Arrhythmogenic Cardiomyopathy: Towards Genotype Based Diagnoses and Management

Authors, Journal, Affiliations, Type, DOI

• Steven A. Muller, Giorgia Bertoli, Jianan Wang, Alessio Gasperetti, Moniek G. P. J. Cox, Hugh Calkins, Anneline S. J. M. te Riele, Daniel P. Judge, Mario Delmar, Richard N. W. Hauer, Gerard J. J. Boink, Marina Cerrone, J. Peter van Tintelen, Cynthia A. James
• Journal of Cardiovascular Electrophysiology, 2025;36:2662–2670
• Johns Hopkins University, UMC Utrecht, NYU Grossman School of Medicine, Amsterdam UMC, UMC Groningen, Medical University of South Carolina — ERN GUARD-Heart network
• Invited Review (based on ECAS 2024 Congress sessions)
• DOI: 10.1111/jce.16519

Overview

Comprehensive invited review from the world's leading ACM centers synthesizing the evidence that ACM diagnosis, risk stratification, and management must shift from genotype-agnostic to genotype-specific. Covers the full genetic architecture with gene-specific natural history for 7 established ACM genes (PKP2, DSP, DSG2, DSC2, JUP, TMEM43, PLN, DES), the inadequacy of 2010 Task Force Criteria for non-PKP2 genotypes, genotype-specific risk calculators (ARVC, DSP, PLN-p.Arg14del), variant-directed flecainide therapy (PKP2cKO mouse model — RCT NCT03685149 pending), and the AAV-mediated PKP2 gene therapy pipeline (three Phase I/II programs: Rocket RP-A601, LEXEO LX2020, Tenaya TN-401). A critical clinical finding: exercise as a penetrance/VA risk factor is gene-specific — harmful in PKP2/TMEM43/gene-elusive ACM but NOT associated with penetrance in PLN-p.Arg14del carriers.

Keywords

ACM, ARVC, cardiac arrest/sudden death, clinical electrophysiology, gene specific, genotype specific

Key Takeaways

Genetic Architecture and Penetrance

• ACM prevalence 1:5000–1:10,000; ~50% harbor a LP/P variant. Generally autosomal dominant with age-related reduced penetrance.
• Male sex, exercise, and multiple LP/P variants increase penetrance risk (but this is gene-dependent — see below).
• Family screening: yield ~33% at first evaluation, ~33% at 4-year serial follow-up. Electrical abnormalities (ECG/Holter) precede structural abnormalities (echo/CMR).
• Penetrance in population-based studies of desmosomal variants is as low as 1–6% (vs much higher in family studies) — context of genetic testing is vital.
• Oligogenic contributions to pathogenesis are suspected; poorly understood genetic factors influence penetrance.

Gene-Specific Natural History

PKP2 (Plakophilin-2)

• Most common ARVC gene; up to two-thirds of ARVC cases. Typically loss-of-function (haploinsufficiency); no evidence specific variants differ in severity.
• Classical right-dominant ARVC: right precordial T-wave inversions, frequent PVCs, RV enlargement/dyskinesis. VAs with LBBB morphology.
• Male sex and exercise are penetrance risk factors. Electrical abnormalities precede structural disease.

DSP (Desmoplakin)

• Associated with biventricular or left-dominant cardiomyopathy (DSP-cardiomyopathy). Rare right precordial TWI; left precordial (V4–V6) TWI with LV disease.
• "Ring-like" LGE on CMR; reduced LVEF in late stage. VAs frequently RBBB morphology.
• "Hot phases": acute episodes of myocardial injury with myocarditis-like symptoms (chest pain, elevated troponin, no CAD) — thought to be immune-mediated; no consensus on treatment (conservative vs immunosuppression).
• Female sex associated with penetrant DSP-cardiomyopathy (contrasts with PKP2). Impact of exercise on penetrance is uncertain.
• 2010 TFC perform poorly for DSP; Padua criteria improve detection.

DSG2 (Desmoglein-2) / DSC2 (Desmocollin-2)

• Encode cardiac-predominant desmosomal cadherins. Both phenotypically similar to PKP2-ARVC: precordial TWI (V1–V3), RV dyskinesis, fibro-fatty replacement.
• VAs with LBBB morphology from RV. More biventricular involvement than typical PKP2-ARVC.
• DSG2: age of onset may be earlier than PKP2-ARVC; autosomal dominant.
• DSC2: often autosomal recessive. Insufficient data to describe penetrance in detail.

JUP (Plakoglobin) — Naxos Disease

• Autosomal recessive (homozygous); woolly hair, palmoplantar keratoses, + ARVC.
• 97% penetrance by adolescence. Right-sided phenotype similar to PKP2-ARVC but significantly more severe. Biventricular involvement not uncommon.
• Prevalence: high in Naxos, Greece; low elsewhere.

TMEM43

• p.Ser358Leu founder variant (Newfoundland, but observed worldwide). First non-desmosomal ARVC gene.
• Nearly fully penetrant in males; highly malignant with very high VA/SCD risk. Poor R-wave progression (more common than precordial TWI). LV dilatation.
• Exercise associated with worse outcomes. Early ICD consideration indicated for at-risk male carriers.
• Considered a highly malignant disease.

PLN (Phospholamban)

• p.Arg14del Dutch founder variant; mixed arrhythmogenic + heart failure phenotype.
• Exercise does NOT influence penetrance, VA, or HF events — unique among ACM genes. Male sex is NOT a risk factor — also unique.
• Micro voltages and precordial TWI on ECG. High arrhythmic risk; relatively high risk of biventricular cardiomyopathy and end-stage HF.
• Dedicated risk calculator usable irrespective of clinical phenotype status (i.e., in gene-positive, phenotype-negative relatives).

DES (Desmin)

• Wide phenotypic spectrum across cardiomyopathy subtypes (DCM, RCM, ACM); often with proximal/distal skeletal myopathy.
• ~80% of LP/P DES carriers develop cardiac phenotype. High burden of advanced cardiac conduction disease — frequently requires CIED.
• Clinically heterogeneous: biventricular, left-dominant, and right-dominant ACM described. Certain variants associated with distinct phenotypes.
• Data on natural history remain limited; no genotype-specific risk stratification tools available.

Diagnosis — Inadequacy of 2010 TFC

• 2010 TFC were developed only for ARVC, not ALVC or biventricular ACM, and validated mostly in PKP2 patients.
• 2010 TFC do not perform well across all ACM genotypes — DSP carriers can present with VAs without fulfilling criteria.
• Padua criteria (2020) yield good diagnostic potential for DSP carriers but poor discrimination against ACM phenocopies.
• Unmet need: evidence-based gene-specific diagnostic criteria.

Family Screening of At-Risk Relatives

• Cascade genetic testing + cardiac screening recommended for relatives of LP/P-positive probands (not genotype-specific yet).
• Screening begins age 10–12 years, repeated 1–3-year intervals (ECG, Holter, echo/CMR).
• New algorithm refines follow-up based on: additional minor TFC beyond family history, symptoms, age 20–30 years.
• DSP and PLN risk scores can be used in gene-positive relatives without definite diagnosis (contrasts with ARVC calculator requiring definite ARVC).
• No genotype-specific family screening studies published — strongly recommended.

Risk Stratification for ICD

• ARVC risk calculator (2019, acm-risk.com): performs adequately in PKP2-ARVC, overpredicts VA risk in gene-elusive ARVC, performs poorly in DSP-ARVC. Only applicable to patients with definite ARVC (2010 TFC).
• DSP risk calculator (Carrick 2024): gene-specific; usable in genotype-positive individuals irrespective of phenotype.
• PLN-p.Arg14del risk calculator (Verstraelen 2021): gene-specific; long-term reliability confirmed.
• All calculators estimate only VA risk — not HF events (important gap for DSP and PLN where HF is a cardinal manifestation).
• Programmed ventricular stimulation added as optional variable to ARVC risk calculator.

Medical Management

• Only beta-blockers currently recommended (preferably long-acting cardioselective, e.g. metoprolol) — evidence limited, no proven SCD prevention in ACM.
• Flecainide: in PKP2cKO mouse model, adrenergic stimulation triggered excess SR Ca²⁺ release through RyR2 → VAs; flecainide (RyR2 blocker + Na⁺ channel blocker) eliminated VA occurrence. Suggests gene-specific antiarrhythmic efficacy in PKP2-ARVC. RCT pending (NCT03685149).
• Prior antiarrhythmic drug studies in ACM have conflicting results — likely due to high genetic heterogeneity of study populations.

Exercise — Gene-Specific Effects

• Exercise associated with penetrance and VAs in: PKP2-ARVC, TMEM43-ARVC, gene-elusive ARVC.
• Exercise NOT associated with penetrance, VA, or HF in PLN-p.Arg14del carriers.
• Exercise effect in DSP is uncertain.
• 2024 HRS athlete consensus recommends gene-specific shared decision-making for exercise.
• Practical: genotype+/phenotype− individuals currently recommended to limit to mild-to-moderate activity ≤150 min/week. PLN carriers may not need restriction if no known VA risk factors. Err on side of caution when no gene-specific data available.

Gene Therapy — AAV-PKP2

• PKP2 fits within AAV packaging limit (<5.0 kb); loss-of-function mechanism ideal for gene replacement.
• AAVrh74-PKP2 (van Opbergen 2024): 100% survival >5 months in PKP2cKO mice (vs 100% mortality at 40–50 days untreated); prevented RV dilation, arrested LV progression, reduced arrhythmia burden; effective even when delivered after disease onset.
• AAV9-PKP2 (Wu 2024): confirmed survival and functional improvement in same model.
• AAV9-PKP2 for human splice-site mutation (Bradford 2023): reduced pathological deficits when given at birth or after disease onset.
• Three Phase I/II programs FDA-approved: Rocket RP-A601, LEXEO LX2020, Tenaya TN-401.
• Key challenge: effective dose estimated at high 10^13 to low 10^14 vg/kg — at threshold of immunogenic risk/hepatotoxicity.
• Solutions in development: MyoAAV4A variant (higher cardiac transduction, lower liver → lower effective dose); local delivery (antegrade intracoronary, retrograde coronary vein) for global cardiac transfer at lower doses.
• CUPID 2 failure in HF attributed to insufficient gene transfer efficiency — underscores importance of this challenge.

Limitations

• No genotype-specific family screening studies published — screening recommendations extrapolated from overall ARVC population (predominantly PKP2).
• Exercise effect in DSP uncertain; no data for many rarer genotypes.
• Antiarrhythmic drug data retrospective with conflicting results due to genetic heterogeneity.
• Flecainide efficacy in human PKP2-ARVC not yet proven — RCT pending.
• Gene therapy effective dose near immunogenic threshold; long-term safety unknown.
• All risk calculators predict only VA, not HF — gap for DSP/PLN where HF is major outcome.
• DES natural history data remain limited.
• DSG2/DSC2 penetrance data insufficient for detailed characterization.

Key Concepts Mentioned

• concepts/Arrhythmogenic-Cardiomyopathy — umbrella disease entity; genotype-specific management framework
• concepts/ARVC-Task-Force-Criteria — 2010 TFC inadequate for non-PKP2 genotypes; Padua criteria alternative
• concepts/Cascade-Family-Screening — 33% yield at baseline + 33% at 4y; new risk-refined algorithm proposed
• concepts/Exercise-Restriction-in-ARVC — gene-specific exercise effect; not applicable to PLN
• concepts/Desmosome — structural basis; DSG2/DSC2/JUP components
• concepts/Final-Common-Pathway — ACM convergence hypothesis
• concepts/Sports-Cardiology-SDM — 2024 HRS gene-specific exercise recommendations
• concepts/AAV-Gene-Delivery — PKP2 fits <5.0 kb; MyoAAV4A variant; local delivery methods

Key Entities Mentioned

• entities/PKP2 — most common ARVC gene; flecainide efficacy in mouse model; 3 Phase I/II gene therapy trials
• entities/DSP — DSP-cardiomyopathy: left-dominant, female sex risk, hot phases, ring-like LGE, dedicated risk calculator
• entities/DSG2 — desmoglein-2; classical ARVC, earlier onset than PKP2, AD, biventricular
• entities/DSC2 — desmocollin-2; classical ARVC, often AR, limited data
• entities/JUP — plakoglobin; Naxos disease (AR), 97% penetrance by adolescence, woolly hair+PPK+ARVC
• entities/TMEM43 — p.Ser358Leu founder; near-fully penetrant males, highly malignant, exercise harm
• entities/PLN — p.Arg14del founder; exercise NOT risk factor (unique), sex NOT risk factor, dedicated calculator
• entities/DES — desmin; wide phenotype spectrum, 80% cardiac, high conduction disease burden
• entities/ARVC — best-characterized ACM subtype; risk calculator overpredicts in gene-elusive, poor in DSP
• entities/ALVC — left-dominant ACM; DSP-cardiomyopathy is archetype
• entities/Flecainide — PKP2cKO mouse efficacy; RCT NCT03685149 pending
• entities/LMNA — potential ACM gene in gene-elusive patients
• entities/FLNC — potential ACM gene; linked to ACM

Wiki Pages Updated

• sources/ACM-Genotype-Mx-JCE-2024 — created
• entities/DSG2 — created
• entities/DSC2 — created
• entities/JUP — created
• entities/TMEM43 — created
• entities/DES — created
• entities/PKP2 — updated
• entities/DSP — updated
• entities/PLN — updated
• entities/ARVC — updated
• concepts/Arrhythmogenic-Cardiomyopathy — updated
• concepts/Exercise-Restriction-in-ARVC — updated
• wiki/sourceindex.md — updated
• wiki/wikiindex.md — updated