Catecholaminergic Polymorphic Ventricular Tachycardia

doi:10.1016/j.pcad.2007.10.005

Progress in Cardiovascular Diseases

Volume 51, Issue 1, July–August 2008, Pages 23-30

https://doi.org/10.1016/j.pcad.2007.10.005 Get rights and content

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly malignant form of arrhythmogenic disorder characterized by exercise- or emotional-induced polymorphic ventricular tachycardia in the absence of detectable structural heart disease. Because of the typical pattern of arrhythmias (bidirectional ventricular tachycardia and the occurrence and severity of arrhythmia correlated well with exercise workload) during exercise stress test, CPVT can be identified promptly. Molecular genetic screening of the genes encoding the cardiac ryanodine receptor and calsequestrin is critical to confirm uncertain diagnosis of CPVT. With the exception of β-blockers, no pharmacologic therapy of proven effectiveness is available: although β-blockers reduce the occurrence of ventricular tachycardia, 30% of patients treated with β-blockers still experience cardiac arrhythmias and eventually require implantable cardioverter defibrillator implantation to prevent cardiac arrest.

Section snippets

Genetic Basis of CPVT

In 1999, Swan et al⁶ studied 2 CPVT families and assigned the CPVT locus to chromosome 1q42-q43. Subsequently, Priori et al⁴ demonstrated that the gene for CPVT encodes the cardiac RyR2: a tetrameric intracellular Ca²⁺-release channel required for cardiac excitation-contraction coupling. These authors identified RyR2 mutations (single amino acid replacements) in 4 families with the typical pattern of CPVT and autosomal dominant pattern of inheritance. Shortly after, Lahat et al⁵ mapped a

Pathophysiology of Arrhythmias in CPVT

Delayed afterdepolarizations (DADs) and triggered activity have been proposed as the arrhythmogenic mechanism in CPVT because the electrocardiographic pattern of this ventricular tachycardia closely resembles the arrhythmias associated with intracellular calcium overload and the DADs observed during digitalis toxicity.³ Interestingly, in agreement with this hypothesis, RyR2 and CASQ2, calcium-handling proteins located in the SR and involved in the release of Ca²⁺ from SR, are responsible for

Clinical Manifestation

Syncope triggered by emotional or physical stress is usually the first clinical manifestation of CPVT.3, 7 The mean age of onset of clinical symptoms is between 7 and 9 years.3, 7 The resting electrocardiogram (ECG) of patients with CPVT is often unremarkable, without QT prolongation, atrioventricular and intraventricular conduction defects, and lack of Brugada-like ST-segment pattern; furthermore, the cardiac imaging examination is normal. Because syncopal events often occur in otherwise

Electrocardiographic Characteristics

As previously stated, the resting ECG is usually normal in patients with CPVT; sinus bradycardia and prominent U waves may be observed in some patients.23, 24 The distinguishing arrhythmia of CPVT is characterized by the alternating QRS axis morphology with a rotation of 180° on a beat-to-beat basis⁷; unfortunately, however, the typical bidirectional VT is not present in all patients: in our study it was documented in 35% of probands, and the remaining patients showed polymorphic VT or

Genotype and Phenotype

Ryanodine receptor mutations can be identified in approximately 70% of patients with CPVT.⁸ To date, more than 70 RyR2 mutations have been reported (more information is available online at: http://www.fsm.it/cardmoc/). All RyR2 mutations identified so far in CPVT are mostly single–base pair substitutions leading to the replacement of highly conserved amino acids. In 2002, Priori et al⁷ demonstrated that the natural history of the disease does not differ when affected individuals with and

Diagnosis and Differential Diagnosis

When observing a syncopal episode induced by exercise or emotion in a child or in a young patient with a normal resting ECG and normal cardiac structure, it is important to consider the diagnosis of CPVT. The highly reproducible progressive worsening of arrhythmias and/or the occurrence of bidirectional VT during exercise stress testing is a diagnostic marker of CPVT. The use of long-term holter recordings or the implant of a loop recorder²⁹ are very valuable for establishing the diagnosis of

Treatment

β-Blockers have been the first therapeutic option for patients with CPVT since the causal association between stress and arrhythmic symptoms of CPVT was recognized. Most widely used β-blockers at centers after large series of patients with LQTS or CPVT are nadolol (1-2 mg/kg per day) or propranolol (2.5-3.5 mg/kg per day). It is important to be aware that the maximal tolerated dose of β-blockers should be prescribed in patients with CPVT to maximize control of arrhythmias. Initial clinical

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Cited by (134)

Catecholaminergic polymorphic ventricular tachycardia (and seizure) caused by a novel homozygous likely pathogenic variant in CASQ2 gene
2024, Gene
Although structural heart disease is frequently present among patients who experience sudden cardiac death (SCD), inherited arrhythmia syndromes can also play an important role in the occurrence of SCD. CPVT2, which is the second-most prevalent form of CPVT, arises from an abnormality in the CASQ2 gene.
We represent a novel CASQ2 variant that causes CPVT2 and conduct a comprehensive review on this topic.
The proband underwent Whole-exome sequencing (WES) in order to ascertain the etiology of CPVT. Subsequently, the process of segregating the available family members was carried out through the utilization of PCR and Sanger Sequencing. We searched the google scholar and PubMed/Medline for studies reporting CASQ2 variants, published up to May 10,2023. We used the following mesh term “Calsequestrin” and using free-text method with terms including “CASQ2”,”CASQ2 variants”, and “CASQ2 mutation”.
The CASQ2 gene was found to contain an autosomal recessive nonsense variant c.268_269insTA:p.Gly90ValfsTer4, which was identified by WES. This variant was determined to be the most probable cause of CPVT in the pedigree under investigation.
CASQ2 variants play an important role in pathogenesis of CPVT2. Notabely, based on results of our study and other findings in the literature the variant in this gene may cause an neurological signs in the patients with CPVT2. Further studies are needed for more details about the role of this gene in CPVT evaluation, diagnosis, and gene therapy.
Characterization of N-terminal RYR2 variants outside CPVT1 hotspot regions using patient iPSCs reveal pathogenesis and therapeutic potential
2022, Stem Cell Reports
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a cardiac channelopathy causing ventricular tachycardia following adrenergic stimulation. Pathogenic variants in RYR2-encoded ryanodine receptor 2 (RYR2) cause CPVT1 and cluster into domains I–IV, with the most N-terminal domain involving residues 77–466. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated for RYR2-F13L, -L14P, -R15P, and -R176Q variants. Isogenic control iPSCs were generated using CRISPR-Cas9/PiggyBac. Fluo-4 Ca²⁺ imaging assessed Ca²⁺ handling with/without isoproterenol (ISO), nadolol (Nad), and flecainide (Flec) treatment. CPVT1 iPSC-CMs displayed increased Ca²⁺ sparking and Ca²⁺ transient amplitude following ISO compared with control. Combined Nad treatment/ISO stimulation reduced Ca²⁺ amplitude and sparking in variant iPSC-CMs. Molecular dynamic simulations visualized the structural role of these variants. We provide the first functional evidence that these most proximal N-terminal localizing variants alter calcium handling similar to CPVT1. These variants are located at the N-terminal domain and the central domain interface and could destabilize the RYR2 channel promoting Ca²⁺ leak-triggered arrhythmias.
Premature ventricular contractions (PVCs) in young athletes
2022, Progress in Cardiovascular Diseases
There is a growing body of literature focusing on the morphology, management, and outcomes of PVCs in athletes. This review summarizes this literature and establishes recommendations on management, treatment, and indications for specialist referral in this patient population. The sports medicine physician's responses and recommendation should be made in conjunction with the athletes wishes. Medications or ablations are not always necessary in all athletes if they are followed with regular evaluations.
Distinct mechanisms mediate pacemaker dysfunction associated with catecholaminergic polymorphic ventricular tachycardia mutations: Insights from computational modeling
2020, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia characterized by stress-induced ventricular arrhythmias, syncope, and/or sudden cardiac death [1–3].
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced ventricular arrhythmia associated with rhythm disturbance and impaired sinoatrial node cell (SANC) automaticity (pauses). Mutations associated with dysfunction of Ca²⁺-related mechanisms have been shown to be present in CPVT. These dysfunctions include impaired Ca²⁺ release from the ryanodine receptor (i.e., RyR2^R4496C mutation) or binding to calsequestrin 2 (CASQ2). In SANC, Ca²⁺ signaling directly and indirectly mediates pacemaker function.
We address here the following research questions: (i) what coupled-clock mechanisms and pathways mediate pacemaker mutations associated with CPVT in basal and in response to β-adrenergic stimulation? (ii) Can different mechanisms lead to the same CPVT-related pacemaker pauses? (iii) Can the mutation-induced deteriorations in SANC function be reversed by drug intervention or gene manipulation?
We used a numerical model of mice SANC that includes membrane and intracellular mechanisms and their interconnected signaling pathways. In the basal state of RyR2^R4496C SANC, the model predicted that the Na⁺-Ca²⁺ exchanger current (I_NCX) and T-type Ca²⁺ current (I_CaT) mediate between changes in Ca²⁺ signaling and SANC dysfunction. Under β-adrenergic stimulation, changes in cAMP-PKA signaling and the sodium currents (I_Na), in addition to I_NCX and I_CaT, mediate between changes in Ca²⁺ signaling and SANC automaticity pauses. Under basal conditions in Casq2^−/−, the same mechanisms drove changes in Ca²⁺ signaling and subsequent pacemaker dysfunction. However, SANC automaticity pauses in response to β–AR stimulation were mediated by I_CaT and I_Na. Taken together, distinct mechanisms can lead to CPVT-associated SANC automaticity pauses. In addition, we predict that specifically increasing SANC cAMP-PKA activity by either a pharmacological agent (IBMX, a phosphodiesterase (PDE) inhibitor), gene manipulation (overexpression of adenylyl cyclase 1/8) or direct manipulation of the SERCA phosphorylation target through changes in gene expression, compensate for the impairment in SANC automaticity. These findings suggest new insights for understanding CPVT and its therapeutic approach.
A de novo heterozygous cardiac ryanodine receptor gene (RYR2) mutation in a catecholaminergic polymorphic ventricular tachycardia patient
2019, Gene Reports
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the most common causes of sudden cardiac death (SCD) during childhood and adolescence. A de novo heterozygous Glu2296Lys mutation in the ryanodine receptor 2 (RyR2) was identified in a 5-year-old boy with CPVT by whole exome sequencing (WES), and it was confirmed by Sanger sequencing. No mutation was found in his healthy parents. Neural network analysis predicted that a Glu2296Lys mutation could decrease the stability of the RYR2 protein, with a confidence score of −0.8831. A STRUM server prediction also confirmed that a Glu2296Lys mutation could reduce RYR2 protein stability. Thus, we confirmed that the Glu2296Lys mutation may play a critical role in the stability of RYR2, which is associated with CPVT. So, the de novo RYR2 mutation may cause CPVT in this patient, but further evidence is needed to prove causality.
Plakophilin-2 Truncation Variants in Patients Clinically Diagnosed With Catecholaminergic Polymorphic Ventricular Tachycardia and Decedents With Exercise-Associated Autopsy Negative Sudden Unexplained Death in the Young
2019, JACC: Clinical Electrophysiology
This study determined if radical plakophilin-2 (PKP2) variants might underlie some cases of clinically diagnosed catecholaminergic polymorphic ventricular tachycardia (CPVT) and exercise-associated, autopsy-negative sudden unexplained death in the young (SUDY).
Pathogenic variants in PKP2 cause arrhythmogenic right ventricular cardiomyopathy (ARVC). Recently, a cardiomyocyte-specific PKP2 knockout mouse model revealed that loss of PKP2 markedly reduced expression of genes critical in intracellular calcium handling. The mice with structurally normal hearts exhibited isoproterenol-triggered polymorphic ventricular arrhythmias that mimicked CPVT.
A PKP2 gene mutational analysis was performed on DNA from 18 unrelated patients (9 males; average age at diagnosis: 19.6 ± 12.8 years) clinically diagnosed with CPVT but who were RYR2-, CASQ2-, KCNJ2-, and TRDN-negative, and 19 decedents with SUDY during exercise (13 males; average age at death: 14 ± 3 years). Only radical (i.e., frame-shift, canonical splice site, or nonsense) variants with a minor allele frequency of ≤0.00005 in the genome aggregation database (gnomAD) were considered pathogenic.
Radical PKP2 variants were identified in 5 of 18 (27.7%) CPVT patients and 1 of 19 (5.3%) exercise-related SUDY cases compared with 96 of 138,632 (0.069%) individuals in gnomAD (p = 3.1 × 10⁻¹³). Cardiac imaging or autopsy demonstrated a structurally normal heart in all patients at the time of their CPVT diagnosis or sudden death.
Our data suggested that the progression of the PKP2-dependent electropathy can be independent of structural perturbations and can precipitate exercise-associated sudden cardiac arrest or sudden cardiac death before the presence of overt cardiomyopathy, which clinically mimics CPVT, similar to the PKP2 knockout mouse model. Thus, CPVT and SUDY genetic test panels should now include PKP2.

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Catecholaminergic Polymorphic Ventricular Tachycardia

Section snippets

Genetic Basis of CPVT

Pathophysiology of Arrhythmias in CPVT

Clinical Manifestation

Electrocardiographic Characteristics

Genotype and Phenotype

Diagnosis and Differential Diagnosis

Treatment

Am J Hum Genet

J Am Coll Cardiol

J Am Coll Cardiol

Heart Rhythm

Heart Rhythm

Bidirectional tachycardia in a child. A study using His bundle electrography

Br Heart J

Catecholamine-induced severe ventricular arrhythmias with Adams-Stokes syndrome in children: report of four cases

Br Heart J