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Catecholaminergic Polymorphic Ventricular Tachycardia.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.
2004 Oct 14 [updated 2014 Mar 06].



Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic syncope occurring during exercise or acute emotion in individuals without structural cardiac abnormalities. Arrhythmias may be well tolerated, with only mild symptoms such as dizziness or lypothymia. The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic). Spontaneous recovery occurs 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 age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve 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% one or more syncopal spells. Sudden death may be the first manifestation of the disease.


The resting electrocardiogram is usually normal. The most important diagnostic test is the exercise stress test, which can reproducibly evoke the typical ventricular tachycardia during acute adrenergic activation (e.g., exercise, acute emotion). The bidirectional tachycardia is defined as a ventricular arrhythmia with an alternating 180°-QRS axis on a beat-to-beat basis; some individuals may have polymorphic VT without a "stable" QRS vector alternans. The onset of arrhythmias during exercise occurs at a heart rate threshold of 100-120 beats per minute and the arrhythmias tend to worsen with increasing workload. Mutation in four genes – RYR2, CASQ2, TRDN, and CALM1 – is known to cause CPVT or related phenotypes of adrenergically induced life-threatening arrhythmias. The presence of other as-yet unidentified loci is postulated


Treatment of manifestations: The use of beta-blockers is the mainstay of CPVT therapy. Although there are no comparative studies, the majority of international referral centers use nadolol (1-2.5 mg/kg/day divided into two doses per day) or propranolol (2-4 mg/kg/day divided into 3-4 doses per day). Non-selective beta-blockers are recommended in all cases in the absence of contraindications (e.g., asthma). Reproducible induction of arrhythmia during exercise allows titration and monitoring of the dose of beta-blockers. When there is evidence of incomplete protection (recurrence of syncope or complex arrhythmias during exercise) with beta blockers, flecainide (100-300 mg/day) should be added. Beta-blockers and flecainide are also indicated for affected individuals who have experienced a previous aborted sudden death. An implantable cardioverter defibrillator (ICD) may be necessary for those with recurrent cardiac arrest while on beta-blocker therapy or for those unable to take beta-blockers. Pharmacologic therapy should be maintained/optimized even in individuals with an ICD in order to reduce the probability of ICD firing. Left cardiac sympathetic denervation (LCSD) can be considered in those who are refractory to other therapies or in those who are intolerant of or have contraindications to beta-blocking therapy; however, due to side effects and recurrence of cardiac events in those with LCSD, pharmacologic therapy should always be optimized prior to considering LCSD. Prevention of primary manifestations: Beta-blockers are indicated for all clinically affected individuals and for individuals with a RYR2 mutation with no history of cardiac events (syncope) or ventricular arrhythmias on exercise stress testing, 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 exercise stress test. Prevention of secondary complications: To avoid exacerbation of allergic asthma, use of the cardiac-specific beta-blocker, metoprolol, may be used; the dose is based on the need of the affected individual (≤3 mg/kg). Anticoagulation may be necessary for some persons with an ICD. Surveillance: Follow-up visits with a cardiologist every six to twelve months (depending on disease severity) to monitor the efficacy of therapy; the limit for any allowed physical activity can be defined on the basis of 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. Agents/circumstances to avoid: Competitive sports and other strenuous exercise; digitalis. Evaluation of relatives at risk: Because treatments and surveillance are available to reduce morbidity and mortality in individuals known to have a disease-causing allelic variant, first-degree relatives of a proband should be offered molecular genetic testing if the family-specific pathogenic variant is known; if the family-specific pathogenic variant is not known, all first-degree relatives of an affected individual should be evaluated with resting ECG, Holter monitoring, and, most importantly, with exercise stress testing.


Autosomal dominant CPVT: RYR2- and CALM1-related CPVT are inherited in an autosomal dominant manner. Each child of an individual with autosomal dominant CPVT has a 50% chance of inheriting the mutation. Autosomal recessive CPVT: CASQ2- and TRDN-related CPVT are inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele. Minor abnormalities (rare and benign arrhythmias) have been reported in heterozygotes in anecdotal cases. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal testing for pregnancies at increased risk for some forms of CPVT is possible if the family-specific pathogenic variant(s) are known.

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