Catecholaminergic Polymorphic Ventricular Tachycardia

Clinical characteristics.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic syncope occurring during exercise or acute emotion in individuals without structural cardiac abnormalities. 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 age of onset of symptoms (usually a syncopal episode) 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.

Diagnosis/testing.

The diagnosis is established in a proband with a structurally normal heart, often normal resting electrocardiogram, and the following findings on exercise stress test – the most important diagnostic test, as it 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. Identification of heterozygous pathogenic variants in RYR2 or CALM1 or of biallelic pathogenic variants in CASQ2 or TRDN can also establish the diagnosis.

Management.

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 2 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 individuals 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, given the side effects and recurrence of cardiac events associated 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 pathogenic variants 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 exercise stress test.

Prevention of secondary complications: To avoid exacerbation of allergic asthma, a cardiac-specific beta-blocker, metoprolol, may be used; the dose should be individualized. 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, 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 ECG, Holter monitoring, and, most importantly, with exercise stress testing.

Genetic counseling.

Autosomal dominant CPVT: CALM1- and RYR2-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 pathogenic variant.

Autosomal recessive CPVT: CASQ2- and TRDN-related CPVT are inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant). 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 heterozygous, and a 25% chance of being unaffected and not a heterozygote.

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 diagnosis are possible options.

Suggestive Findings

Catecholaminergic polymorphic ventricular tachycardia (CPVT) should be suspected in individuals who have one or more of the following [Priori et al 2013a]:

• Syncope occurring during physical activity or acute emotion; mean onset age seven to 12 years. Less frequently, first manifestations may occur later in life; individuals with first event up to age 40 years are reported.
• History of exercise- or emotion-related palpitations and dizziness in some individuals
• Sudden unexpected cardiac death triggered by acute emotional stress or exercise
• Family history of juvenile sudden cardiac death triggered by exercise or acute emotion
• Exercise-induced polymorphic ventricular arrhythmias
  • ECG during a graded exercise (exercise stress test)* allows ventricular arrhythmias to be reproducibly elicited in the majority of affected individuals. Typically, the onset of ventricular arrhythmias is 100-120 beats/min.
  • With increase in workload, the complexity of arrhythmias progressively increases from isolated premature beats to bigeminy and runs of non-sustained ventricular tachycardia (VT). If the affected individual continues exercising, the duration of the runs of VT progressively increases and VT may become sustained.
  • An alternating 180°-QRS axis on a beat-to-beat basis, so-called bidirectional VT, is often the distinguishing presentation of CPVT arrhythmias.
  • Some individuals with CPVT may also present with irregular polymorphic VT without a "stable" QRS vector alternans [Swan et al 1999, Priori et al 2002].
  • Exercise-induced supraventricular arrhythmias (supraventricular tachycardia and atrial fibrillation) are common [Leenhardt et al 1995, Fisher et al 1999].
• Ventricular fibrillation occurring in the setting of acute stress
• Absence of structural cardiac abnormalities

*Note: The resting ECG of individuals with CPVT is usually normal, although some authors have reported a lower-than-normal resting heart rate [Postma et al 2005] and others have observed a high incidence of prominent U waves [Leenhardt et al 1995, Aizawa et al 2006]. Overall these features are inconsistent and not sufficiently specific to allow diagnosis. Therefore, in many instances the origin of the syncope may be erroneously attributed to a neurologic disorder. The exercise stress test is the single most important diagnostic test. In the present authors' series, the mean time interval to diagnosis after the first symptom was 2±0.8 years [Priori et al 2002].

Establishing the Diagnosis

According to the most recent version of the International Guidelines on sudden cardiac death [Priori et al 2015], the diagnosis of CPVT is established:

• In the presence of a structurally normal heart, normal resting ECG, and exercise- or emotion-induced bidirectional or polymorphic ventricular tachycardia;
  OR
• In individuals who have a heterozygous pathogenic variant in RYR2 or CALM1 or biallelic pathogenic variants in CASQ2 or TRDN (see Table 1).

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing

• Sequence analysis of RYR2 can be performed first and followed by sequence analysis of CASQ2 if no pathogenic variant is found. If no pathogenic variant in CASQ2 is found, sequence analysis of CALM1 and TRDN should be performed next, keeping in mind that pathogenic variants in CALM1 and TRDN are extremely rare causes of CPVT.
• Gene-targeted deletion/duplication analysis of RYR2 can be performed next if a pathogenic variant in RYR2 or CALM1 or biallelic pathogenic variants in CASQ2 or TRDN have not been identified (see Table 1).

A multigene panel that includes CALM1, CASQ2, RYR2, and TRDN and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes CALM1, CASQ2, RYR2, and TRDN) fails to confirm a diagnosis in an individual with features of CPVT. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by cardiac electrical instability exacerbated by acute activation of the adrenergic nervous system. If untreated the disease is highly lethal, as approximately 30% of those affected experience at least one cardiac arrest and up to 80% one or more syncopal spells.

Two clinical studies [Leenhardt et al 1995, Priori et al 2002] have contributed to the understanding of the natural history of CPVT.

The main clinical manifestation of CPVT is episodic syncope occurring during exercise or acute emotion. The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic). This may be associated with:

• Spontaneous recovery when these arrhythmias self-terminate,
  OR
• Ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available.

Sudden death may be the first manifestation of the disorder in previously asymptomatic individuals (no history of syncope or dizziness) who die suddenly during exercise or while experiencing acute emotions [Priori et al 2002, Krahn et al 2005, Watanabe et al 2013].

Note: As there is no structural abnormality of the myocardium, several individuals have tolerated the arrhythmias rather well, with only mild symptoms such as dizziness or faintness. If such symptoms reproducibly recur during exercise, further clinical investigations for CPVT may be indicated.

The mean age of onset of CPVT symptoms (usually a syncopal episode) is between age seven and twelve years [Leenhardt et al 1995, Priori et al 2002, Postma et al 2005]; onset as late as the fourth decade of life has been reported.

Instances of SIDS (sudden infant death syndrome) have been associated with pathogenic variants in RYR2 [Tester et al 2007].

Family history of sudden death in relatives younger than age 40 years is present in approximately 30% of probands with CPVT [Priori et al 2002, Watanabe et al 2013].

Other. A single case report highlighted the possible proarrhythmic effect of an insulin tolerance test (ITT), driven by severe hypokalemia and adrenergic activation secondary to the metabolic imbalance induced by the test [Binder et al 2004]. Of note, RYR2 is expressed in pancreatic beta cells responsible for insulin secretion, suggesting that altered glucose metabolism can represent a manifestation of RYR2-related CPVT [Santulli et al 2015].

Genotype-Phenotype Correlations

CASQ2 and RYR2. Available evidence suggests that the clinical features of CASQ2- and RYR2-related CPVT are virtually identical. Lahat et al [2001] reported a mild QT interval prolongation in their initial paper; however, this was not confirmed in subsequent reports [Postma et al 2002]. CASQ2-CPVT may be more severe and more resistant to beta-blockers; however, comparisons with large series of individuals are not available. Individuals with polymorphic VT without a "stable" QRS vector alternans are more likely to have pathogenic variants in CASQ2.

Priori et al [2002] and Lehnart et al [2004] reported genotype-phenotype correlations by comparing the clinical characteristics of affected individuals with and without RYR2 pathogenic variants. These data show the following:

• The natural history of the disease does not appear to differ when affected individuals with and without RYR2 pathogenic variants are compared.
• The average age of onset of the disease in both study groups (i.e., age of the first syncope) is seven to twelve years

The variant-specific clinical course of CPVT was analyzed by Lehnart et al [2004], who did not find a significant difference in mortality rates or pattern of arrhythmias among a small cohort of individuals with the RYR2 pathogenic variants p.Pro2328Ser, p.Gln4201Arg, and p.Val4653Phe.

Penetrance

The mean penetrance of RYR2 pathogenic variants is 83% [Author, unpublished data]. Therefore, asymptomatic individuals with RYR2-related CPVT are a minority. Too few individuals with CASQ2, CALM1, and TRDN have been reported to date to allow a robust estimate of the penetrance. All described individuals do show the clinical phenotype.

Nomenclature

CPVT has also been referred to as familial polymorphic ventricular tachycardia (FPVT).

Prevalence

The true prevalence of CPVT in the population is not known. An estimate of CPVT prevalence is 1:10,000.

The high prevalence of simplex cases (i.e., single occurrences in a family) and lethality at a young age suggest that the overall prevalence of CPVT is significantly lower than that of other inherited arrhythmogenic disorders such as long QT syndrome (1:7,000-1:5,000).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT), the following evaluations are recommended:

• Resting ECG
• Holter monitoring, as arrhythmias develop when heart rate increases
• Exercise stress test both for diagnosis and monitoring of therapy
• Echocardiogram and/or MRI to evaluate for structural defects
• Consultation with a clinical geneticist and/or genetic counselor

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) [Priori et al 2013b] (full text) and summarized in the recent version of the European Society of Cardiology (ESC) guidelines on ventricular arrhythmias [Priori et al 2015] (full text).

Beta-blockers are the first therapeutic choice (class I indication) of proven efficacy for about 60% of individuals with CPVT [Leenhardt et al 1995, Priori et al 2002]. The proposed mechanism of action in an individual with CPVT is inhibition of adrenergic-dependent triggered activity. This effect can be due to both heart rate reduction and direct effect on calcium release from the sarcoplasmic reticulum. Chronic treatment with full-dose beta-blocking agents prevents recurrence of syncope in the majority of affected individuals.

The reproducible induction of arrhythmia during exercise allows effective dose titration and monitoring. Recommended drugs are 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). Nadolol is reported to be more effective than selective beta blockers [Leren et al 2016]. However, selective beta-blockers can be used in individuals with asthma or other respiratory conditions. Importantly, the dose of beta-blockers should always be individualized with exercise stress testing. It is important to note that efficacy needs to be periodically retested [Heidbüchel et al 2006] (see Surveillance).

Flecainide. Clinical [van der Werf et al 2011] and experimental [Liu et al 2011] data show that to improve arrhythmia control, flecainide (100-300 mg/day) can be given along with beta-blockers to persons who have recurrence of syncope or complex arrhythmias during exercise (class IIa). Although controlled clinical trials are lacking, the evidence for effectiveness of flecainide is sufficient to indicate the use of this drug whenever beta-blockers are not sufficient to control arrhythmias. Beta-blockers and flecainide are also indicated for affected individuals who have experienced a previous aborted sudden death to reduce the probability of implantable cardioverter defibrillator (ICD) shocks (class IIb). The antiarrhythmic effects of flecainide appear to be independent from the specific CPVT genetic subtype [Watanabe et al 2013].

Implantable cardioverter defibrillator (ICD) implantation in addition to beta-blockers with or without flecainide is recommended in individuals with a diagnosis of CPVT who experience cardiac arrest, recurrent syncope or polymorphic/bidirectional VT despite optimal therapy. Furthermore, in those individuals in whom the highest tolerated dose of beta-blockers fails to adequately control arrhythmias [Priori et al 2002, Sumitomo et al 2003], an ICD can be considered for primary prevention of cardiac arrest/sudden death [Zipes et al 2006]. Whenever possible, 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) may be considered in those with a diagnosis of CPVT who experience recurrent syncope, polymorphic/bidirectional VT, or several appropriate ICD shocks while on beta-blocker and flecainide and in those who are intolerant of or with contraindication to beta-blocker therapy (class IIb). However, LCSD is not without side effects, including palpebral ptosis, elevation of the left hemidiaphragm, and lack of sweating from the left arm and face. Recurrences of cardiac events have been also reported in those with LCSD. Therefore, pharmacologic therapy should always be optimized prior to considering LCSD.

Prevention of Primary Manifestations

Beta-blockers are indicated for primary prevention in all clinically affected individuals (see Treatment of Manifestations) and in individuals with pathogenic variants in the genes associated with CPVT who have a negative exercise stress test (class IIa). Recommended drugs are nadolol (1-2.5 mg/kg/day) or propranolol (2-4 mg/kg/day). For symptomatic individuals with CPVT, the maximum tolerated dosage should be maintained. Flecainide can be added for primary prevention of cardiac arrest when beta-blockers alone cannot control the onset of arrhythmias during exercise stress test.

Prevention of Secondary Complications

Secondary complications are mainly related to therapy.

Beta-blockers could worsen allergic asthma. Therefore, the cardiac-specific beta-blocker, metoprolol, could be indicated in some individuals with CPVT who have a history of asthma. The dose of metoprolol is based on the need of the affected individual (≤3 mg/kg). Note: It is important to keep in mind that metoprolol and newer beta-blockers (e.g., bisorpolol) may not have the same efficacy as nadolol or propranolol; the reasons for this are under investigation.

For persons with an ICD, anticoagulation to prevent formation of thrombi may be necessary (particularly in children who require looping of the right ventricular catheter).

Surveillance

Regular follow-up visits to the cardiologist every six to twelve months (depending on the severity of clinical manifestations) are required in order to monitor therapy efficacy. These visits should include the following:

• Resting ECG
• Exercise stress test, performed at the maximal age-predicted heart rate. For individuals on beta-blocker therapy (in whom maximal heart rate cannot be reached), the test should be performed at the highest tolerated workload.
• Holter monitoring
• Echo and MRI at least every two years

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 are always contraindicated. All individuals showing exercise-induced arrhythmias should avoid physical activity, with the exception of 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 [Heidbüchel et al 2006]. 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 activities.

Digitalis favors the onset of cardiac arrhythmias due to delayed afterdepolarization (DAD) and triggered activity; therefore, digitalis should be avoided in all individuals with CPVT.

Evaluation of Relatives at Risk

Because treatment and surveillance are available to reduce morbidity and mortality, first-degree relatives should be offered clinical work up and molecular genetic testing if the family-specific pathogenic variant(s) are known. Indeed, the availability of effective preventive therapies can reduce the number of fatal arrhythmic events if individuals with pathogenic variants are diagnosed early.

If the family-specific pathogenic variant(s) are not known, all first-degree relatives of an affected individual should be evaluated with resting ECG, Holter monitoring, and – most importantly – exercise stress testing.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Beta-blockers (preferentially nadolol or propranolol) should be administered throughout pregnancy in affected women.

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.