Download pdf - Arrhythmogenic right ventricular dysplasia

Arrhythmogenic Right Ventricular DysplasiaA United States Experience

Darshan Dalal, MD, MPH; Khurram Nasir, MD, MPH; Chandra Bomma, MD; Kalpana Prakasa, MD;Harikrishna Tandri, MD; Jonathan Piccini, MD; Ariel Roguin, MD; Crystal Tichnell, MGC;

Cynthia James, PhD, ScM; Stuart D. Russell, MD; Daniel P. Judge, MD; Theodore Abraham, MD;Philip J. Spevak, MD; David A. Bluemke, MD, PhD; Hugh Calkins, MD

Background—Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy characterized by rightventricular dysfunction and ventricular arrhythmias. The purpose of our study was to describe the presentation, clinicalfeatures, survival, and natural history of ARVD in a large cohort of patients from the United States.

Methods and Results—The patient population included 100 ARVD patients (51 male; median age at presentation, 26[interquartile range {IQR}, 18 to 38; range, 2 to 70] years). A familial pattern was observed in 32 patients. The mostcommon presenting symptoms were palpitations, syncope, and sudden cardiac death (SCD) in 27%, 26%, and 23% ofpatients, respectively. Among those who were diagnosed while living (n�69), the median time between firstpresentation and diagnosis was 1 (range, 0 to 37) year. During a median follow-up of 6 (IQR, 2 to 13; range, 0 to 37)years, implantable cardioverter/defibrillators (ICD) were implanted in 47 patients, 29 of whom received an appropriateICD discharge, including 3 patients who received the ICD for primary prevention. At follow-up, 66 patients were alive,of whom 44 had an ICD in place, 5 developed signs of heart failure, 2 had a heart transplant, and 18 were on drugtherapy. Thirty-four patients died either at presentation (n�23: 21 SCD, 2 noncardiac deaths) or during follow-up(n�11: 10 SCD, 1 of biventricular heart failure), of whom only 3 were diagnosed while living and 1 had an ICDimplanted. On Kaplan-Meier analysis, the median survival in the entire population was 60 years.

Conclusions—ARVD patients present between the second and fifth decades of life either with symptoms of palpitationsand syncope associated with ventricular tachycardia or with SCD. Diagnosis is often delayed. Once diagnosed andtreated with an ICD, mortality is low. There is a wide variation in presentation and course of ARVD patients, which canlikely be explained by the genetic heterogeneity of the disease. (Circulation. 2005;112:3823-3832.)

Key Words: arrhythmia � cardiomyopathy � death, sudden � heart failure � tachycardia

Arrhythmogenic right ventricular dysplasia (ARVD) is aninherited cardiomyopathy characterized by right ventric-

ular (RV) dysfunction and ventricular arrhythmias.1,2 Onpathological examination, patients with ARVD demonstratefibrofatty replacement of the myocardium of the RV.3 Studieshave shown that ARVD is present in up to 20% of individualswho experience sudden cardiac death (SCD) and is even morecommon among athletes who die suddenly.3–6

ARVD was first described in 1977 by Fontaine et al.7 Theclinical features of 24 French patients with this conditionwere first reported by Marcus et al in 1982.1 During theensuing 22 years, relatively few studies have been publisheddescribing the clinical features and outcomes of patients withARVD.1,8–21 The great majority of these studies have in-volved European populations.1,8–16 In fact, only 2 indepen-dent series of ARVD patients from the United States, involv-

Clinical Perspective p 3832

ing 20 and 12 patients, respectively, have been reported in theliterature.17,18

The purpose of this study was to describe the clinicalcharacteristics and outcomes of a large cohort of ARVDpatients from the United States. Particular attention wasfocused on defining the presenting symptoms, time to diag-nosis, and long-term outcomes of these patients.

Methods

Patient RecruitmentPatients were identified from the Johns Hopkins ARVD registry.This registry was initiated in 1998 and prospectively enrolls patientsreferred to the Johns Hopkins ARVD Program with a possiblediagnosis of ARVD. The study protocol was approved by the Johns

Received February 15, 2005; revision received October 13, 2005; accepted October 17, 2005.From the Division of Cardiology (D.D., K.N., C.B., K.P., H.T., J.P., A.R., C.T., C.J., S.D.R., D.P.J., T.A., D.A.B., H.C.), Department of Radiology

(D.A.B.), and Division of Pediatric Cardiology (P.J.S.), The Johns Hopkins University School of Medicine, Baltimore, Md.The online-only Data Supplement, which contains Table I and Table II, can be found with this article at

http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.105.542266/DC1.Correspondence to Hugh Calkins, MD, 600 N Wolfe St, Carnegie 530, Baltimore, MD 21287. E-mail [email protected]© 2005 American Heart Association, Inc.

Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.105.542266

3823

Arrhythmia/Electrophysiology

by guest on February 3, 2016http://circ.ahajournals.org/Downloaded from

http://circ.ahajournals.org/

Hopkins Medicine institutional review board. Written, informedconsent was obtained from each patient. All medical records wereobtained at enrollment. Subsequently, patients were contacted atyearly intervals to determine the occurrence of events during thatperiod.

Patient Evaluation and Clinical TestingThe patient’s medical history was obtained both by review ofmedical records and by patient interview. Information regarding thepresenting symptoms as well as major clinical events (includingsyncope, sustained ventricular tachycardia [VT], implantable cardio-verter/defibrillator [ICD] implantation, catheter ablation, appropriateICD discharge, heart failure, cardiac transplantation, SCD, and othercauses of death) was recorded by age. Patients and family memberswere also interviewed to determine the family history.

The results of noninvasive testing, including ECG, signal-averaged ECG (SAECG), Holter monitoring, echocardiogram, andMRI, were obtained in those diagnosed while living. QRS durationand the duration of the S-wave upstroke on a 12-lead ECG weremeasured with the image analysis software SigmaScan Pro (version5.0).22 The presence of epsilon waves and the distribution of T-waveinversion on the ECG were also determined.22 SAECGs with the useof time-domain analysis with a bandpass filter of 40 Hz wereevaluated in patients who did not have a preexisting complete orincomplete right bundle branch block pattern. The SAECG wasconsidered positive for late potentials if any 2 of the following werepresent: (1) filtered QRS duration �114 ms; (2) low-amplitudesignal duration �38 ms; or (3) root mean square voltage �20 mV.23

The results of Holter monitoring, baseline ECG, and exercise stresstest were used to determine the presence of sustained or nonsustainedVT as well as the morphology of ventricular ectopy and/or VT. Theseverity and extent of RV dysfunction were also determined.

Diagnosis of ARVDThe diagnosis of ARVD was established on the basis of the criteriaset by the Task Force of the Working Group of Myocardial andPericardial Disease of the European Society of Cardiology and of theScientific Council on Cardiomyopathies of the International Societyand Federation of Cardiology.24 Autopsy diagnosis was establishedin patients whose first clinical presentation was death. Patients withthe recommended gross as well as histopathological evidence ofARVD were considered to have been diagnosed with ARVD.3,21

Statistical AnalysesCategorical variables were expressed as frequency (percentage).Continuous variables were expressed as mean�SD. Variables withskewed distributions were expressed as median (interquartile range[IQR], range). Kaplan-Meier survival analysis was used to examinesurvival (from all cardiac causes of death) since first presentation.Kaplan-Meier analysis was also used to examine the freedom fromthe following events since birth (ie, by age): (1) any symptom, (2)ventricular arrhythmia, (3) onset of heart failure, and (4) cardiacdeath. These analyses were performed separately in those patientswho were diagnosed with ARVD while living and those in whom thediagnosis was established on autopsy. All statistical analyses wereperformed with STATA statistical software (version 8.2).

ResultsPatient PopulationThe patient population was composed of 100 patients diag-nosed with ARVD. The clinical features of the patients aresummarized in Tables 1 and 2 (and listed for individualpatients in the online-only Data Supplement Tables I and II).Sixty-nine of the 100 patients were diagnosed with ARVD

TABLE 1. Demographic Characteristics, Athletic Participation, and PresentingSymptoms in the Entire Patient Population

CharacteristicDiagnosed While Alive

(n�69)Diagnosed on Autopsy

(n�31)Total

(n�100)

Demographics

Age at presentation, mean�SD, y 30�12 29�15 29�13

Gender (male) 36 (52) 15 (48) 51 (51)

Race

White 65 (94) 30 (97) 95 (95)

Black 1 (1.5) 1 (3) 2 (2)

Hispanic 2 (3) � � � 2 (2)

Middle Eastern 1 (1.5) � � � 1 (1)

Actively involved in athletic activity 37 (54) 12 (39) 49 (49)

Presenting symptoms

Palpitations 25 (36) 2 (6) 27 (27)

Syncope 21 (30) 5 (16) 26 (26)

Dyspnea 9 (13) � � � 9 (9)

Near syncope 8 (12) 1 (3) 9 (9)

Nausea, vomiting, and diaphoresis 6 (9) � � � 6 (6)

Dizziness or lightheadedness 14 (20) � � � 14 (14)

Peripheral edema 3 (4) � � � 3 (3)

Chest pain 2 (3) � � � 2 (2)

Death � � � 23 (74) 23 (23)

Resuscitated from SCD 1 (1.5) � � � 1 (1)

Asymptomatic 15 (22) � � � 15 (15)

Data are represented as frequency (%) except for age at presentation, which is expressed asmean�SD.

3824 Circulation December 20/27, 2005



while living (online-only Data Supplement Table I), and 31patients were diagnosed with ARVD on autopsy (online-onlyData Supplement Table II). There were 51 men. The medianage at presentation was 26 (IQR, 18 to 38; range, 2 to 70)years. Ninety-five were white, 2 were black, 2 were Hispanic,and 1 was of Middle-Eastern origin. Forty-nine were rou-tinely involved in sports or exercise. Thirty-two patients from19 families had evidence for the familial form of ARVD,including 19 (22%) of the 87 index cases in the studypopulation.

Presenting SymptomsTable 1 summarizes the presenting symptoms among the 100patients in this series. Palpitations, syncope, and death werethe most common presenting symptoms (27%, 26%, and23%, respectively). Fifteen patients were asymptomatic at thetime of first presentation. ARVD was suspected in thesepatients on the basis of family history suggestive of ARVD orpremature SCD or an abnormal ECG pattern at a routinephysical examination. Fatal ventricular arrhythmia leading toSCD was the first manifestation of ARVD in 22 patients. Of

these, 1 was resuscitated and survived the presenting episodeof SCD, and 21 died. Two additional patients presented withdeath from noncardiac causes.

Characteristics of Patients Diagnosed With ARVDWhile LivingSummarized in Table 2 (and listed in the online-only DataSupplement Table I) are the results of clinical testing of the69 ARVD patients who were diagnosed with ARVD whileliving. The diagnosis of ARVD was established on the basisof the presence of (1) 2 major criteria (n�23); (2) 1 majorplus 2 minor criteria (n�36); and (3) 4 minor criteria (n�10).It is notable that only 1 patient (patient 17) had a “structurallynormal” right ventricle. All patients demonstrated 1 or moreECG abnormalities characteristic of ARVD. The most com-mon ECG abnormalities detected were delayed S-wave up-stroke and T-wave inversions in 91% and 81% of the patients,respectively.

Clinical Course of Patients Diagnosed With ARVDWhile LivingShown in Figure 1A and summarized in Figure 2 is theclinical course of each of the 69 patients in this series whowere diagnosed with ARVD while living. Each patient isrepresented as a straight line, and the major events in thecourse of the disease are plotted by the age at which the eventtook place.

The median age at presentation was 29 (IQR, 20 to 36;range, 2 to 63) years. All patients except 1 presentedclinically after the onset of adolescence. This patient (patient1) was a 2-year-old white girl who presented with a syncopalepisode. Her ECG demonstrated sustained monomorphic VT,which was terminated by cardioversion. She experiencedanother syncopal episode at the age of 3 years. The patientunderwent MRI evaluation at the age of 6 years and waseventually diagnosed with ARVD on the basis of the taskforce criteria. An ICD was implanted at that time. The oldestpatient (patient 69) was a 63-year-old white man whopresented with palpitations associated with sustained VT,which was cardioverted externally. Diagnosis was established1 year later when he developed recurrent VT. An ICD wasimplanted then. Neither of these patients received any ICDdischarge during follow-up.

The median age at diagnosis was 33 (IQR, 26 to 43; range,6 to 72) years, and the median time between first presentationand diagnosis was 1 (IQR, 0 to 6; range, 0 to 34) year. Amongthe 69 patients who were diagnosed while living, the medianfollow-up was 6 (IQR, 2 to 13; range, 0 to 37) years.

As shown in Figure 2, 26 patients presented with anepisode of symptomatic sustained VT. Nine patients whoinitially presented with symptoms in the absence of docu-mented VT subsequently developed sustained VT. After theepisode of VT, 31 of these 35 patients underwent placementof an ICD, 11 of whom also underwent 1 or more catheterablation procedure. Four of these patients were treated withdrug therapy alone, 2 (patients 5 and 49) of whom experi-enced SCD within 3 years of presentation. One patient(patient 39) of the 22 who presented with ventricular fibril-lation, was successfully resuscitated from cardiac arrest. He

TABLE 2. Clinical Data and International Task Force Criteriain the 69 ARVD Patients Who Were Diagnosed While Living

Clinical Characteristic n�69

Imaging and cine imaging studies

Severe dilatation and reduction of RVEF with noLV impairment*

21 (30)

Localized ventricular aneurysms* 7 (10)

Severe segmental dilatation of the RV* 7 (10)

Mild dilatation and reduction of RVEF with no LVimpairment†

36 (67)

Mild segmental dilatation of RV† 8 (12)

Regional RV hypokinesis† 37 (54)

ECG abnormalities

Prolongation of QRS in leads V1 through V3* 40 (58)

Presence of epsilon waves* 20 (29)

Inverted T waves in leads V1 through V3 orbeyond†

56 (81)

S-wave upstroke �55 ms in leads V1 through V3 53/58 (91)

SAECG abnormalities

Late potentials on SAECG† 40/59 (67)

Arrhythmias

LBBB type VT documented† 51/66 (77)

Frequent ventricular extrasystoles† 35/52 (67)

Family history

Family history confirmed by biopsy or autopsy* 12 (17)

SCD in family at �35 years of age† 4 (6)

Family members diagnosed by the presentcriteria†

6 (9)

Histopathological study of biopsy/autopsy specimen

Infiltration of RV by fat with presence ofsurviving strands or cardiomyocytes (n�25)*

12/29 (41)

Data are represented as frequency (%). EF indicates ejection fraction; LV, leftventricle; and LBBB, left bundle branch block.

*Major criteria; †minor criteria.

Dalal et al ARVD: A United States Experience 3825



received both an ICD and catheter ablations during follow-up.In addition to these 32 patients in whom an ICD wasimplanted after an episode of sustained VT (n�31) or abortedSCD (n�1), an ICD was implanted on a prophylactic basis in15 patients, including 3 asymptomatic patients. Three of these15 patients subsequently experienced appropriate ICD ther-apy. Of the total 47 patients who had an ICD implanted,

29 (62%) received at least 1 appropriate ICD therapy duringa median of 4 (IQR, 2 to 6; range, 0 to 20) years after the ICDimplantation. Among the 69 patients, there were only 3deaths (2 SCD [patients 5 and 49] and 1 due to heart failure[patient 6]). All 3 patients had 1 or more episodes of syncope,and only 1 (patient 6) had an ICD in place at the time ofdeath.

Figure 1. Clinical course of each of the 69 patients in this series who were diagnosed with ARVD while living (A) and 31 patients diag-nosed on autopsy (B). Each patient is represented as a straight line, and the major events in the course of the disease are plotted bythe age at which the event took place. The initiation of each line represents the first clinical presentation, and the termination of the linerepresents either a terminal event or the censoring due to the end of follow-up. The junction of the dotted line and the solid line repre-sents the age at which the patient was diagnosed with ARVD. The following symbols represent different events that occurred in the his-tory of the disease: �, syncope; �, first documented VT; �, termination of VT by external cardioversion; ‘, catheter ablation of VT; U,ICD implantation; �, appropriate ICD therapy; ▫, onset of heart failure; , heart transplant; and �, death.




Clinical Characteristics of Patients DiagnosedWith ARVD on AutopsySummarized in Figure 2 (and listed in online-only DataSupplement Table II) are the characteristics of 31 patients (15male) who were diagnosed with ARVD for the first time atautopsy. The median age was 24 (IQR, 16 to 39; range, 13 to70) years. Twenty-nine of these patients experienced acardiac arrest. Eighteen patients (62%) were involved inroutine activity, 9 (31%) were involved in active exercise, 1(3.5%) was pregnant, and 1 (3.5%) was in bed at the time ofdeath. The cardiac arrest was the first symptom of ARVD in21 patients. Two patients died of a condition other thanARVD but were diagnosed with ARVD on autopsy.

On gross examination, the mean heart weight was 357�68(range, 250 to 500) g in women and 417�106 (range, 240 to650) g in men (P�0.08). RV dilatation was moderate tosevere in 9 patients (29%) and mild in 20 patients (65%). Themean RV wall thickness was 2.7�2.2 mm. On microscopicexamination, RV myocardial loss, either complete or withfew myocardial cells, was seen in all heart specimens. Fattyinfiltration of RV myocardium (except for a thin endomyo-cardial layer and trabeculae) alone was seen in 9 hearts(29%). Fibrofatty infiltration was seen in 22 hearts (71%).Inflammatory infiltrates were seen in 7 (23%) of the heartspecimens.

Eight of these 31 patients had other symptoms beforedeath. Importantly, 5 of these 8 patients experienced 1 or

more episodes of syncope. The median time between presen-tation and death in these 8 patients was 1.5 (IQR 1 to 3, range0 to 4) years. The age and the sequence of events thatoccurred in each of the patients diagnosed on autopsy arerepresented in Figure 1B.

Survival and Heart Failure in ARVDAs shown in Figure 2, 31 patients in the cohort of 100experienced SCD. Six patients developed right-sided heartfailure, one of whom (patient 6) progressed to biventricularheart failure and died at the age of 27 years while awaitingheart transplant. Two patients died of causes other thanARVD. Two patients (patients 37 and 62) underwent cardiactransplantation after developing incessant VT. One of thesepatients (patient 62) also had significant right-sided heartfailure. Sixty-six of the ARVD patients in this series werealive at last follow-up, of whom 44 had an ICD in place, 20were on medical therapy alone, and 2 had a transplantedheart.

Figure 3 shows the Kaplan-Meier curve for survival freefrom ARVD-related deaths in the 100 patients since their firstclinical presentation (causes of death other than ARVD wereexcluded). In the entire patient population, there were 32deaths from cardiac causes (31 SCD and 1 from biventricularheart failure). In 24 of the 31 patients diagnosed on autopsy,SCD was the first presenting symptom. The remaining 7SCDs all occurred within 5 years of first presentation. None

Figure 2. Schematic outline and quantifi-cation of the presentation, treatment, ar-rhythmia, and outcome in the entirepatient population. Sx indicates symp-toms; Asx, asymptomatic; VF, ventricularfibrillation; Abl, catheter ablation of VT;Rec VT, recurrent VT; HF, heart failure;and w/o, without. *These patients died ofnoncardiac causes of death; autopsyrevealed findings consistent with ARVD.†These patients experienced fatal VF lead-ing to SCD; they could not be resusci-tated. ‡This patient died because of biven-tricular heart failure at the age of 27 years;she had an ICD in place at the time ofdeath and was awaiting a heart transplant.




of the 7 patients had an ICD implanted at the time of death.Only 3 deaths occurred among the 69 patients who werediagnosed with ARVD while living. Two of these deathswere SCDs, which occurred within 5 years of first clinicalpresentation in patients without an implanted ICD, and 1death occurred as a result of biventricular heart failure andoccurred 14 years after the first clinical presentation. Thepatient had an ICD implanted at the time of death and wasawaiting a heart transplant.

Figure 4 shows the results of Kaplan-Meier survivalanalysis by age for the 100 patients in the study with thefollowing outcomes: (1) any symptom, (2) ventricular ar-rhythmia, (3) heart failure, and (4) cardiac death. Shown inFigure 4A are the results of this analysis in the 69 patientsdiagnosed while living, and shown in Figure 4B are theresults of the analysis in the 31 patients who were diagnosedon autopsy. The survival curves show that none of theseevents are common before the onset of adolescence.

Among the 69 patients diagnosed while living, half of theARVD patients had their first clinical presentation (experi-enced symptoms) by the age of 32 years. The development ofsymptoms mirrors the development of ventricular arrhythmia,and half the individuals develop VT by the age of 41 years.Heart failure was a rare event, occurring in �25% of patientswho survive up to the age of 56 years. Death also wasextremely rare among those diagnosed while living, and it isnotable that only 3 patients (described above) experiencedcardiac death during follow-up. The death-free survival timein 94% of this group of patients was �60 years.

The median age at first clinical presentation (24 years)among the 31 patients diagnosed on autopsy was not signif-

icantly lower than that in those diagnosed while living(P�0.16). However, the median age at cardiac death (25years) in this group was significantly lower than that in the 69patients diagnosed while living (P�0.001). The small differ-ence between the age at presentation and the age at deathreflects the fact that the majority of these patients experiencedSCD as their first clinical presentation, and those who did notexperience SCD as their first presenting symptom experi-enced it shortly after their first presentation.

When we performed Kaplan-Meier analysis after combin-ing the entire patient population (n�100; results not shown),the median age at first presentation was 30 years. By the ageof 60 years, nearly 50% of the patients experienced cardiacdeath. Heart failure was experienced by �25% of patientswho survived up to the age of 70 years.

DiscussionThe results of this study describe in detail the presentation,clinical characteristics, and follow-up of 100 ARVD patientsfrom the United States. This is the largest cohort of ARVDpatients from the United States, and the results of this studyallow us to compare the clinical features of these patients withthose of the previously described European populations ofARVD patients. The results also provide important insightsinto the natural history and treatment of this rare but poten-tially life-threatening inherited cardiomyopathy.

Prior StudiesSince first described �20 years ago,1,7 ARVD has fascinatedthe cardiology community.20,25,26 The great majority of priorstudies have focused on particular aspects of ARVD such as

Figure 3. Kaplan-Meier survival analysis demonstrating proportion of patients surviving free from cardiac causes of death since firstclinical presentation.




Figure 4. Kaplan-Meier survival analysis demonstrating proportion of patients free from (1) any symptom, (2) ventricular arrhythmia, (3)cardiac death, and (4) onset of heart failure since birth among the 69 patients diagnosed while living (A) and from (1) any symptom and(2) cardiac death among the 31 patients diagnosed on autopsy (B). The numbers below the graph represent the subjects at risk of theevent and those having the event in each decade of life. The numbers in parentheses represent the percentage of patients, among thetotal number at risk, experiencing the event.




diagnostic testing,22,27,28 ICD therapy,29–31 and clinical fea-tures of the disease.1,10,15 In contrast, few studies havedescribed the clinical course and natural history of patientswith ARVD. Five of the most prominent studies haveincluded 12, 15, 35, 45, and 130 European patients, respec-tively.11–14,32 There have been only 2 independent studiesfrom the United States, involving 1218 and 2017 ARVDpatients.

Presentation of ARVDThe results of this study provide several important insightsinto the clinical presentation of ARVD in the United States.First, ARVD patients typically present between the secondand fifth decades of life. Although only 8 patients presentedbefore the onset of adolescence or after 50 years of age, theage at presentation ranged widely between 2 and 70 years. OnKaplan-Meier analysis, one half the patients remained symp-tom free for 35 years of life. The marked variability in age ofpresentation suggests that ARVD remains concealed forvarying periods of time in different individuals.

Second, the results of our study highlight the wide spec-trum of presenting symptoms. The most common presentingsymptoms were palpitations, syncope, and death. This vari-ability of clinical presentation in our study is consistent withprior studies.1,2,10,33 The underlying basis for the wide vari-ability of clinical presentation requires further research. It islikely that genetic and other modifying factors such asexercise and/or viral myocarditis may account for some ofthis variability.3,5,34

Third, the results of this study highlight the close linkbetween ARVD and SCD. Our findings confirm the recentfindings of Tabib et al6 as well as those from the priorlandmark studies reported by Thiene et al,3 Corrado et al,4

and Basso et al35 that the incidence of SCD due to ARVDdecreases after the fourth decade of life. Our study alsoconfirms the findings that a large proportion of these patientshave SCD during routine activity.6,35 The 8 patients (26%)experiencing SCD and subsequently diagnosed on autopsy,who had prior symptoms, represent an important subset ofpatients who may have benefited from earlier diagnosis andICD implantation. Furthermore, 8 of the 11 patients (diag-nosed while living [n�3] or on autopsy [n�8]) who died ofcardiac causes had experienced a syncopal episode beforeSCD. Our data support the importance of syncope as aprognostic factor in ARVD, as suggested by Marcus et al.14

Clinical Characteristics of ARVD PatientsOur findings are consistent with the results of prior studiesthat described the clinical characteristics of patients withARVD.1,9,10 Notably, in this study, among those diagnosedwith ARVD while living, �95% of patients had 1 or moreECG features of ARVD, �70% had an abnormal SAECG,and all patients except 1 had a structurally abnormal RV. Themarked similarity of clinical characteristics of ARVD be-tween this and prior studies suggests the similarity betweenpatients from the United States and Europe and almostcertainly reflects the use of the task force criteria.

Family HistoryA familial pattern of inheritance of the disease was observedin 32 patients in 19 families in our series. This likelyrepresents an underestimate of true prevalence of familialpattern because systematic screening of all family memberswas not performed. Furthermore, we relied on the task forcecriteria to establish a diagnosis of ARVD while screeningfamily members. Hamid et al10 recently proposed that lessstringent criteria be used for the diagnosis when screeningfamily members who are likely to be evaluated at an earlierstage of the disease. The incidence of familial pattern ofARVD in our series fits within the wide range of 15% to 50%described in the literature.36,37

Clinical Course and Natural History of ARVDThe results of our study call attention to the variable clinicalcourse experienced by patients with ARVD. First, it isnotable that one half of the patients with ARVD presentedwith a malignant or potentially malignant ventricular arrhyth-mia. This fact emphasizes the importance of screening familymembers of patients with known ARVD. An additional 44%of the remaining patients experienced a sustained ventriculararrhythmia during the course of the disease. These findingsmake it clear that arrhythmic events are the most importantmanifestation of ARVD. This also helps explain why patientswith ARVD, once treated with an ICD, have an excellentprognosis. Second, in our patient population, progression toheart failure was uncommon, occurring in �10% of patients.Only 1 patient progressed from right heart failure to abiventricular heart failure and subsequently died while await-ing a heart transplant. Prior studies have reported up to 20%incidence of heart failure among ARVD patients.13,14,32,38 Therecent study published by Hulot et al32 reported a muchhigher incidence of death from heart failure. The difference inincidence of and mortality as a result of heart failure isprobably due to the more advanced disease in the tertiary carehospitals in which the studies were conducted as opposed tothe Web-based recruitment system used in our study. It is alsolikely that the study samples included in different studiesrepresent different phenotypes of the disease. In fact, thestudy reported by Marcus et al,14 which included patientsfrom both France and the United States, showed a highincidence of heart failure among the series from France (8 of22 patients) compared with a zero incidence among thepatients from the United States. Finally, the results of ourstudy further demonstrate that diagnosis and subsequenttreatment are associated with excellent survival. Among the69 patients diagnosed while living, only 2 experienced SCD,neither of whom had an ICD in place. Our findings differfrom those reported by Hulot et al,32 which indicate an overalldeath rate of 21 of 130 patients. This is likely explained bythe lower use of ICD therapy. In fact, none of the 31 patientsfrom our patient population who died suddenly had an ICD inplace. Our data indicate that the median survival free fromcardiac death in ARVD patients is �60 years. This type ofanalysis has not been performed previously in ARVDpatients.




Study LimitationsThe patients in our study population either were referred to usbecause of clinical symptoms and diagnosis of ARVD orwere screened because of a diagnosis of ARVD in a familymember. This ascertainment bias as well as familial cluster-ing (although the majority of the patients [87%] were unre-lated probands) may have influenced the results of our study.Accordingly, the findings of our study may not be directlyapplicable to the entire population of ARVD patients, whichmay comprise a large number of patients with a milder formof the disease. The Kaplan-Meier analyses may thereforehave underestimated the true event-free survival time amongARVD patients. However, because of the complexity ofestablishing ARVD diagnosis, lack of a single sensitivemarker for the disease, and the rarity of the disease, it isvirtually impossible to avoid this ascertainment bias. Anotherimportant limitation of our study lies in the fact that the studypopulation was composed of 2 different subsets of patients:those diagnosed while living and followed prospectively(n�69) and those diagnosed on autopsy (n�31). The burdenof SCD experienced by ARVD patients may have beenoverestimated by this selection bias. Finally, among thepatients diagnosed on autopsy, although each of the his-topathological specimens was evaluated by a pathologist,precise information about the extent and the distribution ofthe disease was not available for analysis.

ConclusionIn conclusion, the results of our study demonstrate thatpatients with ARVD have highly variable ages and symptomsat presentation and that most patients with ARVD experiencesymptomatic, potentially life-threatening arrhythmias duringfollow-up. Although SCD is a common presenting symptom,once diagnosed, the incidence of SCD is rare, and the overallprognosis of ARVD is excellent. This largely reflects thewidespread use of ICDs in the United States. Few patientswith ARVD progress to heart failure. These findings areconsistent with the previously described 4 possible phases ofARVD: (1) the concealed phase; (2) an overt electric disor-der; (3) RV failure; and (4) a biventricular pump failure.39

The onset and the duration of each of these phases varywidely among individuals. Further research is needed toidentify which clinical and/or genetic factors account for thediffering clinical course of ARVD patients. It is likely that theresults from the North American ARVD Registry and theinternational ARVD registry may provide important informa-tion in the future.40,41

AcknowledgmentsThe Johns Hopkins ARVD Program is supported by the BogleFoundation, the Campanella family, the Wilmerding Endowment,and National Institutes of Health grant 1 UO1 HL65594-01A1. Thiswork was also supported by a grant from the Donald W. ReynoldsFoundation.

DisclosureDr Judge receives support from the D.W. Reynolds Foundation forthe study of sudden cardiac death. Dr Calkins receives support fromGuidant, Medtronic, and St Jude.

References1. Marcus FI, Fontaine GH, Guiraudon G, Frank R, Laurenceau JL,

Malergue C, Grosgogeat Y. Right ventricular dysplasia: a report of 24adult cases. Circulation. 1982;65:384–398.

2. Marcus FI, Fontaine G. Arrhythmogenic right ventricular dysplasia/car-diomyopathy: a review. Pacing Clin Electrophysiol. 1995;18:1298–1314.

3. Thiene G, Nava A, Corrado D, Rossi L, Pennelli N. Right ventricularcardiomyopathy and sudden death in young people. N Engl J Med.1988;318:129–133.

4. Corrado D, Basso C, Schiavon M, Thiene G. Screening for hypertrophiccardiomyopathy in young athletes. N Engl J Med. 1998;339:364–369.

5. Corrado D, Thiene G, Nava A, Rossi L, Pennelli N. Sudden death inyoung competitive athletes: clinicopathologic correlations in 22 cases.Am J Med. 1990;89:588–596.

6. Tabib A, Loire R, Chalabreysse L, Meyronnet D, Miras A, Malicier D,Thivolet F, Chevalier P, Bouvagnet P. Circumstances of death and grossand microscopic observations in a series of 200 cases of sudden deathassociated with arrhythmogenic right ventricular cardiomyopathy and/ordysplasia. Circulation. 2003;108:3000–3005.

7. Fontaine G, Guiraudon G, Frank R, Vedel J, Grosgogeat Y, Cabrol C,Facquet J. Stimulation studies and epicardial mapping in ventriculartachycardia: study of mechanism and selection for surgery. In: HEKulbertus (ed). Reentrant Arrythmias. Lancaster, Pa: MTP Publishing;1977; 334–350.

8. Daliento L, Turrini P, Nava A, Rizzoli G, Angelini A, Buja G, ScognamiglioR, Thiene G. Arrhythmogenic right ventricular cardiomyopathy in youngversus adult patients: similarities and differences. J Am Coll Cardiol. 1995;25:655–664.

9. Corrado D, Basso C, Thiene G, McKenna WJ, Davies MJ, Fontaliran F,Nava A, Silvestri F, Blomstrom-Lundqvist C, Wlodarska EK, Fontaine G,Camerini F. Spectrum of clinicopathologic manifestations of arrhyth-mogenic right ventricular cardiomyopathy/dysplasia: a multicenter study.J Am Coll Cardiol. 1997;30:1512–1520.

10. Hamid MS, Norman M, Quraishi A, Firoozi S, Thaman R, Gimeno JR,Sachdev B, Rowland E, Elliott PM, McKenna WJ. Prospective evaluationof relatives for familial arrhythmogenic right ventricular cardiomyopa-thy/dysplasia reveals a need to broaden diagnostic criteria. J Am CollCardiol. 2002;40:1445–1450.

11. Pinamonti B, Di Lenarda A, Sinagra G, Silvestri F, Bussani R, CameriniF, for the Heart Muscle Disease Study Group. Long-term evolution ofright ventricular dysplasia-cardiomyopathy. Am Heart J. 1995;129:412–415.

12. Lemery R, Brugada P, Janssen J, Cheriex E, Dugernier T, Wellens HJ.Nonischemic sustained ventricular tachycardia: clinical outcome in 12patients with arrhythmogenic right ventricular dysplasia. J Am CollCardiol. 1989;14:96–105.

13. Blomstrom-Lundqvist C, Sabel KG, Olsson SB. A long term follow up of15 patients with arrhythmogenic right ventricular dysplasia. Br Heart J.1987;58:477–488.

14. Marcus FI, Fontaine GH, Frank R, Gallagher JJ, Reiter MJ. Long-termfollow-up in patients with arrhythmogenic right ventricular disease. EurHeart J. 1989;10(suppl D):68–73.

15. Nava A, Bauce B, Basso C, Muriago M, Rampazzo A, Villanova C,Daliento L, Buja G, Corrado D, Danieli GA, Thiene G. Clinical profileand long-term follow-up of 37 families with arrhythmogenic right ven-tricular cardiomyopathy. J Am Coll Cardiol. 2000;36:2226–2233.

16. Berder V, Vauthier M, Mabo P, De Place C, Laurent M, Almange C,Daubert C. Characteristics and outcome in arrhythmogenic right ventric-ular dysplasia. Am J Cardiol. 1995;75:411–414.

17. Kullo IJ, Edwards WD, Seward JB. Right ventricular dysplasia: the MayoClinic experience. Mayo Clin Proc. 1995;70:541–548.

18. Link MS, Wang PJ, Haugh CJ, Homoud MK, Foote CB, Costeas XB,Estes NA III. Arrhythmogenic right ventricular dysplasia: clinical resultswith implantable cardioverter defibrillators. J Interv Card Electrophysiol.1997;1:41–48.

19. Fontaine G, Chemla D, Fornes P. Arrhythmic right ventricular cardiomy-opathy. Am J Cardiol. 2000;86:483–484.

20. Marcus FI. Update of arrhythmogenic right ventricular dysplasia. CardElectrophysiol Rev. 2002;6:54–56.

21. Corrado D, Basso C, Nava A, Thiene G. Arrhythmogenic right ventricularcardiomyopathy: current diagnostic and management strategies. CardiolRev. 2001;9:259–265.

22. Nasir K, Bomma C, Tandri H, Roguin A, Dalal D, Prakasa K, Tichnell C,James C, Jspevak P, Marcus F, Calkins H. Electrocardiographic featuresof arrhythmogenic right ventricular dysplasia/cardiomyopathy according




to disease severity: a need to broaden diagnostic criteria. Circulation.2004;110:1527–1534.

23. Breithardt G, Cain ME, el Sherif N, Flowers N, Hombach V, Janse M,Simson MB, Steinbeck G. Standards for analysis of ventricular latepotentials using high resolution or signal-averaged electrocardiography: astatement by a Task Force Committee between the European Society ofCardiology, the American Heart Association and the American College ofCardiology. Eur Heart J. 1991;12:473–480.

24. McKenna WJ, Thiene G, Nava A, Fontaliran F, Blomstrom-Lundqvist C,Fontaine G, Camerini F. Diagnosis of arrhythmogenic right ventriculardysplasia/cardiomyopathy: Task Force of the Working Group Myocardialand Pericardial Disease of the European Society of Cardiology and of theScientific Council on Cardiomyopathies of the International Society andFederation of Cardiology. Br Heart J. 1994;71:215–218.

25. Fontaine G, Chemla D, Fornes P. Arrhythmic right ventricular cardiomy-opathy. Am J Cardiol. 2000;86:483–484.

26. Corrado D, Basso C, Thiene G. Arrhythmogenic right ventricular cardio-myopathy: diagnosis, prognosis, and treatment. Heart. 2000;83:588–595.

27. Bluemke DA, Krupinski EA, Ovitt T, Gear K, Unger E, Axel L, Boxt LM,Casolo G, Ferrari VA, Funaki B, Globits S, Higgins CB, Julsrud P, LiptonM, Mawson J, Nygren A, Pennell DJ, Stillman A, White RD, Wichter T,Marcus F. MR imaging of arrhythmogenic right ventricular cardiomyop-athy: morphologic findings and interobserver reliability. Cardiology.2003;99:153–162.

28. Nasir K, Rutberg MP, Tandri H, Berger R, Tomaselli G, Calkins H.Utility of SAECG in arrhythmogenic right ventricle dysplasia. Ann Non-invasive Electrocardiol. 2003;8:112–120.

29. Corrado D, Leoni L, Link MS, Della BP, Gaita F, Curnis A, Salerno JU,Igidbashian D, Raviele A, Disertori M, Zanotto G, Verlato R, Vergara G,Delise P, Turrini P, Basso C, Naccarella F, Maddalena F, Estes NA III,Buja G, Thiene G. Implantable cardioverter-defibrillator therapy for pre-vention of sudden death in patients with arrhythmogenic right ventricularcardiomyopathy/dysplasia. Circulation. 2003;108:3084–3091.

30. Roguin A, Bomma CS, Nasir K, Tandri H, Tichnell C, James C, RutbergJ, Crosson J, Spevak PJ, Berger RD, Halperin HR, Calkins H. Implantablecardioverter-defibrillators in patients with arrhythmogenic right ventric-ular dysplasia/cardiomyopathy. J Am Coll Cardiol. 2004;43:1843–1852.

31. Wichter T, Paul M, Wollmann C, Acil T, Gerdes P, Ashraf O, Tjan TD,Soeparwata R, Block M, Borggrefe M, Scheld HH, Breithardt G, Bocker

D. Implantable cardioverter/defibrillator therapy in arrhythmogenic rightventricular cardiomyopathy: single-center experience of long-termfollow-up and complications in 60 patients. Circulation. 2004;109:1503–1508.

32. Hulot JS, Jouven X, Empana JP, Frank R, Fontaine G. Natural history andrisk stratification of arrhythmogenic right ventricular dysplasia/cardiomy-opathy. Circulation. 2004;110:1879–1884.

33. Fontaine G, Fontaliran F, Hebert JL, Chemla D, Zenati O, Lecarpentier Y,Frank R. Arrhythmogenic right ventricular dysplasia. Annu Rev Med.1999;50:17–35.

34. Bowles NE, Ni J, Marcus F, Towbin JA. The detection of cardiotropicviruses in the myocardium of patients with arrhythmogenic right ventric-ular dysplasia/cardiomyopathy. J Am Coll Cardiol. 2002;39:892–895.

35. Basso C, Thiene G, Corrado D, Angelini A, Nava A, Valente M. Arrhyth-mogenic right ventricular cardiomyopathy: dysplasia, dystrophy, or myo-carditis? Circulation. 1996;94:983–991.

36. Fontaine G, Fontaliran F, Hebert JL, Chemla D, Zenati O, Lecarpentier Y,Frank R. Arrhythmogenic right ventricular dysplasia. Annu Rev Med.1999;50:17–35.

37. Fontaine G, Gallais Y, Fornes P, Hebert JL, Frank R. Arrhythmogenicright ventricular dysplasia/cardiomyopathy. Anesthesiology. 2001;95:250–254.

38. Pinamonti B, Sinagra G, Salvi A, Di Lenarda A, Morgera T, Silvestri F,Bussani R, Camerini F. Left ventricular involvement in right ventriculardysplasia. Am Heart J. 1992;123:711–724.

39. Thiene G, Nava A, Angelini A, Daliento L, Scognamiglio R, Corrado D.Anatomoclinical aspects of arrhythmogenic right ventricular cardiomy-opathy. In: Baroldi G, Camerini F, Goodwin JF, eds. Advances in Car-diomyopathy. Berlin, Germany: Springer Verlag; 1990:387–408.

40. Corrado D, Fontaine G, Marcus FI, McKenna WJ, Nava A, Thiene G,Wichter T. Arrhythmogenic right ventricular dysplasia/cardiomyopathy:need for an international registry: European Society of Cardiology and theScientific Council on Cardiomyopathies of the World Heart Federation.J Cardiovasc Electrophysiol. 2000;11:827–832.

41. Marcus F, Towbin JA, Zareba W, Moss A, Calkins H, Brown M, Gear K.Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C):a multidisciplinary study: design and protocol. Circulation. 2003;107:2975–2978.

CLINICAL PERSPECTIVEArrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy characterized by right ventriculardysfunction and ventricular arrhythmias. The results of our study provide important insights into the presentation andclinical course of patients with ARVD. From a clinical perspective, 3 findings of this report should be highlighted. First,the results of this study demonstrate that ARVD typically presents between the second and fifth decades of life withpalpitations, syncope, or sudden death. Although most patients who experience sudden death have no prior warningsymptoms, an important subset of patients experience syncope before sudden death. These findings emphasize theimportance of screening family members and also being alert to the potential for ARVD among patients with syncope.Second, the results of this study demonstrate that patients with ARVD, once treated with an implantable cardioverter/defibrillator (ICD), have an excellent prognosis. None of the ARVD patients who died suddenly had undergone ICDimplantation. It is important to emphasize, however, that the patients in this series met the very strict task force criteria forARVD. We do not advocate routine ICD placement in patients with only borderline or suggestive evidence of ARVD.Finally, the results of our study reveal that progression to right- or left-sided heart failure is rare, occurring in �10% ofpatients in this series. We are hopeful that advancements in the understanding of the genetic basis of ARVD will help tounravel many of the remaining mysteries of this disease during the next 5 years.




Judge, Theodore Abraham, Philip J. Spevak, David A. Bluemke and Hugh CalkinsJonathan Piccini, Ariel Roguin, Crystal Tichnell, Cynthia James, Stuart D. Russell, Daniel P.

Darshan Dalal, Khurram Nasir, Chandra Bomma, Kalpana Prakasa, Harikrishna Tandri,Arrhythmogenic Right Ventricular Dysplasia: A United States Experience

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2005 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/CIRCULATIONAHA.105.542266

2005;112:3823-3832; originally published online December 12, 2005;Circulation.

http://circ.ahajournals.org/content/112/25/3823World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://circ.ahajournals.org/content/suppl/2005/12/08/CIRCULATIONAHA.105.542266.DC1.htmlData Supplement (unedited) at:

http://circ.ahajournals.org//subscriptions/

is online at: Circulation Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer this process is available in the

click Request Permissions in the middle column of the Web page under Services. Further information aboutOffice. Once the online version of the published article for which permission is being requested is located,

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialCirculationin Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions:


http://circ.ahajournals.org/content/112/25/3823

http://circ.ahajournals.org/content/suppl/2005/12/08/CIRCULATIONAHA.105.542266.DC1.html

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

http://circ.ahajournals.org//subscriptions/
