteries, but the clinical significance of this observation remains controversial. ^108,121,122 Myocardial perfusion scanning using radioisotopes such as thallium-201 has been used to study the pathophysiology of myocardial ischaemia. Although an association between impaired myocardial perfusion and a history of syncope or resuscitated cardiac arrest has been reported in children, ¹⁶⁰ larger studies in young adults showed no association between reversible perfusion defects and exertional chest pain or electrocardiographic ST segment changes. ^161,162

Family Evaluation

All patients should be counselled on the implications of the diagnosis for their families. Careful analysis of the pedigree can reassure relatives who are not at risk of inheriting the disease. ⁵ For those who may be at risk, clinical screening with electrocardiograms and echocardiography may be appropriate after counselling. Current guidelines recommend screening with a 12-lead electrocardiogram and echocardiogram at intervals of 12 to 18 months, usually starting at the age of 12 years, unless there is a malignant family history of premature sudden death, the child is symptomatic or a competitive athlete in intensive training, or there is a clinical suspicion of left ventricular hypertrophy. Screening continues until full growth and maturation are achieved, usually by the age of 18 to 21 years. Following this, if there are no signs of phenotypic expression, screening approximately every 5 years is advised, as the onset of left ventricular hypertrophy may be delayed until well into adulthood in some families. ^55,163–168

It is now possible to offer relatively rapid genetic testing to individuals with unequivocal disease. If a mutation causing disease is identified, relatives can be offered predictive testing. Again, this should be performed only after appropriate genetic counselling and consideration of issues relating to autonomy, confidentiality and psychosocial harm, including loss of self-esteem, stigmatisation or discrimination, and guilt.

Treatment of Symptoms Caused by Obstruction of the Left Ventricular Outflow Tract

By convention, obstruction of the left ventricular outflow tract is defined as a pressure gradient greater than or equal to 30 mm Hg, ^12,104 but theoretical models examining the relationship between the gradient and stroke volume predict that only gradients in excess of 50 mm Hg are likely to represent significant obstruction to ventricular ejection. ¹⁰⁴ The first-line strategy for control of symptoms in patients with obstructive disease is medical therapy with β-adrenergic receptor blockers, such as propranolol, given at 1 to 2 mg/kg per dose, or more cardioselective drugs such as atenolol, metoprolol, nadolol, and bisoprolol. At standard doses, β-blockers can reduce symptoms of chest pain, dyspnoea, and presyncope on exertion, although they probably do not reduce obstruction under resting conditions. Studies using very large doses of propranolol, up to 23 mg/kg per day, in children and adolescents have reported improved long-term survival, ¹⁶⁹ but this is not generally accepted practice, as side effects of β-blockers are common, and even moderate doses can affect growth and school performance in young children, or trigger depression in children and adolescents. ⁵ If β-blockade is unsuccessful, the addition of the class I antiarrhythmic disopyramide can reduce obstruction and improve symptoms. ^170–172 This effect is exerted via its negative inotropic action. Disopyramide is usually well tolerated in children, but initiation at a low dose is recommended, as some patients may experience marked anticholinergic effects. As disopyramide causes accelerated atrioventricular nodal conduction, and may increase the ventricular rate during atrial fibrillation, it is usually administered in combination with a β-blocker. Disopyramide causes prolongation of the QT interval, and so the electrocardiogram must be monitored regularly. Other drugs that prolong the QT interval, such as sotalol or amiodarone, should be avoided.

The calcium antagonist verapamil improves symptoms caused by obstruction, probably by relieving myocardial ischaemia and reducing myocardial contractility. ^110,173 Chronic oral therapy has been shown to be effective in children with both obstructive and non-obstructive forms of the disease. ¹⁷⁴ Side effects include constipation and hair loss. In patients with severe symptoms caused by large gradients and pulmonary hypertension, verapamil can cause severe haemodynamic deterioration, ^175,176 and so should be used with caution.

Several options are available to patients with obstructive hypertrophic cardiomyopathy who do not tolerate drugs, or whose symptoms are refractory to medical therapy. The gold standard ^177–181 is septal myotomy or myectomy, in which a trough of muscle is removed from the ventricular septum via an aortic incision. Recently, extended myectomies to the level of the papillary muscle have been performed. ¹⁸² In the hands of experienced surgeons, the mortality is less than 1%, and the rate of success is high, with complete and permanent abolition of the gradient, and a marked improvement in symptoms and exercise capacity in over nine-tenths of patients. Non-fatal complications include complete heart block requiring insertion of a permanent pacemaker in less than one-twentieth of patients, and inadvertent creation of small ventricular septal defects. In most cases, a single procedure is required to achieve a permanent reduction in gradient, but repeated operations may be needed in very young children, possibly resulting from a limited initial myectomy due to a small aortic diameter, or from continued remodeling of the left ventricular outflow tract.

Atrioventricular, or dual-chamber, pacing has been shown to reduce gradients in uncontrolled, observational studies including one performed in children, ^183–185 and in two randomised controlled clinical trials. The randomised trials showed no objective improvement in exercise capacity and a symptomatic effect no better than placebo, ^186,187 except possibly in elderly patients with relatively mild hypertrophy.

An alternative to surgery for adults with obstructive disease is ablation of the ventricular septum by injection of 95% alcohol into a septal perforating coronary artery. This produces an area of localised myocardial necrosis within the basal septum. ^188,189 Myocardial damage is kept to a minimum by first visualising the area supplied by the perforator branch using echocardiographic contrast injection. ¹⁹⁰ Although short-term results are promising, the long-term effects are unknown, and there is potential for the resulting myocardial scar to act as a substrate for ventricular arrhythmia and sudden death. This, and the fact that the results in children and adolescents are often suboptimal, means that alcohol septal ablation is not recommended for use in this age group.

Management of Symptoms in Non-obstructive Disease

In patients without obstruction of the left ventricular outflow tract, chest pain and dyspnoea are usually caused by diastolic dysfunction and myocardial ischaemia. Treatment in this group of patients is empirical, and often suboptimal. Both β-blockers and calcium antagonists such as verapamil and diltiazem can improve symptoms by improving left ventricular relaxation and filling, reducing left ventricular contractility, and relieving myocardial ischaemia. Other drugs, such as nitrates and inhibitors of angiotensin-converting enzyme, may be beneficial in some patients, but should be used with caution in those in whom obstruction can be provoked, as they can exacerbate the gradient by virtue of their vasodilating effects. Adults who develop end-stage disease should receive conventional treatment for cardiac failure, including inhibition of angiotensin-converting enzymes, and use of angiotensin II receptor antagonists, spironolactone, β-blockers such as carvedilol or metoprolol, digoxin, and if necessary, cardiac transplantation.

Prevention of Sudden Cardiac Death

Although the overall risk of sudden death in children and adults is only approximately 1% per year, a significant minority of individuals have a much greater risk of ventricular arrhythmia and sudden death. ¹⁹¹ The mechanism of sudden death is thought to be ventricular arrhythmia in the majority, and several triggers are recognised, including atrial arrhythmia, myocardial ischaemia, and exercise. ¹⁹² The most reliable predictor is a history of previous cardiac arrest. ^124,193 In patients without such a history, the most clinically useful markers of risk are a family history of sudden cardiac death, ^27,194 unexplained syncope unrelated to neurocardiogenic mechanisms, a flat or hypotensive response of blood pressure to upright exercise, ^155,157,195 non-sustained ventricular tachycardia on ambulatory electrocardiographic monitoring or during exercise, ^123,147,157 and severe left ventricular hypertrophy on echocardiography, defined as a maximal left ventricular wall thickness of 30 mm or more. ^196,197 Importantly, these markers of increased risk can all be identified non-invasively. Studies have shown that patients with none of these features have a low risk of sudden death, less than 1% per year, whereas those with two or more risk factors are at substantially higher risk of dying suddenly, with an estimated annual mortality rate of 3% for those with two risk factors, rising to 6% in those with three or more risk factors. ¹⁵⁷ Patients with a single risk factor represent a more difficult group, as the annual death rate in this group is low, but the confidence intervals are wide, suggesting that some individuals with a single risk factor may be twice as likely to die suddenly than patients without risk factors. The evaluation of risk in these patients, therefore, has to be tailored to the individual, taking into account the significance of the risk factor—for example, a particularly malignant family history may be sufficient to trigger primary preventative measures in the absence of a second risk factor—as well as patient specific variables such as age ( Fig. 49-8 ). ^157,198 Several studies have shown that obstruction of the left ventricular outflow tract is associated with increased cardiovascular mortality, including sudden death. ^199,200 The absolute risk of sudden death associated with obstruction in isolation is low, but it may represent an incremental risk factor in combination with other conventional markers. ¹⁹⁹

The key features in the management of patients with hypertrophic cardiomyopathy. ACEI, angiotensin-converting enzyme inhibitor, AF, atrial fibrillation; BP, blood pressure; ICD, implantable cardioverter-defibrillator; LVOTO, left ventricular outflow tract obstruction; VF/VT, ventricular fibrillation/ventricular tachycardia.

(Adapted from Elliott p, Mckenna WJ: Hypertrophic cardiomyopathy. Lancet 2004;363:1881–1891.)

Although the algorithm for stratification of risk described above has been applied with some success to children and adolescents, ¹²⁵ extrapolation of data derived from adults may not always be appropriate for children. Of the conventional markers of an increased risk for sudden death, unexplained syncope, severe left ventricular hypertrophy, and a family history of sudden death have been reported as being particularly relevant to young individuals. ^{27,157,194,196,197,201} The response of blood pressure to exercise, however, may not be a sensitive marker of the risk in children, and whilst non-sustained ventricular tachycardia is a poor prognostic marker in this population, most children and teenagers who die of hypertrophic cardiomyopathy do not have this arrhythmia. ¹¹⁹

In patients who are considered to be at high risk, insertion of an implantable cardioverter-defibrillator should be regarded as the treatment of choice. ⁵ Retrospective registry data demonstrates that implantable cardioverter-defibrillators prevent sudden death in predominantly adult populations, with annual appropriate discharge rates of one-tenth in those undergoing secondary prevention, in other words, those with a history of cardiac arrest or sustained ventricular arrhythmia, and in one-twentieth of groups selected for primary prevention because of risk factors. ²⁰² In children, appropriate discharge rates are higher at 71% per year in those chosen for secondary prevention, ^125,203 and 4% per year in those having primary prevention. Despite the life-saving benefits of implantable cardioverter-defibrillators, an increased incidence of complications has been reported in children compared with adults, including a higher rate of inappropriate discharges for supraventricular or sinus tachycardia, an increased risk of infection, complications with leads related to growth, ^204–206 and the psychological sequels of appropriate and inappropriate discharges. ^207,208 Prior to the advent of implantable cardioverter-defibrillators, amiodarone was used to prevent sudden death in patients considered at high-risk. ²⁰⁹ The drug, however, does not prevent sudden cardiac death in this group at high-risk. ¹²⁵ Amiodarone does, nonetheless, remain useful for the treatment of atrial fibrillation.

Enterovirus

Historically, the most commonly implicated virus in myocarditis has been the coxsackie B enterovirus. ²³³ Strains with marked cardiotropic virulence have been identified. ²³⁴ A causal association between enteroviruses and myocarditis was initially suggested by studies showing a relationship between rising titres of coxsackievirus B antibodies in the serum and acute symptomatic presentation ^235,236 More recently, the enteroviral genome has been detected in myocardial biopsies of patients with myocarditis and dilated cardiomyopathy. ²³⁷ The pathogenic mechanism relates cleavage of dystrophin by the coxsackievirus protease, which disrupts the cytoskeletal structural integrity of the cardiac myocyte. ²³⁸

Adenovirus

An early study using viral cultures and serological markers showed the presence of adenovirus in one-sixth of children with acute myocarditis. ²³⁹ More recently, adenovirus DNA has been identified using polymerase chain reaction in up to two-fifths of samples from explanted hearts or endomyocardial biopsies in children with acute myocarditis. ^240–243 In one study, adenovirus was identified more frequently than enterovirus in both children and adults with myocarditis. ²⁴⁴ Coxsackievirus and adenovirus are known to share a common cellular receptor. ^245,246

Parvovirus

Parvovirus B19 infection is common in humans, usually causing erythema infectiosum. There are several reports of myocarditis associated with parvovirus infection, with one recent study finding viral DNA in one-tenth of endomyocardial biopsy samples taken from adults with histological evidence of myocardial inflammation or left ventricular dysfunction. ²⁴⁷ Childhood parvovirus myocarditis has also been reported with sudden cardiac death. ^248–252

Other Viruses

Many other viruses have been implicated in myocarditis in children, including cytomegalovirus, hepatitis C virus, and herpes simplex virus. In addition, the human immunodeficiency virus has been associated with myocarditis and left ventricular dysfunction. ^253–255

Electrocardiography

Transient electrocardiographic abnormalities occur commonly during community viral endemics, with most patients remaining asymptomatic. ²¹² In childhood studies, the electrocardiographic changes described include non-specific ST segment and T wave abnormalities, pathological Q waves, T wave inversion, and low QRS voltages. ^226,228 Electrocardiographic changes that mimic acute myocardial infarction have also been described. ^223,224 Myocarditis also causes atrioventricular block and ventricular arrhythmia, ranging from the presence of frequent ventricular extrasystole to sustained ventricular tachycardia. ^212,223,224 These electrocardiographic abnormalities are frequently asymptomatic, but occasionally may be associated with symptoms such as palpitation, presyncope, or syncope. In some cases, the only electrocardiographic manifestation of myocarditis may be a sinus tachycardia.

Chest Radiography

The chest radiograph may show an increased cardiothoracic ratio, increased pulmonary venous markings, and pulmonary oedema in some patients with acute myocarditis. The heart size may be normal in patients with acute, haemodynamically compromising left ventricular dysfunction, and in those with transient electrocardiographic abnormalities.

Echocardiography

Echocardiographic findings are varied and often non-specific, although the echocardiogram is rarely entirely normal in myocarditis, other than in some patients presenting only with ventricular ectopy. Evidence of impaired left ventricular systolic performance, with reduced fractional shortening and ejection fraction, is common. ²⁶⁹ Regional abnormalities of wall motion occur commonly, and functional mitral regurgitation, in the setting of left ventricular dilation, may also be found. Left or right ventricular thrombus may be present. Evidence of left ventricular diastolic impairment may also be detected. Less frequently, right ventricular systolic and diastolic function may also be compromised. Pericardial effusions are common. In the neonatal period and early infancy particularly, echocardiography has an important role in excluding anomalous coronary arterial anatomy, in particular, anomalous origin of the left coronary artery from the pulmonary trunk, as well as left-sided obstructive lesions, which can have a similar clinical presentation to myocarditis.

Cardiac Biomarkers

Routine blood tests such as full blood count and erythrocytic sedimentation rate are not usually helpful in confirming the diagnosis of myocarditis. Markers of myocardial injury may be of use. ^270,271 Troponin I has a high specificity for diagnosing myocarditis but a sensitivity of only 34%. ²⁷¹ Creatine kinase and its cardiac isoform CK-MB are less sensitive and specific than troponin, and are therefore not clinically useful for screening. Increased levels of autoantibodies against myocardial proteins have also been reported, and correlate with progressive worsening of ventricular function. ^272,273

Endomyocardial Biopsy

Cardiac catheterisation with right ventricular endomyocardial biopsy remains the gold standard diagnostic test for myocarditis, albeit the analysis using the Dallas criterions suffers from several important limitations. Immunohistochemical staining of samples can be used to obtain precise characterisation of lymphocyte subtypes. ²⁷⁴ The quantification of major histocompatibility complex and intercellular cell adhesion molecule induction using molecular immunohistochemical techniques has been demonstrated to have a higher sensitivity than the Dallas criterions for diagnosing myocarditis, although this may represent a subgroup of patients with a more chronic form of myocardial injury. ^275,276

Viral Polymerase Chain Reaction

The confirmation of a viral cause for myocarditis has been the subject of much recent interest. The diagnosis of viral myocarditis previously was based on the presence of positive viral cultures or serological confirmation of an antiviral immune response. These methods, however, are time consuming and have a low diagnostic yield. Polymerase chain reaction techniques have been shown successfully and rapidly to detect the presence of viral genome in samples from patients with myocarditis and dilated cardiomyopathy, including children. ^242,244,277

Cardiac Magnetic Resonance Imaging

Cardiac magnetic resonance imaging can demonstrate myocardial inflammation and myocyte injury, including the presence of pericellular and cellular oedema. In addition, the technique can provide useful anatomical and functional information. Although there have been no studies in children with myocarditis, data from adults ²⁷⁸ may be applicable to children.

General Principles

The first-line treatment is supportive. General principles of stabilisation include afterload reduction, anticoagulation, diuresis, and inotropic support. Patients with fulminant acute myocarditis may require intensive intravenous haemodynamic support. Diuretics and vasodilators, such as nitroprusside or glyceryl trinitrate, are the mainstay of afterload reduction. In some cases, mechanical assist devices or extracorporeal membrane oxygenation may be required. ^279–282

Following initial stabilisation, treatment for patients with symptoms and signs of cardiac failure should follow current guidelines set out by the International Society for Heart and Lung Transplantation. ²⁸³ This includes the use of inhibitors of angiotensin-converting enzyme and diuretics. The addition of β-blocking agents such as carvedilol should also be considered in patients with compensated cardiac failure. In addition, patients with left ventricular enlargement should receive anticoagulation with aspirin or warfarin. Patients with intractable and deteriorating cardiac failure may require cardiac transplantation.

Familial Dilated Cardiomyopathy

Familial disease occurs in over a third of adult patients. ³⁰⁵ The reported prevalence of familial dilated cardiomyopathy in children is much lower, from one-twentieth to one-sixth, ^302,303 but this is likely to represent an underestimate, resulting from reduced awareness of the inherited nature of the condition among paediatricians, and possibly a higher prevalence of metabolic or syndromic causes in children. A number of genetic mutations can cause dilated cardiomyopathy. ⁵³ In most cases, these are transmitted as an autosomal dominant trait, but other forms of inheritance, including autosomal recessive, X-linked and mitochondrial also occur.

Autosomal Dominant Dilated Cardiomyopathy

Autosomal dominant inheritance accounts for approximately one-quarter of all cases, ³⁰⁶ and was the commonest mode of inheritance in the study from North America, accounting for two-thirds of familial cases. ³⁰² Two major forms of autosomal dominant dilated cardiomyopathy are recognised, namely, isolated (or pure), and dilated cardiomyopathy associated with disease of the cardiac conduction system. In many cases, there may also be a skeletal myopathy.

Genes implicated in the isolated form include cytoskeletal (δ-sarcoglycan, ³⁰⁷ β-sarcoglycan, ³⁰⁸ desmin, ^309,310 and sarcomeric protein genes including α-cardiac actin, ³¹¹ troponin T, ³¹² β-myosin heavy chain, ³¹² troponin C, ³¹³ and α-tropomyosin. ³¹⁴ Although a number of genes have been mapped when dilated cardiomyopathy is associated with disease of the conduction system, ^53,315 only one has been identified to date. Mutations in the lamin A/C gene, which encodes a nuclear envelope intermediate filament protein, usually results in atrial arrhythmia and progressive atrioventricular conduction disease, which precede the development of dilated cardiomyopathy by several years. ^316–318 The pathophysiological mechanisms remain poorly understood. Some mutations result in dilated cardiomyopathy and conduction disease alone, ³¹⁷ whereas others lead to juvenile-onset muscular dystrophies, including Emery-Dreifuss muscular dystrophy ^319,320 and familial partial lipodystrophy with insulin-resistant diabetes. ³²¹

X-linked Dilated Cardiomyopathy

X-linked inheritance accounts for up to one-twentieth of familial cases of dilated cardiomyopathy. ^{302,322–324} In the study from North America, ³⁰² neuromuscular disorders accounted for one-quarter of cases, and nine-tenths were caused by Duchenne, Becker, and Emery-Dreifuss muscular dystrophies. Patients were significantly older at presentation than children with other causes of dilated cardiomyopathy, and almost all were male, reflecting the X-linked inheritance. Their outcome was poor, with only half surviving or free from transplantation after 5 years. ³⁰² X-linked dilated cardiomyopathy, also caused by mutations in the dystrophin gene, was first described in 1987 in young males with severe disease and rapid progression of congestive cardiac failure to death or transplantation. ³²⁵ The condition is characterised by raised isoforms of creatine kinase in the serum, but does not result in clinical signs or symptoms of muscular dystrophy as in Duchenne or Becker muscular dystrophies. Female carriers develop dilated cardiomyopathy in their fifties, and progression of the disease is slower.

Barth syndrome, made up of dilated cardiomyopathy, skeletal myopathy, and neutropaenia, is an X-linked disorder cause by mutations in the G4.5 gene, which encodes the protein tafazzin. ^326,327 The condition typically presents in male neonates or young infants, producing congestive cardiac failure, neutropaenia, and 3-methylgutaconic aciduria. Although some children die in infancy, usually due to progressive cardiac failure, sudden death, or sepsis, most survive infancy, but the dilated cardiomyopathy persists. Mutations in the G4.5 gene also cause isolated dilated cardiomyopathy, endocardial fibroelastosis, and left ventricular non-compaction, with or without the other features of Barth syndrome. ^328,329

Other Causes of Dilated Cardiomyopathy in Childhood

Myocarditis is an important cause of dilated cardiomyopathy, accounting for one-sixth to one-third of cases in population-based studies. ^302,303 The features of myocarditis were discussed in the preceding section of this chapter. Inborn errors of metabolism account for less than one-twentieth of cases. Of these, mitochondrial disorders are the commonest, accounting for almost half, followed by Barth syndrome, accounting for one-quarter, and primary or systemic deficiency of carnitine, accounting for another tenth. ³⁰² Patients with metabolic disease causing cardiac disease typically present in infancy, and three-quarters are male. Malformation syndromes are rarely associated with dilated cardiomyopathy, accounting for only 1% of cases. ³⁰² Hypocalcaemic rickets, however, can present as an isolated dilated cardiomyopathy in infancy. ^330–334

Symptoms

Infants with dilated cardiomyopathy typically present with poor feeding, tachypnoea, respiratory distress, diaphoresis during feeding, and failure to thrive. Older children and adults initially present with reduced exercise tolerance and dyspnoea on exertion. With worsening left ventricular function, dyspnoea at rest, orthopnoea, paroxysmal nocturnal dyspnoea, peripheral oedema, and ascites develop. In children in particular, symptoms may occur related to mesenteric ischaemia as a result of insufficient cardiac output to perfuse the gastrointestinal tract. This can produce abdominal pain after meals, nausea, vomiting, and anorexia. Symptoms related to arrhythmia, such as palpitation, presyncope, and syncope may occur at any age.

Physical Examination

Features of low cardiac output include persistent sinus tachycardia, weak peripheral pulses, and in advanced disease, hypotension. In older children, the jugular venous pressure may be elevated. Signs of respiratory distress resulting from pulmonary oedema may be present, particularly in infants and younger children, and include intercostal and subcostal recession, nasal flaring, and during acute decompensations, grunting. Palpation of the precordium usually reveals a displaced apical impulse. Hepatomegaly and ascites are common in patients with congestive cardiac failure, including infants. Peripheral oedema may also be seen, affecting the legs and sacrum in older children, and the face and scrotum in infants.

Auscultation of the heart may reveal the presence of a third, and sometimes a fourth, heart sound. In patients with functional mitral regurgitation, there may be a pansystolic murmur at the apex radiating to the axilla, but frequently no murmurs are heard, even in the presence of mitral incompetence, especially if cardiac output is very low. Auscultation of the chest may reveal basal crackles. Indeed, infants may present with wheezing that is difficult to distinguish from asthma or bronchiolitis. Examination of other systems is important, as it may reveal clues to the possible aetiology. In particular, examination of the neuromuscular system may reveal features of mild or subclinical skeletal myopathy. Ophthalmological examination is important if mitochondrial disorders are suspected.

Electrocardiography

The electrocardiogram in dilated cardiomyopathy may be normal, ³⁰¹ but more typically shows sinus tachycardia and non-specific changes in the ST segments and T waves, most commonly in the inferior and lateral leads ( Fig. 49-10 ). In patients with extensive left ventricular fibrosis, abnormal Q waves in the septal leads may be present. Evidence of atrial enlargement and voltage criterions for ventricular hypertrophy, usually involving the left but occasionally both biventricles, are common. All degrees of atrioventricular block may be seen, and raise the possibility of mutations in the lamin A/C gene. Supraventricular and ventricular arrhythmias are also common. In children, arrhythmias occur in up to half, and half of these are atrial. ³³⁶ Studies in predominantly adult populations have shown a prevalence of non-sustained ventricular tachycardia in just over two-fifths, ³³⁷ albeit that ventricular tachycardia is less common in children, occurring in only one-tenth of cases. ³³⁶

The 12-lead electrocardiogram from a 2-year-old with familial idiopathic dilated cardiomyopathy, showing non-specific ST segment and T wave abnormalities.

Chest Radiography

The chest X-ray is frequently abnormal. An increased cardiothoracic ratio is typical, reflecting left ventricular and left atrial dilation. In addition, patients with pulmonary oedema have signs of increased pulmonary vascular markings. Pleural effusions may also be present.

Echocardiography

In general, the presence of ventricular end-diastolic dimensions greater than two standard deviations above body surface area–corrected means, or greater than 112% of predicted dimension, and fractional shortening of less than 25% are sufficient to make the diagnosis. ^4,301,338 These criterions have some limitations, and therefore a number of other useful parameters of left ventricular function are usually measured. These include ejection fraction, myocardial performance index, and assessment of cardiac output, using velocities in the aorta and left ventricular outflow tract as assessed with pulsed and continuous wave Doppler. Cross sectional echocardiography is also used to determine whether intracavitary thrombus is present in the ventricles or atriums ( Fig. 49-11 ). Colour flow Doppler interrogation is used to determine the presence, and quantify the severity, of functional mitral and tricuspid regurgitation. In addition, pulsed and continuous wave Doppler interrogation can be used to estimate pulmonary arterial pressures. Patients frequently have abnormalities of diastolic left ventricular function. These include impaired relaxation or pseudo-normal patterns of mitral inflow and pulmonary venous flow. Occasionally, patients with severe disease have restrictive left ventricular physiology. Tissue Doppler systolic and diastolic annular velocities are significantly lower compared to controls, ³³⁹ but further studies are needed to assess whether these parameters have a prognostic role.

Echocardiographic features of dilated cardiomyopathy. A shows an apical four-chamber view from a child with dilated cardiomyopathy. Note the dilated left ventricular cavity with thin walls. B is a parasternal long-axis view, again showing a dilated, thin-walled left ventricle, but with thrombus in the left ventricular cavity.

(Courtesy of Dr Jan Marek, Great Ormond Street Hospital, London, United Kingdom.)

Cardiac Biomarkers

Levels of creatine kinase should be measured in the serum of all patients with dilated cardiomyopathy, as this may provide important clues to its aetiology. Other cardiac biomarkers, such as troponin I and troponin T, also may be elevated, suggesting the possibility of inflammatory or ischaemic causes. Levels of B-type natriuretic peptide are elevated in the plasma of children with chronic cardiac failure, and serve to predict rates of survival, hospitalisation, and listing for cardiac transplantation. ³⁴⁰

Exercise Testing

Symptom limited exercise testing using a treadmill or bicycle, combined with analysis of respiratory gases, is a useful technique to assess functional limitation and progression of disease in those in a stable condition. The children have lower durations of exercise, consume less oxygen, and have lower systolic pressures at peak exercise than their normal peers. ³⁴¹ The use of the technique as a prognostic tool, however, has not been assessed. Exercise testing remains useful, nonetheless, in the evaluation of children prior to transplantation. The detection of respiratory markers of severe lactic acidaemia during metabolic exercise testing can be caused by mitochondrial or metabolic causes.

Cardiac Catheterisation

Cardiac catheterisation with endomyocardial biopsy may be a useful adjunct in the investigation of some children, but its use is declining with improved non-invasive techniques. Endomyocardial biopsy may be diagnostic for myocarditis, although as already discussed, the diagnostic yield is low. It can also prove valuable in identifying metabolic or mitochondrial disorders. Haemodynamic assessment of left ventricular end-diastolic and pulmonary arterial pressures can be carried out in the catheter laboratory, but this has been superseded by echocardiographic techniques, which are non-invasive and do not require exposure to irradiation or general anaesthesia.

Cardiac Magnetic Resonance Imaging

This is a useful alternative technique for imaging in patients with poor echocardiographic windows. In addition, the detection of fibrosis with gadolinium contrast enhancement may provide an imaging-guided method to improve the diagnostic yield of endomyocardial biopsies. ³⁴²

Diuretics

There are no published studies evaluating the effects of diuretics in reducing mortality or improving symptoms in children. ²⁸³ Loop and thiazide diuretics, nonetheless, should be used in all patients with fluid retention due to cardiac failure to achieve a euvolaemic state. They should not be used as monotherapy, as they exacerbate neurohormonal activation, which may contribute to progression of the disease. ³⁰¹ Spironolactone, a specific antagonist of aldosterone, reduces relative mortality by almost one-third in adults with severe cardiac failure and ejection fractions less than 35%. ³⁴³ Side effects include hyperkalaemia, although this is infrequent in the presence of normal renal function, and gynaecomastia.

Inhibitors of Angiotensin-converting Enzyme and Blockers of Angiotensin Receptors

Activation of the renin-angiotensin-aldosterone system is central to the pathophysiology of cardiac failure, regardless of the underlying aetiology. ^283,301 Multiple large clinical trials have shown that inhibition of angiotensin-converting enzyme improves symptoms, reduces hospitalisations, and reduces cardiovascular mortality in adults with cardiac failure. ^344–347 Furthermore, such inhibition or blockade also reduces the rate of progression of disease in asymptomatic patients. A substantial proportion of patients taking inhibitors of angiotensin-converting enzyme in clinical practice are not titrated to the target doses reported in many trials, but evidence suggests that higher doses are associated with a greater reduction in the combined risk of death or transplantation. ³⁴⁸ In most cases, the inhibitors are well tolerated, the most common side effects being a troublesome cough and symptomatic hypotension, which can be prevented with careful up-titration of doses. First-dose hypotension is more problematic when inhibition is obtained using captopril than with the newer agents. A number of small observational studies have reported a beneficial effect in children with cardiac failure. ^{283,349–352} Only one retrospective report has described the effect of inhibition on mortality in children, showing improved survival during the first year of treatment but not subsequently. ³⁵¹

Blockers of the angiotensin receptors have similar haemodynamic effects to inhibitors of angiotensin-converting enzyme, but with fewer side effects. Clinical trials in adults with cardiac failure have shown similar haemodynamic effects, efficacy, and safety, ^353,354 and the blockers are currently recommended for adults who do not tolerate inhibition of the angiotensin-converting enzyme. Recent studies have suggested that combined treatment with inhibitors and blockers may be more beneficial in preventing ventricular remodeling than either drug alone, but has no additional impact on survival. ^355,356 There is no data relating to efficacy or safety regarding the use of the blockers in children with cardiac failure.

Current recommendations for children with dilated cardiomyopathy are that inhibitors of angiotensin-converting enzyme should be routinely used in all individuals with moderate or severe left ventricular dysfunction regardless of the presence of symptoms. Patients who are intolerant of these agents should be considered for blockade of the angiotensin receptors. ²⁸³ The use of inhibitors of angiotensin-converting enzyme is not recommended as initial therapy in patients with decompensated left ventricular dysfunction. ²⁸³

Beta-Blockers

Excess sympathetic activity contributes to cardiac failure, and several multi-centric, placebo-controlled trials using carvedilol, ^357,358 metoprolol, ³⁵⁹ and bisoprolol ³⁶⁰ have shown substantial reductions in mortality in adults with symptoms of cardiac failure but in relatively good condition. Beta-blockade is usually well tolerated, but side effects include bradycardia, hypotension, and retention of fluid. The drugs should be started at low doses and carefully uptitrated, and they should not be started in patients with decompensated cardiac failure. A recent trial has suggested that they can be started safely before use of inhibitors of angiotensin-converting enzyme for patients in stable cardiac failure. ³⁶¹ Their reported use in children with cardiac failure is limited. Small observational studies using carvedilol ^362–364 and metoprolol ³⁶⁵ have shown clinically important improvements in left ventricular systolic performance and functional class. In addition, carvedilol appears to delay the time to transplantation or death. ³⁶⁶ The results of the first randomised controlled trial in paediatric cardiomyopathy, from the multi-centre Paediatric Carvedilol Study Group, were recently published. ³⁶⁷ Although there was a trend towards benefit in those receiving carvedilol in terms of all-cause mortality, cardiovascular mortality, and hospitalisation for cardiac failure, this was not statistically significant. It is likely that carvedilol and other β-blockers do improve outcomes for some children with cardiac failure, but larger studies with longer follow-up are needed to confirm this. At present, there are no specific recommendations regarding β-blockade in children with compensated cardiac failure, but their routine use is increasing.

Digitalis

Digoxin improves symptoms in adults with cardiac failure, ³⁶⁸ but no benefit in terms of survival has been demonstrated in studies of large cohorts. ²⁸³ High levels of digoxin in the serum may be associated with increased mortality in some patients. ³⁶⁹ The drug is still widely used to treat cardiac failure in infants and children, but there is little data to support its efficacy. Current guidelines recommend the use of low doses to improve symptoms in children with symptomatic cardiac failure, including those with dilated cardiomyopathy, but not for asymptomatic individuals. ²⁸³

Novel Pharmacological Therapies

Nesiritide, a recombinant B-type natriuretic peptide with diuretic, natriuretic, and vasodilator effects, and used in adults with decompensated cardiac failure, has recently been shown to be safe in children, producing improvements in urinary output and functional state. ^370,371 Its value over more conventional therapies remains to be determined.

Anticoagulation

The annual risk of thromboembolism in children with dilated cardiomyopathy is unknown, but is likely to be low. The cumulative risk of systemic embolisation in a patient diagnosed at a young age, nonetheless, is substantial. ³⁷² In adults with dilated cardiomyopathy, intramural thrombosis and systemic thromboembolisation are found in up to half, with an incidence between 1.5% and 3.5% per year. ³⁷³ Anticoagulation with warfarin is advised in patients in whom an intracardiac thrombus is identified echocardiographically, and in those with a history of thromboembolism. There is no trial data to guide prophylactic anticoagulation in those with dilated cardiomyopathy, but patients with severe ventricular dilation and moderate to severe systolic impairment may benefit from anticoagulation using warfarin.

Treatment of Arrhythmias

Whilst arrhythmias are common in patients with dilated cardiomyopathy, negative chronotropic and proarrhythmic effects limit the use of many commonly used antiarrhythmic agents. Data on the effect of amiodarone on survival in dilated cardiomyopathy is contradictory, ^374,375 but the use of implantable cardioverter-defibrillators was associated with a reduction in overall mortality of almost one-quarter. ³⁷⁶ Amiodarone, therefore, appears to be safe in patients with dilated cardiomyopathy, and may be effective at preventing or treating atrial arrhythmias, but does not prevent sudden death. In adults, insertion of an implantable cardioverter-defibrillator is recommended for those having symptomatic ventricular arrhythmias, and in those with ventricular arrhythmias and an ejection fraction less than 35%. ³⁷⁶ This will prevent sudden death, and can serve as a bridge to transplantation. The role of implantable cardioverter-defibrillators as primary prophylaxis in children has not been addressed.

Non-pharmacological Treatment of Advanced Dilated Cardiomyopathy

Cardiac transplantation remains the mainstay of management of children with intractable cardiac failure symptoms and end-stage disease ( Fig. 49-12 ). A number of other approaches aimed at improving symptoms and stabilising the disease or delaying transplantation have now emerged.

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