Clinical Guidance

Gain-of-function pathogenic variants in RYR2 are associated with the typical CPVT phenotype (reproducible exercise-/emotion-induced bidirectional VT with structurally normal heart) while the much less frequently observed loss-of-function variants can cause ventricular fibrillation and sudden death in the absence of inducible arrhythmias . No genotype-phenotype correlations for CASQ2, CALM1, CALM2, CALM3, KCNJ2, TECRL, or TRDN have been identified.

Source: GeneReviews — "Catecholaminergic Polymorphic Ventricular Tachycardia"

Penetrance

The mean penetrance of RYR2 pathogenic variants is 83% [Author, unpublished data]. Therefore, asymptomatic individuals with RYR2-related CPVT are a minority. To date, biallelic CASQ2 pathogenic variants have been 100% penetrant in reported individuals. Too few individuals with heterozygous CASQ2, KCNJ2, CALM1, CALM2, or CALM3-related CPVT have been reported to date to allow a robust estimate of penetrance.

Source: GeneReviews — "Catecholaminergic Polymorphic Ventricular Tachycardia"

Diagnostic Criteria

Suggestive Findings

Catecholaminergic polymorphic ventricular tachycardia (CPVT) should be suspected in individuals who have one or more of the following :

Source: GeneReviews — "Catecholaminergic Polymorphic Ventricular Tachycardia"

Differential Diagnosis

Short-coupled ventricular tachycardia (SC-torsade de pointes [TdP]) is a clinical entity presenting with life-threatening polymorphic ventricular arrhythmias resembling in part the pattern of arrhythmias observed in individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT). SC-TdP presents with polymorphic ventricular tachycardia (VT) occurring in the setting of a structurally normal heart and in the absence of any overt baseline EKG abnormality. However, the onset of SC-TdP is not clearly related to adrenergic stimuli (exercise or emotion) and is not associated with the typical bidirectional pattern of CPVT-related tachycardia.

Source: GeneReviews — "Catecholaminergic Polymorphic Ventricular Tachycardia"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Catecholaminergic Polymorphic Ventricular Tachycardia

System/Concern | Evaluation | Comment

Cardiac

| Resting EKG | Baseline

Holter monitoring | To assess arrhythmias that develop when heart rate

Exercise stress test1 | Baseline for diagnosis monitoring of therapy

Echocardiogram /or MRI | To evaluate for structural defects

Genetic

counseling | By genetics professionals2 | To inform affected persons their families re nature, MOI, implications of CPVT to facilitate medical personal decision making

CPVT = catecholaminergic polymorphic ventricular tachycardia; MOI = mode of inheritance

1. Exercise stress test should be performed until maximal tolerated effort, as some individuals have high heart rate threshold for induction of arrhythmias.

2. Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Management of CPVT is summarized in a specific consensus document from the Heart Rhythm Association (HRS) and the European Heart Rhythm Association (EHRA) (full text), and in the recent version of the European Society of Cardiology (ESC) guidelines on ventricular arrhythmias (full ...

Source: GeneReviews — "Catecholaminergic Polymorphic Ventricular Tachycardia"

Clinical Guidance

Competitive sports and other strenuous exercise are always contraindicated for individuals with CPVT. All individuals showing exercise-induced arrhythmias should avoid physical activity, except for light training for those individuals showing good suppression of arrhythmias on exercise stress testing while on therapy. It is important to note that efficacy needs to be periodically retested . The risk for arrhythmias during sports in individuals who have pathogenic variants in genes associated with CPVT but no clinical phenotype (no exercise-induced arrhythmias) is not known; thus, it may be safest for these individuals to refrain from intense physical activity. Digitalis favors the onset of cardiac arrhythmias as a result of delayed afterdepolarization and triggered activity; therefore, digitalis should be avoided in all individuals with CPVT.

Source: GeneReviews — "Catecholaminergic Polymorphic Ventricular Tachycardia"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Catecholaminergic Polymorphic Ventricular Tachycardia"

Surveillance Guidelines

Table 6.

Recommended Surveillance for Individuals with Catecholaminergic Polymorphic Ventricular Tachycardia

System/Concern | Evaluation | Frequency

Monitoring

therapy

efficacy | Cardiologist eval to incl:

• Resting EKG

• Exercise stress test, performed at maximal age-predicted heart rate. For those on beta-blocker therapy (in whom maximal heart rate cannot be reached), test should be performed at highest tolerated workload.

• Holter monitoring

• Echocardiogram MRI at least every 2 yrs

| • Every 6-12 mos (per severity of clinical manifestations)

• Follow-up visits are very important esp until puberty, as body weight rapidly drug dosages must be continually adjusted.

Limitation on

physical activity | • Can be defined on basis of exercise stress test done in hospital setting

• Use of commercially available heart rate monitoring devices for sports participation can be helpful in keeping heart rate in safe range during physical activity but should not be considered as alternative to medical follow-up visits.

• Since heart rate threshold for onset of arrhythmias is often reproducible in the same person, the advice for allowed exercise intensity should be individualized based on results of exercise stress test.

| Review at each visit.

Source: GeneReviews — "Catecholaminergic Polymorphic Ventricular Tachycardia"