Management of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

Definition & Epidemiology

CPVT is a rare inherited arrhythmia syndrome in which exercise or emotional stress provokes life‑threatening bidirectional or polymorphic ventricular tachycardia despite a structurally normal heart and a normal resting ECG. 1
Diagnosis requires a structurally normal heart, a normal ECG, and exercise‑ or emotion‑induced bidirectional or polymorphic VT. 1
The estimated prevalence of CPVT is approximately 1 in 10 000 individuals. 1
Clinical manifestations usually appear in the first decade of life, although late‑onset cases have been reported. 1, 2

Two principal genetic forms exist: an autosomal‑dominant variant caused by pathogenic mutations in the cardiac ryanodine‑receptor gene (RyR2) and a rare autosomal‑recessive variant due to mutations in the cardiac calsequestrin gene (CASQ2). 1
About 50 % of autosomal‑dominant CPVT cases are attributable to RyR2 mutations. 2
CPVT diagnosis is confirmed in individuals who carry pathogenic RyR2 or CASQ2 mutations. 1
Additional genes (KCNJ2, ANK2, TRDN, CALM1) have been identified, but their role as true CPVT phenocopies remains uncertain. 1

Patients typically present with syncope, cardiac arrest, or sudden cardiac death triggered by physical activity or emotional stress. 1
Resting ECG and echocardiography are characteristically normal, making the diagnosis challenging. 1
Holter monitoring at rest usually shows no ventricular extrasystoles or nonsustained VT. 2
The hallmark arrhythmia is bidirectional VT (beat‑to‑beat alternating QRS axis by ~180°); irregular polymorphic VT or ventricular fibrillation may also occur. 2

An exercise stress test that elicits bidirectional or polymorphic VT is the cornerstone for establishing the diagnosis. 1
During exercise testing, isolated premature ventricular complexes typically precede runs of nonsustained VT that lengthen with continued exertion and may become sustained. 2
Both supraventricular and ventricular arrhythmias are reproducibly induced by exercise stress testing. 2
Catecholamine infusion has been suggested as an adjunctive test, but its sensitivity is not clearly defined. 1
Invasive electrophysiology studies with programmed ventricular stimulation are not recommended for risk stratification because the arrhythmia is not inducible with programmed stimulation. 1, 2

Independent predictors of future arrhythmic events include: diagnosis during childhood, absence of beta‑blocker therapy, and persistence of complex arrhythmias on exercise testing despite full‑dose beta‑blockers. 1
A prior cardiac arrest confers the highest risk of subsequent events. 2
Recurrence of sustained VT, hemodynamically intolerable VT, or syncope while on beta‑blockers signals an elevated risk profile. 2

Exercise restriction combined with beta‑blockers lacking intrinsic sympathomimetic activity constitutes first‑line therapy. 1
Nadolol is the most frequently used beta‑blocker in referral centers, although comparative efficacy data among beta‑blockers are lacking. 1
Beta‑blocker therapy should be offered to genetically positive family members even after a negative exercise test. 1

Flecainide should be added to beta‑blockers in patients with recurrent syncope or polymorphic/bidirectional VT despite optimal beta‑blockade. 1
Flecainide markedly reduces ventricular arrhythmia burden and is the preferred adjunct when beta‑blocker control is incomplete. 1, 3
In patients who already have an implantable cardioverter‑defibrillator (ICD), flecainide should be considered to lower the incidence of appropriate ICD shocks. 1

Left cardiac sympathetic denervation may be considered for patients with recurrent syncope or VT (or multiple appropriate ICD shocks) despite beta‑blockers ± flecainide, or for those intolerant or contraindicated to beta‑blockers. 1
Additional long‑term data are required to fully quantify the efficacy of denervation. 1, 3

Survivors of cardiac arrest should receive beta‑blockers and an ICD; flecainide may be added if arrhythmic control on exercise testing remains inadequate. 4
An ICD should be contemplated in patients who do not achieve arrhythmic control with beta‑blockers and flecainide. 4
If syncope occurs while the patient is on a beta‑blocker, ICD implantation is recommended. 2
ICD programming should incorporate long detection delays before shock delivery to avoid painful shocks that increase sympathetic tone and may precipitate a malignant cycle of recurrent shocks and arrhythmias. 5

Beta‑blockers can prevent syncope even when ventricular arrhythmias are still inducible during exercise testing. 2
Electrophysiological testing is not useful for management because the CPVT arrhythmia is not inducible with programmed ventricular stimulation. 2