Genetics of Dilated Cardiomyopathy

Despite a comprehensive evaluation, a significant proportion of patients with DCM have no obvious cause of the cardiomyopathy and are assigned a diagnosis of idiopathic DCM. Extensive family-based studies 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 at least 20% to 35% of them, thereby establishing a diagnosis of familial DCM.⁸ Familial DCM is now thought to have a genetic basis of diverse ontology (see Table 65-2).⁹ Recent studies in families with familial DCM suggest that a genetic cause can be identified in at least 30% of cases and perhaps in as high as 40% to 50% as extrapolated from studies of individual genes or small numbers of genes in gene discovery publications (see Table e65-1). Even though familial DCM is now considered a genetic disease, the issue of whether idiopathic DCM has a genetic basis in cases in which there is no evidence of familial DCM has not been resolved completely.¹⁰ 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 (see Fig. 65-2).⁵ Occasionally, asymptomatic but clinically detectable DCM is discovered serendipitously during routine or preprocedure medical screening, usually prompted by subtle abnormalities on the ECG that lead to 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 easily detectable asymptomatic DCM. This principle underlies the observation that the family history is much less sensitive than clinical screening via echocardiography in detecting DCM among family members of an individual with a new diagnosis of idiopathic DCM and emphasizes the necessity of clinical screening of all first-degree family members when a new diagnosis of any cardiomyopathy has been made (Table 65-3).

Molecular Genetics of Familial Dilated Cardiomyopathy

The genes shown to cause familial DCM are classified by subcellular location (gene ontology). As shown in Table 65-2, most of the implicated genes encode sarcomere, Z-disk, or cytoskeleton proteins. The broad representation of other genes encoding a wide variety of proteins demonstrates the diverse pathways that can lead to the “final phenotype” of DCM.¹⁰ 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). The diverse subcellular locations of genes implicated in DCM differentiates this form of cardiomyopathy from HCM (see also Chapter 66) and arrhythmogenic cardiomyopathy (ACM), which are caused by variants in genes encoding sarcomeric or desmosomal proteins, respectively (see Tables 65-1, 65-2, and e65-1). Recently, truncating variants in the giant scaffolding protein titin (TTN) have been suggested to cause 25% of cases of DCM.¹¹ However, up to 3% of controls also carried TTN truncating variants, and a genome-wide strategy that demonstrated the impact and relevance of TTN truncating variants also identified some truncating variants that were not associated with DCM,¹² which makes assessment of pathogenicity problematic from the standpoint of clinical genetic testing. In addition to locus heterogeneity, the molecular genetics of DCM is also characterized by allelic heterogeneity; that is, mutations commonly occur at many locations in a DCM gene, and many mutation sites in genes shown to cause both DCM and HCM are specific to that cardiomyopathy type (see Fig. e65-1). So-called overlap phenotypes are not uncommon, particularly for sarcomeric genes, wherein mutations that have been shown to cause DCM, HCM, and RCM may be seen in an extended pedigree. Indeed, all three phenotypes (HCM, RCM, DCM) have been reported with the same mutation in an extended family.¹³

Approach to Clinical Genetic Evaluation, Including Genetic Testing

Guidelines for evaluation and clinical genetic testing for DCM, applicable to all cardiomyopathies with a possible genetic cause (see Table 65-3), 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.^4,17 However, as noted earlier, even if obtained by a skilled professional, the family history might be negative because DCM may be asymptomatic in family members. Accordingly, clinical screening of all first-degree relatives is essential, including a history, physical examination, ECG, and echocardiography at a minimum. If evidence of DCM is identified in a relative, screening of that relative’s first-degree relatives is indicated (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 mutation (in one or more clearly affected family members) can permit molecular genetic testing of other preclinical, but at-risk family members and thereby aid in their risk stratification. Those who test negative for the family mutation should have a significantly reduced risk for the development of DCM, whereas those with a family DCM mutation should undergo enhanced clinical screening to detect early disease, with the rationale that early intervention, usually with angiotensin-converting enzyme (ACE) inhibitors or beta blockers, may delay or prevent progression of the disease.

Genetic testing is now conducted by next-generation sequencing in panels of DCM genes ranging from 20 to 30 or more. Pan-cardiomyopathy panels now also contain more than 50 genes, and their competitive cost structure suggests that large test panels will quickly become the norm.¹⁸ Genetic testing should always be conducted within the context of genetic counseling, the goals of which are to review the genetic inheritance patterns and clinically relevant facts regarding idiopathic and familial DCM and ensure that a comprehensive family history has been completed and properly interpreted, including identification of at-risk relatives. Counseling is also essential to provide information regarding the risks, benefits, and limitations of clinical genetic testing, including the possible consequences of uncertain or inclusive results or the discovery of heritable disease and its potential psychological implications.^8,10 These processes are time-consuming and require specialized knowledge, and guidelines suggest that referral of patients to individuals or centers with experience should be considered if local resources for their completion are not available.⁴

The recommendation for genetic testing recognizes that with the greater number of genes being tested in pan-cardiomyopathy panels, a greater number of variants of unknown or uncertain significance may be encountered.¹⁸ Clinicians ordering clinical genetic testing must understand this concept and be prepared to deal with this reality as the results become available. The emergence of next-generation sequencing of panels of genes has fueled an extremely active period for reevaluation of testing strategies, including approaches to interpreting large numbers of variants.^14,19 All of this will require careful, comprehensive translational research to understand the optimal testing strategies, including large databases of disease-associated variants.

Therapy for Dilated Cardiomyopathy

Therapy for DCM is similar to that for all types of systolic dysfunction (see Chapter 25). As with all heart failure patients, avoidance of excessive dietary sodium is crucial. Beta-blocking drugs and ACE inhibitors/angiotensin receptor blockers (ARBs) are the mainstay of therapy to prevent progressive disease, even in the absence of symptoms, and diuretics are the cornerstone of therapy to reduce peripheral edema and pulmonary congestion in those with symptomatic disease, with the addition of aldosterone antagonists (spironolactone and eplerenone) in more advanced cases. Ivaradibine, a selective heart rate–lowering drug approved in Europe, may be added for patients who have a suboptimal heart rate–lowering effect with beta blockade or who cannot tolerate beta-blocking agents. Attention should be paid to treatment of atrial arrhythmias (see Tachycardia-Induced Cardiomyopathy, later). In selected patients, cardiac resynchronization therapy should be considered, sometimes even early in the course of the disease, and in those with advanced disease, referral for a ventricular assist device or cardiac transplantation may be needed (see also Chapters 28 and 29).

Alcoholic and Diabetic Cardiomyopathies

Excessive alcohol intake is cardiotoxic and may be manifested as DCM (considered in detail in Chapter 68). Unique features worthy of stressing include the fact that it rarely occurs without a history of drinking at least 90 g of alcohol daily for at least 5 years, which represents a minimum of at least eight standard drinks daily.²⁰ The condition may be reversible with abstinence from alcohol but progresses if the patient continues to drink. The importance of obtaining as accurate an alcohol history as possible cannot be overstressed. In addition to its role in DCM, heavy alcohol use is associated with hypertension, which can aggravate DCM and may be refractory to treatment.

The existence of a specific diabetic cardiomyopathy independent of the effect of diabetes on the vasculature is debated, both in terms of its existence and, among those who believe it to exist, in the form that it takes.²¹ Subtle abnormalities in both systolic and diastolic function do seem to be prevalent in diabetic patients, but their clinical relevance to the development of overt disease is unclear (see Chapter 61).

Arrhythmogenic Cardiomyopathy

ACM is a genetically determined cardiomyopathy characterized by fibrofatty replacement of the myocardium. Formerly called “arrhythmogenic right ventricular dysplasia/cardiomyopathy,” it is better termed ACM because it is now recognized that biventricular involvement occurs in up to 50% of cases and that a small proportion of cases affect predominantly the left ventricle (Fig. 65-4). The disorder is 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) right ventricular (RV) abnormalities are obvious without any clinical manifestation of RV dysfunction but with the development of 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 (Fig. e65-2). LV dilation and failure may also arise at this stage or may occur later (sometimes referred to as phase 4).²²

The electrical manifestations of ACM are a reflection of 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 RV involvement is often the “triangle of dysplasia,” an area involving the RV outflow tract, an area below the tricuspid valve, and the RV apex; this is the most common area of RV thinning, regional dilation, and aneurysm formation. This anatomic area and its abnormalities in ACM are responsible for the typical ECG appearance during sinus rhythm and a typical monomorphic ventricular tachycardia (VT) characterized by left bundle branch block morphology with a superior axis²³ (Fig. 65-5).

Genomic Cause of Arrhythmogenic Cardiomyopathy

Unlike genetic DCM, which has a final common phenotype despite its extensive locus heterogeneity, ACM is driven by molecular genetic alterations in genes encoding proteins that are key for cell-to-cell adhesion (Fig. 65-6).²⁴ 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 myocytes²⁴ in the pathogenesis of ACM. In addition to desmosomes, the intercalated disc includes gap junctions mediating small-molecule communication. Mechanical coupling is mediated through the desmosome and adherens junctions (see Chapter 21), and disruptions of desmosomal proteins have been associated with ACM. The classic hallmark of ACM, 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.²⁴

Molecular Genetics.

When a genetic cause can be identified, mutations in the genes encoding plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmoplakin (DSP) account for most genetic causes of ACM (see Table e65-1 and Fig. 65-6). Other genes encoding desmosomal proteins (desmocollin [DSC2], junction plakoglobin [JUP]) or affecting desmosomal physiology (e.g., transmembrane protein [TMEM]) have been implicated (see Table e65-1). The degree of locus heterogeneity is similar for HCM and ACM, in which five or fewer genes contribute to most of the identifiable genetic cause. However, as for DCM and HCM, the genes implicated in ACM 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 ACM 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 ACM and prompted the molecular genetic discovery of other desmosomal proteins. Other mutations 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.²⁴ 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 ACM. Carvajal syndrome is caused by a frameshift mutation in DSP, which encodes desmoplakin.²⁴ Other mutations in DSP have been identified with only ACM 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 ACM, 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.

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