Arrhythmogenic Right Ventricular Dysplasia

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CHAPTER 65 Arrhythmogenic Right Ventricular Dysplasia

Arrhythmogenic right ventricular dysplasia (ARVD) is a rare, progressive genetic cardiomyopathy that is characterized clinically by ventricular arrhythmias and sudden death, and histologically by fibrofatty infiltration of the right ventricle. Although symptomatic ventricular arrhythmias and sudden death are the most common manifestations of the disease, either right ventricular or biventricular heart failure may be observed. This chapter discusses various aspects of ARVD including etiology and pathogenesis, clinical manifestations, differential diagnosis, and treatment options, with special focus on diagnostic imaging techniques, in particular MRI, which is the current noninvasive diagnostic modality of choice in ARVD.

PREVALENCE AND EPIDEMIOLOGY

Although the exact incidence of ARVD is unknown, the prevalence has been estimated to be 0.02% of the general population.2 ARVD reportedly is more prevalent (0.8%) in certain parts of northern Italy (Veneto) and Greece (Naxos Island).3,4 ARVD most commonly manifests after puberty and before age 50 years.5,6 ARVD is more common in highly athletic individuals. It is an important cause of sudden cardiac death in young individuals, particularly in athletes, accounting for 5% of sudden deaths in individuals younger than 35 years in the United States, and 25% of deaths in athletes in the Veneto region of Italy.7 ARVD is believed to be more common than reported because of its frequently asymptomatic clinical course, difficulty in diagnosis using conventional noninvasive methods, and frequent misdiagnosis.

ETIOLOGY AND PATHOPHYSIOLOGY

The exact pathogenesis of ARVD remains speculative, but it is most widely believed to be due to genetic abnormalities mainly affecting cardiac desmosomal structure and function. In the United States, the most common reported genetic abnormality in ARVD is a mutation in plakophillin-2 (PKP2), which is a desmosomal protein and is present in more than one third of patients. Desmosomal mutations are believed to disrupt cell-cell adhesion, which provokes myocyte detachment and death under conditions of high mechanical stress, as suggested by its frequent occurrence in athletics and the thinnest portions of the right ventricle, such as the inferior subtricuspid region, right ventricular apex, and right ventricular infundibulum—together termed the triangle of dysplasia (Fig. 65-1).8 This leads to a compensatory repair process characterized by inflammation and fibrofatty substitution. Familial ARVD accounts for 30% to 80% of cases, and most commonly shows an autosomal dominant inheritance, with age-dependent penetrance and variable clinical expression, which can be attributed to the complex interplay of age, gender effects, and environmental influences such as exposure to viruses and athletic activity with the underlying genetic background in the ultimate disease causation and progression. Mere inheritance of a genetic abnormality does not imply “disease” for the same reason. To date, at least 11 distinct subtypes of autosomal dominant ARVD are known, and at least seven genes have been implicated in ARVD (Table 65-1).9

Genetic mutations are also implicated in determining the ventricular predominance in ARVD. Chain-termination mutations causing truncation of the C-terminal domain of desmoplakin can disrupt cytoskeletal integrity, predisposing to predominant left ventricular involvement. Conversely, defects in the N-terminal domain of desmoplakin can result in a primary dysfunction of cell adhesion, leading to predominant right ventricular disease.8

In addition to genetic causes, other important proposed etiologic mechanisms of ARVD are (1) apoptosis (programmed cell death), (2) inherited metabolic or ultrastructural defects leading to myocardial dystrophy, and (3) secondary complication of a prior primary right ventricular myocarditis on the basis of frequently found myocardial inflammatory infiltrates and isolation of coxsackie B and enteroviral RNA viruses in some biopsy samples.10

Pathologically, ARVD is characterized by gradual myocyte loss and fibrofatty infiltration, which starts in the subepicardial region and gradually involves the endocardium, often sparing the trabecular myocardium. Plexiform arrangement of the residual myocardial fibers, separated by fat and fibrosis, leads to electrical instability and provides a conduit for a reentrant phenomenon. This situation explains the arrhythmogenic propensity characteristic of this disease, which can be worsened further by superimposed myocarditis that occurs frequently in ARVD because of the genetic susceptibility.11 A myocardial dysplastic process and the associated loss of its strength and integrity are responsible for the varying degrees of structural derangement and functional disturbances of the heart seen in ARVD.

MANIFESTATIONS OF DISEASE

Diagnosis

Diagnosis of ARVD is challenging and is currently based on family history and morphofunctional, ECG, histopathologic, and clinical findings as proposed by the Task Force of Cardiomyopathies in 1994 (Table 65-2).14 The diagnosis is made in the presence of two major criteria, one major criterion and two minor criteria, or four minor criteria. Various modifications of the existing Task Force criteria are being increasingly proposed and emphasize the increment in the diagnostic sensitivity of these criteria for less severe forms of the disease and asymptomatic first-degree relatives of affected probands. These modifications include more comprehensive characterization of ECG and echocardiographic criteria, inclusion of mutation analysis, and descriptions of left ventricular involvement.15,16

TABLE 65-2 Task Force Criteria for the Diagnosis of Arrhythmogenic Right Ventricular Dysplasia

  Major Criteria Minor Criteria
Global or regional dysfunction and structural alterations* Severe dilation and reduction of right ventricular ejection fraction with no (or only mild) left ventricular impairment Mild global right ventricular dilation or ejection fraction reduction with normal left ventricle
  Localized right ventricular aneurysms (akinetic or dyskinetic areas with diastolic bulging) Mild segmental dilation of right ventricle
  Severe segmental dilation of right ventricle Regional right ventricular hypokinesia
Tissue characterization of wall Fibrofatty replacement of myocardium on endomyocardial biopsy specimen  
Repolarization abnormalities   Inverted T waves in right precordial leads (V2 and V3) in individuals >12 yr old in absence of right bundle branch block
Depolarization or conduction abnormalities Epsilon waves or localized prolongation (>110 ms) of the QRS complex in right precordial leads (V1-V3) Late potentials (signal-averaged ECG)
Arrhythmias   Left bundle branch block ventricular tachycardia (sustained and nonsustained) by ECG, Holter, or exercise testing
    Frequent ventricular extrasystoles (>1000/24 hr) (Holter)
Family history Familial disease confirmed at necropsy or surgery Family history of premature sudden death (<35 yr old) owing to suspected right ventricular dysplasia
    Familial history (clinical diagnosis based on present criteria)

* Detected by echocardiography, angiography, MRI, or radionuclide scintigraphy.

As per the standard diagnostic algorithm for ARVD, all patients with clinical suspicion of ARVD first undergo noninvasive testing, which includes a 12-lead ECG, signal-averaged ECG, 24-hour Holter monitor, and cardiac imaging. If the results are consistent with a diagnosis or a high degree of suspicion of ARVD based on the Task Force criteria, at our institution we typically recommend patients to undergo further invasive testing, including right ventricular angiography, endomyocardial biopsy, and electrophysiology testing, for confirmation of the diagnosis and exclusion of other potential etiologies, such as sarcoidosis. The standard of reference for the diagnosis of ARVD has been the histopathologic demonstration of fibrofatty replacement of right ventricular myocardium either on an endomyocardial biopsy specimen or at autopsy. Endomyocardial biopsy carries the risk of perforation of right ventricular free wall, however, and has low sensitivity because of frequent sampling error owing to the segmental, patchy nature of the disease. One particularly important role of endomyocardial biopsy is to distinguish sarcoidosis from ARVD.

Electrocardiogram Evaluation

At least one ECG abnormality (Table 65-3) is detectable in more than 90% of patients with ARVD. A newly proposed marker of delayed right ventricular activation, prolonged S wave upstroke (≥55 ms) in V1 to V3, is the most prevalent ECG marker and correlates with disease severity and ventricular tachycardia induction on electrophysiology testing.17 Signal-averaged ECG is used to detect delayed ventricular activation owing to slowed propagation in the fibrofatty myocardium of ARVD. Late potentials on signal-averaged ECG (two or more of the following: filtered QRS duration ≥114 ms, duration of the low-amplitude signal <40 µV in the terminal portion of filtered QRS (LAS40) ≥38 ms, and root mean square voltage of the terminal 40 ms of filtered QRS (RMS40) <20 µV) form a minor diagnostic criterion for ARVD as per the Task Force criteria. Similar to extent of right precordial T wave inversion, late potentials on signal-averaged ECG are correlated with the extent of right ventricular involvement in ARVD. More recently, our group found that using filtered QRS 110 ms or greater identifies ARVD patients with inducible ventricular tachycardia more accurately than does conventional signal-averaged ECG criteria.18 T wave inversions and signal-averaged ECG abnormalities are more commonly seen in left-sided involvement in ARVD.

TABLE 65-3 Electrocardiogram Features of Arrhythmogenic Right Ventricular Dysplasia

* Minor Task Force criterion in the absence of right bundle branch block in individuals >12 yr old.

Major Task Force criterion.

These electrical abnormalities are believed to be caused by intraventricular myocardial defect (parietal block) rather than definite alteration of conduction in the bundle branch (septal block).

Imaging Techniques and Findings

Cine Angiography

Right ventricular cine angiography has been regarded as the traditional gold standard, with high specificity and positive and negative predictive values in ARVD diagnosis. It is performed using two orthogonal views in 30 degrees right anterior oblique and 60 degrees left anterior oblique during sinus rhythm with careful evaluation of structure and function of the right ventricle. Coexistence of subtricuspid and anterior infundibular wall bulging and hypertrophic trabeculae has been shown to have 96% sensitivity and 87.5% specificity in angiographic diagnosis of ARVD.10 Invasiveness of the procedure, frequent ventricular ectopy during catheter manipulation and contrast injection, and interobserver variability in the visual assessment of right ventricular wall motion abnormalities are important limitations. Because of these limitations, and the availability of other, more quantitative imaging tools such as MRI, right ventricular cine angiography plays only a small role today in the evaluation of patients with suspected ARVD. Table 65-4 lists major angiographic features of ARVD.

TABLE 65-4 Angiographic Features of Arrhythmogenic Right Ventricular Dysplasia

Echocardiography

Two-dimensional echocardiography is an important first-line imaging tool for diagnosis and follow-up in ARVD because of its noninvasiveness, low cost, wide availability, and ease of performance. Echocardiographic abnormalities associated with the Task Force criteria for ARVD are summarized in Table 65-5. A right ventricular outflow tract long-axis diameter greater than 30 mm on echocardiography has been found to have the highest sensitivity and specificity for the diagnosis of ARVD. Right ventricular dysfunction has been defined as a fractional area contraction less than 32%, or the presence of segmental right ventricular wall motion abnormalities (mostly observed in anterior and apical walls) for the purpose of echocardiographic diagnosis of ARVD.21

TABLE 65-5 Echocardiography Features Associated with Task Force Criteria for Arrhythmogenic Right Ventricular Dysplasia

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