The term cardiomyopathy denotes an exclusive group of disorders in which the primary defect is in the myocardium, affecting cardiac myocyte structure and/or function. The primary defect, however, does not need to be exclusive to the heart. It can also involve other tissues and organs, as in cardiomyopathies arising from metabolic disorders and mitochondrial myopathies. Myocardial dysfunction can also occur because of systemic, infiltrative, restrictive, toxic, and endocrine disorders, coronary atherosclerosis, and valvular pathologies. In such conditions, the primary defect is not in the myocardium. Thus, myocardial involvement is considered secondary. In a sense, cardiac involvement in such disorders does not meet the pure definition of cardiomyopathy.
Cardiomyopathies are classified according to their phenotypic characteristics. The four common groups are hypertrophic, dilated, arrhythmogenic, and restrictive cardiomyopathy. Phenotypic classification, although clinically convenient and useful, does not necessarily reflect the molecular and genetic basis of cardiomyopathies.
Genetic Basis of Hypertrophic Cardiomyopathy
HCM is a relatively common autosomal dominant disease diagnosed clinically by the presence of unexplained cardiac hypertrophy.90,91 Commonly, a left ventricular wall thickness of 13 mm or greater, in the absence of hypertension or valvular heart disease, is used to define HCM.90 The prevalence of HCM is approximately 1 in 500 in young adults.92 It is likely higher in the elderly population because of age-dependent penetrance.
Cardiac hypertrophy, the clinical hallmark of HCM, is asymmetric in approximately two-thirds of the cases with predominant involvement of the interventricular septum (Fig. 55–7). Hence, the term asymmetric septal hypertrophy is used to describe this condition. Occasionally, hypertrophy is restricted to apex of the heart (apical HCM). Morphologically, the left ventricular cavity is small and the left ventricular ejection fraction, a measure of global systolic function, is increased. However, more sensitive indices of myocardial function show impaired contraction and relaxation secondary to “myocyte disarray.”93,94 Diastolic function is commonly impaired, leading to an increased left ventricular end-diastolic pressure and thus frequently to symptoms of heart failure.
Main pathologic features of hypertrophic cardiomyopathy. A. Gross cardiac hypertrophy with predominant involvement of the interventricular septum and a small left ventricular cavity. B. Myocyte disarray and hypertrophy. C. Interstitial fibrosis.
Patients with HCM exhibit protean clinical manifestations ranging from minimal or no symptoms to severe heart failure. The clinical manifestations often do not develop until the third or fourth decades of life, but the onset is variable. The majority of patients are asymptomatic or mildly symptomatic. Predominant symptoms include dyspnea, chest pain, palpitations, and/or syncope. Severe systolic heart failure is uncommon. It occurs in a small fraction of patients in whom the disease evolves into a dilated cardiomyopathy (DCM) phenotype. In contrast, cardiac diastolic function is usually impaired and left ventricular end-diastolic pressure is elevated. A dynamic left ventricular outflow is present in approximately 25% of the patients. It could contribute to mitral regurgitations and symptoms of heart failure. Left ventricular outflow tract obstruction is an important determinant of heart failure in patients with HCM.95 Cardiac arrhythmias, in particular atrial fibrillation and nonsustained ventricular tachycardia, are relatively common and are associated with adverse clinical outcome.96 Wolff-Parkinson-White (WPW) syndrome is present in about 5% of patients with HCM.97 Its presence suggests the possibility of a phenocopy, typically a glycogen storage disease (discussed later in this chapter).98
Unexplained syncope is a serious symptom.99,100,101 It is often a result of serious cardiac arrhythmias and associated with an increased risk of sudden cardiac death (SCD).99,101,102 HCM, although uncommon, is the most common cause of SCD in young, competitive athletes.103 It accounts for almost half of all cases of SCD in athletes younger than 35 years of age in the United States.103 SCD is often the first and tragic manifestation of HCM in young apparently healthy individuals. Table 55–6 lists the factors associated with an increased risk of SCD. Overall, in the assessment of the risk of SCD, the combination of all known risk factors should be considered. In the absence of major risk factors for SCD, HCM has a relatively benign course with an estimated annual mortality of about 1% in the adult population and even less in those who have undergone a defibrillator implantation.91,104 Apical HCM is characterized by giant T-wave inversion in the precordial leads on the electrocardiogram. The overall prognosis of patients with apical HCM is similar to those with the garden-variety form of HCM.91,105
TABLE 55–6.Potential Risk Factors for SCD in Patients with HCM ||Download (.pdf) TABLE 55–6. Potential Risk Factors for SCD in Patients with HCM
|Aborted SCD (sudden cardiac arrest) |
|Family history of SCD (more than 1 victim of SCD) |
|Causal mutations, including double mutations |
|Genetic background (modifier genes, which might be obtained by family history) |
|History of unexplained syncope |
|Severe cardiac hypertrophy |
|Sustained and repetitive nonsustained ventricular tachycardia |
|Left ventricular outflow tract gradient |
|Histologic phenotypes (interstitial fibrosis and myocyte disarray) |
|Abnormal blood pressure response to exercise |
The pathologic hallmark of HCM is cardiac myocyte disarray.106 It is defined as maligned, distorted, and often short and hypertrophic myocytes oriented in different directions (Fig. 55–7). Myocyte disarray often comprises more than 20% of the ventricle, as opposed to < 5% of the myocardium in normal hearts.107,108 It is more prominent in the interventricular septum, but commonly is found throughout the myocardium. Other pathologic features of HCM include myocyte hypertrophy, interstitial fibrosis, thickening of media of intramural coronary arteries and, on occasion, malpositioned mitral valve with elongated leaflets. In addition to cardiac hypertrophy and myocyte disarray, interstitial fibrosis is also associated with the risk of SCD, mortality, and morbidity in patients with HCM.109,110 Late gadolinium enhancement is used as a surrogate marker for interstitial fibrosis and is a predictor of the risk of SCD in patients with HCM.109,110 Other pathologic features of HCM include thickening of the media of intramural coronary arteries, abnormal positioning of the mitral valve apparatus, and elongated mitral valve leaflets.
Molecular Genetics of Hypertrophic Cardiomyopathy
HCM is a genetically heterogeneous disease with an autosomal dominant mode of inheritance. Approximately two-thirds of patients have a family history of HCM. In the remainder, the disease is sporadic. Familial and sporadic cases both are caused primarily by mutations in contractile sarcomere proteins.90,91 In sporadic cases, mutations are de novo and could be transmitted to the offspring of the index cases.111 Because hypertrophy is a common response of the heart to all forms of injury or stimuli, a phenotype of hypertrophy in the absence of an increased external load could also occur because of mutations in genes encoding proteins other than sarcomere proteins. As such, unexplained cardiac hypertrophy, which clinically denotes HCM, could also occur in storage disorders, metabolic disorders, mitochondrial diseases, and triplet repeat syndromes, as well as congenital heart diseases.90,112 Although the gross phenotype is similar, the pathogenesis of HCM caused by different classes of mutant proteins, at least in part, could differ. Therefore such conditions are considered phenocopy (diseases mimicking HCM).
Causal Genes and Mutations
The pioneering works of Christine and Jonathan Seidman have led to elucidation of the molecular genetic basis of HCM. In 1990, an arginine-to-glutamine substitution at codon 403 (R403Q) in the β-myosin heavy chain (MHC) was identified as the first causal mutation.113 Since then, several hundred different mutations in more than a dozen genes encoding sarcomere proteins have been identified (Table 55–7). Consequently, HCM (excluding phenocopy conditions) is considered a disease of contractile sarcomere proteins (Fig. 55–8). Systematic screening of sarcomere genes suggests that mutations in MYHC and MYBPC3, which encode β-MHC and myosin-binding protein C (MYBPC3), respectively, are the most common causes of human HCM, together accounting for approximately half of all cases.114,115,116,117 Mutations in TNNT2 and TNNI3, encoding cardiac troponin T and I, respectively, are relatively uncommon, each accounting for approximately 3% to 5% of HCM cases.117 Thus, mutations in MYH7, MYBPC3, TNNT2, and TNNI3 collectively account for approximately 60% of all HCM cases. A small fraction of HCM cases are caused by mutations in genes encoding αtropomyosin (TPM1), titin (TTN), cardiac α-actin (ACTC), telethonin (TCAP), and essential and regulatory light chains (MYL3 and MYL2, respectively).90 Rare mutations in several other genes coding for thick and think filament of the sarcomeres as well as the Z-disk proteins have been reported.118,119 Likewise, rare mutations in non-sarcomere proteins, including calcium regulatory proteins, are associated with HCM.118,119 Overall, the causal genes and mutations for approximately two-thirds of HCM cases have been identified. The remainder remain to be identified and/or might be caused by phenocopy conditions.
TABLE 55–7.Causal Genes for Hypertrophic Cardiomyopathy ||Download (.pdf) TABLE 55–7. Causal Genes for Hypertrophic Cardiomyopathy
|Gene product ||Gene ||Frequency ||Predominant Mutations |
|Genes Coding for Thick-Filament Proteins |
|β-Myosin heavy chain ||MYH7 ||~25% ||Missense mutations |
|Myosin binding protein-C ||MYBPC3 ||~25% ||Splice-junction and insertion/ deletion |
|α-Myosin heavy chain ||MYH6 ||Rare ||Missense and rearrangement mutations (association) |
|Essential myosin light chain ||MYL3 ||< 3% ||Missense mutations |
|Regulatory myosin light chain ||MYL2 ||< 3% ||Missense and 1 truncation |
|Muscle ring protein 1 (MuRF1) ||TRIM63 ||< 1% ||Missense and stop codon |
|Genes Coding for Thin-Filament Proteins |
|Cardiac α-actin ||ACTC ||< 3% ||Missense mutations |
|Cardiac troponin T ||TNNT2 ||~3-5% ||Missense mutations |
|Cardiac troponin I ||TNNI3 ||~3-5% ||Missense and deletion |
|Cardiac troponin C ||TNNC1 ||Rare ||Missense mutations (association) |
|α-Tropomyosin ||TPM1 ||< 3% ||Missense mutations |
|Titin ||TTN ||< 3% ||Missense mutations |
|Z Disk Proteins |
|Telethonin (Tcap) ||TCAP ||Rare ||Missense mutations |
|Myozenin 2 ||MYOZ2 ||1:250 ||Point mutations |
|α-Actinin ||ACTN2 ||Rare ||Point mutations |
|Caveolin 3 ||CAV3 ||Rare ||Point mutations |
|Phospholamban ||PLN ||Rare ||Point mutations |
|Calsequestrin ||CASQ2 ||Rare ||Point mutations |
|Junctophilin 2 ||JPH2 ||Rare ||Point mutations |
Schematic representation of sarcomere proteins involved in cardiomyopathies.
Molecular Genetics of HCM Phenocopy
A phenotypic feature of several diseases, particularly storage diseases, is cardiac hypertrophy mimicking HCM, and hence such conditions are referred to as HCM phenocopy. Despite phenotypic similarities, however, the distinction between true HCM and HCM phenocopy is important, as the pathogenesis of the two conditions differs. Table 55–8 provides a partial list of HCM phenocopy conditions. The prevalence of HCM phenocopy is not precisely known, but might comprise approximately 5% to 10% of the clinically diagnosed adult cases with HCM, and even more in children.120,121,122 A prototypic example of HCM phenocopy is Fabry disease, an X-linked lysosomal storage disease.121,122 Fabry disease is present in approximately 1% to 5% of cases with the clinical diagnosis of HCM in the adult population.122,123 The causal gene is GLA on chromosome Xq22, which codes for lysosomal hydrolase α-galactosidase A (α-Gal A) protein.124 The phenotype results from deficiency of α-Gal A, also known as ceramide trihexosidase. Deficiency of the enzyme results in deposits of glycosphingolipids in multiple organs, including the heart. The phenotype is characterized by angiokeratoma, renal insufficiency, proteinuria, neuropathy, transient ischemic attack, stroke, anemia, corneal deposits, and cardiac hypertrophy. Cardiac hypertrophy, which is often indistinguishable from the true HCM, is associated with high QRS voltage, conduction defects, cardiac arrhythmias, and SCD. Other cardiac phenotypes include valvular regurgitation, coronary artery disease, myocardial infarction, and aortic annular dilatation.121,122,123 The disease predominantly affects males. Female carriers could exhibit a milder form. The diagnosis is established by measuring α-Gal A levels and activity in leukocytes. However, in many cases the diagnosis is difficult to establish, both at the genetic level as well as after measurement of α-Gal A enzymatic activity. Enzyme replacement therapy using human α-Gal A (agalsidase α) or recombinant human α-Gal A (agalsidase β) has been advocated with some evidence of improvement in progression and reversal of the disease.125,126,127,128
TABLE 55–8.Genes Known to Cause Hypertrophic Cardiomyopathy Phenocopy ||Download (.pdf) TABLE 55–8. Genes Known to Cause Hypertrophic Cardiomyopathy Phenocopy
|Gene Symbol ||Protein ||Frequency |
|GLA ||α-Galactosidase A ||3% |
|PRKAG2 ||adenosine monophosphate activated protein kinase, γ subunit ||1–2% |
|LAMP2 ||Lysosome-associated membrane protein 2 ||1–2% |
|MOY6 ||Unconventional myosin 6 ||Rare |
|FRDA ||Frataxin (Friedreich ataxia) ||Rare |
|PTPN11 ||Protein tyrosine phosphatase, nonreceptor type 11 ||Uncommon, higher in children |
|DMPK, DMWD ||Myotonin protein kinase (Myotonic dystrophy) ||Uncommon |
|TTR ||Transthyretin ||Rare |
|FHL1 ||Four and a half LIM domain 1 ||Rare |
|MTTG, MTTI ||Mitochondrial genes ||Rare |
Glycogen storage disease caused by mutations in the PRKAG2 gene is another HCM phenocopy.98,129,130,131,132 Cardiac hypertrophy results predominantly from storage of glycogen in myocytes but probably also from cardiac myocyte proliferation.133 The gene encodes the γ2 regulatory subunit of adenosine monophosphate (AMP)-activated protein kinase (AMPK), which is considered the energy biosensor of the cell. Mutations in PRKAG2 lead to cardiac hypertrophy, conduction defects, and WPW.98,129,132
HCM phenocopy also occurs in trinucleotide repeat syndromes, a group of genetic disorders caused by expansion of naturally occurring trinucleotide repeats. HCM phenocopy occurs in Friedreich ataxia, an autosomal recessive neurodegenerative disease caused by expansion of GAA repeat sequences in the intron of FRDA.134
HCM phenocopy also occurs in patients with Noonan syndrome. The phenotype is characterized by dysmorphic facial features, pulmonic stenosis, mental retardation, bleeding disorders, and cardiac hypertrophy, as discussed earlier.73
Metabolic diseases also cause HCM phenocopy. Refsum disease, Pompe disease (glycogen storage disease type II), Danon disease, Niemann-Pick disease, Gaucher disease, hereditary hemochromatosis, and CD36 deficiency are examples of metabolic disorders that cause HCM phenocopy.112,135 Defective mitochondrial oxidative phosphorylation pathways also cause HCM phenocopy. Kearns-Sayre syndrome is a mitochondrial disease characterized by a triad of progressive external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction defects, and less frequently HCM phenocopy.112,135,136
A remarkable feature of HCM is the presence of considerable variability in its phenotypic expression, whether it is the degree of cardiac hypertrophy or the risk of SCD.137,138 The molecular basis of such variability is not fully known. It is probably partly because of the diversity of the causal genes and mutations, which impart a spectrum of functional and structural defects. In addition, the presence of multiple mutations simultaneously present, detected in a small fraction of patients, is associated with a severe phenotype.19,139 Environmental factors, such as competitive sports and exercise, could potentially contribute to the phenotypic expression of HCM. However, there is insufficient data to support their contributions to the phenotype.
Causal genes and mutations are the primary determinant of expressivity of cardiac phenotype, including the severity of hypertrophy and the risk of SCD. Initial genotype-phenotype correlation studies implied gene- and mutation-dependent phenotypic expression of HCM. For example, p.R403Q mutation was considered a high-risk mutation associated with increased risk of SCD (Fig. 55–9). Likewise, patients with mutations in MYH7 were shown to have more severe hypertrophy than patients with mutations in MYBPC3 or TNNT2.140,141,142,143,144 Likewise, the overall impression is that TNNT2 mutations, despite exhibiting a milder hypertrophic phenotype, were associated with a higher risk of SCD.140,145,146,147 Such generalizations, however, are not broadly applicable as the results of genotype–phenotype correlation studies in HCM are subject to a large number of confounding factors, including the small size of the families, small number of families with identical mutations, low frequency of each mutation, phenotypic variability, homozygosity for the causal mutations or compound mutations, and the influence of modifier genes and environmental factors. Collectively, the existing data indicate that mutations exhibit highly variable linical, electrocardiographic E, echocardiographic, and cardiac magnetic resonance imaging (MRI) manifestations, and no particular phenotype is mutation specific.
Kaplan-Meier survival curves in patients with hypertrophic cardiomyopathy. Shown are survival curves in two families with two different mutations, namely arginine-to-glutamine substitution at amino acid 403 (R403Q) and glutamine-to-lysine change at amino acid 930 (Q930L) in the MYH7.
The presence of considerable phenotypic variability among affected members of different families with identical causal mutations emphasizes the significance of the genetic background to phenotypic expression of HCM. Genes other than the causal genes that affect the phenotype are referred to as the “modifier” genes. Unlike the causal genes, modifier genes are neither necessary nor sufficient to cause HCM.148 However, they influence the severity of cardiac hypertrophy, risk of SCD, and expression of other cardiac phenotypes in HCM. DNA polymorphisms, including SNPs located in the coding or regulatory regions or splice junctions in genes involved in cardiac hypertrophy, are the prime candidates to modify phenotypic expression of HCM. The specific modifier genes in HCM are largely unknown. Five modifier loci have been mapped through genome-wide linkage studies and several genes have been implicated.149,150,151,152,153 The effect sizes of the modifier loci are considerable, as the loci in homozygous form could influence expression of cardiac hypertrophy markedly. Functional variants of genes coding for the components of the renin-angiotensin-aldosterone system are the most extensively studied candidates. ACE, encoding angiotensin-I converting enzyme 1 (ACE-1), was the first gene implicated as a modifier of cardiac phenotype, including severity of cardiac hypertrophy and the risk of SCD in human HCM.152,153 Observational data show cardiac hypertrophy accelerates during puberty and adolescence in patients with HCM.154 The findings are in accord with the role of growth factors in contributing to expression of cardiac hypertrophy.155 Differential expression of four-and-a-half domains protein 1 (FHL1) in human HCM has been shown, and alternative 5′ start usage is considered a modifier of cardiac phenotype, including sex-dependent differences, in a mouse model of HCM.156,157 Overall, the final phenotype in HCM is determined not only by the causal mutations but also by the effects of modifier genes, environmental factors, epigenetic and epistatic factors, and posttranscriptional and posttranslational modifications of the proteins.
Pathogenesis of Hypertrophic Cardiomyopathy
As the diversity of the causal mutations would suggest, there is no single initial defect that is common to all mutations (Table 55–9). The diversity of the clinical phenotypes, such as hypertrophic, dilated, or restrictive cardiomyopathy arising from mutations in the same gene further adds to the complexity of the pathogenesis. Topography of the causal mutation is likely to be important, as the initial defect is likely to be triggered by protein domain. Given that each sarcomere protein has multiple functions, mutations in different domains of the same protein could impart several initial defects.
TABLE 55–9.Initial Defects Caused by Mutations in Sarcomere Proteins ||Download (.pdf) TABLE 55–9. Initial Defects Caused by Mutations in Sarcomere Proteins
Altered actomyosin interaction
Altered cardiac myocyte and myofibril contractile performance
Altered protein-protein binding
Altered Ca2+ affinity of myofibrillar force generation
Altered myofibrillar adenosine triphosphatase activity
Altered sarcomere assembly
Altered subcellular localization of sarcomere proteins
The causal mutation initiates a series of molecular events, which begins with alteration of the molecular structure and function of the protein (see Table 55–9). Because the majority of mutant sarcomere proteins differ from the wild type only by a single amino acid (missense mutations), the mutant proteins typically incorporate into the sarcomere, albeit sometimes inefficiently. Following incorporation, mutant sarcomere proteins exert diverse functional defects, such as alterations in myofibrillar Ca2+ sensitivity and ATPase activity. Altered calcium sensitivity of the myofibrils seems to be a common biological effect of the sarcomere protein mutations.158 Functional phenotypes lead to activation of secondary molecules, which are largely unknown, but expected to include activating of many intracellular signaling pathways. The secondary molecular phenotype mediates induction of the morphologic and histologic phenotypes. Accordingly, hypertrophy and fibrosis are considered secondary phenotypes because of activation of intermediary molecular phenotypes (see Fig. 55–10).
Sequence of phenotype characterization in the pathogenesis of cardiomyopathies.
Many HCM mutations involve deletions or truncations that are considered null alleles because of the possible expression of unstable mRNA and proteins.114,116,117,158 Although there might be a partial allelic compensation (the wild type allele partly compensating the deficiency of the encoded protein), a truncation or a null mutation might lead to haploinsufficiency and alter stoichiometry of the sarcomere proteins, resulting in HCM. Regardless of the initial primary defect, cardiac hypertrophy, the clinical hallmark of HCM, is considered a compensatory phenotype resulting from upregulation and activation of various trophic and mitotic factors. The predominant involvement of the left ventricle and its frequent absence in the low-pressure right ventricle, despite equal expression of mutant sarcomere protein in both, suggest contribution of the environment, such as the loading conditions, to the development of hypertrophy. Furthermore, variation in hypertrophic response because of the genetic background, its absence early on in life, and its attenuation through pharmacologic interventions, at least in animal models, supports the secondary nature of hypertrophy. The primary impetus for hypertrophy is not well defined. It is likely to involve altered Ca2+ sensitivity of the myofilaments and activation of various calcium-dependent and independent signaling pathways in response to increased cell mechanical stress.
In keeping with the diversity of cardiac phenotypes in HCM, expression levels of a variety of genes, in response to the mutant protein, are altered. Expression of genes encoding contractile sarcomere proteins, cytoskeletal proteins, ion channels, intracellular signaling transducers, proteins maintaining the reduction–oxidation state, and those involved in transcriptional and translation machinery are changed.156,159 Likewise, expression of a number of microRNAs (miRs) is disregulated and circulating levels of a number of miRs are increased in patients with HCM.160,161,162 Plasma levels of miR-29a are associated with cardiac hypertrophy and fibrosis in patients with HCM.160,163
Potential New Therapeutic Interventions
Current pharmacologic interventions in HCM are empiric without a firm evidence of efficacy in regression of hypertrophy, fibrosis, and disarray. Pharmacological therapy is restricted primarily to the use of beta-blockers and, on occasion, calcium channel blockers and antiarrhythmic drugs, as indicated. Nonpharmacological interventions include surgical septal myectomy (Morrow procedure) and catheter-based septal ablation, typically upon infusion of alcohol to the main septal branch of the left anterior decending coronary artery, and are very effective in reducing the left ventricular outflow tract obstruction, improving symptoms, and even possibly survival. However, septal myectomy, whether surgical or catheter-based, does not address the underlying pathology as hypertrophy, fibrosis, and disarray typically persist. Currently, there is no suitable method to correct the underlying genetic defect in humans. Therefore, the emphasis has been on prevention, reversal, and attenuation of the phenotype through pharmacologic interventions aimed at blockade of intermediary molecular phenotypes of genetic interventions in animal models. Recent studies have shown potential clinical usefulness of angiotensin II receptor blockers, beta-hydroxy-beta-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, and antioxidants in prevention, attenuation, and reversal of cardiac phenotypes in animal models of HCM.164,165,166,167,168,169 However, preliminary data in human patients with HCM have not shown significant benefits of statins.170,171 Likewise, blockade of the renin-angiotensin-aldosterone system has shown only a modest, if any, beneficial effect.172,173,174,175,176 Preliminary studies suggest potential beneficial effects of pretreatment with diltiazem, an L-type calcium channel blocker, on echocardiographic indices of cardiac size and function in HCM mutation carriers.177 Randomized clinical trials in human patients with HCM using N-acetylcysteine (HALT-HCM), eleclazine (LIBERTY-HCM), and several others are ongoing (https://clinicaltrials.gov).
Genetic Basis of Primary Dilated Cardiomyopathy
Primary DCM is a disease of the myocardium that manifests by dilatation of the left ventricle along with a gradual decline in contractility. The diagnosis is based on a left ventricular ejection fraction of less than 0.45 and a left ventricular end-diastolic diameter of > 2.7 cm/m2. Primary DCM has a prevalence of 40 cases per 100,000 individuals and an incidence of 5 to 8 cases per 100,000 persons.178 Patients with DCM are often asymptomatic in the early stages, but gradually develop symptoms and signs of heart failure, syncope, cardiac arrhythmias, and SCD. A significant number of affected relatives of patients with DCM are asymptomatic and are diagnosed for the first time on additional testing (such as an echocardiogram or electrocardiogram [ECG]).179 A normal history and physical examination in a subject at risk, particularly in the early decades of life, does not exclude DCM. A family history of DCM is present in approximately half of all index cases with idiopathic DCM. In the remainder, DCM is considered sporadic. Familial DCM is commonly inherited as an autosomal dominant disease, which clinically manifests during the third and fourth decades of life.179
An X-linked DCM is suspected when only male members of a family exhibit symptoms and signs of DCM and there is no male-to-male transmission. Three common forms of X-linked DCM have been identified: Duchenne/Becker muscular dystrophies, Emery-Dreifuss syndrome, and Barth syndrome. DCM also occurs in multi-organ disorders, such as mitochondrial DNA mutations, triplet repeat syndromes, and metabolic disorders.
Molecular Genetics of Dilated Cardiomyopathy
DCM is an extremely heterogeneous disease, as indicated by the heterogeneity of the mapped loci and genes for familial DCM (Table 55–10). The predominant mode of inheritance is autosomal dominant; however, autosomal recessive and X-linked DCM also occur. The most common causal gene for primary DCM is TTN, which encodes the giant sarcomere protein titin.180 Several causal genes for autosomal dominant DCM have been identified. Several causal genes encode sarcomere proteins, which are also known to cause HCM. Thus, despite the contrasting phenotypes of HCM and DCM, mutations in sarcomere genes can cause either of the very different phenotypes. Because many of the known causal genes for DCM involve the myocyte cytoskeleton, DCM is mostly, but not exclusively, a disease of cytoskeletal proteins.
TABLE 55–10.Causal Genes for Dilated Cardiomyopathy (DCM) ||Download (.pdf) TABLE 55–10. Causal Genes for Dilated Cardiomyopathy (DCM)
|Gene product ||Gene ||Prevalence/Phenotype |
|Sarcomere Filaments || || |
|Titin ||TTN ||The most common gene, ~25% of DCM cases, Also causes HCM |
|β-Myosin heavy chain ||MYH7 ||~ 5%, Also causes HCM |
|Cardiac α-actin ||ACTC ||Also causes HCM |
|Cardiac troponin T ||TNNT2 ||Also causes HCM |
|Cardiac troponin I ||TNNI3 ||Also causes HCM |
|Cardiac troponin C ||TNNC1 ||Also causes HCM |
|α-Tropomyosin ||TPM1 ||Also causes HCM |
|Cytoskeletal || || |
|α-Sarcoglycan ||SGCA ||Limb–girdle muscular dystrophy |
|β-Sarcoglycan ||SGCB || |
|δ-Sarcoglycan ||SGCD || |
|Dystrophin ||DMD ||Muscular dystrophy |
|Cysteine and glycine rich protein 3 ||CSRP3 || |
|Ankyrin repeat domain 1 ||ANKRD1 ||~ 1% |
|Intermediary Filaments || || |
|Desmin ||DES ||Also causes RCM |
|αB-crystallin ||CRYAB ||Desminopathy |
|Z Disk || || |
|LIM domain binding 3 (Z-band alternative Spliced PDZ motif) ||LDB3 || |
|Telethonin (T-cap) ||TCAP || |
|Alpha actinin 2 ||ACTN2 || |
|Nuclear Membrane || || |
|Lamin A/C ||LMNA ||DCM, laminopathies, progeria |
|Emerin ||EMD || |
|Vinculin ||VCL ||Metavincluin isoform |
|Desmosomes || || |
|Desmoplakin ||DSP ||Also causes ARVC |
|Others || || |
|Taffazin (G4.5) ||TAZ ||Ventricular noncompaction |
|RNA-binding motif protein 20 ||RBM20 ||Spliceosome protein |
|Bcl2-associated athanogene 3 ||BAG3 ||Co-chaperone |
|Sodium channel ||SCN5A ||Sodium channel |
|Phospholamban ||PLN ||Inhibitor of SERCA2 |
|ATP binding cassette subfamily C member 9 ||ABCC9 ||SUR2 protein subunit of K channels |
|Potassium channel, voltage gated KQT-like subfamily Q, member 1 ||KCNQ1 ||Potassium channel. |
|Troponin I interacting kinase ||TNNI3K ||DCM, conduction defect, atrial fibrillation |
Causal Genes and Mutations
The gene encoding cardiac α-actin (ACTC) was the first causal gene identified for autosomal dominant DCM.181 Subsequently, mutations in genes encoding additional components of the sarcomere, namely MYH7, TNNT2, TTN, and TCAP, were found in patients with DCM. Using next-generation sequencing of a large DCM cohort, truncating mutations in TTN were found to be responsible for 25% of the cases of DCM.180 Because mutations in ACTC, MYH7, and TNNT2 are also known to cause HCM, these findings point to the commonality of the genetic basis of DCM and HCM. The diversity of the phenotype may reflect the topography of the causal mutations on the protein as well as the genetic background of the individuals. The molecular basis of such extreme phenotypic diversity remains largely unknown.
Mutations in several cytoskeletal proteins, such as delta sarcoglycan, beta sarcoglycan, metavinculin, and dystrophin, are important causes of DCM.182 Mutations in alpha sarcoglycan (adhalin) cause an autosomal recessive form of DCM that occurs in conjunction with limb-girdle muscular dystrophy. Mutations in cysteine and glycine-rich protein 4 (CSRP3) and LIM domain-binding protein 3 (LDB3), members of muscle LIM proteins, also cause DCM.
Another intriguing category of genes causing DCM is genes encoding for ion channels, suggesting the presence of overlap syndromes between arrhythmias and heart failure. Mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel, as well as mutations SCN5A, which codes for a sodium channel and is a causal gene for Brugada syndrome, cause DCM.183,184 A mutation in KCNQ1, encoding a potassium channel, is also associated with cardiac arrhythmias and DCM.185 Cardiac arrhythmias are often the main presentation of this category of DCM and typically disproportionate to cardiac dysfunction. The term arrhythmogenic cardiomyopathy encompasses this group of DCM.
Mutations in the gene encoding lamin A/C (LMNA), which is a nuclear envelope protein, are important causes of DCM, typically in conjunction with conduction defect. LMNA interacts with large segments of chromatin. Consequently, LMNA mutations cause a diverse array of phenotypes including DCM, progressive conduction disease, atrial arrhythmias, SCD, muscular dystrophy, lipodystrophy, insulin resistance, and progeria.186
A subgroup of DCM is caused by protein aggregation in the myocardium (proteotoxicity).187,188 Mutations in the intermediary filament protein desmin and its associated protein alpha/B-crystallin cause DCM in part through protein aggregation in the myocardium.188 Often, such mutations lead to a phenotype of cardiac and skeletal myopathy that is referred to as desmin-related myopathy.
Finally, mutations in RNA-binding motif protein 20 (RBM20), which regulates RNA spicing, cause DCM by influencing splicing of cardiac genes.189,190 Collectively, these findings indicate the diversity of the causal genes responsible for DCM and render DCM genetically among the most heterogeneous diseases, with mutations affecting the integrity of the sarcomere and cytoskeleton being the main causes.
Genotype-Phenotype Correlation in Dilated Cardiomyopathy
Given the extreme genetic heterogeneity of DCM, the focus of genotype-phenotype correlation is on the presence of concomitant phenotype, cardiac or otherwise, that might offer clues to the underlying pathogenesis of the disease. Typically, mutations in genes encoding cardiac sarcomere proteins, such as MYH7, TNNT2, and TPM1 cause isolated forms of DCM without accompanying phenotypes, such as conduction defects, deafness, or skeletal myopathy. In contrast, mutations in the LMNA gene typically cause DCM in conjunction with progressive conduction defects, atrial arrhythmias, and SCD.186 In addition, LMNA mutations also cause an autosomal-dominant form of Emery-Dreifuss syndrome.191 Mutations in desmin and alphaB-crystallin genes are commonly associated with skeletal myopathy as well as DCM with unique pathologic features, a phenotype referred to as the desmin-related myopathy.187 Mutations in the dystrophin gene commonly lead to skeletal and cardiac myopathy. The severity of the myopathic phenotype is partly determined by the type of mutation. Those that are frame-shift mutations—for example, insertion or deletion of a single base—cause a severe form, whereas missense mutations often lead to a mild form of DCM and muscular dystrophy. Mutations in the 5′ region of the dystrophin gene are associated with DCM without skeletal involvement.192
Cardiac involvement is quite common in triplet repeat syndromes and includes DCM, conduction disorders, and arrhythmia. Prevalence of cardiac involvement increases with advancing age, and approximately three-quarters of adult patients exhibit conduction defects, such as first-degree atrioventricular block and intraventricular conduction defects.193 There is also a correlation between the severity of the disease and the severity of cardiac involvement and the number of CTG repeats.193
Pathogenesis of Dilated Cardiomyopathy
A diverse array of mechanisms is likely to be involved in the pathogenesis of hereditary DCM. Among notable mechanisms are impaired sarcomere structure and function, cytoskeletal integrity and mechanical force transmission, and impaired ATPase activity.182,194 Identification of mutations in MLP, LDB3, and TCAP emphasize the significance of the Z disk in maintaining normal cardiac function. Similarly, identification of mutations in the dystrophin-associated protein complex as causes of DCM signifies the role of sarcolemma in the pathogenesis of DCM. Mutations in the dystrophin gene lead to decreased expression levels of dystrophin, a major cytoskeletal protein in skeletal and cardiac muscles. Decreased levels of dystrophin are expected to impair mechanical coupling and myocyte shortening. Interestingly, using the CRISPR-Cas9 system to target the mutant dystrophin leads to increase dystrophin levels and improvement of muscle and cardiac phenotype.195,196,197,198
Pathogenesis of DCM resulting from mutations in desmin and alphaB-crystallin involves deposition of desmin and alphaB-crystallin aggregates in the myocardium.187 The molecular pathogenesis of DCM caused by mutations in lamin A/C or emerin remains largely unknown, but is likely to involve perturbed epigenetic regulation of gene expression as well as disruption of integrity of the cytoskeleton.186 The pathogenesis of cardiomyopathies in patients with the triplet repeat syndromes is not fully known, but pertains to altered splicing of cardiac genes (multiple species of transcripts resulting from inclusion or exclusion of one or several coding exons).186 It is evident that there is no unique mechanism, but multiple mechanisms are involved in the pathogenesis of DCM caused by various genes and mutations.
Genetic Basis of Arrhythmogenic Cardiomyopathy
Arrhythmogenic cardiomyopathy (AC), also known as arrhythmogenic right ventricular cardiomyopathy (ARVC), is an uncommon cardiomyopathy with characteristic clinical and pathologic features.199,200,201 It is best defined as primary cardiomyopathy whose cardinal manifestation is cardiac arrhythmias, typically ventricular tachycardia, and it occurs disproportionate to cardiac dysfunction. This is contrast to ventricular tachycardia in DCM, which typically occurs in the presence of severely depressed cardiac function. The disease often has a “concealed” stage, which is characterized by minor ventricular arrhythmias and subtle pathologic findings. It is followed by symptomatic ventricular arrhythmias and gradual progression to right-heart failure and, finally, global cardiac failure. The prototypic form of AC is ARVC, which predominantly involves the right ventricle until in advanced stages, when the left ventricle is also involved.201,202 The clinical phenotype comprises ventricular arrhythmias, primarily originating from the right ventricle, SCD, and heart failure. Involvement of the left ventricle typically portends an advanced stage and a poor prognosis.202 In addition, left dominant AC is also described. The pathologic phenotype is characterized by the gradual replacement of the cardiac myocytes by adipocytes and fibrosis (Fig. 55–11).
Histologic features of arrhythmogenic right ventricular dysplasia (ARVC). Fibrofatty infiltrate in the right ventricle is shown.
Electrocardiographic features include the characteristic and yet uncommon epsilon wave, depolarization and repolarization abnormalities in the right precordial leads, and ventricular arrhythmias originating from the right ventricle.203,204
AC is an important cause of SCD in young and apparently healthy individuals.201,205,206 In the US population, it accounts for 3% to 5% of SCD associated with physical activity in the young athletes.103 In some reports, AC was found in up to 25% of the cases of nontraumatic SCD.207,208,209 Collectively, the data suggest ARVC is an important cause of SCD in young, competitive athletes.
Significant fatty infiltration of the myocardium could be present in normal individuals, particularly in the elderly. Cor adiposum (fatty infiltration of the myocardium) is distinguished from true ARVC by the absence of right ventricular myocardial thinning, myocyte atrophy and apoptosis, patchy fibroadipocytic replacement of myocytes, predominantly in the right ventricle, and lymphocytic myocarditis.210 Right ventricular dilatation, fibrosis, myocyte atrophy, and excess adipocytes have been observed in patients with Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, and myotonic dystrophy. The distinction between muscular dystrophies and ARVC is usually not problematic because of the skeletal involvement in muscular dystrophies. Given the difficulty in the accurate diagnosis of ARVC, the Task Force committee recommends requirement of two major criteria, or one major and two minor criteria, or four minor criterial for the diagnosis of ARVC.211
Molecular Genetics of Arrhythmogenic Cardiomyopathy
Classic ARVC, which is a subtype of AC, is a primarily genetic disorder of intercalated disk proteins (Table 55–11). Mutations in several genes encoding protein constituents of intercalated disks, which include desmosomes, are established causes of ARVC. Mutations in DSP, JUP, PKP2, DSC2, and DSG2, encoding desmosomal proteins desmoplakin (DP), plakoglobin (PG), plakophilin 2 (PKP2), desmocollin 2, and desmoglein 2 (DSG2), are among the most common causes of ARVC (see Table 55–11). Mutations in PKP2 appear to be the most common causes of ARVC, accounting for approximately 25% of the cases. A significant number of PKP2 mutations cause a frameshift and hence are expected to lead to premature termination of the proteins. DSG2 and DSP genes each account for approximately 10% of the ARVC cases.
TABLE 55–11.Causal Genes for Arrhythmogenic Cardiomyopathy ||Download (.pdf) TABLE 55–11. Causal Genes for Arrhythmogenic Cardiomyopathy
| ||Gene Symbol ||Protein ||Prevalence |
|Classic intercalated disk proteins ||PKP2 ||Plakophilin 2 ||~25% |
| ||DSP ||Desmoplakin ||~10% |
| ||DSG2 ||Desmoglein 2 ||~10% |
| ||DSC2 ||Desmocollin 2 ||~10% |
| ||JUP ||Plakoglobin ||< 5% |
| ||CTNNA3? ||αT-Catenin ||< 5% |
|Nuclear membrane ||TMEM43 ||Transmembrane protein 43 ||< 5% |
| ||LMNA ||Lamin A/C ||< 5% |
|Sarcomere/Intermediate filament ||DES ||Desmin ||< 5% |
| ||TTN ||Titin ||< 5% |
|Calcium homeostasis ||PLN ||Phospholamban ||< 5% |
| ||RYR2? ||Ryanodine receptor 2 ||< 5% |
|Ion channel ||KCNQ1? ||IKs channels ||< 5% |
|Mitotic factor ||TGFB3 ? ||Transforming growth factor β3 ||< 5% |
A subgroup of arrhythmogenic cardiomyopathy, because of expression of desmosome proteins in the skin and the heart, exhibits cardiocutaneous manifestations including keratoderma and woolly hair. The classic cardiocutaneous syndrome is Naxos disease (described first in a family from the island of Naxos in Greece), which is caused by a recessive truncating mutation in JUP, encoding junction protein plakoglobin.212,213 Carvajal syndrome is another form of a cardiocutaneous syndrome wherein the left ventricle is the predominant site of involvement as opposed to the right ventricle in Naxos disease.199,212 Carvajal syndrome is caused by mutations in the DSP gene.212
Mutations in TMEM43 encoding transmembrane protein 43 are considered rare causes of classic ARVC.214,215 The initially discovered mutation was considered fully penetrant and was associated with a high risk of lethal cardiac arrhythmias.215 Not much is known about the structure and function of TMEM43 and the mechanisms by which it leads to AC, except that it appears to be a nuclear membrane protein with yet-to-be determined function.
ARVC also added to the diversity of phenotypic expression of the LMNA gene, which causes over a dozen distinct phenotypes.216 Likewise, the gene encoding phospholamban (PLN) and Titin (TTN) are considered causal genes for AC, presenting as DCM and ventricular arrhythmias.217,218
Point mutations in the 5′ untranslated region of the TGFB3 gene have been associated with ARVC.219 However, the causal role of these variants in ARVC remains unsettled.
Idiopathic right ventricular outflow tract tachycardia and stress-induced (catecholaminergic) polymorphic ventricular tachycardia, caused by mutations in cardiac ryanodine receptor (RYR2), often present with arrhythmias resembling those in ARVC.220,221 The absence of structural or histologic cardiac abnormalities suggests phenocopy and not true ARVC.
Pathogenesis of Arrhythmogenic Cardiomyopathy
The molecular pathogenesis of AC is largely unknown. The prevailing hypothesis implicates impaired mechanical integrity of myocyte-myocyte attachment as the instigator of activation of the mechanosensitive signaling pathways.222,223 Among the pathways activated by impaired mechano-transduction is the Hippo pathway, which is activated in AC.224 Activation of the upstream molecules of Hippo pathways through cascade phosphorylation of the downstream molecules leads to phosphorylation and inactivation of the YAP molecules, which results in reduced gene expression through the TEAD transcription factor.224 YAP also interacts with beta-catenin, the effector of the canonical Wnt signaling pathway, leading to cytoplasmic sequestration of beta-catenin and reduced gene expression through the TCF7L2 transcription factor.223,224 Additional mechanisms, such as partial translocation of membrane JUP to the nucleus, also further suppress gene expression through the canonical Wnt signaling.223,225 Suppression of the canonical Wnt signaling in a subset of cardiac cells leads to their differentiation to adipocytes.
The heart is a cellular heterogeneous organ. The molecular events described above also occur in cells other than mature and terminally differentiated myocytes. The latter cells are not expected to transdifferentiate. Prevailing data suggest that a subset of cardiac mesenchymal cells, in addition to cardiac myocytes, express desmosome proteins and differentiate to adipocytes in AC.225,226 The origin of fibrosis in AC and its molecular mechanisms are unknown.
Genetic Basis of Restrictive Cardiomyopathy
Restrictive cardiomyopathy (RCM) is a heart-muscle disease characterized by severely enlarged atria as a result of elevated right and left ventricular filling pressures, normal or reduced ventricular volumes, and usually preserved global systolic function.227 The clinical manifestations are those of heart failure, often with predominance of right-sided signs and symptoms. The age of onset of the disease is variable, and the prognosis is relatively poor. RCM can occur because of systemic infiltrative disorders, such as amyloidosis and sarcoidosis, and storage diseases such as Fabry disease.227,228 Such disorders are also genetic in etiology, but their hemodynamic phenotype exhibits a restrictive physiology, and hence they phenocopy true RCM. Imaging, systemic tests, and pathology are needed to sometimes decipher these different forms of RCM.
Molecular Genetics of Restrictive Cardiomyopathy
RCM partly shares a genetic etiology with DCM and HCM, as mutations in the sarcomere gene could lead to either of the phenotypes.229,230,231,232,233 In addition, a subset of patients with HCM or DCM exhibits a predominantly restrictive hemodynamic physiology. Accordingly, mutations in MYH7, TNNT2, TNNI3, TTN, and MYPN cause RCM.229,232,233,234 Mutations in DES, encoding intermediary filament desmin, are also causes of familial RCM, occurring in conjunction with skeletal myopathy and atrioventricular conduction defects with an autosomal dominant pattern of inheritance.235 As discussed, the phenotype of restrictive hemodynamic physiology resembling RCM also occurs in various other conditions including Noonan syndrome, caused by mutations in the protein tyrosine phosphatase, nonreceptor type II.233
Genetic Basis of Cardiomyopathies in Triplet Repeat Syndromes
Cardiac involvement is common in neuromuscular disorders. A subset of neuromuscular disorders involves expansion of the naturally occurring GC-rich triplet repeats in genes and is referred to as triplet repeat syndromes.236,237,238,239 The group comprises more than 10 different diseases, including myotonic muscular dystrophy and Huntington disease. Cardiac involvement is common in several forms of triplet repeat syndromes and is a major determinant of morbidity and mortality.238,239 The phenotype commonly includes DCM, HCM, conduction disorders, and arrhythmias. Average life expectancy of the affected individuals is about 30 to 40 years.
Genetic Basis of Cardiomyopathies in Myotonic Dystrophy
Myotonic dystrophy (DM) is an autosomal dominant disorder with highly variable penetrance.238,239,240 The estimated prevalence of DM is approximately 1 in 8000 in the North American population.238,239,240 It is the second most common muscular dystrophy after Duchenne muscular dystrophy. DM commonly manifests itself as progressive degeneration of muscles and myotonia, cardiomyopathy, conduction defects, male-pattern baldness, infertility, premature cataracts, and endocrine abnormalities.238,239,240 Cardiomyopathy is a common phenotypic manifestation of myotonic DM.238,239 Cardiac conduction defects, such as first-degree atrioventricular block and intraventricular conduction defects, are present in approximately three-quarters of adult patients.
Expansion of CTG (CUG in mRNA) repeats in the 3′ untranslated region of the DMPK gene, encoding dystrophica myotonica protein kinase, and is the underlying pathogenic mutation in myotonic dystrophy.241 The number of CTG repeats in normal individuals varies between 5 and 37. It expands from 50 to more than several thousand in patients with DM.241 The length of the CTG repeats often correlates with the severity of clinical phenotypes, including conduction defects and cardiomyopathy. Expansion of the repeats leads to folding of the RNA into hairpin-like structures and a number of biological events, including transcriptional, translational, and posttranslational changes. Among notable changes is sequestration of muscle blind-like protein-1 (MBNL1) and increased expression of ETR3-like factor-1 (CELF1), which are involved in regulating splicing of various genes, including genes encoding cardiac sarcomere proteins.242,243,244
The second gene responsible for DM is zinc finger protein 9 (ZNF9), located on 3q21.245 Expansion of a CCTG tetranucleotide repeats in the first intron of ZNF9 leads to expression of abnormal RNA. The underlying mechanisms responsible for various phenotypic effects of the triplet repeat expansion in ZNF9 are less well understood.244
Genetic Basis of Cardiomyopathies in Friedreich Ataxia
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease. It primarily involves the central and peripheral nervous system and less frequently manifests as cardiomyopathy and occasionally as diabetes mellitus.246 FRDA is caused by the expansion of the GAA trinucleotide repeats in intron 1 of FRDA.247 The encoded protein is frataxin, which is a soluble mitochondrial protein with 210 amino acids. Cardiac involvement can manifest as either DCM or HCM. The severity of clinical manifestations of FRDA also correlates with the size of the repeats. The pathogenesis of cardiomyopathies in FRDA is likely to involve impaired iron homeostasis, leading to iron accumulation in the mitochondria, and increased oxidative stress.246
Genetic Basis of Cardiomyopathies in Neuromuscular Disorders
Duchenne and Becker Muscular Dystrophies
The phenotype is characterized by progressive degeneration of skeletal and cardiac muscle function with an incidence of 1 in 3500 newborn males.248 It commonly manifests itself during the first or second decades of life in male patients as mild, but progressive, skeletal myopathy, early contractures, and cardiomyopathy. Female family members are commonly spared. However, they may exhibit a mild phenotype, typically late in life. Duchenne muscular dystrophy is a severe form and Becker muscular dystrophy a milder form of the disease. Patients with Becker muscular dystrophy typically show onset of muscular symptoms in the second or third decades of life. This is in contrast to patients with Duchenne muscular dustrophy, who typically exhibit neuromuscular symptoms within the first decade of life. Cardiac involvement includes progressive atrioventricular block, arrhythmia, loss of P-wave amplitude on the ECG, atrial standstill, DCM, akinesis/dyskinesis of the walls, particularly the posterobasal wall, and SCD.249 Often DCM is the primary feature of Duchenne and Becker muscular dystrophies. Approximately 90% of patients will eventually develop DCM. Death often occurs by the third decade of life.
The gene responsible for Duchenne and Becker muscular dystrophies is dystrophin, located on Xp21, which encodes a large cytoskeletal protein. Mutations, which are typically frame-shift variants, result in the absence of dystrophin.250 DCM can also occur in the absence of skeletal myopathy. Mutations leading to a frameshift induce a severe form, while missense mutations often lead to a mild form of the disease. Mutations in the 5′ region of the dystrophin gene can cause DCM without skeletal involvement.
The molecular mechanisms are diverse and include altered mechano-transduction and stretch-activated channels, calcium sensitivity, NO signaling, mitochondrial dysfunction, and oxidative stress, among others.249 A number of experimental approaches are used to induce expression of dystrophin; stop-codon read-through therapies, upregulation of utrophin, CRISPR-Cas9-mediated gene editing, and recombinant viruses have been used to increase expression of dystrophin and alleviate muscle pathology.249
Emery-Dreifuss Muscular Dystrophy
Emery-Dreifuss muscular dystrophy is an X-linked degenerative disorder characterized by mild, but progressive, skeletal and cardiac myopathy.251 Clinical features include muscle weakness and atrophy, flexion deformities of the elbows, and mild pectus excavatum. Cardiac phenotypes include cardiomyopathy, arrhythmia, SCD, conduction defects, loss of P-wave amplitude on the ECG, and atrial standstill.
The first causal gene identified for Emery-Dreifuss muscular dystrophy is EMD, which encodes nuclear membrane protein emerin.252 Likewise, mutations in LMNA, encoding nuclear membrane protein lamin A/C, also cause Emery-Dreifuss muscular dystrophy.253 Finally, mutations in FHL1, TMEM43, SYNE1, and SYNE2 have been associated with phenotypic variants of Emery-Dreifuss muscular dystrophy.251,254
DCM is a major phenotypic component of the Barth syndrome, an X-linked disorder characterized by skeletal and cardiac myopathy, neutropenia, and abnormal mitochondria. Barth syndrome is caused by mutations in TAZ encoding tafazzin (formerly known as G4.5), which is involved in fatty acid metabolism.255 The majority of the mutations are missense mutations, but frameshift and splice junction mutations have also been described. Mutations affect levels of unsaturated cardiolipin leading to mitochondrial dysfunction and oxidative stress, leading to muscle weakness and DCM.256
Genetic Basis of Cardiomyopathies in Storage Disorders
Cardiomyopathies observed in storage diseases encompass a group of disorders in which there is the primary metabolic abnormality in the heart (Table 55–12). This metabolic abnormality also may involve other organs; however, cardiac involvement is direct and not a consequence of secondary changes in other organs. Secondary involvement of the myocardium in systemic metabolic disorders is not included in this section. The phenotype typically resembles that of HCM or DCM caused by mutation in sarcomere proteins (phenocopy).
TABLE 55–12.Selected Metabolic Cardiomyopathies ||Download (.pdf) TABLE 55–12. Selected Metabolic Cardiomyopathies
|Protein ||Symbol ||Mutations/Phenotype |
|AMP-activated protein kinase, γ2 regulatory subunit ||PRKAG2 ||Point and insertion mutations, HCM, WPW, and conduction defect |
|Acid maltase gene ||GAA ||Pompe disease, DCM, HCM, conduction defects |
|Phytanoyl-CoA hydroxylase ||PAHX or PHYH ||DCM, HCM, and conduction defects |
A prototype of storage cardiomyopathies is glycogen storage disease type II (glycogenosis type II or Pompe disease).257 Pompe disease is an autosomal recessive disorder caused by mutations in GAA gene, which encodes acid alpha-galactosidase. Mutations lead to deficiency of α-1,4-glucosidase (acid maltase), which degrades α-1,4 and α-1,6 linkages in glycogen, maltose, and isomaltose. Deficiency of the enzyme leads to storage of glycogen in lysosomal membranes. Phenotypic expression of Pompe disease includes HCM, DCM, conduction defects, and muscular hypotonia. A high-protein diet and recombinant acid α-glucosidase have been used effectively to treat this disorder. Enzyme replacement therapy with algucosidase alpha early in the course of the diseases has beneficial clinical effects.257
Fabry disease, which is a relatively common HCM phenocopy, was discussed under HCM. In brief, it is an X-linked lysosomal storage disease caused by mutations in GLA, which encodes α-galactosidase.121,122,123,124 Mutations lead to deficiency of α-galactosidase A and deposits of glycosphingolipids in multiple organs, including the heart. Enzyme replacement therapy with human agalsidase α or recombinant agalsidase β imparts beneficial effects.125,126,127,128
Mutations in the gene encoding the AMP-activated γ2 noncatalytic subunit of protein kinase A (PRKAG2) cause a glycogen storage disease with phenotypic expression as HCM and WPW syndrome.98,129,130,131,132 AMP-activated kinase is a biosensor of the cellular energy state. Cardiac involvement varies from a predominant phenotype of preexcitation and conduction abnormalities to a predominant phenotype of cardiac hypertrophy.
Refsum disease is an autosomal recessive disorder characterized clinically by a tetrad of retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, and elevated protein levels in the cerebrospinal fluid.258 Cardiac involvement includes ECG abnormalities, which are common. Cardiac hypertrophy and heart failure are uncommon. Mutations in the gene encoding phytanoyl-coenzyme A (CoA) hydroxylase (PAHX or PHYH) are responsible for Refsum disease.259,260 Mutations reduce the enzymatic activity and lead to accumulation of phytanic acid, an unusual branched-chain fatty acid in tissues and body fluids.258
The heart is also involved in patients with mucopolysaccharidosis, Niemann-Pick disease, and Gaucher disease. Cardiac phenotype entails cardiomyopathies, valvular disease, and obstructive coronary artery disease.261 Table 55–13 lists various forms of mucopolysaccharidosis and the associated cardiovascular phenotypes.
TABLE 55–13.Causal Genes for Mucopolysaccharidosis (MPS) ||Download (.pdf) TABLE 55–13. Causal Genes for Mucopolysaccharidosis (MPS)
|Disease ||Gene ||Protein ||Phenotype |
|MPSI ||IDUA ||α-L-iduronidase ||Hurler syndrome, cardiomyopathy, valvular heart disease |
|MPSII ||IDS ||Iduronate-2-sulfatase ||Valvular heart disease, heart failure, obstructive coronary artery disease |
|MPSIIIA ||SGSH ||Heparan-N-sulfatase ||Cardiac hypertrophy |
|MPSIIIB ||NAGLU ||α-N-acetylglucosaminidase ||Charcot-Marie-Tooth disease type 2V, Sanfilippo syndrome |
|MPSIIIC ||HGSNAT ||Acetyl-CoA:α-glucosaminide acetyltransferase ||Cardiac hypertrophy |
|MPSIIID ||GNS ||N-acetylglucosamine 6-sulfatase ||Cardiac hypertrophy |
|MPSIVA ||GALNS ||N-acetylgalactosamine-6-sulfate sufatase ||Valvular heart disease |
|MPSIVB ||GLB1 ||β-Galactosidase 1 || |
|MPSVI ||ARSB ||N-acetylgalactosamine-4-sulfatase (Arylsulfatase B) ||Valvular heart disease, cardiomyopathy |
|MPSVII ||GUSB ||β-D-Glucuronidase || |
Hereditary hemochromatosis is an autosomal recessive disease commonly caused by mutations in HFE gene on chromosome 6p12.3.262 The encoded protein regulates iron absorption and leads to iron storage in various organs including liver and heart.262 Cardiac involvement includes cardiac hypertrophy, heart failure, atrial fibrillation, and conduction defects.
Genetic Basis of Cardiomyopathies in Mitochondrial Disorders
Cardiomyopathies are common in patients with mitochondrial disorders. Mitochondrial cardiomyopathy exhibits a matrilineal transmission. Mitochondrial DNA (mtDNA) is a circular double-stranded genome of approximately 16.5 kb, encoding 13 polypeptides of the respiratory chain complexes I, III, IV, and V subunits; 2 ribosomal RNAs; and 22 tRNAs (transfer ribonucleic acids). Each mitochondrion has multiple copies of mtDNA, and each cell contains thousands of mitochondria. Nuclear genes encode for the vast majority of mitochondrial proteins that primarily regulate mitochondrial function. Thus, mutations in nuclear genes are the primary causes of mitochondrial myopathies. Examples include mutations in SCO2, FRDA, and ATP12 leading to HCM seen in patients with Leigh syndrome and Friedreich ataxia.263 Mutations in genes encoding mitochondrial oxidative phosphorylation pathways often result in a complex phenotype involving multiple organs, including the heart. Cardiac involvement can lead to hypertrophy as well as dilatation. Mitochondrial DNA mutations typically result in a significant degree of heteroplasmy, because of the presence of a very large number of mitochondria in each cell, and multiple copies of mtDNA in each mitochondria. Heteroplasmy increases over time as the mitochondria multiply. In general, the majority of the mtDNA must mutate in order to affect mitochondrial function and lead to a clinical phenotype.
Kearns-Sayre syndrome is a mitochondrial disease caused by sporadically occurring mutations in mtDNA. Kearns-Sayre syndrome is characterized by a triad of progressive external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction defects.264 The classic cardiac abnormality in Kearns-Sayre syndrome is conduction defects; however, DCM and HCM are also rarely observed.264
l-Carnitine deficiency is a cause of mitochondrial myopathy resulting from mutations in nuclear DNA.265 The phenotype is characterized by skeletal myopathy, congestive heart failure, abnormalities of the central nervous system and liver, and rarely, HCM. Carnitine is an important component of fatty acid metabolism and is necessary for the entry of long-chain fatty acids into mitochondria. Mutations in the chromosomal gene encoding solute carrier family 22, member 5 (SLC22A5), also known as OCTN2 transporter, impair transport of carnitine to mitochondria and cause systemic carnitine deficiency.266 Similarly, mutations in genes encoding enzymes involved in the transfer and metabolism of carnitine can cause carnitine deficiency. The list includes carnitine mitochondrial carnitine palmitoyltransferase I (CATI or CPT-1), located in the outer mitochondrial membrane; carnitine-acylcarnitine translocase (SLC25A20), located in the inner membrane; and carnitine palmitoyl transferase 2 (CPTII).267 Mutations in genes coding for enzymes involved in carnitine biosynthesis, such as TMLHE and BBOX1, are also involved in carnitine deficiency.265
Mitochondria regulate fatty-acid oxidation as a major energy source in the heart. Mutations in proteins regulating fatty-acid beta-oxidation, such as CPTIII, MTP, and VLCAD, lead to lipid accumulation in cardiac muscle and heart failure, typically in conjunction with hypotonia, hypoglycemia, encephalopathy, hepatic dysfunction, skeletal myopathy, and SCD.267 Likewise, mutations in ABHD5 and PNPLA2, encoding alpha/beta-hydrolase domain-containing protein 5 and patatin-like phospholipase domain containing 2, respectively, lead to neutral lipid storage disease that occasionally involves the heart.267