Aetiology

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]

Genetics

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.

CPVT Risk Calculator (Lieve et al, EHJ 2025)^[2]

First validated risk prediction model for RYR2-CPVT on beta-blocker monotherapy (n=743 derivation, n=129 validation; c-index 0.67 for AE, 0.74 for near-fatal/fatal AE):

Predictors of arrhythmic events (AE):

History of arrhythmic syncope prior to diagnosis (×0.51)
History of sudden cardiac arrest prior to diagnosis (×0.60)
Age at beta-blocker initiation (×−0.04 per year, younger = higher risk)

Additional predictor for near-fatal/fatal AE: Severity of ventricular arrhythmia before beta-blocker initiation

5-year risk = 1 − 0.911^exp(linear predictor). Low risk (0–5%), intermediate (5–20%), high (>20%)

Prevalence

~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

Diagnosis

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

Investigations

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

Treatments

ESC 2022 Guidelines - CPVT

Key Updates from ESC 2022:

Flecainide reduces exercise-induced ventricular arrhythmias in CPVT, additive to beta-blockade^[9]
Can be used as add-on therapy to beta-blockers
Effective in reducing exercise-induced ventricular ectopy

Reference: Zeppenfeld K et al. 2022 ESC Guidelines for management of patients with ventricular arrhythmias and prevention of sudden cardiac death. Eur Heart J 2022;43:3997-4126^[1]

Lifestyle modifications (ALL patients):

Strict avoidance of competitive sports and strenuous exercise
Avoid emotional stress/startling situations where possible

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

Beta-blockers, HIGHEST tolerated dose (Grade 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)
  - 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 (Grade 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])

ICD therapy, with important caveats:

Secondary prevention after cardiac arrest (Grade I)
Primary prevention if syncope despite beta-blockers, especially high-risk patients
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 (Lieve et al, EHJ 2025^[2], validated CPVT risk model):

Prior arrhythmic syncope before diagnosis, strongest predictor (HR ×0.51)
Prior sudden cardiac arrest, very high risk (HR ×0.60)
Younger age at beta-blocker initiation = higher risk (×−0.04/year)
High risk (>20% 5-year AE rate) → escalate beyond beta-blocker monotherapy

Left cardiac sympathetic denervation (LCSD):

For recurrent events despite beta-blockers + flecainide (Grade 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

Emerging therapies:

Gene therapy for RYR2-CPVT, preclinical studies underway
RYR2-specific stabilisers (e.g. flecainide acts partly via RYR2 direct binding)

Related Resources

Complications

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

Risk Stratification

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

Pregnancy Management

ESC 2018 Pregnancy Guidelines - CPVT (mWHO Class III)

PRECONCEPTION COUNSELLING:

Risk stratification: mWHO Class III (HIGH RISK)
- All CPVT patients are high-risk due to catecholamine-triggered arrhythmias
- Pregnancy = major physiological stress (increased sympathetic tone, increased heart rate, emotional stress)
- Labour/delivery = peak catecholamine surge
Reported pregnancy outcomes:
- 20-30% experience arrhythmic events during pregnancy/delivery/postpartum
- Increased VT episodes compared to baseline
- Cardiac arrest reported during labour in inadequately treated patients
- WITH optimal beta-blocker therapy: outcomes generally good
Mandatory baseline assessment:
- Exercise stress test to maximum exertion (assess arrhythmia threshold and suppression)
- Holter monitoring (arrhythmia burden on current therapy)
- Review beta-blocker dosing - must be on MAXIMUM tolerated dose
- ICD interrogation if present (programming, battery, lead integrity)
Essential medication optimization BEFORE conception:
- Beta-blockers (NON-NEGOTIABLE): Nadolol 80-240mg/day OR propranolol 160-480mg/day (divided doses)
- Target: Complete suppression of exercise-induced ventricular ectopy
- If ectopy persists: Add flecainide 100-200mg BD (safe in pregnancy, used if needed)
- NEVER pregnant without adequate beta-blocker therapy - can be FATAL
ICD considerations:
- If not already implanted but considering: LCSD (left cardiac sympathetic denervation) safer alternative in women planning pregnancy
- ICD shocks can trigger catecholamine storm → more VT (problematic in pregnancy)
- LCSD + beta-blockers + flecainide = 90% event-free
Genetic counselling:
- Autosomal dominant: 50% transmission risk
- RYR2 dominant form: High penetrance (70-80%)
- Recessive forms (CASQ2): Nearly 100% penetrance if homozygous
Pregnancy should be DISCOURAGED if:
- Recurrent syncope/cardiac arrest despite maximal therapy
- Persistent exercise-induced VT despite nadolol + flecainide + LCSD
- Inadequate arrhythmia control

PREGNANCY MANAGEMENT:

Monitoring frequency:
- Fortnightly cardiology review throughout pregnancy (high-risk)
- Holter monitoring each trimester or if any symptoms
- Exercise test AVOIDED during pregnancy (VT risk) - defer until postpartum
Beta-blocker therapy - CRITICAL:
- Continue MAXIMUM doses throughout pregnancy
- Nadolol 80-240mg/day (preferred, long half-life) OR propranolol 160-480mg/day
- NEVER reduce dose - pregnancy increases metabolic clearance, may need HIGHER doses
- Monitor resting heart rate - target 60-70 bpm at rest
- If ectopy on Holter: Consider uptitrating beta-blocker or adding flecainide
Flecainide:
- Safe in pregnancy (extensive experience in SVT treatment)
- Continue if already on pre-pregnancy (100-200mg BD)
- Add if arrhythmia breakthrough on beta-blocker alone
Activity restriction:
- Absolute avoidance of strenuous physical activity
- No exercise beyond gentle walking
- Avoid emotional stress where possible
- Ensure adequate rest
Red flags - immediate review:
- Palpitations, dizziness, presyncope, syncope
- ICD shocks (appropriate or inappropriate)
- Any arrhythmic symptoms

LABOUR & DELIVERY - HIGHEST RISK PERIOD:

Delivery planning:
- Mandatory delivery at tertiary centre with cardiac anaesthesia, ICU, ECMO capability
- MDT meeting at 28-30 weeks (early planning essential)
- Aim delivery 37-38 weeks (avoid late-pregnancy stress but minimize prematurity)
- Cardiology, cardiac anaesthetics, obstetrics, neonatology present at delivery
Mode of delivery:
- Elective caesarean section under epidural STRONGLY PREFERRED
- Rationale: Controlled environment, reduced maternal effort, reduced catecholamine surge
- Vaginal delivery possible if patient preference BUT high risk due to unpredictable labour stresses
Anaesthesia strategy:
- Epidural (preferred): Slowly titrated to avoid catecholamine surge from pain
- Combined spinal-epidural acceptable
- General anaesthesia: Avoid if possible (intubation = major sympathetic stimulus); if needed, ensure deep beta-blockade, consider remifentanil infusion
- CRITICAL: Minimize stress, pain, anxiety - all trigger catecholamine release
Intrapartum beta-blockade:
- Continue oral beta-blocker throughout (give with sips of water even if NBM)
- IV esmolol infusion available as backup (short-acting beta-blocker for immediate control)
- Propranolol 40-80mg 2 hours pre-caesarean if elective
Intrapartum monitoring:
- Continuous ECG monitoring (5-lead minimum)
- Arterial line (BP monitoring, blood gas access)
- Defibrillator pads placed prophylactically
- External defibrillator immediately available (ICD may not terminate VF effectively if patient deteriorates)
- IV magnesium sulphate available (torsades treatment if VT degenerates)
VT management during delivery:
- IV esmolol bolus 500mcg/kg over 1 minute (immediate beta-blockade)
- IV magnesium sulphate 2g over 10 minutes
- Electrical cardioversion if unstable
- If refractory: IV amiodarone (fetal risk acceptable in emergency)
- Expedite delivery if VT during labour (remove stressor)
Avoid obstetric medications:
- Ergometrine: Contraindicated (hypertension → catecholamine surge)
- Syntocinon acceptable but give SLOWLY (not bolus)

POSTPARTUM:

Critical monitoring period (48-72 hours):
- CCU/HDU monitoring for 48-72 hours (high VT risk persists)
- Continuous ECG monitoring
- Emotional stress, sleep deprivation, pain → catecholamine triggers
Beta-blocker management:
- Continue MAXIMUM doses - do NOT reduce
- Propranolol/nadolol safe with breastfeeding
- Sleep deprivation increases sympathetic tone - partner support essential for night feeds
Gradual risk reduction:
- Arrhythmic risk gradually decreases over 3-6 months postpartum
- Monitor closely first 3 months
Exercise testing:
- Repeat exercise test at 6 months postpartum
- Ensure arrhythmia suppression maintained on current therapy
Contraception: All methods safe; progesterone-only preferred
Breastfeeding: Safe; beta-blockers compatible
Counsel AGAINST further pregnancies if significant arrhythmic events during pregnancy/delivery

ABSOLUTE REQUIREMENTS FOR SAFE PREGNANCY:

MAXIMUM dose beta-blocker therapy - non-negotiable
Complete or near-complete arrhythmia suppression on pre-pregnancy exercise test
Delivery at specialized tertiary centre with full resuscitation capability
Multidisciplinary team involvement throughout pregnancy
Patient understanding of risks and commitment to medication compliance

THIS IS A VERY HIGH-RISK PREGNANCY

CPVT pregnancy requires expert management at specialized centre
Maternal mortality risk if inadequately treated
Labour/delivery = peak risk for VF/cardiac arrest
With optimal therapy and careful planning: good outcomes achievable

Follow-up

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.

Key Points

Exercise testing to maximal exertion is ESSENTIAL for diagnosis - do not skip^[1]
ALL diagnosed patients require beta-blockers at maximum tolerated doses^[1]
Do NOT stop beta-blockers abruptly (can be fatal)
Competitive sports and strenuous exercise are ABSOLUTELY contraindicated^[1]
Screen first-degree relatives with exercise test + genetic testing if variant known
ICD does NOT replace medical therapy - continue beta-blockers
ICD shocks can trigger more arrhythmias - ensure maximal medical therapy first^[1]
Normal resting ECG does NOT exclude CPVT - diagnosis requires exercise test
Repeat exercise tests to monitor therapy - aim for complete arrhythmia suppression
Pregnancy is HIGH RISK (mWHO III) - requires tertiary centre delivery with maximum beta-blockade

References & Review Date

Last reviewed: June 2026

Zeppenfeld K, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997–4126. doi:10.1093/eurheartj/ehac262
Lieve KV, et al. Catecholaminergic polymorphic ventricular tachycardia mediated by ryanodine receptor 2: a validated risk stratification. Eur Heart J. 2025. doi:10.1093/eurheartj/ehaf965
van der Werf C, et al. Flecainide reduces life-threatening ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol. 2011;57(22):2244–2254. doi:10.1016/j.jacc.2011.01.026
Walsh R, et al. Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death. Eur Heart J. 2022;43(15):1500–1510. doi:10.1093/eurheartj/ehac052
Joint Formulary Committee. British National Formulary (BNF). bnf.nice.org.uk
Luo S, Gómez AM. Catecholaminergic polymorphic ventricular tachycardia: a narrative review of recent advances in genetics, mechanisms, diagnosis, and treatment. Asian Heart J. 2025;1:97–110. doi:10.1097/ah9.0000000000000018
Abbas M, Miles C, Behr E. Catecholaminergic polymorphic ventricular tachycardia. Arrhythm Electrophysiol Rev. 2022;11:e20. doi:10.15420/aer.2022.09
Aggarwal A, Stolear A, Alam MM, et al. Catecholaminergic polymorphic ventricular tachycardia: clinical characteristics, diagnostic evaluation and therapeutic strategies. J Clin Med. 2024;13(6):1781. doi:10.3390/jcm13061781
van der Werf C, et al. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol. 2011;57(22):2244–2254. doi:10.1016/j.jacc.2011.01.026

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)