Catecholaminergic Polymorphic Ventricular Tachycardia

Excerpt

Clinical characteristics: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic syncope occurring during exercise or acute emotion. The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic). Spontaneous recovery may occur when these arrhythmias self-terminate. In other instances, ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. The mean onset of symptoms (usually a syncopal episode) is between age seven and 12 years; onset as late as the fourth decade of life has been reported. If untreated, CPVT is highly lethal, as approximately 30% of affected individuals experience at least one cardiac arrest and up to 80% have one or more syncopal spells. Sudden death may be the first manifestation of the disease.

Diagnosis/testing: The diagnosis of CPVT is established in the presence of a structurally normal heart, normal resting EKG, and exercise- or emotion-induced bidirectional or polymorphic ventricular tachycardia OR in individuals who have a heterozygous pathogenic variant in RYR2, CALM1, CALM2, CALM3, CASQ2, or KCNJ2 or biallelic pathogenic variants in CASQ2, TECRL, or TRDN.

Management: Treatment of manifestations: Recent studies have demonstrated that (1) nadolol is the most effective beta blocker in CPVT; (2) nonselective beta blockers (nadolol and propranolol) are superior to selective beta blockers; (3) a significant burden of life-threatening arrhythmias persists after left cardiac sympathetic denervation; (4) an implantable cardioverter defibrillator is effective for those individuals in whom arrhythmias are not adequately controlled by drug therapy.

Prevention of primary manifestations: Beta blockers are indicated for all clinically affected individuals, and for individuals with a pathogenic variant(s) in one of the genes associated with CPVT with a negative exercise stress test, since sudden death can be the first manifestation of the disease. Flecainide can be added for primary prevention of a cardiac arrest when beta blockers alone cannot control the onset of arrhythmias during an exercise stress test.

Surveillance: Follow-up visits with a cardiologist every six to 12 months (depending on disease severity) are very important, especially until puberty, since body weight increases rapidly and drug dosages must be continually adjusted. Limitation on physical activity can be defined on the basis of an exercise stress test done in the hospital setting; the use of commercially available heart rate-monitoring devices for sports participation can be helpful in keeping the heart rate in a safe range during physical activity, but should not be considered as an alternative to medical follow-up visits; allowed exercise intensity should be individualized based on exercise stress test results.

Agents/circumstances to avoid: Competitive sports and other strenuous exercise; use of digitalis.

Evaluation of relatives at risk: Because treatment and surveillance are available to reduce morbidity and mortality, first-degree relatives of a proband should be offered molecular genetic testing if the family-specific pathogenic variant(s) are known; if the family-specific variant(s) are not known, all first-degree relatives of an affected individual should be evaluated with resting EKG, Holter monitoring, echocardiography, and – most importantly – exercise stress testing.

Genetic counseling: RYR2-, CALM1-, CALM2-, CALM3-, and KCNJ2-related CPVT are inherited in an autosomal dominant manner.

CASQ2-related CPVT is typically inherited in an autosomal recessive manner. However, because a subset of individuals (still unquantified but rare) with heterozygous CASQ2 pathogenic variants show a mild CPVT phenotype, autosomal dominant inheritance may not be ruled out for CASQ2-related CPVT, and clinical screening is indicated accordingly in individuals who are heterozygous for a CASQ2 pathogenic variant.

TECRL- and TRDN-related CPVT are inherited in an autosomal recessive manner.

1. Autosomal dominant inheritance. Each child of an individual with autosomal dominant CPVT has a 50% chance of inheriting the pathogenic variant.

2. Autosomal recessive inheritance. If both parents are known to be heterozygous for a CASQ2, TECRL, or TRDN pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygote testing for at-risk relatives requires prior identification of the CASQ2, TECRL, or TRDN pathogenic variants in the family.

Once the CPVT-related pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.