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Q1: Definition, genetics and mechanism (3 min)
Q1a. Define arrhythmogenic cardiomyopathy in one line and contrast the umbrella term ACM with ARVC.[1]
Q1b. Which gene is most commonly mutated in autosomal-dominant disease? Name the eponymous recessive syndromes and their genes.[9]
Q1c. Explain the "wounded healer" hypothesis: how does a desmosomal mutation produce fibro-fatty replacement and the characteristic arrhythmia?[6]
Expected: PKP2 — the only gene in the ESC "very common" tier, over 10% of tested cases (19% of probands in Xu's series); Naxos = JUP recessive (woolly hair + palmoplantar keratoderma + ARVC, 100% penetrant by adolescence); Carvajal = DSP recessive (predominantly left ventricular, manifesting in childhood); plakoglobin relocates from desmosome to nucleus, suppresses Wnt/beta-catenin and activates Hippo-YAP, diverting cardiac progenitors to adipogenesis; RV preferentially affected due to thin wall and high wall stress; surviving myocyte strands conduct slowly producing epsilon wave and re-entrant LBBB-superior-axis VT.[4][9][10]
Q2: Diagnosis and investigations (4 min)
Q2a. A young athlete has T-wave inversion V1-V3 without RBBB and a small terminal deflection in V1-V3. What is the ECG diagnosis and what is the named deflection?[1]
Q2b. Reproduce the 2010 Modified Task Force Criteria — the six categories and the diagnostic combinations for definite, borderline, and possible ACM.[1]
Q2c. How do the Padua 2020 criteria differ from the 2010 Task Force criteria for imaging and for the epsilon wave?[3]
Q2d. Distinguish idiopathic RVOT VT from ARVC VT using axis, QRS morphology and response to adenosine.[1]
Expected: epsilon wave; six TFC categories (imaging, biopsy, repolarisation, depolarisation, arrhythmia, family); definite = 2 major / 1 major + 2 minor / 4 minor from different categories, borderline = 1 major + 1 minor / 3 minor, possible = 1 major / 2 minor; 2010 TFC CMR major = regional RV akinesia, dyskinesia or dyssynchrony PLUS either RVEDV/BSA ≥ 110 mL/m2 (M) or ≥ 100 (F) OR RVEF ≤ 40%; Padua keeps that structure but judges dilatation and systolic dysfunction against imaging-, age- and sex-specific nomograms, adds contrast-enhanced CMR tissue characterisation plus a parallel set of LV criteria, and demotes the epsilon wave from major to minor; RVOT VT = inferior axis + smooth QRS + adenosine-sensitive; ARVC VT = superior axis + notched QRS + scar on CMR.[1][3][4]
Q3: Management (3 min)
Q3a. A patient with definite ARVC and sustained VT attends your clinic. What is the first-line drug class, a named agent with its dose, and what does the registry evidence say about sotalol?[2]
Q3b. List the ESC Class I indications for ICD in ACM. In which genotypes should an ICD be considered despite LVEF above 35%?[2]
Q3c. What is the role of catheter ablation, and why is an ICD still needed after successful ablation?[4]
Expected: beta-blockers are first-line in symptomatic patients — the AHA/ACC names atenolol 25-100 mg orally once or twice daily; amiodarone or sotalol are add-ons for arrhythmic symptoms or to reduce ICD shocks, and the North American ARVC Registry found neither beta-blockers nor sotalol protective, with amiodarone superior in a small subgroup; Class I ICD = survivors of cardiac arrest and ventricular arrhythmia causing haemodynamic instability, while haemodynamically tolerated sustained VT is Class IIa; LMNA, TMEM43, truncating FLNC, PLN, DSP and RBM20 are the high-risk genotypes in which an ICD is considered above LVEF 35% — IIa with additional risk factors, IIb without; ablation reduces the arrhythmia burden but does NOT replace the device because the substrate progresses — ablation without a back-up ICD is only a IIb option in selected patients with tolerated VT.[2][4][5]
Q4: Lifestyle, family and prognosis (2 min)
Q4a. What lifestyle advice is mandatory at diagnosis?[4]
Q4b. How do you screen the first-degree relatives of a confirmed proband, and at what age do you start?[4]
Q4c. How do you express prognosis in ACM, and what factors predict adverse outcome?[6]
Expected: moderate- and high-intensity exercise including competitive sport is not recommended (ESC Class III), regular low-to-moderate activity is encouraged (Class I), and genotype-positive phenotype-negative relatives should avoid high-intensity exercise (Class IIb); cascade-screen first-degree relatives with 12-lead ECG, ambulatory ECG and cardiac imaging from about age 10-12, repeated every 1-3 years, plus genetic cascade once the pathogenic variant is identified — a relative negative for the familial variant can be discharged; prognosis is a risk category, not one number — high risk above 10% arrhythmic events per year (Class I ICD), intermediate 1-10%, low under 1%, with reported overall mortality of 0.08-3.6% per year across series; adverse predictors — prior cardiac arrest or sustained VT, arrhythmic syncope, severe RV or LV dysfunction, high 24-h PVC count, NSVT, number of leads with T-wave inversion, younger age, male sex, high-risk genotype.[4][6][7][8]
References10ShowHide
- [1]Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria Circulation, 2010.PMID 20172911
- [2]Zeppenfeld K, Tfelt-Hansen J, de Riva M, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death Eur Heart J, 2022.PMID 36017572
- [3]Corrado D, Perazzolo Marra M, Zorzi A, et al. Diagnosis of arrhythmogenic cardiomyopathy: The Padua criteria Int J Cardiol, 2020.PMID 32561223
- [4]Iezzi L, Sorella A, Galanti K, et al. Arrhythmogenic cardiomyopathy diagnosis and management: a systematic review of clinical practice guidelines and recommendations with insights for future research Eur Heart J Qual Care Clin Outcomes, 2025.PMID 40386976
- [5]Marcus GM, Glidden DV, Polonsky B, et al. Efficacy of antiarrhythmic drugs in arrhythmogenic right ventricular cardiomyopathy: a report from the North American ARVC Registry J Am Coll Cardiol, 2009.PMID 19660690
- [6]Corrado D, Basso C, Judge DP Arrhythmogenic Cardiomyopathy Circ Res, 2017.PMID 28912183
- [7]Cadrin-Tourigny J, Bosman LP, Nozza A, et al. A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy Eur Heart J, 2019.PMID 30915475
- [8]Corrado D, Basso C, Rizzoli G, Schiavon M, Thiene G. Does sports activity enhance the risk of sudden death in adolescents and young adults? J Am Coll Cardiol, 2003.PMID 14662259
- [9]Protonotarios N, Tsatsopoulou A, Anastasakis A, et al. Genotype-phenotype assessment in autosomal recessive arrhythmogenic right ventricular cardiomyopathy (Naxos disease) caused by a deletion in plakoglobin J Am Coll Cardiol, 2001.PMID 11691526
- [10]Xu T, Yang Z, Vatta M, et al. Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy J Am Coll Cardiol, 2010.PMID 20152563