Arrhythmogenic Cardiomyopathy

Meet the patient

A 19-year-old rower slumps over the finish line unconscious, and comes round in the ambulance with an ECG showing T-wave inversion across V1 to V3 and a tiny notch riding the end of his QRS. He has palpitated through training for six months, always in the last kilometre, and an uncle died suddenly at 41 playing football. The registrar calls it benign RVOT ectopy and reaches for reassurance.^[1][4]

Two exam questions are now live, and the second is the one that buries patients: is this ARVC or benign RVOT VT? (the axis and the QRS settle it in thirty seconds) and may he go back in the boat? (no — not until arrhythmogenic cardiomyopathy is excluded). Hold those two questions and everything below slots into place.^[1][6]

The one spectrum, three faces — and why ARVC grew into ACM

Arrhythmogenic cardiomyopathy is an inherited heart-muscle disease in which ventricular myocardium is progressively replaced by fibro-fatty scar — classically in the right ventricle, but increasingly in the left, and often both. It used to be called arrhythmogenic right ventricular cardiomyopathy (ARVC); the umbrella widened to ACM once autopsy series showed left ventricular involvement in up to 76 percent of affected hearts, usually subepicardial or mid-mural in the free wall.^[5][12]

Four pillars hold the disease up, and examiners want them named in order: a genetic substrate (usually autosomal-dominant desmosomal mutation); a structural phenotype of fibro-fatty substitution beginning at the RV inflow, outflow and apex; an electrical phenotype of slow conduction — epsilon waves, late potentials, re-entrant VT; and a clinical phenotype of palpitations, syncope and sudden death in the young, almost always exertion-related.^[1][8]

The criteria have tightened with the science: the 1994 ESC Task Force gave way to the quantitative 2010 Modified Task Force Criteria (Marcus), then to the 2020 Padua CMR criteria (Corrado) that finally let the MRI carry its weight.^[3]

The triangle of dysplasia — why the right ventricle takes the beating

The right ventricle is preferentially scarred because it is the thinnest-walled chamber under the highest wall stress when you exercise. Repeat that sentence in a viva and you have earned the mechanism marks.^[1]

The disease homes in on three regions — the RV inflow, the RV outflow tract, and the RV apex — the triangle of dysplasia, where wall stress is highest and the myocardium shears apart first under load. Endurance sport is not a bystander here: it is the loading condition that detonates the genotype. In the 21-year Veneto cohort, competitive athletes carried a relative risk of sudden death from ARVC of 5.4 (95% CI 2.5 to 11.2) compared with non-athletes — the five-fold multiplier you quote in the viva.^[1][6]

Etymology for viva gold: dysplasia, from Greek dys (bad) plus plasis (formation) — badly formed. The name predates the genetic era; the original Italian pathologists saw a ventricle that looked malformed, fatty and thin, and the word survived the discovery that the malformation is acquired, gene by gene, year by year.^[8]

Three faces on imaging, one family of genes

Classify ACM along three axes — phenotype, genotype, and phase — and never blur them. The first axis is which ventricle is scarred.^[1]

^[1]

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The second axis is genotype — and this is the cluster to memorise. A pathogenic variant is found in up to 73 percent of probands, and the desmosomal genes carry most of that yield; the rest are non-desmosomal.^[2]

The desmosomal cluster, in descending yield as the ESC grades it: PKP2 (plakophilin-2) — the single commonest and the only gene in the "very common" tier (over 10 percent of tested cases; 19 percent of probands in Xu's series), usually truncating variants; DSC2 (desmocollin-2) and DSG2 (desmoglein-2) — "common", 1 to 10 percent of tested cases each; DSP (desmoplakin) — under 1 percent but with strong evidence, and the gene behind left-dominant disease and exercise-triggered myocarditis; and JUP (plakoglobin) — under 1 percent, recessive, and the cause of Naxos disease.^[9][13]

Two named syndromes travel with this cluster and examiners love them: Naxos disease — recessive JUP, the triad of woolly hair, palmoplantar keratoderma and ARVC, and the cardiomyopathy is 100 percent penetrant by adolescence in homozygotes (the youngest in Protonotarios' series met criteria at 13); and Carvajal syndrome — recessive DSP, the same skin-and-hair triad but with predominantly left ventricular disease manifesting in childhood.^[16][17]

The classic trap — the genotypes that kill with a preserved EF. LMNA, FLNC-truncating variants and TMEM43 run a 5 to 10 percent annual sudden-death rate, and PLN, DSP and RBM20 a 3 to 5 percent rate, whatever the ejection fraction is doing. The ESC therefore considers an ICD at LVEF above 35 percent in these six genotypes — class IIa when additional risk factors are present, class IIb when they are not. The EF is a lagging indicator here, and waiting for it to fall is how patients die.^[13]

The non-desmosomal tail: TMEM43 (Newfoundland founder, one of the highest-risk genotypes), LMNA (overlap with DCM and conduction disease), PLN p.Arg14del (Netherlands founder, biventricular with mid-wall LV scar), plus DES, CDH2, CTNNA3, SCN5A and RBM20. Compound and digenic heterozygosity is common — Xu found PKP2 variants in trans in 9 of 38 PKP2 probands and a second desmosomal-gene variant in 16 of 38 (42 percent) — and pedigrees show wide intra-familial variability, from severe early-onset disease to asymptomatic carriers.^[9][10]

The four phases — concealed, electrical, failing, burnt-out

ACM moves through four named phases, and a patient can die in any of them — including the first. This is the phase rule examiners want reproduced.^[1]

1. Concealed phase — silent structural change, normal tests, no symptoms; the first presentation may be sudden cardiac death on the track.
2. Overt electrical phase — palpitations, syncope, non-sustained or sustained VT, almost always exertion-triggered.
3. RV dysfunction phase — right-heart failure with raised JVP, oedema, hepatomegaly.
4. Biventricular burnt-out phase — indistinguishable from dilated cardiomyopathy, both ventricles failing, arrhythmias refractory.^[1]

How common, who, and how lethal

^{[2] [12]}

Among 60 young people (mean age 22.3 years) dying suddenly in the Veneto region over seven years, 12 (20 percent) had ACM at autopsy; across studies of sudden death in athletes, ACM accounts for roughly 10 to 15 percent of cases. Veneto is not a uniquely Venetian disease — it is where systematic autopsy study and universal pre-participation screening found it first. The geography is exam gold.^[12]

Risk accelerators to name on autopilot: male sex (male predominance among probands), competitive endurance sport (the 5.4-fold relative risk from the Veneto cohort), family history of premature sudden death, and founder ancestry (Veneto, Naxos, the Dutch PLN cluster, Newfoundland).^[2][6][12]

Why the scar forms — the wounded-healer hypothesis

The unifying model is the wounded healer: a mechanically weak desmosome tears under load, the dying myocytes are replaced by fat and fibrous tissue, and that scar both conducts slowly and re-enters. Five steps, each with a clinical fingerprint.^[8]

Step 1 — a defective desmosome. A mutation in PKP2, DSP, DSG2, DSC2 or JUP weakens the intercalated disc. Desmosomes anchor desmin filaments to the cadherins (desmoglein, desmocollin) through plakoglobin and plakophilin, and bolt them to the cytoskeleton through desmoplakin. Break any link and the junction turns friable.^[1]

Step 2 — exercise shears the myocytes apart. The thin-walled, high-stress right ventricle takes the load; repetitive stretch during endurance sport detaches cardiomyocytes, fastest at the triangle of dysplasia. This is the mechanistic reason sport is not a lifestyle choice here, it is a disease accelerator.^[1]

Step 3 — death and inflammatory repair. Detached myocytes die by apoptosis and necrosis. A macrophage infiltrate clears the debris — often misread histologically as myocarditis — and the gap is patched with fibroblasts and, characteristically, adipocytes.^[1][10]

Step 4 — fat, through Hippo and Wnt. Desmosomal dysfunction shunts plakoglobin out of the junction and into the nucleus, where it suppresses canonical Wnt signalling and fires up the Hippo effector YAP/TAZ, diverting cardiac progenitors toward fat. That is the histological signature — surviving myocyte strands swimming in fat.^[8]

Step 5 — slow conduction and re-entry. The fibro-fatty scar insulates surviving muscle, conducting slowly and fractionally — the surface epsilon wave and the late potentials on signal-averaged ECG. Slow conduction plus unidirectional block is the substrate for re-entrant VT, with a macro-re-entrant circuit around RV scar exiting near the apex or inflow — the classical LBBB VT with a superior axis.^[1]

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How the patient walks in — and the trap of the normal examination

The presentation tracks the four phases and is wildly variable, even within one family. A normal examination does not exclude ACM — the diagnosis is driven by the ECG and imaging, not the stethoscope.^[1][4]

Palpitations are the commonest symptom; they may be isolated PVCs, NSVT, or sustained VT. Syncope or pre-syncope that is exertion-related presages sudden death and mandates urgent evaluation — do not file it as vasovagal. Cardiac arrest can be the first manifestation at any stage, often during or just after exercise, and those who present with VF or sudden death are typically much younger (median 23 years) than those who present with sustained monomorphic VT (median 36 years). In the burnt-out phase, right-heart failure dominates — oedema, raised JVP, hepatomegaly, effort intolerance.^[1][12]

The classic trap — a normal exam in early disease. Between events the patient looks and sounds well. Auscultation only turns abnormal late (an S3, a wide fixed-split S2, tricuspid regurgitation in RV failure). The dermatological phenotypes are the exception: Naxos brings woolly hair and palmoplantar keratoderma, Carvajal the striate keratoderma — spot the skin and you have the genotype.^[1]

The symptom that decides the work-up is exertion. An athlete with palpitations or syncope during sport is assumed to harbour ACM, HCM, long QT, an anomalous coronary or myocarditis until proven otherwise. The trigger is the clue, not the symptom.^[6]

Read the ECG like the consultant does — EPSILON, with a scene

The ECG is the cornerstone of diagnosis, and the findings cluster into one memorable signature. Picture the consultant turning to the board after the arrest: she writes seven letters and says if you cannot rule ARVC in or out with this, you have not looked hard enough.^[1]

The high-yield findings, then the mnemonic:^[1]

• Epsilon wave — reproducible low-amplitude signals between the end of the QRS and the onset of the T wave in V1 to V3. Highly specific but insensitive: it is recorded in patients with advanced disease who already meet other major criteria, and the 2020 Padua revision downgraded it from a major to a minor criterion.
• T-wave inversion V1 to V3 or beyond without complete RBBB — the commonest repolarisation abnormality, and a major Task Force criterion in anyone over 14 years.
• Terminal activation delay — at least 55 ms from the S-wave nadir to the end of the QRS (including R') in V1, V2 or V3, in the absence of complete RBBB; this is the delayed S-wave upstroke, and it is a minor criterion in both the 2010 and Padua sets.
• Localised prolongation of right precordial QRS duration with a relatively normal V6 — the parietal block. This was a major criterion in the 1994 set; the 2010 revision folded it into the epsilon wave and it is no longer scored separately.
• Low limb-lead voltages in advanced disease; frequent PVCs of LBBB morphology with superior axis, NSVT or sustained VT.
• Late potentials on signal-averaged ECG — filtered QRS at least 114 ms, RMS voltage of the terminal 40 ms below 20 microV, low-amplitude signal duration at least 38 ms; any one of the three, in the absence of a standard QRS of 110 ms or more, is a minor Task Force criterion.^[1][12][13]

^[1]

The scene that fixes the mnemonic: epsilon wave on the strip, prolonged S-upstroke in V1, superior-axis VT on the monitor, inverted T waves across the precordial leads, late potentials on the signal-averaged ECG, an idiopathic label you have now refused, the triangle of dysplasia on the MRI, and no RBBB to explain any of it. Seven findings, one disease.^[1]

Two ECG subtleties examiners test: incomplete or complete RBBB is common and does not exclude ACM (TWI extending into V4 to V6 still points to it), and TWI in V1 to V3 in a child under 14 years may be a normal juvenile pattern — do not over-diagnose ACM before adolescence unless other criteria are present.^[1]

The 30-second bedside fork — ARVC VT or benign RVOT VT?

This is the single most decisive bedside discriminator in the topic, and it is decided by the axis and the QRS. Get it wrong and you reassure a patient who is about to die, or you implant a defibrillator in someone who needed an ablation and a cup of tea.^[1]

^[1]

The discriminator line: superior axis plus notched QRS plus scar on the MRI equals ARVC; inferior axis plus smooth QRS plus adenosine-sensitive equals benign RVOT VT. One sentence, full marks.^[1]

The wider differential — and the mimics that also scar the RV

Several diseases produce VT, syncope and an abnormal RV, and each carries a different management. Name them with a discriminator, not a list.^[2]

^[1]

The classic trap — recurrent viral myocarditis that is actually DSP

When one patient keeps presenting with exertion-triggered, troponin-positive chest pain and patchy late gadolinium enhancement, it is not bad luck with viruses — it is desmoplakin. Poller and colleagues showed that truncating DSP variants cause familial recurrent exercise-triggered myocarditis that masquerades as viral illness, and the clue to stop calling it myocarditis and start calling it genetics is a family history of sudden death or dilated cardiomyopathy.^[10]

The same trap runs the other way: the older patient labelled idiopathic dilated cardiomyopathy may be a burnt-out ARVC — a prior history of palpitations or syncope, RV predominance, and an epsilon wave redirect the diagnosis and the family screen.^[5]

Make the diagnosis with the 2010 Task Force math

The diagnostic strategy is the 2010 Modified Task Force Criteria in six categories — and the arithmetic is the exam favourite. Definite is 2 major, or 1 major plus 2 minor, or 4 minor from different categories; borderline is 1 major plus 1 minor, or 3 minor from different categories; possible is 1 major, or 2 minor from different categories.^[1]

The six categories, graded major or minor by how specifically each feature points to ACM:^[1]

1. Imaging (global or regional dysfunction). Regional RV akinesia, dyskinesia or aneurysm is required, plus a quantitative cut-off: on echo, PLAX RVOT at least 32 mm, PSAX RVOT at least 36 mm, or fractional area change 33 percent or less (major); on CMR, regional RV akinesia, dyskinesia or dyssynchrony plus either RVEDV/BSA at least 110 mL/m2 (male) or 100 mL/m2 (female) or RVEF 40 percent or less (major).^[1] The 2020 Padua update keeps the same structure but replaces the fixed volume and EF thresholds with imaging-, age- and sex-specific nomograms, and adds contrast-enhanced CMR tissue characterisation and a parallel set of left ventricular criteria.^[3][13]
2. Tissue characterisation (biopsy). Residual myocytes below 60 percent by morphometry (or below 50 percent if estimated) with fibrous replacement of RV free wall myocardium in at least one sample is major; 60 to 75 percent (50 to 65 percent if estimated) is minor. Note what the criterion demands — a free-wall sample — while everyday practice samples the safer septum, which is why biopsy is insensitive and is reserved for equivocal cases.^[1][13]
3. Repolarisation. Major: TWI V1 to V3 or beyond, without complete RBBB, in anyone over 14 years. Minor: TWI V1 to V2, TWI V4 to V6, or TWI V1 to V4 with complete RBBB.^[1]
4. Depolarisation or conduction. Major: epsilon wave in V1 to V3. Minor: late potentials on SAECG (any one of the three parameters, when the standard QRS is under 110 ms); terminal activation duration at least 55 ms in V1, V2 or V3 without complete RBBB. Those two are the whole minor list — there is no QRS-ratio criterion in the 2010 set.^[1][13]
5. Arrhythmia. Major: sustained or non-sustained VT of LBBB morphology with superior axis (negative or indeterminate in II, III, aVF and positive in aVL). Minor: VT of RV outflow configuration — LBBB with inferior axis — or of unknown axis; more than 500 ventricular extrasystoles in 24 hours on Holter. Atrial fibrillation is a complication of advanced disease, not a Task Force criterion.^[1][13]
6. Family history. Major: ARVC confirmed in a first-degree relative meeting criteria; ARVC confirmed at autopsy or surgery in a first-degree relative; a pathogenic mutation in the patient. Minor: a history of ARVC in a first-degree relative who cannot be formally assessed; premature sudden death under 35 years in a first-degree relative; ARVC confirmed pathologically or by criteria in a second-degree relative.^[1]

^[1]

The Padua 2020 update in one line: it upgrades diagnosis from ARVC to the whole ACM spectrum by adding contrast-enhanced CMR tissue-characterisation criteria, plus depolarisation and repolarisation ECG abnormalities and ventricular-arrhythmia features for the left ventricular phenotype — and it demotes the epsilon wave from major to minor. The authors say so themselves: the proposed criteria still need validation in large cohorts.^[3][13]

Investigations that change management

A handful of tests do the diagnostic work; everything else is context. First-line is the 12-lead ECG plus signal-averaged ECG, a 24-hour Holter (extended if suspicion is high), and a transthoracic echocardiogram, then cardiac MRI, which is what lets the Padua criteria read the tissue rather than only the wall motion.^[1][3]

The Holter quantifies PVC burden — more than 500 PVCs in 24 hours is the minor Task Force criterion, and the 24-hour PVC count is one of the predictors in the ARVC risk calculator — and it captures the VT morphology. Exercise ECG is used cautiously because ACM arrhythmias are exertion-triggered; it may unmask TWI or VT in recovery, so do not run it in overt disease without monitoring.^[1][7]

Genetic testing is both a diagnostic and a public-health tool: a pathogenic variant is itself a major Task Force criterion and triggers cascade screening of every first-degree relative with ECG, ambulatory monitoring, echo and CMR. Programmed electrical stimulation has not disappeared — inducible sustained VT is still used to sharpen an individual ICD decision (class IIa), and the ESC supports an ICD in symptomatic patients with moderate RV (under 40 percent) or LV (under 45 percent) dysfunction who have either NSVT or inducible sustained monomorphic VT.^[2][13]

Management — no sport, beta-blocker first, ICD when it counts

Four parallel streams — lifestyle, drugs, devices, ablation or surgery — and the lifestyle line is the one juniors under-prescribe. Hold the streams in that order.^[2]

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^{[2] [13]}

The time-critical scenario first: monomorphic or polymorphic VT with haemodynamic compromise in a young person. Run the ALS pathway — ABCDE, correct potassium and magnesium, and treat the triggers (ischaemia, fever, electrolytes, pro-arrhythmic drugs, sympathomimetics). Pulseless VT or VF: immediate defibrillation with high-quality CPR, adrenaline and amiodarone as per the ALS algorithm. Stable monomorphic VT: intravenous antiarrhythmic infusion under continuous monitoring; unstable VT: synchronised DC cardioversion under sedation. Once stabilised, plan an ICD — these patients recur.^[2][11]

1. Lifestyle — the most under-prescribed intervention. Moderate- and high-intensity exercise, including competitive sport, is not recommended in individuals with ARVC (ESC class III); regular low-to-moderate-intensity exercise in those able to do it is recommended (class I); and in genotype-positive, phenotype-negative relatives, high-intensity exercise and competitive sport should be avoided (class IIb). The relative risk of sudden death from ARVC in competitive athletes was 5.4 in the Veneto cohort, and the disease itself progresses faster under load.^[6][13]

Recreational low-intensity activity (gentle walking, golf) is permitted in carriers without phenotype; high-intensity isometric weightlifting is not. Occupational restrictions hit commercial pilots, drivers, divers and HGV licences.^[13]

The classic trap — the sport that kills

The single most preventable cause of sudden death in ACM is the sport the patient is still playing. Everyone remembers the beta-blocker and forgets the lifestyle line; that is the recurring trainee error, and it is the one that costs lives. After Italy made pre-participation ECG screening mandatory, sudden cardiovascular death in screened Veneto athletes fell by 89 percent (3.6 to 0.4 per 100,000 person-years) while the unscreened non-athletic population did not change — and the fall was driven predominantly by fewer deaths from cardiomyopathies, in parallel with more athletes being identified and disqualified.^[14]

2. Pharmacological therapy. Beta-blockers come first, and the antiarrhythmics are add-ons, not substitutes:^[2]

• Beta-blockers — recommended as first-line therapy in symptomatic patients by the ESC; advised in ARVC whether or not there are arrhythmias or an ICD (class IIa). The AHA/ACC is the one document that names a drug and a dose: atenolol 25 to 100 mg orally once or twice daily, titrated against ambulatory monitoring or exercise testing.^[2][13]
• Amiodarone or sotalol — added for arrhythmic symptoms or to reduce ICD shocks. Be honest about the evidence: in the North American ARVC Registry neither beta-blockers nor sotalol appeared protective, and sotalol carried an increased risk of ICD shocks, while amiodarone — in only 10 patients — showed superior efficacy. ESC-cited data likewise show amiodarone or class I drugs trending to lower VT recurrence than sotalol.^[2][15]
• In higher-risk patients the drug ladder is adjunctive: an ICD goes in, and drugs exist to suppress frequent VT recurrences and shocks.^[11][13]

In the burnt-out phase, treat heart failure exactly as dilated cardiomyopathy — ACE inhibitor or ARB or ARNI, beta-blocker, MRA, SGLT2 inhibitor, diuretics for congestion, and CHA2DS2-VASc-based anticoagulation for atrial fibrillation. Avoid QT-prolonging drugs (macrolides, fluoroquinolones, ondansetron, methadone) in patients on sotalol or amiodarone.^[1]

3. Implantable cardioverter-defibrillator — the therapy that aborts sudden death when nothing else will. Indications follow the ESC framework, and every guideline frames the decision as shared with the patient:^[2][13]

• Class I: survivors of sudden cardiac arrest, and patients with ventricular arrhythmia causing haemodynamic instability.
• Class IIa: haemodynamically tolerated sustained VT; arrhythmic (unexplained) syncope; severe RV dysfunction (RV fractional area change 17 percent or less, or RVEF 35 percent or less); symptomatic patients with moderate RV (under 40 percent) or LV (under 45 percent) dysfunction who also have NSVT or inducible sustained monomorphic VT. ARVC with LVEF 35 percent or below is treated under the DCM recommendations.
• Genotype-driven: in LMNA, FLNC-truncating, TMEM43, PLN, DSP and RBM20 carriers an ICD is considered above an LVEF of 35 percent — class IIa with additional risk factors, class IIb without them.
• Not indicated: asymptomatic gene carriers without phenotype and without documented ventricular arrhythmia — surveillance, not device.^[2][13]

Device specifics for ACM: up to 97 percent of arrhythmia episodes in ARVC ICD recipients are sustained monomorphic VT, and 92 percent of them terminate with anti-tachycardia pacing — which is the argument for a device that can deliver ATP. Where bradycardia pacing, resynchronisation and ATP are not anticipated, the ESC prefers a subcutaneous ICD (class IIa), which avoids leads in a thinned, perforation-prone RV free wall.^[2][13]

The named trap — ablation feels like a cure, and it is not

Catheter ablation reduces the arrhythmia burden; it does not replace the defibrillator. Everyone reaches for ablation after the first storm and thinks the problem is solved — it is not, and the ICD stays in. ARVC VT is macro-re-entrant with critical isthmuses on the epicardial RV surface, so every society supports a combined endocardial–epicardial approach; the HRS gives an epicardial approach a class I indication after a failed endocardial attempt. Ablation without a back-up ICD is only a class IIb option, in selected patients with recurrent haemodynamically stable VT. Recurrence is common because the substrate keeps progressing. Do coronary angiography before epicardial ablation to avoid arterial injury.^[1][13]

Advanced therapy for refractory disease: cardiac sympathetic denervation for VT storm; heart transplantation as the final option for severe unresponsive heart failure or for VT/VF refractory to ablation and ICD therapy, in experienced centres; LVAD as a bridge.^[13]

Subtypes and scenarios you will meet

• Classic RV-dominant (ARVC) — the textbook phenotype; PKP2 the commonest gene; beta-blocker plus ICD if high-risk plus no competitive sport.^[1][13]
• Left-dominant ACM — subepicardial or mid-wall LV scar, lateral TWI, often DSP, LMNA, PLN, DSG2; no epsilon wave (LV scar does not slow RV activation); lower ICD threshold in LMNA and DSP even with preserved LVEF.^[5][13]
• Naxos disease (recessive JUP) — woolly hair, palmoplantar keratoderma, ARVC that is 100 percent penetrant by adolescence; an ICD is indicated to prevent sudden death.^[16][17]
• Carvajal syndrome (recessive DSP) — striate keratoderma and woolly hair with predominantly left ventricular disease, manifesting in childhood and more often with heart failure.^[17]
• Familial exercise-triggered myocarditis (DSP) — recurrent troponin-positive chest pain with patchy LGE; genetic cascade is the key to escaping the viral myocarditis label.^[10]
• ACM in the athlete — pre-participation ECG detects TWI V1 to V3 and LBBB PVCs; definite ACM means disqualification from competitive sport; Italian screening cut athlete sudden cardiovascular death by 89 percent, chiefly by removing cardiomyopathy from the field.^[14]
• LMNA-associated ACM — high sudden-death risk (5 to 10 percent per year) at preserved LVEF; the ESC drives the ICD decision with the LMNA-specific risk score rather than a raw EF threshold.^[13]
• TMEM43 p.S358L (Newfoundland) — one of the three highest-risk genotypes (5 to 10 percent annual sudden death); an ICD is considered in male carriers, and in female carriers with LVEF under 45 percent or NSVT.^[13]

Complications and the pitfalls that lose marks

• Sudden cardiac death — the dominant mode of death in the young, exertion-related.
• Recurrent monomorphic VT, VT storm, appropriate ICD shocks — the commonest sustained arrhythmia; ablation reduces shock burden.
• Inappropriate ICD shocks — atrial fibrillation or SVT with aberrancy, or T-wave oversensing; programming and beta-blockade help.
• Right-heart failure then biventricular failure in the burnt-out phase; atrial fibrillation (anticoagulate by CHA2DS2-VASc).
• Device complications — lead perforation of the thinned RV free wall, infection, pneumothorax; favour S-ICD.
• RV thrombus and pulmonary embolism — scarred RV aneurysms are thrombogenic; consider anticoagulation in RV akinesia with low flow.^[1]

The pitfalls examiners reach for: mislabelling ARVC VT as benign RVOT VT (check the axis and the QRS); missing TWI V1 to V3 in an athlete over 14 (dismissed as early repolarisation); failing to screen the family; letting the patient return to competitive sport; misdiagnosing DSP myocarditis as viral; placing a transvenous lead in a paper-thin RV (consider S-ICD); treating the arrhythmia but not the heart failure; accepting a single normal ECG or MRI in a gene carrier (penetrance is age-, sex- and exercise-dependent, so re-screen at intervals).^[1][10][13]

Prognosis, disposition, and the relatives you must screen

Mortality in ACM is not one number — it is a risk category. Reported overall mortality ranges from 0.08 to 3.6 percent per year across series, and in a meta-analysis of about 600 high-risk patients who received an ICD the annual cardiac death rate was 0.9 percent. Stratify instead: the high-risk category (over 10 percent estimated arrhythmic events per year) covers prior cardiac arrest or sustained VT and severe RV, LV or biventricular dysfunction, and carries a class I ICD indication; intermediate risk is 1 to 10 percent per year; low risk under 1 percent. The Cadrin-Tourigny ARVC risk calculator (arvcrisk.com) puts a number on the primary-prevention decision from seven predictors — age, sex, cardiac syncope in the previous 6 months, NSVT, 24-hour PVC count, number of leads with T-wave inversion and RVEF. It was derived in 528 patients with no prior sustained arrhythmia, and LVEF, late gadolinium enhancement and genotype are not in the model.^[7][12][13]

Disposition: first-degree relatives are evaluated with 12-lead ECG, ambulatory ECG and cardiac imaging, starting at about 10 to 12 years of age and repeated every 1 to 3 years, because penetrance is age-, sex- and exercise-dependent; a relative who is negative for the familial variant can be discharged. All definite ACM belongs in a specialist inherited cardiac conditions clinic with a cardiology-and-genetics MDT, and the ESC is explicit that psychological support belongs in that package. Driving and occupational advice matter — a group 2 licence (HGV or PCV) is forfeited, private driving restricted after ICD, syncope or VT. Beta-blockers should be continued through pregnancy.^[2][13]

Evidence and guidelines that score marks

• Marcus 2010 (Modified Task Force Criteria, Circulation) — the quantitative redefinition of the 1994 criteria; six categories; the international diagnostic standard.^[1]
• Corrado 2020 (Padua criteria, International Journal of Cardiology) — extends diagnosis to the left ventricle with contrast-enhanced CMR tissue characterisation, swaps fixed volume thresholds for imaging-specific nomograms, and demotes the epsilon wave to a minor criterion; endorsed by the ESC, which notes it still lacks external validation.^[3][13]
• ESC 2022 Ventricular Arrhythmia and SCD Guideline (Zeppenfeld) — the current European standard for risk stratification and ICD thresholds, with genotype-specific advice for LMNA, DSP, PLN, TMEM43.^[2]
• Sen-Chowdhry 2008 (JACC) — defined left-dominant ACM as a distinct entity; shifted the umbrella from ARVC to ACM.^[5]
• Marcus 2009 (North American Multidisciplinary Study, Heart Rhythm) — clinical presentation and diagnostic evaluation in a large cohort.^[4]
• Corrado 2003 (JACC) — sports activity and the risk of sudden death in the young; the evidence behind mandatory ECG screening and disqualification.^[6]
• Marcus 2006 (Circulation) — the mechanistic explanation, from observation to the desmosomal hypothesis.^[8]
• Xu 2010 (JACC) — compound and digenic heterozygosity contributes to ARVC, explaining intra-family variability.^[9]
• Cadrin-Tourigny 2019 (Eur Heart J) — the ARVC risk calculator for primary-prevention ICD decisions in patients with no prior sustained arrhythmia.^[7]
• Corrado 2006 (JAMA) — the 89 percent fall in athlete sudden cardiovascular death after mandatory Italian pre-participation screening.^[14]
• Marcus GM 2009 (JACC, North American ARVC Registry) — neither beta-blockers nor sotalol were protective; amiodarone looked superior in a small subgroup.^[15]
• Iezzi 2025 (Eur Heart J Qual Care Clin Outcomes) — systematic review reconciling the ESC, AHA/ACC, HRS and European Task Force recommendations for ACM.^[13]
• Poller 2020 (J Am Heart Assoc) — DSP truncating variants cause familial recurrent exercise-triggered myocarditis masquerading as viral.^[10]
• Corrado 2017 (Circ Res) — the reference review for epidemiology, pathology and the risk-category pyramid.^[12]

The mantra

Epsilon wave and TWI V1 to V3, superior-axis LBBB VT, no competitive sport, beta-blocker first, and an ICD when the risk category says so — because nothing else aborts the arrhythmia.^[1][2]

Ward-round test — three stems, thirty seconds each

Stem 1 — the rower who collapses at the finish line (answer)ShowHide

A 19-year-old rower syncopes during a race. The ECG shows T-wave inversion V1 to V3 and frequent LBBB PVCs. The registrar calls it benign and wants to clear him to play. What do you do? Model: Do not clear him. Exertional syncope with TWI V1 to V3 and LBBB ectopy in a young athlete is arrhythmogenic cardiomyopathy until proven otherwise — alongside HCM, long QT, anomalous coronary and myocarditis. Stand him down from competitive sport immediately and work him up with signal-averaged ECG, 24-hour Holter, transthoracic echo and cardiac MRI read against the Padua criteria, plus a three-generation family history and genetic cascade screening. Only when the 2010 Task Force math and the MRI exclude ACM may he return — and a definite diagnosis means competitive sport is out for good.^[1][6][13]

Stem 2 — recurrent monomorphic VT, LBBB, superior axis (answer)ShowHide

A 26-year-old presents with recurrent monomorphic VT. The VT is LBBB morphology with a superior axis (negative in II, III, aVF) and a notched, slurred QRS. Adenosine does not terminate it. Benign RVOT VT or ARVC? Model: This is ARVC, not benign RVOT VT — and the discriminator is the axis. Superior axis (negative in the inferior leads) with a notched, slurred QRS that is adenosine-insensitive points to a scar-related macro-re-entrant circuit exiting from the RV inflow or apex; benign RVOT VT is focal, has an inferior axis, a smooth rapid QRS, and terminates with adenosine. Confirm with CMR (Padua criteria — RV akinesia or aneurysm, subepicardial or mid-wall LGE) and genetic testing; start a beta-blocker, restrict sport, and risk-stratify for an ICD.^[1]

Stem 3 — the family where viral myocarditis keeps recurring (answer)ShowHide

A 23-year-old has had three admissions in two years for troponin-positive chest pain after exercise, each labelled viral myocarditis, with patchy subepicardial late gadolinium enhancement on CMR. Her father died of dilated cardiomyopathy at 45. What is the diagnosis, and what do you do? Model: This is DSP-related arrhythmogenic cardiomyopathy presenting as familial recurrent exercise-triggered myocarditis (Poller 2020) — not recurrent viral illness. The clue is the combination of exertional triggering, patchy non-ischaemic LGE, and a family history of DCM or sudden death. Cascade to desmosomal genetic testing; if a DSP truncating variant is found, screen every first-degree relative with ECG, ambulatory monitoring, echo and CMR, restrict competitive sport, and risk-stratify for an ICD — DSP is one of the six high-risk genotypes in which an ICD is considered above an LVEF of 35 percent.^[10][13]

References17ShowHide

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