Clinical characteristics.

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

Diagnosis/testing.

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

Management.

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

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

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

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

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

Genetic counseling.

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

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

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

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

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

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 is age seven to 12 years. Less frequently, first manifestations may occur later in life; individuals with a first event up to age 40 years have been 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 bidirectional or polymorphic ventricular arrhythmias
  • EKG 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 90-120 beats per minute.
  • 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 [Priori et al 2021].
  • Notably, 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

* Note: The resting EKG of individuals with CPVT is usually normal. 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, particularly in the precordial leads [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, Giudicessi & Ackerman 2019].

Establishing the Diagnosis

According to the most recent version of the International Guidelines on Sudden Cardiac Death [Priori et al 2015, Al-Khatib et al 2018, Wilde et al 2022], the diagnosis of CPVT is established:

• In the presence of a structurally normal heart, normal resting EKG, and exercise- or emotion-induced bidirectional or polymorphic ventricular tachycardia;
  OR
• In individuals who have a heterozygous pathogenic (or likely pathogenic) variant in RYR2, CALM1, CALM2, CALM3, CASQ2, or KCNJ2 or biallelic pathogenic (or likely pathogenic) variants in CASQ2, TECRL, or TRDN (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype:

• A multigene panel that includes the genes listed in Table 1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. 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. (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.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used, and yields results similar to a multigene panel with the additional advantage that exome sequencing includes genes recently identified as causing CPVT whereas some multigene panels may not. Genome sequencing is also possible.
  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% have one or more syncopal spells.

Few clinical studies [Leenhardt et al 1995, Priori et al 2002, Roston et al 2018] 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 bidirectional or polymorphic ventricular tachycardia (VT).

• Spontaneous recovery may occur when these arrhythmias self-terminate;
  OR
• VT 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]. Atypical triggers (e.g., playing musical instruments or even rest) have been reported in a minority of individuals [Roston et al 2018]. However, the correct identification of triggers is often difficult, and is a common limitation of rare disease registry data.

The mean onset of CPVT symptoms (usually a first syncopal episode) is between age seven and 12 years [Leenhardt et al 1995, Priori et al 2002, Postma et al 2005, Roston et al 2018]; onset as late as the fourth decade of life has been reported.

Instances of 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 pro-arrhythmic effect of an insulin tolerance test, 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].

Typical vs atypical CPVT phenotype. Typical CPVT can be diagnosed with the demonstration of reproducible exercise-induced bidirectional or polymorphic VT in the presence of a structurally normal heart and normal baseline/resting EKG. Atypical CPVT is associated with arrhythmias and/or syncope / cardiac arrest triggered by adrenergic activation in the absence of a reproducible pattern of arrhythmias. Other findings may occur in atypical CPVT. For details regarding genetic differences in these phenotypes, see Phenotype Correlations by Gene.

Phenotype Correlations by Gene

The typical CPVT phenotype is caused by the presence of pathogenic variants in RYR2 or CASQ2 [Priori et al 2021].

Atypical CPVT is caused by pathogenic variants in the "rare" genes:

• CALM1, CALM2, and CALM3 (also called calmodulinopathies), which can also be associated with QT prolongation *
• TRDN, which can be associated with mild skeletal myopathy / proximal muscle weakness, T-wave inversions, and transient QT prolongation >480 ms [Clemens et al 2019] *
• KCNJ2, which can be associated with bidirectional VT without adrenergic trigger in the absence of the typical Andersen-Tawil extracardiac manifestations [Wilde et al 2022]
• Preliminary observations suggest that TECRL may be associated with CPVT and QT interval prolongation as clinical phenotypes (but not isolated long QT syndrome) [Moscu-Gregor et al 2020]. This observation awaits further confirmation.

* Although all CALM1, CALM2, and CALM3 pathogenic variants alter calcium handling, further data are needed to determine if these phenotypes should be defined as CPVT with variable expressivity (as a result of unidentified pathophysiologic mechanisms) or as mechanistically distinct disorders.

Genotype-Phenotype Correlations

Gain-of-function pathogenic variants in RYR2 are associated with the typical CPVT phenotype (reproducible exercise-/emotion-induced bidirectional VT with structurally normal heart) [Priori et al 2021] while the much less frequently observed loss-of-function variants can cause ventricular fibrillation and sudden death in the absence of inducible arrhythmias [Zhong et al 2021].

No genotype-phenotype correlations for CASQ2, CALM1, CALM2, CALM3, KCNJ2, TECRL, or TRDN have been identified.

Penetrance

The mean penetrance of RYR2 pathogenic variants is 83% [Author, unpublished data]. Therefore, asymptomatic individuals with RYR2-related CPVT are a minority. To date, biallelic CASQ2 pathogenic variants have been 100% penetrant in reported individuals. Too few individuals with heterozygous CASQ2, KCNJ2, CALM1, CALM2, or CALM3-related CPVT have been reported to date to allow a robust estimate of penetrance.

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 or less.

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 (1:5,000-1:7,000).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

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 in the recent version of the European Society of Cardiology (ESC) guidelines on ventricular arrhythmias [Priori et al 2015] (full text). Recent studies have demonstrated that (1) nadolol is the most effective beta blocker in individuals with CPVT; (2) non-selective beta blockers (nadolol and propranolol) are superior to selective beta blockers; (3) a significant burden of life-threatening arrhythmias persists after left cardiac sympathetic denervation; (4) an implantable cardioverter defibrillator is effective for those individuals in whom arrhythmias are not adequately controlled by drug therapy [Mazzanti et al 2022, Peltenburg et al 2022].

Prevention of Primary Manifestations

Beta blockers are indicated for primary prevention in all clinically affected individuals (see Management, Treatment of Manifestations) and in individuals with pathogenic variants in the genes associated with CPVT who have a negative exercise stress test. 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 an exercise stress test.

Surveillance

Agents/Circumstances to Avoid

Competitive sports and other strenuous exercise are always contraindicated for individuals with CPVT. All individuals showing exercise-induced arrhythmias should avoid physical activity, except for 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 activity.

Digitalis favors the onset of cardiac arrhythmias as a result of delayed afterdepolarization 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 evaluation and molecular genetic testing if the family-specific pathogenic variant(s) are known. 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 EKG, Holter monitoring, echocardiography, 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.

See MotherToBaby for information on medication use during pregnancy.

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.

Mode of Inheritance

RYR2, CALM1, CALM2, CALM3, and KCNJ2-related catecholaminergic polymorphic ventricular tachycardia (CPVT) are inherited in an autosomal dominant manner.

CASQ2-related CPVT is typically inherited in an autosomal recessive manner. However, because a subset of individuals (still unquantified but rare) with heterozygous CASQ2 pathogenic variants show a mild CPVT phenotype [Wilde et al 2022], autosomal dominant inheritance may not be ruled out for CASQ2-related CPVT, and clinical screening is indicated in individuals who are heterozygous for a CASQ2 pathogenic variant.

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

Autosomal Dominant Inheritance – Risk to Family Members

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. The frequency of de novo RYR2 pathogenic variants is estimated to be 30%-40%; however, accurate frequency data are not available.
• If the proband is the only family member known to have CPVT, recommendations for the evaluation of the parents of a proband include a maximal exercise stress test and molecular genetic testing if a molecular diagnosis has been established in the proband.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells. (Note: Parental mosaicism for a CPVT-related pathogenic variant has not been reported to date.)
• The family history of some individuals diagnosed with autosomal dominant CPVT 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. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).

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 and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known CPVT-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. (Note: Parental mosaicism for a CPVT-related pathogenic variant has not been reported to date.)
• If the parents are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for CPVT because of the possibility of reduced penetrance in a heterozygous parent or the theoretic 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 and/or is known to have the pathogenic variant, members of the parent's family are at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a CASQ2, TECRL, or TRDN pathogenic variant. However, it is possible (although likely rare) that one or both parents of a proband are themselves affected.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CPVT-related pathogenic variant and to allow reliable recurrence risk assessment. A maximal exercise stress test can also be considered for the parents of a proband with autosomal recessive CPVT.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or, theoretically, as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Individuals who are heterozygous for a pathogenic variant in CASQ2 may show a mild CPVT phenotype and clinical screening is indicated accordingly (see Surveillance). Individuals who are heterozygous for a pathogenic variant in TECRL or TRDN are usually asymptomatic but current data are limited and a clinical evaluation could be considered.

Sibs of a proband

• If both parents are known to be heterozygous for a CASQ2, TECRL, or TRDN pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Individuals who are heterozygous for a pathogenic variant in CASQ2 may show a mild CPVT phenotype and clinical screening is indicated (see Surveillance). Individuals who are heterozygous for a pathogenic variant in TECRL or TRDN are usually asymptomatic but current data are limited and a clinical evaluation could be considered.

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

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for a CASQ2, TECRL, or TRDN pathogenic variant.

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.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CALM1, CALM2, CALM3, CASQ2, RYR2, TECRL, and TRDN are involved in the control of intracellular calcium fluxes, sarcoplasmic reticulum (SR) calcium release, and the cytosolic free Ca²⁺ concentration.

RYR2 encodes the ryanodine receptor (RyR2), which 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, RyR2 releases the Ca²⁺ ions stored in the SR that are required for contraction of the muscle fibers. The RYR2 pathogenic variants found in individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT) have been shown to cause Ca²⁺ "leakage" from the 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.

CALM1, CALM2, and CALM3 are three genes that encode for an identical protein, calmodulin (CaM) [Fischer et al 1988], which contains typical calcium-binding sites (EF hands) that, like RyR2, also interact with the voltage-dependent calcium channels (CaV1.3). For this reason, the mechanisms leading from pathogenic variant to the clinical phenotype can be considered similar for all three genes. The altered CaM has reduced calcium-binding affinity and impaired CaM-RyR2 interactions at low calcium concentration. Calcium release in the presence of altered CaM shows significantly increased duration of Ca2+ release events; and lower frequency of Ca2+ oscillations [Prakash et al 2022]. These effects may lead to RyR2 channel instability and "leakage" similar to that observed for RYR2 pathogenic variants [Gomez-Hurtado et al 2016, Badone et al 2018].

CASQ2 encodes the cardiac isoform of calsequestrin, calsequestrin-2 (CASQ2), an SR protein functionally and physically related to RyR2. CASQ2 forms polymers at the level of the terminal cisternae of the SR in close proximity to the RyR2; its function is that of buffering the Ca²⁺ ions. The available data suggest that the pathophysiology of CASQ2-related CPVT may be related to the following mechanisms: loss of polymerization of CASQ monomers, loss of calcium buffering capability, and indirect destabilization of the RyR2 channel-opening process.

KCNJ2 encodes inward rectifier potassium channel 2, a potassium ion channel that conducts inwardly rectifying potassium current responsible for maintenance of the normal resting membrane potential of myocardial cells.

TRDN encodes triadin, an SR protein functionally and physically related to RyR2. Lack of triadin is associated with a reduction of CASQ2 levels and ultrastructural abnormalities of the T tubules, which affects the calcium release process and, more specifically, results in a calcium leak during diastole similar to that observed with RYR2 pathogenic variants.

Few studies have functionally assessed the effect of pathogenic variants in TECRL leading to CPVT. The most interesting insights come from an expression study in induced pluripotent stem cell-derived cardiomyocytes [Devalla et al 2016]. This study revealed that TECRL pathogenic variants are associated with elevated diastolic Ca2+, smaller amplitude, and slower decay of cytosolic Ca2+ transients. Adrenergic stimulation resulted in increased delayed afterdepolarization (DAD) amplitude and triggered arrhythmia in the same way as shown with RYR2 pathogenic variants. TECRL pathogenic variants were also shown in experimental models to cause impaired mitochondrial function with consequent reduced cardiac contractility [Hou et al 2022].

Mechanism of disease causation. In order to generate a CPVT phenotype there must be a diastolic calcium overload that activates the sodium calcium exchanger leading to DAD and triggered activity (TA) [Priori et al 2021]. This pathway involves several genes, many of which have been associated with CPVT.

In order to activate the DAD-TA arrhythmogenesis, the RyR2 channel is destabilized during the diastolic phase with a consequent leakage of calcium ions that follow the concentration gradient from the SR (high concentration) to the cytosol (low concentration). This condition is therefore the result of a gain-of-function effect.

A leaky RyR2 channel can be caused by RYR2 pathogenic variants (encoding the channel pore) that directly affects channel stability.

CASQ2 pathogenic variants invariably reduce the amount of expressed CASQ2. Since CASQ2 serves as an SR calcium buffer but also as an RyR2 stabilizer, reduced CASQ2 levels as a result of CASQ2 loss-of-function variants lead to increased RyR2 function.

While the functional consequence of RYR2 and CASQ2 pathogenic variants are reasonably well understood, knowledge gaps still exist for the rare CPVT-related genes. Available evidence shows that CALM1, CALM2, CALM3, and TECRL pathogenic variants lead to RyR2 leakage and propensity to DAD-TA, but the exact mechanisms are still under investigation.

A subset of RYR2 pathogenic variants have the opposite effect of reducing the release of calcium through the channel. These are defined as loss-of-function pathogenic variants that severely reduce cytosolic Ca2+ activation and abolish luminal Ca2+ activation of RyR2 channels [Zhong et al 2021]. The mechanism by which this triggers sudden cardiac rhythm disruption is still unclear.

Author Notes

SG Priori's Molecular Cardiology lab

Molecular Cardiology, ICS Maugeri (in Italian)

Acknowledgments

We acknowledge the contribution of the European Research Council (ERC) and the EU-Rhythmy CPVT research project for the development of gene therapies for CPVT and calcium-related sudden death syndromes.

Revision History

• 23 June 2022 (ha/sw) Comprehensive update posted live
• 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

Published Guidelines / Consensus Statements

• Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, Gillis AM, Granger CB, Hammill SC, Hlatky MA, Joglar JA, Kay GN, Matlock DD, Myerburg RJ, Page RL. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2018;72:e91-e220.
• Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekvål TM, Spaulding C, Van Veldhuisen DJ. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Available online. 2015. Accessed 4-19-23.
• Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C; Document Reviewers, Ackerman M, Belhassen B, Estes NA 3rd, Fatkin D, Kalman J, Kaufman E, Kirchhof P, Schulze-Bahr E, Wolpert C, Vohra J, Refaat M, Etheridge SP, Campbell RM, Martin ET, Quek SC. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Available online. 2013. Accessed 4-19-23.
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