The Dilated, Restrictive, and Infiltrative Cardiomyopathies

Genetics of Dilated Cardiomyopathy

In a significant proportion of patients with DCM, no obvious cause can be found even with a comprehensive clinical evaluation; these patients are assigned a diagnosis of idiopathic DCM . Family-based studies from the 1990s have shown that if clinical screening with an electrocardiogram (ECG) and/or echocardiogram is conducted in the first-degree family members of patients with DCM, evidence of DCM will be found in 10% to 20% or more, thereby establishing a diagnosis of familial DCM . Familial DCM is now known to have a genetic basis of diverse ontology (see Fig. 52.2 ). Despite the discovery of many genes, plausible genetic cause can only be identified in 25% to 30% of familial cases, with lower sensitivity in sporadic cases of DCM, as more stringent analytical approaches have become the norm. In the largest series to date of 1040 individuals with DCM, with presumed mostly sporadic disease and assuming a mendelian paradigm, sensitivity of testing was approximately 15% when the enrichment of rare variants was assessed compared to population controls. Truncating variants in the giant scaffolding protein titin ( TTN ) have been shown to be the most common, associated with 10% to 20% of cases of DCM depending upon cohort studied ( Fig. 52.4 ). Penetrance issues are also highly relevant for TTN , also illustrated by genetics-first approaches, with evidence suggesting a marked reduction in penetrance in individuals of African ancestry compared to European ancestry. The proportion of rare variants thought to be causative of DCM attributed to any specific gene is much smaller, usually ranging from less than 1% to 3% ( eTable 52.1 ). Even though familial DCM is now considered to have a genetic basis due to the observed heritability, the issue of whether sporadic DCM (that is, where no evidence of familial DCM is apparent after clinical screening of relatives) has a genetic basis has not been resolved. While some sporadic cases will show pathogenic or likely pathogenic variants, many will only harbor a rare variant of unknown significance or no variants in any known DCM genes.

Patients with DCM typically have an asymptomatic phase for many years before symptomatic heart failure, an arrhythmia, or an embolic event develops later in the course of the disease ( Fig. 52.5 ). Occasionally, asymptomatic but clinically detectable DCM is discovered serendipitously during routine or preprocedural medical screening, usually prompted by subtle abnormalities on an ECG that prompt an echocardiogram. The time span needed for clinical disease to develop illustrates the remarkable ability of the myocardium to maintain normal—or close to normal—cardiac output and filling pressure for years despite clinically detectable asymptomatic DCM. This principle underlies the observation that the family history is much less sensitive than clinical screening by echocardiography in detecting DCM among family members of an individual with a new diagnosis of idiopathic DCM. This also emphasizes the necessity of clinical screening of all first-degree family members when a new diagnosis of any cardiomyopathy has been made.

Genetics of Familial Dilated Cardiomyopathy

The genes shown to cause familial DCM are classified by subcellular location (gene ontology). As shown in Figure 52.2 and eTable 52.1 , most of the implicated genes encode sarcomere, Z-disc, or cytoskeleton proteins. The broad representation of other genes encoding a wide variety of proteins demonstrates the diverse pathways that can lead to a final phenotype of DCM. Presumably, other yet unknown pathways may also be relevant in the pathogenesis of DCM. More than 30 genes have been identified to cause DCM (referred to as locus heterogeneity) of diverse subcellular localization ( Fig. 52.6 ). The diverse subcellular locations of genes implicated in DCM differentiate this form of cardiomyopathy from HCM (see also Chapter 54 ) and ARVC, which are caused by variants in genes encoding sarcomeric or desmosomal proteins, respectively (see Fig. 52.2 ). In addition to locus heterogeneity, the molecular genetics of DCM is also characterized by allelic heterogeneity; that is, rare variants commonly occur at many locations in a DCM gene, and many rare variant sites in genes shown to cause both DCM and HCM are specific to that cardiomyopathy ( eFig. 52.1 ). So-called overlap phenotypes particularly for sarcomeric genes have occasionally been reported, wherein rare variants that have been shown to cause DCM, HCM, and RCM may be seen in an extended pedigree. One family has been reported showing all three phenotypes (HCM, RCM, DCM) with one TNNT2 rare variant.

Clinical Genetics of Dilated Cardiomyopathy

DCM is characterized by a relatively unitary final phenotype of “generic” DCM. That is, for almost all genes implicated in DCM, there are no unique or distinguishing clinical features that have been associated with specific gene rare variants. The only general variation in phenotype commonly recognized ^, is “DCM with prominent conduction system disease,” which has been observed in lamin A/C ( LMNA ) DCM and some cases of sodium channel ( SCN5A ) or desmin ( DES ) DCM (see eTable 52.1 ). Occasionally, a clinically mild muscular dystrophy phenotype can be identified in patients with LMNA cardiomyopathy and a new diagnosis of DCM. However, if the muscular dystrophy is prominent, in most cases it will have been identified in a neuromuscular clinic with DCM being an incidental finding at the time of evaluation. Regardless of the setting, when a new diagnosis of idiopathic DCM is made, vigilance in detecting syndromic disease is essential, with particular attention being directed to neuromuscular phenotypes.

Most cases of familial DCM are transmitted via autosomal dominant inheritance, with the offspring of a mutation carrier having a 50% chance of inheriting the rare variant ( Fig. 52.7 ). Autosomal recessive disease has been reported, particularly in consanguineous families. X-linked DCM resulting from rare variants in the gene for Duchenne muscular dystrophy (DMD) in patients without any findings of muscular dystrophy has been reported both in males and in carrier females, although the prevalence of DMD-DCM in cohorts of patients with idiopathic DCM has not been studied systematically. Mitochondrial DCM has also been reported, particularly in the setting of syndromic disease.

Familial DCM is characterized by age-dependent penetrance, which means that an individual harboring a DCM-causing allele will manifest evidence of the DCM phenotype with increasing age. ^, Most genetic DCM cases become evident in the fourth to seventh decades, although DCM occurring in adolescence, childhood, or infancy is not uncommon. Variations in the age at onset of DCM are common across families with rare variants in the same DCM gene, at times marked, and even in family members of an extended pedigree with the same rare variant (see Fig. 52.7 ). Penetrance in familial DCM is commonly incomplete; that is, an individual with a disease-causing allele may not manifest any aspect of the disease phenotype (see Fig. 52.7 ). Also, expression is variable in that the clinical features and the phenotype can vary significantly between individuals in the same family or between families with the same rare variant. Both incomplete penetrance and variable expressivity confound the assessment of familial DCM in family pedigrees. This is particularly relevant for a newly discovered or novel candidate rare variant in a family because full segregation of the candidate rare variant with the disease phenotype in one or more extended families is one of the most helpful approaches for determining the pathogenicity of such variants.

Incomplete penetrance and variable expressivity at times result in marked phenotypic variability within and between families with DCM, even with the same rare variant. The explanation for this phenomenon is not clear. Both environmental and genetic factors have been postulated and range from intrinsic (e.g., hypertension) and extrinsic phenomic components (e.g., toxins, viruses, adverse or favorable drug exposure) to a combination of various genomic variants resulting in a different genetic milieu (e.g., a second rare variant in a different disease gene, risk alleles in the same or other relevant DCM pathways, variability in epigenetics or gene expression, and others).

Allelic heterogeneity, in which rare variants in one gene can give rise to different and distinct phenotypes seemingly unrelated to one another (see Fig. 52.2 and eFig. 52.1 ), is also observed with some DCM genes, and knowledge of these allelic variants can be critical when considering a genetic diagnosis of DCM. One of the most remarkable examples is LMNA , which encodes the proteins lamin A and lamin C, key components of the inner nuclear membrane. For example, mutations in LMNA cause a distinctive DCM phenotype in which conduction system disease and arrhythmia occur before the onset of DCM. Mutant lamin proteins also cause a variety of syndromic diseases spanning striated muscle, adipose, nerve, and vascular tissues. These phenotypes, collectively termed the laminopathies , include skeletal myopathies (autosomal dominant Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy type 1B, and others [see Chapter 100 ]), lipodystrophy syndromes, peripheral neuropathy, and accelerated aging syndromes, most notably Hutchinson-Gilford progeria.

Approach to Clinical Genetic Evaluation

With a new cardiomyopathy diagnosis a genetic evaluation should be initiated. ^, A genetic evaluation precedes genetic testing, and at times may not require genetic testing. Genetic testing ( Fig. 52.8 ) is always recommended to be performed as a component of a genetic evaluation. ^, Components of a genetic evaluation for a new diagnosis of cardiomyopathy include five key tasks ( Table 52.2 ). This first two are fundamental and will help define the nature and extent of the cardiomyopathy observed in a patient and include (1) a comprehensive family history for at least three generations, and (2) the clinical screening of all first-degree relatives for cardiomyopathy (see Fig. 52.7 ). Evidence of cardiomyopathy in closely related family members defines familial cardiomyopathy, and this clinical determination is strong evidence for genetic etiology. This information may also aid in the interpretation and inferences drawn from genetic test results. If local evaluative expertise is not available, (3) a referral for expert evaluation is recommended, especially for complex clinical or genetic cases, or infants or children where syndromic and metabolic disease should be considered and excluded. Then (4) genetic testing (see Fig. 52.8) and (5) genetic counseling should be provided for DCM, ARVC, HCM, and RCM, all of which have been shown to have a genetic basis. ^,

The sixth item (see Table 52.2 ) provides guidance for cardiovascular specialists who are sent individuals who have secondary (sometimes referred to as incidental) genetic findings in genes known to cause cardiovascular disease, such as the cardiomyopathies. In most cases these variants have been observed in clinical exome testing or expanded medically relevant gene panels. In short, a search for the relevant phenotypic features of the condition should be undertaken, ^, understanding that penetrance in a “genetics-first” approach rather than a “phenotype-first” approach may give dramatically different penetrance estimates (e.g., for ARVC variants ), as noted above. The remaining items (see Table 52.2 ) reflect current medical or device interventions, including a recommendation for early ICD use as may be indicated by a specific genetic diagnosis that incurs substantial risk of sudden cardiac death before LV systolic dysfunction reaches an ejection fraction less than 35%.

Guidelines for evaluation and clinical genetic testing for DCM, applicable to all cardiomyopathies with a possible genetic cause (see Fig. 52.8 ), include a comprehensive three- to four-generation search of the family history for any evidence of any type of cardiomyopathy, muscular dystrophy, or other evidence of syndromic disease that may have a cardiomyopathy component. However, as noted earlier, even if it is obtained by a skilled genetics professional, the family history may well be negative because DCM is commonly asymptomatic in family members. Accordingly, cardiovascular clinical screening of all first-degree relatives is essential; history taking, a physical examination, an ECG, and echocardiography should be acquired at a minimum. If evidence of DCM is identified in a relative, screening of that relative’s first-degree relatives is indicated (i.e., stepwise or cascade clinical screening).

Genetic testing, within the context of genetic counseling, is indicated with any evidence of familial disease because identification of a disease-associated rare variant (in one or more clearly affected family members) can permit molecular genetic testing of other at-risk family members with preclinical disease and thereby aid in their risk stratification. Those who test negative for the family’s disease-associated rare variant should have a significantly reduced risk for the development of DCM; those harboring the family DCM rare variant should undergo enhanced clinical screening to detect early DCM, with the rationale that early drug intervention, for example with an angiotensin-converting enzyme (ACE) inhibitor or a beta blocker, may delay or prevent progression of the disease.

Therapy for Dilated Cardiomyopathy

Therapy for DCM is similar to that for all types of heart failure with a reduced ejection fraction and is discussed in detail in Chapter 50 . Attention should be paid to treatment of atrial arrhythmias (see Tachycardia-Induced Cardiomyopathy, later). In selected patients, cardiac resynchronization therapy should be considered (see Chapter 58 ), and/or referral for a ventricular assist device or cardiac transplantation may be also needed (see also Chapter 59, Chapter 60 ).

Arrhythmogenic Right Ventricular Cardiomyopathy

ARVC is now considered a genetically determined cardiomyopathy that has been historically characterized by lethal arrhythmias in relatively young adults and with fibrofatty replacement of the myocardium, especially of the right ventricle. The ARVC nomenclature is preserved to reflect the current medical literature. Some have proposed to change the nomenclature to the simpler “arrhythmogenic cardiomyopathy” while enlarging the “arrhythmic” phenotypes well beyond the conventional task force-specific ARVC category, but issues have been noted with this approach including an effort to take into account the arrhythmias that occur in cardiomyopathies beyond ARVC. A recognized misnomer in the ARVC term is that biventricular involvement occurs in up to 50% of cases and a small proportion of cases affect predominantly the left ventricle ( eFigs. 52.2 and e52.3 ). Nevertheless, the current approach works well: the applied task force criteria ( eTable 52.2 ) provide a reasonable sensitivity to a specific gene ontology, that is, genes encoding proteins of the desmosome (see Fig. 52.6 ). The disorder is classically conceptualized as having three stages: an early subclinical phase in which imaging studies are negative but during which sudden cardiac death can still occur; next, a phase in which (usually) RV abnormalities are obvious without any clinical manifestation of RV dysfunction but with the development of a symptomatic ventricular arrhythmia; and, finally, progressive fibrofatty replacement and infiltration of the myocardium leading to severe RV dilation and aneurysm formation and associated right-sided heart failure (see eFig. 52.2 ). LV dilation and failure may also arise at this stage or may occur later (sometimes referred to as phase 4). Exercise is a key facilitator of arrhythmias at all stages of disease. ^{, ,}

The electrical manifestations of ARVC reflect the pathologic disturbance. In the early stage, slow conduction and electrical uncoupling may lead to a fatal arrhythmia. As the disease progresses, fibrofatty infiltration results in inhomogeneous activation and a further delay in conduction. The predominant site of cardiac involvement, known as the triangle of dysplasia, was believed to involve the RV outflow tract, an area below the tricuspid valve, and the RV apex. However, recent data suggest that the RV apex is only involved in advanced disease and that an area involving the basal inferior and anterior right ventricle and the posterolateral left ventricle may be most commonly involved. Patients with ARVC exhibit a typical monomorphic ventricular tachycardia (VT) characterized by left bundle branch block morphology with a superior axis and typical T wave inversions extending to V ₃ or beyond. A classic “epsilon wave” in the right precordial leads is a specific but insensitive finding ( Fig. 52.9 ).

Genomic Cause of Arrhythmogenic Right Ventricular Cardiomyopathy

Unlike genetic DCM, which has extensive locus heterogeneity, ARVC is driven by rare variants in genes encoding proteins that are key for cell-to-cell adhesion ( eFig. 52.4 ). Extensive work over the past decade has implicated genes encoding the desmosome, one of three key components of the intercalated disc, the end-to-end connection between ventricular myocytes, ^, in the pathogenesis of ARVC. In addition to desmosomes, the intercalated disc includes gap junctions mediating small-molecule communications. Mechanical coupling is mediated through the desmosome and adherens junctions (see Chapter 46 ), and disruptions of desmosomal proteins have been associated with ARVC. The classic hallmark of ARVC, fibrofatty replacement, is now understood to be related to aberrant Wnt signaling of desmosomal proteins, as well as direct plakoglobin signaling, which transforms myocytes into adipocytes with disease progression. ^,

ETABLE 52.2

Revised Task Force Criteria for the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy

Modified from Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J . 2010;31:806.

Diagnostic Terminology for Revised Criteria

Definite diagnosis: 2 major criteria, or 1 major and 2 minor criteria, or 4 minor criteria from different categories Borderline: 1 major criterion and 1 minor criterion, or 3 minor criteria from different categories Possible: 1 major criterion, or 2 minor criteria from different categories

I. Global and/or Regional Dysfunction and Structural Alterations

Major Criteria

By two-dimensional echocardiography: Regional RV akinesia, dyskinesia, or aneurysm and one of the following (end diastole): Parasternal long-axis view of RVOT (PLAX) ≥32 mm (≥19 mm/m 2 ) Parasternal short-axis view of RVOT (PSAX) ≥36 mm (≥21 mm/m 2 ) Or Fractional area change <33% By MRI: Regional RV akinesia, dyskinesia, or dyssynchronous RV contraction and one of the following: Ratio of RVEDV to BSA ≥110 mL/m 2 (male) or ≥100 mL/m 2 (female) or RVEF ≤40% By RV angiography: Regional RV akinesia, dyskinesia, or aneurysm

Minor Criteria

By two-dimensional echocardiography: Regional RV akinesia or dyskinesia and one of the following (end diastole): PLAX RVOT ≥29 to <32 mm (≥16 to <19 mm/m 2 ) PSAX RVOT ≥32 to <36 mm (≥18 mm to <21 mm/m 2 ) Or Fractional area change >33% to ≤40% By MRI: Regional RV akinesia, dyskinesia, or dyssynchronous RV contraction and one of the following: Ratio of RVEDV to BSA ≥100 to <110 mL/m 2 (male) or ≥100 to <110 mL/m 2 (female) or RVEF <40% to ≤45%

II. Tissue Characterization of Wall

Major Criteria

Residual myocytes <60% by morphometric analysis (or <50% if estimated), with fibrous replacement of RV free wall myocardium in at least one sample, with or without fatty replacement of tissue seen on endomyocardial biopsy

Minor Criteria

Residual myocytes 60%–75% by morphometric analysis (or 50%–65% if estimated), with fibrous replacement of RV free wall myocardium in at least one sample, with or without fatty replacement of tissue seen on endomyocardial biopsy

III. Repolarization Abnormalities

Major Criteria

Inverted T waves in right precordial leads (V 1 , V 2 , and V 3 ) or beyond in individuals >14 years of age (in absence of complete right bundle branch block QRS ≥120 msec)

Minor Criteria

Inverted T waves in leads V 1 and V 2 in individuals >14 years of age (in absence of complete right bundle branch block) or in V 4 , V 5 , or V 6

Inverted T waves in leads V 1 , V 2 , V 3 , and V 4 in individuals >14 years of age in presence of complete right bundle branch block

IV. Depolarization/Conduction Abnormalities

Major Criteria

Epsilon wave (reproducible low-amplitude signals between end of QRS complex to onset of T wave) in right precordial leads (V 1 –V 3 )

Minor Criteria

Late potentials by signal-averaged ECG in at least 1 of 3 parameters in absence of QRS duration ≥110 msec on standard ECG

Filtered QRS duration ≥114 msec

Root mean square voltage of terminal 40 msec <20 μV

Terminal activation duration of QRS ≥55 msec measured from nadir of S wave to end of QRS complex, including R′ in V 1 , V 2 , or V 3 in absence of complete right bundle branch block

BSA , Body surface area; ECG , electrocardiogram; PLAX , parasternal long-axis; PSAX , parasternal short-axis; RVEDV , RV end-diastolic volume; RVEF , RV ejection fraction; RVOT , RV outflow tract.

Molecular Genetics

When a genetic cause can be identified, rare variants in the genes encoding plakophilin 2 ( PKP2 ), desmoglein 2 ( DSG2 ), and desmoplakin ( DSP ) account for most genetic causes of ARVC (see eTable 52.1 and Fig. 52.2 ). Rare variants in other genes encoding the desmosomal proteins (desmocollin [ DSC2 ], junction plakoglobin [ JUP ]) or affecting desmosomal physiology (e.g., transmembrane protein [ TMEM ]) also cause ARVC (see Fig. 52.6 ; eTable 52.1 ). The ClinGen gene-validity curation for ARVC has found these six genes to have definitive evidence. The degree of locus heterogeneity is similar for HCM and ARVC, in which five or fewer genes contribute to most of the identifiable genetic causes. However, as for DCM and HCM, the genes implicated in ARVC show extensive allelic heterogeneity.

Clinical Genetics

The autosomal recessive syndromic Naxos disease , so named because it was discovered on the Greek island of Naxos, is manifested as ARVC cosegregating with palmoplantar keratoderma and wooly hair. Molecular genetic analysis has shown a homozygous two–base pair frameshift deletion of JUP , which encodes plakoglobin. This observation first implicated the desmosome in ARVC and prompted the molecular genetic discovery of other desmosomal proteins. Other rare variants in JUP have also been associated with cutaneous disease or wooly hair phenotypes, although cardiovascular phenotypes have not been identified in most of these allelic variants. A second autosomal recessive syndromic disease, Carvajal syndrome , resembles Naxos disease in that individuals have palmoplantar keratoderma and wooly hair, but individuals with Carvajal syndrome manifest DCM, not ARVC. Carvajal syndrome is caused by a frameshift rare variant in DSP , which encodes desmoplakin. Other rare variants in DSP have been identified with only ARVC or with only skin or hair manifestations. Even though reduced penetrance and variable expressivity are commonly observed in all genetic cardiomyopathies, these features may be particularly prominent in ARVC, recently highlighted in a genetics first study where penetrance was estimated to be only 6%, in part because of the difficulty of assessing the phenotype and also because the arrhythmia component may be the only feature of the disease in some individuals long before structural changes can be identified. ARVC has also been noted to have highly variable penetrance, in part attributed to an oligogenic basis in some.