Clinical Diagnosis

The clinical presentation of catecholaminergic polymorphic ventricular tachycardia (CPVT) includes the following main features:

• 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-related 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 are common [Leenhardt et al 1995, Fisher et al 1999].
• Syncope occurring during physical activity or acute emotion; mean onset age seven to nine 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
• 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 inconstant 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 authors' series, the mean time interval to diagnosis after the first symptom was 2±0.8 years [Priori et al 2002].

Molecular Genetic Testing

Genes. The three genes in which mutations are known to cause CPVT are:

• RYR2 (autosomal dominant), encoding the cardiac ryanodine receptor channel [Laitinen et al 2001, Priori et al 2001b];
• CASQ2 (autosomal recessive), encoding calsequestrin, a calcium buffering protein of the sarcoplasmic reticulum (SR) [Lahat et al 2001].
• TRDN (autosomal recessive), encoding triadin, a CASQ2 and RyR2 partner protein that regulates sarcoplasmic reticulum calcium release [Roux-Buisson et al 2012].

Evidence for further locus heterogeneity. Because causative mutations are identified in only approximately 55%-65% of individuals with CPVT, it is likely that other genes (loci) contribute to disease pathogenesis; no additional loci have been mapped to date.

ANKB. A mutation in ANKB, the gene encoding ankyrin-B, was reported in a single individual with polymorphic ventricular tachycardia similar to CPVT [Mohler et al 2004]. The role of ANKB mutations in causation of CPVT has yet to be elucidated.

KCNJ2. Some authors have claimed that KCNJ2 mutations responsible for Andersen-Tawil syndrome (ATS) may also cause CPVT; however, ATS is a distinct disorder (see Differential Diagnosis).

Clinical testing

RYR2

• Sequence analysis/mutation scanning of select exons. Most RYR2 mutations seen in CPVT appear to cluster in specific regions of the gene: codons 2200-2500 (FKBP12.6 binding domain) or starting from codon 3700 (Ca²⁺ binding domain and transmembrane domain [C-terminus]). Therefore, some laboratories sequence only those exons encompassing these critical regions; however, a recent analysis showed that 24% of mutations occur outside such “canonical” clusters.

TRDN

• TRDN mutations have been identified in two families: one 4-bp deletion, one nonsense mutation and one missense mutation.

Interpretation of test results. Sequence analysis cannot detect deletions, duplications, or exonic or multiexonic skipping.

For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. Molecular genetic testing is indicated in individuals with CPVT:

Single gene testing

• Unless the family history strongly suggests an autosomal recessive pattern of transmission, a proband with CPVT should be tested first for mutations in RYR2 either:
  • By sequence analysis of select exons followed by sequence analysis of the entire coding region if an RYR2 mutation is not identified
    
    or
  • By sequence analysis of the entire coding region.
• Non-consanguineous parents of normal phenotype may harbor heterozygous CASQ2 or TRDN [Roux-Buisson et al 2012] mutations. They may have a compound heterozygous, clinically affected baby [di Barletta et al 2006]. Therefore, molecular genetic testing for mutations in CASQ2 and TRND may be indicated if no mutations in RYR2 are detected.
• If a mutation in RYR2 is not identified in an individual with CVPT who represents a simplex case (i.e., the only affected person in the family) or if the family history is consistent with autosomal recessive inheritance, sequence analysis of CASQ2 is performed.

Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having CPVT is use of a multi-gene panel. The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest. . See Differential Diagnosis.

Molecular genetic testing may be indicated in individuals who do not have CPVT but have findings (or have a relative with findings) that could be related to CPVT, including the following:

• Idiopathic ventricular fibrillation, which may be caused by CPVT
• Family members of individuals with sudden unexplained death occurring during acute stress [Priori & Chen 2011]. Note: The yield of the analysis in these cases is unknown (and probably low).
• SIDS (sudden infant death syndrome), which has been associated with mutations in RYR2 [Tester et al 2007]. However, it is unclear whether systematic RYR2 screening is indicated and cost effective for this population [Ackerman et al 2011].

Carrier testing for relatives at risk for autosomal recessive CASQ2-related CPVT requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for autosomal recessive CASQ2-related CPVT and are not at risk of developing the disorder. The risk for heterozygous carriers of TRND mutations is currently unknown.

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation(s) in the proband.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the proband.

Genetically Related (Allelic) Disorders

Although some have suggested that arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) may be caused by RYR2 mutations in a few cases (designated ARVC2) that present with mild or "concealed" right ventricular myocardium abnormalities [Tiso et al 2001], these observations have not been confirmed by others. Thus, the clinical relevance of this possible association is as yet unknown.

No phenotypes other than those discussed in this GeneReview are known to be associated with mutations in TRDN.

Natural History

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 since approximately 30% of those affected experience at least one cardiac arrest and up 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). 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. Of 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 lypothymia. If such symptoms reproducibly recur during exercise, further clinical investigations for CPVT may be indicated.

CPVT is a cause of "idiopathic" ventricular fibrillation in previously asymptomatic individuals (no history of syncope or dizziness) who die suddenly during exercise or while experiencing acute emotions. Growing evidence shows that sudden cardiac death can be the first manifestation of CPVT caused by RYR2 mutations [Priori et al 2002, Krahn et al 2005].

The mean age of onset of CPVT is between age seven and nine 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 mutations in RYR2 [Tester et al 2007].

Others have suggested that RYR2 mutations may underlie near-drowning or drowning, especially after the exclusion of the diagnosis of long QT syndrome type 1 (see Romano-Ward syndrome) [Choi et al 2004].

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

Genotype-Phenotype Correlations

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].

At present no data support a role for genotype in risk stratification and management. Usually CASQ2 mutations appear more severe and more resistant to beta-blockers.

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 mutations. These data show the following:

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

The mutation-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 mutations p.Pro2328Ser, p.Gln4201Arg, and p.Val4653Phe.

Penetrance

The mean penetrance of RYR2 mutations is 83% [Author, unpublished data]. Therefore, asymptomatic individuals with RYR2-related CPVT are a minority.

Anticipation

Anticipation has not been reported.

Prevalence

The true prevalence of CPVT in the population is not known. An estimate of CPVT prevalence is approximately 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 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 to evaluate for structural defects

Note: Although the association between RYR2 mutations and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) has not been conclusively established, cardiac echo and/or nuclear magnetic resonance may be indicated to assess structural abnormalities in the right ventricle.

Treatment of Manifestations

Beta-blockers are the only therapeutic choice of proven efficacy for about 60% of individuals with CPVT [Leenhardt et al 1995, Priori et al 2002]. Beta-blockers antagonize the effect of catecholamines by reducing heart rate and by a direct electrophysiologic effect at the myocyte level. The proposed mechanism of action on an individual with CPVT is inhibition of adrenergic-dependent triggered activity. Chronic treatment with full-dose beta-blocking agents prevents recurrence of syncope in the majority of individuals.

The reproducible induction of arrhythmia during exercise allows effective dose titration and monitoring. Recommended drugs are nadolol (1-2.5 mg/kg/day) or propranolol (2-4 mg/kg/day), because of long-standing experience with their use in inherited arrhythmogenic diseases; however, other compounds may be equally effective. No data or controlled studies are available to suggest which beta-blocker is more effective. The above-mentioned doses are those most widely used; however, the dose of beta-blockers should always be individualized, if possible, until arrhythmias are not inducible on exercise stress testing.

It is important to note that efficacy needs to be periodically retested [Heidbuchel et al 2006] (see Surveillance).

Recent clinical [van der Werf et al 2011] and experimental [Liu et al 2011] data suggest that to improve arrhythmia control, flecainide can be given along with beta-blockers to persons who are not responsive to beta-blockers alone (i.e., persons who have recurrence of syncope or complex arrhythmias during exercise).

Implantable cardioverter defibrillator (ICD). Although beta-blockers have been reported to be highly effective [Postma et al 2005], an implantable cardioverter defibrillator (ICD) may become necessary for secondary prevention of recurrent cardiac arrest. 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 ICD in order to reduce the probability of ICD firing.

Prevention of Primary Manifestations

Beta-blockers are indicated for primary prevention in all clinically affected individuals (see Treatment of Manifestations). Although no quantitative data on actual risk for cardiac arrest as the first manifestation of the disease are available, this treatment is probably also indicated for individuals with an RYR2 mutation and no history of cardiac events (syncope) or no ventricular arrhythmias on exercise stress testing. 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.

Prevention of Secondary Complications

Secondary complications are mainly related to therapy.

Beta-blockers could worsen allergic asthma. Therefore, cardiac-specific beta-blocker, metoprolol, could be indicated in some individuals with CPVT who have a history of asthma.

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 every six to 12 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 least at the highest tolerated workload.
• Holter monitoring

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 [Heidbuchel et al 2006].

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].

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 mutation is known.

If the family-specific mutation is 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

A clinical trial is ongoing to test for the effectiveness and safety of flecainide in CPVT (NCT01117454).

Left cardiac sympathetic denervation (LCSD). The direct pathophysiologic role of sympathetic activation could support surgical removal of sympathetic nerves to the heart (i.e., LCSD). LCSD reduces the amount of catecholamines released in the heart when the sympathetic nervous system is activated. Of course this intervention does not affect circulating catecholamines. Recently Wilde et al [2008] demonstrated that LCSD was effective in three patients whose symptoms were not adequately controlled by beta-blockers. This approach may also be considered for individuals with intractable arrhythmic storms in order to reduce the number of ICD shocks.

Additional pharmacologic treatments. Additional pharmacologic treatment has been proposed for CPVT, but in the past failures with sodium channel blockers [Leenhardt et al 1995, Sumitomo et al 2003] and amiodarone [Leenhardt et al 1995] have been reported. Other authors have reported partial effectiveness with verapamil [Sumitomo et al 2003, Swan et al 2005]. However, these reports remain anecdotal and have not been independently confirmed. Furthermore, the effect of chronic treatment with high doses of beta-blockers and calcium antagonists on cardiac contractility in children is not known. At present, calcium antagonists cannot be considered an alternative for persons unresponsive to ICDs.

Recently Watanabe et al [2009] demonstrated that flecainide prevents arrhythmias in a mouse model of CPVT. Furthermore, flecainide completely prevented CPVT in two persons who were previously highly symptomatic on conventional drug therapy. These data have been recently confirmed and the underlying mechanism explained [Liu et al 2011, van der Werf et al 2011].

JTV519 (also known as K201) is an experimental drug that stabilizes the ryanodine receptor and has proven to be effective in vitro in counteracting the RyR2 channel instability caused by some CPVT-causing mutations [Lehnart et al 2004]. However, experimental data obtained in a CPVT mouse model do not support a significant antiarrhythmic effect with this drug [Liu et al 2006].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

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

CASQ2-related CPVT and TRDN-related CPVT are inherited in an autosomal recessive manner.

One or more additional CPVT-related genes probably exist, disease-causing mutations 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 gene mutation. Accurate data on the prevalence of de novo mutations are not available but they are estimated at approximately 40%. This finding suggests 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 mutation include a maximal exercise stress test and molecular genetic testing if the mutation has been identified in the proband.

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%.
• If a disease-causing mutation cannot be detected in the DNA extracted from the leukocytes of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

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

Other family members of a proband. 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 and therefore carry one mutant allele.
• Heterozygotes (carriers) are asymptomatic. Minor abnormalities (rare and benign arrhythmias) have been reported in anecdotal cases.

Sibs of a proband

• 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 neither affected nor a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• 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 disease-causing mutation in CASQ2 or TRDN.

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

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations 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 mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation or less likely that a parent has germline mosaicism. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Testing of asymptomatic at-risk family members. Testing of asymptomatic at-risk family members for CPVT is possible using the techniques described in Molecular Genetic Testing. Although this testing is not useful in predicting age of onset, severity, or specific symptoms that may occur in asymptomatic individuals, it does allow for initiation of treatment and surveillance. When testing at-risk individuals for CPVT, an affected family member should be tested first to identify specific gene mutation(s).

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as CPVT are not common. 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. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation(s) have been identified.

Molecular Genetic Pathogenesis

RYR2, CASQ2, and TRDN are involved in the same intracellular metabolic pathway, devoted to the control of intracellular calcium fluxes and the cytosolic free Ca²⁺ concentration.

The RYR2 mutations 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 [Jiang et al 2002, George et al 2003, Wehrens et al 2003]. 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 has been clearly shown that the pathogenesis of arrhythmias in CPVT is related to the onset of delayed after depolarizations (DADs) and triggered activity. Furthermore, cardiac cells isolated from mice with a mutation orthologous to the human p.Arg4497Cys (a typical and relatively common CPVT-causing mutation) present DAD also at baseline, suggesting that RyR2 function is also altered in the unstimulated setting.

In vitro expression of CASQ2 mutations has consistently shown an enhanced responsiveness of RyR2s to luminal Ca²⁺, which in turn leads to the generation of extrasystolic spontaneous Ca²⁺ transients, DADs, 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].

Expression of the human TRDN p.Thr59Arg in COS-7 cells resulted in intracellular retention and degradation of the mutant 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). However, direct functional studies are lacking.

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Suggested Reading

1. Eisner DA, Venetucci LA, Trafford AW. Life, sudden death, and intracellular calcium. Circ Res. 2006;99:223–4. [PubMed: 16888244]
2. George CH, Jundi H, Thomas NL, Fry DL, Lai FA. Ryanodine receptors and ventricular arrhythmias: emerging trends in mutations, mechanisms and therapies. J Mol Cell Cardiol. 2007;42:34–50. [PubMed: 17081562]
3. Priori SG, Napolitano C. Cardiac and skeletal muscle disorders caused by mutations in the intracellular Ca2+ release channels. J Clin Invest. 2005;115:2033–8. [PMC free article: PMC1180555] [PubMed: 16075044]
4. Priori SG, Napolitano C. Intracellular calcium handling dysfunction and arrhythmogenesis: a new challenge for the electrophysiologist. Circ Res. 2005;97:1077–9. [PubMed: 16306448]
5. Priori SG, Napolitano C. Role of genetic analyses in cardiology: part I: mendelian diseases: cardiac channelopathies. Circulation. 2006;113:1130–5. [PubMed: 16505190]
6. Scheinman MM, Lam J. Exercise-induced ventricular arrhythmias in patients with no structural cardiac disease. Annu Rev Med. 2006;57:473–84. [PubMed: 16409161]
7. 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. [PubMed: 22828895]
8. van der Werf C, Kannankeril PJ, Sacher F, Krahn AD, Viskin S, Leenhardt A, Shimizu W, Sumitomo N, Fish FA, Bhuiyan ZA, Willems AR, van der Veen MJ, Watanabe H, Laborderie J, Haïssaguerre M, Knollmann BC, Wilde AA. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol. 2011;57:2244–54. [PMC free article: PMC3495585] [PubMed: 21616285]
9. 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]
10. 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]
11. 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]

Author Notes

Fondazione Salvatore Maugeri
Web: www.fsm.it/cardmoc

Revision History

• 7 February 2013 (cd) Revision: multi-gene 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 to live Web site
• 22 May 2006 (cn) Revision: Prenatal diagnosis available for RYR2 and CASQ2
• 14 October 2004 (me) Review posted to live Web site
• 1 June 2004 (cn) Original submission