Ventricular Tachycardias in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy that is characterized by ventricular arrhythmias, increased risk of sudden death, and abnormalities of right ventricular structure and function.1–4 Although structural involvement of the right ventricle predominates, a left dominant form of ARVD/C has been described.⁵ In most patients in the United States, structural abnormalities of the right ventricle predominate.⁶ The pathologic hallmark of ARVD/C is right ventricular myocyte loss with fibrofatty replacement. Since the first detailed clinical description of the disorder in 1982,¹ significant advances have been made in our understanding of all aspects of this disease. Over the past decade, mutations in most desmosomal proteins and in some nondesmosomal proteins have been identified as the genetic basis of ARVD/C. Because a pathogenic mutation can be identified in approximately 50% of affected individuals, genetic testing has emerged as an important diagnostic tool.^7,8 The purpose of this chapter is to provide a concise and up-to-date review of the current state of knowledge regarding the natural history, clinical presentation, pathogenesis, diagnosis, and treatment of patients with ARVD/C. Specific emphasis is placed on discussing the characteristics of and therapeutic approaches to ventricular arrhythmias that occur in patients with ARVD/C.

Clinical Presentation and Natural History

ARVD/C is an unusual condition with an estimated prevalence in the general population of 1 per 5000. This is roughly tenfold less common than hypertrophic cardiomyopathy, which occurs in about 1 per 500 of the general population.

Patients usually present during the second to fifth decades of life with palpitations, light-headedness, syncope, or sudden death.1–4,9 In our experience, it is extremely rare for clinical signs or symptoms of ARVD/C to manifest before the age of 12 years or after the age of 60 years.

Although ARVD/C is predominantly a disease of the right ventricle,1–4 it is well established that involvement of the left ventricle (LV) is not uncommon, particularly when magnetic resonance imaging (MRI) is used to detect subtle abnormalities in LV function in patients with advanced disease. Left-dominant arrhythmogenic cardiomyopathy also occurs in and is defined by early disease of the LV, often affecting the posterolateral wall, in the absence of significant right ventricle (RV) systolic dysfunction.⁵ Left-dominant disease is more commonly seen in patients with desmoplakin mutations.^5,7

Histopathology

Postmortem examination of patients with ARVD/C often shows RV myocardial atrophy with wall thinning, aneurysms, and global dilatation of the RV. Initial studies evaluating the histology of ARVD/C in autopsy cases described two possible pathologic patterns: fatty and fibrofatty replacement of the myocardium.² However, it has been shown that the clinical profile of patients with purely fatty replacement of the myocardium did not fit the diagnosis of ARVD/C. In fact, fatty infiltration of the heart occurs physiologically and increases with age and body weight. Thus, revised task force criteria include fibrofatty replacement with less than 60% residual myocytes as a major diagnostic criterion and with 60% to 75% residual myocytes as a minor diagnostic criterion.⁸ The presence of fat alone and/or fatty replacement in the absence of fibrosis is insufficient to be considered a diagnostic criterion for ARVD/C.⁸ Another common histologic finding includes patchy lymphocytic inflammatory infiltrates surrounding areas of myocyte necrosis.²

Etiology

In most cases, ARVD/C is inherited in an autosomal dominant pattern with significantly variable penetrance and expressivity. Among probands diagnosed with this disease, screening of first-degree relatives identifies other affected individuals in approximately 50% of cases.7,9 In a minority of cases, ARVD/C is inherited in an autosomal recessive pattern as part of a cardiocutaneous syndrome such as Naxos disease or Carvajal syndrome, the latter of which is also characterized by woolly hair and palmoplantar keratodermia.

Linkage mapping and candidate gene evaluation studies performed on patients with the autosomal dominant form of ARVD/C at first were not productive because of the significant variability in penetrance and expressivity of the disease. It was the evaluation of patients with Naxos syndrome—a disease with 100% penetrance by the time of adolescence—that revealed a disease-causing mutation: a homozygous deletion of two base pairs found in the plakoglobin gene located in the 17q21 locus.¹⁰ The gene encodes a key component of desmosomes, which are complex intercellular adhesion structures found in stratified epithelial cells of the skin, as well as in myocytes. Desmosomes are composed of three major groups of proteins: Cadherins are transmembrane proteins that provide actual mechanical coupling between individual cells and include desmoglein and desmocollin. Desmoplakin is a plakin family protein that serves to anchor the desmosomal structure to the intermediate filaments of the cell. Finally, Armadillo proteins including plakoglobin and plakophilin link desmoplakin and the cadherin tails.

Identification of defective desmosomal proteins in Naxos syndrome led to studies investigating their role in other arrhythmogenic cardiomyopathies. Carvajal syndrome, another cardio-cutaneous syndrome characterized by left-dominant arrhythmogenic cardiomyopathy, was shown to be associated with a recessive mutation in desmoplakin.¹¹ Other genetic mutations were subsequently identified in the autosomal dominant form of ARVD/C and include desmoplakin, desmoglein-2, desmocollin-2, and plakophilin-2 genes.⁷ Mutations in several extra-desmosomal genes such as those encoding transforming growth factor-β₃ (TGF-β₃), cardiac ryanodine receptor (RyR2), Titin, and transmembrane protein 43 (TMEM43) have also been implicated in specific types of atypical forms of ARVD/C. In the United States, a desmosomal protein mutation can be identified in approximately 50% of ARVD/C patients.⁷ The most commonly mutated genes are plakophilin-2 (45%) and desmoglein-2 (9%). Although 86% of patients in this series had a single heterozygous gene mutation, 7% showed compound heterozygosity and another 7% showed digenic heterozygosity. This is important to note because clinicians need to be aware that some individuals with ARVD/C may have more than one mutation in one or more of the many desmosomal proteins. Other candidate genes are likely to be identified in the future. Thus it is possible for the affected individual (the proband) to have more than one defective gene. All of the genetic abnormalities have not yet been identified; therefore, first-degree relatives may not have the known gene but could have inherited the unknown gene mutation. Finding a pathogenic gender mutation in the proband but not in the first-degree relative does not completely exclude the possibility of desmosomal mutation in the first-degree relative.

It is also important to recognize that not all variants identified in a desmosomal protein are causal mutations. A recent study compared the results of genetic testing in 93 ARVD/C probands, 82 ARVD/C probands from published reports, and 427 healthy controls.¹² Mutations were found in 58% of ARVD/C cases versus 16% of controls. Radical mutations were observed in 43% of ARVD/C cases versus 0.5% of controls. In contrast, 21% of ARVD/C cases demonstrated missense mutations versus 16% of controls. The authors concluded that radical mutations are high-probability ARVD/C-associated mutations, whereas rare missense mutations need to be interpreted with caution.

Pathogenesis

Initial attempts to explain the pathogenesis of ARVD/C produced several hypotheses, including the dysplastic theory, which held that atrophy with fibrofatty replacement of the RV myocardium in ARVD/C was a congenital, developmental defect. This led to the original description of the syndrome as arrhythmogenic right ventricular dysplasia. It is now clear, however, that the structural defects in ARVD/C are not present at birth but actually develop progressively throughout childhood and early adulthood.

The genetics of ARVD/C has provided support for the hypothesis that the disease may be caused by desmosomal dysfunction. The pathogenic mechanisms are not fully clear, but several theories have been advanced.⁹ Defective desmosomal proteins may lead to impaired mechanical coupling between individual cells, resulting in myocyte uncoupling, especially under conditions that increase myocardial strain. The resulting inflammation, fibrosis, and adipocytosis may be a nonspecific response to injury, similar to that seen in other forms of myocardial damage. This pathogenic model can explain the observation that prolonged strenuous exertion, which increases myocardial strain, significantly increases the risk of earlier clinical onset of the disease and augments the risk of sudden death.¹³ It also explains why the RV, which is more distensible than the LV because of its thinner wall and asymmetric shape, is more often involved in ARVD/C, especially in its early stages. Furthermore, defects in mechanical coupling of myocytes may also lead to impairment in electrical coupling.^14,15 Ultrastructural evaluation of the myocardium of patients with ARVD/C has revealed reduced expression of several intercalated disc proteins, including connexin43, a key component of gap junctions.¹⁵ This finding may account for the development of conduction delay and arrhythmias even in the absence of significant structural defects in the early “concealed” phase of the disease. Recent studies have shown that PKP2 haploinsufficiency leads to INa deficit in murine hearts. The results of this study suggest that there cross-talk occurs between the desmosome and the sodium channel complex. The sodium channel dysfunction that follows may contribute to the development of ventricular arrhythmias in patients with ARVD/C.¹⁶

The mechanisms that lead to variability in penetrance and expressivity of the disease still are not fully understood. Family members with identical genotypes and even monozygotic twins show significant differences in symptoms, in the presence and distribution of structural changes, and in the rate of disease progression. This observation has led to the “second hit” hypothesis, which suggests that modifier genes and/or environmental factors are likely responsible for phenotypic heterogeneity.

Diagnostic Approach

Because of significant heterogeneity in manifestations of the disease, no single gold-standard diagnostic test for ARVD/C is available. Instead, diagnosis relies on a scoring system with major and minor criteria based on demonstration of a combination of defects in RV morphology and function, characteristic depolarization/repolarization abnormalities on electrocardiogram (ECG), characteristic tissue pathology, typical arrhythmias, family history, and results of genetic testing. Thus the initial evaluation of all patients suspected of having ARVD/C should consist of physical examination and clinical history (including family history of arrhythmias or sudden death), ECG, signal-averaged ECG (SAECG) (if available), 24-hour Holter monitoring, and comprehensive noninvasive imaging of both ventricles. If this noninvasive work-up is suggestive but not diagnostic of ARVD/C, further testing should be considered to establish the diagnosis, including electrophysiological testing with or without electroanatomical mapping and endomyocardial biopsy. Although right ventriculography was commonly used in the past, in our experience ventriculography is rarely needed because of the availability of high-quality echocardiography and MRI.

The standard 12-lead ECG is abnormal in most patients with ARVD/C.3,17,18 Because of this observation, the finding of a normal ECG in a patient with ARVD/C renders the diagnosis of ARVD/C extremely unlikely but does not completely exclude the diagnosis. T wave inversion (TWI) in the right precordial leads (V₁ to V₃) is the most common ECG manifestation of ARVD/C and is considered a major diagnostic criterion⁸ (Box 87-1). TWI in leads V₁ and V₂ is a minor criterion. A complete or incomplete right bundle branch block (RBBB) pattern is a common finding in patients with ARVD/C, especially those with severe structural disease, and its presence obscures the interpretation of known depolarization abnormalities.¹⁸ In patients with incomplete RBBB, TWIs through V₃ still appear to be the feature with optimal sensitivity and specificity. However, in patients with complete RBBB, an R/S ratio <1 in V₁ seems to provide optimal sensitivity and specificity (88% and 86%, respectively) in diagnosing ARVD/C.¹⁸ T wave inversion beyond V₃ in patients with complete RBBB is another feature of ARVD/C. Epsilon waves, which are distinct low-frequency deflections in the ECG that occur after the QRS and before the T wave, are far less common and are a marker of advanced ARVD/C. In stating this, we should note that the frequency with which an epsilon wave is identified varies greatly according to the specific definition used. In our experience, many in the field refer to any delayed potential as an epsilon wave. When this liberal criterion is applied, epsilon waves are common. On the other hand, if a stricter definition is used, requiring that the potential be distinct from the QRS complex, the prevalence of epsilon potentials is rare. New diagnostic criteria for ARVD/C include terminal activation delay, which is defined as a prolonged duration of time (>55 milliseconds) from the S wave to the termination of the QRS complex, as a minor criterion for ARVD/C.⁸