ICCnotes(beta)

Inherited Cardiac Conditions reference

Open this condition in the interactive app →

Arrhythmogenic Cardiomyopathy (ACM)

Quick Summary

Definition: A usually genetic cardiomyopathy characterised by fibrofatty or fibrotic myocardial scarring, predisposing to ventricular arrhythmias and sudden death; classically right ventricular but often left-dominant or biventricular.[1]

  • Prevalence: 1 in 2,000 to 1 in 5,000[8]; an important cause of SCD in the young and in athletes (a leading cause in some regions, e.g. the Veneto); male predominance 3:1[1]
  • Key genes: PKP2 (most common, RV-dominant), DSP/FLNC/PLN (LV-dominant), TMEM43 (associated with high arrhythmic risk, especially in males)
  • Phenotypes: ARVC (right-dominant), ABVC (biventricular), ALVC (left-dominant, underdiagnosed); all share fibro-fatty scarring
  • Hallmark: Non-ischaemic myocardial scarring → ventricular arrhythmias; CMR LGE now central to diagnosis (2024 European TF criteria)
  • High-risk features: Sustained VT/VF, syncope, extensive LV/RV involvement, TMEM43/PLN variants, prior cardiac arrest
  • First-line Mx: Beta-blockers titrated to the maximum tolerated dose where arrhythmias are present (Class I), sports restriction, ICD decisions informed by the ARVC risk calculator (ARVCrisk.com) alongside genotype and phenotype, consider ablation for recurrent VT

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
  • In genotype-positive/phenotype-negative gene carriers, avoidance of moderate-to-high-intensity exercise may be considered on an individualized basis; this is a weak recommendation (not an absolute prohibition), and the guideline does not distinguish by specific gene for ARVC, unlike its LMNA/TMEM43 exception for DCM/NDLVC carriers[1]
  • 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). The 2023 ESC guideline gives a population prevalence of 0.078%, and notes that the complexity of the diagnostic criteria limits how accurately the true prevalence can be established[1]

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.[2] 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

1. General measures:

  • Avoid competitive sports and intense endurance exercise (can accelerate disease)
  • Moderate recreational activity generally acceptable
  • Genetic counselling and family cascade testing, see the Genetic Testing page

2. Medical therapy:

  • Beta-blockers (Class I[1]): First-line where arrhythmias are present, titrated to the maximum tolerated dose. HR reduction at >50% target dose was 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[7]
    • Nadolol (non-cardioselective; preferred by some centres): start 40 mg once daily → target 80–160 mg once daily (UK import / SPECIALS)
  • Flecainide (Class IIa add-on[1]): If beta-blocker alone insufficient. Some cohort data, including a PKP2-enriched population, report benefit as an add-on antiarrhythmic (Rolland et al 2022[5]), but this should not be read as proven genotype-specific superiority for every PKP2 patient, use is phenotype- and arrhythmia-specific under specialist supervision.
    • 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 (Class 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 (Class 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)

3. Device therapy / catheter ablation:

  • ICD:
    • Secondary prevention (Class I): Cardiac arrest or sustained VT with syncope → ICD indicated[3]
    • Primary prevention (Class 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. Scope: it was derived in patients with a definite ARVC diagnosis by the 2010 Task Force Criteria and no prior sustained ventricular arrhythmia, in cohorts made up largely of PKP2 carriers and gene-elusive patients, and performs less well in left-dominant disease. Integrate it with genotype, extent of LV involvement, scar, ventricular function, syncope and arrhythmia burden rather than applying it uncritically across all ACM phenotypes
    • 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 (Class 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

4. Advanced heart failure and/or transplant referral:

  • Heart transplantation for end-stage disease / refractory arrhythmia

5. Emerging therapies:

  • Gene therapy: PKP2 gene therapy has arrested or reversed disease features in murine models; early-phase (phase 1) clinical trials are underway. Not yet a clinical treatment option
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: SCD Risk Reassessment Interval

Comprehensive SCD risk stratification (ESC 2023):

  • 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] (ICD indications are detailed below and in the Treatments section).

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 generally avoided, as exercise can accelerate disease progression and arrhythmia risk in ACM; individualized discussion for low-intensity recreational activity (ESC 2020)[6]
  • Low-intensity recreational activity only (walking, light golf), discuss individually

Pregnancy Management

Pregnancy in ARVC/ACM - individualized risk assessment (2025 ESC pregnancy approach)

Pregnancy raises sympathetic tone and volume load, which can increase arrhythmic risk in ARVC/ACM, particularly in those with a history of ventricular arrhythmia or significant RV/LV dysfunction. Risk should be assessed individually using baseline RV/LV function, arrhythmia history and genotype where known, rather than assigned to a fixed universal risk class or a single diameter/function-based cut-off for contraindication.[1][14]

Medication: beta-blockers are generally continued through pregnancy for arrhythmia suppression. Flecainide, sotalol and amiodarone use should be phenotype- and arrhythmia-specific, individualized decisions rather than a fixed universal pregnancy protocol, weighing arrhythmia control against the specific safety profile of each agent in pregnancy.

Monitoring: surveillance frequency (clinical review, echo/CMR, Holter) should be individualized to the patient's baseline severity and arrhythmia history rather than a fixed universal schedule for every patient.

Activity: strong avoidance of high-intensity and endurance exercise, which is broadly supported outside pregnancy, reasonably continues to apply in pregnancy; specific activity advice should be individualized with specialist input.

Delivery: mode and timing of delivery should be decided by the Pregnancy Heart Team based on the patient's functional status and arrhythmia history, not a fixed universal rule.[14]

Genetic considerations: where a pathogenic variant is identified (e.g. TMEM43, DSP, FLNC), this should inform counselling about arrhythmic or LV-involvement risk and transmission risk to offspring, but does not by itself dictate a fixed monitoring or delivery protocol.

Contraception and future pregnancy: discuss the full range of options through non-directive counselling; the decision, including whether to consider a future pregnancy, is led by the patient.

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 / StableAdvanced / Complicated
FrequencyEvery 2–3 yrs (1–2 yrly if young/athlete)Every 1–2 yearsEvery 3–6 months
Clinical reviewSymptoms, exercise historyPalpitations, syncope, exercise historyAs above + device interrogation
ECGEach screening visitAnnual 12-leadEach visit
EchocardiographyEach screening visitEvery 1–2 years (RV size/function)6-monthly
Holter / ambulatoryPeriodic (early arrhythmia)Annual (PVC count, NSVT)6-monthly or symptom-directed
Exercise testCounsel re: endurance-exercise restrictionPeriodic (exertional arrhythmia)As indicated
CMRConsider (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

  • Consider genetic testing in all cases (enables family cascade screening)
  • Left ventricular involvement (DSP, FLNC) can mimic DCM - check carefully
  • High false-positive rate on imaging - use Task Force Criteria strictly
  • Screen first-degree relatives with ECG, echo and Holter from childhood rather than from a fixed age, continuing into adulthood because penetrance is age-related[1]
  • Avoid endurance and competitive sports - can accelerate disease progression[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]
  • ICD implantation does NOT prevent disease progression
  • Preconception counselling essential - arrhythmic risk may increase in pregnancy

References & Review Date

Last reviewed: August 2026

  1. 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
  2. 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
  3. 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
  4. Cappelletto C, et al. Antiarrhythmic therapy and risk of cumulative ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy. Int J Cardiol. 2021;334:58–64. doi:10.1016/j.ijcard.2021.04.069
  5. Rolland T, et al. Safety and efficacy of flecainide associated with beta-blockers in arrhythmogenic right ventricular cardiomyopathy. Europace. 2022;24(2):278–284. doi:10.1093/europace/euab182
  6. 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
  7. Joint Formulary Committee. British National Formulary (BNF). bnf.nice.org.uk
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. Knops RE, et al. Subcutaneous or transvenous defibrillator therapy (PRAETORIAN). N Engl J Med. 2020;383(6):526–536. doi:10.1056/NEJMoa1915932
  14. 2025 ESC Guidelines for the management of cardiovascular disease during pregnancy. Eur Heart J. 2025. doi:10.1093/eurheartj/ehaf193