Overview of Arrhythmias and ECG Changes in ARVC
Claire Kirkby (Inherited Arrhythmia Nurse Specialist, Barts Health)
Charlotte Aldridge (Arrhythmia Nurse Specialist, Barts Health)
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a genetic disease of the myocardium predominantly affecting the Right Ventricle (RV) (1, 2). Fibrofatty infiltration of the heart muscle creates repolarisation/depolarisation defects and structural changes predisposing sufferers to potentially life threatening ventricular arrhythmias and heart failure. ARVC, as the name suggests, has traditionally been regarded as a disease primarily of the RV; only affecting the LV at the later stages of the disease as biventricular failure presents. Involvement of the LV is now known to occur much earlier in the disease progression and can occur in isolation. This has lead to a shift towards re-terming this disorder as simply Arrhythmogenic Cardiomyopathy (AC). Pathological changes that present in ARVC are typically described in 4 stages;
• Myocycte loss due to cell apoptosis and necrosis (3)
• Fatty scar forming from the epicardium to endocardium
• RV (and/or LV) wall thinning and chamber dilation
• Aneurysm formation
These changes will ultimately culminate in RV and/or LV dysfunction and may precipitate ventricular arrhythmias (4). In the early stages of the disease process it was believed that any structural changes would be restricted to a region of the RV termed the ‘triangle of dysplasia’ i.e. the inflow tract, outflow tract and apex; these areas were considered particularly vulnerable to aneurysm formation (5, 6).
ARVC is perceived as a disease of the cardiac desmosome as the majority of documented genetic mutations encode for the proteins that form these intercellular electrical and mechanical connections between myocytes. Genetic inheritance of the disease usually follows an autosomal dominant pattern with the exception of the recessively inherited Naxos disease and Carvajal syndrome (6). The broad spectrum of genetic mutations that can cause ARVC means that phenotypic expression is variable. Penetrance of the disease is also variable; an individual may have the genetic mutation but never develop the disease.
Clinical manifestations of ARVC typically do not appear until the 2nd to 4th decade despite the genetic mutation being present from birth (7) but can potentially present from the 1st to 8th decade (5). Symptoms associated with ARVC include palpitations, chest pain, syncope and presyncope, but can vary according to the patient’s age and the stage of disease progression, (3). In the earlier stages of the disease structural changes may be minimal (3) and the patient asymptomatic, but despite this they still remain at risk of sudden cardiac death (SCD), especially during exercise. Tragically, cardiac arrest may be the first sign of the disease. ARVC has been found to account for unexplained SCD in 10% of young people (8) and 11-22 % of young athletes (1).
Establishing a definitive diagnosis of the ARVC is incredibly challenging for clinicians as the disease can remain concealed, symptoms are non-specific in nature and no single test alone can confirm presence of the disease (2). The priority for diagnosis is early detection of the condition and screening for the relatives of ARVC sufferers. In 1994 the Task force of the European society of Cardiology, Scientific Council on Cardiomyopathies of the International Society and the Federation of Cardiology created a set of criteria for ARVC diagnosis based on medical history, morphological / structural / functional changes, ECG findings, arrhythmias and family history of SCD (2). Whilst these criteria were considered highly specific for ARVC, they lacked the sensitivity required for early detection or family screening and were based on qualitative rather than quantitative data (9). Significant advances in technology, particularly cardiac imaging, and genetics since then are now reflected in the revised 2010 Task Force Criteria (TFC). This comprehensive list of criterion encompasses a range of diagnostic parameters, adopting a quantitative approach, enabling diagnosis to make when only subtle signs of the disease are present and facilitating diagnosis through family screening. Confirmation of ARVC can be confirmed on the basis of 2 major criterions, 1 major and 2 minor or 4 minor criterion.
Arrhythmia in ARVC
Myocardial electrical instability in ARVC can initiate a range of arrhythmias from ventricular extrasystoles to non-sustained or sustained (>30 seconds in duration) VT and ventricular fibrillation (VF) causing SCD (10). The most frequently seen arrhythmia in ARVC is non-sustained or sustained monomorphic ventricular tachycardia (VT) originating from the RV, giving rise to a left bundle branch block (LBBB) morphology (1) with a superior axis (if originating from the apex), and is classified as a major TFC ( Figure1) (3).
Figure 1: Ventricular Tachycardia in a patient with ARVC
In one study, VT with a LBBB morphology was observed in 79% of patients with ARVC and was the first arrhythmia experienced in 39% of this group (11). If the LV is involved, VT can originate from the LV and a right bundle branch morphology will be present (1). VT can also originate from the RVOT and appears with a LBBB and inferior axis but is only listed as minor criteria as idiopathic benign VT commonly arises from this area. Both the benign form of RVOT VT and that resulting from ARVC are seen in young people, present similarly and are often triggered by exercise. It is essential to distinguish between both forms of VT to avoid a false diagnosis of ARVC and ensure appropriate treatment. For example, RVOT VT is more amenable to catheter ablation as its underlying mechanism is one of triggered activity in a focal area (12).
The mechanism of ventricular arrhythmia (VA) in ARVC is commonly scar- related macro re-entry; Fibro-fatty replacement of the myocardium provides the ideal substrate for re-entrant pathways to form (13). Alternatively, triggered activity as, a consequence of Ca++ overload, has been reported in a small percentage of ARVC sufferers who have a genetic mutation in the Ryanodine Receptor and results in VA’s secondary to early or delayed after depolarisations (14, 15).
VT will often present during exercise as enhancement of the sympathetic nervous system triggers premature beats and re-entrant pathways (1).
Frequent ventricular ectopics can be observed in nearly a quarter of all ARVC patients, presence of more than 500 during Holter monitoring is classified as a minor criterion in the TFC (3) and unlike non sustained or sustained VT, are not linked with higher rate of mortality (10,11).
Due to fibro-fatty replacement of the RV free-wall, depolarization takes longer which is observed by the presence of epsilon waves and terminal activation delay (TAD) on the ECG and a positive signal-averaged ECG (SAECG).
An epsilon wave (arrow Figure 2) is a low-amplitude signal between the end of the QRS and beginning of the T wave . It is the most specific characteristic of ARVC  but lacks sensitivity and is generally seen later in the disease course since its presence is associated with a greater degree of RV involvement . It is only observed in between 9-32% of patients with ARVC [19, 20, and 21].
Figure 2: Epsilon Waves on an ECG and Diagram
The SAECG is a form of high-resolution electrocardiography, specially adapted to detect small electrical potentials at the end of the QRS complex (late potentials) and localized conduction delay which are difficult to detect using standard ECG techniques. In the diagnosis of ARVC, the TFC require just 1 of the 3 markers to be positive . In this context, the SAECG has a sensitivity of 69% and specificity of 92%. Interestingly, if all 3 of the markers are positive specificity increases to 100%, but sensitivity drops to 33% . The SAECG cannot help predict ventricular arrhythmias (VAs) in ARVC .
Terminal Activation Delay
TAD is measured from the nadir of the S wave to the end of the QRS complex; this is positive when it exceeds 55ms  (Figure 3) and reflects delayed depolarization. Terminal activation delay develops early in the disease process , occurring in 90% of ARVC patients with mild or localized disease and in 95% of patients with moderate and severe ARVC, whereas it only occurs in 7% of patients with right ventricular outflow tract ventricular tachycardia and 2% of controls .
Figure 3 – Terminal Activation Delay on an ECG and Diagram
T wave inversion (TWI) in V1 is a normal variant on a 12-lead ECG. TWI beyond V1 (V1-V3) is also seen in many healthy individuals, most notably in children under the age of 12 years, athletes, Afro-Caribbean’s and women . TWI is a sensitive marker for ARVC which develops early in the condition and, if present in V1-V3 assigns the patient a major point, or a minor point if it only spreads to V2. The TFC team stated that although TWI is seen in ~6% of the healthy population, it is a “reasonably” specific marker for ARVC .
In the literature the prevalence of TWI V1-V3 ranges from 40-85% in ARVC [26, 19, 20, 21, and 11]. TWI is associated with disease progression and can also be dynamic in 12% of patients . TWI V1-V3 is normally the second most common ECG abnormality in ARVC, behind TAD [19, 20]. In cases where ARVC primarily affects the LV, TWI presents in left precordial leads, V4, V5 and V6 .
Management is largely based on preventing SCD caused by VAs and reducing the risk of heart failure (HF). SCD due to VAs can occur at any point in the disease course. HF is primarily caused by myocardial loss and therefore cannot be controlled, but rate-related heart failure due to recurrent VAs can generally be avoided . Due to the wide clinical presentation and varied disease course, management should be individualised to the patient .
Current NICE guidelines recommend that ICD’s can be a treatment option for people with familial conditions such as ARVC. Several factors require the consideration of an ICD - these are: involvement of the left ventricle, bi-ventricular dysfunction with clinical signs of HF, previous cardiac arrest, VT with haemodynamic compromise, VF and syncope. The British Heart Rhythm Society recommends an ICD in patients who have ventricular fibrillation, a cardiac arrest or poorly tolerated VT. An ICD should be considered in those with ventricular arrhythmias and severe structural disease. They state that the benefits of an ICD in asymptomatic patients may not outweigh the risks. Of the patients with an ICD inserted 48-78% had an appropriate ICD therapy. Fourteen percent of ARVC patients had an ICD-related complication and 16-33% had inappropriate shocks [30, 31]. VT-stimulated during invasive electrophysiological studies has variable ability at predicting appropriate ICD therapy and therefore has limited practical value [11, 30, 32, 33, 34, 35, and 36].
Anti-arrhythmic drugs that help to control recurrent VAs include amiodarone, sotalol and beta-blockers. An ablation for VAs is of limited use in ARVC due to the progressive nature of the condition. However, in circumstances of symptomatic, drug-resistant VAs, an ablation may help .
Patients with ARVC are advised to restrict exercise to “mild” or “moderate” . It has been suggested that exercise increases the mechanical force on the heart and causes the weakened desmosome to breakdown causing the RV enlargement and VAs [38,39]. Due to the genetic link of ARVC, screening should be offered to all first-degree relatives.
1. Romero J, Mejia-Lopez E, Manrique C and Lucariello R. Arrthymogenic Right Ventricular Cardiomyopathy (ARVC/D): A systematic literature review. Clinical Medicine Insights: Cardiology. 2013; 7: 97-114
2. Vermes E, Strohm O, Otmani A, Childs H, Duff Hand Friedrich MG. Impact of Revision of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Task Force Criteria on its prevalence by CMR criteria. Journal of American College of Cardiology.2011;4(3):282-287
3. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MGPJ, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Saffitz JE, Yoerger Sanborn DM, Steinberg JS, Tandri H, Thiene G, Towbin JA, Tsatsopoulou A, Wichter T and Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation. 2010;121(13):1533-1541
4. Basso C, Corrado D, Marcus FI, Nava A and Thiene G. Arrhythmogenic Right Ventricular Cardiomyopathy. Lancet. 2009;373:1289-300
5. Femia G, Hsu C, Singarayar S, Sy Ra, Kilborn M, Parker G, McGuire M, Semsarian C and Puranik R. Impact of new task force criteria in the diagnosis of arrthythmogenic right ventricular cardiomyopathy. International Journal of Cardiology. 2014;171: 179-183
6. Chellamuthu S, Smith AM, Thomas SM, Hill C, Brown PWG, and Al-Mohammed A. Is cardiac MRI an effective test for arrhythmogenic right ventricular cardiomyopathy diagnosis? World Journal of Cardiology.2014:6(7):675-681
7. Nava A, Bauce B, Basso C, Muriago M, Rampazzo A, Villanova C, Daliento L, Buja G, Corrado D, Danieli GA and Thiene G. Clinical profile and long-term follow-up of 37 families with arrhythmogenic right ventricular cardiomyopathy. Journal of the American College of Cardiology. 2000;36(7):2226-2233
8. Tabib A, Loire R, Chalabreysse L, Meyronnet D, Miras A, Malicier D, Thivolet F, Chevalier P and Bouvagnet P. Circumstances of death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and/or dysplasia. Circulation. 2003; 108(24):3000-3005.
9. Sen-Chowdhry S, Lowe MD, Sporton SC and McKenna WJ. Arrhythmogenic right ventricular cardiomyopathy: clinical presentation, diagnosis, and management. The American Journal of Medicine. 2004; 117(9):685-695.
10. Ainsworth CD, Skanes AC, Klein GJ, Gula LJ, Yee R and Krahn AD. Differentiating arrhythmogenic right ventricular cardiomyopathy from right ventricular outflow tract ventricular tachycardia using multi-lead QRS duration and axis. Heart Rhythm. 2006; 3(4):416-423.
11. Hulot JS, Jouven X, Empana JP, Frank R and Fontaine G. Natural history and risk stratification of arrhythmogenic right ventricular dysplasia/ cardiomyopathy. Circulation. 2004; 110(14):1879-1884).
12. O'Donnell D, Cox D, Bourke J, Mitchell L and Furniss S. Clinical and electrophysiological differences between patients with arrhythmogenic right ventricular dysplasia and right ventricular outflow tract tachycardia. European Heart Journal. 2003; 24(9):801-810.
13. Arbelo E and Josephson ME. Ablation of ventricular arrhythmias in arrhythmogenic right ventricular dysplasia: clinical reviews. Journal of Cardiovascular Electrophysiology. 2010;21(4):473-486
14. Kannankeril PJ, Mitchell BM, Goonasekera SA, Chelu MG, Zhang W, Sood S, Kearney DL, Danila CI, De Biasi M, Wehrens XHT, Pautler RG, Roden DM, Taffet GE, Dirksen RT, Anderson ME and Hamilton SL. Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy. Proceedings of the National Academy of the Sciences of the United States of America. 2006; 103(32):12179-12184.
15. George CH, Higgs GV and Lai FA. Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes. Circulation Research. 2003; 93(6):531-540).
16. Peters S and Trummel M. Diagnosis of arrhythmogenic right ventricular dysplasia-cardiomyopathy: value of standard ECG revisited. Annals of Non-invasive Electrocardiology. 2003; 8(3):238-245.
17. You CC, TsengYT and Hsieh MH. An epsilon wave in arrhythmogenic right ventricular cardiomyopathy/dysplasia. International Journal of Cardiology. 2007;119(2):e63-e64
18. Marcus FI and Zareba W. The electrocardiogram in right ventricular cardiomyopathy/dysplasia. How can the electrocardiogram assist in understanding the pathologic and functional changes of the heart in this disease? Journal of Electrocardiology. 2009; 42(2):136.e1-136.e5.
19. Piccini JP, Nasir K, Bomma C, Tandri H, Dalal D, Tichnell C, James C, Crosson J and Calkins H. Electrocardiographic findings over time in arrhythmogenic right ventricular dysplasia/cardiomyopathy. American Journal of Cardiology. 2005; 96(1):122-126.
20. Nasir K, Bomma C, Tandri H, Roguin A, Dalal D, Prakasa K, Tichnell C, James C, Jspevak P, Marcus F and Calkins H. Electrocardiographic features of arrhythmogenic right ventricular dysplasia/cardiomyopathy according to disease severity: A need to broaden diagnostic criteria. Circulation. 2004; 110(12):1527-1534.
21. Peters S, Trummel M, Koehler B and Westermann KU. The value of different electrocardiographic depolarization criteria in the diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Journal of Electrocardiology. 2007; 40(1):34-37.
22. Kamath GS, Zareba W, Delaney J, Koneru JN, McKenna W, Gear K, Polonsky S, Sherrill D, Bluemke D, Marcus F and Steinberg JS. Value of the signal-averaged electrocardiogram in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm. 2011; 8(2):256-262.
23. Cox MGPJ, Van Der Smagt JJ, Wilde AAM, Wiesfeld ACP, Atsma DE, Nelen MR, Rodriguez L-M, Loh P, Cramer MJ, Doevendans PA, Van Tintelen JP, De Bakker JMT and Hauer RNW. New ECG criteria in arrhythmogenic right ventricular dysplasia/ cardiomyopathy. Circulation: Arrhythmia and Electrophysiology. 2009; 2(5):524-530.
24. 24, Marcus FI. Prevalence of T-wave inversion beyond V1 in young normal individuals and usefulness for the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia. American Journal of Cardiology. 2005; 95(9):1070-1071.
25. McKenna WJ, Thiene G, Nava A, Fontaliran F, Blomstrom-Lundqvist C, Fontaine G and Camerini F, on behalf of the Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology, supported by the Schoepfer Association. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. British Heart Journal. 1994; 71:215-218.
26. Quarta G, Ward D, Tome Esteban MT, Pantazis A, Elliott PM, Volpe M, Autore C and McKenna WJ. Dynamic electrocardiographic changes in patients with arrhythmogenic right ventricular cardiomyopathy. Heart. 2010; 96(7):516-522.
27. Sen-Chowdhry S, Syrris P, Prasad SK, Hughes SE, Merrifield R, Ward D, Pennell DJ and McKenna WJ. Left-dominant arrhythmogenic cardiomyopathy: an under-recognized clinical entity. Journal of the American College of Cardiology. 2008; 52(25):2175-2187.
28. Nasir K, Tandri H, Rutberg J, Tichnell C, Spevak P, Crossan J, Baughman KL, Kasper EK, Tomaselli GF, Berger R and Calkins H. Filtered QRS duration on signal-averaged electrocardiography predicts inducibility of ventricular tachycardia in arrhythmogenic right ventricle dysplasia. Pacing and Clinical Electrophysiology. 2003; 26(10):1955-1960.
29. Arbelo E and Josephson ME. Ablation of ventricular arrhythmias in arrhythmogenic right ventricular dysplasia: clinical reviews. Journal of Cardiovascular Electrophysiology. 2010; 21(4):473-486.
30. Corrado D, Leoni L, Link MS, Della Bella P, 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 III NAM, Buja G and Thiene G. Implantable cardioverter-defibrillator therapy for prevention of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation. 2003; 108(25):3084-3091.
31. 31.Tavernier R, Gevaert S, De Sutter J, De Clercq A, Rottiers H, Jordaens L and Fonteyne W. Long term results of cardioverter-defibrillator implantation in patients with right ventricular dysplasia and malignant ventricular tachyarrhythmias. Heart. 2001; 85(1):53-56.
32. Buja G, Estes IIINAM, Wichter T, Corrado D, Marcus F and Thiene G. Arrhythmogenic right ventricular cardiomyopathy/dysplasia: risk Stratification and therapy. Progress in Cardiovascular Diseases. 2008; 50 (4):282-293.
33. Lemola K, Brunckhorst C, Helfenstein U, Oechslin E, Jenni R and Duru F. Predictors of adverse outcome in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy: long term experience of a tertiary care centre.Heart. 2005; 91(9):1167-1172.
34. Roguin A, Bomma CS, Nasir K, Tandri H, Tichnell C, James C, Rutberg J, Crosson J, Spevak PJ, Berger RD, Halperin HR and Calkins H. Implantable cardioverter-defibrillators in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Journal of the American College of Cardiology. 2004; 43(10):1843-1852.
35. Wichter T, Paul M, Wollmann C, Acil T, Gerdes P, Ashraf O, Tjan T, Soeparwata R, Block, Borggrefe M, Scheld HH, Breithardt G and Böcker D. Implantable cardioverter/defibrillator therapy in arrhythmogenic right ventricular cardiomyopathy single-centre experience of long-term follow-up and complications in 60 patients. Circulation.2004; 109:1503-1508.
36. Garrett CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, O’Callaghan P, Stuart G and Watkins H. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with familial sudden cardiac death syndromes. Europace. 2010.12; 1156-1175.
37. Maron BJ, Chaitman BR, Ackerman MJ, De Luna AB, Corrado D, Crosson JE, Deal BJ, Driscoll DJ, Estes III NAM, Araujo CGS, Liang DH, Mitten MJ, Myerburg RJ, Pelliccia A, Thompson PD, Towbin JA and Van Camp SP. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation. 2004; 109(22):2807-2816.
38. Kirchhof P, Fabritz L, Zwiener M, Witt H, Schafers M, Zellerhoff S, Paul M, Athai T, Hiller K-H, Baba HA, Breithardt G, Ruiz P, Wichter T and Levkau B. Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice. Circulation. 2006; 114(17):1799-1806.
39. Heidbuchel H, Hoogsteen J, Fagard R, Vanhees L, Ector H, Willems R and Van Lierde J. High prevalence of right ventricular involvement in endurance athletes with ventricular arrhythmias: Role of an electrophysiologic study in risk stratification. European Heart Journal. 2003; 24(16):1473-1480.
Click here to download the editorial as a PDF file.