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Long-term clinical outcome of arrhythmogenic right ventricular cardiomyopathy in individuals with a p.s358l mutation in tmem43 following implantable cardioverter defibrillator therapy

Paper commented by the Working Group on Myocardial and Pericardial Diseases

Myocardial Disease

Authors: Hodgkinson KA, Howes AJ, Boland P, Shen XS, Stuckless S, Young TL, Curtis F, Collier A, Parfrey PS, Connors SP.

Circ Arrhythm Electrophysiol. 2016 Mar; 9(3) - pii: e003589. doi: 10.1161/CIRCEP.115.003589

Commented by: Fernando Dominguez and Pablo Garcia-Pavia

Heart Failure and inherited cardiac Disease Unit
Hospital Universitario Puerta de Hierro, Madrid, Spain


The genetic subtype of arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by the p.S358L mutation in TMEM43 presents a complete penetrance and is modified by sex, as the median age of death in untreated males is 40 years and 67 years in untreated females, due primarily to sustained ventricular arrhythmias. Implantable cardioverter defibrillator (ICD) treatment based on genotype alone provides a significant survival advantage, so primary prophylaxis is indicated.

In the paper by Hodgkinson, et al, the authors present long-term data (median follow-up 8.5 years) after implantable cardioverter defibrillator (ICD) for primary and secondary prophylaxis in males and females with ARVC caused by the p.S358L mutation in TMEM43.


To determine whether ICD discharges for ventricular tachycardia/ventricular fibrillation are equivalent to an aborted death, and assess relevant clinical predictors.


The authors prospectively studied 24 multiplex families segregating an autosomal dominant p.S358L mutation in TMEM43. They compared survival in 148 mutation carriers with an ICD to 148 controls matched for age, sex, disease status, and family.

Serial retrospective clinical data on all individuals were obtained where available (including clinical events, cardiac and genetic testing).


Of 80 male mutation carriers with ICDs (median age at implantation 31 years), 61 (76%) were for primary prophylaxis; of 68 females (median age at implantation 43 years), 66 (97%) were for primary prophylaxis. In males, irrespective of indication, survival was better in the ICD group compared with control group (relative risk 9.3 [95% confidence interval 3.3–26] for primary prevention and 9.7 [95% confidence interval 3.2–29.6] for secondary prophylaxis). For primary prophylaxis females, the relative risk was 3.6 (95% confidence interval 1.3–9.5). ICD discharge-free survival for ventricular tachycardia/ventricular fibrillation ≥ 240 beats per minute was equivalent to the control survival rate. Ectopy (≥ 1000 premature ventricular complexes/24 hours) was the only independent clinical predictor of ICD discharge in males, and no predictor was identified in females.


The authors conclude that ICD therapy is indicated for primary prophylaxis in postpubertal males and in females ≥ 30 years with the p.S358L TMEM43 mutation. Furthermore, they state that ICD termination of rapid ventricular tachycardia/ ventricular fibrillation can reasonably be considered as an aborted death.


ARVC-5 is a rare form of ARVC caused by a missense mutation within the gene of transmembrane protein 43 (TMEM43) on chromosome 3p25. It was first described in 2005 in 15 families from the island of Newfoundland, Canada (1,2). The same p.S358L founder mutation was later identified in families from Germany, Denmark and USA (3), suggesting a common ancestor.

ARVC-5 is a fully penetrant and sex influenced disease. Male subjects present heart failure and SCD at a younger age than females, and symptom onset is closely followed by death (2). In this context, a previous study from the same group showed that ICD therapy for primary prophylaxis based on genotype offers a survival benefit in male ARVC-5 patients (4).

The present study by Hodgkinson et al aims to answer several questions (5). First of all, whether the survival benefit previously described in males persists with a longer follow up. The answer is yes, as males benefit from ICD therapy compared to controls irrespective of the indication (primary or secondary prophylaxis). In addition, the authors intend to figure out if ICD therapy for primary and secondary prophylaxis is equally beneficial for males and females. In this case, even though males present a substantial survival benefit whatever the indication of ICD (RR of death with no ICD 9.3 and 9.7 for primary and secondary prophylaxis, respectively), females still present a significant benefit from primary prophylaxis ICD implantation (RR 3.6 95% CI 1.3-9.5). Thirdly, Hodgkinson et al wonder whether a shock due to VT or VF equals an aborted cardiac death in this disease. Although this a complex question to answer, the authors are convincing with their argument, as ICD discharge-free survival for VT/VF greater than 240 beats per minute was equivalent to the control survival rate. Hence, appropriate discharge of the ICD for ventricular arrhythmias > 240 bpm may be comparable to SCD. Finally, the authors investigate clinical test predictors of appropriate ICD discharges in order to elucidate pre-implantation risk factors. Although there was an association of left ventricular function, ECG poor R wave progression and <29 years of age at implant for ICD shocks in the univariate analysis, the only independent and significant predictor was > 1000 premature ventricular contractions (PVC) in 24h in male patients. Taking into account the high risk of SCD in ARVC5, ICD implantation for primary prophylaxis is usually based on genotype alone in postpuberal males, but prepuberal males could benefit from 24h ECG holter in order to stratify risk based on these results. Regarding females, it is usually safe to wait to the late twenties/early thirties, as events tend to occur later (median life expectancy of 71 years) (1).

The last SCD ESC guidelines (6) contemplate ICD for primary prevention in selected high-risk ARVC patients after assessing family history, severity of RV and LV function, lifelong risk of complications and impact of an ICD on lifestyle, socioeconomic status and psychological health. As it has been proved in this article, ARVC 5 patients clearly benefit from primary prevention ICD based on genotype findings. Furthermore, we should not only rely on guidelines, as ARVC 5 predominantly affects the left ventricle and some patients do not even meet ARVC diagnostic criteria according to the 2010 ARVC Task Force Criteria (7).

To sum up, a prompt diagnosis is basic in ARVC 5 in order to decide ICD implantation and modify the course of disease. Both genetic testing detecting a TMEM34 mutation and a high index of clinical suspicion are of utmost importance for this purpose.


  1. Merner ND, Hodgkinson KA, Haywood AF, Connors S, French VM, Drenckhahn JD, Kupprion C, Ramadanova K, Thierfelder L, McKenna W, Gallagher B, Morris-Larkin L, Bassett AS, Parfrey PS, Young TL. ND, Hodgkinson KA, Haywood A et al. Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Is a Fully Penetrant, Lethal Arrhythmic Disorder Caused by a Missense Mutation in the TMEM43 Gene. Am J HumGenet. 2008;82 :809–21.
  2. Hodgkinson KA, Connors SP, Merner N ,Haywood A, Young TL, McKenna W, Gallagher B, Curtis F, Bassett A, Parfrey P. The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43. Clin Genet. 2013;83:321–31
  3. Milting H, Klauke B, Christensen AH, Musebeck J, Walhorn V, Grannemann S, Munnich T, Saric T, Rasmussen TB, Jensen HK, Mogensen J, Baecker C, Romaker E, Laser KT, zu Knyphausen E, Kassner A, Gummert J, Judge DP, Connors S, Hodgkinson K, Young TL, van der Zwaag PA, van Tintelen JP and Anselmetti D. The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus. Eur Heart J 2015;36:872-81.
  4. Hodgkinson KA, Parfrey PS, Bassett AS, Kupprion C, Drenckhahn J, Norman MW, Thierfelder L, Stuckless SN, Dicks EL, McKenna WJ, Connors SP. The impact of implantable cardioverter-defibrillator therapy on survival in autosomal-dominant arrhythmogenic right ventricular cardiomyopathy (ARVD5). J Am Coll Cardiol. 2005;45:400–408.
  5. Hodgkinson KA, Howes AJ, Boland P, Shen XS, Stuckless S, Young TL, Curtis F, Collier A, Parfrey PS and Connors SP. Long-Term Clinical Outcome of Arrhythmogenic Right Ventricular Cardiomyopathy in Individuals With a p.S358L Mutation in TMEM43 Following Implantable Cardioverter Defibrillator Therapy. Circulation Arrhythmia and electrophysiology. 2016;9.
  6. Authors/Task Force M, Priori SG, Blomstrom-Lundqvist C et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015.
  7. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Saffitz JE, Sanborn DM, Steinberg JS, Tandri H, Thiene G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/ dysplasia: proposed modification of the Task Force Criteria. Eur Heart J. 2010;31:806–814. doi: 10.1093/eurheartj/ehq025
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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