Key Facts

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterised by adrenergically-mediated polymorphic or bidirectional ventricular tachycardia in the presence of a structurally normal heart and a normal resting ECG. It is a potent cause of sudden cardiac death in children and young adults.

Epidemiology

• Estimated prevalence: 1 in 10,000
• Onset typically in childhood: mean age at first event ~7-12 years
• Males and females equally affected
• Accounts for ~12% of autopsy-negative sudden cardiac death in the young

Aetiology

• RYR2 (ryanodine receptor 2): autosomal dominant, ~60% of cases
• CASQ2 (calsequestrin 2): autosomal recessive, ~5% of cases
• Other rare genes: TRDN, CALM1, CALM2, CALM3
• ~25% genetically unresolved

Pathophysiology

• Mutations cause abnormal calcium release from the sarcoplasmic reticulum during adrenergic stimulation
• Diastolic calcium leak triggers delayed afterdepolarisations (DADs)
• DADs reach threshold and produce ectopic beats, VT, and potentially VF
• The heart is structurally normal; arrhythmias are purely functional and catecholamine-dependent
• Bidirectional VT results from alternating ventricular foci activated by triggered activity

Typical Presentation

• Syncope during exercise or emotional stress in a child/adolescent
• May present as 'seizures' (misdiagnosed as epilepsy)
• First presentation may be cardiac arrest or sudden death
• Family history of juvenile sudden death or exercise-related syncope

Characteristic Features

• Normal resting ECG
• Normal resting echocardiogram
• Exercise provokes: isolated PVCs → bigeminy → bidirectional VT → polymorphic VT → potential VF
• The arrhythmia severity is dose-dependent on heart rate/catecholamine levels

Red Flags

• Syncope during exercise in a young person with normal resting ECG
• Family history of sudden cardiac death <40 years
• Previous cardiac arrest
• Bidirectional VT on exercise testing

Bedside

• Resting 12-lead ECG: typically normal (may show sinus bradycardia or U waves)

Bloods

• U&Es, Mg²⁺, Ca²⁺: exclude metabolic causes
• TFTs: hyperthyroidism

Imaging

• Echocardiography: structurally normal heart (mandatory to exclude other causes)
• Cardiac MRI: normal; excludes ARVC

Special Tests

• Exercise stress testing: gold standard diagnostic test
  • Reproduces arrhythmia: PVCs → bigeminy → bidirectional VT → polymorphic VT
  • Arrhythmia typically appears at HR ~120-130 bpm
  • Must be performed in a setting with defibrillation capability
• Holter monitoring: may capture exercise-related arrhythmias
• Adrenaline infusion test: alternative to exercise testing in children unable to exercise
• Genetic testing: RYR2 and CASQ2 — essential for diagnosis and family cascade screening

Non-pharmacological

• Restriction of competitive sports and strenuous exercise (class I recommendation)
• Moderate recreational exercise may be permitted with specialist guidance and beta-blocker cover
• Avoid emotional triggers where possible
• Family screening: genetic cascade testing + exercise testing in first-degree relatives

Pharmacological

• Beta-blockers (first-line):
  • Nadolol 1-2.5 mg/kg/day (preferred — long-acting, non-selective)
  • Dose titrated to suppress exercise-induced arrhythmias on repeat stress testing
  • Must not be discontinued abruptly
• Flecainide 100-150mg BD (or 2-3 mg/kg/day in children):
  • Added if beta-blocker alone insufficient
  • Specifically effective in CPVT — blocks RYR2-mediated calcium release
  • Watanabe trial: flecainide reduced arrhythmia burden significantly in CPVT
• Verapamil: may be considered as adjunct

Surgical/Interventional

• ICD: for cardiac arrest survivors or recurrent syncope/VT despite maximal medical therapy
  • Caution: ICD shocks can trigger catecholamine release → arrhythmia storm
  • Must be combined with beta-blocker + flecainide to minimise shocks
• Left cardiac sympathetic denervation (LCSD): reduces events by ~50%; considered when medications fail or as adjunct

Referral Criteria

• All suspected CPVT: referral to inherited cardiac conditions service
• All first-degree relatives: screening with exercise testing + genetic testing
• Genetic counselling for affected families

• Untreated CPVT: ~30% cardiac event rate by age 30; up to 50% by age 40
• Beta-blocker therapy reduces events to ~20-30% over long-term follow-up
• Beta-blocker + flecainide: further reduces events to ~10-15%
• ICD reduces mortality but inappropriate shocks and catecholamine storms are significant issues
• LCSD: ~50% reduction in events when added to medical therapy
• Compliance with beta-blockers is critical — non-adherence is the leading cause of breakthrough events
• RYR2 mutations generally have better prognosis than CASQ2

Exercise Test Arrhythmia Progression in CPVT

Comparison of Inherited Arrhythmia Syndromes