Cardiomyopathies: from genetics to the prospect of treatment

REVIEW

Review

Cardiomyopathies: from genetics to the prospect of treatment Wolfgang-M Franz, Oliver J Müller, Hugo A Katus Cardiomyopathies are defined as diseases of the myocardium associated with cardiac dysfunction ranging from lifelong symptomless forms to major health problems such as progressive heart failure, arrhythmia, thromboembolism, and sudden cardiac death. They are classified by morphological characteristics as hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular (ARVC), and restrictive cardiomyopathy (RCM). A familial cause has been shown in 50% of patients with HCM, 35% with DCM, and 30% with ARVC. In HCM, nine genetic loci and more than 130 mutations in ten different sarcomeric genes and in the ␥2 subunit of AMP-activated protein kinase (AMPK) have been identified, suggesting impaired force production associated with inefficient use of ATP as the crucial disease mechanism. In DCM, 16 chromosomal loci with defects of several proteins also involved in the development of skeletal myopathies have been detected. These mutated cytoskeletal and nuclear transporter proteins may alter force transmission or disrupt nuclear function, resulting in cell death. Further DCM mutations have also been identified in sarcomeric genes, which indicates that different defects of the same protein can result in either HCM or DCM. In ARVC, six genetic loci and mutations in the cardiac ryanodine receptor, which controls electromechanical coupling, and in plakoglobin and desmoglobin (molecules involved in desmosomal cell-junction integrity), have been identified. Yet, no genetic linkage has been shown in RCM. Apart from disease-causing mutations, other factors, such as environment, genetic background, and the recently identified modifier genes of the renin-angiotensin, adrenergic, and endothelin systems are likely to result in the wide variety of RCM clinical presentations. Treatment options are symptomatic and are mainly focused on treatment of heart failure and prevention of thromboembolism and sudden death. Identification of patients with high risk for major arrhythmic events is important because implantable cardioverter defibrillators can prevent sudden death. Clinical and genetic risk stratification may lead to prospective trials of primary implantation of cardioverter defibrillators in people with hereditary cardiomyopathy. Congestive heart failure is a major public health problem in industrialised countries.1 Up to 50 million of the 1000 million people who inhabit the 47 nations in the European Society of Cardiology might have a heart-failure related problem.2 Every year in the USA, around 4·9 million patients are treated with estimated costs of US$18·8 billion, 1 million are admitted to hospital, and about 550 000 new cases of heart failure are diagnosed.3 Prevalence of congestive heart failure has been estimated at between 1% and 2%.2,4 Despite advances in treatment, mortality associated with heart failure remains high. In 1998, heart failure contributed to 240 000 deaths in the USA. Patients with heart failure are classified broadly into two groups on the basis of left ventricular dysfunction: patients with cardiomyopathy resulting from ischaemic (40–74%) and non-ischaemic heart disease (26–35%).5,6,7 In the nonischaemic group hypertension (17%), valvular heart disease (13%), and idiopathic cardiomyopathies (10%) are the main underlying causes.4 Concise analysis of a highly selected group, of patients from a tertiary centre with unknown cardiomyopathy showed that 50% of patients with non-ischaemic heart failure had been diagnosed as having idiopathic cardiomyopathy.8 Several classifications for idiopathic cardiomyopathy have been developed.9 Lancet 2001; 358: 1627–37 Medizinische Klinik und Poliklinik Grosshadern, Klinikum der Universität München, München, Germany (W-M Franz MD); and Medizinische Klinik II, Universitätsklinikum Lübeck, Lübeck, Germany (O J Müller MD, H A Katus MD) Correspondence to: Dr Wolfgang-M Franz, Medizinische Klinik und Poliklinik I-Grosshadern, Klinikum der Universität München, Marchioninistrasse 15, D-81377 München, Germany (e-mail: [email protected])

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Cardiomyopathies are now defined as diseases of the myocardium associated with cardiac dysfunction.10 Four categories of disease are distinguished by morphological and haemodynamical characteristics (panel 1): dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). This classification system also includes specific cardiomyopathies that can be associated with ischaemia, valvular dysfunction, hypertension, myocarditis, metabolic disorders, systemic diseases, muscular dystrophies, neuromuscular disorders, toxic agents, and late pregnancy. Ischaemic cardiomyopathy is a misleading term because it should be used only if coronary heart disease cannot sufficiently explain heart failure according to the classification system. In clinical practice, however, ischaemic cardiomyopathy is used to describe heart failure attributable to myocardial ischaemia. Among the causes of specific cardiomyopathies, genetic factors have not yet been integrated into the current classification system. The role that heritable gene mutations have in cardiomyopathies is increasingly well understood and might substantially alter the knowledge of idiopathic cardiomyopathies.11 In the future, systematic data bases of genetic alterations could affect risk stratification and clinical decisions. In this review, we have summarised clinical presentations, highlighted genetic and molecular findings, and outlined current and future treatments for cardiomyopathies that have a known genetic cause.

Hypertrophic cardiomyopathy Clinical presentation HCM is characterised by left ventricular hypertrophy that is usually asymmetric and can affect various regions of the ventricle (panel 1). Typical histomorphological changes include myocyte hypertrophy and myofibrillar disarray.

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The prevalence of HCM is about 1 in 500 young adults.12 Clinical presentation of HCM ranges from lifelong symptomless forms to sudden cardiac death resulting from mechanical or electrical abnormalities in young adults.13 Likewise, onset of typical symptoms such as dyspnoea, angina, syncope, embolism, congestive heart failure attributable to diastolic dysfunction, myocardial ischaemia, mitral valve regurgitation, arrhythmias, and outflow tract obstruction seems highly variable (panel 1). Diagnosis is often made on the basis of heart murmur, abnormal electrocardiogram, or abnormal results from a screening echocardiogram in athletes or relatives of a patient with known HCM. Two-dimensional echocardiography allows measurement of left ventricular dysfunction, location and extent of hypertrophy, and measurement of intraventricular gradients, which are increased by the Valsalva manoeuvre.14 For proper diagnosis of HCM, other conditions resulting in hypertrophic alterations such as hypertensive heart disease, valvular or supravalvular aortic stenosis, need to be ruled out. Several variants of HCM can be distinguished by morphological criteria. Most patients (70%) present with an asymmetric hypertrophy of the septum and anterior wall of the left ventricle (subaortic variant). Basal septal hypertrophy (⬎15 mm) is seen in about 15–20% of cases, and is frequently associated with arterial hypertension in elderly patients (hypertensive variant). Concentric left ventricular hypertrophy is seen in about 8–10% of patients (diffuse variant). Apical or lateral wall hypertrophies are very rare in the western world (⬍2%). In Japan, however, the apical variant occurs in up to 25% of people with HCM.15 About 25% of patients have hypertrophic obstructions of the left ventricular outflow tract resulting in systolic gradients. In addition to subaortic obstruction, diffuse hypertrophy of mid-ventricular septum and papillary muscles can occur (mid-cavity variant). As the disease progresses, a DCM-like left ventricular dilation can develop in 10–15% of patients (DCM-like variant).16 Catheterisation of the heart shows diastolic dysfunction, mitral regurgitation, and sometimes a systolic pressure gradient between aorta and left ventricular chamber, which increases with the Valsalva manoeuvre. Dynamic characteristics such as postextrasystolic potentiation, Brockenbrough-Braunwald signs, and aortic pressure wave forms of spike-and-dome contours distinguish subaortic stenosis in HCM from valvular and supravalvular forms of

outflow tract obstructions. As well as abnormal shapes and systolic anterior movement of the mitral valve, patients with HCM might present with perfusion abnormalities that could result from compression of intramyocardial branches of coronary arteries. The role of compression of epicardial coronary vessels (myocardial bridging) in HCM is disputed.17 Genetics HCM is an autosomal dominant familial disease in about 50% of patients.18 Patients who do not have a family history of the disease probably have sporadic mutations or mild forms of familial HCM in which phenotypic changes are difficult to detect. Genetic analyses have causally linked nine different chromosomal loci with HCM. Eight of these genes encode cardiac sarcomere proteins, and the recently discovered PRKA␥2 encodes the ␥2 subunit of AMP-activated protein kinase (AMPK) (panel 2).19–28 Two further disease-causing genes have been detected in sporadic cases of HCM.29,30 All these proteins have different roles within the contraction-relaxation cycle and contribute to energy homeostasis of the heart. ␣-myosin heavy chain and ␤-myosin heavy chain interact with actin filaments by hydrolysis of ATP to develop mechanical force; troponin T, troponin I, ␣-tropomyosin, myosin light chain-1, and myosin light chain-2 have regulatory functions; myosin binding protein C has a structural role; and the largest cardiac protein, titin, helps to transmit force (figure).31 About 35% of familial HCM can be attributed to mutations in the gene that codes for ␤-myosin heavy chain, 20% to gene mutations in myosin binding protein C, 15% to gene mutations in troponin T, and less than 3% to mutations of the ␣-tropomyosin gene.21 60% of French and Asian people with HCM have gene mutations, indicating that not all known mutations have been detected.22,32 Furthermore, every gene can have many different mutations. At least 65 mutations in the gene that codes for ␤-myosin heavy chain, 30 in myosin binding protein C, 14 for troponin T, eight for troponin I, eight for myosin light chain-2, four for ␣-tropomyosin, two for myosin light chain-1, two for ␣-actin, one for titin, one for ␣-myosin heavy chain, and two for PRKA␥2 have been identified and can be seen at: http://www.angis.org.au/Databases/Heart/Heartbreak.html (accessed Sept 24, 2001).

Panel 1: Characteristics of cardiomyopathies

Clinical Heart failure Arrhythmias

Sudden death Haemodynamical Systolic function

Hypertrophic cardiomyopathy

Dilated cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy

Restrictive cardiomyopathy

Occasional (LV) Atrial and ventricular arrhythmias

Frequent (LV or BV) Atrial and ventricular arrhythmias, conduction defects Frequent (ND)

Frequent (RV) Ventricular tachycardia (RV), conduction defects

Frequent (BV) Atrial fibrillation

Frequent (ND)

1·5% per year

Reduced

Normal–reduced

Near normal

Reduced

Reduced

Severely reduced

0·7–11% per year

Diastolic function

Hyperdynamic, outflow tract obstruction (occasionally) Reduced

Morphological Cavity size Ventricle Atrium Wall thickness

Reduced (LV) Enlarged (LV or BA) Enlarged (RV) Normal–enlarged (LA) Enlarged (LA or BA) Enlarged (RV) Enlarged, asymmetric (LV) Normal–reduced (LV or BV) Normal–reduced (RV)

Normal or reduced (BV) Enlarged (BA) Normal (BV)

LV=left ventricle. BV=both ventricles. RV=right ventricle. ND=not determined. BA=both atria. LA=left atrium. RA=right atrium.

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Panel 2: Gene defects associated with hypertrophic cardiomyopathy (HCM) Gene product

Chromosome Risk of frequent sudden death

␤-myosin heavy chain

14q11·2–12 High (R403Q, R453C, R719W)

Troponin T Troponin I ␣-tropomyosin Myosin binding protein C Myosin light chain-1 Myosin light chain-2 Actin AMP-activated protein kinase ␥2 ␣-myosin heavy chain Titin

Remarks

Degree of hypertrophy correlates with risk of sudden death 1q3 High (Int15G1_A, ∆E160, R92Q, 179N) High risk of sudden death, mild or absent hypertrophy 19q13.4 High (∆K183) Apical variant of HCM, occasionally DCM-like features in elderly patients 15q22 High (V95A) Usually favourable prognosis, high phenotypical variability 11p11.2 Low Benign clinical course, progressive hypertrophy with rather late onset 3p21 Low Papillary muscle thickening, rare cases 12q23–24.3 Low Papillary muscle thickening, rare cases 15q14 Low Some mutations might also cause primary DCM 7q3 Low Associated with Wolff-Parkinson-White syndrome Spontaneous Low Spontaneous Not applicable

Late onset, rare Only one patient reported

DCM=dilated cardiomyopathy.

Most defects of the ␤-myosin heavy chain gene are missense mutations (panel 2). Some of these mutations (L908V, G256E, and V606M) are associated with a benign clinical course and near-normal life expectancy.19,33 R403Q, R453C, and R719W are malignant mutations associated with substantial hypertrophy and reduction of life expectancy by up to 50% compared with benign gene defects.33 The defective protein is integrated into the thick filament and acts in a dominant negative way that results in a diminished actin-activated ATPase activity and reduced production of force.34 Therefore, hypertrophy could possibly be a means of compensation for low force generation. Another potential mechanism for hypertrophy might be increased cardiac contractility. This mechanism seems to occur with rare defects of myosin light chain-1, myosin light chain-2, and ␣-tropomyosin genes that cause high Ca2+ sensitivity and thus increase force production.25,35 The rare phenotype of mid-ventricular chamber thickening has been associated with myosin light chain-1 and myosin light chain-2 mutations.25 Individuals with mutated ␣-tropomyosin usually show low penetrance and have near-normal life expectancies, apart from those with mutation V95A, which is associated with a high incidence of sudden death despite only mild hypertrophic changes.36 A substantial proportion of genetically affected adults with a benign HCM phenotype can be attributed to the gene for the cardiac myosin binding protein C protein. Typically, prevalence and hypertrophy progress with increasing age. Myosin binding protein C is a structural component of the sarcomere, and binds myosin heavy chain in thick filaments and titin in elastic filaments. In patients with myosin binding protein C, myosin light chain-1, myosin light chain-2, and ␣-tropomyosin gene mutations, hypertrophy seems associated with hypercontractility.37 By contrast with other HCM-causing defects, myosin binding protein C mutants lacking the myosin-binding and titin-binding domains seemingly do not integrate into the sarcomere. Thus, in this case, lack of functional protein rather than a dominant-negative effect could cause HCM.24 Another HCM-causing mutation whose carriers present with mild ventricular hypertrophy is in the gene for troponin T. Unlike mutated forms of myosin binding protein C, defective forms of troponin T are associated with a poor prognosis.20 Expression of the human deletion protein mutant, delex16, in transgenic rats, resulted in

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only mild hypertrophy and a high incidence of ventricular tachycardia, fibrillation, and sudden death.38 The high risk of sudden death in patients with troponin T defects is attributed to altered cardiac energy consumption resulting from an increase in the metabolic cost of force production.39 Thus, myocardial energy demands cannot be met by these genetically altered cardiomyocytes. Cardiac troponin I is the inhibitory component of the troponin complex. One deletion and seven missense mutations were identified in unrelated Japanese families with familial hypercholesterolaemia.22 Three of these Asian troponin I mutations were associated with the apical variant of this disease.22,23 HCM patients with one of these mutations (the deletion mutant ∆K183) have substantial disease penetrance. This mutation is associated with sudden death at any age and DCM-like features can develop in elderly patients.23 Ventricular dilation can be thought of as a transitional form of an HCM that occurs during disease progression. By contrast, mutations in different regions of the cardiac actin gene can cause two separate forms of cardiomyopathy, HCM or DCM.26,40 Analyses of the actin gene in HCM families showed two missense mutations in exon 5 close to two mutations that cause familial DCM (panel 2). This phenotypic heterogeneity can be explained by the specific localisation of the mutations, which cause different secondary changes in the contractile pathway. Both upstream HCM mutations are localised to the surface of actin near a putative myosin-binding site,26 whereas the downstream DCM mutants are located within the immobilised end of actin that cross-binds to anchor polypeptides of the dystrophin-sarcoglycan complex in the sarcolemma (figure). HCM might develop by hypertrophy compensating for inadequate contraction because of impaired myosin binding.26 In DCM, altered actin has been suggested to impair force transmission by defective attachment to anchor polypeptides.40 Therefore, actin mutations seem to lead to HCM if force generation within the sarcomere is affected, and to DCM if force transmission is affected. However, abnormalities of force generation might not be the underlying mechanism of HCM, because no consistent changes in contractile properties are shared by all these mutated sarcomere proteins. Instead, all these mutants seem to result in inefficient use of ATP, which suggests that an inability

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Laminin ␣-2

␦-Sarcoglycan

Extracellullar matrix

Dystroglycans

Dystrophin-associated

Plasma membrane

Emerin

glycoproteins

Lamin A/C Dystrophin

Nucleus

Chromatin

DCM Desmin ␤-Myosin heavy chain

Actin Titin

Z-disc Myosin binding protein C HCM

Myosin light chains-1/2

Actin

␣-Tropomyosin ␣-Actinin ␣-Catenin

ARVC

Troponin I

Troponin T

Plakoglobin

Cytoplasm Cadherins

Plasma membrane

Molecular interaction of affected proteins in dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) Defective proteins that cause DCM=red, HCM=yellow, ARVC=green, and those that cause either DCM or HCM=blue.

to maintain normal ATP levels could be the central abnormality. This theory might be supported by the discovery of the role of a mutant PRKA␥2 gene in HCM (panel 2), which in active form acts as a central sensing mechanism protecting cells from depletion of ATP supplies.28 Therefore, the unifying pathogenetic mechanism in all HCM-like diseases might be energy depletion causing myocardial dysfunction. Although one mutation can account for a specific phenotype, morphological changes that differ between family members carrying the same mutation cannot be explained. Environmental factors such as exercise, and minor cardiovascular abnormalities such as

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hypertension or small intraventricular gradients might contribute to variations in phenotype. Individual genetic backgrounds have been shown to be important, and this work has led to identification of modifier genes that encode proteins of the renin-angiotensin system. Analysis of polymorphisms of the angiotensin converting enzyme in patients with HCM showed that the DD genotype (deletion homozygote), associated with raised plasma concentrations of this enzyme, correlates with the extent of hypertrophy and incidence of sudden death.41 A polymorphism of cardiac chymase, which mainly generates angiotensin II in the myocardium, seems also to modify the HCM

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phenotype.42 Polymorphisms of the angiotensinogen and angiotensin II receptor-1 genes were identified as predisposing factors for cardiac hypertrophy in HCM.43,44As well as components of the renin-angiotensin system, other factors, such as endothelin-1 and tumour necrosis factor α, have been identified as modifier genes associated with HCM.45 Thus, clinical variability of HCM might result not only from genetic and allelic heterogeneity, but also from individual genetic background, which should be assessed by analysis of modifier genes. Since identical mutations in unrelated patients are rare, familial HCM is thought to be a consequence of individual founders. Clinical management HCM is a complex myocardial disease with a diverse clinical course ranging from a lifelong symptom-free presentation to progressive heart failure, sudden death, and stroke associated with atrial fibrillation. There is no cure for HCM and, because of its clinical heterogeneity, no uniform treatment strategy.46 Instead, components of treatment regimens for other cardiovascular diseases are used to treat symptoms. In cases of palpitations, angina, or dyspnoea high-dose ␤-blockers or verapamil-type calcium antagonists should be the first drugs given.47 A diuretic can be added if congestive symptoms persist.46 Chronic atrial fibrillation occurs in 25% of patients with HCM, and should be treated with oral anticoagulants to prevent systemic thromboembolism and stroke.48 If symptoms are refractory to drugs and the patient has a left-ventricular-outflow-tract gradient of more than 50 mm Hg, surgical myotomy-myectomy (Morrow procedure), transcoronary ablation of septal hypertrophy, or dual chamber pacing can be applied.49–51 In the Morrow procedure, a small amount of muscle is surgically resected from the subaortic portion of the septum. The symptomatic benefits largely result from reduction or abolition of outflow tract gradients, which normalises left ventricular pressure. Despite excellent results and low mortality (1–2%) in specialised surgical centres, this technique is not widespread. Few surgical centres have staff with the necessary experience to do this operation, and patients with HCM are often unsuitable candidates for surgery. A novel catheterbased technique has been developed, in which the obstructing myocardium is infarcted by injection of ethanol into the septal branch of the left anterior descending coronary artery.50 This procedure has substantially reduced septal thickness and outflow-tract obstruction, leading to clinical improvement. However, widespread clinical use of this method is hampered by concerns about the high frequency of complete atrioventricular block (17%) requiring pacemaker implantation, mortality of 1–4%, and theoretical risk of infarction-related ventricular arrhythmias.52 Surgical myectomy remains the first choice of treatment if additional operations, such as coronary artery bypass graft surgery, or mitral or aortic valve replacement are considered. Dual chamber pacing has been used in patients with obstructive HCM as an alternative to septal ablation techniques. In this method a substantial initial reduction in the gradient (about 40–50%) has been seen.51 The mechanism by which pacing reduces left-ventricular-outflow gradient, improves symptoms in obstructive HCM, or both is unclear. Because long-term pacing periods were unaccompanied by an objective improvement in cardiovascular performance in most patients, dual chamber pacing is not a routine technique.53

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In addition to treatment of HCM, prophylaxis of sudden death is also important even in symptom-free patients. Risk stratification is now especially important because of the increasing availability of implantable cardioverter-defibrillators and their proven efficacy in prevention of sudden death in patients with HCM.54 The features that most reliably identify high-risk patients include age (⬍30 years) at diagnosis, aborted cardiac arrest, symptomatic ventricular tachycardia on Holter monitor, and a family history of HCM with sudden death. Other indicators of increased risk, such as detection of non-sustained ventricular tachycardia in 48 h Holter monitoring, syncope, exercise bloodpressure response, and left ventricular wall thickness have low positive, but high negative, predictive values.55 Therefore, absence of these risk factors indicates a good prognosis of disease. The presence of two or more risk factors is associated with a 4–5% yearly risk of sudden death.55 Thus, prophylactic antiarrhythmic therapy is important. Obstruction of the outflow tract is not thought to be a risk factor for sudden death.56 However, the magnitude of the hypertrophy is directly related to the risk of sudden death and is a strong predictor of disease prognosis. Young patients with extreme hypertrophy, even with few or no symptoms, have a substantial long-term risk and require prophylactic antiarrhythmic therapy. The efficacy of implantable cardioverter-defibrillators for primary and secondary prevention of sudden death in HCM patients has been shown in a retrospective multicentre trial.54 Appropriate defibrillation, mainly triggered by ventricular tachycardia or fibrillation, was 5% and 11% per year for primary and secondary prevention groups, respectively. These findings might lend support to the theory that these antiarrhythmic events are the main mechanisms for sudden death. More than a third of patients were taking amiodarone at the time of implantable cardioverterdefibrillator discharge. Amiodarone no longer seems the first line antiarrhythmic drug for HCM patients—the only results that support its protective effect are from a retrospective, non-randomised case-control study from 1985. Treatment recommendations for patients with single risk factors have not yet been developed because few genotyped families exist. Different genes carry diverse clinical prognoses, which might allow identification of individuals at high risk. Mutations of the genes encoding myosin light chain-1, myosin light chain2, myosin binding protein C, and ␣-myosin heavy chain result in better disease prognoses than defects in ␤myosin heavy chain, troponin T, and troponin I. Furthermore, distinct mutations in the same gene have different risks of sudden death (panel 2). The missense mutations R403Q, R453C, and R719W of ␤-myosin heavy chain and V95A of ␣-tropomyosin as well as the deletion mutants of troponin T (Int15 G1→A) and troponin I (∆K183) are thought to be highly malignant.20,23,33,36 By contrast, L908V, G256E, V606M of ␤-myosin heavy chain and R92L of troponin T are generally associated with near-normal life expectancy. From the diagnostic point of view, malignant disease might be predictable with ␤-myosin heavy chain mutations by the extent of ventricular hypertrophy. However, for clinicians, identification of malignant mutations of troponin T, troponin I, and ␣-tropomyosin genes will be important, even in symptom-free patients. In the future, a global registry of cardiomyopathic mutations will contribute to genetic risk stratification and could lead to prospective clinical trials analysing prevention of sudden death.

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Dilated cardiomyopathy Phenotype DCM is a heart muscle disease characterised by dilation and impaired contraction of the left or both ventricles that results in progressive heart failure and sudden cardiac death from ventricular arrhythmia. DCM is also frequently associated with conduction defects. Histomorphological changes typically include extensive areas of subendocardial, focal interstitial, and perivascular fibrosis as well as hypertrophic and atrophic myofibres. The prevalence of DCM in a general population is 40–50 cases per 100 000.57 Specific types of DCM are associated with specific cardiac or systemic disorders such as neuromuscular disorders, glycogen storage diseases, mucopolysaccharidosis, and disorders of fatty acid metabolism, especially those occurring in childhood.58,59 Clinical presentation of DCM ranges from symptomless forms to heart failure, stroke from thromboembolism, arrhythmias, and sudden cardiac death.60 Fatigue, weakness, and exercise intolerance resulting from diminished cardiac output are often progressive. About a third of patients have chest pain. DCM presents similarly in all patients: marked dilation of the left ventricular cavity, normal or thin wall thickness, and globally reduced systolic and disturbed diastolic function can be detected from echocardiograms (panel 1). Cardiac catheterisation usually shows raised filling pressure. The hallmark of DCM is left ventricular enlargement with a reduction of ejection fraction and cardiac output. Endomyocardial biopsies in non-transplant patients with advanced heart failure show that around 15% have specific heart-muscle disorders such as inflammatory myocarditis, amyloidosis, sarcoidosis, and haemochromatosis. Coronary arteriography usually shows that vessels are normal. However, coronary vasodilation capacity can be impaired by increase of left ventricular filling pressure, which causes anginal pain, abnormal Q waves on electrocardiograms, or regional left ventricular wall motion abnormalities in some patients. Genetics About 35% of adult patients present with familial DCM,61 but there is no universal classification system for this disease. Familial DCM can be divided into four major groups according to distinct clinical presentation: 1) DCM with rapid progression in young men, 2) DCM with mainly left ventricular dysfunction, 3) DCM with early conduction disease, and 4) DCM with sensorineural hearing loss (panel 3).62–70 Skeletal muscle might be associated with all phenotypic presentations. Results from genetic studies have linked familial DCM with several chromosomal loci. Analysis of genes associated with skeletal muscle dystrophy or HCM has identified specific mutations that result in inherited DCM.62,63 For example, a rare form of X-linked DCM mainly occurs in young men and has rapid progression. The dystrophin gene was a promising candidate for this disease because cardiomyopathy is frequently noted in patients with Duchenne and Becker muscular dystrophy. Dystrophin is a subsarcolemmal rod-shaped protein encoded by a gene on the X chromosome. The protein is thought to stabilise the sarcomere by attaching the actin cytoskeleton to the extracellular matrix via the dystrophinassociated glycoprotein complex (figure). The cardiac phenotype of some dystrophin mutations could result from alteration of the promoter region required for specific expression of this protein in cardiomyocytes, or from conformational changes of dystrophin rod or hinge regions.62,63 Deletion of exon 29 from the midrod region

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disrupts sarcoglycan assembly in heart but not skeletal muscle.63 ␣-dystroglycan, ␤-dystroglycan, and the sarcoglycan subcomplex form the dystrophin-associated glycoprotein complex that links dystrophin via laminin ␣2 to the extracellular matrix.58 Distinct dystroglycans can be absent in patients with X-linked DCM as a result of mutations in the dystrophin gene. Sarcoglycan mutations cause several forms of limb girdle muscular dystrophy that are occasionally associated with DCM.71 Defects in the ␦-sarcoglycan gene result in limb girdle muscular dystrophy 2F that is autosomally recessive.72 Different mutations in the same gene can cause primary DCM presenting with high incidence of sudden death and congestive heart failure without symptoms of muscular dystrophy.66 The role of the dystrophin-associated glycoprotein complex in the development of DCM has been clarified by work in mice showing that cleavage of dystrophin by an enteroviral protease results in disruption of this complex.73 Since these alterations have similar effects to DCM caused by dystrophin or sarcoglycan mutations, disruption of cytoskeletal integrity could be a common feature of hereditary and acquired forms of DCM. Conduction abnormalities associated with cardiomyopathy are frequent in Emery-Dreifuss muscular dystrophy presenting with joint contractures in early childhood.58 This type of muscular dystrophy occurs either as an X-linked disease caused by mutations of the emerin gene, or as an autosomal dominant trait resulting from mutations of lamin A/C.74,75 Both these genes encode proteins of the nuclear membrane and might regulate molecular movement between cytoplasm and nucleus. Five of 11 families with DCM and conduction disease had defects of lamin A/C, which suggests that mutations of this gene frequently cause this particular phenotype.67 The mechanism by which mutations of the lamin A/C gene alter cardiac function is not known but could be dysfunction of the nuclear membrane resulting in cell death. By contrast with the other proteins affected in DCM, lamin A/C does not bind to cytoskeletal proteins. Therefore, impaired function of the nuclear membrane could be an alternative mechanism for disease. Conduction abnormalities associated with DCM are also common in desmin myopathy.76,77 A desmin mutation has been detected in a family with a history of DCM without skeletal muscle involvement.68 The main cardiac manifestation of this mutation might be explained by the distinct localisation within the desmin gene affecting the protein structure that is mainly relevant for the function of cardiomyocytes. Desmin is associated with Z-lines and intercalated discs (figure), and with stabilisation of sarcomere and attachment of Z-discs to plasma membrane. A defective desmin protein could result in impaired force transmission or in contraction-induced cellular damage. Furthermore, desmin also attaches to the nuclear envelope, thus defects in the nuclear membrane might be another cause of cellular damage. Identification of mutated actin genes in two families with predominant left-ventricular dysfunction40 further supported the hypothesis that development of DCM results from impaired anchoring of the sarcomere. One of these defects was located in a shared binding domain for ␣-actinin and dystrophin, which are both associated with Z-bands and intercalated discs. By contrast, mutations in the myosin binding region of actin resulted in compensatory hypertrophy that produced the phenotype of HCM.26 Therefore, mutations in actin can lead to HCM if they affect force generation, or to DCM if force transmission from sarcomere to surrounding syncytium is

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Panel 3: Gene defects associated with dilated cardiomyopathy (DCM) Gene product

Chromosome

Skeletal involvement

Frequent sudden death (SD) or rapid progressive heart failure (HF)

Dystrophin

Xp21

Mild

HF

Tafazzin

Xq28

Mild

HF

Troponin T ␦-Sarcoglycan ␤-MHC Actin

1q3 5q33–q34 14q11·2–12 15q14

Not reported SD, HF (⌬k210) None/subclinical SD, HF (⌬k238) None HF (S532P, F764L) Not reported

NK

1q32

Not reported

NK

2q31

None

NK

9q13–22

None

NK

1Oq21–23

Not reported

Lamin A/C

1q21·3

None/mild

Desmin

2q35

None/severe

NK NK

2q14–q22 3p22–25

Not reported Not reported

NK

6q23

Severe

NK

6q23–24

None

tRNA-Lys

Mitochondrial Mild DNA

HF

SD

Remarks

DCM with rapid progression in young men Rapid progression to end-stage heart failure Usually fatal in infancy, rare survival to adults

Mutations of the same gene cause primary muscle dystrophy (MD)

Becker and Duchenne MD Barth Syndrome Endocardial fibroelastosis

DCM with mainly LV dysfunction Early-onset ventricular dilatation HCM Early-onset ventricular dilatation Limb girdle MD 2F Early-onset ventricular dilatation HCM Defect located in dystrophin-binding HCM region First to second decade, incomplete penetrance Native American family, incomplete penetrance Large Italian family, incomplete penetrance Mitral valve prolapse, occasionally sudden death DCM with early conduction disease Frequently in DCM with conduction Emerey-Dreifuss MD, abnormalities limb girdle MD 2B Syncope, can develop severe skeletal Desmin myopathy myopathy Frequently ventricular tachycardia Associated with sick sinus syndrome and stroke Associated with adult onset limb girdle MD DCM with sensorineural hearing loss Associated with juvenile sensorineural hearing loss Involvement of organs with high oxidative metabolism: heart, cochlea, brain, skeletal muscle

LV=left ventricular. HCM=hypertrophic cardiomyopathy. MHC=myosin heavy chain. NK=not known.

affected. Other DCM mutations causing early-onset ventricular dilation have been identified in ␤-myosin heavy chain (S532P, F764L) and troponin T (∆K210) genes. These discoveries support the hypothesis that different defects of the same protein can result in HCM or DCM.65 Finally, specific mutations in mitochondrial DNA leading to altered energy production might have a substantial role in development of DCM with sensorineural hearing loss.70,78,79 Cardiac and cochlear effects could result from the high oxidative metabolism in these organs. The wide range of clinical presentations that can occur within one family is poorly understood. Polymorphisms of endothelin receptor type A, ␤1–adrenoceptor and ␤2–adrenoceptor, or AMPD1 gene could cause some of the phenotypic differences.80–84 Other promising candidates for development of DCM are muscle LIM protein and metavinculin. Lack of muscle LIM protein, a structural protein linking sarcomeres to the cytoskeleton, leads to development of DCM in transgenic mice.85 Absence of metavinculin, a protein that forms intercalated discs that mediate attachment of

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sarcomeres to the plasma membrane, has been described in only one patient with DCM.86 Further candidate genes for DCM are those that encode calpain-3, laminin ␣-2, myotonin-protein kinase, and emerin, which are also associated with skeletal myopathies with variable cardiac effects.58 Clinical management From genetic analyses, familial DCM is frequently associated with primary skeletal myopathies. Therefore, patients presenting with muscular dystrophy should receive cardiological assessment. A family history should be carefully obtained for congestive heart failure, sudden cardiac death, conduction disease, atrial fibrillation, and stroke. Similarly, patients presenting mainly with DCM should have neurological assessment of muscular involvement. Because of the high incidence of familial DCM, a family history should be used to identify affected relatives for clinical and genetic assessment. Specific treatments for most patients with DCM are not available. The main targets of treatment are control of symptoms and disease progression by drugs, and

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prevention of thromboembolism and sudden cardiac death.60 Activation of the renin-angiotensin-aldosterone system has a central role in the pathophysiology of heart failure. Therefore, all patients should receive high dose angiotensin converting enzyme inhibitors. Since such inhibition usually results in a transient decrease in aldosterone concentrations, the aldosterone antagonist spironolactone should be given to patients with moderate or severe heart failure.87 When appropriate, angiotensin II receptor antagonists can serve as alternatives88 but these do not inhibit bradykinin metabolism, and thus do not have a potentially beneficial vasodilatory effect. Because of the clear mortality benefit of ␤-blockade, all patients, including those with severe heart failure, should receive carefully measured doses of metoprolol, bisoprolol, or carvedilol.5,7 Diuretics can also be given to improve congestive symptoms. Since there is a substantial risk of thromboembolic complications in patients with DCM, anticoagulants are advisable in patients with atrial fibrillation, evidence of intracardiac thrombus formation, or history of stroke. Despite the lack of prospective randomised trials, patients with more than moderate ventricular dilation and moderate-to-severe systolic dysfunction should be advised to take vitamin K antagonists. If symptoms of heart failure are resistant to drugs, heart transplantation, partial left ventriculectomy (Batista procedure), or left ventricular assist devices are further treatment possibilities.60 Ventricular resynchronisation therapy by left ventricular or biventricular stimulation is a possible new option for patients with advanced heart failure and intraventricular conduction disturbances.89 Rapid disease progression must be monitored, especially in young men with suspected X-linked DCM or Becker muscular dystrophy. Such progression could affect clinical decisions, since malignant mutations of the dystrophin gene have been associated with rapid progression into end-stage heart failure.63 These patients should be prepared for transplantation early after initial diagnosis. DCM can frequently be complicated by sudden cardiac death. Patients with aborted cardiac arrest or sustained ventricular tachycardia, who also had left ventricular ejection fraction of 35% or less, derived substantially more benefit from treatment with implantable cardioverter defibrillators than those with better preserved ventricular function.90 Compared with amiodarone treatment, patients with implantable cardioverter defibrillators had a 28% reduction in relative risk of death resulting from an almost 50% reduction in arrhythmic death.90 Furthermore, decreased heart rate variability, and combination of non-sustained ventricular tachycardia with a left ventricular end-diastolic diameter of 70 mm or with an ejection fraction of 30% or less, are independent predictors for malignant arrhythmias or sudden death.91

Whether patients without symptomatic ventricular arrhythmias, family history of sudden cardiac death, or both benefit from implantable cardioverter defibrillators has not yet been shown.92 Identification of risks associated with specific gene mutations could help to select patients who are most suitable for primary treatment with these devices.

Arrhythmogenic right ventricular cardiomyopathy ARVC, formerly called arrhythmogenic right ventricular dysplasia, is characterised by progressive fibrofatty replacement of right ventricular myocardium with progressive effects on the right ventricle.93 The incidence and prevalence of this disease are not documented. Clinical presentation is characterised by arrhythmias of right ventricular origin ranging from premature beats to sustained ventricular fibrillation resulting in sudden death.93 A study of sudden death in a northern Italian population of young people showed that previously undiagnosed ARVC seems to cause 20% of such events. Disease progression often leads to effects on the left ventricle and subsequent heart failure, and can mimic DCM.93 However, by contrast with DCM, ARVC affecting both ventricles generally presents with disproportional right ventricular dilation and dysfunction. Replacement of the right ventricular myocardium by fibrofatty tissue seems to be a degenerative process caused by progressive death of cardiomyocytes. Apoptosis and inflammation, sometimes comparable with an active myocarditis, are seen in the affected region. However, whether these findings are the cause or an effect is not known. Since ARVC presents as familial disease in at least 30% of patients, genetic factors might be important. Linkage studies have been used to map the disease to several loci (panel 4).94 Apart from a few families, hereditary transmission is autosomally dominant. Mutations in the cardiac ryanodine receptor gene have been identified in four separate families from northern Italy.94 The ryanodine receptor plays a crucial part in electromechanical coupling by control of release of calcium from the sarcoplasmic reticulum into the cytosol. Therefore, defects in this receptor could result in an imbalance of calcium homeostasis that might trigger cell death. In families with recessive transmission, ARVC cosegregates with palmoplantar keratosis and woolly hair (Naxos disease). Molecular analyses have shown defects in the plakoglobin gene in one family and in the gene for desmoglobin in three others. Plakoglobin and desmoglobin are proteins that maintain desmosomal cell junction integrity (figure).95,96 Disruption of desmosomal function by defective proteins might lead to death of myocytes under mechanical stress. The pathogenetic

Panel 4: Gene defects associated with arrhythmogenic right ventricular cardiomyopathy Gene product Plakoglobin Desmoplakin Ryanodine receptor NK NK NK NK NK

Chromosome 17q21 6p23–p24 1q42

Inheritance Autosomal recessive Autosomal recessive Autosomal dominant

2q32 3p23 1Op12–p14 14q12 14q23

Autosomal dominant Autosomal dominant Autosomal dominant Autosomal dominant Autosomal dominant

Remarks Associated with palmoplantar keratoderma and woolly hair (Naxos disease) Associated with palmoplantar keratoderma and woolly hair (Naxos disease) Identification of four different mutations in independent families

NK=not known.

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mechanism of defective cellular junctions in this familiar form of ARVC seems to be similar to that in DCM, which also presents with ventricular dilation and is associated with defective cytoskeletal proteins. However, identification of further gene mutations that cause ARVC will establish whether apoptosis from defective cellular junctions or impaired calcium homeostasis damages the right ventricle. The importance of the right, rather than the left, ventricle in ARVC could result from affected proteins having different roles or expression in right and left ventricular myocardium. Diagnosis of ARVC is based on structural, histological, electrocardiographic, and genetic factors. However, because these criteria have not been prospectively assessed in a large population many patients with mild disease could be missed. Furthermore, right ventricular fibrofatty replacement could easily be missed in endomyocardial biopsies, which for safety are usually taken from the septal region often unaffected by ARVC. Whether magnetic resonance imaging could produce a useful analysis of the ventricular wall is not yet known. Treatment for AVRC ranges from ␤-blocker, class I or class III antiarrhythmic drugs, and catheter ablation in patients presenting with non-lifethreatening ventricular tachycardia, to implantable cardioverter defibrillators in patients with high risk of sudden death.97 As yet, no prospective studies have assessed the best treatment approach. Patients with heart failure should receive standard treatments for this disorder. With disease progression heart transplantation might be required.

Conclusion Identification of cardiomyopathy-causing mutations has shed new light on molecular and functional mechanisms. Location of the defect within a gene affects development of clinical phenotype. Functional studies and development of transgenic models are needed to understand the pathways leading from altered gene to clinical phenotype. Given the range of phenotypes in familial cardiomyopathies, the role of modifier genes will also need to be identified. When routine identification of clusters of mutations becomes possible by rapid screening methods and improved technology for gene sequencing, a systematic analysis of cardiomyopathies could lead to tailored therapy for patients with different genotypes.

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dysfunction: SCD-HEFT and MADIT-II. J Am Coll Cardiol 1999; 83: 91–97. 93 Corrado D, Basso C, Thiene G, et al. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenterstudy. J Am Coll Cardiol. 1997; 30: 1512–20. 94 Tiso N, Stephan DA, Nava A, et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet 2001; 10: 189–94. 95 McKoy G, Protonotarios N, Crosby A, et al. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair. Lancet 2000; 355: 2119–24. 96 Norgett EE, Hatsell SJ, Carvajal-Huerta L, et al. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet 2000; 9: 2761–66. 97 Corrado D, Fontaine G, Marcus FI, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: need for an international registry. Study Group on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy of the Working Groups on Myocardial and Pericardial Disease and Arrhythmias of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the World Heart Federation. Circulation 2000; 101: E101–06.

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