CHAPTER 62: ARRHYTHMOGENIC CARDIOMYOPATHY

Arrhythmogenic cardiomyopathy is a rare primary myocardial disease that is clinically characterized by life-threatening ventricular arrhythmias secondary to fibrofatty replacement of ventricular myocytes.^1,2,3

In the first systematic description of 24 adult cases in 1982, Marcus et al⁴ outlined the profile of right ventricular (RV) dysplasia as a pathologic condition primarily affecting the right ventricle and characterized by partial or total absence of RV musculature due to substitution by fatty and fibrous tissue. The authors distinguished conditions in which the RV myocardium was almost completely absent from those in which the fatty and fibrous tissue was limited to portions of the right ventricle. The former showed cardiomegaly and clinically manifested with congestive heart failure. The latter showed mild RV remodeling and minimally impaired cardiac dysfunction. When ventricular tachycardia was the principal manifestation, the condition was termed arrhythmogenic RV dysplasia (ARVD).⁴ The authors additionally described 34 adult cases and provided the clinical profile of the disease:

• Clinical presentation is characterized by ventricular tachycardia, supraventricular arrhythmias, right heart failure, or asymptomatic cardiomegaly.

• Electrocardiogram (ECG) shows T wave inversion in the right precordial leads.

• Increased RV diastolic dimensions.

• Onset is in young adult age.

• Prevalence is higher in males than in females.

In 1988, Thiene et al⁵ described the morphologic features of RV cardiomyopathy in 12 young people who died suddenly. Findings included:

• Normal or moderately increased heart weights

• Lipomatous transformation (6 of 12 patients) or a fibrolipomatous (6 of 12 patients) transformation of the RV free wall

• Substantially spared left ventricle

• Occasional myocardial degeneration and necrosis, with or without inflammatory infiltrates

In 1994, an International Task Force grouped criteria for the clinical diagnosis of arrhythmogenic RV cardiomyopathy/dysplasia (ARVC/D).⁶ These criteria were aimed at facilitating recognition and interpretation of the clinical and pathologic features of ARVC/D and were grouped according to:

• Structural and histologic features

• ECG and arrhythmic features

• Familial features

These features were incorporated into criteria that were subdivided into major and minor categories according to the specificity of their association with ARVC/D. These criteria revealed high specificity, but low sensitivity, for early and familial disease.⁶

In 2010, task force criteria were modified to improve the diagnosis and management of ARVC/D. The modified criteria incorporated new knowledge on the genetic basis of the disease, improving diagnostic sensitivity and maintaining diagnostic specificity (Table 62–1). The structural, histologic, ECG, arrhythmic, and genetic features were structured in major and minor criteria. The task force document formally introduced the biventricular variant and the left dominant variant.⁷ These latter criteria support the broader new term of arrhythmogenic cardiomyopathy (ACM). Therefore, the disease is currently called ACM, ARVC/D, ARVC, or ARVD. In this chapter, the disease is named according to the task force criteria—ACM.

The involvement of the left ventricle in ACM had been originally described by Marcus et al⁴ and confirmed in several additional studies. Importantly, task force criteria are easy to apply to classical and manifested forms in adults, but not in children. Recent studies report that many pediatric patients do not meet the current ACM diagnostic criteria, resulting in delays in diagnosis and treatment. According to pediatric cardiologists, the current criteria need further revision to encompass pediatric manifestations of the disease, suggesting that modified pediatric criteria would facilitate prompt diagnosis and management of ACM and structured research with the goal of improving outcomes.⁸

Epidemiology

The prevalence of ACM is estimated to range from 1 in 1000 to 1 in 5000 in the general population.^1,2,3,9 A small proportion of patients progress to left ventricular (LV) dysfunction with ventricular arrhythmias remaining the clinical hallmark.¹⁰ The prevalence of clinical manifestations is higher in males than in females (3:1) and typically manifests in young adults.^11,12 Of 439 index patients described by Groeneweg et al,¹¹ only four presented before the age of 13 years and none before the age of 10 years. The reasons for delayed manifestation may be related to the time required for completion of intercalated disk maturation or the need for prolonged exposure to exercise.¹¹

Pathobiology

ACM is an inherited cardiomyopathy, with autosomal dominant inheritance in the majority of cases and recessive inheritance in a minority.¹³ Classical right-sided ACM is a genetic disease of the intercalated disks, which are the sites of contact between adjacent myocytes.

Intercalated Disks

Intercalated disks are highly specialized cell-cell junctions; they are the units of electromechanical continuity between cardiac myocytes¹⁴ and are comprised of gap junctions, adherens junctions, and desmosomes (Fig. 62–1).

• Gap junctions (nexus, communicating junctions) are located in the lateral parts of the intercalated disks. Gap junctions mediate ionic traffic between adjacent cells and provide the basis for functional cell coupling. Key structural proteins are connexins; the connexins predominantly expressed by cardiac myocytes are Cx43, Cx40, and Cx45.

• Adherens junctions (fasciae adhaerentes) are located in the transverse parts of the intercalated disks where the actin filaments of the sarcomeres are anchored and connected with the plasma membrane. This anchorage provides the intercellular “mechanical continuity” between the myocytes supporting the transmission of force between cells and synchronous contraction and relaxation. Key structural proteins are nondesmosomal cadherins that are calcium-dependent transmembrane glycoproteins.

• Desmosomes (maculae adhaerentes) are located in both the transverse and lateral parts of the intercalated disks: they reinforce the adherens junctions and fix adjacent cells. Desmosomes bind desmin on the intracellular side, spans the cell membrane, and bind adjacent desmosomes on the extracellular side. Desmosome-forming proteins include plakophilin-2, desmoglein 2, desmocollin 2, plakoglobin, and desmoplakin.

Since the first detailed clinical description of ACM,⁴ significant advances in imaging, epidemiology, animal models, and protein biochemistry have accelerated our understanding of disease pathogenesis and progression. However, much of our current understanding of ACM pathobiology is derived from genetic findings of rare, yet severe, autosomal recessive forms of cardiocutaneous diseases, including Naxos disease and Carvajal disease. For example, Naxos disease, characterized by fully penetrant ACM, wooly hair, and palmoplantar keratoderma,¹⁵ was the first direct evidence for dysfunction in the desmosomal gene product plakoglobin in ACM (truncation of final 56 residues of protein).¹⁶ Subsequently, desmoplakin loss-of-function variants that inhibit the ability of desmoplakin to associate with desmin (see below) were implicated in Carvajal syndrome, a cardiocutaneous disease associated with left-dominant cardiac phenotype.¹⁷ Since these original discoveries, advances in gene sequencing have revealed a host of protein pathways now linked with ACM pathogenesis. With rare exceptions, these findings illustrate a crucial role of a key cardiac membrane domain—the desmosome—in ACM pathobiology.

The Cardiac Desmosome

The cardiac desmosome is a central feature of the myocyte intercalated disk, a multifunctional membrane domain essential for both myocyte electrical and structural coupling. The desmosome is primarily composed of three families of proteins: cadherins, plakins, and armadillo proteins. Desmosomal cardiac cadherins are type 1 transmembrane proteins that include desmocollin (encoded by DSC2) and desmoglein (encoded by DSG2). These proteins span the extracellular space to physically link adjacent cardiomyocytes. The intracellular domains of desmocollin and desmoglein directly associate with plakins and armadillo linker proteins to integrate the membrane with the underlying intermediate filament network. In the heart, these linker proteins are primarily desmoplakin (encoded by DSP), plakophilin 2 (encoded by PKP2), and plakoglobin (encoded by JUP), whereas desmin (encoded by DES) is the central component of the intercalated disk intermediate filament network that extends across the length of the myocyte. Desmoplakin homodimers connect plakofillin 2 at the amino-terminal domain and desmin at the carboxy-terminal domain. Together, this multiprotein complex has fundamental roles in regulating mechanical force within myocytes and also between adjacent myocytes and myocyte networks.

Notably, the role of the desmosome for normal cardiac function is clearly illustrated by human gene mutations in PKP2, JUP, DSP, DSG2, and DSC2 associated with autosomal dominant ACM.¹⁸ For example, in the United States alone, approximately 50% to 60% of ACM patients harbor a loss-of-function gene variant in at least one of five desmosomal genes.¹⁸ PKP2 remains the most common ACM gene (45%), with DSG2 loss-of-function variants present in nearly 10% of human ACM cases.¹⁹ As discussed later in this chapter, approximately 86% of ACM patients harbor a single heterozygous gene variant, 7% show compound heterozygosity, and 7% show digenic heterozygosity (> 1400 variants identified to date; see www.arvcdatabase.info).^18,19 Desmosome and nondesmosome genes reported to date as being associated with ACM are routinely tested and contribute as major criteria to the diagnosis (Table 62–2).

Based on the central role of the cardiac desmosome in regulating inter- and intracellular mechanical forces, ACM pathophysiology has historically been attributed to dysfunction in desmosomal proteins, resulting in structural instability of this critical membrane domain. Thus, in the “degeneration” or “inflammation” models for ACM pathobiology, structurally compromised desmosomes are more sensitive to mechanical strain/forces, resulting in damaged cell-cell junctions, myocyte uncoupling, and ultimately inflammation, fibrosis, necrosis, and potentially adipogenesis.^20,21,22 These models are supported by multiple lines of evidence, including the following: (1) aberrant myocyte intercalated disk coupling in human ACM samples as observed by electron microscopy²³; (2) abnormal myocyte intercalated disk widening in mice harboring human ACM variants as observed by electron microscopy²⁴; (3) prevalence of ACM phenotypes in conditions of myocardial strain¹⁹; (4) accelerated ACM phenotypes and increased risk for sudden cardiac death (SCD) in athletes²⁵; (5) impact of disease on right ventricle (thin, distensible wall) versus left ventricle¹⁹; (6) reduced adhesive strength of cells expressing small interfering RNAs that silence selective desmosomal proteins²⁶; and (7) accelerated ACM phenotypes in animal models harboring mutant desmosome genes following mechanical stress.^27,28 However, not all data necessarily support loss of cell adhesion in disease pathogenesis. For example, Hariharan et al²⁹ indicated that although neonatal rat ventricular myocytes deficient in plakoglobin or plakophilin showed reduced cell-cell adhesion, these same cultures expressing human ACM plakoglobin or plakophilin loss-of-function mutations displayed no significant differences in cell-cell adhesion. However, these same mutant myocytes displayed sheer stress phenotypes that were reversed by inhibition of glycogen synthase kinase 3β (GSK3β).²⁹ Further, Asimaki et al³⁰ have consistently identified decreased plakoglobin junctional expression in ACM samples, supporting the complexity of the disease, the variability in phenotypic penetrance/expressivity,¹⁹ and the likelihood of secondary contributing pathogenic signaling mechanisms, as described below.

More recently, a second, yet non–mutually exclusive model for ACM pathobiology has emerged that frames the desmosome as a multifunctional signaling node for the myocyte. Specifically, the second model converges on nonjunctional transcriptional pathways mediated by the Wnt (wingless-related integration site) axis. In this model, in the nondiseased heart, baseline Wnt signaling is critical for normal cardiogenic transcriptional signaling.¹⁸ This signaling is mediated by regulation of T-cell factor/lymphoid enhancer factor (Tcf/Lef) transcription factors by nuclear β-catenin (β-catenin is also found at cell junctions at baseline).¹⁸ Also central to this model is the localization of junctional plakoglobin. In nondiseased heart, plakoglobin is concentrated at the intercalated disk membrane.¹⁸ In fact, nonmembrane (cytosolic) populations of plakoglobin are maintained at low concentrations by ubiquitination and proteasomal degradation.¹⁸ Although the precise mechanisms are still being elucidated, it is now thought that in ACM, compromised junctional infrastructure increases the cytosolic pool of plakoglobin. Ultimately, diffusion of this pool into the nucleus is proposed to suppress β-catenin/Wnt signaling to transition procardiogenic transcriptional signaling to transcriptional programming favoring inflammation, apoptosis, and adipogenesis.³¹ Notably, expression, activity, and translocation of β-catenin are central to this pathway. Outstanding questions related to this model are the relative levels of junctional/cytosolic/nuclear plakoglobin and β-catenin at baseline and in disease, the impact of the local signaling environment (eg, activity of GSK3β on plakoglobin/β-catenin), the relative half-lives of plakoglobin/β-catenin in disease, and the specific roles/downstream targets of Tcf/Lef transcriptional signaling based on nuclear plakoglobin/β-catenin concentrations.

The impact of altered Wnt signaling in ACM pathogenesis was first described by Lombardi et al.³² Mice lacking Dsp expression display suppression of the β-catenin/Wnt pathway favoring apoptosis, fibrosis, and adipogenesis.³² In further support of this model, altered desmoplakin expression in a human-derived cardiomyocyte cell line alters plakoglobin nuclear translocation, ultimately altering β-catenin/Tcf/Lef transcriptional signaling and adipogenesis.³¹ Moreover, Wnt signaling is reduced in mice expressing a mutant form of plakoglobin lacking the C-terminus, resulting in nuclear plakoglobin translocation and adipogenesis.³² Finally, in seminal work from the Marion Laboratory, fate-mapping techniques identified a select population of cardiac progenitor cells as the primary source of adipocytes in the heart.³³ These foundational data have sparked a wealth of studies that have elucidated new and unanticipated signaling pathways in the heart likely related to ACM pathogenesis.³⁴ Further, this work has suggested that ACM is a disease of multiple cardiac cell types, an observation that may further explain the variability in clinical presentation and disease progression.

Nondesmosomal Proteins

Although ACM pathogenesis has largely been attributed to dysfunction of the desmosome, new protein pathways associated with ACM continue to add to our understanding of disease pathophysiology. Mutations in junctional nondesmosomal proteins, intermediate filaments, nonjunctional proteins, sarcomeric proteins, membrane-anchored proteins, and adipogenic factors have been reported in patients with ACM phenotypes (often described as overlapping syndromes).

αT-catenin3 (CTTNA3) is a cell adhesion molecule. In cardiac intercalated disks, CTNNA3 is a component of the adherens junction, or area composita. Mice with deletion of the Ctnna3 gene (αT-catenin–null mice) develop progressive cardiomyopathy. The loss of αT-catenin does not seem to affect adherens junction and desmosomal proteins; the exception is the desmosomal protein plakophilin-2. In fact, immunogold labeling at the intercalated disk demonstrates preferential reduction of plakophilin-2 at the area composita compared with the desmosome.³⁵ The p.Val281Asp (c.281T > A) and c.2293_2295delTTG (p.del765Leu) mutations have been identified in two probands with ACM³⁶; yeast two-hybrid and cell transfection experiments suggested a causal relationship between CTNNA3 mutations and ACM.

The desmin (DES) gene encodes a muscle-specific class III intermediate filament. Homopolymers of this protein form an intracytoplasmic filamentous network connecting myofibrils to each other and to the plasma membrane. DES mutations are associated with restrictive cardiomyopathy, desmin-related myopathy, a familial cardiac and skeletal myopathy, and distal myopathies. Searching for the genetic cause of autosomal dominant myofibrillar myopathy with ACM in a Swedish family, Hedberg et al³⁷ identified the p.(Pro419Ser) Ser mutation in the DES gene. In a series of 91 ACM index cases (including 53 negative and 38 positive for mutations in desmosomal genes), mutations in the DES gene were found in two cases: (1) the p.(Lys241Glu) substitution was detected in one patient who also carried the p.(Thr816ArgfsX10) mutation in the PKP2 gene; and (2) p.(Ala213Val) was found in a second patient and was not associated with mutations in the desmosomal genes.³⁸ The LMNA gene encodes lamin A/C, which is a major structural component of the nuclear lamina. LMNA mutations are associated with different phenotypes (see Chap. 58). LMNA mutations were identified in 4 of 108 patients with ACM phenotype (borderline in 27 and definite in 81); three patients had severe RV involvement.³⁹ During follow-up, there were two sudden deaths and one death from congestive heart failure. These three patients had conduction abnormalities on resting 12-lead ECG. Myocardial tissue from two patients showed myocyte loss and fibrofatty replacement, and one patient had reduced/absent plakophilin-2 staining of the intercalated disks in the myocardium.³⁹ Dilated cardiomyopathy (DCM)/ACM overlapping phenotype may be observed in patients who carry LMNA mutations⁴⁰ and in patients with ACM and Charcot-Marie-Tooth phenotype.⁴¹

The transmembrane protein 43 (TMEM43) gene encodes an inner nuclear membrane protein termed LUMA that interacts with lamin A/C and emerin. The missense mutation c.1073C>T (p.(Ser358Leu)) in TMEM43 causes ACM and was identified in a founder population from Newfoundland. The p.(Ser358Leu)-associated phenotype is highly malignant and is characterized by poor R-wave progression, early ventricular ectopy, LV dilatation, heart failure, and early death.^42,43 TMEM43 mutations, including p.(Ser358Leu), have been identified in individuals not from Newfoundland.⁴⁴ Further studies confirmed that TMEM43 ACM subtype is a sex-influenced lethal ACM, with a unique ECG finding, LV dilatation, heart failure, and early death. The genetic presymptomatic diagnosis has the greatest clinical utility.⁴⁵ TMEM43 sequencing is now incorporated into clinical genetic testing for ACM patients.^46,47 TMEM43 protein is active in an adipogenic pathway regulated by Peroxisome proliferator-activated receptor γ (PPARγ; an adipogenic transcription factor); this may explain the fibrofatty replacement of the myocardium. The pathogenetic mechanisms of this mutation are poorly understood. Mutant TMEM43 exhibits normal cellular localization and does not disrupt integrity and localization of other nuclear envelope and desmosomal proteins.⁴⁷

The phospholamban (PLN) gene encodes a protein that is a major substrate for the cAMP-dependent protein kinase in cardiac muscle and inhibits cardiac muscle sarcoplasmic reticulum Ca²⁺-ATPase in the unphosphorylated state; inhibition is relieved by phosphorylation of the protein. Mutations in this gene cause ACM, DCM with refractory congestive heart failure, and familial hypertrophic cardiomyopathy (HCM).^48,49

The ryanodine receptor-2 (RYR2) gene encodes a receptor located in cardiac muscle sarcoplasmic reticulum. The protein is a component of a calcium channel that is constituted of a tetramer of the ryanodine receptor proteins and a tetramer of FK506-binding protein 1B proteins, which supplies calcium to cardiac muscle. Mutations in this gene are more commonly associated with stress-induced polymorphic ventricular tachycardia and less commonly with ARVD (9% of ACM probands).^50,51

The titin (TTN) gene encodes a large abundant protein of striated muscle. The protein is divided into two regions, an N-terminal I-band and a C-terminal A-band. Mutations in this gene are associated with DCM; familial HCM; limb-girdle, type 2 muscular dystrophy; early-onset myopathy with fatal cardiomyopathy; proximal myopathy with early respiratory muscle involvement; and tardive tibial muscular dystrophy. In a screening study including 39 ACM families, 13% (5 of 39 families) carried TTN rare variants (11 affected subjects).⁵² TTN variants were further investigated and were identified in seven families; the prominent Thr2896Ile mutation showed complete segregation with the ACM phenotype in one large family. This mutation affects a highly conserved immunoglobulin-like fold located in the spring region of titin and reduces the structural stability and increases the propensity for degradation of the immunoglobulin-like domain. Carriers of TTN mutations demonstrated history of sudden death (5 of 7 families), progressive myocardial dysfunction ending in death or heart transplantation (8 of 14 cases), frequent conduction disease (11 of 14 cases), and incomplete penetrance (86%).⁵³

The transforming growth factor-β3 (TGFB3) gene encodes a secreted member of the TGF-β family that is involved in embryogenesis and cell differentiation.⁵⁴ Typically, TGFB3 mutations cause Loeys-Dietz syndrome type 5. However, mutation screening of the promoter and untranslated regions (UTRs) of the TGFB3 gene identified a nucleotide substitution (c.–36G>A) in the 5′ UTR of the gene invariably associated with the classical, right-sided ACM phenotype and an additional mutation (c.1723C>T) in the 3′ UTR of one proband. Both nucleotide changes were absent in control subjects. In vitro expression assays with constructs containing the mutations showed that mutated UTRs were two-fold more active than wild-types.

ADAM17 (a disintegrin and metalloproteinase 17 or tumor necrosis factor-α converting enzyme) sheds a number of ligands by cleavage of substrates (eg, ligands for the epidermal growth factor receptor and tumor necrosis factor-α) in the juxtamembrane region, plays a role in ligand-independent Notch signaling, and sheds cell adhesion molecules including desmoglein 2.⁵⁵ A homozygous loss-of-function ADAM17 mutation causes the autosomal recessive neonatal inflammatory skin and bowel disease type 1, which is characterized by severe skin inflammation, increased susceptibility to infection, bowel inflammation, and cardiomyopathy. The cardiomyopathy and other phenotypes in this syndrome may be related, in part, to impaired ADAM17-mediated DSG2 processing.⁵⁶

ACM is an underrecognized clinical entity that is associated with SCD in young people, particularly athletes.^57,58 In those aged ≤ 35 years, ACM accounts for 11% of cases of SCD overall and 22% of cases in young athletes.⁵⁷ The annual mortality in patients with ACM is reported to be as high as 2.3%.⁵⁹ Several studies have suggested a male predominance^60,61; however, more recent studies have demonstrated no sex differences in terms of prevalence or clinical presentation.^11,62,63,64

Those with ACM typically present between the second and fifth decades of life.⁵⁸ Symptoms are heterogeneous but most commonly reflect the presence of ventricular arrhythmias, which can range from isolated premature ventricular contractions (PVCs) to sustained ventricular tachycardia (VT). Supraventricular arrhythmias also occur in 14% of ACM patients, with atrial fibrillation being the most frequently reported.⁶⁵ In a study of 129 probands, symptoms on presentation included palpitations in 56%, dizziness in 29%, syncope in 26%, chest pain in 19%, and cardiac arrest in 22%.⁶⁴ Symptoms related to right heart failure are present in 6%.⁵⁹ These findings are consistent with other studies.^3,58,66,67

ACM has the following three phases of pathophysiologic progression (Fig. 62–2).⁶⁶

1. Concealed stage: Individuals are asymptomatic, but potentially exposed to the risk of life-threatening arrhythmias during exertion. Diagnostic studies, including ECG, ambulatory monitoring, and imaging, may be normal.

2. Electrical stage: Electrical myocardial changes occur leading to minor ECG changes and increased risk of ventricular arrhythmias, which may manifest as symptomatic PVCs or VT on ambulatory monitoring. Hence, individuals have an increased risk of SCD. Subtle myocardial changes may also be present; however, RV dysfunction is not apparent.

3. Structural stage: There is progressive fibrofatty infiltration with loss of normal ventricular myocardium, which increases the risk of ventricular arrhythmias and SCD. Structural changes are apparent with RV dilatation and aneurysm formation. RV, LV, or biventricular dysfunction may occur depending on the extent of structural abnormalities⁶⁷ (Figs. 62–3 and 62–4).

Alternatively, the natural history of classical right-sided ACM can be divided into four stages in which the concealed and electrical stages are similarly defined but the structural stage distinguishes the overt RV failure with overall preserved LV function from the final phase, which is marked by overt LV involvement and biventricular heart failure.¹⁰ The left-dominant ACM is characterized by primary (but not necessarily exclusive) LV involvement, and biventricular ACM is defined by early and parallel involvement of both ventricles.

Naxos disease and Carvajal syndrome are distinctive forms of ACM that are inherited in an autosomal recessive manner in association with extracardiac manifestations including wooly hair and plantopalmar keratoderma.⁶⁸ Carvajal syndrome is a variant of Naxos disease with predominant LV involvement.

Evaluation and Diagnosis

As a result of variable phenotypic expression, diagnosis is obtained from multiple diagnostic modalities that are used to satisfy major and minor criteria established by the International Task Force.⁷ The diagnostic modalities and criteria used for the diagnosis of ACM as part of the 2010 revised Task Force Criteria are reviewed below. The diagnosis requires fulfillment of certain major and minor criteria, as shown in Table 62–1.

• A definite diagnosis of ACM is established when two major, or one major and two minor, or four minor criteria from different categories are fulfilled.

• Borderline cases are defined as meeting one major and one minor or three minor criteria from different categories.

• Possible ACM is established when one major or two minor criteria from different categories are met.

12-Lead Electrocardiogram

Repolarization abnormalities consisting of T-wave inversion (TWI) in leads V₁ through V₃ or beyond occur in 87% of patients with ACM but in only < 3% of young healthy adults.^69,70 The sensitivity and specificity of TWI in V₁ through V₃ for ACM, in the absence of a right bundle branch block (RBBB), are 71% and 96%, respectively.⁷¹ The sensitivity and specificity of TWI in V₁ through V₃ in the presence of an RBBB are suboptimal. In this situation, TWI in V₁ through V₄ improves the sensitivity and specificity for ACM. A similar pattern of TWI in the precordial leads may be seen in asymptomatic athletes.⁷² This finding lacks specificity in this population, and other criteria need to be carefully evaluated prior to establishing a diagnosis of ACM.

As a result of structural remodeling, electrical conduction through the right ventricle is abnormal and delayed. This results in characteristic ECG abnormalities, including delayed terminal activation of the S-wave upstroke in the right precordial leads. A prolonged S-wave upstroke ≥ 55 ms (measured from the nadir of the S wave to end of QRS) in leads V₁ through V₃ is present in 95% of patients with ACM and only about 2% of normal individuals.⁶⁹ The presence of delayed terminal activation cannot be interpreted on ECG when an RBBB is present. Epsilon waves, which are low-amplitude signals that represent late potentials, may be seen in between the QRS and T waves in the right precordial leads^69,71 and represent a major criterion for the diagnosis of ACM (Fig. 62–5).

ECG may also demonstrate ventricular arrhythmias, particularly PVCs and rarely nonsustained VT. These typically have a left bundle branch block (LBBB) morphology and may have an inferior axis (similar to patients with idiopathic right ventricular outflow tract [RVOT] VT) or superior axis in the inferior leads. Ventricular arrhythmias with an LBBB morphology and a superior axis in a young adult should raise suspicion for ACM.

Signal-Averaged Electrocardiogram

Signal-averaged ECG (SAECG) averages multiple QRS complexes to improve the signal-to-noise ratio and improve detection of late potentials. Although now infrequently used, detection of late potentials by SAECG is a minor criterion in current revision of the Task Force criteria.⁷ Late potentials are considered to be present if one or more of the following three abnormal findings are present^7,73: filtered QRS duration ≥ 114 ms, duration of terminal QRS < 40 μV is ≥ 38 ms, or root-mean-square voltage of terminal 40 ms is ≤ 20 μV. Late potentials may also be present in other disease processes that cause myocardial scar and, normally, SAECG is considered positive if two of three of the above criteria are present. However, in ACM, the sensitivity and specificity are similar whether one or more of the abnormalities are present.⁷ Therefore, the current Task Force criteria require that only one of the three abnormalities in the SAECG be present.

Ventricular Arrhythmias

Ventricular arrhythmias are an important manifestation of ACM, with 48% of individuals presenting with fatal or near-fatal events.³ Frequent PVCs and VT occur in 67% and 77% of patients, respectively. Following an established diagnosis, up to 41% of patients will experience sustained monomorphic VT or polymorphic VT/ventricular fibrillation (VF) over 3 years of follow-up.⁷⁴ As previously stated, the morphology of VT is typically LBBB and may have an inferior or superior axis. Holter monitoring is beneficial in establishing the etiology of symptoms and to assess PVC burden; however, it is less useful in determining the morphology of the ventricular ectopy as a result of a limited number of leads. A burden of > 500 PVCs per 24 hours is a minor criterion for ACM.

Cardiac Imaging

RV angiography, transthoracic echocardiography, and cardiac magnetic resonance imaging (CMRI) can be used to evaluate for structural and functional abnormalities of the right ventricle. RV angiography, although rarely performed, may demonstrate regional RV wall abnormalities, including dyskinesia, akinesia, or aneurysm formation. Transthoracic echocardiography is more commonly used, and in addition to providing information on regional wall abnormalities, it can provide information regarding RV dimensions and function. In a study of ACM probands, Yoerger et al⁷⁵ demonstrated that RV dimensions were significantly larger and RV function, as measured by fractional area change, was significantly decreased in probands compared to controls. The RVOT was the most commonly enlarged area, and RV morphologic changes were present in many probands, with excessive trabeculations seen in 54%, hyperreflective moderator band seen in 34%, and sacculations seen in 17% of ACM probands, but not controls (Fig. 62–6). Quantitative measures of RVOT enlargement and RV function were instituted in the current revision of the Task Force criteria (Table 62–1). Major criteria values were selected to yield a specificity of > 95%, and minor criteria values were selected to yield a sensitivity equal to specificity.⁷

Echocardiography provides a relatively limited assessment of RV structure and function as a result of the inherent limitation in assessing a complex three-dimensional chamber with limited two-dimensional views. These limitations are overcome with CMRI, which can provide a superior assessment of regional and global function as well as provide information on tissue characteristics (ie, fibrosis and intramyocardial fat).^76,77 A recent study comparing CMRI versus echocardiography demonstrated that only 50% of patients with imaging-positive CMRI had echocardiographic criteria for ACM.⁷⁸ Tissue characterization by CMRI and longer follow-up confirm three patterns of disease expression⁶⁷:

1. Classic: Predominant RV involvement with little or no LV involvement

2. Left dominant: Mostly LV involvement with little RV involvement

3. Biventricular: Both the right and left ventricles are equally affected

CMRI has also shown that the RV apex, which together with the RV inflow tract and RVOT has been historically described as the triangle of dysplasia,⁴ is only involved in advanced stages of the disease.⁷⁹ The triangle of dysplasia involves the epicardial subtricuspid region, RV basal anterior wall, and posterolateral left ventricle, with the RV apex being mostly spared.⁷⁹

Although CMRI has emerged as the preferred imaging modality for ACM, it is also one of the most common reasons for misdiagnosis. Common pitfalls include misinterpretation of variants of normal RV wall motion and inaccurate interpretation of intramyocardial fat infiltration.⁸⁰ It is important to note that, in pediatric ACM patients, intramyocardial fat infiltration and myocardial fibrosis are uncommon findings by CMRI.⁸¹

Endomyocardial Biopsy

Endomyocardial biopsy is rarely performed, but may be helpful in establishing a diagnosis of ACM when the etiology of cardiomyopathy or structural changes are unclear. The American College of Cardiology/American Heart Association consensus guidelines give a Class IIa (Level of Evidence C) indication for endomyocardial biopsy in patients with heart failure when a specific diagnosis is suspected that would influence therapy.⁸² The demonstration of fibrofatty infiltration with loss of normal RV myocardium supports the diagnosis (Table 62–1).^7,83 There is a high rate of false negatives and low sensitivity as a result of the patchy nature of disease and predilection for specific areas of the right ventricle.⁸³ Thus, conventional RV septal wall or LV biopsies are not helpful because these areas are commonly spared. Diagnostic yield may be improved by using electroanatomic voltage mapping to guide biopsy.⁸⁴ However, there is increased risk of cardiac perforation and tamponade with RV free wall biopsy.

Family History and Genetic Testing

The genetic bases of ACM are reviewed in the pathobiology section of this chapter. The predominant inheritance pattern is autosomal dominant with variable penetrance and expressivity, although an autosomal recessive inheritance pattern has been described with the cardiocutaneous syndromes of Naxos disease and Carvajal syndrome.⁶⁸ Approximately 60% of probands will have an identifiable pathogenic mutation.¹¹ Identification of a pathogenic mutation on genetic testing is a major criterion for the diagnosis of ACM (Table 62–1).⁷ Currently, one of the major roles of genetic testing in ACM is for mutation-specific screening of family members following the identification of a pathogenic mutation in the proband. The Heart Rhythm Society and European Heart Rhythm Association expert consensus guidelines give this indication a Class I recommendation.⁸⁵ Although genetic testing may be useful for confirmed cases (Class IIa) or considered for borderline cases (Class IIb), it is not recommended (Class III) for those fulfilling only a single minor Task Force criterion.⁸⁵ The clinical genetic and molecular workup in the proband and his or her family should be performed as in other familial cardiomyopathies and include clinical and genetic screening of first-degree relatives (see Chap. 9). The major difference between ACM and other cardiomyopathies is that, in the Task Force criteria, a “first-degree relative who meets current Task Force criteria” is defined as possibly affected. The same diagnosis, possible ACM, is formulated when “a pathogenic mutation categorized as associated or probably associated with ACM is found in the patient under evaluation.”⁷ In non-ACM cardiomyopathies, relatives of affected members are usually not considered as possibly affected, and clinically healthy carriers of pathologic mutations are usually defined as “healthy carriers” and not possibly affected. The difference may appear semantic; however, the impact of pathologic mutations in ACM is higher than in other genetic cardiomyopathies.

A positive family history of ACM is a risk factor for disease, with over a third of family members of affected individuals developing disease.^11,86,87 The cumulative 5-year and 10-year probabilities of developing ACM in first-degree family members are 7% and 21%, respectively, with siblings of probands having a three-fold higher risk compared to parents or children.⁸⁶ Pathogenic mutations are identified in 36% to 72% of selected family members, and up to 40% of these individuals will fulfill Task Force criteria for ACM.^11,88 Disease will still occur in 18% of those who are mutation negative.¹¹ Additionally, the presence of symptoms or the occurrence of more than one genetic variant in family members increases the likelihood of Task Force criteria–confirmed disease.^11,86,88 The constellation of findings highlights the complexity of the genetics of ACM and firmly support the screening of family members of affected individuals (Figs. 62–7 and 62–8).

Other Diagnostic Modalities

Although not part of the Task Force criteria for diagnosis of ACM, isoproterenol and exercise testing have recently demonstrated potential benefit in the workup of selected individuals.^89,90 The diagnostic value of isoproterenol was evaluated in a recent study of 412 consecutive patients referred to a tertiary center for PVCs or suspected ACM.⁸⁹ Isoproterenol infusion of 45 μg/min was administered for 3 minutes, and the test was considered positive if there were polymorphic PVCs with one or more couplet or sustained/nonsustained VT with LBBB excluding outflow tract morphology. The test was positive in 91% of patients with ACM versus 11% in others (P < .0001). During a mean follow-up of 5.6 years, six patients who did not initially have ACM were subsequently diagnosed with disease. Interestingly, all six patients had positive isoproterenol tests. The sensitivity, specificity, positive predictive value, and negative predictive value were 91.4%, 88.9%, 43.2%, and 99.1%, respectively. These promising results need confirmation by other investigators prior to widely recommending this test.

When comparing asymptomatic gene carriers versus healthy controls, exercise treadmill testing was found to more frequently induce depolarization abnormalities on ECG, including appearance of epsilon waves, PVCs, and new QRS terminal activation duration ≥ 55 ms.⁹⁰ Similar findings were seen in patients with ACM and history of ventricular arrhythmias or cardiac arrest, suggesting that exercise treadmill testing may have a role in identifying a developing substrate so that medical surveillance can be targeted at these individuals.

Risk Stratification and Implantable Cardioverter-Defibrillator Implantation

There are no prospective, randomized clinical trials to elucidate which individuals are at highest risk for SCD and would benefit from implantable cardioverter-defibrillator (ICD) implantation. However, based on observational studies in ACM patients, a history of prior cardiac arrest, sustained ventricular arrhythmias, unexplained syncope, younger age, extensive RV dysfunction, LV dysfunction, and the presence of heart failure are independently associated with subsequent ventricular arrhythmias.^{59,74,91,92,93,94,95,96,97} In a study of patients receiving ICD for definite or probable ACM, 48% received an appropriate ICD therapy during a mean follow-up of 5 years.⁹⁸ The only independent predictors of ICD therapy were the presence of nonsustained VT and inducibility at electrophysiology study. The role of electrophysiology study for risk stratification is unclear because studies provide conflicting evidence.^91,93,98,99 Based on available data, the International Task Force provided consensus statements regarding high-, intermediate-, and low-risk factors (Table 62–3) and when ICD implantation is recommended (Fig. 62–9).¹⁰⁰ The only Class I recommendation is for patients at high risk based on a history of aborted SCD, sustained VT, or severe dysfunction of the right ventricle, left ventricle, or both. The estimated risks for major arrhythmic events for the high-, intermediate-, and low-risk groups are > 10%, 1% to 10%, and < 1% per year, respectively.¹⁰⁰

Pharmacologic Therapy

Similar to heart failure that occurs in other settings, patients with ACM and heart failure should undergo treatment with β-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and diuretics. Additionally, because ventricular arrhythmias may be driven by exercise or increased sympathetic tone,^35,101 β-blocker therapy should be instituted in these patients. They also have a role in treating inappropriate ICD therapies as a result of supraventricular arrhythmias. However, for patients with scar-related reentrant VT, β-blockers are less effective, and amiodarone or sotalol should be used to decrease the risk of recurrent ventricular arrhythmias.^102,103,104 Antiarrhythmic drugs do not reduce mortality and should not be used in place of ICDs. They are best used to reduce recurrent VT/VF episodes in those with an ICD in place.

Catheter Ablation

Catheter ablation is an option for the treatment of VT in ACM (Fig. 62–10). Its primary role is for the control of VT in patients with ICDs despite antiarrhythmic drug therapy or as an alternative to antiarrhythmic drugs. Similar to antiarrhythmic drugs, ablation does not reduce mortality and should not be used in place of ICDs. Initial results with endocardial ablation alone were disappointing.^105,106,107 These suboptimal results are not entirely surprising because ACM is a diffuse and extensive process that typically involves the RV epicardium.¹⁰⁸ Combined epicardial and endocardial catheter ablation has provided better results.^{108,109,110,111,112,113} In a recent report of 62 ACM patients who underwent endocardial ablation with adjuvant epicardial ablation for VT, the VT-free survival during a mean follow-up of > 4 years was 71%.¹¹³ Prior to ablation, 87% of patients had failed antiarrhythmic drugs, and following ablation, the majority were on β-blockers only or required no therapy.

Cardiac Transplantation

Approximately 2% to 4% of ACM patients undergo cardiac transplantation.^11,58 In a report from the John Hopkins ARVD Program Registry of 18 patients who underwent cardiac transplantation, 1-year survival was 94%, and 88% were alive at a mean follow-up of 6 years.¹¹⁴ ACM patients who have severe drug refractory heart failure or ventricular arrhythmias that are recurrent despite ICD therapy, antiarrhythmic drugs, and catheter ablation may require heart transplantation.

Exercise Restriction

Individuals with ACM are prone to ventricular arrhythmias and SCD during exercise and competitive sports.^2,5,7 In a murine model, endurance training was shown to accelerate the development of RV dysfunction and arrhythmias in ACM desmosome mutation carriers.¹¹⁵ These findings were confirmed in human studies of desmosome mutation and nondesmosome mutation carriers with the demonstration that frequent exercise or endurance exercise was associated with increased risk of VT/VF, heart failure, structural abnormalities, and earlier onset of disease.^25,116 These findings confirm that exercise is a disease modifier in ACM. Based on these findings, recent guidelines from the American Heart Association and American College of Cardiology recommend that individuals with definite, borderline, or possible ACM refrain from competitive sports with the possible exception of low-intensity class 1A sports.¹¹⁷ Exercise restriction to prevent disease progression and decrease risk of ventricular arrhythmias should be a treatment strategy in all ACM patients.

The differential diagnosis of ACM includes idiopathic RVOT VT (RVOT-VT), sarcoidosis, myocarditis, dilated cardiomyopathy, Brugada syndrome, athlete’s heart, RV infarction, Chagas disease in endemic areas, pulmonary hypertension and congenital heart disease.

Right Ventricular Outflow Tract Ventricular Tachycardia

Idiopathic RVOT-VT should be differentiated from early ACM, when gross structural abnormalities are absent. Diagnosis is based on clinical data (Task Force criteria), pathology (endomyocardial biopsy), and imaging such as echocardiography and CMRI or positron emission tomography demonstrating or excluding scar and inflammation.^118,119 In general, in RVOT-VT:

• Twelve-lead surface ECG and SAECG are normal during sinus rhythm.

• A single VT morphology with LBBB pattern and an inferior axis is commonly recorded.¹²⁰

• The application of an ECG-based scoring system can clarify the diagnosis. The scoring system provides 3 points for sinus rhythm anterior T-wave inversions in leads V₁ to V₃ and during ventricular arrhythmia, 2 points for QRS duration in lead I ≥ 120 ms, 2 points for QRS notching, and 1 point for precordial transition at lead V₅ or later. A score ≥ 5 correctly distinguishes ACM from RVOT-VT in more than 90% of cases (sensitivity 84%; specificity 100%; positive predictive value 100%; negative predictive value 91%).¹²¹

• QRS duration during VT is longer (≥ 120 ms in lead I).¹²²

• Notched QRS complexes and precordial transition in lead V₆ occur in ACM, but not in RVOT-VT.¹²³

• RVOT-VT is difficult to induce by programmed ventricular stimulation.¹¹⁹

Cardiac Sarcoidosis

Cardiac sarcoidosis can mimic ACM. Task Force criteria do not reliably distinguish between the two conditions. In a study of patients with suspected ACM and investigated with endomyocardial biopsy, cardiac sarcoidosis was identified in 15% of cases.¹²⁴ In a series of 18 patients with proven cardiac sarcoidosis or ACM, cardiac sarcoidosis was characterized by reduced LV ejection fraction, a significantly wider QRS, right-sided apical VT, and more inducible forms of monomorphic VT.¹²⁵ Additional signs in favor of sarcoidosis include respiratory and systemic symptoms, high-grade atrioventricular conduction block, septal involvement, and proven absence of familial disease. The diagnosis is confirmed by endomyocardial pathology and imaging studies (see. Chap. 63).

Myocarditis

Cardiac phenotypes mimicking ACM include RV myocarditis. In a series of 30 consecutive patients with a noninvasive diagnosis of ACM, 29 had an abnormal voltage map. Three-dimensional electroanatomic mapping–guided endomyocardial biopsy confirmed the diagnosis of ACM in 15 patients and myocarditis in the remaining 15. Clinical features, structural and functional RV abnormalities, and three-dimensional electroanatomic mapping findings did not distinguish ACM from myocarditis.¹²⁶ ACM phenotype can also mimic acute myocarditis, as demonstrated in a 21-year-old woman who presented with fulminant lymphocytic myocarditis and subsequently developed isolated RV dysfunction with imaging and ECG criteria for ACM.¹²⁷

Dilated Cardiomyopathy

DCM is particularly difficult to distinguish from nonclassic ACM. Phenotype overlapping can be complicated by genetic overlapping as the same disease genes can cause either DCM or ACM. Early arrhythmic manifestations typically occur in ACM; however, they can also occur in DCM, particularly in patients who carry mutations in genes associated with high arrhythmogenic risk, such as LMNA.³⁹ Overlapping of ACM and DCM phenotypes may occur in patients with TTN mutations^52,53 and PLN mutations.^48,49

Brugada Syndrome

Brugada syndrome can mimic ACM. Both conditions may demonstrate RV conduction delay, and mutations typically occurring in Brugada syndrome were found in ACM patients and vice versa.^128,129 ECG markers that reflect ventricular conduction delay in ACM have been observed in patients with spontaneous or drug-induced type 1 ECG pattern of Brugada syndrome.¹³⁰ However, the presence of structural abnormalities supports the diagnosis of ACM.

Chagas Disease

Patients diagnosed with Chagas disease may demonstrate early and frequent RV involvement.¹³¹ In a recent case-control and prevalence study including 31 controls and 61 patients with indeterminate form of Chagas disease, RV systolic dysfunction was present in 26%.¹³² Chagasic cardiomyopathy is associated with decreased expression of the gap junction protein Cx43.¹³³ In endemic areas, Chagas disease should be included in the list of differential diagnoses with ACM.

Athlete’s Heart

ACM can be mimicked by RV changes that may develop in endurance athletes.¹³⁴ The differential diagnosis of athlete’s heart and ACM is a difficult clinical problem. In a recent series of 1009 Olympic athletes (mean age, 24 ± 6 years; 64% males) participating in skill, power, mixed, and endurance sport, RV enlargement compatible with major and minor Task Force diagnostic criteria for ACM was observed in 41 (4%) and 319 (32%) athletes, respectively. Therefore, experts recommend referring to the 95th percentiles as reference values, or alternatively, only major diagnostic Task Force criteria for ACM may be appropriate.¹³⁵

ACM is a genetic cardiomyopathy characterized clinically by life-threatening ventricular arrhythmias and structurally by fibrofatty substitution of the RV wall in its classic right-sided form and of both the LV and RV walls in biventricular and left dominant variants. The diagnostic workup is guided and supported by the modified Task Force criteria (2010), which are based on combined clinical, instrumental, and genetic major and minor criteria. Family screening is recommended for relatives of probands diagnosed with ACM, as it allows preclinical and early diagnosis. In patients who are diagnosed early, clinical monitoring and primary prevention of SCD improves mortality. Genetic criteria, both clinical and molecular, are major diagnostic contributors and genetic testing is now recommended by official guidelines. Exercise is a key environmental trigger that may promote the development of the disease in susceptible individuals and influence the evolution; therefore, restriction of exercise is recommended in patients diagnosed with ACM.