High Arrhythmic Burden but Low Mortality during Long-term Follow-up in Arrhythmogenic Right Ventricular Cardiomyopathy

Heart, Lung and Circulation (2016) 25, 275 281 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2015.08.019 ORIGINAL ARTICLE High Arrhythmic Burden but Low Mortality during Long-term Follow-up in Arrhythmogenic Right Ventricular Cardiomyopathy Andrew Martin, FRACP a,b, Jackie Crawford, NZCS c, Jonathan R. Skinner, FRACP, MD c,d*, Warren Smith, FRACP a, on behalf of the Cardiac Inherited Diseases Group a Green Lane Cardiovascular Services, Auckland City Hospital, Auckland, New Zealand b Faculty of Medicine and Health Sciences, University of Auckland, Auckland, New Zealand c Green Lane Paediatric and Congenital Cardiac Services, Starship Children s Hospital, Auckland, New Zealand d Department of Paediatrics, Child and Youth Health, University of Auckland Received 5 June 2015; accepted 27 August 2015; online published-ahead-of-print 28 September 2015 Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with a high incidence of ventricular tachyarrhythmia and sudden death. The mainstay of management is the implantable cardioverter defibrillator (ICD). A small number of patient cohorts have generated a large number of reports. Methods Prospective registry data supplemented with clinical and ICD records of 30 patients with ARVC fulfilling the 2010 modified Task Force Criteria. This cohort has not been reported on previously. Results Median age at diagnosis: 46yrs (range 21-68); 20 (80%) male; six (19%) Maori. Duration of follow-up: 7.4yrs (range 1.7-23). Implantable cardioverter defibrillator implantation in 26; three (12%) for resuscitated sudden cardiac death; 17 (65%) for symptomatic ventricular tachyarrhythmia; three (12%) for syncope; and three (12%) for family history of sudden death attributable to ARVC. Two patients died during follow-up, one had an ICD, though died of a carcinoma. Thirteen (50%) experienced appropriate ICD therapy with median time to therapy 12 months, and four (15%) experienced inappropriate shock therapy. Male gender was an independent predictor of appropriate ICD therapy (HR 1.6, 95% CI 1.5-2.7, P=0.01). Conclusions The long-term prognosis of patients with ARVC is favourable although high proportions receive appropriate ICD therapy. Male gender is an independent predictor of appropriate ICD therapy. Keywords Arrhythmogenic right ventricular cardiomyopathy/dysplasia Cardiomyopathy Death Sudden Implantable cardioverter defibrillators Electrophysiology Introduction Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) is an inheritable heart muscle disease with a natural history that is associated with ventricular tachyarrhythmias and sudden cardiac death (SCD). Histologically it is characterised by fibro fatty substitution of the right ventricular (RV) myocardium, and in addition to ventricular tachyarrhythmia it results in mechanical RV dysfunction [1 4]. *Corresponding author at: Green Lane Paediatric and Congenital Cardiac Services, Starship Children s Hospital, Private Bag 92024, Auckland 1142, New Zealand. Tel.: +64 9 3074949; fax: +64 9 6310785, Email: jskinner@adhb.govt.nz 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.

276 A. Martin et al. Observational studies have demonstrated the efficacy of the implantable cardioverter defibrillator (ICD) in preventing SCD in patients with ARVC [5 10] and have resulted in guideline recommendations that these be implanted in those who have survived a cardiac arrest, and for the primary prevention of SCD in high risk individuals [11]. Additionally, several studies have reported that patients with ARVC who undergo ICD placement have a high probability of receiving an appropriate ICD therapy for treatment of a sustained ventricular arrhythmia [5,8,12 14]. These cohorts report on data that has median follow-up durations from 3.3 to 6.7 years, with little information on the occurrence of rapid ventricular tachycardia/fibrillation (VT/VF) and overall prognosis [5,7,14]. At present there is a paucity of prospective long-term data to provide definite guideline recommendations for primary prevention. Furthermore the subjects in these reports reside in Europe and North America and have been described on several occasions, in both single centre and multicentre reports. While these reports have been used to develop diagnostic criteria for ARVC and indications and outcome for the use of ICDs, these data may not be applicable in other regions of the world [3,5,7,8,12,15,16]. Local data from Australasia has not previously been reported, and it is important to compare and contrast these with that from Europe and North America, particularly with respect to VT/VF and overall prognosis. Table 1 2010 Revised Taskforce Criteria for the diagnosis of arrhythmogenic right ventricular cardiomyopathy Global or regional dysfunction and structural alterations Tissue characterisation of the wall Repolarisation abnormalities Major criteria Minor Criteria Echocardiography: Regional RV akinesia, dyskinesia, or aneurysm, and 1 of (at end diastole): PLAX RVOT >32 mm, PSAX RVOT >36 mm, or fractional area change <33%. Cardiac MRI: Regional RV akinesia or dyskinesia or dyssynchronous RV contraction, and 1 of the following: RVEDV >110mL/m 2 (male) >100mL/m 2 (female), or RVEF <40%. RV angiography: Regional RV akinesia, dyskinesia, or aneurysm. Residual myocytes <60% by morphometric analysis, with fibrous replacement of the RV free wall myocardium in >1 sample, with or without fatty replacement of tissue on endomyocardial biopsy. Inverted T waves in right precordial leads (V 1-3 ) or beyond in those >14 years of age in the absence of a complete RBBB. Echocardiography: Regional RV akinesia or dyskinesia, and 1 of (at end diastole): PLAX RVOT 29-32 mm, PSAX RVOT 32-36 mm, or fractional area change 33-40%. Cardiac MRI: Regional RV akinesia or dyskinesia or dyssynchronous RV contraction, and 1 of the following: RVEDV 100-110mL/m 2 (male) 90-100mL/m 2 (female), or RVEF 40-45%. Residual myocytes 60-75% by morphometric analysis, with fibrous replacement of the RV free wall myocardium in >1 sample, with or without fatty replacement of tissue on endomyocardial biopsy. Inverted T waves in leads V 1-2 in those aged >14 years (in the absence of a complete RBBB) or in V 4-6. Inverted T waves in leads V 1-4 in those aged >14 years in the presence of a complete RBBB. Depolarisation abnormalities Epsilon wave in the right precordial leads V 1-3. Late potentials by SAECG in >1 of 3 parameters in the absence of a QRS duration of >110ms on the standard ECG. Arrhythmias Ventricular tachycardia of left bundle-branch morphology with superior axis. Ventricular tachycardia of left bundle-branch morphology with inferior axis. >500 ventricular extrasystoles per 24 hours (Holter). Family history ARVC confirmed in a first-degree relative. ARVC confirmed pathologically at autopsy or surgery in a first-degree relative. Identification of a pathogenic mutation categorised as associated or probably associated with ARVC in the patient under evaluation. History of ARVC in a first-degree relative in whom it is not possible or practical to determine whether the family member meets current Task Force criteria. Premature sudden death (<35 years of age) due to suspected ARVC in a first-degree relative. ARVC confirmed in a second-degree relative. A definite diagnosis of ARVC is made when 2 Major or 1 Major and 2 Minor or 4 Minor criteria are present [22]. ARVC Arrhythmogenic right ventricular cardiomyopathy; MRI Magnetic resonance imaging; PLAX Parasternal long axis view; PSAX Parasternal short axis view; RBBB Right bundle branch block; RV Right ventricle; RVEDV Right ventricular end diastolic volume; RVEF Right ventricular ejection fraction; RVOT Right ventricular outflow tract; SAECG Signal averaged ECG.

Follow-up of ARVC 277 The Cardiac Inherited Disease Registry of New Zealand (CIDRNZ) is a consent based and ethically approved clinical registry for patients with inherited heart disease, and has been in place in the Northern Region of New Zealand since 2003. The Cardiac Inherited Diseases Group (CIDG) manages this, and comprises a collaborative group of physicians and scientists. National registry enrolment became possible in 2009. Patients are voluntarily referred to this registry by their treating cardiologist, and when probands are identified, cascade clinical screening is carried out in family members to identify at risk asymptomatic individuals. Genetic testing is ongoing in this cohort, with few results at present. We describe the arrhythmia burden and mortality amongst a previously unreported cohort of ARVC patients from New Zealand. Patients and Methods Patient Population The CIDRNZ was established in the northern region of New Zealand in 2003, with the ability to add cases from throughout New Zealand from 2009 onward [17 20]. The northern region (defined as Northland, Auckland, Waitemata, Counties Manukau, and Waikato district health boards), comprises 2.1 million people (which is nearly half of New Zealand s population) and includes the cities of Auckland and Hamilton [21]. The National Registry coordinator is based in Auckland and earlier northern regional registration (prior to the establishment of the national registry) has resulted in an uneven distribution of case registrations throughout New Zealand. The study population consists of 30 patients with definite ARVC who have been voluntarily reported to the CIDRNZ. Patient information is entered into a secure web-based database, and data used for this report was extracted from this and supplemented where required by hospital clinical records. Diagnosis of ARVC All patients fulfilled current diagnostic criteria for definite ARVC recommended by the 2010 modification of the Task Force Criteria for the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia [22]. The diagnosis is established by the presence of two major criteria, or one major criterion plus two minor criteria, or four minor criteria (Table 1). Classification of ICD Discharges Appropriate interventions included an ICD shock or antitachycardia overdrive pacing delivered in response to a VT/VF. An inappropriate shock was diagnosed when neither VT/VF were present, including rapid ventricular rates resulting from supraventricular tachyarrhythmias, sinus tachycardia, or device malfunction. The clinical Cardiac Physiologist performed adjudication between appropriate and inappropriate therapy at the time of ICD interrogation. Statistical Analysis Continuous data are expressed as median and range, unless stated otherwise. Comparisons between continuous variables were performed using a Student t-test, and nominal variables were compared with a Fisher s exact test. The cumulative probability of event free survival was determined by the Kaplan-Meier method. Multivariate analysis was performed using the variable that was found to be statistically significant in univariate analysis. A value of P < 0.05 was considered statistically significant. Results Patient Characteristics The patient population consisted of 30 patients who fulfilled the 2010 modified Task Force Criteria for ARVC, with median duration of clinical follow-up 7.4 years (range 1.7-23). Table 2 summarises the clinical characteristics of the study population. The median age at the time of diagnosis was 46 years (range 21-68), 25 (80%) were male, and six (19%) Table 2 Characteristics of the 30 patients with arrhythmogenic right ventricular cardiomyopathy N = 30 Age at diagnosis (median, IQR, years) 46 (37-55) Duration of follow-up (median, IQR, years) 7.4 +/- 5.2 (4.9-10.7) Male gender 24 (80%) ICD in situ 26 (87%) ICD therapy Appropriate therapy 13 (50%) Inappropriate shock therapy 4 (15%) Major diagnostic criteria Diffuse RV involvement 27 (90%) Repolarisation abnormality 21 (70%) Depolarisation abnormality 7 (23%) Arrhythmia 8 (27%) Family history 4 (13%) Arrhythmia Sustained or non-sustained VT LB morphology with inferior axis 19 (63%) LB morphology with superior axis 8 (27%) No arrhythmia 3 (10%) Medical therapy * Beta blocker 11 (37%) Sotalol 6 (20%) Flecainide 3 (10%) Amiodarone 4 (13%) No medical therapy 6 (20%) * At time of ICD implant, or at time of diagnosis if ICD not in situ. ICD - implantable cardioverter defibrillator; LB - Left bundle; RV - right ventricle; VT - ventricular tachycardia.

278 A. Martin et al. patients were of Maori ethnicity. Presenting symptoms at the time of diagnosis were resuscitated SCD in three patients (10%), symptomatic ventricular arrhythmia in 21 (70%), syncope in three (10%), and three (10%) were asymptomatic with the diagnosis made following cascade evaluation of a family member proband. Major RV structural abnormalities demonstrated by echocardiography, cardiac MRI, or right ventricular angiography were present in 27 (87%) patients. Standard 12-lead ECGs demonstrated T-wave inversion in V 1-3 in 21 (68%), and Epsilon waves were present in seven (23%). Eight (27%) had either sustained or non-sustained VT that had a left bundle branch block morphology with superior axis. Four (13%) had a first degree relative who fulfilled the 2010 Modified Taskforce criteria for ARVC. Mortality and ICD Therapy Two patients died during follow-up; one with an ICD in situ died from metastatic adenocarcinoma, and the other, who declined ICD implantation at age 29, died suddenly at age 44, 23 years after the initial diagnosis was made. Twenty-six patients (84%) underwent ICD implantation, and their characteristics are described in Table 3. The indication for ICD implantation was resuscitated SCD in three (12%) patients, symptomatic ventricular tachyarrhythmia in 17 (65%), syncope in three (12%), and a family history of sudden cardiac death in three (12%). Thirteen patients (50%) received appropriate ICD therapy, with the median interval between implantation and therapy of 12 months (range 1-53). Kaplan-Meier analysis of actual survival in the entire cohort, and survival free of appropriate ICD therapy is shown in Figure 1. Compared with the 97% actual patient survival at 10 years, the rates of survival free of appropriate ICD therapy were 77% at 12 months, 65% at 24 months, 54% at 36 months, and 50% at 48 months of follow-up. There was no difference in the rate of appropriate ICD therapy between Maori and non-maori. Inappropriate ICD therapy occurred in four Table 3 Characteristics of the 26 patients who had an Implantable Cardioverter Defibrillator implanted Overall N = 26 Appropriate therapy N = 13 No appropriate therapy N = 13 P value Age at ICD implantation median (IQR) years 47 45 47 0.71 (38-56) (39-58) (37-51) Duration of follow-up after ICD implantation 6.7 7.4 5.8 0.95 median (IQR) years (3.3-9.3) (3.3-9.3) (3.4-9.8) Male gender 20 (77%) 13 (100%) 7 (54%) 0.01 Indication for ICD Resuscitated sudden cardiac death 3 (12%) 2 (15%) 1 (8%) 1.00 Symptomatic arrhythmia 17 (65%) 10 (77%) 7 (54%) 0.41 Syncope 3 (12%) 1 (8%) 2 (15%) 1.00 Family history of SCD 3 (12%) 0 (0%) 3 (23%) 0.22 Inappropriate ICD shock 4 (15%) 2 (15%) 2 (15%) 1.00 Major diagnostic criteria Diffuse RV involvement 25 (96%) 13 (100%) 12 (92%) 1.00 Repolarisation abnormality 18 (69%) 10 (77%) 8 (62%) 0.67 Depolarisation abnormality 6 (23%) 2 (15%) 4 (31%) 0.64 Arrhythmia 7 (27%) 6 (46%) 1 (8%) 0.07 Family history 4 (15%) 0 (0%) 4 (31%) 0.10 Arrhythmia prior to ICD implantation Sustained or non-sustained VT 23 (88%) 13 (100%) 10 (77%) LB morphology with inferior axis 16 (62%) 7 (54%) 9 (69%) 0.69 LB morphology with superior axis 7 (27%) 6 (46%) 1 (8%) 0.07 No arrhythmia 3 (12) 0 (0%) 3 (23%) 0.22 Medical therapy at time of ICD implantation Beta blocker 11 (42%) 8 (62%) 3 (23%) 0.11 Sotalol 5 (19%) 2 (15%) 3 (23%) 1.00 Flecainide 2 (8%) 1 (8%) 1 (8%) 1.00 Amiodarone 3 (13%) 2 (15%) 1 (8%) 1.00 No medical therapy 5 (19%) 0 (0%) 5 (38%) 0.03 ARVC Arrhythmogenic right ventricular cardiomyopathy; ICD Implantable cardioverter defibrillator; IQR Interquartile range; LB Left bundle; RV Right ventricle; SCD Sudden Cardiac Death; SD Standard deviation; VT Ventricular tachycardia.

Follow-up of ARVC 279 Figure 1 Kaplan-Meier analysis of cumulative survival free of appropriate Implantable Cardioverter Defibrillator (ICD) therapy compared with actual patient survival in a cohort of 30 patients with Arrhythmogenic Right Ventricular Cardiomyopathy. The divergence between these lines reflects an estimate of the survival benefit derived by ICD therapy. The estimated mortality reduction at 4 years is 47%. (15%) patients. Reasons for inappropriate ICD therapy were atrial fibrillation with elevated ventricular rate in (87%) three, and T-wave over sensing in one. Predictors of Appropriate ICD Therapy Univariate and multivariate predictors of appropriate ICD therapy are listed in Table 4. The only predictor of appropriate ICD therapy was male gender (hazard ratio 1.9, 95% confidence interval 1.1 to 3.1, P=0.01), and this remained an independent predictor on multivariate analysis (hazard ratio 1.6, 95% confidence interval 1.5 to 2.7, P=0.01). No appropriate ICD therapy occurred in the three asymptomatic patients implanted solely on the basis of a family history of SCD. Table 4 Predictors of appropriate Implantable Cardioverter Defibrillator therapy Univariate analysis Multivariate analysis HR 95% CI P value HR 95% CI P value Male gender 1.9 1.1 3.1 0.01 1.6 1.5 2.7 0.01 Age <35 years 0.9 0.75 1.6 1.00 Proband status 1.3 0.97 1.8 0.22 Maori ethnicity 2.0 0.44 9.1 0.64 Syncope 0.5 0.05 4.9 1.00 Symptomatic ventricular arrhythmia 1.4 0.80 2.6 0.41 Diffuse RV involvement 1.1 0.93 1.3 1.0 Right precordial T-wave inversion 1.1 0.70 1.8 1.0 Epsilon wave 0.5 0.11 2.3 0.64 CI - Confidence Ratio; HR - Hazard Ratio; ICD - Implantable cardioverter defibrillator; RV - Right ventricle.

280 A. Martin et al. Antiarrhythmic Medical Therapy Antiarrhythmic medical therapy was prescribed to 21 of the 26 patients that received an ICD (81%) at the time of device implantation (Tables 2, 3). Thirteen of these 21 (62%) received appropriate ICD therapy during follow-up. Of the 13 patients that did not receive appropriate ICD therapy, eight were prescribed antiarrhythmic medical therapy at the time of device implantation. There were five patients who received an ICD, not prescribed antiarrhythmic medical therapy, and did not receive appropriate ICD therapy during follow-up. The indication for ICD implantation in these five were: one with a history of symptomatic ventricular tachyarrhythmia; one with syncope; and includes all three asymptomatic patients in whom the diagnosis of ARVC was made following cascade evaluation of a family member proband who had experienced SCD. Of the four patients that did not receive an ICD, three of these were prescribed antiarrhythmic medication at the time they were diagnosed with ARVC (one each receiving Sotalol, Amiodarone, and Flecainide). Discussion This study reports the outcomes of 30 previously unpublished patients from the New Zealand Registry with ARVC, 26 of whom had ICDs implanted during follow-up. These results provide insight into the long-term clinical course of patients diagnosed and managed in our region, including our indigenous Maori population. This report complements existing data regarding the important role of ICD therapy in the treatment of ventricular tachyarrhythmia in those with ARVC. Major Findings This study has four main findings. First, during long-term follow-up, those with ICDs have a high incidence of appropriate therapy, with 50% experiencing appropriate therapy within four years of device implantation. These patients have a low incidence of inappropriate shock therapy, and no disease specific mortality was seen in those with an ICD in situ. Second, no asymptomatic patient experienced appropriate ICD therapy where ICD implantation was performed solely due to a family history of SCD due to ARVC. Third, male gender was independently associated with a higher incidence of appropriate ICD therapy. Finally, there was no significant difference between Maori and non-maori in terms of clinical characteristics or rate of ICD therapy (both appropriate and inappropriate), although the numbers are small for such a comparison at this stage. Comparison with Prior Studies Arrhythmogenic right ventricular cardiomyopathy/dysplasia is a rare condition, and for this reason all previous studies have been limited by small patient cohorts and relatively short follow-up durations. For these same reasons no prospective randomised data exists regarding the management of these patients. Our cohort of 30 patients, while small, is the first describing those from Australasia and provides the longest published follow-up data regarding clinical events including ventricular tachyarrhythmia and death (median follow-up 7.4 years). Previously, the cohort with the longest follow-up data was published by Wichter et al. in 2004 describing 60 patients from a single institution who were followed for a mean of 6.7 years [5]. The largest multicentre series was published by Corrado et al. in 2003 reports on 132 patients from 23 institutions with a mean follow-up time of 3.3 years [12], with a subsequent report from the same group in 2010 detailing the clinical outcomes of 106 patients from six centres who had an ICD implanted in a prophylactic fashion with a mean follow-up of 4.8 years. Bhonsale et al. have published the largest single centre series in 2011 consisting of 84 patients with a mean follow-up of 4.7 years [16] The annual incidence of appropriate ICD therapy in our study is similar to previous reports [8,14,15]. We did not identify syncope as a risk factor for appropriate ICD therapy in our study, as only three patients had syncope prior to ICD implantation. We noted male gender as an independent risk factor for appropriate ICD therapy, as found by Hodgkinson et al. [13] However in the larger cohorts described by Bhonsale et al. and Corrado et al. this was not the case [15,16]. Our findings support the general consensus that patients with ARVC managed with an ICD do well despite most receiving appropriate therapy. No patient in our study received appropriate ICD device therapy when an ICD was implanted solely because of a family history of SCD. Two prospective series of patient cohorts from the northern hemisphere described by Bhonsale et al. and Corrado et al. have demonstrated similar findings with very low rates of appropriate ICD therapy in this specific subgroup [15,16]. The consistency of these data across different populations suggest that ICD device implantation may not be warranted in these particular patients. Study Limitations The patient cohort is small and although patients were enrolled prospectively some data were collected retrospectively. Conclusions Patients with ARVC receiving ICDs have high rates of appropriate therapy during follow-up and male gender is an independent risk factor. During a median follow-up of 7.4 years no patient who received an ICD died. Our data supports previous work suggesting ICD therapy may not be warranted in all asymptomatic patients with a family history of SCD, although larger studies are needed to further evaluate this hypothesis and other risk factors associated with SCD. Disclosures The authors have no disclosures to declare.

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