Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder characterized by distinctive pathologic findings, abnormalities of impulse conduction and repolarization, and a propensity for life-threatening ventricular arrhythmias. In the past several years, new findings have yielded a greater understanding of the clinical spectrum of this disorder, and has provided important insights into the disease etiology. The 1995 World Health Organization/International Society and Federation of Cardiology (WHO/ ISFC) task force classified this disorder as a unique form of cardiomyopathy; the term "dysplasia" was abandoned, because it wrongly implies that a congenital anomaly is present (87).

Clinical Presentation

ARVC is a disease of young adults, with 80% of cases diagnosed before the age of 40 yr (88). There is a marked male predominance (3:1). The prevalence of ARVC has been estimated at 1:5000, which may be an underestimate because of difficulties in diagnosis (89). Most patients request medical attention because of symptoms related to ventricular arrhythmias (such as pre-syncope/syncope, palpitations, aborted cardiac arrest, or sudden death), which are commonly provoked by exercise. The ventricular tachycardia (VT) is monomorphic with a left bundle-branch block (LBBB) morphology, which is consistent with the right ventricular origin of the arrhythmia (88) (Fig. 8). Occasionally, sudden death is the first manifestation of the disorder. There appears to be a marked geographic variation in the prevalence of ARVC. In Italy, ARVC is the most common cause of sudden death in athletes, accounting for 25% of cases (90); in the rest of the world, ARVC is implicated in <5% of athletic field deaths (91). Approximately 25% of ARVC patients who are referred for treatment of VT have concomitant supraventricular arrhythmias (AF, atrial tachycardia, and atrial flutter, in descending order of frequency) (92).

Pathology

It is now well-recognized that ARVC can present with a spectrum of clinical and pathologic manifestations. The "pure form" of ARVC consists of dilatation and thinning of the right ventricle, with aneurysms and fissures located in the infundibular, apical, and subtricuspid areas ("the triangle of dysplasia") (93). The typical histologic pattern consists of replacement of midmural and/or external layers of myocardium by fatty tissue and fibrosis ("fibrofatty replacement") (94). The abnormal areas are embedded within strands or sheets of normal myocardium. ARVC is distinguished pathologically from benign fatty infiltration of the heart by the presence of right ventricular myocardial thinning, associated fibrosis, and histologic evidence of inflammation (94). The fatty infiltration of ARVC is preferentially distributed in the triangle of dysplasia, whereas benign fatty infiltration occurs uniformly throughout the heart. In the "pure form" of ARVC, minimal pathologic changes are observed in the left ventricle (95).

Right ventricular outflow tract (RVOT) tachycardia has traditionally been regarded as an "idiopathic" VT, which occurs in the absence of structural abnormalities of the right ventricle. Recent evidence indicates that some patients with RVOT VT have structural abnormalities typical of ARVC that are confined to the infundibulum (96). The localized nature of these changes probably accounts for the low incidence of sudden death among patients with RVOT VT, as monomorphic VT is less likely to degenerate into VF when the anatomic substrate for reentry is absent.

In patients with longstanding ARVC, the disease can progress to involve the left ventricle (biventricular dysplasia). Biventricular dysplasia more commonly presents with CHF, and can be mistaken for idiopathic dilated cardiomyopathy. The identification of fatty infiltration within the left and right ventricular myocardium should lead to the correct diagnosis. A recent autopsy study compared patients with biventricular dysplasia with patients who had isolated right ventricular involvement (97). Patients with biventri-cular dysplasia more commonly had longstanding disease, clinical heart failure, warning symptoms, and clinical ventricular arrhythmias. Severe right ventricular thinning and inflammatory infiltrates were also more common among patients with concomitant left ventricular involvement. Notably, sudden cardiac death was the first manifestation of ARVC in 70% of the cases with isolated right ventricular involvement.

Etiology

Familial ARVC has been recognized since the initial descriptions of this disorder

(98). Previous estimates of the prevalence of familial ARVC were based on the identification of a living family member with overt ARVC or a family history of premature sudden cardiac death. Using these clinical criteria, ARVC had been classified as familial in 30% of cases (87). Although no gene has yet been identified, five loci have been mapped in families demonstrating autosomal dominant transmission: 1q42 (89), 2q32

(99), 3p23 (100), 14q12 (101), 14q23 (89). In addition, a form of the disease (Naxos disease) is coinherited with a skin disorder as an autosomal recessive trait and maps to 17q21 (102). When the causative genes are identified and genetic screening is available, it is likely that a greater proportion of ARVC cases will be classified as familial. In one recent study, signal-averaged electrocardiograms (SAECGs) and ECGs were performed in asymptomatic family members of ARVC patients in order to screen for occult ARVC (103). In 7 of the 12 families examined, the ARVC case had been classified as sporadic. The combined incidence of late potentials or abnormal ECG

Table 6

Diagnostic Criteria for Right Ventricular Dysplasia/Cardiomyopathy

I. Global and/or Regional Dysfunction and Structural

Alterations*

Severe dilatation and reduction of right ventricular ejection fraction with no (or only mild) LV impairment.

Localized right ventricular aneurysms (akinetic or dyskinetic areas with diastolic bulging).

Severe segmental dilatation of the right ventricle.

Mild global right ventricular dilatation and/or ejection fraction reduction with normal left ventricle.

Mild segmental dilatation of the right ventricle.

Regional right ventricular hypokinesia.

II. Tissue Characterization of Walls

Fibrofatty replacement of myocardium on endomyocardial biopsy.

III. Repolarization Abnormalities

Inverted T waves in right precordial leads (V2 and V3) (people aged >12 years, in absence of right bundle branch block).

IV. Depolarization/Conduction Abnormalities

Epsilon waves or localized prolongation (>110 ms) of the QRS complex in right precordial leads (V,-V3).

Late potentials (signal-averaged ECG).

V. Arrhythmias

Left bundle branch block type ventricular tachycardia (sustained and nonsustained) (ECG, Holter, exercise testing).

Frequent ventricular extrasystoles (>1000/24 hours) (Holter).

VI. Family History

Familial disease confirmed at necropsy or surgery.

Familial history of premature sudden death (< 35 years) due to suspected right ventricular dysplasia.

Familial history (clinical diagnosis based on present criteria).

* Detected by echocardiography, angiography, magnetic resonance imaging, or radionuclide scintigraphy. ECG = electrocardiogram-LV = left ventricle.

(Reproduced with permission from: Marcus et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy. PACE 1995;18:1306.)

findings in asymptomatic family members was 38%. One or more family members with abnormal ECG/SAECG findings were detected for all seven of the "sporadic" cases. Although definitive imaging studies were not performed to confirm the diagnosis of ARVC in the family members with abnormal ECG/SAECG findings, this study supports the hypothesis that many cases of ARVC currently classified as sporadic may actually be familial.

Other etiologic factors must be considered to explain cases of ARVC that are truly sporadic and to account for the marked variability in the severity of the clinical presentation that exists among affected family members with ARVC. The severity of the clinical phenotype appears to be significantly influenced by the magnitude of inflammation that is present (95). The presence of acute inflammation is synonymous with myocarditis, which may be the result of multiple causes (infectious or autoimmune). Although genetic factors may also contribute to an autoimmune response, it is likely that the degree of inflammation is determined in part by environmental factors. Recent evidence also indicates that myocardial atrophy in ARVC may be mediated by apoptosis, or programmed cell death (104).

Diagnosis

The criteria for the diagnosis of ARVC are based on the demonstration of the structural alterations, ECG manifestations, arrhythmias, and family history that are characteristic of the disorder (88) (Table 6). Numerous imaging techniques have been evaluated for their utility in the detection of ARVC, including echocardiography,

Epsilon Wave

Fig. 9. ECG during sinus rhythm in a patient with arrhythmogenic right ventricular dysplasia. There is a small upright deflection in lead V1 just after the QRS complex (epsilon wave). Also note the T-wave inversion in leads V1-V3. (Reproduced with permission from: Marcus et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy. PACE 1995;18:1301.)

Fig. 9. ECG during sinus rhythm in a patient with arrhythmogenic right ventricular dysplasia. There is a small upright deflection in lead V1 just after the QRS complex (epsilon wave). Also note the T-wave inversion in leads V1-V3. (Reproduced with permission from: Marcus et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy. PACE 1995;18:1301.)

electron-beam CT, MRI, and right ventricular contrast angiography. A "routine" echocardiography study may lack sufficient sensitivity to detect subtle right ventricular abnormalities, although experienced laboratories have reported satisfactory results (105). MRI is uniquely suited to detect fatty infiltration, but caution is needed when attempting to distinguish between benign fatty infiltration and ARVC (106). The "gold standard" for diagnosis remains contrast right ventricular angiography, which is useful to demonstrate right ventricular size and function, wall bulgings, and deep fissures (107,108). The choice of imaging modality should ultimately be determined by the experience of the individual laboratories with the diagnosis of ARVC. Right-ventricular endomyocardial biopsy lacks sufficient sensitivity to detect the histological findings of ARVC, which are localized to the right ventricular free wall rather than the septum (88). Biopsy of the right ventricular free wall is not recommended because of an increased risk of perforation. In one report, plasma brain natriuretic peptide levels were significantly increased among ARVC patients who presented with sustained VT compared to patients with RVOT VT or normal controls (109); however, these results must be confirmed in a larger population of patients with ARVC before this test is used for diagnostic purposes.

The ECG findings in ARVC consist of epsilon waves (Fig. 9), localized prolongation of the QRS in leads V1-V3 (>100 ms), and right precordial T-wave inversion (87). Although many patients with ARVC have positive time-domain signal-SAECGs, almost one-third of ARVC patients with spontaneous or inducible sustained monomorphic VT (SMVT) have normal tracings (110). In one study, the combination of time- and frequency-domain analyses of the SAECG yielded improved sensitivity (100%) and specificity (94%) for the diagnosis of ARVC (111). A major limitation of this study is that ARVC patients with SMVT were compared with normal controls; the results of this test among patients with ARVC but without VT are unknown.

200msec.

Fig. 10. Fractionated intracardiac right ventricular electrograms recorded from a patient with arrhyth-mogenic right ventricular dysplasia. (Reproduced with permission from: Tada et al. Usefulness of electron-beam computed tomography in arrhythmogenic right ventricular dysplasia. Relation to electrophysiologic abnormalities and left ventricular involvement. Circulation 1996;94(3):440.)

200msec.

Fig. 10. Fractionated intracardiac right ventricular electrograms recorded from a patient with arrhyth-mogenic right ventricular dysplasia. (Reproduced with permission from: Tada et al. Usefulness of electron-beam computed tomography in arrhythmogenic right ventricular dysplasia. Relation to electrophysiologic abnormalities and left ventricular involvement. Circulation 1996;94(3):440.)

Electrophysiologic Findings

When endocardial electrograms are recorded from the right ventricles of patients with ARVC during sinus rhythm, significant fractionation is observed (112) (Fig. 10). This finding is consistent with slow conduction, which is an important substrate for reentrant ventricular arrhythmias. This substrate can be detected noninvasively by the presence of epsilon waves and QRS prolongation on the standard ECG and by SAECG (88,111). VT is usually induced using programmed stimulation, which is characteristic of a reentrant mechanism. In contrast to RVOT VT, multiple morphologies of mono-morphic VT are often induced in patients with ARVC. The presence of fibrofatty infiltration in many regions of the right ventricle is believed to create the substrate for multiple reentrant circuits, which accounts for the presence of multiple VT morphologies. Repolarization abnormalities have also been demonstrated in patients with ARVC using body-surface mapping, which may reflect local prolongation of repolarization in the regions affected by ARVC (113). Others have demonstrated that ARVC is characterized by an increase in repolarization dispersion, which favors the occurrence of unidirectional block and reentrant ventricular arrhythmias (114).

Risk Stratification

Several clinical features have been identified that are associated with an adverse prognosis among patients with ARVC. These include a history of syncope (115), sustained ventricular arrhythmias (116), the presence of left ventricular involvement

(97), and right ventricular failure (117). It appears that late potentials are more closely related to the extent of right ventricular disease than with the occurrence of ventricular arrhythmias (114). No data is presently available regarding the utility of invasive electrophysiologic studies for risk stratification. The occurrence of sudden cardiac death during follow-up remains unpredictable in many instances. In particular, patients with isolated right ventricular involvement, which is believed to represent an early form of the disease, are more likely to present with sudden cardiac death as the first manifestation of their disease (97).

Management

Because of the rarity of this disorder, no controlled studies have been performed to compare the efficacy of treatment with antiarrhythmic drugs or nonpharmacologic therapies. In one retrospective study, 81 patients with ARVC and documented sustained VT or NSVT were examined (118). The 42 patients who had inducible sustained VT during EPS were treated with a variety of antiarrhythmic drugs in a nonrandom fashion. A response to a drug was considered to be present if there was no spontaneous arrhythmia recurrence and if the VT was no longer inducible or rendered more difficult to induce during follow-up EPS. Using these criteria, sotalol had a higher efficacy rate (68.4%) than class I drugs, amiodarone, beta-blockers, or verapamil (0-15%). Different criteria were used to determine drug efficacy for the 39 patients who had NSVT induced at EPS. Arrhythmia recurrence was determined using a combination of 48-h Holter monitoring and exercise stress testing. A drug response was defined as the abolition of sustained VT and NSVT, and a >70% reduction in the frequency of ventricular runs (3-10 consecutive beats). Sotalol had the highest efficacy rate (82.8%), followed by verapamil (50%), beta-blockers (28.6%), amiodarone (25%), and other agents (0-17%). Follow-up data was available on 33 patients who were discharged on antiarrhythmic drugs (14 ± 13 mo); 4 (12%) had nonfatal relapses of their clinical ventricular arrhythmia. The determination of drug efficacy in this study is obviously limited by nonrandom treatment assignment, as well as spontaneous variability in the prevalence of arrhythmias during serial EPS, Holter monitors, or exercise tests. Other investigators have reported favorable results with empiric treatment with amiodarone, sotalol, or beta-blockers. The arrhythmic death rate among patients treated with empiric antiarrhythmic drugs in 1-2% per yr (95). It is unclear whether this relatively low sudden-death rate is related to drug efficacy or an intrinsically more benign clinical course among patients with ARVC compared to other forms of heart-muscle disease.

Limited data is available regarding the use of implantable cardioverter defibrillators (ICDs) for patients with ARVC. Link et al. reported on a series of 12 patients who were treated with ICDs (119). Three patients presented with cardiac arrest, four patients presented with syncope, and five patients presented with presyncope. Nine of the 12 patients had inducible sustained VT, and antiarrhythmic drug testing was unsuccessful in all 8 patients for whom it was attempted. During an average of 22 mo of follow-up, 8 of 12 patients had appropriate therapy delivered by the ICD. One sudden death occurred in a patient who depleted therapy following multiple successful cardioversions for VT, because of prompt reinitiation of VT each time that sinus rhythm was reestablished. Although pacing and sensing parameters were less desirable compared to patients with other disorders who underwent ICD implantation at the same institution, defibrilla-tion thresholds were not significantly different. Adjunctive treatment with sotalol may have slowed the rate of recurrent VTs sufficiently to allow termination of the arrhythmia with anti-tachycardia pacing rather than cardioversion in some instances.

In the absence of definitive data, treatment recommendations for ARVC are necessarily arbitrary. All ARVC patients should be prohibited from engaging in strenuous exercise, which provoke arrhythmias in a significant proportion of patients. It is our practice to treat patients who present with aborted cardiac arrest, syncope, or presyncope with ICD implantation in order to provide definitive sudden-death protection. Adjunctive treatment with beta-blockers, sotalol, or amiodarone may be required to decrease the frequency of ICD shocks. Radiofrequency ablation of VT may be useful in selected patients who receive frequent shocks and do not respond adequately to antiarrhythmic drugs (120). Therapy should be individualized for patients who present with palpitations or who are asymptomatic. Screening of asymptomatic family members can be justified as long as the limitations of available diagnostic techniques are discussed. The potential benefits of identifying an asymptomatic family member are that these individuals can be provided with genetic counseling, and the risk for sudden death may be decreased by restriction of physical activity and treatment with beta-blockers. A reasonable approach to screening would include a standard ECG, SAECG, Holter monitoring, and exercise stress testing to detect ventricular arrhythmias (103). If abnormalities are detected, the diagnosis should be confirmed with an imaging study.

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