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The cardiomyopathies
Current Paediatrics (2002) 12, 206^211
c 2002 Elsevier Science Ltd doi:10.1054/cupe.2001.0286, available online at http://www.idealibrary.com on
The cardiomyopathies Michael Burch* and Sanjay Prasadw *Consultant Paediatric Cardiologist and Transplant Physician, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK and wFellow in Adult Cardiology, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
KEYWORDS cardiomyopathy; hypertrophic cardiomyopathy; dilated cardiomyopathy; restrictive cardiomyopathy
Summary Cardiomyopathies are heart muscle diseases that are classi¢ed by pathophysiology: (i) dilated, (ii) hypertrophic, (iii) restrictive. Speci¢c cardiomyopathies are those with a distinct disease association. Most dilated cardiomyopathy in childhood is idiopathic, but speci¢c causes must be excluded as treatment can be directed towards the cause.Dilated cardiomyopathy has a poor prognosis with approximately 60% of children surviving 5 years from presentation. Medical and surgical therapy is improving but ultimately transplantation may be required.Idiopathic hypertrophic cardiomyopathyis a disease of the sarcomere relating to familial defects in genes encoding contractile proteins. Sudden death is common but can be prevented by implanting cardioverter de¢brillators in high-risk cases. Restrictive cardiomyopathy is uncommon, it appears more rapidly progressive when presenting in younger patients although the prognosis and molecular genetic causes are not well de¢ned.
c 2002 Elsevier Science Ltd
PRACTICE POINTS K
K
K
K
Cardiomyopathies (CM) are heart muscle diseases and are classi¢ed according to the dominant pathophysiology: F dilated CM (64% of cases of CM) F hypertrophic CM (28%) F restrictive CM F arrhythmogenic right ventricular CM F unclassi¢ed CM (those that do not ¢t into the above categories) Speci¢c cardiomyopathies are diseases of heart muscle as classi¢ed from the above four groups, but there are distinct disease associations, e.g. dilated cardiomyopathy with anthracycline toxicity A variety of aetiologies have been described for the speci¢c dilated cardiomyopathies. Most cases are idiopathic. The genetics are varied and it is highly heterogeneous. The prognosis remains poor but is better in younger children. Medical and surgical treatments are improving. Transplantation may be required The most common hypertrophic CM is autosomal dominantly inherited and caused by mutations in sarcomeric proteins. It is the most common cause of sudden death in young adults.Reducing the risk of sudden death is achieved by the use of an implantable cardioverter de¢brillator in high-risk groups
Correspondence to: MB.
RESEARCH DIRECTIONS Molecular genetic advances are key to the main cardiomyopathies. This will aid risk strati¢cation and guide treatment with, for instance, de¢brillators. Ultimately, therapy may have a molecular basis For end stage heart failure, permanently implantable-assist devices are becoming realistic, but molecular advances including myocyte implantation may be achievable
THE CARDIOMYOPATHIES The cardiomyopathies are diseases of cardiac muscles associated with cardiac dysfunction. The classi¢cation of this group of diseases has proved di⁄cult. In 1995, the World Health OrganizationTask Force published revised de¢nitions,1 but these are still not ideal. Classi¢cation is largely according to the dominant pathophysiology.
WHO classi¢cation of cardiomyopathy by pathophysiology 1. Hypertrophic cardiomyopathy. Hypertrophied left and/or right ventricle (28% of childhood cardiomyopathies). 2. Dilated cardiomyopathy. Dilated left or both ventricles with impaired contraction (64% of childhood cardiomyopathies).
THE CARDIOMYOPATHIES
207
3. Restrictive cardiomyopathy. Restrictive ¢lling and reduced diastolic volume of either or both ventricles with normal or near normal systolic function and wall thickness. 4. Arrythmogenicright ventricle cardiomyopathy. Progressive ¢bro fatty replacement of the right ventricular myocardium later involving the left ventricle. 5. Unclassi¢ed cardiomyopathies. In the past, cardiomyopathies were de¢ned as being of unknown cause and were, therefore, considered separately from heart muscle problems caused by known diseases. In recent years, with advances in molecular genetics, the underlying disease processes are beginning to be understood for many of the cardiomyopathies, so that subdivisions into primary and secondary cardiomyopathies is no longer relevant.
Speci¢c cardiomyopathies Heart muscle problems associated with known diseases are currently termed ‘speci¢c cardiomyopathies’, and are a subclassi¢cation of the pathophysiological group, i.e. dilated cardiomyopathy may be secondary to adriamycin toxicity. When no association is known, the cardiomyopathy may just be de¢ned by its pathophysiology (e.g. dilated cardiomyopathy) or it could be termed idiopathic dilated cardiomyopathyFalthough this term is not commonly used.The groups of speci¢c cardiomyopathies and the associated pathophysiological types are listed in Table 1 as diseases of the myocardium associated with cardiac dysfunction. The ¢rst four of the speci¢c cardiomyopathies listed in Table 1 are predominantly adult diseases. Ischaemic, valvular and hypertensive cardiomyopathies have cardiac disease out of proportion to the primary problem. Peripartum cardiomyopathy is a mixed group of diseases causing cardiac dysfunction in the perinatal period.
Table 1 Speci¢c cardiomyopathies* Disease
Type of cardiomyopathy
Ischaemic CM Valvular CM Hypertensive CM Peripartum CM In£ammatory CM Metabolic General system disease Muscular dystrophies Neuromuscular disorders Sensitive and toxic reactions
DCM DCM/HCM HCM/RCM DCM DCM DCM/HCM/RCM DCM DCM/HCM HCM/DCM DCM
*CM, cardiomyopathy; D, dilated; H, hypertrophic; R, restrictive.
In£ammatory cardiomyopathy is myocarditis with cardiac dysfunction. It is ‘dilated’ by pathophysiology. It may be infectious, typically enteroviral (coxsackie) or adenovirus, but many other viruses including HIV and hepatitis C and non-viral causes (bacteria, fungal, protozoal) are known to occur. Fulminant myocarditis appears to have a better prognosis than chronic in£ammation, and complete recovery can occur. Histologically giant cell formation is associated with a poor prognosis. In general, the management is similar to idiopathic dilated cardiomyopathy. Immune suppression and immunoglobulin therapy await evaluation in randomized trials. In South America, Chagas disease is a common cause. Autoimmune causes of dilated cardiomyopathy are well described and are seen with connective tissue diseases, SLE, polyarteritis, rheumatoid, scleroderma and dermatomyositis.Other systemic diseases that can cause cardiomyopathy include sarcoidosis and leukaemia. The muscular dystrophies are associated with cardiac muscle disease, Duchenne being associated with hypertrophic changes initially, with dilated cardiomyopathy developing later. Becker cardiomyopathy is usually, but not always, less severe than Duchenne. Some X-linked cases of dilated cardiomyopathy without skeletal myopathy have been shown to have de¢cient cardiac dystrophin. Metabolic cardiomyopathy includes inborn errors of metabolism and mitochondrial diseases. Mitochondrial disease may be suspected when there is a maternal inheritance, epilepsy, familial diabetes, deafness and skeletal myopathy. Initially, hypertrophic changes may be seen with poor contraction. Barth syndrome is a mitochondrial disease with dilated cardiomyopathy, it is X-linked and there is cyclical neutropaenia. Improvement may occur with carnitine therapy (as with other mitochondrial diseases). In¢ltration of the myocardium occurs in a variety of cardiomyopathies causing a range of pathophysiologies including hypertrophic, dilated and restricted. Causes include Pompes disease (glycogen storage disease II), which causes a severe hypertrophic cardiomyopathy and is usually fatal in infancy. Fabrys, haemochromatosis and amyloidosis are more severe in adult life. Toxic reactions can cause dilated cardiomyopathy; this can occur with anthracycline, radiation, alcohol and cocaine abuse.
Dilated cardiomyopathy (Fig.1) The speci¢c associated diseases are discussed above, and should always be sought. Most dilated cardiomyopathy (DCM) in childhood is of unknown cause and this can be frustrating when extensive investigations for associated disease are negative. Paediatricians must be aware that congenital heart disease, such as an anomalous coronary artery, can present as a dilated cardiomyopathy.This may be apparent on echocardiography but angiography is sometimes needed.The aetiology of the idiopathic group
208
CURRENT PAEDIATRICS
Figure 1 MRI scan of a patient with dilated cardiomyopathy. Left-hand ¢gure shows the heart in end-diastole; right-hand ¢gure shows the heart in end-systole.The left ventricle is grossly dilated and function is severely impaired.
is probably varied and viral myocarditis (acute and chronic) and autoantibody disease may contribute. Speci¢c abnormalities of the myocyte cytoskeleton have been detected and a wide variety of inheritance patterns recorded including recessive, X-linked and dominant (the most common). There is an age-related penetrance, which makes screening and counselling di⁄cult. The inheritance has been described as a molecular maze.2 Recently, an abnormality in myosin has been described in familial dilated cardiomyopathy.3 Treatment is essentially that of chronic heart failure. Diuretics are used to relieve symptoms. Data from excellent adult trials of medical therapy can be used to guide paediatric practice, where smaller numbers make such studies di⁄cult. In essence, there is now overwhelming evidence in favour of the use of angiotensin converting enzyme inhibitors such as enalapril and captopril.4 Aldosterone antagonists such as spironolactone are also bene¢cial and beta-blockers too can be used e¡ectively, particularly carvedilol.5 The prognosis of DCM in childhood is poor with 5-year survival of 60%,6 with many deaths occurring shortly after presentation. The outlook appears better in children under 2 years of age. Surgical techniques such as mitral valve surgery and ventricular reduction have been undertaken in adults, but are used less widely in children. Left ventricular assist devices may be required for intractable heart failure.7 Ultimately, cardiac transplantation may be required.
Hypertrophic cardiomyopathy (Fig. 2) Hypertrophic cardiomyopathy represents a heterogenous group of disorders, and this diversity is more apparent in childhood than at any other age (Table 2).
Familial hypertrophic cardiomyopathy Hypertrophic cardiomyopathy is a primary disease of cardiac muscle in the absence of valvar stenosis, hypertension, or other disease processes. Inheritance is autosomal dominant with variable phenotypic expression. Defects in genes encoding three contractile proteins (cardiac troponinT, beta-myosin heavy chain, and alphatropomyosin) can create the phenotypic expression.8,9 Ultimately, the diagnosis of familial hypertrophic cardiomyopathy depends on molecular identi¢cation of the offending gene or the abnormal gene product. Histologically, there is myocyte disarray. The prevalence is around 0.2% of the population. In the UK, this disorder is a leading cause of sudden death, particularly in otherwise healthy young persons such as athletes. Familial hypertrophic cardiomyopathy is characterized by myocardial hypertrophy and a wide spectrum of symptoms, including dyspnoea, palpitations, light-headedness, chest pain and syncope. Syncope occurs in15^25% of adult subjects. Although syncope is less common in childhood, it is strongly associated with the risk of sudden death. There is an annual death rate of 2^ 4% from sudden death, which can occur even in asymptomatic individuals. Electrocardiography results are abnormal in about 90% of patients and may show a wide variety of patterns. Echocardiographic features of hypertrophic cardiomyopathy have been well described. Mild or marked left, right or biventricular hypertrophy can be detected by echocardiography.The distribution of hypertrophy in hypertrophic cardiomyopathy is characteristically asymmetrical, less commonly it is symmetrical or apical. The anatomical pattern has not proved to be predictive of outcome but is a primary determinant of out£ow obstruction and is an important factor in surgical planning.
THE CARDIOMYOPATHIES
209
Figure 2 Cardiac MRI scan of a patient with hypertrophic cardiomyopathy.Top left ¢gure shows a four-chamber view demonstrating gross hypertrophy of the left ventricular wall. Top right ¢gure shows the left ventricular out£ow tract. The bottom two show a short-axis view of the thickened left ventricle in end-diastole and end-systole, respectively.
Table 2 Causes of hypertrophy 1. Hypertension 2. Congenital heart disease 3. Infant of diabetic mother 4. Drugs, e.g. prenatal and postnatal corticosteroids, tacrolimus, anabolic steroids 5. Metabolic disease, e.g.GSD II,III, and IV,Fabrys,I cell disease, mucopolysaccharidosis, carnitine de¢ciency 6. SyndromesFNoonan, Leopard, Friedreich’s ataxia, Beckwith^Weidemann,Costello 7. Familial hypertrophic cardiomyopathy
Other echocardiographic ¢ndings include dynamic mitral regurgitation and left ventricular out£ow obstruction. Out£ow obstruction is present in less than half of the patients with familial hypertrophic cardiomyopathy and is not predictive of outcome, with symptomatic patients without obstruction faring more poorly than those who have gradients. The magnitude of out£ow obstruction appears unrelated to the occurrence of ventricular tachycardia or risk of sudden death. High-grade arrythmias are elicited in some patients and have a negative prognostic implication. A hypotensive response to exercise appears to represent a risk for sudden death but more de¢nitively, a normal exercise blood pressure response identi¢es a low-risk cohort. Primary histological abnormality of focal myocardial disarray is not unique to familial hypertrophic
cardiomyopathy and cannot be reliably detected on biopsy specimens. Di¡erentiation between physiological hypertrophy secondary to athletic participation and pathological hypertrophy in familial hypertrophic cardiomyopathy is a frequent and important problem in young adults. The cardiac responses to chronic, intensive exercise has been well characterized and include dilation and hypertrophy with preservation of myocardial contractility.The hypertrophic response is most intense in sports that elicit a marked rise in blood pressure during exercise, such as rowing, wrestling and power lifting. Wall thickness 413 mm, is occasionally found in athletes, and the not infrequent occurrence of mild left ventricular hypertrophy in patients with familial hypertrophic cardiomyopathy result in a signi¢cant incidence of diagnostic ambiguity. ECG has not been particularly helpful in di¡erentiation because of the frequent presence of ECG abnormalities in athletes. Echocardiographic and clinical features that increase the probability of familial hypertrophic cardiomyopathies include: (a) a family history of hypertrophic cardiomyopathy or early sudden death (b) signi¢cant regional di¡erences in hypertrophy (c) diastolic dysfunction (d) abnormal ultrasonic myocardial re£ectivity (e) absence of deconditioning-induced regression of hypertrophy, and
210
CURRENT PAEDIATRICS
(f) abnormalities in coronary £ow reserve. Ultimately, di¡erentiation by available techniques is simply not possible in some subjects. In infants, restrictive symptoms predominate. High dose beta-blockers may be helpful; disopyramide has been used to reduce the out£ow gradient. Surgery, asynchronous dual chamber pacing, and non-surgical septal ablation are all treatment options where pharmacological agents have been unsuccessful. Surgical or pharmacological reduction in the out£ow gradient in symptomatic patients is usually associated with a reduction in symptoms, although the incidence of sudden death is not improved. In general, dynamic out£ow obstruction is not a negative prognostic factor, and interventions aimed at reducing the gradient are justi¢ed only in as much as symptomatic bene¢t can be anticipated. Ventricular tachycardia or ¢brillation is probably the mechanism of sudden death in hypertrophic cardiomyopathy. The implantable de¢brillator is highly e¡ective in terminating malignant ventricular arrhythmias in these patients and should be o¡ered to patients in the high-risk category for primary and secondary prevention of sudden death.10 Avoidance of strenuous exercise is generally recommended for patients with familial hypertrophic cardiomyopathy. Major adverse risk factors include a family history of sudden death, resuscitated cardiac arrest, exerciseinduced hypotension, syncope and symptomatic nonsustained ventricular tachycardia on Holter recording. Additionally, the extent of hypertrophy may be prognostic. Patients free of all risk factors are considered to be at low risk, and interventions (other than for symptoms such as chest pain or exercise intolerance) are not indicated. With two or more risk factors or with syncope alone, risk is considered high and aggressive management such as with an implantable cardioverter-de¢brillator is recommended. No consensus has been reached on management of intermediate-risk patients. Additional negative prognostic factors such as evidence of ischaemia on exercise thallium testing, marked QT dispersion, and myocardial bridging can also be useful in management decisions for these patients.Genotyping may help more accurate risk strati¢cation and guidance of treatment.11 Systolic function is nearly always normal or hyperdynamic. Sudden death in patients referred to tertiary care centres is seen annually in 3^5% of adults and 6 ^ 8% of children. Recent population studies indicate a much lower annual mortality (0.1^1%), which indicates a major referral bias in these statistics.12
Restrictive cardiomyopathy (Fig. 3) This is the least common form of cardiomyopathy and is unusual among children, where causes include some forms of storage disease.13 Clinical features are
Figure 3 Transoesophagealechocardiogram of a patient with advanced cardiac in¢ltrative disease (top ¢gure) shows thickened myocardial walls and restrictive physiologic features with markedly decreased ratio of pulmonary venous systolic-todiastolic £ow (middle ¢gure) and shortened deceleration time (100 ms) of transmitral in£ow E-wave velocity (bottom ¢gure).
THE CARDIOMYOPATHIES
comparable to those in adults, with normal ventricular size and function, severe elevation in diastolic ¢lling pressure and distinct atrial dilatation.14 Unlike adults, paediatric cases have been almost consistently idiopathic despite tissue analysis in nearly all, although several cases were familial. Di¡erentiation from many of the secondary causes, such as myocardial non-compaction (persistence of embryonic or ‘spongy’ myocardium), can be made on morphological criteria. Endomyocardial biopsy is sometimes undertaken to exclude any potentially treatable disorder. A striking feature in children is the poor prognosis, with a 2-year survival rate of about 50%.15 Survival, therefore, appears to be even more limited than has been described in adults.Younger patients with respiratory symptoms, thromboembolism, increased cardiothoracic ratio on chest radiogram or patients with endocardial ¢broelastosis appear to have a worse prognosis. Anticoagulation is recommended because a 25% incidence of thromboembolism has been seen in children. Therapy is otherwise non-speci¢c and usually is of very limited bene¢t.The onset of irreversible elevation in pulmonary vascular resistance can occur within 1^ 4 years in these patients, and early cardiac transplantation is therefore recommended to avoid the need for heart and lung transplantation.
Right ventricular dysplasia Right ventricular dysplasia is an idiopathic cardiomyopathy associated with sudden cardiac death. It is of unclear aetiology but thought to be an autosomal dominant disorder with variable expression and penetrance.This cardiomyopathy mainly a¡ects the right ventricle although the left ventricle may also be a¡ected. Histologically, it is characterized by a lipomatous or ¢brolipomatous transformation of the right ventricular myocardium.The presence of adipose tissue together with ¢brosis and myocyte hypertrophy in young patients strongly suggests right ventricular dysplasia. Patients commonly present with asymptomatic cardiomegaly (10%) or recurrent ventricular arrhythmias of left bundle branch block morphology. It has been described as a cause of ventricular tachycardia in children with apparently normal hearts. A family history of cardiomyopathy, or sudden death in a close relative also can be a clue to the diagnosis.16,17 On ECG, typically there is a T-wave inversion in right precordial leads and localized prolongation of QRS complex in right precordial leads.Ventricular tachycardia and frequent ventricular extrasystoles may be seen.On echo,
211
or better MRI, there may be cardiomegaly with a dilated impaired right ventricle.
REFERENCES 1. Richardson P, McKenna W, Bristow M et al. Report of the World Health Organisation/International Society and Federation of Cardiology Task Force on the de¢nition and classi¢cation of cardiomyopathies. Circulation1996; 93(5): 841. 2. Komajda M.Genetics of dilated cardiomyopath: a molecular maze? Heart 2000; 84(5): 463^ 464. 3. Kamisago M, Sharma S D, De Palma S R et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 2000; 343(23): 1688 ^1696. 4. The SOLVD Investigators. N Engl J Med1991; 325(5): 293^302. 5. Packer M, Coats A S, Fowler M R et al. E¡ect of Carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344: 1651^ 1658. 6. Burch M, Siddiqi S A,Celermajer D E et al. Dilated cardiomyopathy in children: determinants of outcome. Br Heart J1994; 72(3): 246 ^ 250. 7. Westaby S, Franklin O, Burch M. New developments in the treatment of cardiac failure. Arch Dis Child 1999; 81(3): 267^277. 8. Burch M, Blair E.The inheritance of hypertrophic cardiomyopathy. Pediat Cardiol 1999; 20(5): 313^316. 9. Marian A J. On genetic and phenotypic variability of hypertrophic cardiomyopathy: nature versus nurture. J Am Coll Cardiol 2001; 38(2): 331^334. 10. Maron B J,Wing-Kuang Shen, Link M S et al. E⁄cacy of implantable cardioverter-de¢brillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 2000; 342: 365^373. 11. Havndrup O, Bundgaard H, Andersen P S, Larsen L A et al. The Val606Met mutation in the cardiac beta-myosin heavy gene in patients with familial hypertrophic cardiomyopathy is associated with a high risk of sudden death at a young age. Am J Cardiol 2001; 87(11): 1315^1317. 12. Maron B J, Casey S A, Poliac L C et al. Clinical course of hypertrophic cardiomyopathy in a regional United States cohort. JAMA 1999; 281: 650. 13. Schutte D P, Essop M R. Clinical pro¢le and outcome of idiopathic restrictive cardiomyopathy. Circulation 2001; 103(14): E83. 14. Hancock E W. Di¡erential diagnosis of restrictive cardiomyopathy and constrictive pericarditis. Heart 2001; 86(3): 343^349. 15. Chen S C, Balfour I C, Jureidini S. Clinical spectrum of restrictive cardiomyopathy in children. J Heart Lung Transplant 2001; 20(1): 90 ^92. 16. Corrado D, Fontaine G, Marcus F L et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: need for an international registry. Study Group on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy of the Woking Groups on Myocardial and Pericardial Disease and Arrhythmias of the European Society Of Cardiology and of the Scienti¢c Council on Cardiomyopathies of the World Heart Federation. Circulation 2000; 101(11): E101^E106. 17. Oakley R M, Ooi O C, Bongso A et al. Myocyte transplantation for myocardial repair: a few good cells can mend a broken heart. Ann Thorac Surg 2001; 71(5): 1724 ^1733.
c 2002 Elsevier Science Ltd doi:10.1054/cupe.2001.0286, available online at http://www.idealibrary.com on
The cardiomyopathies Michael Burch* and Sanjay Prasadw *Consultant Paediatric Cardiologist and Transplant Physician, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK and wFellow in Adult Cardiology, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
KEYWORDS cardiomyopathy; hypertrophic cardiomyopathy; dilated cardiomyopathy; restrictive cardiomyopathy
Summary Cardiomyopathies are heart muscle diseases that are classi¢ed by pathophysiology: (i) dilated, (ii) hypertrophic, (iii) restrictive. Speci¢c cardiomyopathies are those with a distinct disease association. Most dilated cardiomyopathy in childhood is idiopathic, but speci¢c causes must be excluded as treatment can be directed towards the cause.Dilated cardiomyopathy has a poor prognosis with approximately 60% of children surviving 5 years from presentation. Medical and surgical therapy is improving but ultimately transplantation may be required.Idiopathic hypertrophic cardiomyopathyis a disease of the sarcomere relating to familial defects in genes encoding contractile proteins. Sudden death is common but can be prevented by implanting cardioverter de¢brillators in high-risk cases. Restrictive cardiomyopathy is uncommon, it appears more rapidly progressive when presenting in younger patients although the prognosis and molecular genetic causes are not well de¢ned.
c 2002 Elsevier Science Ltd
PRACTICE POINTS K
K
K
K
Cardiomyopathies (CM) are heart muscle diseases and are classi¢ed according to the dominant pathophysiology: F dilated CM (64% of cases of CM) F hypertrophic CM (28%) F restrictive CM F arrhythmogenic right ventricular CM F unclassi¢ed CM (those that do not ¢t into the above categories) Speci¢c cardiomyopathies are diseases of heart muscle as classi¢ed from the above four groups, but there are distinct disease associations, e.g. dilated cardiomyopathy with anthracycline toxicity A variety of aetiologies have been described for the speci¢c dilated cardiomyopathies. Most cases are idiopathic. The genetics are varied and it is highly heterogeneous. The prognosis remains poor but is better in younger children. Medical and surgical treatments are improving. Transplantation may be required The most common hypertrophic CM is autosomal dominantly inherited and caused by mutations in sarcomeric proteins. It is the most common cause of sudden death in young adults.Reducing the risk of sudden death is achieved by the use of an implantable cardioverter de¢brillator in high-risk groups
Correspondence to: MB.
RESEARCH DIRECTIONS Molecular genetic advances are key to the main cardiomyopathies. This will aid risk strati¢cation and guide treatment with, for instance, de¢brillators. Ultimately, therapy may have a molecular basis For end stage heart failure, permanently implantable-assist devices are becoming realistic, but molecular advances including myocyte implantation may be achievable
THE CARDIOMYOPATHIES The cardiomyopathies are diseases of cardiac muscles associated with cardiac dysfunction. The classi¢cation of this group of diseases has proved di⁄cult. In 1995, the World Health OrganizationTask Force published revised de¢nitions,1 but these are still not ideal. Classi¢cation is largely according to the dominant pathophysiology.
WHO classi¢cation of cardiomyopathy by pathophysiology 1. Hypertrophic cardiomyopathy. Hypertrophied left and/or right ventricle (28% of childhood cardiomyopathies). 2. Dilated cardiomyopathy. Dilated left or both ventricles with impaired contraction (64% of childhood cardiomyopathies).
THE CARDIOMYOPATHIES
207
3. Restrictive cardiomyopathy. Restrictive ¢lling and reduced diastolic volume of either or both ventricles with normal or near normal systolic function and wall thickness. 4. Arrythmogenicright ventricle cardiomyopathy. Progressive ¢bro fatty replacement of the right ventricular myocardium later involving the left ventricle. 5. Unclassi¢ed cardiomyopathies. In the past, cardiomyopathies were de¢ned as being of unknown cause and were, therefore, considered separately from heart muscle problems caused by known diseases. In recent years, with advances in molecular genetics, the underlying disease processes are beginning to be understood for many of the cardiomyopathies, so that subdivisions into primary and secondary cardiomyopathies is no longer relevant.
Speci¢c cardiomyopathies Heart muscle problems associated with known diseases are currently termed ‘speci¢c cardiomyopathies’, and are a subclassi¢cation of the pathophysiological group, i.e. dilated cardiomyopathy may be secondary to adriamycin toxicity. When no association is known, the cardiomyopathy may just be de¢ned by its pathophysiology (e.g. dilated cardiomyopathy) or it could be termed idiopathic dilated cardiomyopathyFalthough this term is not commonly used.The groups of speci¢c cardiomyopathies and the associated pathophysiological types are listed in Table 1 as diseases of the myocardium associated with cardiac dysfunction. The ¢rst four of the speci¢c cardiomyopathies listed in Table 1 are predominantly adult diseases. Ischaemic, valvular and hypertensive cardiomyopathies have cardiac disease out of proportion to the primary problem. Peripartum cardiomyopathy is a mixed group of diseases causing cardiac dysfunction in the perinatal period.
Table 1 Speci¢c cardiomyopathies* Disease
Type of cardiomyopathy
Ischaemic CM Valvular CM Hypertensive CM Peripartum CM In£ammatory CM Metabolic General system disease Muscular dystrophies Neuromuscular disorders Sensitive and toxic reactions
DCM DCM/HCM HCM/RCM DCM DCM DCM/HCM/RCM DCM DCM/HCM HCM/DCM DCM
*CM, cardiomyopathy; D, dilated; H, hypertrophic; R, restrictive.
In£ammatory cardiomyopathy is myocarditis with cardiac dysfunction. It is ‘dilated’ by pathophysiology. It may be infectious, typically enteroviral (coxsackie) or adenovirus, but many other viruses including HIV and hepatitis C and non-viral causes (bacteria, fungal, protozoal) are known to occur. Fulminant myocarditis appears to have a better prognosis than chronic in£ammation, and complete recovery can occur. Histologically giant cell formation is associated with a poor prognosis. In general, the management is similar to idiopathic dilated cardiomyopathy. Immune suppression and immunoglobulin therapy await evaluation in randomized trials. In South America, Chagas disease is a common cause. Autoimmune causes of dilated cardiomyopathy are well described and are seen with connective tissue diseases, SLE, polyarteritis, rheumatoid, scleroderma and dermatomyositis.Other systemic diseases that can cause cardiomyopathy include sarcoidosis and leukaemia. The muscular dystrophies are associated with cardiac muscle disease, Duchenne being associated with hypertrophic changes initially, with dilated cardiomyopathy developing later. Becker cardiomyopathy is usually, but not always, less severe than Duchenne. Some X-linked cases of dilated cardiomyopathy without skeletal myopathy have been shown to have de¢cient cardiac dystrophin. Metabolic cardiomyopathy includes inborn errors of metabolism and mitochondrial diseases. Mitochondrial disease may be suspected when there is a maternal inheritance, epilepsy, familial diabetes, deafness and skeletal myopathy. Initially, hypertrophic changes may be seen with poor contraction. Barth syndrome is a mitochondrial disease with dilated cardiomyopathy, it is X-linked and there is cyclical neutropaenia. Improvement may occur with carnitine therapy (as with other mitochondrial diseases). In¢ltration of the myocardium occurs in a variety of cardiomyopathies causing a range of pathophysiologies including hypertrophic, dilated and restricted. Causes include Pompes disease (glycogen storage disease II), which causes a severe hypertrophic cardiomyopathy and is usually fatal in infancy. Fabrys, haemochromatosis and amyloidosis are more severe in adult life. Toxic reactions can cause dilated cardiomyopathy; this can occur with anthracycline, radiation, alcohol and cocaine abuse.
Dilated cardiomyopathy (Fig.1) The speci¢c associated diseases are discussed above, and should always be sought. Most dilated cardiomyopathy (DCM) in childhood is of unknown cause and this can be frustrating when extensive investigations for associated disease are negative. Paediatricians must be aware that congenital heart disease, such as an anomalous coronary artery, can present as a dilated cardiomyopathy.This may be apparent on echocardiography but angiography is sometimes needed.The aetiology of the idiopathic group
208
CURRENT PAEDIATRICS
Figure 1 MRI scan of a patient with dilated cardiomyopathy. Left-hand ¢gure shows the heart in end-diastole; right-hand ¢gure shows the heart in end-systole.The left ventricle is grossly dilated and function is severely impaired.
is probably varied and viral myocarditis (acute and chronic) and autoantibody disease may contribute. Speci¢c abnormalities of the myocyte cytoskeleton have been detected and a wide variety of inheritance patterns recorded including recessive, X-linked and dominant (the most common). There is an age-related penetrance, which makes screening and counselling di⁄cult. The inheritance has been described as a molecular maze.2 Recently, an abnormality in myosin has been described in familial dilated cardiomyopathy.3 Treatment is essentially that of chronic heart failure. Diuretics are used to relieve symptoms. Data from excellent adult trials of medical therapy can be used to guide paediatric practice, where smaller numbers make such studies di⁄cult. In essence, there is now overwhelming evidence in favour of the use of angiotensin converting enzyme inhibitors such as enalapril and captopril.4 Aldosterone antagonists such as spironolactone are also bene¢cial and beta-blockers too can be used e¡ectively, particularly carvedilol.5 The prognosis of DCM in childhood is poor with 5-year survival of 60%,6 with many deaths occurring shortly after presentation. The outlook appears better in children under 2 years of age. Surgical techniques such as mitral valve surgery and ventricular reduction have been undertaken in adults, but are used less widely in children. Left ventricular assist devices may be required for intractable heart failure.7 Ultimately, cardiac transplantation may be required.
Hypertrophic cardiomyopathy (Fig. 2) Hypertrophic cardiomyopathy represents a heterogenous group of disorders, and this diversity is more apparent in childhood than at any other age (Table 2).
Familial hypertrophic cardiomyopathy Hypertrophic cardiomyopathy is a primary disease of cardiac muscle in the absence of valvar stenosis, hypertension, or other disease processes. Inheritance is autosomal dominant with variable phenotypic expression. Defects in genes encoding three contractile proteins (cardiac troponinT, beta-myosin heavy chain, and alphatropomyosin) can create the phenotypic expression.8,9 Ultimately, the diagnosis of familial hypertrophic cardiomyopathy depends on molecular identi¢cation of the offending gene or the abnormal gene product. Histologically, there is myocyte disarray. The prevalence is around 0.2% of the population. In the UK, this disorder is a leading cause of sudden death, particularly in otherwise healthy young persons such as athletes. Familial hypertrophic cardiomyopathy is characterized by myocardial hypertrophy and a wide spectrum of symptoms, including dyspnoea, palpitations, light-headedness, chest pain and syncope. Syncope occurs in15^25% of adult subjects. Although syncope is less common in childhood, it is strongly associated with the risk of sudden death. There is an annual death rate of 2^ 4% from sudden death, which can occur even in asymptomatic individuals. Electrocardiography results are abnormal in about 90% of patients and may show a wide variety of patterns. Echocardiographic features of hypertrophic cardiomyopathy have been well described. Mild or marked left, right or biventricular hypertrophy can be detected by echocardiography.The distribution of hypertrophy in hypertrophic cardiomyopathy is characteristically asymmetrical, less commonly it is symmetrical or apical. The anatomical pattern has not proved to be predictive of outcome but is a primary determinant of out£ow obstruction and is an important factor in surgical planning.
THE CARDIOMYOPATHIES
209
Figure 2 Cardiac MRI scan of a patient with hypertrophic cardiomyopathy.Top left ¢gure shows a four-chamber view demonstrating gross hypertrophy of the left ventricular wall. Top right ¢gure shows the left ventricular out£ow tract. The bottom two show a short-axis view of the thickened left ventricle in end-diastole and end-systole, respectively.
Table 2 Causes of hypertrophy 1. Hypertension 2. Congenital heart disease 3. Infant of diabetic mother 4. Drugs, e.g. prenatal and postnatal corticosteroids, tacrolimus, anabolic steroids 5. Metabolic disease, e.g.GSD II,III, and IV,Fabrys,I cell disease, mucopolysaccharidosis, carnitine de¢ciency 6. SyndromesFNoonan, Leopard, Friedreich’s ataxia, Beckwith^Weidemann,Costello 7. Familial hypertrophic cardiomyopathy
Other echocardiographic ¢ndings include dynamic mitral regurgitation and left ventricular out£ow obstruction. Out£ow obstruction is present in less than half of the patients with familial hypertrophic cardiomyopathy and is not predictive of outcome, with symptomatic patients without obstruction faring more poorly than those who have gradients. The magnitude of out£ow obstruction appears unrelated to the occurrence of ventricular tachycardia or risk of sudden death. High-grade arrythmias are elicited in some patients and have a negative prognostic implication. A hypotensive response to exercise appears to represent a risk for sudden death but more de¢nitively, a normal exercise blood pressure response identi¢es a low-risk cohort. Primary histological abnormality of focal myocardial disarray is not unique to familial hypertrophic
cardiomyopathy and cannot be reliably detected on biopsy specimens. Di¡erentiation between physiological hypertrophy secondary to athletic participation and pathological hypertrophy in familial hypertrophic cardiomyopathy is a frequent and important problem in young adults. The cardiac responses to chronic, intensive exercise has been well characterized and include dilation and hypertrophy with preservation of myocardial contractility.The hypertrophic response is most intense in sports that elicit a marked rise in blood pressure during exercise, such as rowing, wrestling and power lifting. Wall thickness 413 mm, is occasionally found in athletes, and the not infrequent occurrence of mild left ventricular hypertrophy in patients with familial hypertrophic cardiomyopathy result in a signi¢cant incidence of diagnostic ambiguity. ECG has not been particularly helpful in di¡erentiation because of the frequent presence of ECG abnormalities in athletes. Echocardiographic and clinical features that increase the probability of familial hypertrophic cardiomyopathies include: (a) a family history of hypertrophic cardiomyopathy or early sudden death (b) signi¢cant regional di¡erences in hypertrophy (c) diastolic dysfunction (d) abnormal ultrasonic myocardial re£ectivity (e) absence of deconditioning-induced regression of hypertrophy, and
210
CURRENT PAEDIATRICS
(f) abnormalities in coronary £ow reserve. Ultimately, di¡erentiation by available techniques is simply not possible in some subjects. In infants, restrictive symptoms predominate. High dose beta-blockers may be helpful; disopyramide has been used to reduce the out£ow gradient. Surgery, asynchronous dual chamber pacing, and non-surgical septal ablation are all treatment options where pharmacological agents have been unsuccessful. Surgical or pharmacological reduction in the out£ow gradient in symptomatic patients is usually associated with a reduction in symptoms, although the incidence of sudden death is not improved. In general, dynamic out£ow obstruction is not a negative prognostic factor, and interventions aimed at reducing the gradient are justi¢ed only in as much as symptomatic bene¢t can be anticipated. Ventricular tachycardia or ¢brillation is probably the mechanism of sudden death in hypertrophic cardiomyopathy. The implantable de¢brillator is highly e¡ective in terminating malignant ventricular arrhythmias in these patients and should be o¡ered to patients in the high-risk category for primary and secondary prevention of sudden death.10 Avoidance of strenuous exercise is generally recommended for patients with familial hypertrophic cardiomyopathy. Major adverse risk factors include a family history of sudden death, resuscitated cardiac arrest, exerciseinduced hypotension, syncope and symptomatic nonsustained ventricular tachycardia on Holter recording. Additionally, the extent of hypertrophy may be prognostic. Patients free of all risk factors are considered to be at low risk, and interventions (other than for symptoms such as chest pain or exercise intolerance) are not indicated. With two or more risk factors or with syncope alone, risk is considered high and aggressive management such as with an implantable cardioverter-de¢brillator is recommended. No consensus has been reached on management of intermediate-risk patients. Additional negative prognostic factors such as evidence of ischaemia on exercise thallium testing, marked QT dispersion, and myocardial bridging can also be useful in management decisions for these patients.Genotyping may help more accurate risk strati¢cation and guidance of treatment.11 Systolic function is nearly always normal or hyperdynamic. Sudden death in patients referred to tertiary care centres is seen annually in 3^5% of adults and 6 ^ 8% of children. Recent population studies indicate a much lower annual mortality (0.1^1%), which indicates a major referral bias in these statistics.12
Restrictive cardiomyopathy (Fig. 3) This is the least common form of cardiomyopathy and is unusual among children, where causes include some forms of storage disease.13 Clinical features are
Figure 3 Transoesophagealechocardiogram of a patient with advanced cardiac in¢ltrative disease (top ¢gure) shows thickened myocardial walls and restrictive physiologic features with markedly decreased ratio of pulmonary venous systolic-todiastolic £ow (middle ¢gure) and shortened deceleration time (100 ms) of transmitral in£ow E-wave velocity (bottom ¢gure).
THE CARDIOMYOPATHIES
comparable to those in adults, with normal ventricular size and function, severe elevation in diastolic ¢lling pressure and distinct atrial dilatation.14 Unlike adults, paediatric cases have been almost consistently idiopathic despite tissue analysis in nearly all, although several cases were familial. Di¡erentiation from many of the secondary causes, such as myocardial non-compaction (persistence of embryonic or ‘spongy’ myocardium), can be made on morphological criteria. Endomyocardial biopsy is sometimes undertaken to exclude any potentially treatable disorder. A striking feature in children is the poor prognosis, with a 2-year survival rate of about 50%.15 Survival, therefore, appears to be even more limited than has been described in adults.Younger patients with respiratory symptoms, thromboembolism, increased cardiothoracic ratio on chest radiogram or patients with endocardial ¢broelastosis appear to have a worse prognosis. Anticoagulation is recommended because a 25% incidence of thromboembolism has been seen in children. Therapy is otherwise non-speci¢c and usually is of very limited bene¢t.The onset of irreversible elevation in pulmonary vascular resistance can occur within 1^ 4 years in these patients, and early cardiac transplantation is therefore recommended to avoid the need for heart and lung transplantation.
Right ventricular dysplasia Right ventricular dysplasia is an idiopathic cardiomyopathy associated with sudden cardiac death. It is of unclear aetiology but thought to be an autosomal dominant disorder with variable expression and penetrance.This cardiomyopathy mainly a¡ects the right ventricle although the left ventricle may also be a¡ected. Histologically, it is characterized by a lipomatous or ¢brolipomatous transformation of the right ventricular myocardium.The presence of adipose tissue together with ¢brosis and myocyte hypertrophy in young patients strongly suggests right ventricular dysplasia. Patients commonly present with asymptomatic cardiomegaly (10%) or recurrent ventricular arrhythmias of left bundle branch block morphology. It has been described as a cause of ventricular tachycardia in children with apparently normal hearts. A family history of cardiomyopathy, or sudden death in a close relative also can be a clue to the diagnosis.16,17 On ECG, typically there is a T-wave inversion in right precordial leads and localized prolongation of QRS complex in right precordial leads.Ventricular tachycardia and frequent ventricular extrasystoles may be seen.On echo,
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or better MRI, there may be cardiomegaly with a dilated impaired right ventricle.
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