2013_Camm_Prevalence of Atrial Arrhythmias in ARVC (2)

7232019 2013_Camm_Prevalence of Atrial Arrhythmias in ARVC (2)

httpslidepdfcomreaderfull2013cammprevalence-of-atrial-arrhythmias-in-arvc-2 18

Prevalence of atrial arrhythmias in arrhythmogenic right

ventricular dysplasiacardiomyopathy

Christian F Camm BM BCh Cynthia A James PhDdagger Crystal Tichnell MGCdagger Brittney Murray MSdagger

Aditya Bhonsale MDdagger Anneline SJM te Riele MDdaggerDagger Daniel P Judge MDdagger Harikrishna Tandri MDdaggerHugh Calkins MD FHRSdagger

From the

New College University of Oxford Oxford United Kingdom dagger

Department of Medicine Division of Cardiology

Johns Hopkins University School of Medicine Baltimore Maryland and Dagger

Department of Medicine Division of Cardiology

University Medical Center Utrecht Utrecht The Netherlands

BACKGROUND Arrhythmogenic right ventricular dysplasiacardio-

myopathy (ARVDC) is an inherited cardiomyopathy characterized

by right ventricular dysfunction and ventricular arrhythmias

Limited information is available concerning atrial arrhythmias in

ARVDC

OBJECTIVE The purpose of this study was to characterize sponta-

neous atrial arrhythmias in a large registry population of ARVDC

patients

METHODS Patients (n frac14 248) from the Johns Hopkins ARVDC

registry who met the diagnostic criteria and had undertaken

genotype analysis were included Medical records of each were

reviewed to ascertain incidence and characteristics of atrial

arrhythmia episodes Detailed demographic phenotypic and

structural information was obtained from registry data

RESULTS Thirty-1047297ve patients with ARVDC (14) experienced one

or more types of atrial arrhythmia during median follow-up of 578

(interquartile range 852) years Atrial 1047297brillation was the most common atrial arrhythmia occurring in 80 of ARVDC patients

with atrial arrhythmias Patients developed atrial arrhythmias at a

mean age of 430 140 years Atrial arrhythmia patients obtained

a total of 22 inappropriate implantable cardioverter-de1047297brillator

shocks during follow-up Older age at last follow-up (P o001) and

male gender (P frac14 044) were associated with atrial arrhythmia

development Patients with atrial arrhythmias had a higher

occurrence of death (P frac14 028) heart failure (P o001) and left

atrial enlargement on echocardiography (P frac14 004)

CONCLUSION Atrial arrhythmias are common in ARVDC andpresent at a younger age than in the general population They

are associated with male gender increasing age and left atrial

enlargement Atrial arrhythmias are clinically important as they are

associated with inappropriate implantable cardioverter-de1047297brillator

shocks and increased risk of both death and heart failure

KEYWORDS Arrhythmogenic right ventricular dysplasia

Arrhythmogenic right ventricular cardiomyopathy Atrial

arrhythmia Atrial 1047297brillation

ABBREVIATIONS AF frac14 atrial 1047297brillation ARVDC frac14 arrhythmogenic

right ventricular dysplasiacardiomyopathy ECG frac14 12-lead

electrocardiogram ICD frac14 implantable cardioverter-de1047297brillator

IQR frac14 interquartile range PKP2 frac14 plakophilin-2 SVT frac14

supraventricular tachycardia TFC frac14 task force criteria VF frac14

ventricular 1047297brillation VT frac14 ventricular tachycardia

(Heart Rhythm 2013101661ndash1668) I 2013 Heart Rhythm Society

All rights reserved

IntroductionArrhythmogenic right ventricular dysplasiacardiomyopathy

(ARVDC) is an inherited cardiomyopathy characterized by

right ventricular dysfunction ventricular arrhythmias and an

increased risk of sudden cardiac death1ndash4 The severity and

progression of ARVDC are highly variable ranging from

asymptomatic disease to severe heart failure5 Sta r ting with

the seminal description of plakoglobin mutations6 we now

know that ARVDC is often a disease of the cardiacdesmosome7 This structure is essential for cardiac integrity

and aids electromechanical coupling of cardiomyocytes

A large number of studies have documented the high

incidence of life-threat ening ventricular arrhythmias in

patients with ARVDC48ndash11 In contrast relatively little

attention has been focused on supraventricular arrhythmias

in patients with ARVDC12ndash14 and existing studies are

limited by sample size and a lack of genotype data Although

unlikely to cause sudden death atrial arrhythmia s are none-

theless associated with increased risk of mortality15 and may

The authors received funding from the Alexandre Suerman Stipend (to

Dr te Riele) the National Heart Lung and Blood Institute (K23HL093350

to Dr Tandri) the St Jude Medical Foundation and Medtronic Inc The

Johns Hopkins ARVDC Program ( ARVDcom) is supported by the Bogle

Foundation the Healing Hearts Foundation the Campanella family

Wilmerding Endowments and the Dr Francis P Chiaramonte Private

Foundation Dr Calkins receives research support from Medtronic and St

Jude Medical Address reprint requests and correspondence Dr Hugh

Calkins Sheikh Zayed Tower ndashRoom 7125R The Johns Hopkins Hospital

1800 Orleans Street Baltimore MD 21287 E-mail address hcalkinsjhmi

edu

1547-5271$-see front matter B 2013 Heart Rhythm Society All rights reserved httpdxdoiorg101016jhrthm201308032



also be associated with an increased risk of morbidity16

Therefore the purpose of this study was to examine the

prevalence and characteristics of supraventricular arrhyth-

mias in patients with ARVDC Particular attention is

focused on determining the relationship between the devel-

opment of atrial arrhythmias patient age and the severity of

ARVDC

MethodsStudy populationThe Johns Hopkins ARVDC Program was established in

1999 with a goal of studying ARVDC and providing care

for patients with this condition Patients with de1047297nite or

possible ARVDC are enrolled in a prospective registry The

study population was identi1047297ed from this registry Inclusion

criteria for this study were registry patients who had under-

taken genotype analysis and m et the 2010 Task Force

Criteria (TFC) for ARVDC17 All registry participants

provided written informed consent The study protocol wasapproved by the Johns Hopkins School of Medicine Institu-

tional Review Board

Clinical phenotypeDetailed clinical information regarding demographics pre-

sentation symptom onset and noninvasive and invasive

studies was obtained for each patient The medical history of

each subject was obtained through review of medical

records clinical evaluation and patient interview A detailed

family history was obtained through patient interview by

genetic counselors with a special interest in ARVDC

Comprehensive mutation testing was performed usingcommercial or resea rch genetic testing on all patients

included in this study18 Genetic testing included sequencing

of 1047297ve ARVDC-associated desmosomal genes (PKP2

DSC2 DSG2 DSP JUP) and the PLN and TMEM43 genes

The diagnosis of ARVDC was based on the presence of

major and m inor diagnostic criteria according to the revised

TFC 201017 The proband was de1047297ned as the 1047297rst person in a

family in whom ARVDC diagnosis was con1047297rmed (ie

ful1047297lled TFC for ARVDC irrespective of family history)

Severity and extent of structural abnormalities were

determined through review of echocardiography cardiac

magnetic resonance imaging and right ventricular angiog-raphy reports Mitral and tricuspid regurgitation was

considered if rated as at least moderately severe on echo-

cardiography reports Enlargement of the right and left atria

was de1047297ned as either present or absent based on the atrial

diameter (in millimeters) recorded

Outcome measuresThe primary outcome was presence of atrial arrhythmias

ascertained from medical records including records of ICD

interrogations Atrial arrhythmias were de1047297ned as a narrow

complex tachycardias with at least one episode lasting Z30

seconds Where available traces were examined and adju-

dicated in addition to reports from the treating physician

Atrial arrhythmias appearing only during electrophysiologic

studies were excluded Type of arrhythmia symptoms and

detection method were recorded Atrial arrhythmias were

categorized into three groups atrial 1047297brillation (AF) atrial

1047298utter and all other supraventricular tachycardias (SVTs)

Secondary outcomes were the development of stage C heart

failure a sustained ventricular arrhythmic event ICD place-

ment and death Stage C heart failure is de1047297ned as patients

with current or past symptoms of heart failure (eg dyspnea

fatigue) associated with underlying structural heart disease19

A sustained arrhythmic event is a composite measure of the

occurrence of sudden cardiac death spontaneous sustained

VTVF or an appropria te ICD intervention for a sustained

ventricular arrhythmia9 Echocardiographic reports were

reviewed for moderate-to-severe tricuspid regurgitation mitral

regurgitation and right and left atrial diameters

Statistical analysisContinuous variables are expressed as mean SD or median

(interquartile Range [IQR]) and compared across groups

using the independent Student t test or Mann-Whitney U testrespectively Categorical variables are reported as frequency

(percentage) and compared between groups using the χ2 or

Fisher exact test The cumulative probability of survival free

of an atrial arrhythmia was determined by the Kaplan-Meier

method and differences in survival between groups was

evaluated with the log-rank test Binary logistical regression

was used to control for age at last follow-up and sex P o05

was considered signi1047297cant SPSS (version 19 IBM

Chicago IL) was used for all statistical analysis

Results

Study populationBaseline demographic data of the 248 patients enrolled in

this study are listed in Table 1 Mean age at last follow-up

was 416 140 years 131 patients (528) were male and

Table 1 Baseline demographic data of the study population

Clinical value Overall population (n frac14 248) Atrial arrhythmias (n frac14 35) No atrial arrhythmias (n frac14 213) P value

Male 131 (528) 24 (686) 107 (502) 044Age at last follow-up (years) 416 140 497 146 403 135 o001Age at ARVDC diagnosis 338 134 394 157 329 128 007Length of ARVDC follow-up 578 (IQR frac14 852) 615 (IQR frac14 123) 556 (IQR frac14 811) 047Desmosomal mutation carrier 136 (548) 14 (400) 122 (573) 057

Values are given as n () mean SD or median (interquartile range [IQR])

ARVDC frac14 arrhythmogenic right ventricular dysplasiacardiomyopathy

Heart Rhythm Vol 10 No 11 November 20131662



136 (548) had known ARVDC-associated genetic muta-

tions (779 PKP2) (See Online Supplement Table 1 for

additional clinical features)

Prevalence of supraventricular arrhythmiasAmong the 248 patients 35 (141) experienced one or

more types of supraventricular arrhythmias (47 total arrhyth-mias) over a median follow-up period of 578 years (IQR frac14

852) The distributions of supraventricular arrhythmias are

shown in Figure 1 AF was most common observed in 28 of

35 patients (80) followed by atrial 1047298utter (11 31) and

other SVTs (8 23) As shown in Figure 1 11 patients

experienced more than one type of atrial arrhythmia with

one patient experiencing all three types

Mean age at time of 1047297rst atrial arrhythmia was 43 14

years Thirty-two (68) of the sentinel arrhythmic events

occurred while the patient was taking antiarrhythmic medi-

cations Five of 47 sentinel atrial arrhythmic events (11)

occurred prior to the 1047297rst documented ventricular event (4 AF1 atrial 1047298utter) There were a total of 22 inappropriate shocks

recorded for atrial arrhythmias in 10 patients six for AF (four

patients) seven for atrial 1047298utter (three patients) and nine for

SVT (four patients) Diagnosis method used for these atrial

arrhythmias is shown in Figure 2 A comparison of the clinical

features of ARVDC patients with AF atrial 1047298utter and other

types of supraventricular arrhythmias is shown in Table 2 No

difference was observed in the age at sentinel atrial arrhythmic

event time since ARVDC presentation gender gene carrier

status proportion taking antiarrhythmic medication at time of

sentinel atrial arrhythmic event or proportion with an ICD at

last follow-up between different types of atrial arrhythmiasAF accounted for 28 of 47 supraventricular arrhythmias

(60) experienced by our patient cohort Twenty-seven of

28 arrhythmias (96) were paroxysmal with a single patient

suffering from persistent AF The average CHADS2 score

was 068 (SD 084) 13 individuals had a CHADS2 score40

(46) Anticoagulation was prescribed in 18 patients (war-

farin 11 aspirin 5 dabigatran 2) There were no recorded

adverse events related to anticoagulation in this patient

group Thromboembolic events recorded in the AF group

included right ventricular thrombus (2) transient ischemic

attack (1) subclavian vein thrombosis (1) pulmonary

embolism (1) and deep vein thrombosis (1) All but one of

these patients is currently anticoagulated

Comparison of patients with and withoutatrial arrhythmiasWe compared clinical characteristics of ARVDC patients

with and without at least one supraventricular arrhythmic

event at last follow-up (Table 1) Patients experiencing atrial

arrhythmias were older at the date of last follow-up (497

146 years vs 403 135 years respectively P o001) and

more likely to be male (686 and 502 respectively P frac14

044) than patients without atrial arrhythmias In bivariate

analysis older age at diagnosis and longer duration of

follow-up were also associated with having at least one

atrial arrhythmic event However binary logistic regression

controlling for age at last follow-up and gender showed no

signi1047297cant association with the remaining demographic

features including duration of follow-up Survival curves

outlining the development of atrial arrhythmias illustrate that

men have a lower lifetime survival free from atrial arrhyth-

mias than do women (Figure 3)

Relationship between supraventricular arrhythmiasand markers of disease severityEchocardiographic reports were available for 210 study

participants (34 with atrial arrhythmias 176 without)

Moderate or severe tricuspid regurgitation was signi1047297cantly

associated with the presence of atrial arrhythmias (294 vs

136 P frac14 022) No association was seen between atrial

arrhythmias and moderate or severe mitral regurgitation

(Table 3) Binary logistical regression controlling for gender

and age at last follow-up removed the statistical signi1047297cance

of tricuspid regurgitation (B frac14 0750 SE frac14 0470 P frac14

110) Both right (529 vs 278 P frac14 008) and left

Figure 1 Venn diagram illustrating the breakdown of atrial arrhythmia

types among the 35 patients experiencing at least one atrial arrhythmic event

Circle area is proportional to total number of patients suffering from that

arrhythmia Numbers within each section correspond to the number of

patient suffering from those arrhythmias SVT frac14 supraventricular

tachycardia

Figure 2 Method used in the diagnosis of the sentinel atrial arrhythmic

event No signi1047297cant difference was seen between atrial arrhythmia types in

the proportion of diagnosis made by any method ECG frac14 12-lead

electrocardiogram ICD frac14 implantable cardioverter-de1047297brillator SVT frac14

supraventricular tachycardia ETT = exercise tolerance test

1663Camm et al Prevalence of Atrial Arrhythmias in ARVDC



(382 vs 102 P o001) atrial enlargement were

signi1047297cantly associated with the presence of atrial arrhyth-

mias following binary logistical regression both right (B frac14

0929 SE frac14 0405 P frac14 022) and left (B frac14 1352 SE frac14

0463 P frac14 004) atrial enlargement remained signi1047297cantLeft ventricular enlargement was present in 1047297ve patients with

atrial arrhythmias (143) No statistically signi1047297cant differ-

ence was seen between the rate of left ventricular enlarge-

ment in those with left atrial enlargement (312 [250]) and

those without (221 [95]) (P frac14 233) Left ventricular

ejection fractions were similar between those with left atrial

enlargement (547 SD frac14 81 n frac14 13) and those without

(547 SD frac14 108 n frac14 21) (P frac14 994) The rate of

hypertension 4140 mm Hg systolic or 90 mm Hg diastolic

was not signi1047297cantly different between those with left atrial

enlargement (321 [143]) and those without left atrial

enlargement (312 [250]) (P frac14 443)

The presence of atrial arrhythmias was associated with heart

failure (343 vs 93 respectively P o001) and death(114 vs 28 respectively P frac14 037) Additionally patients

with atrial arrhythmias were signi1047297cantly more likely to be

placed on antiarrhythmic therapies (829 vs 413 respec-

tively P o001) No other markers of disease severity were

signi1047297cantly associated (Table 4) Following binary logistical

regression analysis controlling for age at last follow-up and

gender the presence of atrial arrhythmias were signi1047297cantly

associated with heart failure (Bfrac14 1646 SEfrac14 0455 Po001)

and death (B frac14 1576 SE frac14 0719 P frac14 028)

Table 2 Demographic features of atrial arrhythmias

Clinical valueAll atrial arrhythmias(n frac14 47) AF (n frac14 28)

Atrial 1047298 utter (n frac14 11)

Other supraventricular tachycardia (n frac14 8) P value

Age at 1047297rst atrial arrhythmia (years) 430 140 4590 1337 3745 1636 4051 1133 NSYears from ARVDC presentation 463 906 454 1075 368 570 627 652 NSProportion male 31 (660) 19 (679) 7 (636) 5 (625) NSDesmosomal mutation carrier 17 (362) 12 (429) 3 (273) 2 (250) NS

Taking antiarrhythmic drug at sentinel atrial arrhythmia

32 (681) 17 (607) 8 (727) 7 (875) NS

Implantable cardioverter-de1047297brillator at last follow-up

41 (872) 25 (892) 9 (818) 7 (875) NS

Values are given as mean SD or n ()

AF frac14 atrial 1047297brillation ARVDC frac14 arrhythmogenic right ventricular dysplasiacardiomyopathy

Figure 3 Kaplan-Meier survival curves for the development of atrial arrhythmias Left panel Development of atrial arrhythmias based on age in years Right

panel Development of atrial arrhythmias based on length of follow-up Four subjects were diagnosed on autopsy (time frac14 0) and thus do not appear in the

numbers at risk ARVDC frac14 arrhythmogenic right ventricular dysplasiacardiomyopathy




DiscussionMain 1047297ndingsThe results of this study reveal that atrial arrhythmias are not

uncommon in patients with ARVDC occurring in 14 of

patients ARVDC patients who develop atrial arrhythmias

are on average older and more likely to be male The

development of atrial arrhythmias was associated with

structural changes including left and right atrial enlargement

Prior studies of atrial arrhythmias in patientswith ARVDCThe presence of atrial arrhythmias in ARVDC was high-

lighted soon after the initial recognition of this cardiomyop-

athy a nd ha s been con1047297rmed in prior cases studies and case

series12ndash142021 Tonet et al14 were the 1047297rst group to assess

the presence of atrial arrhythmias in patients with ARVDC

Evaluation of 72 ARVDC patients presenting with ventric-

ular arrhythmias demonstrated a 24 prevalence rate with

AF the most common arrhythmia (59) The presence of

right atrial enlargement and tricuspid regurgitation were both

suggested by this group as factors in the development of

atrial arrhythmias In a similar population of 47 patientsBrembilla-Perrot et al13 demonstrated a 15 prevalence rate

and an increased susceptibility to the development of atrial

arrhythmias under programmed electrical stimulation

Jaoude et al22 assessed the progression of ECG tracings

during follow-up of 74 patients with ARVDC This yielded

a 4 prevalence of atrial arrhythmias (three patients)

However this study did not further categorize the arrhyth-

mias or the patients presenting with these arrhythmias

Recently Chu et al12 highlighted a prevalence rate of 42

in a retrospective analysis of 36 ARVDC patients under-

going ablation for ventricular arrhythmias There was a

nonsigni1047297

cant trend toward older age in the atrial arrhythmia group however there was no difference in gender Tricuspid

regurgitation was signi1047297cantly associated with the develop-

ment of atrial arrhythmias in contrast association with right

atrial enlargement was not signi1047297cant

Atrial arrhythmias in the Johns HopkinsARVDC RegistryThe results of the present study con1047297rm and extend the 1047297ndings

of prior studies of atrial arrhythmias in patients with ARVDC

This is the 1047297rst study directly assessing the presence and nature

of atrial arrhythmias in a large research database Previous

studies characterizing atrial arrhythmia type and prevalencehave focused on particular subpopulations of ARVDC patients

mdashthose diagnosed with ventricular arrhythmias14 or patients

undergoing ventricular ablation12 The current study provides

novel insights using data from a large specialist registry and

highlights key features important to the practicing physician

regarding the development of atrial arrhythmias in this group

Overall prevalenceThe 1047297rst important 1047297nding of this study is the prevalence of

atrial arrhythmias (AF atrial 1047298utter and other SVTs) in

patients with ARVDC was 14 This rate is similar to the149 reported by Brembilla-Perrot et al13 The lower

prevalence in this study compared with the 42 r eported

by Chu et al12 and the 25 reported by Tonet et al14 may be

related to population selection In these prior studies patients

were limited to those undergoing ventricular ablation therapy

and those presenting with ventricular arrhythmias respec-

tively both markers of more severe disease Given the high

proportion of paroxysmal AF in our current study (2728

[96]) the low rate of atrial arrhythmias (41) demon-

strated by Jaoude et al22 likely re1047298ects the lack of compre-

hensive assessment of patient records examining for atrial

arrhythmias which were instead identi1047297

ed solely throughECG assessment

Table 4 Association of disease severity markers with atrial arrhythmias

Clinical valueOverall population(n frac14 248)

Atrial arrhythmias(n frac14 35)

No atrial arrhythmias(n frac14 213) P value

Dead 10 (40) 4 (114) 6 (28) 038ICD 239 (923) 32 (914) 197 (925) 738Sustained arrhythmic event 164 (661) 25 (714) 139 (653) 565Premature ventricular complex count (n frac14 179) 2430 (IQR frac14 4620) 2530 (IQR frac14 4820) (n frac14 21) 2380 (IQR frac14 4650) (n frac14 157) 790Heart failure 32 (129) 12 (343) 20 (94) o001Antiarrhythmic therapy at last follow-up 117 (472) 29 (829) 88 (413) o001

Values are given as n () nN () or median (interquartile range [IQR])

A sustained arrhythmic event is a composite measure of the occurrence of sudden cardiac death spontaneous sustained ventricular tachycardiaventricular

1047297brillation or an appropriate implantable cardioverter-de1047297brillator (ICD) intervention for a sustained ventricular arrhythmia

Table 3 Echocardiographic features associated with atrial arrhythmias


Tricuspid regurgitation 34 (162) 10 (294) 24 (136) 022Mitral regurgitation 9 (43) 2 (59) 7 (40) 64Right atrial enlargement 67 (319) 18 (529) 49 (278) 008Left atrial enlargement 31 (148) 13 (382) 18 (102) o001

Values are given as n ()




Age and gender AF and other atrial arrhythmias ar e age dependent and more

likely to be seen in male patients2324 AF has a population

prevalence of 21 by age 8023 Atrial arrhythmias were

shown to be similarly age and gender dependent within our

ARVDC population Additionally the mean age of 430

140 years illustrates a high disease burden in an age group

that normally has a AF prevalence o0525 Furthermoreour study has shown that older ARVDC patients were more

likely to have experienced an atrial ar rhythmia which

supports the earlier 1047297ndings of Chu et al12 The mean age

of 43 years in this population is lower than the 51 and 52

years seen in previous studies1213 The lower age range seen

in our population may in part represent increased recog-

nition of ARVDC as a condition over the past decade with

better diagnostic clari1047297cation following publication of

improved TFC in 2010 Increased use of genetic screening

in family members7 as suggested by Heart Rhythm Society

guidelines26 following proband diagnosis (and hence their

meeting TFC at an earlier stage of disease) may explain thesigni1047297cant association with negative genetic screening

results and atrial arrhythmias (due to the potential diagnosis

of such individuals at an earlier stage of disease progression)

an association that was not maintained when regression

controlled for age at last follow-up and gender Unlike age

gender has not been shown to be a signi1047297cant predisposing

factor in previous studies in this area12 These results suggest

the possibility that atrial arrhythmias are occurring in older

individuals with a predisposition to AF that is triggered by

the presence of ARVDC

Diagnosis method and ICDA large proportion of atrial arrhythmias were diagnosed in

this study using ICDs (both during routine follow-up and as a

result of inappropriate shocks) and Holter monitors This

suggests that many atrial arrhythmias in this population may

be concealed with only 340 of all atrial arrhythmias being

1047297rst demonstrated using an ECG tracing This is consistent

among different atrial arrhyt hm ia types and has not been

shown previously Tonet et al14 showed that the majority of

their atrial arrhythmias (82) were diagnosed using a

standard 12-lead ECG tracing The increased diagnostic

prevalence of other techniques likely results from their increased utilization in the diagnosis and management of

ARVDC over the past 2 decades However the fact that

17 of all atrial arrhythmias were initially diagnosed

following an inappropriate ICD shock and the presence of

22 inappropriate shocks within our atrial arrhythmia pop-

ulation highlights the need for better awareness and control

of these arrhythmias

Disease severityIt has been previously suggested that atrial arrhythmias may

be associated wit h the presence or development of more

severe disease1214 In this study the presence of atrialarrhythmias showed a variable association with factors

suggestive of disease severity Death and heart failure both

were more prevalent in the atrial arrhythmia group How-

ever it is not clear whether either atrial arrhythmias or heart

failure played a causative role in the development of the

other Although statistically signi1047297cant the small number of

deaths in our study population suggests that the clinical

signi1047297cance of this 1047297nding is less clear The increased

utilization of antiarrhythmic agents in the atrial arrhythmia group is potentially a result of the atrial arrhythmia burden

rather than suggestive of increased ventricular arrhythmia

burden Although atrial arrhythmias in general and AF in

particular are associated with an increased mortality rate

in the general population15 the increased rate of heart failure

in this population likely added to this

PathophysiologyThe pathophysiology behind the development of atrial

arrhythmias in ARVDC is far from clear Atrial enlargement

is a known risk factor for atrial arrhythmias especially AF27Several groups have previously suggested a role for the right

atrial dilation often seen in ARVDC in the development of

atrial arrhythmias1214 The limited availability of cardiac

magnetic resonance imaging data within this population

makes structural analysis of the atria dif 1047297cult However we

demonstrated a correlation between atrial arrhythmias and

tricuspid regurgitation using echocardiographic imagining

in support of previous studies12 However this 1047297nding

cannot fully explain the prevalence of atrial arrhythmias

within the ARVDC population Although a correlation with

both left and right atrial enlargement and atrial arrhythmias

was also identi1047297ed the known limitations of echocardiog-raphy when viewing the atria limit the validity of these

results Left atrial enlargement is a known effect of AF28

which suggests that the structural changes seen both in this

study and by previous groups may be a result of the atrial

arrhythmias rather than a causative factor

Desmosome mutations and the resulting dysfunction are

known to be a major pathologic mechanism in ARVDC

Desmosomes are found throughout the cardiac system

including the atria Evidence for a pathologic role of the

atria in ARVDC remains limited however support for a

desmosomal basis to atrial arrhythmias in this population is

multifactorial A small autopsy case series (two patients withARVDC) by Morimoto et al29 showed the presence of fatty

tissue within the sinoatrial node of both patients Direct atrial

involvement with ARVDC is further suggested by the

1047297nding of atrial involvement in 17 of cats in an ARVD

C model30 Additionally the postnatal loss of desmoplakin

within the cardiac conduction system has been shown to lead

to sinoatrial node dysfunction in mice31 Furthermore work

by Platonov et al32 has demonstrated evidence for altered

electrical conduction within the atria of ARVDC patients

Despite this suggestive evidence data directly relating to

atrial involvement in patients with ARVDC are lacking The

thin-walled nature of the atria makes biopsy unwiseFurthermore despite cardiac magnetic resonance imaging




proving itself to be an excellent imaging modality for

ventricular involvement33 resolution of the atria remains

poor Without further evidence relating to a direct role of the

atria in ARVDC it remains uncertain whether atrial

arrhythmias are due to desmosomal dysfunction within the

atria right atrial enlargement as a result of right ventricular

dysfunction or a combination of both mechanisms

Clinical implicationsAn atrial arrhythmia prevalence of 14 in this ARVDC

population highlights the need for vigilance among treating

clinicians This is further supported by the increased mortal-

ity and heart failure prevalence associated with these

patients Furthermore our study demonstrates that atrial

arrhythmias are a common cause of inappropriate shocks in

patients with ARVDC This 1047297nding has important implica-

tions for programming of ICDs to minimize the risk of

inappropriate shocks should an atrial arrhythmia occur The

association with male gender and increasing age suggeststhat these factors should guide clinicians when considering

evaluation of ARVDC patients for atrial arrhythmias

However the lack of additional association with length of

follow-up suggests that clinical vigilance should not depend

on this factor

Study limitationsThis study has a number of limitations First data were

obtained retrospectively as part of a large registry as such

there is likely to be variability in the completeness of data

records and the standard of evaluation each patient receivedboth in regard to their ARVDC as a whole and any atrial

arrhythmias in particular Although this does provide some

limitations to the data it also highlights a situation similar to

that encountered by many practicing physicians who may

lack complete data regarding a patient Second the use of

echocardiographic report data to rate valvular regurgitation

and atrial size is a potential limitation because echocardio-

grams are notorious for poor imaging of the right atrium and

the quality of the data contained within reports is likely to be

affected by examiner experience This limitation may be

compounded by the lack of corroborating imaging Addi-

tionally length of time between echocardiogram and last follow-up or sentinel atrial arrhythmia was variable This

may have resulted in some related factors being missed

ConclusionThe results of this study demonstrate that atrial arrhythmias

are common in patients with ARVDC and when seen occur

at a signi1047297cantly younger age when compared to the general

population Other associated factors include male gender

presence of heart failure and right atrial enlargement We

suggest that clinicians caring for patients with ARVDC

should consider the presence of atrial arrhythmias in suchpatients particularly bearing in mind the above associations

AcknowledgmentsWe are grateful to the ARVDC patients and their families

who made this work possible

AppendixSupplementary data

Supplementary data associated with this article can be foundin the online version at httpdxdoiorg101016jhrthm

201308032

References1 Basso C Corrado D Marcus FI Nava A Thiene G Arrhythmogenic right

ventricular cardiomyopathy Lancet 20093731289ndash1300

2 Marcus FI Fontaine GH Guiraudon G et al Right ventricular dysplasia a report

of 24 adult cases Circulation 198265384ndash398

3 Thiene G Nava A Corrado D Rossi L Pennelli N Right ventricular cardiomyopathy

and sudden death in young people N Engl J Med 1988318129ndash133

4 Dalal D Nasir K Bomma C et al Arrhythmogenic right ventricular dysplasia a

United States experience Circulation 20051123823ndash3832

5 Hulot J-S Jouven X Empana J-P Frank R Fontaine G Natural history and risk

strati1047297cation of arrhythmogenic right ventricular dysplasiacardiomyopathy

Circulation 20041101879ndash1884

6 McKoy G Protonotarios N Crosby A et al Identi1047297cation of a deletion in plakoglobin

in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma

and woolly hair (Naxos disease) Lancet 20003552119ndash2124

7 Sen-Chowdhry S Syrris P McKenna WJ Role of genetic analysis in the

management of patients with arrhythmogenic right ventricular dysplasiacardio-

myopathy J Am Coll Cardiol 2007501813ndash1821

8 Arbelo E Josephson ME Ablation of ventricular arrhythmias in arrhythmogenic

right ventricular dysplasia J Cardiovasc Electrophysiol 201021473ndash486

9 Bhonsale A James CA Tichnell C et al Risk strati1047297cation in arrhythmogenic

right ventricular dysplasiacardiomyopathy associated desmosomal mutation

carriers Circ Arrhythm Electrophysiol 20136569ndash578

10 Bhonsale A James CA Tichnell C et al Incidence and predictors of implantable

cardioverter-de1047297

brillator therapy in patients with arrhythmogenic right ventric-ular dysplasiacardiomyopathy undergoing implantable cardioverter-de1047297brillator

implantation for primary prevention J Am Coll Cardiol 2011581485ndash1496

11 Piccini JP Dalal D Roguin A et al Predictors of appropriate implantable

de1047297brillator therapies in patients with arrhythmogenic right ventricular dysplasia

Heart Rhythm 200521188ndash1194

12 Chu AF Zado E Marchlinski FE Atrial arrhythmias in patients with arrhythmo-

genic right ventricular cardiomyopathydysplasia and ventricular tachycardia

Am J Cardiol 2010106720ndash722

13 Brembilla-Perrot B Jacquemin L Houplon P et al Increased atrial vulnerability

in arrhythmogenic right ventricular disease Am Heart J 1998135748ndash754

14 Tonet JL Castro-Miranda R Iwa T Poulain F Frank R Fontaine GH Frequency

of supraventricular tachyarrhythmias in arrhythmogenic right ventricular dyspla-

sia Am J Cardiol 1991671153

15 Benjamin EJ Wolf PA DrsquoAgostino RB Silbershatz H Kannel WB Levy D

Impact of atrial 1047297brillation on the risk of death the Framingham Heart Study

Circulation 199898946ndash

95216 Wolf PA Abbott RD Kannel WB Atrial 1047297brillation as an independent risk factor

for stroke the Framingham Study Stroke 199122983ndash988

17 Marcus FI McKenna WJ Sherrill D et al Diagnosis of arrhythmogenic right

ventricular cardiomyopathydysplasia proposed modi1047297cation of the Task Force

Criteria Eur Heart J 201031806ndash814

18 Den Haan AD Tan BY Zikusoka MN et al Comprehensive desmosome

mutation analysis in North Americans with arrhythmogenic right ventricular

dysplasiacardiomyopathy Circ Cardiovasc Genet 20092428ndash435

19 Hunt SA Baker DW Chin MH et al ACCAHA Guidelines for the Evaluation

and Management of Chronic Heart Failure in the Adult Executive SummarymdashA

Report of the American College of CardiologyAmerican Heart Association Task

Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the

Evaluation and Management of Heart Failure) Developed in Collaboration With

the International Society for Heart and Lung Transplantation Endorsed by the

Heart Failure Society of America Circulation 20011042996ndash3007

20 Lui CY Marcus FI Sobonya RE Arrhythmogenic right ventricular dysplasia masquerading as peripartum cardiomyopathy with atrial 1047298utter advanced

atrioventricular block and embolic stroke Cardiology 20029749ndash50




21 Morady F Shen EN Scheinman MM Unusual features of arrhythmogenic right

ventricular dysplasia Am J Cardiol 198453639ndash640

22 Jaoude SA Leclercq JF Coumel P Progressive ECG changes in arrhythmogenic right

ventricular disease Evidence for an evolving disease Eu Heart J 1996171717ndash1722

23 Alonso A Agarwal SK Soliman EZ et al Incidence of atrial1047297brillation in whites

and African-Americans the Atherosclerosis Risk in Communities (ARIC) study

Am Heart J 2009158111ndash117

24 Granada J Uribe W Chyou PH et al Incidence and predictors of atrial 1047298utter in

the general population J Am Coll Cardiol 2000362242ndash2246

25 Kannel WB Wolf PA Benjamin EJ Levy D Prevalence incidence prognosisand predisposing conditions for atrial 1047297brillation population-based estimates

Am J Cardiol 1998822Nndash9N

26 Ackerman MJ Priori SG Willems S et al HRSEHRA expert consensus

statement on the state of genetic testing for the channelopathies and cardiomyo-

pathies this document was developed as a partnership between the Heart Rhythm

Society (HRS) and the European Heart Rhythm Association (EHRA) Heart

Rhythm 201181308ndash1339

27 McManus DD Xanthakis V Sullivan LM et al Longitudinal tracking of left

atrial diameter over the adult life course clinical correlates in the community


28 Wozakowska-Kapłon B Changes in left atrial size in patients with persistent

atrial 1047297brillation a prospective echocardiographic study with a 5-year follow-up

period Int J Cardiol 200510147ndash52

29 Morimoto S Sekiguchi M Okada R et al [Two autopsied cases of arrhythmo-

genic right ventricular dysplasia] J Cardiol 1990201025ndash1036

30 Fox PR Maron BJ Basso C Liu SK Thiene G Spontaneously occurring

arrhythmogenic right ventricular cardiomyopathy in the domestic cat a new

animal model similar to the human disease Circulation 2000102

1863ndash

187031 Mezzano V Wright A Lyon R et al A novel role for the desmosomal cell-cell

junction protein desmoplakin in mouse sinoatrial node pacemaker function

Circulation 2012126A15773

32 Platonov PG Christensen AH Holmqvist F Carlson J Haunsoslash S Svendsen JH

Abnormal atrial activation is common in patients with arrhythmogenic right

ventricular cardiomyopathy J Electrocardiol 201144237ndash241

33 Sen-Chowdhry S Prasad SK Syrris P et al Cardiovascular magnetic resonance

in arrhythmogenic right ventricular cardiomyopathy revisited comparison with

task force criteria and genotype J Am Coll Cardiol 2006482132ndash2140




also be associated with an increased risk of morbidity16

Therefore the purpose of this study was to examine the

prevalence and characteristics of supraventricular arrhyth-

mias in patients with ARVDC Particular attention is

focused on determining the relationship between the devel-

opment of atrial arrhythmias patient age and the severity of

ARVDC

MethodsStudy populationThe Johns Hopkins ARVDC Program was established in

1999 with a goal of studying ARVDC and providing care

for patients with this condition Patients with de1047297nite or

possible ARVDC are enrolled in a prospective registry The

study population was identi1047297ed from this registry Inclusion

criteria for this study were registry patients who had under-

taken genotype analysis and m et the 2010 Task Force

Criteria (TFC) for ARVDC17 All registry participants

provided written informed consent The study protocol wasapproved by the Johns Hopkins School of Medicine Institu-

tional Review Board

Clinical phenotypeDetailed clinical information regarding demographics pre-

sentation symptom onset and noninvasive and invasive

studies was obtained for each patient The medical history of

each subject was obtained through review of medical

records clinical evaluation and patient interview A detailed

family history was obtained through patient interview by

genetic counselors with a special interest in ARVDC

Comprehensive mutation testing was performed usingcommercial or resea rch genetic testing on all patients

included in this study18 Genetic testing included sequencing

of 1047297ve ARVDC-associated desmosomal genes (PKP2

DSC2 DSG2 DSP JUP) and the PLN and TMEM43 genes

The diagnosis of ARVDC was based on the presence of

major and m inor diagnostic criteria according to the revised

TFC 201017 The proband was de1047297ned as the 1047297rst person in a

family in whom ARVDC diagnosis was con1047297rmed (ie

ful1047297lled TFC for ARVDC irrespective of family history)

Severity and extent of structural abnormalities were

determined through review of echocardiography cardiac

magnetic resonance imaging and right ventricular angiog-raphy reports Mitral and tricuspid regurgitation was

considered if rated as at least moderately severe on echo-

cardiography reports Enlargement of the right and left atria

was de1047297ned as either present or absent based on the atrial

diameter (in millimeters) recorded

Outcome measuresThe primary outcome was presence of atrial arrhythmias

ascertained from medical records including records of ICD

interrogations Atrial arrhythmias were de1047297ned as a narrow

complex tachycardias with at least one episode lasting Z30

seconds Where available traces were examined and adju-

dicated in addition to reports from the treating physician

Atrial arrhythmias appearing only during electrophysiologic

studies were excluded Type of arrhythmia symptoms and

detection method were recorded Atrial arrhythmias were

categorized into three groups atrial 1047297brillation (AF) atrial

1047298utter and all other supraventricular tachycardias (SVTs)

Secondary outcomes were the development of stage C heart

failure a sustained ventricular arrhythmic event ICD place-

ment and death Stage C heart failure is de1047297ned as patients

with current or past symptoms of heart failure (eg dyspnea

fatigue) associated with underlying structural heart disease19

A sustained arrhythmic event is a composite measure of the

occurrence of sudden cardiac death spontaneous sustained

VTVF or an appropria te ICD intervention for a sustained

ventricular arrhythmia9 Echocardiographic reports were

reviewed for moderate-to-severe tricuspid regurgitation mitral

regurgitation and right and left atrial diameters

Statistical analysisContinuous variables are expressed as mean SD or median

(interquartile Range [IQR]) and compared across groups

using the independent Student t test or Mann-Whitney U testrespectively Categorical variables are reported as frequency

(percentage) and compared between groups using the χ2 or

Fisher exact test The cumulative probability of survival free

of an atrial arrhythmia was determined by the Kaplan-Meier

method and differences in survival between groups was

evaluated with the log-rank test Binary logistical regression

was used to control for age at last follow-up and sex P o05

was considered signi1047297cant SPSS (version 19 IBM

Chicago IL) was used for all statistical analysis

Results

Study populationBaseline demographic data of the 248 patients enrolled in

this study are listed in Table 1 Mean age at last follow-up

was 416 140 years 131 patients (528) were male and

Table 1 Baseline demographic data of the study population


Male 131 (528) 24 (686) 107 (502) 044Age at last follow-up (years) 416 140 497 146 403 135 o001Age at ARVDC diagnosis 338 134 394 157 329 128 007Length of ARVDC follow-up 578 (IQR frac14 852) 615 (IQR frac14 123) 556 (IQR frac14 811) 047Desmosomal mutation carrier 136 (548) 14 (400) 122 (573) 057

Values are given as n () mean SD or median (interquartile range [IQR])

ARVDC frac14 arrhythmogenic right ventricular dysplasiacardiomyopathy










































































tachycardia









































32 (681) 17 (607) 8 (727) 7 (875) NS


41 (872) 25 (892) 9 (818) 7 (875) NS




































nonsigni1047297




































































































































































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Documents

2013_Camm_Prevalence of Atrial Arrhythmias in ARVC (2)