Arrhythmogenic Right Ventricular Cardiomyopathy: Clinical Presentation, Diagnosis, and Management

Srijita Sen-Chowdhry, MA, MBBS, Martin D. Lowe, MBBS, PhD, Simon C. Sporton, MBBS, MD, William J. McKenna, MD, DSc
Arrhythmogenic right ventricular cardiomyopathy, also known as right ventricular dysplasia, is a genetically determined heart muscle disease associated with arrhythmia, heart failure, and sudden death. Autosomal dominant inheritance is typical. The identication of causative mutations in cell adhesion proteins has shed new light on its pathogenesis. Fibrofatty replacement of the myocardium, the hallmark pathologic feature, may be a response to injury caused by myocyte detachment. Sudden death is often the rst manifestation in probands, emphasizing the importance of evaluating asymptomatic relatives for the disease. Standardized guidelines facilitate the clinical diagnosis of right ventricular dysplasia. However, familial studies have highlighted the need to broaden the diagnostic criteria, which are highly specic but lack sensitivity for early disease. Modications have been proposed for the diagnosis of right ventricular dysplasia in relatives. Early right ventricular dysplasia is characterized by a concealed phase in which electrocardiographic and imaging abnormalities are often absent, but patients may nonetheless be at risk for arrhythmic events. Detection at this stage remains a clinical challenge, underscoring the potential value of mutation analysis in identifying affected persons. Serial evaluation of patients with suspected right ventricular dysplasia is recommended as clinical features may develop during the follow-up period. The onset of symptoms such as palpitation or syncope may herald an active phase of a previously quiescent disease, during which patients are at increased risk for sudden death. Greater awareness of right ventricular dysplasia among physicians and judicious use of implantable cardioverter-debrillators may help to prevent unnecessary deaths. Am J Med. 2004; 117:685 695. 2004 by Elsevier Inc.

rrhythmogenic right ventricular cardiomyopathy, also known as right ventricular dysplasia, is a genetically determined heart muscle disease associated with arrhythmia, heart failure, and sudden death. Autosomal dominant inheritance with incomplete penetrance is characteristic, although autosomal recessive variants are also recognized (1 4). The salient pathologic feature is loss of myocardium in the right ventricle, with brofatty replacement (5). Patients may present with symptoms such as palpitation, dizzy spells, and syncope. Sudden cardiac death is often the rst manifestation, conspicuously in young people engaged in strenuous activity (59). With the advent of implantable cardioverter-debrillators, and recognition of the need to evaluate asymptomatic relatives, these deaths are now largely avoidable. However, prevention of arrhythmic death requires timely diagnosis, which in turn is dependent on promoting awareness of the disease among primary care providers and specialists. This review aims to provide a contempo-

rary view of the clinical features and management of right ventricular dysplasia for the general physician.

NATURAL HISTORY
Classically, the natural history of right ventricular dysplasia is considered to include four distinct phases (10). In the rst concealed phase, patients are often asymptomatic, but may nonetheless be at risk of sudden death, notably during extreme exertion. Structural changes, when present, are subtle and may be conned to one region of the so-called triangle of dysplasia: the inow, outow, and apical portions of the right ventricle. Symptomatic ventricular arrhythmia is seen in the second overt phase, accompanied by more obvious morphologic and functional abnormalities of the right ventricle. The third phase is characterized by diffuse right ventricular disease, which results in right-sided heart failure with relatively preserved left ventricular function. Notable left ventricular involvement with biventricular pump failure occurs in the fourth advanced stage, leading to a phenotype that may resemble dilated cardiomyopathy. A multicenter study of patients with a pathologic diagnosis of right ventricular dysplasia at transplantation or autopsy found evidence of brofatty replacement of the left ventricle in 76% of the hearts examined. Left ventricular involvement correlated with age, arrhythmic events, and clinical heart failure (11).
0002-9343/04/$see front matter 685 doi:10.1016/j.amjmed.2004.04.028

From the Department of Cardiology, The Heart Hospital, London, United Kingdom. Professor McKenna and Dr. Sen-Chowdhry were supported by the British Heart Foundation. This ongoing work was supported by European Community Research Contract No. QLG1-CT-2000-01091. Requests for reprints should be addressed to William J. McKenna, MD, DSc, Cardiology in the Young, The Heart Hospital, 16-18 Westmoreland Street, London W1G 8PH, United Kingdom, or william. mckenna@uclh.org. Manuscript submitted November 26, 2003, and accepted in revised form April 22, 2004. 2004 by Elsevier Inc. All rights reserved.

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The spectrum of disease expression may, however, be far broader than was previously appreciated. Among the relatives of probands with right ventricular dysplasia, a minority fulll diagnostic criteria for dilated cardiomyopathy without any evidence of right ventricular disease (12). Variants of right ventricular dysplasia that primarily affect the left ventricle have also been identied in vivo and at postmortem (1315).

PATHOGENESIS
The identication of disease-causing mutations in the cell adhesion proteins plakoglobin and desmoplakin has provided insight into the pathogenesis of right ventricular dysplasia (13). Impaired functioning of the cell adhesion complex under conditions of mechanical stress is thought to cause myocyte detachment and death. The injury may be accompanied by an inammatory response; focal myocarditis with scattered lymphocyte inltrates was detected in 67% of cases of right ventricular dysplasia in one postmortem series (16). Since regeneration of cardiac myocytes is limited, repair by brofatty replacement takes place, with consequent ventricular remodeling. The inverse relation between wall stress and wall thickness may explain the increased susceptibility of the thin-walled right ventricle, and the predilection of early disease for its thinnest portions, represented by the triangle of dysplasia. Further gene identication studies are currently in progress; the availability of comprehensive mutation analysis may eventually solve the conundrum of detecting early right ventricular dysplasia.

nosis (1719). The 12-lead electrocardiogram (ECG), echocardiogram, and signal-averaged ECG are normal in patients with idiopathic right ventricular outow tract tachycardia; however, this is also true of many patients with early right ventricular dysplasia. That idiopathic right ventricular outow tract tachycardia has no hereditary basis is a valuable means of differentiating these two conditions clinically. Right ventricular dysplasia is reported to be familial in at least 30% to 50% of cases (10,12,20), and the relatively low penetrance of dominant forms suggests that this estimate is conservative. The importance of obtaining a complete family history is therefore reinforced. Of note, sudden death or heart failure in a relative may have been misattributed to ischemic heart disease, while in milder cases palpitation and syncope may never have been reported to a physician.

Survivors of Ventricular Fibrillation with No Previous Cardiac History

Cardiac arrest was the rst manifestation of right ventricular dysplasia in less than 10% of live index cases (12,21). However, more than half of the probands in the studies cited had suffered sudden death, with the diagnosis established on postmortem. The underrepresentation of ventricular brillation as a mode of presentation among patients probably reects the poor rates of survival from out-of-hospital cardiac arrests. Exclusion of right ventricular dysplasia is mandatory in patients who have no evidence of ischemic heart disease. The differential diagnosis includes hypertrophic cardiomyopathy, dilated cardiomyopathy, Brugada syndrome, long QT syndrome, and anomalous coronary arteries.

CLINICAL PRESENTATION
Clinicians should be alert to the possibility of right ventricular dysplasia in several circumstances.

Patients with Isolated Right Ventricular Failure in the Absence of Pulmonary Hypertension
Presentation with heart failure is uncommon (11,21), accounting for fewer than 10% of live index cases in a recent series (12). A primary myocardial disorder should be considered in such cases after excluding right ventricular infarction, valve lesions, left-to-right shunts, and other congenital defects such as Ebsteins anomaly. Cardiac sarcoidosis has also been known to mimic right ventricular dysplasia (22,23).

Young or Middle-Aged Patients with Palpitation, Presyncope, or Syncope in the Apparent Absence of Other Cardiac Disease
In a series of 75 consecutive probands with right ventricular dysplasia from a tertiary referral center (12), 32% of live cases presented with syncope and 55% with palpitation and presyncope. Chest pain and dyspnea may also occur. Symptoms are frequently precipitated by exercise. The notion that right ventricular dysplasia is unlikely to manifest in later life is worth dispelling; the condition may present at any age. Suspicion is heightened by arrhythmia of right ventricular origin, which can range from isolated ventricular extrasystoles to ventricular tachycardia. The main differential in these cases is idiopathic right ventricular outow tract tachycardia, a focal arrhythmic disorder that is widely reported to have an excellent prog686 November 1, 2004 THE AMERICAN JOURNAL OF MEDICINE

Family Members of Patients with A Conrmed Diagnosis on Clinical Assessment or Postmortem Examination
The genetic etiology of right ventricular dysplasia, coupled with the high incidence of sudden death as its rst clinical manifestation, underscores the importance of evaluating relatives for the disease. Systematic evaluation from early adolescence is recommended; presentation in childhood is rare (24). A clinical diagnosis of right ventricular dysplasia was conrmed in 10% to 40% of the family members investigated in two major studies (12,21).

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Table 1. Recommended Workup for Patients with Suspected Right Ventricular Dysplasia at Initial and Subsequent Evaluations Initial Evaluation Inquiry about symptoms Family history 12-lead ECG Signal-averaged ECG Exercise test Ambulatory ECG monitoring Echocardiogram X X X Suggested X X X Follow-up Evaluation X Update as necessary X Suggested X X Suggested yearly Comment Direct questioning about palpitation, syncope, and presyncopal symptoms is advised. Pedigree should be updated with outcome of familial evaluation. Interpretation may be difcult in children under the age of 12 years. May require referral to tertiary center. Interpretation by experienced operator critical. Performed to detect ventricular arrhythmia. Right ventricular dilation, impaired systolic function, and wall motion abnormalities are sought. Careful examination of the left ventricle is also warranted. May require referral to tertiary center. Interpretation by experienced operator critical.

Magnetic resonance scan

ECG electrocardiogram.

Suggested

Suggested 13 yearly

Family Members of Sudden Cardiac Death Victims in Whom Right Ventricular Dysplasia Was Not Excluded on Postmortem
An expert pathologic opinion is invaluable when evaluating family members of sudden cardiac death victims. In its absence, right ventricular dysplasia should be considered part of the differential diagnosis, as the disease may have been missed on postmortem without rigorous

macroscopic and histologic examination of the right ventricle.

Relatives of Patients with Apparent Dilated Cardiomyopathy

Both advanced right ventricular dysplasia and familial forms of the disease may mimic dilated cardiomyopathy (12,25). The possibility of right ventricular dysplasia

Table 2. Task Force Criteria for the Diagnosis of Right Ventricular Dysplasia in Probands* Family history Major: familial disease conrmed at necropsy or surgery. Minor: family history of premature sudden death (35 years of age) due to suspected right ventricular dysplasia; family history (clinical diagnosis based on present criteria). ECG depolarization/conduction abnormalities Major: epsilon waves or localized prolongation (110 ms) of QRS complex in right precordial leads (V1V3). Minor: late potentials on signal-averaged ECG. ECG repolarization abnormalities Minor: inverted T waves in right precordial leads (V2 and V3) in persons 12 years of age and in the absence of right bundle branch block. Arrhythmias Minor: sustained or nonsustained left bundle branch block-type ventricular tachycardia documented on ECG or Holter monitoring or during exercise testing; frequent ventricular extrasystoles (1000/24 hours on Holter monitoring). Global or regional dysfunction and structural alterations Major: severe dilatation and reduction of right ventricular ejection fraction with no or mild left ventricular involvement; localized right ventricular aneurysms (akinetic or dyskinetic areas with diastolic bulgings); severe segmental dilatation of right ventricle. Minor: mild global right ventricular dilatation or ejection fraction reduction with normal left ventricle; mild segmental dilatation of right ventricle; regional right ventricular hypokinesia. Tissue characteristics of walls Major: brofatty replacement of myocardium on endomyocardial biopsy.
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Table 3. Proposed Modication of Task Force Criteria for the Diagnosis of Familial Right Ventricular Dysplasia* Right ventricular dysplasia in a rst-degree relative plus one of the following: ECG: T-wave inversion in right precordial leads (V2 and V3) Signal-averaged ECG: Late potentials seen on signal-averaged ECG Arrhythmia: Left bundle branch block-type ventricular tachycardia on ECG, Holter monitoring, or during exercise testing; 200 extrasystoles over a 24-hour period Structural or functional abnormality of the right ventricle: Mild global right ventricular dilatation or reduction in ejection fraction with normal left ventricle; mild segmental dilatation of the right ventricle; regional right ventricular hypokinesia
* Applicability is conned to rst-degree relatives who do not full the original task force guidelines (12). ECG electrocardiogram.

should therefore be considered when assessing the relatives of patients with dilated cardiomyopathy, particularly in the presence of a prominent family history of sudden cardiac death.

INITIAL EVALUATION
The suggested workup for patients with suspected right ventricular dysplasia is outlined in Table 1. Follow-up assessments may be conducted along similar lines. Instances of sudden cardiac death are of foremost importance when compiling a detailed pedigree; however, a history of recurrent syncope or unexplained heart failure in a relative may also be relevant. It is worthwhile attempting to obtain postmortem reports and, where the index of suspicion is high, any tissue that may have been retained after autopsy. Occasionally, re-examination of blocks and histologic slides by an expert cardiac pathologist may yield a diagnosis of right ventricular dysplasia when the cause of death was previously ascribed to myocarditis or heart failure, or indeed unascertained. Clinical diagnosis of right ventricular dysplasia is challenging owing to the nonspecic nature of associated ndings and the absence of a single diagnostic test. Recognition of these difculties led an international task force to propose standardized criteria for right ventricular dysplasia in 1994 (32). Structural, histologic, electrocardiographic, arrhythmic, and genetic features of the disease are subdivided into major and minor criteria according to their specicity (Table 2). The presence of two major, one major plus two minor, or four minor criteria from different categories is considered diagnostic. Based predominantly on tertiary center experience with symptomatic index cases, the task force guidelines are highly specic but lack sensitivity for early disease. Their primary application is in establishing a denitive diagnosis in probands. The full complement of cardiac investigations may be unremarkable in the concealed phase of right ventricular dysplasia. Pivotal to this concept are reports of patients initially diagnosed with idiopathic right ventricular outow tract tachycardia on the basis of normal ECGs and imaging; right ventricular dysplasia was later conrmed after the development of typical clinical features in one

Asymptomatic Patients, Especially Athletes, with Incidental Findings Compatible with Right Ventricular Dysplasia during Cardiovascular Evaluation
Right ventricular dysplasia is a recognized cause of sudden death during sporting activity. The risk is well documented in competitive and endurance athletes, although not exclusive to these groups (6 9). While the pickup rate from screening programs is highly variable, right ventricular dysplasia is identied consistently in a substantial proportion of athletes, many of whom are asymptomatic (26,27). Unfortunately, physiologic adaptations to training may obscure the diagnosis. Right ventricular enlargement, for example, is well documented in endurance athletes, and probably reects increased hemodynamic loading during physical exercise (28,29). The interpretation of electrocardiographic abnormalities in elite athletes is more controversial (8,27,30,31). In the absence of obvious structural changes on imaging, frequent ventricular extrasystoles or inverted T waves in leads V1 to V3 may be considered benign. While a denitive means of detecting early right ventricular dysplasia is still lacking, however, caution is justied before attributing these features to athletes heart syndrome. A similar dilemma arises when the physician is confronted by incidental ndings compatible with right ventricular dysplasia during routine health examinations of asymptomatic persons. Offering patients further evaluation and follow-up is advised in both the above scenarios; the recommended investigations are noninvasive, and the consequences of a missed diagnosis may be catastrophic.
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Figure 1. Algorithm outlining the diagnostic approach in patients with suspected right ventricular dysplasia.

case (33), and on postmortem examination in another (34). Arrhythmic events may therefore precede the development of other clinical ndings in early right ventricular dysplasia. The importance of continued follow-up for pa-

tients with presumed idiopathic right ventricular outow tract tachycardia is also underlined. The need to broaden the diagnostic criteria has been addressed in the setting of familial right ventricular dysTHE AMERICAN JOURNAL OF MEDICINE Volume 117 689

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Table 4. Common Electrocardiographic Features in Patients with Right Ventricular Dysplasia* Electrocardiographic Pattern Normal Reported Prevalence in Probands (Varies by Cohort) Up to 40% of patients with symptomatic ventricular tachycardia and right ventricular dysplasia in rst year of follow-up 6% to 15% 14% to 18% Up to 98% of patients fullling task force criteria for right ventricular dysplasia 5% 23% using standard recording technique; 75% when highly amplied and modied recording techniques are employed in adjunct 50% to 80% 54%

Depolarization abnormalities Complete right bundle branch block Incomplete right bundle branch block Prolongation of QRS complex to 110 ms in V1V3 in absence of right bundle branch block Right precordial R-wave reduction Epsilon waves in right precordial leads

Late potentials on signal-averaged ECG Repolarization abnormalities Inverted T waves in V1V3 in absence of right bundle branch block
* Data from references 35 to 37. Abnormalities cited in the task force criteria. ECG electrocardiogram.

plasia. Prospective evaluation of relatives has identied a subset with only one of the minor criteria for right ventricular dysplasia besides a conrmed family history. This is insufcient for diagnosis according to the original task force guidelines. As a corollary of autosomal dominant inheritance, however, rst-degree relatives of probands with right ventricular dysplasia have a 50% probability of carrying the causative mutation. A single recognized fea-

ture of right ventricular dysplasia in a relative is therefore likely to represent disease expression. Modied criteria have been proposed for the diagnosis of familial right ventricular dysplasia to reect this (Table 3) (12). The algorithm in Figure 1 outlines the recommended diagnostic approach. In the presence of symptoms, both clinician and patient are generally assured of the need to proceed to car-

Figure 2. Typical 12-lead electrocardiogram from a patient fullling task force criteria for right ventricular dysplasia. Inverted T waves in the right precordial leads are noted. Also present are 3 ventricular extrasystoles of left bundle branch block conguration and inferior axis, indicating an origin in the right ventricular outow tract.
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Figure 3. Echocardiograms from 2 patients with right ventricular dysplasia demonstrating a dilated right ventricle (RV) in different views.

diac evaluation. However, the same cannot be said of asymptomatic relatives, in whom the psychological effects must be weighed against the prospect of detecting a potentially life-threatening but treatable disease. Apprehension may be heightened by equivocal ndings on investigations; the uncertainty is often frustrating for patients and referring physicians. In the majority of patients, anxiety can be allayed by an open discussion emphasizing the noninvasive nature of the assessment

offered and the benets of early diagnosis. Media reports of high-prole cases have brought the disease to public awareness, and a substantial number of patients will have browsed extensive resources available online. However, many remain unaware that the complications of right ventricular dysplasia, namely arrhythmia and heart failure, are amenable to treatment, and that sudden death may be prevented. The existence of effective therapies should therefore be highlighted.

Figure 4. Cardiac magnetic resonance image from patient with right ventricular dysplasia demonstrates localised dilation of the right ventricle (black arrows) below the tricuspid valve (left). The volume of the right ventricle was markedly enlarged. Fatty replacement of the myocardium (black arrows) in the right ventricle of a patient fullling task force criteria for right ventricular dysplasia (right).
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Table 5. Proposed Risk Factors for Unfavourable Prognosis in Right Ventricular Dysplasia* Clinical Marker Previous cardiac arrest Syncope or sustained ventricular tachycardia with impairment of consciousness Increased QRS dispersion

Assessment Clinical history Direct inquiry regarding symptoms A difference of 40 ms between the maximum and minimum QRS values occurring in any of the 12 ECG leads Direct inquiry regarding symptoms Echocardiography or cardiac magnetic resonance Regional wall motion abnormalities or dilation and impairment of systolic function in the left ventricle Inverted T waves in the precordial leads beyond V3

Early onset of symptoms Severe right ventricular dilation Left ventricular involvement

* Data from references 48 to 51. Clinical markers that warrant consideration of implantable cardioverter-debrillator therapy. ECG electrocardiographic.

INVESTIGATIONS Electrocardiographic Findings

Recognized electrocardiographic features of right ventricular dysplasia and their reported prevalence in probands are summarized in Table 4 (3537). Depolarization abnormalities in right ventricular dysplasia are thought to reect slowed propagation in the right ventricular free wall, as opposed to altered conduction in the bundle branch. Although right bundle brunch block and incomplete right bundle branch block are consistently observed in a proportion of affected patients, their relatively common occurrence among normal subjects precludes their inclusion in the task force criteria. Prolongation of the QRS complex to 110 ms in leads V1 to V3 in the absence of right bundle branch block is considered more specic and represents a major criterion. Delayed activation of some right ventricular bers may be manifest on the surface ECG as epsilon waves, small-amplitude deections occurring in the transition of the QRS complex and the ST segment. When localized to the right precordial leads, their presence is highly suggestive of right ventricular dysplasia. Noise reduction and ltering techniques in a signal-averaged ECG facilitate detection of the equivalent sign of late potentials in 50% to 80% of established cases (12,21,38,39). Right precordial R-wave reduction is an additional recognized feature (35). Repolarization abnormalities include the characteristic pattern of T-wave inversion in leads V1 to V3 (Figure 2). The guidelines exclude T-wave changes due to right bundle branch block, and stipulate age over 12 years, as altered repolarization in the right precordial leads may be a normal variant in children. A higher prevalence of Twave abnormalities has also been observed in apparently healthy subjects of Afro-Caribbean descent (40). Among relatives with isolated cardiac abnormalities, the most frequent ndings were inverted T waves in the
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right precordial leads (41%) and late potentials on the signal-averaged ECG (31%) (12). Either feature is considered strongly suggestive of disease expression in the presence of a conrmed family history of right ventricular dysplasia (12).

Evidence of Arrhythmia
Ambulatory electrocardiographic monitoring and supervised exercise testing are essential additions to the 12-lead ECG in any patient undergoing evaluation for suspected right ventricular dysplasia. Ventricular arrhythmia of left bundle branch block conguration, indicating right ventricular origin, is a minor criterion in probands, many of whom are referred on this basis for discrimination of right ventricular dysplasia from idiopathic right ventricular arrhythmia. Either 1000 ventricular extrasystoles in a 24-hour period, or documented ventricular tachycardia, is requisite. A small proportion of relatives demonstrate ventricular tachycardia or frequent ventricular extrasystoles as the sole cardiac abnormality. Within the context of a family history of right ventricular dysplasia, the reduced criterion of 200 ventricular extrasystoles in 24 hours may imply disease expression (12).

Imaging
Evaluation of the heart by one of the common imaging modalities is an integral part of the diagnostic workup, serving both to identify the morphologic features of right ventricular dysplasia and to exclude other causes of heart disease. Structural abnormalities in right ventricular dysplasia may be localized, in the form of patchy wall thinning and segmental dilation, or diffuse, with global dilation of the right ventricle. Functional impairment ranges from mild regional wall motion abnormalities to generalized hypokinesia. Right ventricular hypertrophy and heavy trabeculation are also reported (41).

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Limitations of imaging in the clinical diagnosis of right ventricular dysplasia should be recognized. A normal imaging study does not exclude right ventricular dysplasia. The spectrum of normal morphology and function within the thin-walled, pyramidal, trabeculated right ventricle is still to be fully dened. Assessment of minor wall motion abnormalities is often difcult and subjective; evaluation by experienced operators is critical (42,43). Echocardiography, with complementary pulsed tissue Doppler techniques, has the benet of being inexpensive and readily available. Visualization of the right ventricle by echocardiography is not always satisfactory, particularly in the presence of thoracic deformities or obesity, but may be enhanced by the use of intravenous contrast. The hallmark features of right ventricular dilation (Figure 3) and reduced ejection fraction were considered severe in 45% of probands who underwent echocardiography, and mild in 26%. Localized aneurysms were found in 10% (12). Prominent morphologic abnormalities were less common among affected relatives; incomplete disease expression in familial right ventricular dysplasia may be associated with subtle structural changes that are not detectable by the standard echocardiogram (12). Cardiac magnetic resonance imaging is not restricted by acoustic windows and offers the added advantage of noninvasive tissue characterization (Figure 4). The key qualier here is the recognition, from postmortem studies, that brofatty replacement is often microscopic rather than overt (44), and hence not discernible by imaging. Even the presence of demonstrable myocardial fat is not sufcient per se for a diagnosis of right ventricular dysplasia; pure adipose inltration has been documented in over 50% of normal hearts in elderly patients (45 47). It is also worth noting the dependence of the high-resolution cardiac magnetic resonance sequences on electrocardiographic triggering; frequent ventricular extrasystoles may result in suboptimal image quality.

Asymptomatic relatives with a normal cardiac evaluation can be reassured that they are at low risk. Serial periodic evaluation is, however, recommended. Evolution of characteristic electrocardiographic features over 5 or 10 years has been documented (37,48), and structural abnormalities may also develop with time. The interval between assessments is determined by age and family history; adolescents may be seen every 6 to 12 months as the disease often becomes manifest in this age group. Older relatives may require less frequent follow-up, especially if the proband presented early in life.

RISK STRATIFICATION: PATIENTS WITH CONFIRMED DISEASE

Identication of patients at risk of sudden cardiac death is one of the key issues in the management of right ventricular dysplasia. Retrospective studies have elicited a number of possible predictors of adverse outcome in probands (Table 5). However, prospective trials will be necessary to verify their validity as prognostic indicators. Risk stratication of relatives is less well dened owing to the paucity of data on long-term outcomes in this group. Clinical experience suggests that the onset of symptoms such as sustained palpitation, dizzy spells, or syncope may herald an active phase of a previously quiescent disease. Prompt re-evaluation is imperative and may reveal previously undocumented electrocardiographic changes or evidence of ventricular tachycardia. With or without new clinical markers, patients appear to be at increased risk of sudden death during these socalled hot phases, and the option of an implantable cardioverter-debrillator should be discussed. Owing to the unpredictable nature of these are-ups, the importance of reporting any untoward cardiac symptoms should be reinforced at each follow-up appointment.

TREATMENT OUTCOME AND FOLLOW-UP: PATIENTS WITH NONDIAGNOSTIC EVALUATION

Symptomatic patients without clear evidence of disease expression may be offered an implantable loop recorder. This option is of particular value when palpitation, dizzy spells, or syncopal episodes are sporadic and unlikely to be captured by standard ambulatory electrocardiographic monitoring. Ascertaining whether such symptoms have an arrhythmic etiology enables appropriate management of patients with underlying cardiac disease and reassurance of others. Alternative causes of arrhythmia, such as long QT syndrome, should also be considered. Patients in whom a diagnosis of right ventricular dysplasia is conrmed or strongly suspected are discouraged from participating in competitive sports and endurance training. Extreme physical exertion is best avoided in daily activities, as is excessive ingestion of stimulants such as pseudoephedrine. Evidence for the efcacy of antiarrhythmic agents in right ventricular dysplasia is largely anecdotal (52,53). The primary indication for drug treatment is to alleviate symptoms such as recurrent palpitation due to frequent ventricular extrasystoles. In the absence of data from controlled clinical trials, pharmacologic therapy is empirical and individualized. The association of arrhythmic events with strenuous activity, together with the observation
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that ventricular tachycardia in right ventricular dysplasia is often preceded by an increased heart rate (54), suggest that sympathetic stimulation may be a precipitant. Firstline use of -adrenergic receptor antagonists, when there are no contraindications, is therefore reasonable. Amiodarone is recommended as add-on therapy if beta-blockers alone prove ineffective in suppressing ventricular arrhythmia. Some authorities advocate sotalol (52); initiation and dose changes should be accompanied by monitoring of the corrected QT interval. Standard heart failure therapy is indicated for patients with impaired ventricular function. Anticoagulation should be considered in patients with atrial brillation, marked ventricular dilation, or ventricular aneurysms; both pulmonary and cerebral embolism are recognized complications (11,55). The implantable cardioverter-debrillator confers optimal protection against sudden death. In current practice, it is rst-line therapy for cardiac arrest survivors, and is also offered to patients with arrhythmic syncope, left ventricular involvement, or ventricular tachycardia that is resistant to drug treatment. Appropriate interventions occur frequently in patients with right ventricular dysplasia, underlining the likely survival benet (56,57). Constraints to more widespread use include potential complications of lead insertion into the diseased right ventricle, infection, the requirement for multiple generator replacements, risks of inappropriate intervention (57), and psychological repercussions associated with the device. Improved risk stratication will undoubtedly clarify the indications. Sustained ventricular tachycardia is frequently terminated by antitachycardia pacing without the need for cardioversion (57), allowing cutback of pharmacologic therapy in patients with debilitating side effects. Insertion of an implantable cardioverter-debrillator may therefore allow cutback or discontinuation of pharmacologic therapy. Where necessary, medication is continued after device placement to reduce the likelihood of discharge.

ACKNOWLEDGMENTS
The authors would like to thank Richard J. Gordon, MD, and Vincent L. Sorrell, MD, for their helpful comments on the manuscript. Echocardiographic images were provided courtesy of Dr. Elias Sevdalis.

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