Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

Monogenic (Mendelian): ~60%, RYR2 (~50–55%) and CASQ2^[1]

Acquired: no acquired form of CPVT, but its hallmark bidirectional VT has acquired mimics to exclude, classically digoxin toxicity

Complex (likely polygenic): ~35–40% gene-elusive^[4]

Inheritance: Autosomal dominant (RYR2, CALM1-3, most common, penetrance 70–80%); autosomal recessive (CASQ2, TRDN, TECRL, nearly 100% penetrance, often more severe)

Genetic yield: ~60% with comprehensive testing. Pathogenic RYR2 variants found in up to 60–65% of probands.

ClinGen-validated genes (Walsh et al, EHJ 2022)^[4]:

• RYR2 (CPVT1, ~55–65%, autosomal dominant), Ryanodine receptor 2 (sarcoplasmic reticulum calcium release channel); gain-of-function missense variants (96%); mutations concentrated in 4 hotspot regions (exons 3–15, 44–50, 83–90, 93–105); de novo variants cause earlier onset and more severe phenotype vs familial forms
• CASQ2 (CPVT2, ~2–5%, autosomal recessive), Calsequestrin 2 (calcium storage protein); may be more severe and more resistant to beta-blockers than RYR2
• TRDN (triadin, autosomal recessive, definitive), rare, severe
• TECRL (trans-2,3-enoyl-CoA reductase-like, autosomal recessive, definitive), rare
• CALM1, CALM2, CALM3 (calmodulin, autosomal dominant, definitive), calmodulin binds RYR2; rare but very high-risk (severe early-onset arrhythmias); often de novo; overlap with LQTS

Disputed/removed genes: KCNJ2, PKP2, SCN5A, deemed unrepresentative of CPVT phenotype or variants too common to be disease-causing (Walsh et al 2022 ClinGen reappraisal)^[4]. ANK2 variants too common in general population.

Pathophysiology: Catecholamine surge → beta-adrenergic activation → abnormal calcium handling → delayed afterdepolarisations → triggered bidirectional/polymorphic VT. Explains why: (1) exercise/emotion trigger arrhythmias, (2) beta-blockers and LCSD are effective, (3) ICD shocks can precipitate VF storms via catecholamine release.

~1 in 10,000 individuals worldwide^[6]

Equal sex distribution; typically presents in childhood or adolescence, average age of onset 7–9 years^[6]

Without treatment, mortality rate up to 30–50% before the age of 40^[6]

RYR2 gain-of-function missense variants (autosomal dominant) account for 55–65% of identified cases; CASQ2 variants (autosomal recessive) for 2–5%^[6]

Resting ECG is often entirely normal, making early clinical recognition and cascade screening critically important

Diagnostic Criteria:

• Exercise or emotion-induced bidirectional or polymorphic VT
• Structurally normal heart
• Absence of QT prolongation on resting ECG
• Typically presents with syncope during exercise/emotional stress

Clinical Features:

• Syncope during exercise or emotional stress (hallmark)
• Seizure-like episodes (arrhythmia-related)
• Sudden cardiac arrest
• Family history of young sudden death or exercise-related syncope
• Normal resting ECG (no QT prolongation, structurally normal heart)

Characteristic arrhythmia pattern:

• Progressive: PVCs → bigeminy → bidirectional VT → polymorphic VT/VF
• Occurs with increasing heart rate/exercise intensity

First-line:

• Resting 12-lead ECG (typically normal; exclude LQTS, Brugada, structural disease)
• Exercise stress test: CRITICAL for diagnosis; perform to maximal exertion
• Look for PVCs, bigeminy, bidirectional VT, polymorphic VT at increasing HR
• Sinus bradycardia or prominent U-waves may be present at rest

Holter monitoring:

• May capture spontaneous arrhythmias
• Less sensitive than exercise testing

Imaging:

• Echocardiography - structurally normal heart (rule out structural disease)
• Cardiac MRI if any doubt about structural abnormality

Genetic testing:

• Recommended in all suspected cases
• Enables cascade family screening
• RYR2 and CASQ2 testing sufficient in most cases

Epinephrine challenge (specialist centres):

• Can unmask CPVT if exercise test negative but high suspicion

1. General measures:

• Strict avoidance of competitive sports and strenuous exercise
• Avoid emotional stress/startling situations where possible
• Genetic counselling and family cascade testing, see the Genetic Testing page

2. Medical therapy (first-line for ALL diagnosed patients):

• Beta-blockers, HIGHEST tolerated dose (Class I^[1]):
  • Nadolol (preferred, non-selective, long-acting, once-daily):
    • Adults: start 40 mg once daily → target 80–160 mg once daily (up to 2–3 mg/kg/day)
    • Children: 1 mg/kg/day → uptitrate to 2–3 mg/kg/day
    • UK: SPECIALS / named patient import, plan ahead; renally cleared (reduce if eGFR <30)
  • Propranolol (alternative if nadolol unavailable):
    • Adults: start 40 mg twice daily → target 80–160 mg twice daily (total up to 320–480 mg/day)^[5]
    • Children: 2–3 mg/kg/day in 3–4 divided doses → uptitrate to 3–4 mg/kg/day
  • Significant but incomplete protection (~60–70% event reduction on monotherapy^[1])
• Flecainide, add-on if breakthrough events or very high risk (Class IIa^[1]):
  • Start 50 mg twice daily → target 100–150 mg twice daily
  • Maximum 300 mg/day; reduce if eGFR <35 ml/min
  • Check QRS widening (<25% increase acceptable); ALWAYS combine with beta-blocker
  • Combination therapy significantly more effective than either alone (van der Werf et al 2011^[3])

3. Device therapy:

• ICD therapy, with important caveats:
  • Secondary prevention after aborted cardiac arrest (Class I)
  • May be considered (Class IIa) for arrhythmogenic syncope and/or documented bidirectional or polymorphic VT persisting on the highest tolerated beta-blocker dose and flecainide, through specialist shared decision-making
  • ICD does NOT replace medical therapy, always combine with maximised beta-blocker + flecainide
  • Key risk: ICD shocks trigger catecholamine surge → can precipitate further VT/VF → electrical storm. LCSD should be considered alongside ICD in high-risk patients
  • Risk stratification informing escalation (Lieve et al, EHJ 2025^[2], validated CPVT risk model): prior arrhythmic syncope before diagnosis, prior sudden cardiac arrest, and younger age at beta-blocker initiation all raise the estimated risk of arrhythmic events; estimate risk with the published model rather than from individual coefficients, and high estimated risk (>20% 5-year AE rate) should prompt escalation beyond beta-blocker monotherapy
• Left cardiac sympathetic denervation (LCSD):
  • For recurrent events despite beta-blockers + flecainide (Class IIa)
  • When ICD is contraindicated or declined
  • Effective in ~70–80% of cases; growing role in CPVT management
  • Reduces adrenergic drive without systemic side effects of high-dose beta-blockers

5. Emerging therapies:

• Gene therapy for RYR2-CPVT (preclinical) and RYR2-specific stabilisers (flecainide acts partly via direct RYR2 binding)

• Exercise or emotion-induced bidirectional or polymorphic VT: causing syncope and sudden death, often in childhood or adolescence^[1]
• ICD shock-triggered electrical storm: a shock releases catecholamines that provoke further VT, so ICDs are adjunctive rather than standalone
• Breakthrough arrhythmia: despite beta-blockade

Very high-risk (ICD recommended):

• Cardiac arrest survivor (secondary prevention)
• Syncope despite optimal medical therapy (beta-blocker + flecainide)

High-risk features:

• Prior cardiac arrest or syncope
• Family history of sudden cardiac death <40 years
• Presentation at young age (<10 years)
• CALM variant (very severe)
• Polymorphic or bidirectional VT on exercise test despite therapy

Risk reduction with therapy:

• Beta-blockers reduce event rate by ~60-70%
• Beta-blocker + flecainide reduces event rate by ~80-90%
• LCSD provides additional protection if medical therapy insufficient

Ongoing monitoring:

• Serial exercise tests to assess therapeutic efficacy
• Target complete suppression of exercise-induced arrhythmias
• If arrhythmias persist, increase beta-blocker dose or add flecainide

Pragmatic surveillance approach informed by ESC 2022 Ventricular Arrhythmia guidelines (which do not mandate fixed monitoring intervals)^[1].

Advanced / complicated = exertional syncope, breakthrough arrhythmia on exercise testing despite therapy, or appropriate ICD therapy.

Genotype-positive / phenotype-negative (G+/P−) = a confirmed pathogenic-variant carrier with no overt disease expression yet.

	Genotype+ / Phenotype−	Uncomplicated / Stable	Advanced / Complicated
Frequency	Annual	Annual	Every 6 months
Clinical review	Symptoms; beta-blocker often started in carriers	Exertional symptoms, syncope, adherence	As above + device check
ECG	Annual (resting ECG normal)	Annual 12-lead	Each visit
Exercise stress test	Periodic (may unmask exertional VA)	Annual (assess suppression of exertional VA)	Repeat after any therapy change
Holter / ambulatory	As indicated	Periodic (exertional ectopy)	As indicated
Family screening	–	Cascade exercise testing ± genetics	–

Disclaimer: This table is general guidance based on published guidelines and does not replace clinical judgement. The responsible clinician is accountable for determining the appropriate, individualised follow-up plan for each patient.

• Exercise testing to maximal exertion is ESSENTIAL for diagnosis - do not skip^[1]
• Normal resting ECG does NOT exclude CPVT - diagnosis requires exercise test
• Screen first-degree relatives with exercise test + genetic testing if variant known
• ALL diagnosed patients require beta-blockers at maximum tolerated doses^[1]
• Do NOT stop beta-blockers abruptly (can be fatal)
• Strict avoidance of competitive sports and strenuous exercise; recreational activity is individualised after specialist assessment, optimised therapy and exercise-test suppression^[1]
• ICD does NOT replace medical therapy - continue beta-blockers
• ICD shocks can trigger more arrhythmias - ensure maximal medical therapy first^[1]
• Pregnancy is higher risk given catecholamine sensitivity; risk level and delivery/therapy plan should be individualized by a Pregnancy Heart Team rather than assigned a single fixed risk class or protocol
• Repeat exercise tests to monitor therapy - aim for complete arrhythmia suppression