Molecular Genetics

Familial disease occurs in approximately 30% to 60% of cases of ARVC. The remainder of patients with ARVC have undiscovered genetic abnormalities or have the disease de novo. Two patterns of inheritance have been described: autosomal dominant disease with incomplete penetrance (most common) and autosomal recessive disease (rare). Autosomal recessive forms of ARVC include Naxos disease (also known as familial palmoplantar keratosis and “mal de Meleda” disease) and Carvajal syndrome (a disorder of LV cardiomyopathy), both of which are associated with skin and hair abnormalities.

The autosomal dominant nonsyndromic ARVC-1 to ARVC-12 as well as the two rare recessive forms (Naxos disease and Carvajal syndrome) have been mapped to 12 genetic loci, with mutations in eight gene loci identified ( Table 29.1 ). Although some identified gene mutations such as ryanodine receptor 2 (RYR2) may be phenocopies of ARVC, a common theme of desmosomal protein mutations has been emerging. In fact, five of the eight gene loci encode desmosomal proteins (plakophilin-2 [PKP2], desmoglein-2 [DSG2], desmoplakin [DSP], desmocollin-2 [DSC2], and junctional plakoglobin [JUP]) have been found in association with the ARVC phenotype in up to 50% of cases. Among genotype-positive probands, mutations in PKP2 appear to be the most common causes of ARVC, accounting for approximately 73% to 79% of cases. Mutations in DSG2 and DSP account for approximately 10% to 14% and 3% to 8% of cases, respectively. Therefore ARVC is currently considered to be, at least in a subset, a disease of the cardiac desmosome.

The majority of disease-causing mutations are insertion/deletion or nonsense mutations, which are expected to cause premature termination of the encoded proteins. Data from the North American ARVC registry showed that 86% of patients had a single heterozygous gene mutation, 7% showed compound heterozygosity, 7% had digenic heterozygosity, and 1% had homozygous mutation. Patients with multiple mutations seem to have early disease onset and a worse arrhythmic course. Mutations can be inherited from a parent or can be the result of a new mutation. Approximately 20% to 30% of patients with ARVC have a family history of ARVC or of SCD.

Mutations in several nondesmosome genes have also been reported to cause ARVC: Transmembrane protein 43 (TMEM43) , transforming growth factor-beta3 (TGFβ3) , desmin (DES) , lamin A/C (LMNA) , titin (TTN) , and phospholamban (PLN) . A mutation in TMEM43, encoding a transmembrane protein with ties to an adipogenic transcription factor, was reported as the cause for ARVC-5, a subtype of ARVC with prominent LV involvement.

Furthermore, mutations in RYR2, encoding the cardiac ryanodine receptor (the major calcium release channel of the sarcoplasmic reticulum in cardiomyocytes, also implicated in familial catecholaminergic polymorphic ventricular tachycardia [CPVT]), result in a form of arrhythmogenic cardiomyopathy (ARVC-2) characterized by exercise-induced polymorphic VT that does not appear to have a reentrant mechanism, occurring in the absence of significant structural abnormalities. Patients do not develop characteristic features of ARVC on the 12-lead electrocardiogram (ECG) or signal-averaged ECG, and global RV function remains unaffected. ARVC-2 shows a closer resemblance to familial CPVT in both etiology and phenotype, and its inclusion under the umbrella term of ARVC remains controversial.

Genotype–phenotype studies have identified an association of genotype with clinical course and disease expression, including the onset of overt disease, LV involvement, and the severity of heart failure. In a multicenter study, 80% of individuals had a single copy of a PKP2 mutation whereas 4% of individuals carried two or more pathogenic mutations. PKP2 mutation carriers are more likely to experience an earlier onset of both symptoms and arrhythmias. PLN mutation carriers presented at a significantly older age yet had worse long-term prognosis, with more LV dysfunction and heart failure. Also, individuals harboring DSP were considerably more likely to develop heart failure and more prominent LV involvement, and are more likely to present with SCD rather than other mutation carriers.

Carriers of single pathogenic mutations in any of the genes appear to exhibit a similar high risk of developing a life-threatening arrhythmia, with no significant differences in survival from life-threatening VT/ventricular fibrillation (VF) among the different genes. Conversely, patients with more than one mutation have considerably worse clinical course with a significantly earlier onset of symptoms and first sustained VT or VF, a greater chance of developing sustained VT or VF, and a fivefold increase in the risk of developing LV dysfunction and heart failure than those carrying a single mutation.

Pathogenesis

Cardiac desmosomes are specialized, multiprotein complexes in the intercalated disks that anchor intermediate filaments to the cytoplasmic membrane in adjacent cardiomyocytes, thereby forming a three-dimensional (3-D) scaffolding and providing mechanical strength and cohesion of cardiomyocytes in the beating heart ( Fig. 29.1 ). Cardiac desmosomes are also responsible for regulating the transcription of genes involved in adipogenesis and apoptosis as well as maintaining proper electrical conductivity through the regulation of gap junctions and calcium homeostasis.

Molecular Structure of the Cardiac Desmosome.

The desmosomal cadherins desmocollin and desmoglein form classic homotypic and heterotypic interactions between cells. These membrane-bound proteins are linked through the Armadillo family members, plakoglobin, and plakophilin to the intermediate filament-binding protein desmoplakin. This complex anchors the desmosome to the cytoskeleton of the cell, and thus indirectly to the sarcomere, the nuclear membrane, and the dystrophin-associated glycoproteins.

(From Ellinor PT, MacRae CA, Thierfelder L. Arrhythmogenic right ventricular cardiomyopathy. Heart Fail Clin . 2010;6:161–177.)

Cardiac desmosomes are composed of three groups of proteins: the cadherin family, the Armadillo family, and the plakin family. The cadherin family is composed of three desmocollins and three desmogleins, which are primarily responsible for anchoring the structure to the membrane. The Armadillo family is composed of plakoglobin and three plakophilins, which form the core structure and possess signaling capabilities. The plakin family is composed of DSP, envoplakin, periplakin, plectin, and pinin, which are responsible for the attachment of the desmosomes to intermediary filaments.

The mechanisms by which the affected desmosomes cause myocyte apoptosis, fibrogenesis, adipogenesis, and slow ventricular conduction, thus leading to impaired RV function and increased arrhythmogenicity, remain to be determined. Mutations in desmosomal genes alter the number or integrity of desmosomes and thereby lead to impaired mechanical coupling and the failure of cell-to-cell adhesion structures during exposure to physical strain, resulting in cardiomyocyte detachment and degeneration, with subsequent inflammation and replacement by fibrofatty tissue. This course may be triggered or aggravated by inflammatory processes (superimposed myocarditis), autonomic dysfunction, or mechanical stretch of the myocardium (e.g., during intense exercise) and lead to myocardial damage, inflammation, and cell death. The reason behind the preferential involvement of the RV in ARVC remains elusive; nonetheless, several factors can make the RV particularly vulnerable to impaired mechanical cellular coupling, more so than the LV, including thinner RV free wall, high distensibility, and variations in preload and stretch. These factors expose the RV to disproportionately greater strain during exercise compared with the LV.

Fibrofatty replacement is a nonspecific repair process also observed in the muscular dystrophies. The architecture of thin surviving myocardial bundles within the fibrofatty tissue creates lengthened conduction pathways, conduction slowing at pivotal points, and conduction block, creating an electrophysiological (EP) substrate for reentry and VT. Furthermore, fibrofatty replacement of the myocardium results in abnormal structure, morphology, geometry, and wall motion of the ventricle.

In addition, impaired desmosomal structure and function can affect other cell-to-cell contact structures in the myocardium. Mutations in desmosomal proteins can impair the expression of interacting proteins at the intercalated disk (e.g., gap junction or sodium channel proteins), giving rise to the impairment of intercellular conductance and promoting ventricular arrhythmogenesis, even in the absence of fibrofatty tissue replacement. In particular, connexin-43 (Cx43) remodeling in the gap junctions, which contributes to delayed conduction and ventricular arrhythmogenesis, is often observed in ARVC patients. Also, a reduction in Cx43 protein can potentially lead to reduced sodium channel expression and function. Abnormal electrical coupling and ion channel dysfunction, leading to electrical instability, can promote arrhythmias and predispose patients to a high risk of SCD, even in the early disease stages, prior to the development of significant ventricular dysplasia and scarring.

In the early disease phase, VF likely reflects acute ventricular electrical instability secondary to acute myocyte death and reactive inflammation, which is often characterized by dynamic T wave inversion, ST segment elevation, and myocardial enzyme release. In later disease stages of ARVC, fibrofatty replacement of RV myocardium creates scar regions that provide the arrhythmogenic substrate for VT. In fact, scar-related macroreentry in areas of abnormal myocardium (similar to that observed in the post–myocardial infarction [MI] setting) is the most common mechanism of VT in ARVC patients. Most reentrant circuits cluster around the tricuspid annulus and the right ventricular outflow tract (RVOT). The critical isthmus contained in these reentry circuits often is a narrow path of tissue with abnormal conduction properties, typically bounded by two approximately parallel conduction barriers that consist of scar areas, the tricuspid annulus, or both.

Of note, among ARVC patients with frequent premature ventricular complexes (PVCs) at baseline, a high degree of association has been reported between induced sustained VT and the clinical PVCs. VT in these patients exhibited features suggestive of a focal mechanism. The site of origin of those catecholamine-facilitated VTs was uniformly the border region of scar, typically in the RVOT and RV basal regions.

Pathology

The most striking morphological feature of ARVC is the diffuse or regional loss (atrophy) of myocardium with subsequent replacement by fibrofatty tissue, leading to localized ventricular wall thinning, sacculations, aneurysms ( eFig. 29.1 ), and segmental hypokinesia. Fibrofatty replacement usually begins in the subepicardium or midmural layers and progresses to the subendocardium. Patchy inflammatory infiltrates can be present in areas of myocardial damage. Myocarditis can reflect an active phase of ARVC during which worsening of ventricular systolic function or ventricular arrhythmia can develop.

Right Ventricular (RV) Aneurysm.

This cardiac computed tomography angiogram shows thinning and aneurysmal dilation of the RV anterior wall and outflow tract (arrows) in a patient with arrhythmogenic right ventricular cardiomyopathy and ventricular tachycardia. Ao , Aorta; LV , left ventricle; PA , pulmonary artery; RV , right ventricle.

In ARVC, the muscle cells affected initially are primarily in the RV, but the LV can be involved later in the course of ARVC or occasionally be an early or predominant site of the disease. The sites of involvement can be localized, and in early disease they are often confined to the so-called triangle of dysplasia—namely, the RVOT, RV apex, and inferolateral wall near the tricuspid valve (which is considered a pathognomonic feature of ARVC, although it is not necessarily present in all cases). More recent evidence suggests that, unlike the other two areas, the RV apex is usually not involved in arrhythmogenesis; histopathologically, myocardium at the apex is often thin and replaced by fat (but not fibrosis) in older persons without ARVC. Thus some of the early reports of ARVC probably included patients with age-related apical thinning and fatty replacement that was mistaken for apical involvement with the disease.

RV trabeculae are not primarily affected by the atrophic process and tend to show a compensatory hypertrophy, resulting in an aspect of increased trabeculation and fissuring of the RV walls. Involvement of the interventricular septum is minimal. In more advanced stages of ARVC, diffuse myocardial involvement leads to global RV dilation and dysfunction. End-stage disease typically exhibits biventricular involvement, usually with multiple aneurysms and a parchment-like appearance of the ventricular free wall. Although several hypotheses have been put forth, currently there is no unifying hypothesis that explains the patchy, yet predictable pattern of RV involvement in ARVC.

Although the dysplastic tissue predominantly involves the RV, the increasing use of advanced imaging studies (cardiac magnetic resonance [CMR]) revealed that LV involvement is common from the early disease stage, but is often clinically subtle. The fibrofatty pattern exhibits a predilection for the LV posteroseptal and posterolateral areas, typically extending from the epicardium to the mid-myocardium, with sparing of the endocardium. In a recent report in a cohort of genetically confirmed ARVC patients, regional cardiac involvement in ARVC mutation carriers had a characteristic pattern involving the RV basal inferior wall, the RV basal anterior wall, and the LV posterolateral wall. RV apical involvement was only observed in advanced cases of ARVC, typically as a part of global RV disease. These findings support the adoption of the broader term “arrhythmogenic cardiomyopathy.” Furthermore, the ARVC phenotype can vary depending on the desmosomal component affected by the primary mutation. Genotype–phenotype correlations have shown “nonclassical” clinical variants in genetically predisposed ARVC patients exhibiting early and more extensive LV involvement, which may either parallel (“biventricular” variant) or exceed (“left dominant” variant) the severity of RV disease.

In ARVC, the regions of abnormal myocardium do not always follow the pattern of dense scar surrounded by a ring of abnormal myocardium, which is often referred to as the scar border zone. Sometimes, abnormal voltages are found alone without a dense scar defining the regions. This is because ARVC is a different process from scarring caused by MI. Infarction causes dense scar surrounded by a border zone because of the ischemic penumbra that surrounds the infarcted territory. However, in ARVC, the process is patchy and can cause inhomogeneous scarring in anatomically disparate areas. Nonetheless, previous data have shown that it is still possible to identify well-demarcated borders around these abnormal regions.

Phases of Clinical Disease Expression

Four clinicopathological stages of ARVC can be considered: (1) “concealed” phase, (2) “overt electrical disorder,” (3) phase of “RV failure,” and (4) phase of “biventricular failure.” Although ARVC is a genetically transmitted disease, it is associated with a long asymptomatic lead time and individuals in their teens may not have any characteristics of ARVC clinically or on screening tests. Early ARVC is often asymptomatic (the “concealed” phase), and is occasionally associated with minor ventricular arrhythmias and subtle RV structural changes. Nonetheless, these patients are still at risk of SCD, especially during intense physical exertion.

With disease progression, the “overt electrical disorder” typically causes symptomatic ventricular arrhythmia (manifesting as palpitations, effort-induced syncope, or cardiac arrest) and more obvious morphological abnormalities detectable by cardiac imaging. Further disease extension results in RV dilation and dysfunction (the “phase of RV failure”), precipitating symptoms and signs of right heart failure. Unless SCD occurs, progressive impairment of cardiac function can result in biventricular heart failure late in the evolution of ARVC, usually within 4 to 8 years after typical development of complete right bundle branch block (RBBB). End-stage disease is often indistinguishable from dilated cardiomyopathy and manifests with congestive heart failure, atrial fibrillation (AF), and an increased incidence of thromboembolic events. Overall, judging the accurate position of the patient on the time scale of the spectrum can be difficult, and some patients can remain stable in the same phase of the disease for several decades.

Ventricular Arrhythmias

ARVC is one of the most arrhythmogenic human heart diseases known. Unlike other cardiomyopathies, electrical instability is present at the very early stages of ARVC; ventricular arrhythmias and SCD are often presenting symptoms before the development of any overt myocardial dysfunction. Ventricular arrhythmias range from isolated ectopy to sustained VT or VF. Approximately 50% of patients with ARVC present with symptomatic ventricular arrhythmias, most commonly sustained and nonsustained monomorphic VT, which are manifested by palpitations, dizziness, or syncope. Importantly, unlike other forms of cardiomyopathies and channelopathies, most syncopal episodes in ARVC are attributable to ventricular arrhythmias (rather than vasovagal or nonarrhythmic causes) and are associated with a poor prognosis. In fact, unexplained syncope is an independent predictor of SCD, with a sensitivity of 40% and a specificity of 90%.

The frequency of ventricular arrhythmias in ARVC varies with the severity of the disease, ranging from 23% in patients with mild disease to almost 100% in patients with severe disease. Ventricular arrhythmias characteristically occur during exercise; up to 50% to 60% of patients with ARVC develop monomorphic VT during exercise testing.

One of the unfortunate features of ARVC is SCD, which is the first clinical manifestation of ARVC in 50% of afflicted individuals. In most patients, the mechanism of SCD in ARVC is the acceleration of VT, with ultimate degeneration into VF. In addition, RV failure and LV dysfunction are independently associated with cardiovascular mortality.

Supraventricular Arrhythmias

Supraventricular arrhythmias are observed in approximately 14% of patients with ARVC, and in up to 25% of those referred for treatment of ventricular arrhythmias. In decreasing order of frequency, supraventricular tachyarrhythmias in these patients include AF, atrial tachycardia (AT), and atrial flutter (AFL). The presence of atrial arrhythmias is associated with increasing disease severity and heart failure. Often, atrial arrhythmias in this population can be asymptomatic, detected only on implantable cardioverter-defibrillator (ICD) interrogation or following an inappropriate ICD shock.

Thromboembolism

Thromboembolic complications occur in approximately 0.5% of ARVC patients annually, and are likely related to thrombus formation in ventricular aneurysms and sacculations, or global ventricular dilatation.

Diagnostic Criteria

There is no single test that is conclusively diagnostic (gold standard) of ARVC in the disease’s early stages. At initial presentation, the ECG can be normal in up to 50% of ARVC patients. Furthermore, up to 36% of ARVC patients presenting with a history of sustained ventricular arrhythmias or cardiac arrest exhibit no major or minor criteria on cardiac imaging (CMR or echocardiogram).

Therefore the diagnosis of ARVC is currently guided by the modified task force criteria, a composite of clinical, imaging, pathological, and ECG features ( Table 29.2 ). According to this scheme, the diagnosis of ARVC is fulfilled by the presence of (1) two major or one major and two minor criteria, or by four minor criteria (definite diagnosis); (2) one major and one minor or three minor criteria (borderline diagnosis); or (3) one major or two minor criteria from different categories (possible diagnosis).

Echocardiography, CMR, and angiography are the current imaging modalities incorporated into the modified task force criteria. Because ARVC is a rare disease, when performing and analyzing these studies it is important to recognize the importance of expert interpretation of the complex-shaped RV and the need for quantitation of RV structure and function, as well as specific protocols for optimal evaluation. Referral to centers with expertise in this field should be considered.

Endomyocardial Biopsy

Definitive diagnosis of ARVC requires histological confirmation. A myocardial biopsy showing myocyte loss (<45% residual myocytes) with fibrosis and fatty infiltration (>40% fibrous tissue and >3% fat) confirms the diagnosis. However, myocardial biopsy lacks sufficient sensitivity (67% in one report) owing to the patchy nature of the disease. For safety reasons, the biopsy is performed mostly in the interventricular septum, which is histopathologically rarely involved in the disease process. Biopsy sampling performed on the RV free wall may improve the ability to diagnose ARVC. However, because of the frequently observed wall thinning with aneurysms or diverticula, free wall sampling is associated with risk of cardiac perforation, particularly when performed at random sites. Therefore the role of endomyocardial biopsy in the diagnosis of ARVC remains controversial.

Electroanatomic voltage mapping, which seems to be an effective technique to detect RV low-voltage regions reflecting fibrofatty myocardial atrophy in ARVC patients, has been shown to improve the diagnostic accuracy of myocardial biopsy by reducing the sampling errors. Endomyocardial biopsies are obtained from low-voltage areas, preferably from the border zone, to minimize the risk of perforation.

Immunohistochemical analysis of conventional biopsy samples to detect a change in the distribution of desmosomal proteins can also improve the sensitivity and specificity of endomyocardial biopsy. Reduced immunoreactive signal levels of plakoglobin at intercalated discs were found to be a consistent feature in patients with ARVC. Nonetheless, more recent studies revealed that sarcoidosis and giant cell myocarditis can cause similar patterns.

Genetic Testing

Molecular genetic analysis can potentially facilitate timely diagnosis, guide interpretation of borderline investigations, and corroborate clinical suspicion of disease in an index case. Although the patient with an established clinical diagnosis of ARVC may not personally benefit from genetic testing (since the presence or absence of a gene defect would not alter the treatment), genetic testing is still recommended because it can enable cascade screening of relatives and the early identification of asymptomatic carriers who must be considered at risk, because the disease is progressive and can appear later, due to the age-related penetrance.

However, sequence analysis of the known desmosomal ARVC-related genes only identifies a responsible mutation in approximately 50% of ARVC probands. Nevertheless, recent studies support the use of genetic testing as a new diagnostic tool in ARVC and suggest a prognostic impact, as the severity of the disease appears different according to the underlying gene or the presence of multiple mutations. Importantly, genetic testing is not recommended for patients with only a single minor criterion according to the 2010 task force criteria.

In a significant proportion of probands, more than one disease-causing mutation can be found (mostly in different genes). Therefore it is recommended that all desmosome genes be tested simultaneously in the proband. Whenever a pathogenic mutation is identified, it becomes possible to establish a presymptomatic diagnosis of the disease among family members and to provide them with genetic counseling to monitor the development of the disease and to assess the risk of transmitting the disease to offspring.

Invasive Electrophysiological Testing

The value of invasive EP testing with programmed ventricular stimulation for the diagnosis and risk stratification in ARVC patients appears to be limited and, hence, is rarely indicated. The inducibility of VT or VF in an EP study was not found to reliably predict arrhythmic events or appropriate ICD therapies.

Nonetheless, electroanatomic voltage mapping can help identify and quantify an electroanatomical scar area (which correlates with fibrofatty myocardial replacement), and was found to be more sensitive than CMR in identifying an RV scar. The extent of RV low-voltage areas appear to predict increased risk of arrhythmic events. In addition, this technique has been shown to be especially useful in distinguishing subclinical ARVC from idiopathic RVOT VT. Substrate mapping can also be used to guide and improve the diagnostic accuracy of myocardial biopsy. Therefore EP testing may be considered in individual patients, but it is not recommended as a routine diagnostic tool.

Importantly, an arrhythmogenic response to high-dose intravenous (IV) isoproterenol (45 µg/min for 3 minutes, regardless of heart rate) can potentially help diagnose ARVC, particularly in the early stages of the disease. The occurrence of polymorphic ventricular arrhythmias (PVCs and sustained and nonsustained VT) with predominant left bundle branch block (LBBB) morphology (different from the typical pattern observed in RVOT VT) during isoproterenol testing (during or within 10 minutes after the cessation of isoproterenol infusion) is highly suggestive of ARVC in the absence of other structural heart disease (sensitivity, 91%; negative predictive value, 99%). In contrast, a sustained monomorphic RVOT VT response during isoproterenol testing is considered a negative response.

Idiopathic Right Ventricular Outflow Tract Tachycardia

In clinical practice, the disease that most frequently mimics ARVC is idiopathic RVOT VT. Although RVOT VT is associated with a benign prognosis with no familial basis, it can be extremely difficult to distinguish from the concealed phase of ARVC, in which typical ECG and imaging abnormalities are absent. Similar to RVOT VT, the VT in ARVC also affects young adults, is commonly catecholamine-facilitated, and can originate from the RVOT. The distinction between the two entities has important prognostic and therapeutic implications ( Box 29.1 ).

Cardiac Sarcoidosis

In the absence of a previous diagnosis of extracardiac sarcoidosis, sarcoid heart disease can present a diagnostic challenge and can mimic the clinical presentation of ARVC with respect to arrhythmic, ECG, and structural cardiac findings. In fact, cardiac sarcoid patients often fulfill the revised task force diagnostic criteria for ARVC (63% in one report). Furthermore, cardiac sarcoidosis is diagnosed in about 15% of patients who are initially suspected to have ARVC.

Several similarities exist between sarcoid heart disease and ARVC. Cardiac sarcoidosis is associated with the replacement of myocytes with noncaseating granulomas. RV involvement (with confluent regions of endocardial and, more predominantly, epicardial RV scarring) is common and appears to be particularly arrhythmogenic. Multiple scar-related monomorphic VTs (predominantly due to scar-related macroreentry) are frequent, and commonly originate from the RV and, hence, exhibit LBBB morphology. The surface ECG during NSR commonly exhibits RBBB, QRS fragmentation, T wave inversion in the right precordial leads, and PVCs. Epsilon waves can be observed with a similar frequency in both ARVC and cardiac sarcoidosis. Furthermore, about 14% to 56% of the patients with cardiac sarcoidosis have detectable abnormalities on echocardiogram, such as LV or RV systolic dysfunction, wall-motion abnormalities, ventricular aneurysm, or basal septum thinning. In contrast to ARVC, a disorder largely confined to the RV free wall, cardiac sarcoidosis typically spares the free wall and involves the septum.

One report suggested that a reduced left ventricular ejection fraction (LVEF) should raise suspicion of cardiac sarcoidosis even if ARVC diagnostic criteria are fulfilled. Compared to patients with ARVC, those with cardiac sarcoidosis tend to have a significantly lower LVEF, significantly wider QRS complexes, and more different morphologies of inducible monomorphic VT, which originate more commonly in the apical region of the RV. In addition, screening for cardiac sarcoidosis should be considered in young patients (<60 years) with unexplained Mobitz II or third-degree AV block, in those with unexplained monomorphic VT, and in those with unexplained nonischemic cardiomyopathy presenting with ventricular arrhythmias. Initial testing typically includes computed tomography (CT) scan of the chest for pulmonary sarcoid and advanced cardiac imaging (CMR or positron emission tomography [PET]). Abnormal finding on those tests should prompt definitive histological diagnosis.

Dilated Cardiomyopathy

ARVC is distinguished from DCM by the greater degree of arrhythmogenicity. Although ventricular arrhythmia is a relatively common finding in DCM, it is rare in the absence of significant ventricular dysfunction, and SCD is seldom the mode of presentation. In contrast, ARVC is associated with a propensity toward ventricular arrhythmias even in the absence of significant ventricular dysfunction. SCD is the first clinical manifestation of the disease in more than 50% of ARVC probands. In addition, regional involvement and aneurysm formation, which are characteristic of ARVC, argue against the diagnosis of DCM.

Athlete’s Heart

The term athlete’s heart refers to a constellation of electrical and structural cardiac adaptations in response to intensive and long-term athletic training. Such physiological cardiac remodeling allows the generation of a large and sustained cardiac output even at rapid heart rates. Although athletic adaptation of the left side of the heart has been well recognized, recent evidence revealed that the athlete’s RV undergoes structural and functional adaptation in synergy with the LV. Physiological remodeling of the RV can manifest electrical and structural changes that mimic those observed in ARVC, including RV enlargement (typically in conjunction with LV enlargement and normal ventricular wall motion), anterior precordial T wave inversion (typically biphasic T wave morphology with preceding convex ST segment elevation), and PVCs of RV origin.

Distinguishing physiological remodeling of the athlete’s RV (generally considered benign and nonarrhythmogenic) from ARVC (which is responsible for as many as 22% of SCDs in young athletes in Europe) has important management and prognostic implications. A false-positive diagnosis can potentially lead to erroneous disqualification from competition, whereas a false-negative diagnosis can result in devastating SCD.

RV dilatation in conjunction with convex ST segment elevation and biphasic anterior T wave inversion, and concomitant enlargement of the left and right sides of the heart with normal wall motion, appear to be benign findings and should not trigger further evaluation for ARVC in asymptomatic athletes without an adverse family history ( Fig. 29.2 ). Conversely, the presence of symmetrical anterior T wave inversion that extends beyond lead V ₁ , preceded by isoelectric or downsloping ST segments, depolarization abnormalities (e.g., Epsilon waves or terminal QRS activation delay), reduced limb lead voltages, PVCs with LBBB morphology and superior axis, and global RV systolic dysfunction or regional wall motion abnormalities, should prompt careful investigation to exclude ARVC.

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