The cardiomyopathies


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The cardiomyopathies

  1. 1. The cardiomyopathies Michael Burch* and Sanjay Prasadw *Consultant Paediatric Cardiologist and Transplant Physician,Great Ormond Street Hospital for Children NHS Trust,Great Ormond Street, LondonWC1N 3JH,UK and w Fellow in Adult Cardiology, Royal Brompton Hospital, Sydney Street, London SW3 6NP,UK KEYWORDS cardiomyopathy; hypertrophic cardiomyopathy; dilated cardiomyopathy; restrictive cardiomyopathy Summary Cardiomyopathies areheartmuscle diseasesthat are classi¢edbypatho- physiology: (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 treatmentcan be directed towards thecause.Dilatedcardiomyopathyhasapoorprognosiswithapproximately 60% ofchil- dren surviving 5 years frompresentation.Medical and surgicaltherapyisimproving but ultimately transplantationmayberequired.Idiopathichypertrophiccardiomyopathyisa disease of the sarcomere relating to familial defects in genes encoding contractile pro- teins. Sudden death is common but can be prevented by implanting cardioverter de¢- brillators in high-riskcases.Restrictive cardiomyopathyis uncommon, it appears more rapidly progressive when presenting in younger patients although the prognosis and moleculargenetic causes are not wellde¢ned. c 2002 Elsevier Science Ltd PRACTICE POINTS K Cardiomyopathies (CM) are heart muscle diseases and are classi¢ed according to the dominant patho- physiology: 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) K Speci¢c cardiomyopathies are diseases of heart muscle as classi¢ed from the above four groups, but there are distinct disease associations, e.g. di- lated cardiomyopathy with anthracycline toxicity K Avariety 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 K The most common hypertrophic CM is autosomal dominantly inherited and caused by mutations in sar- comericproteins.Itis themostcommoncause of sud- den deathinyoung adults.Reducing theriskof sudden death is achieved by the use of an implantable cardio- verter de¢brillator in high-risk groups RESEARCHDIRECTIONS Molecular genetic advances are key to the main cardio- myopathies. This will aid risk strati¢cation and guide treatmentwith, for instance, de¢brillators. Ultimately, therapy may have a molecular basis For end stage heart failure, permanently implanta- ble-assist devices are becoming realistic, but molecu- lar advances including myocyte implantation may be achievable THE CARDIOMYOPATHIES The cardiomyopathies are diseases of cardiac muscles as- sociated 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).Correspondence to: MB. Current Paediatrics (2002) 12, 206^211 c 2002 Elsevier Science Ltd doi:10.1054/cupe.2001.0286, available online at on
  2. 2. 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. Arrythmogenicrightventriclecardiomyopathy.Progressive ¢bro fatty replacement of the right ventricular myocardium later involving the left ventricle. 5. Unclassi¢edcardiomyopathies. In the past, cardiomyopathies were de¢ned as being of unknown cause and were, therefore, considered sepa- rately from heartmuscleproblems causedbyknown dis- eases. In recent years, with advances in molecular genetics, the underlying disease processes are beginning to be understood for many of the cardiomyopathies, so that subdivisionsinto primary and secondarycardiomyo- pathies 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 thepathophysiologicalgroup, i.e. di- lated cardiomyopathy may be secondary to adriamycin toxicity. When no association is known, the cardiomyo- pathy may just be de¢ned by its pathophysiology (e.g. dilated cardiomyopathy) or it could be termed idiopathic dilated cardiomyopathyFalthough this term is not com- monlyused.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 mixedgroup of diseases causing cardiac dysfunction in the perinatal period. In£ammatory cardiomyopathy is myocarditis with car- diac dysfunction. It is ‘dilated’ by pathophysiology. It may be infectious, typically enteroviral (coxsackie) or adeno- virus, but many other viruses including HIVand 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 com- plete recovery can occur. Histologically giant cell forma- tion is associated with a poor prognosis. In general, the managementis similar to idiopathic dilated cardiomyopa- thy. 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 dis- eases, SLE, polyarteritis, rheumatoid, scleroderma and dermatomyositis.Other systemic diseases thatcan cause cardiomyopathy include sarcoidosis and leukaemia. The muscular dystrophies are associated with cardiac muscle disease, Duchenne being associated with hyper- trophic changes initially, with dilated cardiomyopathy de- veloping 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 in- heritance, epilepsy, familial diabetes, deafness and skele- tal myopathy. Initially, hypertrophic changes may be seen with poor contraction. Barth syndrome is a mitochon- drial disease with dilated cardiomyopathy, it is X-linked and there is cyclical neutropaenia.Improvement may oc- cur with carnitine therapy (as with other mitochondrial diseases).In¢ltration of the myocardium occurs in a vari- ety of cardiomyopathies causing a range of pathophysiol- ogies including hypertrophic, dilated and restricted. Causesinclude 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 associateddiseases 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.Thismay be apparent on echocardiography but angiography is sometimes needed.The aetiology of the idiopathic group Table 1 Speci¢ccardiomyopathies* Disease Type ofcardiomyopathy Ischaemic CM DCM Valvular CM DCM/HCM Hypertensive CM HCM/RCM Peripartum CM DCM In£ammatory CM DCM Metabolic DCM/HCM/RCM Generalsystem disease DCM Musculardystrophies DCM/HCM Neuromusculardisorders HCM/DCM Sensitive andtoxic reactions DCM *CM, cardiomyopathy; D, dilated; H, hypertrophic; R, restrictive. THE CARDIOMYOPATHIES 207
  3. 3. is probably varied and viral myocarditis (acute and chronic) and autoantibody disease may contribute. Spe- ci¢c abnormalities of the myocyte cytoskeleton have been detected and a widevariety of inheritance patterns recordedincludingrecessive, X-linkedanddominant (the most common). There is an age-related penetrance, which makes screening and counselling di⁄cult. The in- heritance has been described as a molecular maze.2 Re- cently, an abnormality in myosin has been described in familial dilated cardiomyopathy.3 Treatment is essentially that of chronic heart failure. Diuretics areused torelieve symptoms.Data from excel- lent 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 ventricu- lar assist devices may be required for intractable heart failure.7 Ultimately, cardiac transplantation may be required. Hypertrophiccardiomyopathy (Fig. 2) Hypertrophic cardiomyopathy represents a heteroge- nous group of disorders, and this diversityismore appar- ent in childhood than at any other age (Table 2). Familialhypertrophiccardiomyopathy Hypertrophic cardiomyopathy is a primary disease of cardiac muscle in the absence of valvar stenosis, hyper- tension, or other disease processes. Inheritance is auto- somal dominant with variable phenotypic expression. Defects in genes encoding three contractile proteins (cardiac troponinT, beta-myosin heavy chain, and alpha- tropomyosin) can create the phenotypic expression.8,9 Ultimately, the diagnosis of familial hypertrophic cardio- myopathy depends on molecular identi¢cation of the of- fending 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 oc- cursin15^25% of adult subjects. Although syncopeisless 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 cardiomyo- pathy have been well described. Mild or marked left, right or biventricular hypertrophy can be detected by echocardiography.The distribution of hypertrophy in hy- pertrophic cardiomyopathy is characteristically asym- metrical, 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 ob- struction and is an important factor in surgical planning. Figure 1 MRI scan of a patient with dilated cardiomyopathy. Left-hand ¢gure shows the heart in end-diastole; right-hand ¢gure shows the heartin end-systole.Theleft ventricleisgrosslydilated and functionis severelyimpaired. 208 CURRENT PAEDIATRICS
  4. 4. Other echocardiographic ¢ndingsinclude 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 hypoten- sive 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 hy- pertrophy in familial hypertrophic cardiomyopathy is a frequent and important problem in young adults. The cardiac responses to chronic, intensive exercisehasbeen well characterized and include dilation and hypertrophy with preservation of myocardial contractility.The hyper- trophic 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 413mm, is occasionally found in athletes, and the not infrequent occurrence of mild left ventricular hypertro- phy in patients with familial hypertrophic cardiomyopa- thy result in a signi¢cant incidence of diagnostic ambiguity.ECGhas notbeen particularlyhelpfulin di¡er- entiation because of the frequent presence of ECG ab- normalities in athletes. Echocardiographic and clinical features that increase the probability of familial hyper- trophic 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 Figure 2 Cardiac MRI scan of a patient withhypertrophiccardiomyopathy.Topleft ¢gure shows a four-chamber view demonstrat- ing 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 ofthethickenedleft ventriclein end-diastole and end-systole, respectively. Table 2 Causes of hypertrophy 1. Hypertension 2. Congenitalheartdisease 3. Infantofdiabetic mother 4. Drugs, e.g. prenatal and postnatal corticosteroids, tacrolimus, anabolic steroids 5. Metabolicdisease, e.g.GSDII,III, and IV,Fabrys,Icelldisease, mucopolysaccharidosis, carnitine de¢ciency 6. SyndromesFNoonan, Leopard, Friedreich’s ataxia, Beckwith^Weidemann,Costello 7. Familialhypertrophiccardiomyopathy THE CARDIOMYOPATHIES 209
  5. 5. (f) abnormalities in coronary £ow reserve. Ultimately, di¡erentiation by available techniques is sim- ply not possible in some subjects. In infants, restrictive symptoms predominate. High dose beta-blockers may be helpful; disopyramide has beenused to reduce the out£owgradient. Surgery, asyn- chronous dual chamber pacing, and non-surgical septal ablation are all treatment options where pharmacologi- cal agents have been unsuccessful. Surgical or pharmaco- logical reduction in the out£ow gradient in symptomatic patients is usually associated with a reduction in symp- toms, although the incidence of sudden death is not im- proved. 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 cardiomyo- pathy. The implantable de¢brillator is highly e¡ective in terminating malignant ventricular arrhythmias in these patients and shouldbe o¡ered to patientsin the high-risk category for primary and secondary prevention of sud- den 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, exercise- induced hypotension, syncope and symptomatic non- sustained ventricular tachycardia on Holter recording. Additionally, the extent of hypertrophy may be prognos- tic.Patients free of allrisk factors are considered to be at low risk, and interventions (other than for symptoms such as chest pain or exercise intolerance) are not indi- cated. With two or more risk factors or with syncope alone, riskis consideredhigh and aggressivemanagement such as with an implantable cardioverter-de¢brillator is recommended.No consensus has been reached on man- agement of intermediate-risk patients. Additional nega- tive prognostic factors such as evidence of ischaemia on exercise thallium testing, marked QT dispersion, and myocardialbridgingcan alsobeusefulinmanagementde- cisions for these patients.Genotyping may help more ac- curate risk strati¢cation and guidance of treatment.11 Systolic function is nearly always normal or hyperdy- namic. Sudden death in patientsreferred to tertiary care centres is seen annually in 3^5% of adults and 6^8% of children. Recent population studies indicate a much low- er 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 Transoesophagealechocardiogramofapatientwith advanced cardiac in¢ltrative disease (top ¢gure) shows thick- ened myocardial walls and restrictive physiologic features with markedly decreased ratio of pulmonary venous systolic-to- diastolic £ow (middle ¢gure) and shortened deceleration time (100 ms) oftransmitralin£ow E-wave velocity (bottom ¢gure). 210 CURRENT PAEDIATRICS
  6. 6. comparable to those in adults, with normal ventricular size and function, severe elevationin diastolic ¢llingpres- sure and distinct atrial dilatation.14 Unlike adults, paedia- tric cases have been almost consistently idiopathic despite tissue analysisin nearly all, although several cases were familial. Di¡erentiation from many of the second- ary causes, such as myocardial non-compaction (persis- tence of embryonic or ‘spongy’ myocardium), can be made on morphological criteria. Endomyocardial biopsy is sometimesundertaken to exclude anypotentially trea- table 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 chestradiogram or patients with endocardial ¢broelastosis appear to have a worse prognosis. Anticoagulation is recommended because a 25% inci- dence of thromboembolism has been seen in children. Therapy is otherwise non-speci¢c and usually is of very limitedbene¢t.The onset of irreversible elevation in pul- monary 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 ventriculardysplasia Right ventricular dysplasia is an idiopathic cardiomyopa- thy associated with sudden cardiac death. It is of unclear aetiology but thought to be an autosomal dominant dis- order with variable expression and penetrance.This car- diomyopathy 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 sug- gests right ventricular dysplasia.Patients commonly pre- sentwith asymptomatic cardiomegaly (10%) orrecurrent ventricular arrhythmias of leftbundle branch block mor- phology. 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 aT-wave inversion in right precordial leads and localized prolongation of QRS com- plex in right precordial leads.Ventricular tachycardia and frequentventricular extrasystolesmaybe seen.On echo, or better MRI, there may be cardiomegaly with a dilated impaired right ventricle. REFERENCES 1. Richardson P, McKenna W, Bristow M et al. 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