Understanding why ACM classically targets the RV requires knowing its unique anatomy:

"Triangle of Dysplasia": The classic sites of fibrofatty replacement in ARVC form a triangle involving:

1. RV inflow (subtricuspid region)
2. RV apex
3. RV outflow tract (RVOT)

Why these regions? They experience the greatest wall stress during ventricular contraction because they are the thinnest parts of the RV with the most mechanical deformation.

Desmosomes (Greek: desmos = bond, soma = body) are specialised cell-cell junctions that rivet adjacent cardiomyocytes together at the intercalated disc. They consist of:

9 chromosomal loci identified, e.g. RyR2, desmoplakin, plakoglobin. ^[2]

When any of these proteins is defective, the desmosome weakens → cardiomyocytes detach under mechanical stress → cell death → repair with fibrous tissue and adipocytes.

The intercalated disc is a composite structure containing:

1. Desmosomes (mechanical coupling)
2. Adherens junctions (mechanical coupling)
3. Gap junctions (connexin-43 — electrical coupling)

Desmosomal mutations disrupt gap junction localisation → loss of electrical coupling → heterogeneous conduction → re-entry → VT/VF. This is why arrhythmias can appear before overt structural changes are visible on imaging.

Genetics: AD inheritance with variable penetrance. ^[1][2]

Key principle: ACM is autosomal dominant with variable penetrance and expressivity ^[1][2]. This means:

• 50% chance of passing on the mutation
• Not everyone with the mutation develops disease (incomplete penetrance)
• Those who do develop it may have different severity (variable expressivity)
• Compound/digenic heterozygosity (≥2 desmosomal variants) → worse prognosis ^[1]

• In HK, genetic testing is increasingly available through the Inherited Cardiac Conditions (ICC) service at Grantham Hospital / Queen Mary Hospital
• PKP2 mutations are the most commonly identified, similar to Caucasian populations
• Family screening with ECG, Holter, and echocardiography is standard practice for first-degree relatives ^[1]
• Genetic counseling is a key management principle ^[1]

The modern classification recognises ACM as a spectrum:

Cardiomyopathies are characterised by exhibiting an inappropriate amount of: ventricular hypertrophy or dilatation, and stiffness. ^[1]

Majority asymptomatic, presents 2nd–5th decade. ^[2] The disease may remain concealed until a catastrophic arrhythmic event, including SCD as the first manifestation.

• Incidental finding (40%) from screening of family members ^[2]
• Roughly 50% of patients present with arrhythmic symptoms
• SCD may be the first manifestation in up to 10–20% of cases

The ECG is a critical screening and diagnostic tool. Understanding each abnormality requires knowing the underlying pathology:

[Adapted from lecture slides and senior notes ^[1][4]]

This is the most critical differential — a young person (< 35) who presents with VT, VF, aborted SCD, or exercise-related syncope. The major structural and electrical conditions to consider:

Cardiac arrest causes: Coronary artery disease (85%), Structural heart disease (10%): AS, HCM, DCM, ARVD, congenital HD; Others (5%): LQTS, Brugada syndrome, WPWS, drug-induced TdP, severe electrolyte imbalance. ^[13]

When ACM presents late with progressive RV dysfunction and signs of right heart failure (elevated JVP, peripheral oedema, hepatomegaly, ascites), the DDx broadens to other causes of predominant right heart failure:

Many ACM patients are identified through incidental ECG findings — particularly T-wave inversion in right precordial leads (V1–V3) ^[2]. This finding, while present in ~90% of ARVC patients, is non-specific ^[2]. The DDx of T-wave inversion in V1–V3 includes:

When you encounter VT of LBBB morphology — meaning the arrhythmia originates from the RV — the key differential is between ACM and a benign entity:

This deserves special emphasis because the overlap between ACM and myocarditis is profound:

• ACM patients undergo periodic inflammatory "hot phases" with myocardial oedema, troponin elevation, and chest pain
• On CMR, these episodes show subepicardial/mid-wall LGE and oedema → exactly like viral myocarditis
• On endomyocardial biopsy, lymphocytic infiltrate is seen → identical to lymphocytic myocarditis
• Endomyocardial biopsy is gold standard, but has risk for cardiac perforation ^[9]
• Many patients initially labelled "myocarditis" are later reclassified as ACM when genetic testing returns positive or when the disease recurs/progresses

How to differentiate: Family history, genetic testing, progressive RV involvement, characteristic ECG (epsilon wave, T-wave inversion V1–V3), and the pattern of structural disease on CMR (fatty infiltration is specific to ACM).

Intense endurance training causes physiological RV remodelling ("athlete's heart"):

• RV dilatation (can be significant)
• Mildly reduced RVEF
• T-wave inversion V1–V2 (training-related)

This can overlap with early ACM, creating a diagnostic dilemma. Key discriminators:

The key constraint is that criteria must come from different categories — you cannot count two minor criteria from the same category as two separate criteria.

This category assesses RV morphology and function using three imaging modalities. The principle: fibrofatty replacement → wall thinning → regional or global dysfunction → detectable on imaging.

Echo / MRI / RV angiography showing RV akinesia, dyskinesia, aneurysms and significant dilatation / reduced systolic function. MRI gold standard. ^[1]

Why these thresholds? The cut-offs were derived from population studies comparing confirmed ARVC patients with healthy controls. They represent the balance between sensitivity and specificity — too liberal and you over-diagnose athlete's heart; too strict and you miss early disease.

Endomyocardial biopsy showing significant fibrous replacement of RV free wall myocardium. ^[1]

Why is biopsy not routinely done?

• Again, not a must to do all investigations, pick the least invasive ones first, and do more invasive ones when still confused or indicated. ^[1]
• The RV free wall is thin (3–5 mm) → risk of perforation during biopsy
• Fibrofatty replacement is often patchy and predominantly in the "triangle of dysplasia" areas → a biopsy from the septum (the safest biopsy site) may miss the disease entirely (sampling error)
• The septum is usually spared in ACM → biopsying the septum gives a false-negative result
• Biopsy of the RV free wall is technically challenging and carries significant risk
• Therefore, biopsy is reserved for cases where non-invasive workup is inconclusive and the diagnosis would change management

Repolarization: T wave inversion at V1–V3 or beyond in patients > 14 y/o without complete RBBB. ^[1]

Why the age cut-off of 14?

• V1 to V3 septal leads → anterior surface of the heart occupied by RV ^[1]. In children and young adolescents, T-wave inversion in V1–V3 is a normal developmental variant (the "juvenile T-wave pattern") reflecting the normal RV dominance of the paediatric heart. By age 14, this pattern should have resolved. Persistence beyond age 14 is abnormal and raises suspicion for RV pathology.

Why exclude complete RBBB?

• Complete RBBB (QRS ≥ 120 ms) causes secondary repolarisation abnormalities including T-wave inversion in V1–V3 as an expected finding. If the T-wave inversion is simply due to RBBB, you cannot attribute it to ACM. However, if T-wave inversion extends to V4 and beyond in the setting of RBBB, it goes beyond what RBBB alone would cause → this becomes a minor criterion.

Depolarization: Epsilon wave. ^[1]

Epsilon wave specific for ARVC, very focal area of conduction delay. ^[15]

Prolonged S wave upstroke (≥ 55 ms from nadir to baseline) ^[2] — This reflects the delayed activation of the RV free wall due to fibrofatty replacement. The depolarisation wavefront reaches the scarred RV wall last, producing a prolonged terminal deflection.

Signal-averaged ECG (SAECG): This is a specialised high-resolution ECG technique that averages multiple QRS complexes to reduce noise and detect late potentials — low-amplitude high-frequency signals at the end of the QRS that indicate slow, fragmented conduction through diseased myocardium. These are the same delayed potentials that produce the epsilon wave on surface ECG, but SAECG can detect them with higher sensitivity.

VT / NSVT of LBBB morphology and superior axis. ^[1]

Why LBBB morphology? Because the arrhythmia originates in the RV → the depolarisation wavefront spreads from right to left = LBBB pattern on surface ECG (V1 is predominantly negative).

Why superior axis? The origin is typically in the RV inferior wall or apex (within the "triangle of dysplasia") → the electrical vector is directed superiorly → negative in inferior leads (II, III, aVF), positive in aVL. This distinguishes ACM-related VT from the more benign idiopathic RVOT VT, which has LBBB morphology but with inferior axis (origin is from the RVOT which is anatomically superior → vector goes down).

Arrhythmogenic right ventricular cardiomyopathy: VT / NSVT / PVC > 500/d (for diagnosis), VT / NSVT / PVC > 1000/d (for prognostication). ^[14]

≥ one 1st degree relative with ARVC diagnosed pathologically / by Task Force Criteria. ^[1]

Why is family history its own category?

• A bit different to both DCM/HCM ^[1] — In DCM and HCM, family history contributes to the clinical picture but isn't a standalone diagnostic criterion category. In ARVC, because the disease has autosomal dominant inheritance with variable penetrance, many family members carry the gene but have subclinical disease. Identifying a family history of confirmed ARVC or a pathogenic mutation in a 1st-degree relative is strong evidence.
• Finding a pathogenic mutation (e.g., PKP2) counts as a major criterion in the family history category, even without a known affected relative.

The ECG is the first and most important screening tool. It is cheap, non-invasive, and abnormal in up to 90% of ARVC patients at the time of diagnosis ^[2].

≥ 1 of 3 parameters abnormal (in the absence of QRS ≥ 110 ms on standard ECG) = Minor depolarisation criterion.

SAECG is essentially a higher-sensitivity method of detecting the same delayed conduction that produces epsilon waves. It averages hundreds of beats to reduce noise and extract these tiny signals. It is most useful when the standard ECG is equivocal.

Echo showing RV akinesia, dyskinesia, aneurysms and significant dilatation / reduced systolic function. ^[1]

Limitations of echocardiography for ACM:

• The RV is the most anterior chamber → just use transthoracic ^[15] (transoesophageal is not better for RV assessment)
• RV geometry is complex (crescent-shaped, wraps around LV) → hard to quantify accurately
• Fatty infiltration is not visible on echo
• Echo may miss early/mild disease → CMR needed

MRI gold standard. ^[1] MRI: fatty infiltration visualized. ^[2]

Pitfalls of CMR in ACM:

• Fat is normally present in the epicardial groove and around the RV → do not over-interpret isolated fatty signals
• Motion artefact in the thin RV free wall can mimic wall motion abnormalities
• Fatty infiltration alone (without wall motion abnormality or fibrosis) is not diagnostic
• CMR cannot be performed in patients with non-MRI-conditional ICDs (though many newer ICDs are MRI-conditional)

Indications for ambulatory cardiac monitoring — Diagnosis of cardiomyopathies / primary arrhythmia syndromes: Arrhythmogenic right ventricular cardiomyopathy: VT / NSVT / PVC > 500/d. ^[14]

Prognostication thresholds:

• > 500 PVCs/day: diagnostic minor criterion ^[14]
• > 1000 PVCs/24 hours: specific minor risk factor for SCD ^[1][14]

Electrophysiological study (EPS) — indicated in suspected arrhythmic aetiology in cardiomyopathy and CHF. ^[5]

When to perform EPS: Not first-line. Reserved for:

• Risk stratification when non-invasive assessment is inconclusive
• Guiding ablation for recurrent VT
• Differentiating ACM-related VT from idiopathic RVOT VT when imaging is equivocal

Endomyocardial biopsy showing significant fibrous replacement of RV free wall myocardium. ^[1]

Mostly involve genes encoding desmosome, intercalated disc and ion channels. ^[1]

Genetic counseling → 3-generation family tree, genetic screening. ^[1]

Screening of relatives by ECG/Holter. ^[2]

Blood tests are not part of the Task Force Criteria but are important for:

No competitive or frequent high intensity endurance exercise that is associated with ↑ ventricular arrhythmias and progression of disease. ^[1]

Exercise: The more exercise you do, the faster you die. ^[1]

Why does exercise matter so much in ACM but not as critically in, say, LQTS?

• In LQTS, exercise triggers arrhythmias via adrenergic stimulation of abnormal ion channels — but exercise doesn't structurally worsen the channel defect.
• In ACM, exercise does both: (1) triggers acute arrhythmias via catecholamine surge AND (2) structurally accelerates disease progression by mechanically stressing weakened desmosomes. It's a double hit.

Beta-blockers for ALL to prevent ventricular arrhythmias. ^[2] Consideration of beta blockers if no ICD. ^[1]

Contraindications (same as general β-blocker contraindications):

• Severe bradycardia / sick sinus syndrome / high-degree AV block (without pacemaker)
• Severe bronchial asthma (relative — can use cardioselective agents cautiously in COPD)
• Acute decompensated heart failure (may worsen haemodynamics acutely — but once stabilised, β-blockers should be initiated/continued)
• Vasospastic angina (β-blockers may worsen coronary vasospasm — uncommon consideration in ACM)

Side effects of beta-blockers: bradycardia, syncope, hypotension, bronchial spasm, impaired glucose tolerance. ^[16]

Antiarrhythmics and beta blockers if recurrent ventricular arrhythmias. ^[1]

Antiarrhythmics are second-line — they are added when β-blockers alone are insufficient, or when patients have recurrent VT episodes or ICD shocks despite β-blockers.

Key principle: Antiarrhythmic drugs in ACM are adjunctive, not protective. They reduce arrhythmia burden and ICD shocks, but they do NOT eliminate the risk of SCD. An ICD remains necessary in high-risk patients even when antiarrhythmics are prescribed.

Antithrombotic therapy if AF, intracavitary thrombosis, thromboembolism. ^[1]

Intractable ventricular arrhythmias / heart failure → LVAD / heart transplant. ^[1]

Cardiac transplantation if develop end-stage HF or refractory VAs. ^[2]

Genetic counseling. ^[1] Screening of relatives by ECG/Holter. ^[2]

Management of RV dysfunction: Symptomatic RV dysfunction: nitrate to reduce preload; may try ACEI / ARB / BB / AA / diuretics. ^[1]

LVEF ≤ 35% — marker of severity, if ARVC has biventricular involvement. ^[1]

When ACM extends to involve the LV (biventricular pattern), the clinical picture becomes indistinguishable from dilated cardiomyopathy (DCM):

LVAD / heart transplant → for intractable ventricular arrhythmias / heart failure. ^[1]