Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome in which adrenergic stimulation provokes bidirectional or polymorphic ventricular tachycardia in a structurally normal heart. It affects about 1 in 10,000 people. Onset is usually between 5 and 15 years, though adult onset occurs.

Without treatment about 30 to 50% have a cardiac event by age 35. The commonest genes are RYR2 (autosomal dominant, about 60%; gain of function of the cardiac ryanodine receptor), CASQ2 (autosomal recessive, a few percent), TRDN, CALM1 to CALM3 and TECRL.

Diagnosis rests on a structurally normal heart and normal resting ECG with exercise- or emotion induced bidirectional or polymorphic ventricular tachycardia or frequent polymorphic ventricular ectopy, or a pathogenic variant.

Pathophysiology. Sarcoplasmic reticulum calcium leaks during diastole through defective RyR2 channels or calsequestrin dysfunction. Calcium overload triggers delayed afterdepolarisations and triggered activity during sympathetic stimulation.

The alternating ventricular exit points produce bidirectional ventricular tachycardia, which degenerates to ventricular fibrillation. Atrial arrhythmias (atrial fibrillation, atrial tachycardia) also occur.

• Syncope or seizure like episodes during exercise, swimming or strong emotion; cardiac arrest.
• Family history of exertional sudden death, drowning or unexplained seizures.
• Examination is normal. Resting ECG is usually normal or shows sinus bradycardia and U waves.
• Exercise induced ventricular ectopy appears at a heart rate of about 100 to 120/min and grows more complex with workload.

Red flags.

• Exertional or emotional syncope, or syncope while swimming
• Seizure like events in a child with a normal EEG
• Cardiac arrest during exertion
• Bidirectional ventricular tachycardia
• Family history of exertional sudden death under 40 years
• Polymorphic ventricular ectopy in a structurally normal heart

• Graded treadmill or cycle ergometer exercise test: the main test. Ventricular ectopy begins at a heart rate of 100 to 120/min and progresses from single ectopic beats to couplets, bidirectional ventricular tachycardia and polymorphic ventricular tachycardia. The arrhythmia resolves on recovery.
• Ambulatory ECG: burden of ectopy and tachycardia during normal activity.
• Epinephrine or isoprenaline infusion testing when exercise is not possible: epinephrine 0.05 to 0.2 microgram/kg/min, with defibrillation available. It is less sensitive than exercise testing.
• Resting ECG, echocardiography and cardiac MRI: exclude structural disease and other channelopathies.
• Genetic testing: RYR2, CASQ2, TRDN, CALM1 to CALM3 and TECRL; yield of about 60 to 65%.
• Cascade screening: exercise testing and genetic testing of first degree relatives. Genotype positive relatives with a negative exercise test are still treated.

Differential diagnosis.

• Andersen-Tawil syndrome (KCNJ2; bidirectional ventricular ectopy with long QU interval, periodic paralysis)
• Long QT syndrome
• Digoxin toxicity or aconitine poisoning (bidirectional ventricular tachycardia)
• Arrhythmogenic right ventricular cardiomyopathy
• Brugada syndrome
• Hypertrophic cardiomyopathy
• Myocarditis
• Anomalous coronary artery origin
• Idiopathic fascicular ventricular tachycardia
• Benign exercise induced ectopy
• Epilepsy and neurally mediated syncope

Lifestyle. Avoid competitive sport, strenuous exertion, swimming alone and emotional stress triggers. Light recreational activity is allowed on treatment after shared decision. Keep an automated defibrillator available in the home and school.

Beta blockers for all patients with a diagnosis and for genotype positive family members.

• Nadolol 0.5 to 1 mg/kg/day orally to start, increased to 1 to 2 mg/kg/day in one or two doses, maximum 2 mg/kg/day, long term. Extend the dosing interval to every 24 to 36 hours at creatinine clearance 31 to 50 mL/min, every 24 to 48 hours at 10 to 30 mL/min, and every 40 to 60 hours under 10 mL/min.
• Propranolol 2 to 4 mg/kg/day orally in 3 to 4 divided doses (or twice daily with a modified release preparation) is the alternative. Metoprolol and atenolol are less effective.
• Titrate on repeat exercise testing to suppress ventricular ectopy and avoid bidirectional ventricular tachycardia. Never stop abruptly. Contraindicated in asthma, severe bradycardia and high grade atrioventricular block without a pacemaker. Missed doses cause events.

Flecainide is added when ectopy, syncope or arrhythmia persists on a beta blocker.

• 50 mg orally twice daily, increased every 1 to 2 weeks to 100 to 150 mg twice daily; in children 2 to 3 mg/kg/day in two doses. Maximum 300 mg daily. Long term.
• Check ECG for QRS widening and reduce the dose when the QRS widens by over 25% from baseline. Trough plasma level 0.2 to 1.0 microgram/mL.
• At creatinine clearance of 35 mL/min or less start at 50 mg twice daily and monitor plasma levels. Reduce in severe liver impairment.
• Contraindicated in structural heart disease, ischaemic heart disease, conduction block and Brugada syndrome. Interacts with CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine), which raise flecainide levels.

Left cardiac sympathetic denervation for events despite a beta blocker and flecainide, or intolerance or contraindication to them. It reduces events substantially.

Implantable cardioverter defibrillator after cardiac arrest despite medical therapy, and for recurrent syncope or polymorphic ventricular tachycardia on a beta blocker plus flecainide. Shocks can provoke further catecholamine surges and electrical storm, so continue medication, programme long detection durations and high rate zones, and use shocks only when needed. Use sedation and beta blocker therapy after shocks.

Acute management of storm. Deep sedation, intravenous beta blockade (propranolol 1 mg intravenously over 1 minute, repeated every 2 minutes if needed, maximum 10 mg; monitor blood pressure and heart rate), defibrillation for pulseless or unstable rhythm, and avoidance of sympathomimetics outside cardiac arrest.

Special groups.

• Pregnancy: continue beta blocker therapy (propranolol or nadolol); the postpartum period carries high risk. Flecainide is continued under specialist supervision with foetal monitoring. Delivery in a unit with defibrillation available.
• Breastfeeding: propranolol is preferred. Flecainide enters milk, so monitor the infant.
• Children: weight based dosing, re-titrated on growth, with school and family training in defibrillator use.

Monitoring. Exercise test 3 to 6 months after any change in therapy and then yearly. Ambulatory ECG yearly. Flecainide plasma level and QRS width after dose changes. Device interrogation every 3 to 6 months. Adherence review at every visit. Cascade screening of first degree relatives.

Referral and escalation. Refer to an inherited cardiac conditions centre. Urgent for syncope on treatment, ventricular tachycardia, device shocks or storm.