Advanced arrhythmias and channelopathies - arrhythmogenic right ventricular cardiomyopathy
Description
- Genetic desmosomal cardiomyopathy - progressive fibrofatty replacement of myocardium, arrhythmia out of proportion to ventricular dysfunction
- Terminology has broadened: "arrhythmogenic cardiomyopathy" (ACM), because the left ventricle is involved in the majority
- Right-dominant (classic ARVC) | Biventricular (commonest) | Left-dominant (ALVC) - often misdiagnosed as myocarditis or DCM
- Replacement progresses epicardium -> endocardium (the reverse of ischaemic scar)
- Hence the value of epicardial mapping and ablation
- "Triangle of dysplasia" - RV inflow, outflow and apex (modern imaging shows basal RV and subtricuspid region, not apex, are the earliest)
- A leading cause of sudden cardiac death in the young and in athletes
Epidemiology
- Prevalence ~1:2000 to 1:5000
- M>F ~3:1 for phenotypic expression and events despite autosomal dominant inheritance
- Attributed largely to exercise exposure
- Presents age 20-50; rare before puberty
- Accounts for up to ~20% of sudden cardiac death in the young; higher in athletes
- Italian (Veneto) and Greek island (Naxos) clusters
- Penetrance is age-related and incomplete (~30-50%) - a variant carrier is not a patient
Aetiopathogenesis
Genetics
- Autosomal dominant, incomplete penetrance, variable expressivity
- Desmosomal genes - mutation found in ~30-60%
- **PKP2 (plakophilin-2) - the commonest, ~25-40%.** Right-dominant, arrhythmia-predominant
- **DSP (desmoplakin) - left-dominant/biventricular*, episodic myocarditis-like chest pain with troponin rise ("hot phases"), high arrhythmic risk*
- DSG2, DSC2, JUP (plakoglobin)
- Non-desmosomal: PLN (phospholamban - Dutch founder variant, biventricular, malignant), FLNC (filamin C - left-dominant, high SCD risk), TMEM43 (Newfoundland founder, malignant in males), DES, LMNA, RBM20
- Recessive cardiocutaneous syndromes:
- Naxos disease (JUP) - woolly hair + palmoplantar keratoderma + ACM
- Carvajal syndrome (DSP) - woolly hair, keratoderma, left-dominant ACM
Mechanism
- Mutant desmosomal protein -> impaired cell-cell adhesion at the intercalated disc
- -> myocyte detachment and death under mechanical stress
- -> inflammation, fibrofatty replacement
- -> scar = re-entry substrate and conduction slowing
- Desmosomal disruption also remodels the gap junction (connexin-43) and the sodium channel at the intercalated disc
- -> electrical instability precedes any structural abnormality - this is why a young carrier with a normal echo can still arrest
- Exercise is the dominant modifier
- Endurance exercise accelerates penetrance, worsens phenotype, increases event rate - dose-dependent
Diagnosis
- *No single test is diagnostic - it is a criteria-based composite. Diagnosis is frequently made late, or wrongly made in athletes with benign RV remodelling*
A. 2010 Task Force Criteria (right-dominant disease)
- Six categories, each major (2 points) or minor (1 point): imaging, tissue characterisation, repolarisation, depolarisation/conduction, arrhythmia, family history/genetics
- Definite = 2 major, or 1 major + 2 minor, or 4 minor. Borderline = 1 major + 1 minor, or 3 minor. Possible = 1 major or 2 minor
- *Blind to left-dominant disease* - the reason for the Padua revision
B. 2020 Padua criteria / 2023 European Task Force criteria
- Adds CMR tissue characterisation (late gadolinium enhancement) as a criterion for both ventricles
- Defines left-dominant and biventricular phenotypes
- LV criteria: LGE in >=1 LV segment (ring-like/subepicardial), LV T-wave inversion in V4-V6, low-voltage limb leads, LV dysfunction/dilatation, PVCs with RBBB morphology
- Genotype is required for the left-dominant diagnosis - phenotype alone overlaps too much with DCM and myocarditis
C. ECG - abnormal in >90% at presentation
- Epsilon wave in V1-V3 - low-amplitude post-QRS deflection; specific but present in <10%
- T-wave inversion V1-V3 in age >14 with complete RBBB absent - major criterion, and the commonest finding
- TWI extending to V4-V6 suggests LV involvement
- Terminal activation duration >=55 ms in V1-V3; prolonged QRS in V1-V3
- Localised QRS prolongation, incomplete or complete RBBB
- Low-limb-lead voltage - suggests LV involvement
- PVCs/VT with LBBB morphology and superior axis = RV free wall origin, major
- LBBB morphology with inferior axis = RVOT origin - much more likely benign idiopathic RVOT VT
D. Imaging
- Echo: RV dilatation, regional akinesia/dyskinesia/aneurysm, reduced RV fractional area change, RVOT dimension
- Major criterion requires a regional wall motion abnormality PLUS a quantitative measurement
- CMR is the key test - RV volumes, regional dysfunction, LGE in RV and LV (subepicardial/mid-wall, ring-like), fat infiltration
- Signal-averaged ECG - late potentials (minor criterion)
- Endomyocardial biopsy - rarely needed; sampling error high, RV free wall risky; use only if the diagnosis is genuinely unresolved or to exclude sarcoid/myocarditis
E. Discriminate from
| Mimic | Discriminator |
|---|---|
| Athlete's heart | Symmetrical biventricular enlargement, normal RV regional wall motion, TWI resolves with detraining, no LGE |
| Idiopathic RVOT VT | Single focus, inferior axis, normal ECG in sinus rhythm, normal imaging, benign |
| Cardiac sarcoidosis | Extracardiac disease, basal septal LGE and AV block, FDG-PET uptake |
| Brugada | Coved ST elevation V1-V2; structural imaging normal |
| Myocarditis | Prodrome, troponin, resolves. But DSP "hot phases" look identical - genotype the recurrent case |
Management
- Goal is preventing sudden death; there is no therapy that halts fibrofatty replacement
A. Exercise restriction - the single most effective intervention
- *No competitive or high-intensity endurance sport - for patients AND for genotype-positive/phenotype-negative carriers*
- Restriction reduces penetrance, arrhythmic events and progression - dose-dependent, so a graded prescription is reasonable rather than total inactivity
- Low-to-moderate recreational activity is permitted
B. Antiarrhythmic and rate control
- Beta blocker in all with definite disease - reduces adrenergic triggering and RV wall stress
- Also consider in phenotype-negative carriers with frequent ectopy
- Sotalol or amiodarone for symptomatic arrhythmia or frequent appropriate shocks
- Flecainide + beta blocker - emerging option for PVC/VT suppression
C. Catheter ablation
- For recurrent sustained VT or repeated appropriate ICD shocks despite drugs
- Epicardial approach is usually required (scar is epicardial) - endocardial-only ablation has high recurrence
- *Ablation reduces shocks; it does NOT replace an ICD*
D. ICD
- Secondary prevention (prior sustained VT, VF or aborted arrest, or syncope with haemodynamic compromise): Class I
- Primary prevention: use the ARVC risk calculator (age, sex, recent syncope, NSVT, PVC burden, TWI lead count, RV EF) rather than single features
- High-risk markers: *severe RV or LV dysfunction, unexplained syncope, NSVT, high PVC burden, extensive TWI, PLN/FLNC/LMNA/TMEM43 genotype, male, proband status*
- Subcutaneous ICD is attractive in the young if no pacing/ATP need
E. Heart failure and end stage
- Standard HF therapy if ventricular dysfunction develops (ACEi/ARNI, beta blocker, MRA, SGLT2i)
- Anticoagulate if aneurysm with thrombus, or AF
- Transplantation for refractory arrhythmia or biventricular failure
F. Family
- Cascade clinical screening (ECG, echo, +/- CMR) of all first-degree relatives from ~10-12 years, repeated every 1-3 years through adolescence and adulthood - penetrance is age-dependent
- Genetic testing and counselling; predictive testing in relatives once a pathogenic variant is identified
Associations
- Naxos disease - woolly hair + palmoplantar keratoderma (JUP, recessive)
- Carvajal syndrome - woolly hair, keratoderma, left-dominant ACM (DSP)
- Endurance athletes - both a modifier of disease and a source of diagnostic confusion
- Sudden death in the young / athletes; family history of premature sudden death
- Recurrent "myocarditis" with chest pain and troponin rise - DSP and FLNC hot phases
- Atrial arrhythmias and RA/RV thrombus in advanced disease
Natural history & complications
- Four phases:
1. Concealed - structurally normal, sudden death can still occur
2. Overt electrical - symptomatic arrhythmia, minor structural change
3. RV failure - global RV dysfunction, LV preserved
4. Biventricular failure - resembles DCM
- Annual mortality ~1-3%; arrhythmic event rate higher
- Highest risk in the first years after diagnosis and in probands
- *The commonest first presentation in the young is sudden cardiac death* - which is the argument for family screening
- Predictors of poor outcome: prior arrest/sustained VT, syncope, severe RV or LV dysfunction, extensive TWI, high PVC burden, PLN/FLNC/TMEM43/LMNA genotype, male sex, continued competitive sport
- Follow-up: annual ECG, Holter, echo; CMR periodically; device checks; re-evaluate exercise adherence at every visit
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