DEFINITION

ARVD is a genetic cardiomyopathy principally involving the right ventricle that is characterized clinically by ventricular arrhythmias and progressive structural alterations in right ventricular size and function. Fibrofatty replacement of the right ventricular myocardium forms the histopathologic hallmark of this disease. There are three patterns of disease expression: (1) classic, characterized by disease limited to the right ventricle with either no or minimal involvement of the left ventricle, which appears late in the course of the disease; (2) left dominant, characterized by early or predominant left ventricular involvement; and (3) biventricular, characterized by parallel involvement of both ventricles from the beginning of disease process.¹

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

FIGURE 65-1 Long-axis view of the right ventricle (RV), showing the triangle of dysplasia, which is formed by the inferior subtricuspid area (short arrow), apex (arrowhead), and infundibulum (long arrow). PA, pulmonary artery; RA, right atrium.

TABLE 65-1 Genetics of Arrhythmogenic Right Ventricular Dysplasia

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

Clinical Presentation

ARVD usually manifests between the second and fifth decades (mean age at diagnosis approximately 30 years). Patients most commonly present with symptomatic ventricular arrhythmias or sudden cardiac death, or may remain asymptomatic, with ARVD discovered only incidentally on routine examination. The most common symptoms are palpitations, syncope, atypical chest pain, and dyspnea. Ventricular arrhythmias are often precipitated by exercise or stress, and range from isolated ventricular premature beats to sustained monomorphic or polymorphic ventricular tachycardia with left bundle branch block morphology, or abrupt ventricular fibrillation, which is the most common underlying cause of sudden cardiac death in ARVD.¹²

In addition to ventricular arrhythmias, about 25% of patients may also show supraventricular arrhythmias, which include atrial fibrillation, atrial tachycardia, and atrial flutter, in that order of frequency.¹³ Left ventricular involvement is associated with an increased incidence of arrhythmic events, more severe right ventricular wall thinning, and heart failure. Frank left-sided heart failure is rare. Figures 65-2, 65-4, and 65-6 illustrate left ventricular involvement in ARVD.

FIGURE 65-2 Contrast-enhanced, multidetector CT image in a patient with ARVD shows right ventricle (RV) (long arrow) and left ventricle (LV) (short arrow) thinning associated with fat replacement. Note also the dilation of the RV and epicardial pacing lead.

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 ^‡