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Catecholaminergic Polymorphic Ventricular Tachycardia

Synonym: Catecholamine-Induced Polymorphic Ventricular Tachycardia (CPVT)

, MD, PhD, , MD, PhD, and , MD.

Author Information

Initial Posting: ; Last Update: October 13, 2016.

Summary

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.

Diagnosis

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.

Table 1.

Molecular Genetic Testing Used in Catecholaminergic Polymorphic Ventricular Tachycardia

Gene 1Proportion of CPVT Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detectable by Test Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
CALM1<1% 5~100%Unknown 6
CASQ22%-5% 7~100%Unknown 6
RYR250%-55% 8~99%Unknown 6, 9
TRDN1%-2% 10~100%Unknown 6
Unknown 1135%-45% 12NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.
6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

7.
8.
9.

Exon 3 RYR2 deletion has been reported in a family with CPVT associated with left ventricular non-compaction [Campbell et al 2015].

10.
11.

A CPVT-like locus has been identified on chromosome 7p14-p22 but screening of candidate genes in the region has not revealed a disease-associated gene [Bhuiyan et al 2007].

12.

Clinical Characteristics

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).

Differential Diagnosis

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle; with time, it may also involve the left ventricle. Most of the genes associated with ARVC code for desmosomal proteins. Individuals with CPVT do not have structural cardiac abnormalities. The evidence of overlapping phenotypes (see Genetically Related Disorders) calls for careful imaging assessment (echocardiogram, MRI) in all individuals with CPVT.

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 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 electrocardiographic 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. Distinguishing between the two disorders is important as there is no known effective therapy for SC-TdP, whereas CPVT usually responds to beta-blocking agents.

Long QT syndrome (LQTS). Exercise-related syncope is also typically found in the LQT1 variant of LQTS. Since incomplete penetrance is possible in LQT1, some individuals may have a normal QT interval and may present with a clinical history similar to that of CPVT (exercise-related syncope and normal ECG). Unlike CPVT, LQT1 does not present with inducible arrhythmia during graded exercise (exercise stress test). The initial description of CPVT by Philippe Coumel included cases with borderline or mildly prolonged QT interval.

Andersen-Tawil syndrome (ATS, LQTS type 7) is an inherited arrhythmogenic disorder caused by mutation of KCNJ2. ATS is characterized by cardiac (QT prolongation, prominent U waves) and extra-cardiac features (distinctive facial features, periodic paralysis). The present authors and others [Postma et al 2006, Tester et al 2006] have observed that some individuals with ATS may develop bidirectional VT similar to that of CPVT. However, ATS is to be considered a distinct disorder with manifestations that may overlap with CVPT in rare instances. In ATS the presence of extracardiac manifestations, the low or absent risk of sudden death, and the lack of a direct relationship of arrhythmias to adrenergic activation distinguish it from CPVT.

Management

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 www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CALM1- and RYR2-related catecholaminergic polymorphic ventricular tachycardia (CPVT) are inherited in an autosomal dominant manner.

CASQ2-related CPVT is typically inherited in an autosomal recessive manner. Autosomal dominant inheritance of CASQ2-related CPVT has been reported in one family to date [Gray et al 2016]. Based on this report, the possibility of autosomal dominant inheritance of CASQ2-related CPVT should be considered in the assessment of risk to family members.

TRDN-related CPVT is inherited in an autosomal recessive manner.

One or more additional CPVT-related genes probably exist, pathogenic variants in which may be inherited in an autosomal recessive or an autosomal dominant manner.

Risk to Family Members – Autosomal Dominant CPVT

Parents of a proband

  • Approximately 50% of individuals with autosomal dominant CPVT have an affected parent.
  • A proband with autosomal dominant CPVT may have the disorder as the result of a de novo pathogenic variant.
    • Accurate data on the prevalence of de novo RYR2 pathogenic variants are not available; prevalence is estimated at 40%, suggesting that some probands with RYR2-related CPVT do not reach reproductive age.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include a maximal exercise stress test and molecular genetic testing if the variant has been identified in the proband.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Note: Although approximately 50% of individuals diagnosed with autosomal dominant CPVT have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or reduced penetrance.

Sibs of a proband

  • The risk to the sibs of a proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for CPVT because of the possibility of reduced penetrance in a parent.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant CPVT has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected, his or her family members are at risk.

Risk to Family Members – Autosomal Recessive CPVT

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic. Minor abnormalities (rare and benign arrhythmias) have been reported in anecdotal cases.
  • It is possible (although likely rare) that one or both parents of a proband are actually themselves affected. Therefore, a maximal exercise stress test and molecular genetic testing can be considered for the parents of a proband with autosomal recessive CPVT.

Sibs of a proband

  • 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 neither affected nor a heterozygote.
  • Heterozygotes (carriers) are usually asymptomatic. Minor abnormalities (rare and benign arrhythmias) have been reported in anecdotal cases.

Offspring of a proband. The offspring of an individual with autosomal recessive CPVT are obligate heterozygotes (carriers) for a pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk family members is possible if the pathogenic variants in the family are known.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant or, less likely, that a parent has germline mosaicism. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Catecholaminergic Polymorphic Ventricular Tachycardia: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Catecholaminergic Polymorphic Ventricular Tachycardia (View All in OMIM)

114180CALMODULIN 1; CALM1
114251CALSEQUESTRIN 2; CASQ2
180902RYANODINE RECEPTOR 2; RYR2
603283TRIADIN; TRDN
604772VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1, WITH OR WITHOUT ATRIAL DYSFUNCTION AND/OR DILATED CARDIOMYOPATHY; CPVT1
611938VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 2; CPVT2
614021VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 3; CPVT3
614916VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 4; CPVT4
615441VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 5, WITH OR WITHOUT MUSCLE WEAKNESS; CPVT5

Molecular Genetic Pathogenesis

CALM1, CASQ2, RYR2, and TRDN are involved in the control of intracellular calcium fluxes, sarcoplasmic reticulum calcium release, and the cytosolic free Ca2+ concentration.

Only one study has assessed the effects of CALM1 pathogenic variants [Nyegaard et al 2012]; thus, the pathophysiology of CALM1-related CPVT is largely unknown. Available data suggest that mutated CALM1 has reduced calcium-binding affinity and impaired calmodulin-ryanodine receptor interaction at low calcium concentration. These effects may lead to ryanodine receptor (RyR2) channel instability and "leakage" similar to that observed for RYR2 pathogenic variants. CALM1 pathogenic variants associated with QT prolongation also reduce the inactivation of the cardiac calcium current [Pipilas et al 2016].

In vitro expression of CASQ2 pathogenic variants has consistently shown an enhanced responsiveness of RyR2 to luminal Ca2+, which in turn leads to the generation of extrasystolic spontaneous Ca2+ transients, fragmented calcium waves delayed afterdepolarizations (DAD), and arrhythmogenic action potentials. This effect may be the result of altered Ca2+ buffering capacity of the calsequestrin polymer or to impaired CASQ2-RyR2 interaction [Viatchenko-Karpinski et al 2004, di Barletta et al 2006]. CASQ2 pathogenic variants also cause ultrastructural abnormalities of the sarcoplasmic reticulum that are detectable at nanoscale level with electron microscopy [Denegri et al 2014]. It is unknown if this has clinical implication (e.g., in the development of cardiomyopathy).

The RYR2 pathogenic variants found in individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT) have been shown to cause Ca2+ "leakage" from the sarcoplasmic reticulum (SR) in conditions of sympathetic (catecholamine) activation [Priori & Chen 2011]. The consequent abnormal increase of the cytosolic free Ca2+ concentration creates an electrically unstable substrate. In a CPVT knock-in mouse model [Cerrone et al 2005, Liu et al 2006], it was clearly shown that the pathogenesis of arrhythmias in CPVT is related to the onset of DADs and triggered activity. Furthermore, cardiac cells isolated from mice with a pathogenic variant orthologous to the human p.Arg4497Cys (a typical and relatively common CPVT-causing variant) present DAD also at baseline, suggesting that RyR2 function is also altered in the unstimulated setting.

Expression of the human TRDN p.Thr59Arg in COS-7 cells resulted in intracellular retention and degradation of the mutated protein. This was confirmed by in vivo expression of the mutant in triadin knock-out mice by viral transduction. The loss of triadin protein is likely to lead to the loss of control of RyR2 opening by CASQ2 (luminal calcium sensor).

CALM1

Gene structure. CALM1 (NM_006888.4, cDNA 4268 bp) contains six exons spread over about 10 kb of genomic DNA on chromosome 14q32.11. Two additional homolog genes (CALM2 and CALM3) are present in the human genome and appear to have similar function. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Only two CALM1 pathogenic variants have been reported in a single study [Nyegaard et al 2012] (see Table 2).

Table 2.

CALM1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein Change
(Alias 1)
Reference Sequences
c.161A>Tp.Asn53IleNM_006888​.4
NP_008819​.1
c.293A>Gp.Asn98Ser
(Asn97Ser)

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. The gene encodes a 149-amino acid protein containing typical calcium binding sites (EF hands). Besides RyR2, CALM1 also interacts with the voltage dependent calcium channels (CaV1.3)

Abnormal gene product. (See Molecular Genetic Pathogenesis.) Calmodulin is widely expressed (especially in the CNS) and extra-cardiac phenotypes can be expected (although poorly investigated to date).

CASQ2

Gene structure. The CASQ2 coding regions encompass 1197 nucleotides and 11 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Twenty-two CASQ2 pathogenic variants have been associated with CPVT, all of which cause a recessive phenotype with the exception of p.Lys180Arg, which is associated with a dominant CPVT phenotype [Gray et al 2016]. See Table 3.

Table 3.

Selected CASQ2 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.62delAp.Glu21GlyfsTer15NM_001232​.3
NP_001223​.2
c.97C>Tp.Arg33Ter
c.539A>Gp.Lys180Arg
c.919G>Cp.Asp307His

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. CASQ2 encodes for the cardiac isoform of calsequestrin, calsequestrin-2, an SR protein functionally and physically related to the ryanodine receptor. CASQ2 protein forms polymers at the level of the terminal cisternae of the SR in close proximity to the ryanodine receptor; its function is that of buffering the Ca2+ ions.

Abnormal gene product. Only one CASQ2 pathogenic variant has been functionally characterized in vitro. The available data suggest that the pathophysiology of CASQ2-related CPVT may be related to the following mechanisms: loss of polymerization of CASQ monomeres, loss of calcium buffering capability, and indirect destabilization of the RyR channel opening process.

RYR2

Gene structure. The RYR2 coding region encompasses 14901 nucleotides on 104 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 150 RYR2 pathogenic variants causing CPVT have been reported to date [Priori & Chen 2011]. Sequencing of the entire coding region and flanking intronic regions is optimal, as 24% of pathogenic variants are located outside of the regions encoding the KBP12.6-binding region, the calcium-binding domain, and the transmembrane domain (C-terminus) [Priori & Chen 2011].

No mutation hot spots have been reported to date.

Exon-spanning deletions have been reported [Marjamaa et al 2009, Medeiros-Domingo et al 2009, Campbell et al 2015, Leong et al 2015].

Table 4.

Selected RYR2 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.6982C>Tp.Pro2328SerNM_001035​.2
NP_001026​.2
c.12602A>Gp.Gln4201Arg
c.13489C>Tp.Arg4497Cys
c.13957G>Tp.Val4653Phe

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The ryanodine receptor (RyR2) is the main Ca2+-releasing channel of the SR in the heart [George et al 2003]. It plays a central role in the so-called "calcium-induced calcium release" process that couples the electrical activation with the contraction phase of the cardiac myocytes. Following the Ca2+ entry through the voltage-gated channels of the plasmalemma, the ryanodine receptor releases the Ca2+ ions stored in the SR that are required for contraction of the muscle fibers.

Abnormal gene product. The calcium concentration gradient between the SR (in the micromolar range) and cytosol (in the nanomolar range) is remarkable. Thus, when RyR2 channels open, the Ca2+ ions may flow easily along their concentration gradient. Every condition that destabilizes the RyR2 structure may cause uncontrolled flux since the electrochemical calcium gradient is high. In vitro studies have shown that defective RyR2 proteins lose the capability to finely control the calcium release process upon adrenergic (catecholamine) stimulation. The "store overload-induced calcium release" hypothesis has been put forth by Jiang et al [2004] and Jiang et al [2005]. According to their model, the effect of RYR2 pathogenic variants would be to reduce the amount of Ca2+ in the SR required to determine spontaneous spillover. This may be due to intramolecular domain-domain interaction as shown by George et al [2006] (and other authors) who demonstrated that mutated ryanodine receptor proteins promote weakened domain interaction ("unzipping") and channel hyperactivation or hypersensitization. Finally, increased sensitivity (increased open probability at a given calcium concentration) to luminal or cytosolic calcium has been reported [Priori & Chen 2011].

TRDN

Gene structure. The longest TRDN transcript variant NM_006073.3 comprises 41 exons. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene; for a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Three TRDN pathogenic variants, all of which cause the clinical phenotype in homozygous or compound heterozygous states, have been associated with CPVT. See Table 5.

Table 5.

TRDN Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.53_56delACAGp.Asp18AlafsTer14NM_006073​.3
NP_006064​.2
c.176C>G 1p.Thr59Arg
c.613C>T 1p.Gln205Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

These variants have been found in the same affected individual, who was compound heterozygous. The genotype of this individual would be designated as c.[176C>G];[613C>T].

Normal gene product. TRDN encodes triadin (OMIM 603283), an SR protein functionally and physically related to the ryanodine receptor. Lack of triadin is associated with a reduction of CASQ2 protein levels and ultrastructural abnormalities of the T tubules similar to those observed in the CASQ2 knock out. This affects the calcium release process and, more specifically, results in a calcium leak during diastole similar to that observed for RYR2 mutants.

Abnormal gene product. Pathogenic variants in TRDN found in persons with CPVT (in 2 families) have been associated with a reduction of protein expression. Although functional studies are lacking it is possible that the loss of triadin leads to an indirect destabilization of the RyR2 channel opening process similar to that observed for pathogenic variants in CASQ2.

References

Published Guidelines / Consensus Statements

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Suggested Reading

  • Adler A, Viskin S. Syncope in Hereditary Arrhythmogenic Syndromes. Cardiol Clin. 2015;33:433–40. [PubMed: 26115829]
  • Crosson JE, Callans DJ, Bradley DJ, Dubin A, Epstein M, Etheridge S, Papez A, Phillips JR, Rhodes LA, Saul P, Stephenson E, Stevenson W, Zimmerman F. PACES/HRS expert consensus statement on the evaluation and management of ventricular arrhythmias in the child with a structurally normal heart. Heart Rhythm. 2014;11:e55–78. [PubMed: 24814375]
  • Eisner DA, Venetucci LA, Trafford AW. Life, sudden death, and intracellular calcium. Circ Res. 2006;99:223–4. [PubMed: 16888244]
  • Denegri M, Avelino-Cruz JE, Boncompagni S, De Simone SA, Auricchio A, Villani L, Volpe P, Protasi F, Napolitano C, Priori SG. Viral gene transfer rescues arrhythmogenic phenotype and ultrastructural abnormalities in adult calsequestrin-null mice with inherited arrhythmias. Circ Res. 2012;2012;110:663–8. [PubMed: 22298808]
  • Hammond-Haley M, Patel RS, Providência R, Lambiase PD. Exercise restrictions for patients with inherited cardiac conditions: Current guidelines, challenges and limitations. Int J Cardiol. 2016;209:234–41. [PubMed: 26897076]
  • Mazzanti A, O'Rourke S, Ng K, Miceli C, Borio G, Curcio A, Esposito F, Napolitano C, Priori SG. The usual suspects in sudden cardiac death of the young: a focus on inherited arrhythmogenic diseases. Expert Rev Cardiovasc Ther. 2014;12:499–519. [PubMed: 24650315]
  • Shan J, Xie W, Betzenhauser M, Reiken S, Chen B, Wronska A, Marks AR. Calcium leak through ryanodine receptors leads to atrial fibrillation in three mouse models of catecholaminergic polymorphic ventricular tachycardia. Circ Res. 2012;111:708–17. [PMC free article: PMC3734386] [PubMed: 22828895]
  • van der Werf C, Nederend I, Hofman N, van Geloven N, Ebink C, Frohn-Mulder IM, Alings AM, Bosker HA, Bracke FA, van den Heuvel F, Waalewijn RA, Bikker H, van Tintelen JP, Bhuiyan ZA, van den Berg MP, Wilde AA. Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives. Circ Arrhythm Electrophysiol. 2012;5:748–56. [PubMed: 22787013]
  • Venetucci L, Denegri M, Napolitano C, Priori SG. Inherited calcium channelopathies in the pathophysiology of arrhythmias. Nat Rev Cardiol. 2012;9:561–75. [PubMed: 22733215]
  • Yano M, Yamamoto T, Ikeda Y, Matsuzaki M. Mechanisms of disease: ryanodine receptor defects in heart failure and fatal arrhythmia. Nat Clin Pract Cardiovasc Med. 2006;3:43–52. [PubMed: 16391617]

Chapter Notes

Revision History

  • 13 October 2016 (sw) Comprehensive update posted live
  • 6 March 2014 (me) Comprehensive update posted live
  • 7 February 2013 (cd) Revision: multigene panels now listed in the GeneTests™ Laboratory Directory; mutations in TRDN identified as causative for CPVT
  • 16 February 2012 (me) Comprehensive update posted live
  • 7 July 2009 (me) Comprehensive update posted live
  • 22 March 2007 (me) Comprehensive update posted live
  • 22 May 2006 (cn) Revision: Prenatal diagnosis available for RYR2 and CASQ2
  • 14 October 2004 (me) Review posted live
  • 1 June 2004 (cn) Original submission
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