Catecholaminergic Polymorphic Ventricular Tachycardia Cases Research Articles

Catecholaminergic Polymorphic Ventricular Tachycardia: Multiple Clinical Presentations of a Genetically Determined Disease.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare, inherited heart rhythm disorder that is caused by variants in genes responsible for cardiac calcium homeostasis. The aim of this study was to analyze different genotype-specific clinical manifestations of this disease. We analyzed five CPVT cases from our institution in the context of specific patient characteristics and genotype-phenotype correlations. In this cohort, three of the index patients were male. The median age at diagnosis was 11 (11-30) years, and median age at disease onset was 12 (12-33) years. Four index patients suffered from syncope, while one female index patient suffered from out-of-hospital cardiac arrest. Two index patients experienced concomitant atrial flutter and atrial fibrillation. Three patients received an implantable cardioverter defibrillator and one patient received an event recorder. All index patients had causative genetic variants in the RYR2-gene. This study presents various phenotypic presentations of patients with CPVT harboring different pathogenic variants in the RYR2 gene, some of which have not previously been described in published studies. Syncope was the most prevalent symptom on admission. Adjustment of beta-blocker therapy may be necessary due to side effects. Moreover, our work further highlights the common occurrence of atrial tachyarrhythmias in these patients.

RYR2-ryanodinopathies: from calcium overload to calcium deficiency.

The sarcoplasmatic reticulum (SR) cardiac ryanodine receptor/calcium release channel RyR2 is an essential regulator of cardiac excitation-contraction coupling and intracellular calcium homeostasis. Mutations of the RYR2 are the cause of rare, potentially lethal inherited arrhythmia disorders. Catecholaminergic polymorphic ventricular tachycardia (CPVT) was first described more than 20 years ago and is the most common and most extensively studied cardiac ryanodinopathy. Over time, other distinct inherited arrhythmia syndromes have been related to abnormal RyR2 function. In addition to CPVT, there are at least two other distinct RYR2-ryanodinopathies that differ mechanistically and phenotypically from CPVT: RYR2 exon-3 deletion syndrome and the recently identified calcium release deficiency syndrome (CRDS). The pathophysiology of the different cardiac ryanodinopathies is characterized by complex mechanisms resulting in excessive spontaneous SR calcium release or SR calcium release deficiency. While the vast majority of CPVT cases are related to gain-of-function variants of the RyR2 protein, the recently identified CRDS is linked to RyR2 loss-of-function variants. The increasing number of these cardiac 'ryanodinopathies' reflects the complexity of RYR2-related cardiogenetic disorders and represents an ongoing challenge for clinicians. This state-of-the-art review summarizes our contemporary understanding of RYR2-related inherited arrhythmia disorders and provides a systematic and comprehensive description of the distinct cardiac ryanodinopathies discussing clinical aspects and molecular insights. Accurate identification of the underlying type of cardiac ryanodinopathy is essential for the clinical management of affected patients and their families.

Clinical Characteristics, Genetic Findings and Arrhythmic Outcomes of Patients with Catecholaminergic Polymorphic Ventricular Tachycardia from China: A Systematic Review

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited cardiac ion channelopathy. The present study aims to examine the clinical characteristics, genetic basis, and arrhythmic outcomes of CPVT patients from China to elucidate the difference between CPVT patients in Asia and Western countries. Methods: PubMed and Embase were systematically searched for case reports or series reporting on CPVT patients from China until 19 February 2022 using the keyword: “Catecholaminergic Polymorphic Ventricular Tachycardia” or “CPVT”, with the location limited to: “China” or “Hong Kong” or “Macau” in Embase, with no language or publication-type restriction. Articles that did not state a definite diagnosis of CPVT and articles with duplicate cases found in larger cohorts were excluded. All the included publications in this review were critically appraised based on the Joanna Briggs Institute Critical Appraisal Checklist. Clinical characteristics, genetic findings, and the primary outcome of spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF) were analyzed. Results: A total of 58 unique cases from 15 studies (median presentation age: 8 (5.0–11.8) years old) were included. All patients, except one, presented at or before 19 years of age. There were 56 patients (96.6%) who were initially symptomatic. Premature ventricular complexes (PVCs) were present in 44 out of 51 patients (86.3%) and VT in 52 out of 58 patients (89.7%). Genetic tests were performed on 54 patients (93.1%) with a yield of 87%. RyR2, CASQ2, TERCL, and SCN10A mutations were found in 35 (71.4%), 12 (24.5%), 1 (0.02%) patient, and 1 patient (0.02%), respectively. There were 54 patients who were treated with beta-blockers, 8 received flecainide, 5 received amiodarone, 2 received verapamil and 2 received propafenone. Sympathectomy (n = 10), implantable cardioverter-defibrillator implantation (n = 8) and ablation (n = 1) were performed. On follow-up, 13 patients developed VT/VF. Conclusion: This was the first systematic review of CPVT patients from China. Most patients had symptoms on initial presentation, with syncope as the presenting complaint. RyR2 mutation accounts for more than half of the CPVT cases, followed by CASQ2, TERCL and SCN10A mutations.

PO-616-04 A NOVEL CPVT-ASSOCIATED CALMODULIN MUTATION CAUSES SEVERE CA2+ LEAKAGE FROM SARCOPLASMIC RETICULUM IN IPSC MODEL BY ACTIVATING THE CARDIAC RYANODINE RECEPTORS

Calmodulin (CaM) is an intermediate calcium-binding messenger protein and it is very unique that three genes (CALM1-3) encode identical CaM proteins in human. Recently, mutations in CALM have been reported to be associated with long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). CALM-related CPVT cases are rare and the underlying disease-causing mechanisms have not been fully elucidated in human cardiomyocytes.

Using hiPSC-CMs to Examine Mechanisms of Catecholaminergic Polymorphic Ventricular Tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited cardiac arrhythmia condition, triggered by physical or acute emotional stress, that predominantly expresses early in life. Gain-of-function mutations in the cardiac ryanodine receptor gene (RYR2) account for the majority of CPVT cases, causing substantial disruption of intracellular calcium (Ca2+ ) homeostasis particularly during the periods of β-adrenergic receptor stimulation. However, the highly variable penetrance, patient outcomes, and drug responses observed in clinical practice remain unexplained, even for patients with well-established founder RyR2 mutations. Therefore, investigation of the electrophysiological consequences of CPVT-causing RyR2 mutations is crucial to better understand the pathophysiology of the disease. The development of strategies for reprogramming human somatic cells to human induced pluripotent stem cells (hiPSCs) has provided a unique opportunity to study inherited arrhythmias, due to the ability of hiPSCs to differentiate down a cardiac lineage. Employment of genome editing enables generation of disease-specific cell lines from healthy and diseased patient-derived hiPSCs, which subsequently can be differentiated into cardiomyocytes. This paper describes the means for establishing an hiPSC-based model of CPVT in order to recapitulate the disease phenotype in vitro and investigate underlying pathophysiological mechanisms. The framework of this approach has the potential to contribute to disease modeling and personalized medicine using hiPSC-derived cardiomyocytes. © 2021 Wiley Periodicals LLC.

B-PO01-008 MULTIPLEX GENOME EDITING FOR THE TREATMENT OF CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia disorder that can cause sudden cardiac death. Variants in the ryanodine receptor type 2 gene (RYR2) cause >60% of CPVT cases. These variants increase RyR2 calcium (Ca2+) leak from the sarcoplasmic reticulum that can trigger ventricular arrythmias. Current therapeutic options are partially effective. Previously, our lab showed that using the CRISPR/Cas9 genome editing system targeting a silent restriction site could disrupt a disease-causing allele preventing VT in a CPVT mouse model with RyR2-R176Q (RQ). To develop a single CRISPR/Cas9 vector that can be used to correct one of several CPVT variants. We designed single guide RNAs (sgRNA) to target the N-terminal RQ and central domain RyR2-R2474S (RS) mutation sites. We cloned vectors with sgRNA targeting RS or RQ, dual guides targeting RS + RQ, and no gRNA as control. We used an in-vitro luciferase assay to determine on and off target editing efficiencies. We generated AAV9 with CRISPR/Cas9 and injected SC p5 mice. 6 weeks after injection, mice underwent ECG stress testing with isoproterenol, caffeine, and programmed electrical stimulation. Isolated ventricular cardiomyocytes loaded with Fluo4 dye were analyzed with confocal line scanning. We found by targeting the RQ site with sgRNA/Cas9, 0/8 mice had pacing-induced VT compared to 6/8 control (p=0.03). Edited cardiomyocytes showed a significant reduction in Ca2+ spark frequency (p<0.01). When targeting the RS site with sgRNA/Cas9, 0/7 mice had inducible VT compared to 6/7 control (p=0.04). The luciferase assay showed similar editing efficiencies with sgRNA and dual gRNA (Δ <10%) with preserved specificity to mutant alleles (>80%). In ongoing experiments, we expect similar efficacies in CPVT mice treated with dual gRNA/Cas9. CRISPR/Cas9 gene editing can treat CPVT by specifically targeting causative mutation sites in multiple channel domains, reducing mutant allele expression and preventing Ca2+ leak. Through successful targeting of the mutation sites, we have promising preclinical data for gene editing as a permanent cure for CPVT.

BASIC AND CLINICAL INSIGHTS IN CATECHOLAMINERGIC (FAMILIAL) POLYMORPHIC VENTRICULAR TACHYCARDIA.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal disease, whose characteristic ventricular tachycardias are adrenergic-dependent. Although rare, CPVT should be considered in the differential diagnosis of young individuals with exercise-induced syncope. Mutations in five different genes (RYR2, CASQ2, CALM1, TRDN, and TECRL) are associated with the CPVT phenotype, although RYR2 missense mutations are implicated in up to 60 % of all CPVT cases. Genetic testing has an essential role in the diagnosis, management, pre-symptomatic diagnosis, counseling, and treatment of the proband; furthermore, genetic information can be useful for offspring and relatives. By expert consensus, CPVT gene testing is a Class I recommendation for patients with suspected CPVT. Beta-adrenergic and calcium-channel blockers are the cornerstones of treatment due to the catecholaminergic dependence of the arrhythmias. Unresponsive patients are treated with an implantable cardioverter-defibrillator to reduce the risk of sudden cardiac death. In the present article, a brief review of the genetic and molecular mechanisms of this intriguing disease is provided.

Modelling CPVT in a dish: Characterization of two novel ryanodine receptor mutations using human induced pluripotent stem cell-derived cardiomyocytes

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac disease exposing afflicted patients to sudden cardiac death. Most CPVT cases have been linked to mutations of the gene encoding ryanodine receptor type 2 (RYR2). RyR2 is a calcium channel located in the membrane of the sarcoplasmic reticulum (SR). It mediates release of calcium stocks from the SR to the cytosol, playing a major role in excitation-contraction coupling. Although several studies have investigated mechanisms underlying CPVT in mice or in vitro models, little has been done concerning functional assessment of CPVT physiopathology in human cardiomyocytes. We aimed at characterizing, at cellular level, CPVT phenotype of patients carrying two new RyR2 mutations. Human induced pluripotent stem cells (hiPSCs) were derived from three CPVT patients. Two patients belonging to the same family carry the R4959Q RyR2 pore mutation. The third patient harbors the Y2476D mutation located in the cytosolic domain of the protein. hiPSCs were differentiated into cardiomyocytes for functional studies. Action potentials were recorded using patch-clamp technique. Calcium handling and contractility were investigated using Ionoptix and CardioExcyte technologies. hiPS-derived cardiomyocytes (hiPS-CMs) from CPVT patients displayed impaired beating properties. Calcium handling properties were also disrupted with changes in calcium transients, accompanied with increased diastolic calcium leak. At last, CPVT hiPS-CMs showed characteristics changes in action potential and arrhythmic events. Coherently with the patients’ phenotype, arrhythmic events were more frequent under beta-adrenergic stress. This work enabled us to characterize two novel CPVT mutations, providing more insight into functional mechanisms involved in this pathology, and further validating the use of human pluripotent stem cells for investigating complex cardiac rhythm disorders.

Catecholaminergic polymorphic ventricular tachycardia patients with multiple genetic variants in the PACES CPVT Registry.

BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is often a life-threatening arrhythmia disorder with variable penetrance and expressivity. Little is known about the incidence or outcomes of CPVT patients with ≥2 variants.MethodsThe phenotypes, genotypes and outcomes of patients in the Pediatric and Congenital Electrophysiology Society CPVT Registry with ≥2 variants in genes linked to CPVT were ascertained. The American College of Medical Genetics & Genomics (ACMG) criteria and structural mapping were used to predict the pathogenicity of variants (3D model of pig RyR2 in open-state).ResultsAmong 237 CPVT subjects, 193 (81%) had genetic testing. Fifteen patients (8%) with a median age of 9 years (IQR 5–12) had ≥2 variants. Sudden cardiac arrest occurred in 11 children (73%), although none died during a median follow-up of 4.3 years (IQR 2.5–6.1). Thirteen patients (80%) had at least two RYR2 variants, while the remaining two patients had RYR2 variants plus variants in other CPVT-linked genes. Among all variants identified, re-classification of the commercial laboratory interpretation using ACMG criteria led to the upgrade from variant of unknown significance (VUS) to pathogenic/likely pathogenic (P/LP) for 5 variants, and downgrade from P/LP to VUS for 6 variants. For RYR2 variants, 3D mapping using the RyR2 model suggested that 2 VUS by ACMG criteria were P/LP, while 2 variants were downgraded to likely benign.ConclusionsThis severely affected cohort demonstrates that a minority of CPVT cases are related to ≥2 variants, which may have implications on family-based genetic counselling. While multi-variant CPVT patients were at high-risk for sudden cardiac arrest, there are insufficient data to conclude that this genetic phenomenon has prognostic implications at present. Further research is needed to determine the significance and generalizability of this observation. This study also shows that a rigorous approach to variant re-classification using the ACMG criteria and 3D mapping is important in reaching an accurate diagnosis, especially in the multi-variant population.

Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals.

The rapid expansion of genetic testing has led to increased utilization of clinical whole-exome sequencing (WES). Clinicians and genetic researchers are being faced with assessing risk of disease vulnerability from incidentally identified genetic variants which is typified by variants found in genes associated with sudden death-predisposing catecholaminergic polymorphic ventricular tachycardia (CPVT). We sought to determine whether incidentally identified variants in genes associated with CPVT from WES clinical testing represent disease-associated biomarkers. CPVT-associated genes RYR2 and CASQ2 variants were identified in one of the world's largest collections of clinical WES referral tests (N=6517, Baylor Miraca Genetics Laboratories) and compared with a control cohort of ostensibly healthy individuals (N=60 706) and a case cohort of CPVT cases (N=155). Within the WES cohort, the rate of rare variants in CPVT-associated genes was 8.8% compared with 6.0% among controls and 60.0% among cases. There was a predominance of variants of undetermined significance (97.7%). After protein topology mapping, WES variants colocalized more frequently to residues with variants found in controls compared with cases. Retrospective clinical evaluation of individuals referred to our institution with WES-positive variants demonstrated no evidence of clinical CPVT in individuals with a low pretest clinical suspicion for CPVT. The prevalence of incidentally identified CPVT-associated variants is ≈9% among WES tests. Variants of undetermined significances in CPVT-associated genes in WES genetic testing, in the absence of clinical suspicion for CPVT, are unlikely to represent markers of CPVT pathogenicity.

New Insights Into the Genetic Basis of Inherited Arrhythmia Syndromes.

Inherited arrhythmia syndromes encompass several different diseases, including long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS), idiopathic ventricular fibrillation (IVF), and progressive cardiac conduction system disease (PCCD).1 The heart is typically structurally normal with no evidence of disease macroscopically. They are an important cause for sudden cardiac death in the young, and an autopsy is typically negative.2,3 Ventricular arrhythmias are caused by mutations of ion channels and their interacting proteins, predominantly involving potassium, sodium, and calcium handling.4 Genetic studies have identified the specific genetic abnormalities that underpin these diseases, even permitting diagnosis in the deceased using postmortem genetic testing (the molecular autopsy).3 Most arrhythmia syndromes are inherited in an autosomal dominant manner, such that first-degree family members have a 50% chance of inheriting the disease. Identification of the mutation allows for predictive genetic testing in other living family members.4 Variable penetrance is common in all arrhythmia syndromes, the same mutation in the same family causing wide variation in phenotype.4 This suggests that other factors such as genetic modifiers and environmental factors may influence the phenotype. This review will highlight the latest developments in understanding the genetic basis of inherited arrhythmia syndromes and discusses the new opportunities and challenges faced with evolving genetic technologies including determining pathogenicity and the utility of large genetic databases. Finally, we will discuss newly described entities that continue the evolving theme of genetic syndromes with phenotypic overlap. Early views that a single genotype associates with a particular phenotype continue to be challenged by our greater understanding of the genotype–phenotype relationship. ### Long QT Syndrome Congenital LQTS is diagnosed in the presence of a prolonged corrected QT (QTc) interval after secondary causes (eg, QT-prolonging medications or electrolyte abnormalities) are excluded.1 The 2013 Heart Rhythm …

GW26-e4458 A long-term misdiagnosis of catecholaminergic polymorphic ventricular tachycardia as epilepsy caused by RyR2 mutation

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare lethal disorder among inherited arrhythmogenic channelopathies, and would be misdiagnosed by neurologists for the analogous symptom of syncope. We aim to describe a long-term misdiagnosis case of CPVT as epilepsy caused by

Mutations in Calmodulin Cause Ventricular Tachycardia and Sudden Cardiac Death

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. Mutations in RYR2, encoding the cardiac sarcoplasmic calcium channel, have been identified as causative in approximately half of all dominantly inherited CPVT cases. Applying a genome-wide linkage analysis in a large Swedish family with a severe dominantly inherited form of CPVT-like arrhythmias, we mapped the disease locus to chromosome 14q31-32. Sequencing CALM1 encoding calmodulin revealed a heterozygous missense mutation (c.161A>T [p.Asn53Ile]) segregating with the disease. A second, de novo, missense mutation (c.293A>G [p.Asn97Ser]) was subsequently identified in an individual of Iraqi origin; this individual was diagnosed with CPVT from a screening of 61 arrhythmia samples with no identified RYR2 mutations. Both CALM1 substitutions demonstrated compromised calcium binding, and p.Asn97Ser displayed an aberrant interaction with the RYR2 calmodulin-binding-domain peptide at low calcium concentrations. We conclude that calmodulin mutations can cause severe cardiac arrhythmia and that the calmodulin genes are candidates for genetic screening of individual cases and families with idiopathic ventricular tachycardia and unexplained sudden cardiac death.

Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease so far related to mutations in the cardiac ryanodine receptor (RYR2) or the cardiac calsequestrin (CASQ2) genes. Because mutations in RYR2 or in CASQ2 are not retrieved in all CPVT cases, we searched for mutations in the physiological protein partners of RyR2 and CSQ2 in a large cohort of CPVT patients with no detected mutation in these two genes. Based on a candidate gene approach, we focused our investigations on triadin and junctin, two proteins that link RyR2 and CSQ2. Mutations in the triadin (TRDN) and in the junctin (ASPH) genes were searched in a cohort of 97 CPVT patients. We identified three mutations in triadin which cosegregated with the disease on a recessive mode of transmission in two families, but no mutation was found in junctin. Two TRDN mutations, a 4 bp deletion and a nonsense mutation, resulted in premature stop codons; the third mutation, a p.T59R missense mutation, was further studied. Expression of the p.T59R mutant in COS-7 cells resulted in intracellular retention and degradation of the mutant protein. This was confirmed after in vivo expression of the mutant triadin in triadin knock-out mice by viral transduction. In this work, we identified TRDN as a new gene responsible for an autosomal recessive form of CPVT. The mutations identified in the two families lead to the absence of the protein, thereby demonstrating the importance of triadin for the normal function of the cardiac calcium release complex in humans.

Clinical effectiveness of pulmonary vein isolation for arrhythmic events in a patient with catecholaminergic polymorphic ventricular tachycardia

An 18-year-old woman with catecholaminergic polymorphic ventricular tachycardia (CPVT) underwent pulmonary vein isolation (PVI) because of frequent and inappropriate shocks from an implantable cardioverter defibrillator (ICD) associated with atrial fibrillation (AF) with a rapid ventricular response. While the PVI did not completely suppress the AF induced by an isoproterenol infusion, the Holter monitor recordings demonstrated a major decrease in the clinical episodes of AF and ventricular tachyarrhythmias in association with a reduced high-frequency (HF) component and ratio of the low-frequency (LF) component power to the HF component (LF/HF) after the PVI. The PVI can decrease the substrates that trigger and maintain the AF when it involves a pulmonary vein origin, and may exert an additional effect on the sympathetic nerve input to the heart. The PVI may be an adjunctive therapy for CPVT cases with drug refractory AF causing inappropriate ICD discharges.

Catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder that causes syncopal episodes related with stress or emotion and even sudden cardiac deaths. Signs and symptoms usually begin in childhood. A suspicion of CPVT should be kept in mind when a child or an adolescent suddenly loses consciousness, particularly if this happens upon physical exercise or sudden mental stress. During the past decade, the knowledge of CPVT genetics and physiology has increased. Exercise testing is essential when suspecting arrhythmogenic origin of syncope, and in the case of CPVT, it may be even more sensitive than Holter monitoring. Beta-antiadrenergic medication can substantially decrease the mortality associated with CPVT. Asymptomatic patients with known CPVT gene defects should also be treated because sudden cardiac death may be the first manifestation of the disease. An implantable cardioverter-defibrillator may also be required in the most severe CPVT cases. In this review, we summarise the current knowledge on the clinical characteristics, diagnostic, genetic and prognostic features of CPVT in children. In all, 133 publications covering 60 years were checked, and those written in English and containing ten or more, mainly paediatric CPVT cases, were included. In addition, a CPVT family with three members and delayed diagnoses until late childhood and adulthood is presented.

A Case of Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial cardiac arrhythmia that is related to RYR2 or CASQ2 gene mutation. It occurs in patients with structurally normal heart and causes exercise-emotion-triggered syncope and sudden cardiac death. We experienced a case of CPVT in an 11 year-old female patient who was admitted for sudden cardiovascular collapse. The initial electrocardiogram (ECG) on emergency department revealed ventricular fibrillation. After multiple defibrillations, sinus rhythm was restored. However, recurrent ventricular fibrillation occurred during insertion of nasogastric tube without sedation in coronary care unit. On ECG monitoring, bidirectional ventricular tachycardia occurred with sinus tachycardia and then degenerated into ventricular fibrillation. To our knowledge, there has been no previous case report of CPVT triggered by sinus tachycardia in Korea. Therefore, we report the case as well as a review of the literature.

Catecholaminergic Polymorphic Ventricular Tachycardia from Bedside to Bench and Beyond

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a primary electrical myocardial disease characterized by exercise- and stress-related ventricular tachycardia manifested as syncope and sudden death. The disease has a heterogeneous genetic basis, with mutations in the cardiac Ryanodine Receptor channel (RyR2) gene accounting for an autosomal-dominant form (CPVT1) in approximately 50% and mutations in the cardiac calsequestrin gene (CASQ2) accounting for an autosomal-recessive form (CPVT2) in up to 2% of CPVT cases. Both RyR2 and calsequestrin are important participants in the cardiac cellular calcium homeostasis. We review the physiology of the cardiac calcium homeostasis, including the cardiac excitation contraction coupling and myocyte calcium cycling. The pathophysiology of cardiac arrhythmias related to myocyte calcium handling and the effects of different modulators are discussed. The putative derangements in myocyte calcium homeostasis responsible for CPVT, as well as the clinical manifestations and therapeutic options available, are described.