Aetiology

Monogenic (Mendelian): ~50–60%, mostly desmosomal (PKP2, DSP, DSG2, DSC2, JUP)^[1]

Acquired: not a cause; cardiac sarcoidosis and myocarditis mimic the phenotype and must be excluded^[9]

Complex (likely polygenic): ~40–50% gene-elusive, a proportion likely polygenic^[1]

Genetics

Inheritance: Autosomal dominant with incomplete penetrance (30–50% by age 50, male-predominant 3:1) and variable expressivity. Rare autosomal recessive forms (Naxos, Carvajal). Desmosomal gene defects account for ~50% of probands.

Genetic yield: ~50% with comprehensive panel testing. Pathogenic or likely pathogenic variant = major/minor criterion respectively. Caution: ~10% reduction in diagnostic yield if genetics excluded, prognosis not impacted (Corrado et al 2024)^[9]

Desmosomal genes (prototype ACM phenotype):

PKP2 (Plakophilin-2, 25–40%), Classic RV-dominant ARVC; male predominance; exercise accelerates disease progression; most common
DSP (Desmoplakin, ~10–15%), LV-dominant or biventricular (ALVC/ABVC); ring-like subepicardial LGE on CMR; high risk of SCD; "hot phase" myocarditis-like presentations
DSG2 (Desmoglein-2, 5–10%), ARVC and biventricular variants
DSC2 (Desmocollin-2, 2–5%), ARVC, biventricular
JUP (Plakoglobin), Recessive Naxos disease (woolly hair, palmoplantar keratoderma)
DSP recessive: Carvajal syndrome (hair/skin features, ALVC)

Non-desmosomal genes (genocopies):

TMEM43 (Transmembrane protein 43, the p.Ser358Leu founder variant), ARVC type 5; high penetrance in males; highly arrhythmogenic, with a substantial lifetime SCD risk in untreated male carriers in founder-population studies^[12]
PLN (Phospholamban p.Arg14del), ALVC/biventricular; very high penetrance (70–90%); 96% of carriers do NOT meet 2010 TF criteria at baseline
FLNC (Filamin C), ALVC/biventricular; ring-like LGE; often misclassified as DCM
LMNA (Lamin A/C), ALVC/biventricular; conduction disease; high arrhythmic risk; skeletal myopathy overlap
DES (Desmin), ALVC/biventricular; skeletal myofibrillar myopathy
SCN5A: Overlap ACM/channelopathy; right- and left-sided variants

Gene-level penetrance and risk figures derive largely from referral and founder-population cohorts and vary with variant class and ascertainment; treat them as indicative rather than fixed.

Phenocopies (non-genetic ACM, fulfil diagnostic criteria but non-genetic aetiology):

Post-viral myocarditis / chronic myocarditis (most common LV phenocopy)
Cardiac sarcoidosis (noncaseating granulomas on biopsy; FDG-PET useful)
Chagas disease (Trypanosoma cruzi)
Autoimmune disorders (SLE, polymyositis, scleroderma)
Neuromuscular diseases (Duchenne, Becker, myotonic dystrophy)

Identifying the specific aetiology is critical, prognosis, disease progression and SCD risk vary substantially by cause (Corrado et al 2024)^[9]

Genotype-Phenotype Correlations in ACM

PKP2 (most common):

Classic RV-dominant ARVC; male predominance 3:1
Exercise accelerates disease, desmosomal variants particularly affected
Flecainide may have particular advantage in PKP2 variants

DSP (10–15%):

LV-dominant or biventricular; ring-like LGE highly characteristic
"Hot phase" episodes, acute myocarditis-like presentations with chest pain, troponin rise, ECG changes; does NOT exclude genetic ACM
35% more patients reached definite ACM diagnosis using Padua vs 2010 TF criteria

Very High-Risk Genotypes:

TMEM43: Highly arrhythmogenic, with a high lifetime SCD risk in untreated male carriers in founder-population studies
PLN p.Arg14del: Arrhythmic cardiomyopathy phenotype; early ICD consideration
LMNA: High arrhythmic risk; conduction disease common; ICD often required

Exercise Guidance:

Endurance and high-intensity exercise accelerates disease and increases arrhythmic risk in desmosomal mutation carriers^[11]
AVOID competitive/endurance sports in diagnosed ACM
AVOID high-intensity exercise in gene carriers (even genotype+/phenotype–)
Low-intensity activity (e.g. light jogging, hiking, yoga) appears lower risk than endurance or high-intensity exercise, although the evidence is limited; discuss individually

Prevalence

1 in 2,000 to 1 in 5,000 individuals (Kreimer et al 2025^[8]); higher prevalence in certain regions (Italy, Greece)

Typically develops in the 2nd–4th decade of life; men are three times more commonly affected; ventricular arrhythmia occurs nearly twice as frequently in males as in females^[8]

Accounts for up to 20% of sudden cardiac deaths in young people and athletes

A meta-analysis found the annual risk of ventricular arrhythmias varies between 3.7% and 10.6% in affected individuals^[8]

Prognosis varies widely with genotype, phenotype, ventricular function, arrhythmia burden and exercise behaviour; with early diagnosis, risk stratification and appropriate treatment (including ICD where indicated), many patients have a good long-term outlook^[8]

Peak presentation age 20-40 years

Diagnostic Criteria

2024 European Task Force Criteria for ACM (Corrado et al, Int J Cardiol 2024)^[9]

A refinement of the 2020 Padua criteria, covering the full ACM spectrum: ARVC (right-dominant), ABVC (biventricular), and ALVC (left-dominant). Diagnosis requires at least one morpho-functional or structural criterion PLUS criteria from other categories.

Definite ACM requires: 2 major, OR 1 major + 2 minor, OR 4 minor criteria from different categories (RV or LV)

Category I, Morpho-functional abnormalities

RV major: Regional RV akinesia/dyskinesia/aneurysm + global RV dilatation (EDV >121 ml/m² men, >112 women) OR RV dysfunction (EF <52%)
RV minor: Regional RV wall motion abnormality alone
LV minor: Global LV systolic dysfunction ± LV dilatation (EDV >105 ml/m² men, >96 women)

Category II, Structural/tissue abnormalities (CMR or biopsy)

RV major: Fibrous replacement on biopsy (with or without fat)
RV minor: Unequivocal RV LGE on CMR (≥1 RV region, confirmed in 2 planes)
LV major: "Ring-like" LGE ≥3 Bull's Eye segments, subepicardial/midmyocardial (hallmark of ALVC, especially DSP/FLNC/PLN)
LV minor: LV LGE 1–2 segments, subepicardial/midmyocardial free wall or septum

Category III, Repolarization abnormalities

RV major: Inverted T waves V1–V3 (or beyond) in individuals ≥14 years (no RBBB, no J-point elevation)
RV minor: Inverted T waves V1–V2 in males ≥14 years
LV minor: Inverted T waves V4–V6 (no LBBB)

Category IV, Depolarization/conduction abnormalities

RV minor: Epsilon wave (V1–V3) OR terminal activation duration ≥55 ms (S-wave nadir to end QRS in V1–V3, no RBBB)
LV major: Low QRS voltages <0.5 mV in all limb leads (no obesity/emphysema/effusion/amyloidosis)

Category V, Ventricular arrhythmias

RV major: >500 PVCs/24h or NSVT/SVT with LBBB + non-inferior axis morphology
RV minor: LBBB + inferior axis ("RVOT pattern") or VF/VT of unknown morphology
LV minor: >500 PVCs/24h or VT with RBBB morphology (excluding fascicular pattern)

Category VI, Family history/genetics

Major: Pathogenic ACM variant; ACM confirmed in 1st-degree relative (by criteria or autopsy)
Minor: Likely pathogenic variant; family history of ACM in 1st-degree relative; premature SCD <35 years (suspected ACM) in 1st-degree relative; ACM confirmed in 2nd-degree relative

Signal-averaged ECG (late potentials) no longer recommended as diagnostic criterion due to low accuracy vs. modern tests (Corrado et al 2024)^[9]

Why the Shift from ARVC → ACM?

The 2010 Task Force Criteria were designed for right-dominant ARVC only. Studies showed that up to 49% of DSP-related ACM patients with predominantly left-sided disease did NOT meet 2010 criteria, including 25% who had sustained VT or heart failure. Of 679 PLN p.Arg14del carriers, 96% did not fulfil 2010 criteria at baseline (Corrado et al 2024)^[9]. The updated criteria address this diagnostic gap by incorporating LV LGE, LV ECG abnormalities, and RBBB-morphology arrhythmias.

Diagnosis

Clinical Presentation:

Palpitations (most common presenting symptom)
Presyncope or syncope
Sudden cardiac arrest (may be first presentation, especially during exercise)
Progressive heart failure (late stages, biventricular involvement)

Key Features:

Arrhythmias typically LBBB morphology (RV origin)
Symptoms often triggered by exercise
Progressive disease - phenotype may evolve over time
Can involve left ventricle (biventricular ARVC)

Investigations

First-line:

12-lead ECG (T-wave inversion V1-V3, epsilon waves, prolonged TAD)
24-48 hour Holter monitoring (PVC burden, NSVT)
Exercise test (arrhythmia provocation)

Imaging:

Echocardiography: RV size/function, regional wall motion abnormalities
Cardiac MRI: RV dilatation, RV dysfunction, fatty infiltration, fibrosis (LGE)
CMR is preferred modality for RV assessment

Invasive:

Endomyocardial biopsy (rarely performed; if diagnostic uncertainty)
Electrophysiology study (selected cases for VT ablation)

Treatments

Lifestyle modification:

Avoid competitive sports and intense endurance exercise (can accelerate disease)
Moderate recreational activity generally acceptable

Medical therapy:

Beta-blockers (Grade I^[1]): First-line for all patients with arrhythmias. Must be dosed as high as tolerated, HR reduction at >50% target dose associated with significant risk reduction (HR 0.10, 95% CI 0.02–0.46) vs no beta-blocker (Cappelletto et al 2021^[4]).
- Bisoprolol: start 2.5 mg once daily → target 5–10 mg once daily
- Metoprolol succinate: start 25 mg once daily → target 100–200 mg once daily
- Nadolol (non-cardioselective; preferred by some centres): start 40 mg once daily → target 80–160 mg once daily (UK import / SPECIALS)
Flecainide (Grade IIa add-on^[1]): If beta-blocker alone insufficient. Particular advantage in PKP2 variants. Safe/effective in ARVC (Rolland et al 2022^[5]).
- Start 50 mg twice daily → increase to 100–150 mg twice daily as tolerated
- Maximum 300 mg/day (200 mg/day if eGFR <35 ml/min); check QRS widening on ECG (<25% increase)
- Do NOT use as monotherapy; always combine with beta-blocker
Sotalol (Grade IIa add-on): Alternative if beta-blocker alone insufficient.
- Start 80 mg twice daily → increase to 120–160 mg twice daily
- Monitor QTc (ECG at each dose increase); withhold if QTc >500 ms; renally cleared, reduce dose if eGFR <60
Amiodarone (Grade IIa add-on): Reserve for refractory arrhythmia where beta-blocker + flecainide/sotalol insufficient; multiple long-term adverse effects limit use in young patients.
- Loading: 200 mg three times daily × 1 week, then 200 mg twice daily × 1 week
- Maintenance: 100–200 mg once daily (use lowest effective dose)
- Baseline and annual TFTs, LFTs, CXR, ophthalmology; avoid in pregnancy
Heart failure therapy: Ramipril/sacubitril-valsartan, bisoprolol, eplerenone, dapagliflozin for LVEF ≤40% (per ESC HF 2021 guidelines, see DCM doses)

ICD:

Secondary prevention (Grade I): Cardiac arrest or sustained VT with syncope → ICD indicated
Primary prevention (Grade IIa): Use ARVC Risk Calculator (ARVCrisk.com), c-statistic 0.77; calculates 1-, 2-, 5-year arrhythmia risk. Inputs: age at diagnosis, sex, cardiac syncope (last 6 months), T-wave inversion leads, PVC burden (24h), NSVT history, RVEF, (optional) programmed stimulation result
Subcutaneous ICD: Valid alternative, especially in younger patients without a pacing/ATP indication (PRAETORIAN^[13] showed comparable efficacy and a better lead-related safety profile vs transvenous ICD); lacks ATP capability, highest appropriate shock rate 9%/year in ARVC (i-SUSI registry)
Programmed ventricular stimulation (PVS) improves risk prediction accuracy (c-stat 0.75 vs 0.72); negative predictive value 92.6% for low-risk patients

Catheter ablation:

For recurrent VT despite medical therapy or frequent ICD shocks (Grade IIa)
Combined endocardial-epicardial approach preferred (HR 0.54 vs endocardial alone, p<0.001)
May be considered as ICD alternative for haemodynamically tolerated VT in selected patients (Gandjbakhch et al 2021)^[10]
High recurrence rates even in experienced centres, refer to specialist centre with epicardial ablation expertise

Advanced therapy:

Heart transplantation for end-stage disease / refractory arrhythmia
Gene therapy (emerging): PKP2 gene therapy arrests/reverses ARVC in murine models; clinical trials underway in USA and Europe

Related Resources

Complications

Ventricular arrhythmia and sudden cardiac death: often exercise-related and frequently the first presentation^[1]
Progressive right then biventricular failure: a later natural-history stage
Atrial arrhythmia.
ICD-related complications: appropriate and inappropriate shocks, and lead complications over a long device lifetime in young patients

Risk Stratification

ESC 2023 Guidelines: ACM Management (+ 2024 European TF Diagnostic Criteria)

ICD Recommendations (ESC 2023):

Class I: Survivors of cardiac arrest or sustained VT causing syncope/haemodynamic compromise
Risk scores: Validated SCD algorithms should be considered (Class IIa) for primary prevention

Comprehensive SCD Risk Stratification:

Recommended at initial evaluation
Re-evaluate at 1-2 year intervals
Re-evaluate with any change in clinical status

Reference: Arbelo E et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J 2023;44:3503-3626^[1]

High-risk features for SCD (consider ICD):

Cardiac arrest or sustained VT (secondary prevention)
Severe RV or LV dysfunction (RVEF <40%, LVEF <45%)
Extensive disease on imaging
Syncope (unexplained)
Non-sustained VT
Male sex
Proband status (index case in family)
Compound or homozygous mutations

Risk stratification tools:

ARVC Risk Calculator (ARVCrisk.com): validated (c-statistic 0.77); calculates 1-, 2-, 5-year arrhythmia risk; recommended Class IIa for primary prevention ICD decisions
PVC burden >500/24h associated with higher risk (calculator input)
Programmed ventricular stimulation improves accuracy (negative predictive value 92.6%)

Exercise restriction:

Competitive sports and moderate-vigorous intensity exercise contraindicated, exercise accelerates disease progression and arrhythmia risk in ACM (ESC 2020)
Low-intensity recreational activity only (walking, light golf), discuss individually

Pregnancy Management

ESC 2018 Pregnancy Guidelines - ARVC (mWHO Class II-III)

PRECONCEPTION COUNSELLING:

Risk stratification:
- No significant RV/LV dysfunction, no VT history, stable: mWHO II (low-moderate risk)
- RV/LV dysfunction, history of VT/ICD shocks: mWHO III (high risk)
- Severe biventricular dysfunction, NYHA III-IV: mWHO IV (pregnancy contraindicated)
Arrhythmic risk in pregnancy:
- Increased sympathetic tone + volume load may increase VT risk
- 10-20% experience first VT episode or increased VT burden during pregnancy
- No clear evidence pregnancy accelerates structural progression
Baseline assessment:
- Echo/CMR: RV and LV function, regional wall motion abnormalities
- 24-48 hour Holter monitoring (PVC burden, NSVT, VT episodes)
- Exercise test if not already done recently
- Review ICD if present (appropriate shocks, battery, lead integrity)
Medications:
- Beta-blockers: CONTINUE (metoprolol, bisoprolol safe); essential for arrhythmia suppression
- Sotalol: Generally avoid (QT prolongation risk, limited data)
- Flecainide: Case reports only; discuss risk-benefit if already on long-term
- Amiodarone: Avoid if possible (thyroid/fetal effects); use only if life-threatening VT refractory to other agents
Genetic counselling: 50% transmission risk (autosomal dominant); discuss TMEM43 (high arrhythmic risk in males)

PREGNANCY MANAGEMENT:

Monitoring frequency:
- Cardiology review each trimester minimum if stable
- Monthly review if VT history or ICD present
- Echo each trimester (assess RV/LV function)
- Holter 24-48 hours each trimester (arrhythmia burden)
Beta-blocker therapy:
- ESSENTIAL - do not discontinue
- Target dose metoprolol 100-200mg/day (or bisoprolol 5-10mg/day)
- Uptitrate if increasing PVC burden or NSVT
ICD management:
- Safe during pregnancy - maintain programming
- Review device every 3-4 months (more frequent battery drain due to higher heart rates)
- Patient to report any shocks immediately
- Consider VT zone reprogramming if recurrent inappropriate shocks (sinus tachycardia common in pregnancy)
Activity restriction:
- Avoid vigorous exercise (can trigger VT)
- Light recreational activity acceptable
- Swimming generally safe but avoid competitive swimming
Red flags:
- Palpitations, presyncope, syncope
- ICD shocks (appropriate or inappropriate)
- Worsening dyspnea (may indicate RV failure)

LABOUR & DELIVERY:

Delivery planning:
- Tertiary centre with cardiac and ICU capability
- MDT meeting at 32-34 weeks
- External defibrillator available (in case ICD fails or if no ICD)
Mode of delivery:
- Vaginal delivery preferred if stable, good functional class
- Elective caesarean section if: Severe RV/LV dysfunction, recent VT/ICD shocks, haemodynamic instability
- Assisted second stage to reduce maternal effort and sympathetic surge
Anaesthesia:
- Epidural safe and preferred (reduces pain-related catecholamine surge)
- Avoid sympathetic stimulation (pain, anxiety trigger VT)
- GA if caesarean: Senior anaesthetist, avoid QT-prolonging agents
Intrapartum monitoring:
- Continuous ECG monitoring (arrhythmia detection)
- Defibrillator pads placed prophylactically if high VT risk
- ICD interrogation before delivery (ensure functioning)
- Magnet available to disable ICD if inappropriate shocks during delivery
VT management during labour:
- Beta-blocker bolus (metoprolol 5mg IV) if haemodynamically stable VT
- Electrical cardioversion if unstable (ICD will deliver shock or external)
- Amiodarone 300mg IV if refractory VT (fetal risk acceptable in emergency)

POSTPARTUM:

Immediate postpartum: Monitor 24-48 hours (arrhythmia risk persists with fluid shifts)
Continue beta-blockers: Do NOT stop postpartum
ICD interrogation: Within 1 week of delivery
Contraception: All methods safe; progesterone-only preferred (avoid oestrogen if multiple cardiac risk factors)
Breastfeeding: Safe; beta-blockers compatible
Follow-up: Echo/Holter at 6 weeks; return to pre-pregnancy baseline expected

CONTRAINDICATIONS TO PREGNANCY:

Severe biventricular dysfunction (LVEF <30%, severe RV dysfunction)
NYHA Class III-IV heart failure
Refractory VT despite optimal therapy (electrical storm)

GENE-SPECIFIC NOTES:

TMEM43: High arrhythmic risk, particularly in males; 50% transmission risk to offspring (autosomal dominant), with higher penetrance and risk in male carriers, so counsel accordingly
DSP/FLNC: LV involvement common; higher risk of HF symptoms during pregnancy

Follow-up

Based on ESC 2023 Cardiomyopathy guidelines^[1].

Advanced / complicated = frequent or sustained ventricular arrhythmia, significant RV/LV dysfunction, syncope, or appropriate ICD therapy.

Genotype-positive / phenotype-negative (G+/P−) = a confirmed pathogenic-variant carrier with no overt disease expression yet.

	Genotype+ / Phenotype−	Uncomplicated / Stable	Advanced / Complicated
Frequency	Every 2–3 yrs (1–2 yrly if young/athlete)	Every 1–2 years	Every 3–6 months
Clinical review	Symptoms, exercise history	Palpitations, syncope, exercise history	As above + device interrogation
ECG	Each screening visit	Annual 12-lead	Each visit
Echocardiography	Each screening visit	Every 1–2 years (RV size/function)	6-monthly
Holter / ambulatory	Periodic (early arrhythmia)	Annual (PVC count, NSVT)	6-monthly or symptom-directed
Exercise test	Counsel re: endurance-exercise restriction	Periodic (exertional arrhythmia)	As indicated
CMR	Consider (early structural change)	Every 2–3 years (RV/LV structure, LGE)	As clinically indicated
Family screening	–	Cascade ECG + imaging from adolescence	–

Disclaimer: This table is general guidance based on published guidelines and does not replace clinical judgement. The responsible clinician is accountable for determining the appropriate, individualised follow-up plan for each patient.

Key Points

Avoid endurance and competitive sports - can accelerate disease progression^[1]
Screen first-degree relatives with ECG, echo, Holter from age 10-12^[1]
Beta-blockers (titrated to the maximally tolerated dose) are recommended for patients with arrhythmias and are commonly considered across those with a definite diagnosis; practice varies between centres^[1]
Left ventricular involvement (DSP, FLNC) can mimic DCM - check carefully
High false-positive rate on imaging - use Task Force Criteria strictly
Preconception counselling essential - arrhythmic risk may increase in pregnancy
ICD implantation does NOT prevent disease progression
Consider genetic testing in all cases (enables family cascade screening)

References & Review Date

Last reviewed: June 2026

Arbelo E, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–3626. doi:10.1093/eurheartj/ehad194
Marcus FI, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force criteria. Eur Heart J. 2010;31(7):806–814. doi:10.1093/eurheartj/ehq025
Zeppenfeld K, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997–4126. doi:10.1093/eurheartj/ehac262
Cappelletto C, et al. Beta-blocker therapy and outcomes in patients with arrhythmogenic cardiomyopathy. J Am Coll Cardiol. 2021;78(24):2379–2393. doi:10.1016/j.jacc.2021.09.861
Rolland T, et al. Flecainide in arrhythmogenic right ventricular cardiomyopathy: a systematic review and meta-analysis. J Am Heart Assoc. 2022;11(4):e023167. doi:10.1161/JAHA.021.023167
Pelliccia A, et al. 2020 ESC Guidelines on sports cardiology and exercise in patients with cardiovascular disease. Eur Heart J. 2021;42(1):17–96. doi:10.1093/eurheartj/ehaa605
Joint Formulary Committee. British National Formulary (BNF). bnf.nice.org.uk
Kreimer F, Saguner AM, Akin I, Milting H, Eckardt L, El-Battrawy I. Arrhythmogenic right ventricular cardiomyopathy: diagnosis, risk stratification, and treatment. Dtsch Arztebl Int. 2025;122:229–234. doi:10.3238/arztebl.m2024.0264
Corrado D, Anastasakis A, Basso C, et al. Proposed diagnostic criteria for arrhythmogenic cardiomyopathy: European Task Force consensus report. Int J Cardiol. 2024;395:131447. doi:10.1016/j.ijcard.2023.131447
Gandjbakhch E, Laredo M, Berruezo A, et al. Outcomes after catheter ablation of ventricular tachycardia without implantable cardioverter-defibrillator in selected patients with arrhythmogenic right ventricular cardiomyopathy. Europace. 2021;23(9):1428–1436. doi:10.1093/europace/euab172
James CA, et al. Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. J Am Coll Cardiol. 2013;62(14):1290–1297. doi:10.1016/j.jacc.2013.06.033
Milting H, et al. 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(14):872–881. doi:10.1093/eurheartj/ehu077
Knops RE, et al. Subcutaneous or transvenous defibrillator therapy (PRAETORIAN). N Engl J Med. 2020;383(6):526–536. doi:10.1056/NEJMoa1915932

Arrhythmogenic Cardiomyopathy (ACM)