Inherited Arrhythmia and Sudden Cardiac Death Syndromes

Channelopathies

Cardiac channelopathies are inherited disorders of myocardial excitability caused by pathogenic variants in genes encoding ion channels or channel-associated proteins, producing malignant ventricular arrhythmias in the absence of overt structural heart disease. They are a major cause of sudden cardiac death in young people and are frequently unmasked by fever, exertion, sleep, drugs, electrolyte disturbance, or adrenergic stress. For MRCP purposes, the prototypical syndromes are long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome; overlap phenotypes occur because single genes may influence several phases of the cardiac action potential.

Electrophysiological basis

The ventricular action potential is governed by a balance between inward depolarising currents and outward repolarising currents. Channelopathies usually arise from either gain-of-function or loss-of-function variants, with the clinical phenotype determined by the current affected, cellular location, autonomic tone, and transmural dispersion of repolarisation.

Action potential phase	Dominant current	Key channels/genes	Pathophysiological consequence
Phase 0	Fast sodium influx, INa	SCN5A	Reduced inward sodium current slows conduction and predisposes to re-entry, particularly in Brugada syndrome and progressive cardiac conduction disease.
Phase 2	L-type calcium influx, ICa,L	CACNA1C, CACNB2	Altered plateau current affects QT duration and early afterdepolarisations.
Phase 3	Potassium efflux, IKr, IKs, IK1	KCNH2, KCNQ1, KCNJ2	Reduced outward current prolongs repolarisation and QT interval; increased outward current may shorten QT.
Calcium handling	Sarcoplasmic reticulum calcium release/reuptake	RYR2, CASQ2, TRDN	Diastolic calcium leak generates delayed afterdepolarisations and bidirectional or polymorphic ventricular tachycardia.

Mechanistically, malignant arrhythmia may arise from triggered activity or re-entry. Early afterdepolarisations occur during prolonged phase 2/3 repolarisation and are facilitated by bradycardia, hypokalaemia, hypomagnesaemia, and QT-prolonging drugs. Delayed afterdepolarisations occur after repolarisation, usually from intracellular calcium overload, and are potentiated by catecholamines. Reduced sodium current produces conduction delay and spatial heterogeneity, allowing phase 2 re-entry and polymorphic ventricular tachycardia or ventricular fibrillation.

Genetic classification and inheritance

Most clinically important channelopathies are autosomal dominant with variable penetrance and expressivity. Penetrance may be as low as 20–30% in some families, so a normal resting ECG does not exclude carriage. Autosomal recessive disease, including biallelic CASQ2-mediated CPVT or Jervell and Lange-Nielsen syndrome, is typically more severe. De novo variants and oligogenic inheritance complicate counselling. Genotype-positive/phenotype-negative individuals require risk-modifying advice because fever, drugs, and electrolyte disturbance may convert a concealed phenotype into a lethal arrhythmia.

Functional category	Typical genetic mechanism	Representative syndrome	Exam-relevant implication
Reduced repolarising potassium current	Loss of function: KCNQ1, KCNH2	Long QT syndrome	Torsades de pointes risk; avoid QT-prolonging drugs and correct K+ to high-normal range.
Reduced depolarising sodium current	Loss of function: SCN5A	Brugada syndrome	Fever and sodium-channel blockers may unmask diagnostic ECG changes.
Abnormal calcium release	Gain of function: RYR2; loss of buffering: CASQ2	CPVT	Resting ECG may be normal; exercise or catecholamine provocation is central.

Clinical evaluation and diagnostic principles

The key clinical clue is syncope with arrhythmic features: abrupt onset, no prodrome, occurrence during exertion, emotion, sleep, fever, or acoustic startle, or a family history of sudden unexplained death under 40 years. Misdiagnosis as epilepsy or vasovagal syncope is common. Initial assessment should include a 12-lead ECG with manual QTc measurement, electrolytes, medication review, echocardiography to exclude structural disease, ambulatory monitoring, and exercise testing where indicated. A QTc is usually calculated by Bazett’s formula, QTc = QT/√RR, but Bazett overcorrects at high heart rates and undercorrects at low heart rates; Fridericia correction is often preferable in tachycardia.

Genetic testing should be phenotype-directed and accompanied by pre-test counselling. Contemporary European and North American guidance supports testing when a definite clinical phenotype is present, using curated gene panels to reduce variants of uncertain significance. Cascade screening of first-degree relatives is central: if a pathogenic or likely pathogenic variant is identified, targeted testing is more informative than repeated broad panels. A negative genetic test does not exclude disease because diagnostic yield varies: approximately 70–80% in definite congenital long QT syndrome, 60% in CPVT, but only about 20–30% in Brugada syndrome.

Risk stratification and management principles

Management is syndrome-specific, but several principles apply. Reversible triggers must be addressed: potassium should generally be maintained above 4.0 mmol/L and magnesium normal; hypocalcaemia, bradycardia, fever, starvation, and interacting drugs should be corrected. Patients should be directed to curated drug-avoidance resources, particularly for QT-prolonging agents and sodium-channel blockers. Family members require cardiology-led evaluation rather than reassurance from a single normal ECG.

Implantable cardioverter-defibrillators prevent sudden death but carry substantial morbidity in young patients, including inappropriate shocks, lead failure, infection, and psychological harm. Therefore, ICD decisions require precise phenotype-based risk assessment. Secondary prevention after resuscitated cardiac arrest or documented sustained ventricular tachycardia is generally accepted. Primary prevention is more selective and depends on genotype, symptoms, ECG severity, inducibility in limited settings, and response to drug therapy. Importantly, ICD implantation does not replace disease-specific pharmacology: beta-blockade is central in adrenergically mediated disease, whereas avoidance of precipitating drugs and aggressive antipyresis are critical in sodium-channel loss-of-function states.

In examination questions, suspect a channelopathy when a young patient has sudden syncope, nocturnal agonal respiration, exertional collapse, polymorphic ventricular tachycardia, torsades de pointes, or a family history of sudden unexplained death with a structurally normal heart. The discriminator is the trigger and ECG pattern: exertion or emotion suggests adrenergic syndromes; fever or rest suggests sodium-channel disease; QT prolongation implies repolarisation abnormality; a normal resting ECG does not exclude CPVT.

Long QT Syndrome

Definition, electrophysiological mechanism and classification

Long QT syndrome (LQTS) is an inherited or acquired disorder of delayed ventricular repolarisation, predisposing to early afterdepolarisations, pause-dependent torsades de pointes, syncope, seizures and sudden cardiac death. The key measurable phenotype is QT prolongation, conventionally corrected for heart rate as QTc. In adults, QTc is generally abnormal if >450 ms in men or >470 ms in women, and high risk when >500 ms. Bazett correction, QTc = QT/√RR, is widely used in examinations but overcorrects at high heart rates and undercorrects at low rates; Fridericia correction, QTc = QT/RR^1/3, is often preferable in tachycardia.

Congenital LQTS is usually autosomal dominant Romano-Ward syndrome; the rare autosomal recessive Jervell and Lange-Nielsen syndrome combines severe QT prolongation with congenital sensorineural deafness. Penetrance is incomplete and expressivity variable; approximately 20–40% of genotype-positive relatives may have a normal or borderline resting QTc. Genetic testing identifies a pathogenic variant in roughly 70–80% of clinically definite cases, predominantly in KCNQ1, KCNH2 and SCN5A.

Subtype	Gene/channel	Current abnormality	Typical trigger	ECG clue	Therapeutic implication
LQT1	KCNQ1, IKs potassium channel	Reduced slow delayed rectifier K+ current	Exercise, especially swimming	Broad-based T waves	Excellent response to beta-blockade; avoid competitive swimming if untreated
LQT2	KCNH2, IKr potassium channel	Reduced rapid delayed rectifier K+ current	Auditory startle, emotion, postpartum period	Low-amplitude, notched or bifid T waves	Strict avoidance of QT-prolonging drugs and hypokalaemia
LQT3	SCN5A, cardiac sodium channel	Gain-of-function late Na+ current	Rest, sleep, bradycardia	Long isoelectric ST segment with late T wave	Consider mexiletine in selected genotype-positive patients

Diagnosis and risk stratification

Diagnosis should not be made from a single automated QTc. Measure from the start of QRS to the end of the T wave in leads II or V5, excluding U waves unless fused. Reversible causes must be excluded: hypokalaemia, hypomagnesaemia, hypocalcaemia, starvation, bradyarrhythmia, myocardial ischaemia and QT-prolonging drugs including macrolides, fluoroquinolones, antipsychotics, tricyclics, methadone, ondansetron, sotalol and amiodarone.

Schwartz diagnostic score component	Points
QTc ≥480 ms	3
QTc 460–479 ms	2
QTc 450–459 ms in males	1
Torsades de pointes	2
T-wave alternans	1
Notched T wave in 3 leads	1
Low heart rate for age	0.5
Syncope with stress / without stress	2 / 1
Family member with definite LQTS / unexplained sudden death <30 years	1 / 0.5

A Schwartz score ≤1 indicates low probability, 1.5–3 intermediate probability, and >3 high probability. Contemporary ESC guidance diagnoses LQTS with QTc ≥480 ms on repeated ECGs, a Schwartz score >3, or a pathogenic LQTS mutation; LQTS should also be considered with QTc ≥460 ms plus unexplained arrhythmic syncope. Major risk markers are prior cardiac arrest, recurrent syncope despite treatment, QTc >500 ms and particularly >550 ms, LQT2 in women, postpartum LQT2, and LQT3 with bradycardic events.

Management

All patients require avoidance of QT-prolonging drugs, correction of electrolytes, fever and starvation avoidance, and cascade screening of first-degree relatives with ECG and genotype-directed testing. Potassium should be maintained in the high-normal range, commonly 4.5–5.0 mmol/L, particularly in LQT2. Competitive sport decisions are individualised, but untreated symptomatic LQTS or QTc >500 ms usually precludes high-intensity participation.

Treatment	Typical adult dosing / indication	Examination points
Nadolol	1–1.5 mg/kg once daily; half-life approximately 20–24 h	Preferred non-selective beta-blocker; best adherence profile; adjust in renal impairment
Propranolol	2–3 mg/kg/day in divided doses; modified-release often 80–160 mg daily	Non-selective; effective, but shorter half-life than nadolol
Metoprolol	Not first-line	Associated with more breakthrough events in congenital LQTS cohorts
Mexiletine	150–200 mg three times daily, titrated; often 4–8 mg/kg/day	Late Na+ current blocker; most useful in LQT3 or QTc shortening demonstrated by acute testing
Left cardiac sympathetic denervation	For recurrent syncope/VT despite maximal beta-blockade or beta-blocker intolerance	Reduces adrenergic trigger burden; not a substitute for ICD after cardiac arrest
ICD	Survivors of cardiac arrest; recurrent arrhythmic syncope despite optimal therapy	Avoid inappropriate shocks; always combine with beta-blockade where tolerated

Beta-blockers are the cornerstone and substantially reduce first and recurrent cardiac events, with greatest efficacy in LQT1 and somewhat less complete protection in LQT2 and LQT3. They are indicated for symptomatic patients, QTc ≥470 ms, and generally genotype-positive patients even with borderline QTc. Acute torsades de pointes is treated with immediate defibrillation if unstable, intravenous magnesium sulfate 2 g over 10–15 minutes followed by infusion if needed, aggressive potassium repletion, withdrawal of offending drugs, and suppression of pauses. In acquired pause-dependent torsades, temporary pacing at 90–110 beats/min or isoprenaline may be used; isoprenaline is generally avoided in congenital adrenergically mediated LQTS, especially LQT1.

Brugada Syndrome

Pathophysiology and Genetics

Brugada syndrome is an inherited arrhythmia syndrome characterised by a coved ST-segment elevation in the right precordial leads and predisposition to polymorphic ventricular tachycardia or ventricular fibrillation, typically in structurally normal hearts. The critical electrophysiological substrate is centred on the right ventricular outflow tract epicardium, where reduced inward sodium current or augmented outward currents exaggerate transmural dispersion of repolarisation. This creates phase 2 re-entry and closely coupled ventricular extrasystoles capable of initiating ventricular fibrillation.

The commonest genetic association is SCN5A loss-of-function, encoding the cardiac sodium channel Na_v1.5, but pathogenic variants are found in only approximately 20–30% of clinically diagnosed cases. Inheritance is usually autosomal dominant with incomplete penetrance and variable expressivity. Male predominance is striking, with men affected approximately 8–10 times more often than women, partly reflecting testosterone-mediated modulation of outward potassium currents. Fever, alcohol excess, large meals, vagotonia, cocaine, tricyclic antidepressants, lithium, and sodium-channel blocking drugs may unmask the phenotype or precipitate arrhythmia.

ECG Classification and Diagnostic Criteria

The diagnostic ECG pattern is dynamic and may require recording V₁–V₂ in high right precordial positions, typically the second or third intercostal spaces, to increase sensitivity for the right ventricular outflow tract signal. Modern classification emphasises type 1 as diagnostic and type 2 as suspicious rather than diagnostic.

Pattern	ECG morphology	Diagnostic significance
Type 1	Coved ST elevation ≥ 2 mm in ≥1 right precordial lead V1–V3, followed by a negative T wave	Diagnostic when spontaneous or induced by sodium-channel blocker in appropriate clinical context
Type 2	Saddleback ST elevation with r′/J-point elevation ≥ 2 mm, ST segment ≥ 1 mm, positive or biphasic T wave	Suggestive only; requires conversion to type 1 for diagnosis

A diagnosis is generally accepted with a type 1 ECG pattern, either spontaneous or drug-induced, plus supportive clinical features such as documented ventricular fibrillation or polymorphic ventricular tachycardia, arrhythmic syncope, nocturnal agonal respiration, family history of sudden cardiac death before age 45 years, or type 1 ECG in relatives. The Shanghai score integrates ECG, clinical history, family history, and genetics; a score ≥3.5 supports a definite diagnosis, 2–3 possible, and <2 nondiagnostic.

Provocation Testing

Sodium-channel blocker challenge is used when Brugada syndrome is suspected but the resting ECG is nondiagnostic. It should be performed in a monitored setting with resuscitation facilities, continuous 12-lead ECG, and immediate drug cessation if type 1 conversion, ventricular arrhythmia, QRS widening >130% of baseline, or marked conduction delay occurs.

Agent	Typical adult protocol	Key points
Ajmaline	1 mg/kg IV over 5–10 min	High sensitivity; widely used in Europe; half-life approximately 10 min
Flecainide	2 mg/kg IV over 10 min, maximum 150 mg	Alternative where ajmaline unavailable; longer half-life, approximately 12–27 h
Procainamide	10 mg/kg IV over 10–20 min	Less sensitive than ajmaline; used more commonly in North America

Ajmaline challenge has reported sensitivity around 80–90% in familial disease, but specificity is imperfect; false positives occur particularly with excessive high-lead interpretation or concealed structural disease. A positive test in an asymptomatic individual without a suggestive phenotype requires careful specialist interpretation rather than automatic labelling.

Risk Stratification

Risk stratification is the key examination issue. The highest-risk group comprises survivors of cardiac arrest or patients with documented spontaneous sustained ventricular arrhythmia; recurrence risk without therapy is substantial, historically 8–10% per year. Spontaneous type 1 ECG carries higher risk than drug-induced type 1. Syncope is important only when convincingly arrhythmic: abrupt, without prodrome, often nocturnal or at rest. Vasovagal syncope is common and should not be overinterpreted.

Asymptomatic patients with drug-induced type 1 ECG have low annual event rates, often <0.5% per year. Risk is increased by male sex, spontaneous type 1 pattern, fragmented QRS, early repolarisation in inferolateral leads, sinus node dysfunction or conduction disease, and pathogenic SCN5A variants, but none alone mandates an implantable cardioverter-defibrillator. Electrophysiological study remains controversial: inducibility has modest positive predictive value and variable reproducibility. Current European guidance gives EPS a limited role in selected asymptomatic patients with spontaneous type 1 ECG, not as a universal screening test.

Management

All patients should receive lifestyle and trigger management: aggressive treatment of fever with paracetamol, avoidance of excessive alcohol and large evening meals, correction of hypokalaemia or hyperkalaemia, and avoidance of sodium-channel blocking or Brugada-provoking drugs. Drug avoidance lists are maintained at brugadadrugs.org and are highly examination-relevant.

Clinical scenario	Recommended management
Aborted sudden cardiac death or documented sustained VT/VF	ICD indicated, unless contraindicated
Spontaneous type 1 ECG with arrhythmic syncope	ICD generally indicated after exclusion of non-arrhythmic syncope
Asymptomatic drug-induced type 1 ECG	No ICD routinely; counselling, trigger avoidance, family evaluation
Electrical storm	Isoproterenol infusion and intensive care monitoring

ICDs reduce sudden death but carry important morbidity, particularly in young patients: inappropriate shocks, lead failure, infection, and psychological burden. Therefore, prophylactic ICD implantation in low-risk asymptomatic individuals is generally avoided. Quinidine, which blocks Ito and reduces epicardial action potential heterogeneity, may be used for recurrent ICD shocks, electrical storm prevention, or where ICD is contraindicated; typical dosing is 300–600 mg orally two or three times daily, limited by diarrhoea, thrombocytopenia, cinchonism, and QT prolongation. Isoproterenol is first-line acute therapy for Brugada electrical storm, commonly initiated at 1–2 micrograms/min IV and titrated to suppress ventricular ectopy and raise heart rate, thereby increasing calcium current and reducing ST elevation. Catheter ablation targeting abnormal epicardial electrograms in the right ventricular outflow tract is increasingly used for recurrent ventricular fibrillation or frequent ICD therapies in expert centres.

Differential Diagnosis

Important mimics include right bundle branch block, early repolarisation, acute anterior myocardial infarction, pulmonary embolism, arrhythmogenic right ventricular cardiomyopathy, hyperkalaemia, hypercalcaemia, pectus excavatum, and lead misplacement. A Brugada ECG pattern caused by reversible metabolic, ischaemic, or pharmacological factors should be distinguished from true Brugada syndrome, although such unmasking may still reveal susceptibility in genetically predisposed individuals.

Catecholaminergic Polymorphic Ventricular Tachycardia

Definition, genetics and pathophysiology

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterised by adrenergically mediated ventricular ectopy, bidirectional ventricular tachycardia (VT) or polymorphic VT in a structurally normal heart with a normal resting ECG. It is a high-risk cause of exertional or emotion-triggered syncope and sudden cardiac death, typically presenting in childhood or adolescence; untreated mortality has historically been reported at approximately 30–50% by age 30–40 years.

The central mechanism is abnormal intracellular calcium handling in the cardiomyocyte sarcoplasmic reticulum. During sympathetic stimulation, increased cyclic AMP and protein kinase A signalling enhance L-type calcium influx and sarcoplasmic reticulum calcium loading. In CPVT, defective calcium release control causes diastolic calcium leak through the ryanodine receptor complex, generating delayed afterdepolarisations via the sodium-calcium exchanger; if threshold is reached, triggered activity produces ventricular ectopy and VT.

Genetic subtype	Gene/protein	Inheritance	Exam-relevant features
CPVT1	RYR2, cardiac ryanodine receptor	Autosomal dominant	Most common, approximately 50–60% of clinically definite cases; incomplete penetrance but high event risk
CPVT2	CASQ2, calsequestrin-2	Autosomal recessive, rarely dominant	Often earlier onset and severe phenotype; may be associated with sinus bradycardia
Rare forms	TRDN, CALM1-3, TECRL, KCNJ2 phenocopies	Variable	Consider in early-onset malignant disease, negative RYR2/CASQ2 testing or syndromic overlap

Clinical phenotype and diagnostic criteria

Patients present with syncope, seizure-like episodes or cardiac arrest precipitated by exercise, acute emotion, startle or catecholamine infusion. Resting ECG is usually normal: QTc is not prolonged, and there is no Brugada pattern. Sinus bradycardia may be present, particularly in children. Echocardiography and cardiac MRI are typically normal and are used to exclude cardiomyopathy, myocarditis and arrhythmogenic right ventricular cardiomyopathy.

According to the 2013 HRS/EHRA/APHRS consensus and contemporary ESC guidance, CPVT is diagnosed in a structurally normal heart with normal resting ECG when exercise or catecholamine stress reproducibly induces bidirectional VT, polymorphic ventricular premature beats or polymorphic VT, especially in an individual younger than 40 years. A pathogenic variant in a CPVT-associated gene is diagnostic in an appropriate phenotype, but a variant of uncertain significance must not be over-interpreted.

Exercise testing pattern

The classical finding is a progressive adrenergic arrhythmia burden: isolated ventricular premature complexes emerge at heart rates around 100–120 beats/min, followed by bigeminy, couplets, non-sustained polymorphic VT and sometimes sustained bidirectional VT. Bidirectional VT shows alternating QRS axis, classically beat-to-beat 180-degree frontal plane axis alternation, but polymorphic VT is more common. Exercise testing has imperfect sensitivity; a negative test does not exclude CPVT, particularly if the patient is taking beta-blockers or is genotype-positive with low penetrance.

• Ambulatory monitoring may capture adrenergic ectopy during daily activity but is less controlled than treadmill or bicycle testing.
• Adrenaline/isoprenaline challenge can be used when exercise testing is impractical, but protocols vary and specificity is inferior to exercise-induced bidirectional or polymorphic VT.
• Family screening requires clinical evaluation and cascade genetic testing for the familial pathogenic variant; first-degree relatives may be asymptomatic yet at risk.

Management

The cornerstone is suppression of adrenergically mediated calcium-triggered arrhythmia. Competitive sport and strenuous exertion are generally avoided, although modern guidance emphasises individualised shared decision-making in expert inherited cardiac disease clinics. Fever and electrolyte disturbance are less central than in Brugada or long QT syndromes, but hypokalaemia and stimulant drugs should be avoided.

Treatment	Typical adult dosing	Key points
Nadolol	1–2 mg/kg once daily; commonly 40–160 mg daily	Preferred non-selective beta-blocker; long half-life approximately 20–24 h; better adherence and event reduction than beta-1 selective agents in observational cohorts
Propranolol	2–4 mg/kg/day in divided doses; modified-release often 80–240 mg daily	Alternative non-selective beta-blocker; shorter half-life approximately 3–6 h for immediate-release
Flecainide	50–150 mg twice daily; target often 100–200 mg/day, adjusted to QRS and renal function	Added for breakthrough ectopy/syncope despite beta-blockade; blocks sodium current and directly reduces RyR2-mediated calcium release; monitor QRS widening, avoid structural heart disease
Left cardiac sympathetic denervation	Surgical removal/ablation of lower stellate and T2–T4 thoracic ganglia	For recurrent events despite maximal medical therapy or beta-blocker intolerance; reduces arrhythmic burden but is not curative
ICD	Secondary prevention in selected survivors despite optimal therapy	Not first-line monotherapy: shocks may provoke catecholamine surge and electrical storm; must be combined with beta-blocker ± flecainide

Beta-blocker therapy should be prescribed at maximally tolerated doses, with repeat exercise testing used to assess suppression of ventricular ectopy at target heart rates. Non-selective agents are favoured; metoprolol and other beta-1 selective drugs have been associated with higher breakthrough event rates in registry data. Flecainide has become standard add-on therapy when exercise-induced complex ectopy persists or clinical events occur despite beta-blockade; small trials and cohort studies demonstrate marked reduction in exercise-induced ventricular arrhythmias, though robust mortality randomised data are lacking because CPVT is rare.

Risk stratification and prognosis

Major adverse predictors include prior cardiac arrest, recurrent syncope, early childhood onset, absent or subtherapeutic beta-blockade, and persistent complex ventricular ectopy on treatment. Genotype alone is insufficient for risk stratification, although biallelic CASQ2 and calmodulin-related disease often behave aggressively. With strict adherence to non-selective beta-blockade, escalation to flecainide when required, family screening and expert follow-up, prognosis is substantially improved; however, non-adherence remains a common cause of sudden death and is a frequent examination theme.

Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC), increasingly termed arrhythmogenic cardiomyopathy when left ventricular or biventricular phenotypes are included, is an inherited myocardial disease characterised by fibro-fatty myocardial replacement, ventricular arrhythmia, and sudden cardiac death, particularly in young adults and athletes. Prevalence is approximately 1:2,000–1:5,000, with autosomal dominant inheritance and incomplete, age-dependent penetrance. It is a high-yield MRCP topic because diagnosis rests on integrating ECG, imaging, rhythm, histology, genetics, and family history rather than a single test.

Pathobiology and genetics

The canonical mechanism is defective desmosomal adhesion, producing mechanical uncoupling, myocyte apoptosis/necrosis, inflammation, and progressive fibro-fatty replacement, typically beginning in the subepicardial right ventricular free wall. Electrical instability may precede overt structural disease because altered desmosomal proteins secondarily disturb sodium current and gap-junction distribution, creating slowed conduction and re-entry. Exercise increases wall stress and penetrance; endurance athletes with pathogenic variants have earlier onset, greater arrhythmic burden, and more rapid ventricular dysfunction.

Gene/protein	Key point
PKP2 / plakophilin-2	Most common genotype; often adult-onset ventricular arrhythmia.
DSP / desmoplakin	Frequently left-dominant disease, myocarditis-like presentations, LV scar.
DSG2, DSC2, JUP	Desmosomal; JUP associated with recessive Naxos disease.
TMEM43, PLN, DES, LMNA	Non-desmosomal mimics/overlap; may carry high arrhythmic or heart failure risk.

Clinical phenotype and diagnostic criteria

Presentation includes palpitations, syncope, sustained monomorphic VT, aborted sudden cardiac death, or incidental ECG abnormalities. VT classically has a left bundle branch block morphology, reflecting right ventricular origin, often with superior axis when arising from the inferior RV. Structural disease commonly affects the “triangle of dysplasia”: RV inflow tract, outflow tract, and apex, although this concept underestimates LV involvement.

The 2010 Revised Task Force Criteria classify major and minor abnormalities across six domains. Diagnosis is definite with 2 major, or 1 major plus 2 minor, or 4 minor criteria from different categories; borderline with 1 major plus 1 minor, or 3 minor; possible with 1 major, or 2 minor. The 2020 Padua criteria expand recognition of left-dominant and biventricular arrhythmogenic cardiomyopathy, incorporating CMR tissue characterisation, particularly late gadolinium enhancement.

Domain	High-yield examples
ECG repolarisation	Major: T-wave inversion V1–V3 or beyond in individuals >14 years without complete RBBB. Minor: T-wave inversion V1–V2.
ECG depolarisation	Epsilon waves in V1–V3 are major but insensitive. Terminal activation duration ≥55 ms in V1–V3 is minor.
Arrhythmia	Major: non-sustained or sustained VT of LBBB morphology with superior axis. Minor: frequent ventricular extrasystoles >500 per 24 hours.
Imaging	Regional RV akinesia/dyskinesia/aneurysm plus quantitative RV dilatation or reduced function on echo, CMR, or angiography.
Histology	Residual myocytes <60% by morphometry with fibrous replacement, with or without fat, is major.
Genetics/family	Pathogenic ARVC mutation is major; confirmed disease in first-degree relative is major.

On CMR, 2010 major thresholds include regional RV wall motion abnormality plus RV end-diastolic volume indexed ≥110 mL/m² in males or ≥100 mL/m² in females, or RV ejection fraction ≤40%. Minor thresholds include RVEDVi ≥100–<110 mL/m² in males, ≥90–<100 mL/m² in females, or RVEF >40–≤45%. CMR sensitivity varies with disease stage and expertise; overdiagnosis from normal RV trabeculation, athlete’s heart, or poor ECG-gating is examinable.

Differential diagnosis

• Idiopathic RV outflow tract VT: structurally normal heart, LBBB/inferior-axis VT, benign response to adenosine or ablation; lacks T-wave inversion V1–V3, RV dysfunction, and family history.
• Cardiac sarcoidosis: AV block, patchy LV/RV scar, extracardiac disease; FDG-PET may show active inflammation.
• Myocarditis: acute troponin rise and oedema; DSP cardiomyopathy may mimic recurrent myocarditis.
• Athlete’s heart: balanced chamber enlargement with preserved function and absence of regional RV akinesia, scar, or pathological arrhythmia.

Management and risk stratification

The key intervention is exercise restriction. Competitive and high-intensity endurance exercise should be avoided; this applies to genotype-positive phenotype-negative individuals because exercise increases penetrance and arrhythmic risk. Family screening includes 12-lead ECG, Holter monitoring, echocardiography and/or CMR, repeated every 1–3 years in at-risk relatives, with cascade genetic testing where a pathogenic variant is identified.

Therapy	Exam-relevant details
Beta-blocker	First-line for symptomatic ectopy/NSVT and adrenergic arrhythmia suppression; e.g. bisoprolol 2.5–10 mg once daily or nadolol 40–160 mg daily if available.
Sotalol	Commonly used for recurrent VT; typical dose 80–160 mg twice daily, renal adjustment required, QT monitoring essential.
Amiodarone	Useful for refractory VT, often 200 mg daily maintenance after loading; long half-life approximately 40–60 days and thyroid, liver, lung toxicity limit long-term use.
Catheter ablation	Reduces recurrent monomorphic VT and ICD shocks, but recurrence is common because disease is epicardial and progressive; combined endocardial/epicardial approaches improve outcomes.
Heart failure therapy	Standard HFrEF treatment when LV or biventricular systolic dysfunction develops; transplantation for refractory arrhythmia or end-stage failure.

ICD implantation is indicated for secondary prevention after cardiac arrest, haemodynamically unstable sustained VT, or sustained VT with significant ventricular dysfunction. Primary prevention is considered for high-risk phenotypes: unexplained syncope, extensive RV/LV dysfunction, NSVT, high PVC burden, inducible VT, male sex, young age, proband status, and high-risk genotypes such as TMEM43 p.S358L or certain DSP/PLN variants. The 2019 HRS consensus and 2022 ESC ventricular arrhythmia guidance emphasise individualised risk assessment rather than prophylactic ICD for all genotype-positive patients. ICD complications are frequent in young patients, including inappropriate shocks and lead failure; therefore the decision requires specialist inherited cardiac conditions input.