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BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a primary arrhythmia disorder characterized by syncope or sudden cardiac death and typically caused by a gain-of-function of the Ryanodine Receptor Type 2 (RyR2) mutation. Calmodulin is a calcium-binding protein responsible for many intracellular signalling pathways and disruptions in function or regulation may lead to potentially fatal arrhythmias. We present a case of a young patient with CPVT found to have an unusual, potentially causative, Calmodulin 2-a protein coding gene (CALM2) mutation. CASE SUMMARY: A 21-year-old female with autism was brought to the ED following cardiac arrest. Bidirectional ventricular tachycardia was captured on electrocardiogram. Propranolol was initiated, and patient had no further episodes of ventricular arrhythmia. A subcutaneous implantable cardioverter defibrillator (ICD) was implanted, and further genetics testing was done. Rapid Whole Genome Sequencing (PGnome®-RAPID) resulted heterozygous variant of uncertain significance in CALM2 gene NM_001743.5 for variant c.136G>A. DISCUSSION: To the authors knowledge, this is the third known record of such mutation in accordance with the International Calmodulin Registry (n = 74). Identification of CALM mutations can help advance the understanding of genetic underpinnings of arrhythmias and underscore necessity of genetic screening and personalized treatment strategies. Subcutaneous ICDs offer a promising therapeutic option while minimizing risks associated with traditional transvenous ICDs.

BACKGROUND: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia. METHODS: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients. RESULTS: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; P=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; P=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; P

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disorder characterized by ventricular arrhythmias induced by physical or emotional stress. Currently, there are limited data available on the long-term prognosis of CPVT. Methods and Results In this study, which included both retrospective and prospective components, 12 patients with CPVT (7 males and 5 females) under 18 years old were enrolled to gather and evaluate demographic, clinical, and genetic data. The mean age at diagnosis onset was 7.0 ± 3.1 years. All patients experienced syncope. The mean follow-up duration was 20.1 years. During the follow-up period, all patients experienced at least one episode of supraventricular tachycardia (SVT). Despite beta-blocker therapy, nine patients experienced syncope (75%), and four patients were noncompliant with their treatment. An implantable cardiac defibrillator (ICD) implantation was performed in 10 patients (83%), and among those 5 (50%) experienced appropriate shocks. Inappropriate shocks were observed in all patients with an ICD. The left cardiac sympathetic denervation was performed in 6 patients (50%). One patient died during the follow-up period. Genetic testing was performed in eight patients, five of whom had RYR2 mutations, one patient had mutations in CASQ2, one in TECRL, and one was gene-elusive. Conclusions The prevalence of cardiac events, even after the initiation of beta-blocker therapy, was found to be distressingly high during long-term follow-up. SVT, such as atrial fibrillation, were found to be more common than previously thought. Combination therapy with a beta-blocker and an IC antiarrhythmic drug shows promise. An individualized approach to the selection of treatment strategies is essential.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is primary electrical heart disease characterized by development of polymorphic, including bidirectional, ventricular tachycardia in response to adrenergic stimulation caused by physical or emotional stress. The major CPVT’s clinical manifestation is faintness caused by exercises, emotional stress, or beta-adrenergic agonists administration. This disease has high mortality rate without any treatment. The difficulties of preclinical diagnosis as well as late diagnosis after CPVT’s clinical signs manifestation dictate the need to analyze and systematize all the data on disease’s causes, clinical manifestations, and existing diagnostic approaches. This work has particular focus on the analysis of the disease molecular genetic causes and the spectrum of associated disorders in patients with CPVT regarding its diagnosis, management, and prognosis. Future research topics were determined for improving diagnosis quality and reducing mortality of patients with CPVT.

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Idiopathic ventricular fibrillation is diagnosed in survivors of sudden cardiac death that has been caused by ventricular fibrillation without known structural or electrical abnormalities, even after extensive investigation. It is a common cause of sudden death in young adults. Although idiopathic ventricular fibrillation is a diagnosis of exclusion, in many cases only a partial investigation algorithm is performed. The aim of this review is to present a comprehensive diagnostic evaluation algorithm with a focus on diagnostic assessment of inherited arrhythmic syndromes and genetic background. [ABSTRACT FROM AUTHOR]

Energy drinks potentially can trigger life-threatening cardiac arrhythmias. It has been postulated that the highly stimulating and unregulated ingredients alter heart rate, blood pressure, cardiac contractility, and cardiac repolarization in a potentially proarrhythmic manner. The purpose of this study was to describe our experience regarding sudden cardiac arrest (SCA) occurring in proximity to energy drink consumption in patients with underlying genetic heart diseases. The electronic medical records of all SCA survivors with proven arrhythmias referred to the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic for evaluation were reviewed to identify those who consumed an energy drink before their event. Patient demographics, clinical characteristics, documented energy drink consumption, and temporal relationship of energy drink consumption to SCA were obtained. Among 144 SCA survivors, 7 (5%; 6 female; mean age at SCA 29 ± 8 years) experienced an unexplained SCA associated temporally with energy drink consumption. Of these individuals, 2 had long QT syndrome and 2 had catecholaminergic polymorphic ventricular tachycardia; the remaining 3 were diagnosed with idiopathic ventricular fibrillation. Three patients (43%) consumed energy drinks regularly. Six patients (86%) required a rescue shock, and 1 (14%) was resuscitated manually. All SCA survivors have quit consuming energy drinks and have been event-free since. Overall, 5% of SCA survivors experienced SCA in proximity to consuming an energy drink. Although larger cohort studies are needed to elucidate the incidence/prevalence and quantify its precise risk, it seems prudent to sound an early warning on this potential risk. [ABSTRACT FROM AUTHOR]

Introduction: We report the case of a 37‐year‐old male athlete, who developed during exercise atrial and ventricular arrhythmias. No structural heart disease. Results: Invasive programmed ventricular stimulation induced ventricular fibrillation. A heterozygous mutation in the CASQ2 gene (c.775G>T, p.E259X) was found. Conclusions: The findings in our patient may suggest some increased ventricular excitability using programmed ventricular stimulation in CASQ2 polymorphic ventricular tachycardia patients. [ABSTRACT FROM AUTHOR]

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a primary electrical heart disease characterized by the development of polymorphic (including bidirectional) ventricular tachycardia in response to adrenergic stimulation. The leading clinical sign of CPVT is syncope provoked by physical or emotional stress, or adrenergic drugs administration. This disease is characterized by high mortality if not treated. The main treatment approach for CPVT is drug therapy with beta-blockers. Recently, however, there are more and more works stating that beta-blockers have lack of efficacy. Combination therapy with the antiarrhythmic drug of the IC class is one of the approaches before implementing the interventional treatment methods in several patients. Interventional methods include cardioverter defibrillator implantation and left side sympathectomy. This paper presents the modern view on the efficacy, safety, and indications for every management method for patients with CPVT.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disorder characterized by ventricular arrhythmias induced by physical or emotional stress. Currently, there are limited data available on the long term prognosis of CPVT. Methods and Results: In this study, which included both retrospective and prospective components, 12 patients with CPVT (7 males and 5 females) under 18 years old were enrolled to gather and evaluate demographic, clinical, and genetic data. The mean age at diagnosis onset was 7.0 ± 3.1 years. All patients experienced syncope. The mean follow up duration was 20.1 years. During the follow-up period, all patients experienced at least one episode of supraventricular tachycardia (SVT). Despite beta-blocker therapy, nine patients experienced syncope (75%), and four patients were noncompliant with their treatment. An implantable cardiac defibrillator (ICD) implantation was performed in 10 patients (83%), and among those 5 (50%) experienced appropriate shocks. Inappropriate shocks were observed in all patients with an ICD. The left cardiac sympathetic denervation was performed in 6 patients (50%). One patient died during the follow-up period. Genetic testing was performed in eight patients, five of whom had RYR2 mutations, one patient had mutations in CASQ2, one in TECRL, and one was gene-elusive. Conclusions: The prevalence of cardiac events, even after the initiation of beta-blocker therapy, was found to be distressingly high during long-term follow-up. SVT, such as atrial fibrillation, were found to be more common than previously thought. Combination therapy with a beta-blocker and an IC antiarrhythmic drug shows promise. An individualized approach to the selection of treatment strategies is essential. [ABSTRACT FROM AUTHOR]

Inherited arrhythmia syndromes (IASs) can cause life-threatening arrhythmias and are responsible for a significant proportion of sudden cardiac deaths (SCDs). Despite progress in the development of devices to prevent SCDs, the precise molecular mechanisms that induce detrimental arrhythmias remain to be fully investigated, and more effective therapies are desirable. In the present study, we screened a large-scale randomly mutagenized mouse library by electrocardiography to establish a disease model of IASs and consequently found one pedigree that exhibited spontaneous ventricular arrhythmias (VAs) followed by SCD within 1 y after birth. Genetic analysis successfully revealed a missense mutation (p.I4093V) of the ryanodine receptor 2 gene to be a cause of the arrhythmia. We found an age-related increase in arrhythmia frequency accompanied by cardiomegaly and decreased ventricular contractility in the Ryr2I4093V/+ mice. Ca2+ signaling analysis and a ryanodine binding assay indicated that the mutant ryanodine receptor 2 had a gain-of-function phenotype and enhanced Ca2+ sensitivity. Using this model, we detected the significant suppression of VA following flecainide or dantrolene treatment. Collectively, we established an inherited life-threatening arrhythmia mouse model from an electrocardiogram-based screen of randomly mutagenized mice. The present IAS model may prove feasible for use in investigating the mechanisms of SCD and assessing therapies. [ABSTRACT FROM AUTHOR]

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe hereditary arrhythmia syndrome predominantly affecting children and young adults. It manifests through bidirectional or polymorphic ventricular arrhythmia, often culminating in syncope triggered by physical exertion or emotional stress which can lead to sudden cardiac death. Most cases stem from mutations in the gene responsible for encoding the cardiac ryanodine receptor (RyR2), or in the Calsequestrin 2 gene (CASQ2), disrupting the handling of calcium ions within the cardiac myocyte sarcoplasmic reticulum. Diagnosing CPVT typically involves unmasking the arrhythmia through exercise stress testing. This diagnosis emerges in the absence of structural heart disease by cardiac imaging and with a normal baseline electrocardiogram. Traditional first-line treatment primarily involves β-blocker therapy, significantly reducing CPVT-associated mortality. Adjunctive therapies such as moderate exercise training, flecainide, left cardiac sympathetic denervation and implantable cardioverter-defibrillators have been utilized with reasonable success. However, the spectrum of options for managing CPVT has expanded over time, demonstrating decreased rates of arrhythmic events. Furthermore, ongoing research into potential new therapies including gene therapies has the potential to further enhance treatment paradigms. This review aims to succinctly encapsulate the contemporary understanding of the clinical characteristics, diagnostic approach, established therapeutic interventions and the promising future directions in managing CPVT. [ABSTRACT FROM AUTHOR]

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a hereditary heart disease characterized by bidirectional or polymorphic ventricular tachycardia and an increased risk of sudden cardiac death. Although trans-2,3-enoyl-CoA reductase like (TECRL) is a newly reported pathogenic gene leading to CPVT that can influence intracellular calcium regulation, the unidentified mechanism underlying the pathogenesis of TECRL deficiency-mediated CPVT remains mainly elusive. In the present study, Tecrl knockout (KO) mice were established and the differentially expressed genes (DEGs) were investigated by RNA-sequencing from the heart tissues. In addition, 857 DEGs were identified in Tecrl KO mice. Subsequently, a weighted gene co-expression network analysis was conducted to discern the pivotal pathways implicated in the Tecrl-mediated regulatory network. Moreover, pathway mapping analyses demonstrated that essential metabolism-related pathways were significantly enriched, notably the fatty acid metabolic process and calcium regulation. Collectively, the data suggested a synergistic relationship between Tecrl deficiency and cardiometabolic and calcium regulation during the development of CPVT. Therefore, further studies on the potential function of TECRL in cardiac tissues would be beneficial to elucidate the pathogenesis of CPVT.

Abstract Backgrounds Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but lethal cardiac ion channelopathy. Delayed diagnosis and misdiagnosis remain a matter of concern due to its rarity and insufficient recognition of this disorder, particularly in developing countries like China. Aims and methods We reported six catecholaminergic polymorphic ventricular tachycardia (CPVT) children diagnosed in our center along with a comprehensive review of Chinese pediatric CPVT patients reported in domestic and overseas literature between January 2013 and December 2021 to provide an essential reference for physicians to deepen their understanding of pediatric CPVT. Results A total of 95 children with CPVT, including our six patients from 21 medical centers were identified. The median age of symptom onset is 8.7 ± 3.0 years. Diagnosis occurred at a median age of 12.9 ± 6.8 years with a delay of 4.3 ± 6.6 years. Selective beta-blockers (Metoprolol and Bisoprolol) were prescribed for 38 patients (56.7%) and 29 (43.3%) patients received non-selective beta-blocker (Propranolol and Nadolol) treatment. Six patients accepted LCSD and seven received ICD implantation at the subsequent therapy. A total of 13 patients died during the disease course. Of the 67 patients with positive gene test results, variants in RYR2 were 47 (70.1%), CASQ2 were 11 (16.4%), and RYR2 accompanied SCN5A were 7 (10.4%). Patients with CASQ2 gene mutations presented with younger symptom onset age, higher positive family history rate and better prognosis than those with RYR2 mutations. Conclusion Chinese pediatric patients with CPVT had a poorer prognosis than other cohorts, probably due to delayed/missed diagnosis, non-standard usage of beta-blockers, unavailability of flecainide, and a lower rate of LCSD and ICD implantation.

Aims In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare inherited arrhythmia syndrome, arrhythmic events can be prevented by medication and lifestyle recommendations. In patients who experience breakthrough arrhythmic events, non-adherence plays an essential role. We aimed to investigate the incidence and potential reasons for non-adherence to medication and lifestyle recommendations in a large, international cohort of patients with CPVT. Methods and results An online multilingual survey was shared with CPVT patients worldwide by their cardiologists, through peer-recruitment, and on social media from November 2022 until July 2023. Self-reported non-adherence was measured using the validated Medication Adherence Rating Scale (MARS) and a newly developed questionnaire about lifestyle. Additionally, validated questionnaires were used to assess potential reasons for medication non-adherence. Two-hundred-and-eighteen patients completed the survey, of whom 200 (92%) were prescribed medication [122 (61%) female; median age 33.5 years (interquartile range: 22–50)]. One-hundred-and-three (52%) were prescribed beta-blocker and flecainide, 85 (43%) beta-blocker, and 11 (6%) flecainide. Thirty-four (17%) patients experienced a syncope, aborted cardiac arrest or appropriate implantable cardioverter defibrillator shock after diagnosis. Nineteen (13.4%) patients were exercising more than recommended. Thirty (15%) patients were non-adherent to medication. Female sex [odds ratio (OR) 3.7, 95% confidence interval (CI) 1.3–12.0, P = 0.019], flecainide monotherapy compared to combination therapy (OR 6.8, 95% CI 1.6–31.0, P = 0.010), and a higher agreement with statements regarding concerns about CPVT medication (OR 1.2, 95% CI 1.1–1.3, P < 0.001) were independently associated with non-adherence. Conclusion The significant rate of non-adherence associated with concerns regarding CPVT-related medication, emphasizes the potential for improving therapy adherence by targeted patient education. [ABSTRACT FROM AUTHOR]

Ventricular arrhythmias in cardiac channelopathies are linked to autonomic triggers, which are sub-optimally targeted in current management strategies. Improved molecular understanding of cardiac channelopathies and cellular autonomic signalling could refine autonomic therapies to target the specific signalling pathways relevant to the specific aetiologies as well as the central nervous system centres involved in the cardiac autonomic regulation. This review summarizes key anatomical and physiological aspects of the cardiac autonomic nervous system and its impact on ventricular arrhythmias in primary inherited arrhythmia syndromes. Proarrhythmogenic autonomic effects and potential therapeutic targets in defined conditions including the Brugada syndrome, early repolarization syndrome, long QT syndrome, and catecholaminergic polymorphic ventricular tachycardia will be examined. Pharmacological and interventional neuromodulation options for these cardiac channelopathies are discussed. Promising new targets for cardiac neuromodulation include inhibitory and excitatory G-protein coupled receptors, neuropeptides, chemorepellents/attractants as well as the vagal and sympathetic nuclei in the central nervous system. Novel therapeutic strategies utilizing invasive and non-invasive deep brain/brain stem stimulation as well as the rapidly growing field of chemo-, opto-, or sonogenetics allowing cell-specific targeting to reduce ventricular arrhythmias are presented. [ABSTRACT FROM AUTHOR]

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a hereditary heart disease characterized by bidirectional or polymorphic ventricular tachycardia and an increased risk of sudden cardiac death. Although trans-2,3- enoyl-CoA reductase like (TECRL) is a newly reported pathogenic gene leading to CPVT that can influence intracellular calcium regulation, the unidentified mechanism underlying the pathogenesis of TECRL deficiency-mediated CPVT remains mainly elusive. In the present study, Tecrl knockout (KO) mice were established and the differentially expressed genes (DEGs) were investigated by RNA-sequencing from the heart tissues. In addition, 857 DEGs were identified in Tecrl KO mice. Subsequently, a weighted gene co-expression network analysis was conducted to discern the pivotal pathways implicated in the Tecrl-mediated regulatory network. Moreover, pathway mapping analyses demonstrated that essential metabolismrelated pathways were significantly enriched, notably the fatty acid metabolic process and calcium regulation. Collectively, the data suggested a synergistic relationship between Tecrl deficiency and cardiometabolic and calcium regulation during the development of CPVT. Therefore, further studies on the potential function of TECRL in cardiac tissues would be beneficial to elucidate the pathogenesis of CPVT. [ABSTRACT FROM AUTHOR]

Backgrounds: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but lethal cardiac ion channelopathy. Delayed diagnosis and misdiagnosis remain a matter of concern due to its rarity and insufficient recognition of this disorder, particularly in developing countries like China. Aims and methods: We reported six catecholaminergic polymorphic ventricular tachycardia (CPVT) children diagnosed in our center along with a comprehensive review of Chinese pediatric CPVT patients reported in domestic and overseas literature between January 2013 and December 2021 to provide an essential reference for physicians to deepen their understanding of pediatric CPVT. Results: A total of 95 children with CPVT, including our six patients from 21 medical centers were identified. The median age of symptom onset is 8.7 ± 3.0 years. Diagnosis occurred at a median age of 12.9 ± 6.8 years with a delay of 4.3 ± 6.6 years. Selective beta-blockers (Metoprolol and Bisoprolol) were prescribed for 38 patients (56.7%) and 29 (43.3%) patients received non-selective beta-blocker (Propranolol and Nadolol) treatment. Six patients accepted LCSD and seven received ICD implantation at the subsequent therapy. A total of 13 patients died during the disease course. Of the 67 patients with positive gene test results, variants in RYR2 were 47 (70.1%), CASQ2 were 11 (16.4%), and RYR2 accompanied SCN5A were 7 (10.4%). Patients with CASQ2 gene mutations presented with younger symptom onset age, higher positive family history rate and better prognosis than those with RYR2 mutations. Conclusion: Chinese pediatric patients with CPVT had a poorer prognosis than other cohorts, probably due to delayed/missed diagnosis, non-standard usage of beta-blockers, unavailability of flecainide, and a lower rate of LCSD and ICD implantation. [ABSTRACT FROM AUTHOR]

Sudden cardiac death (SCD) in children is a devastating event, often linked to primary electrical diseases (PED) of the heart. PEDs, often referred to as channelopathies, are a group of genetic disorders that disrupt the normal ion channel function in cardiac cells, leading to arrhythmias and sudden cardiac death. This paper investigates the unique challenges of risk assessment and stratification for channelopathy-related SCD in pediatric patients—Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, long QT syndrome, Anderson–Tawil syndrome, short QT syndrome, and early repolarization syndrome. We explore the intricate interplay of genetic, clinical, and electrophysiological factors that contribute to the complex nature of these conditions. Recognizing the significance of early identification and tailored management, this paper underscores the need for a comprehensive risk stratification approach specifically designed for pediatric populations. By integrating genetic testing, family history, and advanced electrophysiological evaluation, clinicians can enhance their ability to identify children at the highest risk for SCD, ultimately paving the way for more effective preventive strategies and improved outcomes in this vulnerable patient group. [ABSTRACT FROM AUTHOR]

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare genetic disorder where catecholamine causes bidirectional ventricular tachycardia, potentially leading to cardiac arrest. In patients undergoing surgery, sympathetic responses can be triggered in situations associated with surgical stimulations as well as high anxiety before the surgery, anesthetic maneuvers such as endotracheal intubation and extubation, and postoperative pain. Therefore, planning for surgery demands meticulous attention to anesthesia during the perioperative period in order to prevent potentially life-threatening arrhythmias. Case: We discuss a case of an 11-year-old male pediatric patient with known CPVT who required elective strabismus surgery for exotropia involving both eyes. After thorough planning of general anesthesia to minimize catecholamine response, sufficient anesthesia and analgesia were achieved to blunt the stressful response during intubation and maintained throughout the surgical procedure. Complete emergence was achieved after deep extubation, and the patient did not complain of pain or postoperative nausea and vomiting. Conclusions: Anesthesiologists should not only be able to plan and manage the catecholamine response during surgery but also anticipate and be prepared for situations that may lead to arrhythmias before and after the procedure. In certain cases, deep extubation can be beneficial as it reduces hemodynamic changes during the extubation process. [ABSTRACT FROM AUTHOR]

CPVT is a rare inherited arrhythmogenic disorder characterized by bidirectional, polymorphic ventricular arrhythmias triggered by catecholamines released during exercise, stress, or sudden emotion in individuals with a normal resting electrocardiogram and structurally normal heart. Mutations in the ryanodine receptor 2 gene are the most common known etiology of this disorder. The c.1195A > G(p.Met399Val) variant in Exon 14 of RyR2 is currently classified as a Variant of Uncertain Significance. We present a case of CPVT caused by this novel disease-causing RyR2 variant and discuss its pathophysiology. The role of SSRIs in treating patients with CPVT unresponsive to mainstream therapies is also highlighted.

Idiopathic ventricular fibrillation is diagnosed in survivors of sudden cardiac death that has been caused by ventricular fibrillation without known structural or electrical abnormalities, even after extensive investigation. It is a common cause of sudden death in young adults. Although idiopathic ventricular fibrillation is a diagnosis of exclusion, in many cases only a partial investigation algorithm is performed. The aim of this review is to present a comprehensive diagnostic evaluation algorithm with a focus on diagnostic assessment of inherited arrhythmic syndromes and genetic background.

Catecholaminergic polymorphic ventricular tachycardia is a primary channelopathy with a high mortality rate if left untreated. In 3 to 5% of catecholaminergic polymorphic ventricular tachycardia patients, mutations in the CASQ2 gene, either in a homozygous or compound heterozygous form, have been identified. In this article, we present a clinical case series of patients from three unrelated families with mutations in the CASQ2 gene, including three novel mutations (p.Leu167Pro, p.Asp325GlyfsTer7, and p.Glu259Ter). All our patients with homozygous or compound heterozygous CASQ2 gene mutations experienced a severe disease course, with early manifestations and resistance to specific anti-arrhythmic treatment, including beta-blockers. They exhibited a wide range of heart rhythm abnormalities, both ventricular and supraventricular, and had a high risk of sudden cardiac death. In all cases, ventricular heart arrhythmias persisted despite regular treatment with specific anti-arrhythmic agents, unless selective left-sided sympathectomy had been performed. The management of this patient group emphasized an individualized approach, combining medical and surgical treatment methods tailored to each patient's unique needs and condition.

Background Catheter ablation of premature ventricular contractions (PVCs) that trigger polymorphic ventricular tachycardia (PVT) or ventricular fibrillation has been reported as a novel therapy to reduce the syncope events in patients with catecholaminergic PVT, whereas the long‐term ablation outcome and its value in improving exercise‐induced ventricular arrhythmias remain unclear. Methods and Results Fourteen consecutive selected patients with catecholaminergic PVT (mean±SD age, 16±6 years; 43% male patients) treated with maximum β‐blockers with no possibility of adding flecainide were prospectively enrolled for catheter ablation. The primary end point was syncope recurrence, and the secondary end point was the reduction of the ventricular arrhythmia score during exercise testing. Twenty‐six PVT/ventricular fibrillation–triggering PVCs were identified for ablation. The trigger beats arose from the left ventricle in 50% of the cases and from both ventricles in 36% of the cases. Purkinje potentials were observed at 27% of the targets. After a mean follow‐up of 49 months after ablation, 8 (57%) patients were free from syncope recurrence. Ablation of trigger beat significantly reduced the syncope frequency (mean±SD, 4.3±1.6 to 0.5±0.8 events per year; P

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited cardiac ion channelopathy where the initial disease presentation is during childhood or adolescent stages, leading to increased risks of sudden cardiac death. Despite advances in medical science and technology, several gaps remain in the understanding of the molecular mechanisms, risk prediction, and therapeutic management of patients with CPVT. Recent studies have identified and validated seven sets of genes responsible for various CPVT phenotypes, including RyR2, CASQ-2, TRDN, CALM1, 2, and 3, and TECRL, providing novel insights into the molecular mechanisms. However, more data on atypical CPVT genotypes are required to investigate the underlying mechanisms further. The complexities of the underlying genetics contribute to challenges in risk stratification as well as the uncertainty surrounding nongenetic modifiers. Therapeutically, although medical management involving beta-blockers and flecainide, or insertion of an implantable cardioverter defibrillator remains the mainstay of treatment, animal and stem cell studies on gene therapy for CPVT have shown promising results. However, its clinical applicability remains unclear. Current gene therapy studies have primarily focused on the RyR2 and CASQ-2 variants, which constitute 75% of all CPVT cases. Alternative approaches that target a broader population, such as CaMKII inhibition, could be more feasible for clinical implementation. Together, this review provides an update on recent research on CPVT, highlighting the need for further investigation of the molecular mechanisms, risk stratification, and therapeutic management of this potentially lethal condition. [ABSTRACT FROM AUTHOR]

Background In childhood and adolescence, cardiac arrhythmias are often benign in the absence of congenital heart defects. Nevertheless, life-threatening inherited arrhythmogenic syndromes can become clinically manifest in early childhood. As early symptoms may be similar in both conditions, thorough workup is fundamental to avoid delayed diagnosis and misdiagnosis. Case summary We present the case of a 26-year-old Caucasian female patient who presented with recurrent non-sustained polymorphic wide complex tachycardia. Structural heart disease was excluded by echocardiography as well as cardiac magnetic resonance imaging. Due to wide complex extrasystoles and couplets with alternating QRS axis occurring at low levels of physical exertion, catecholaminergic polymorphic ventricular tachycardia (CPVT) was suspected and further investigated. Epinephrine testing in combination with an electrophysiological (EP) study with placement of a coronary sinus catheter and subsequent programmed stimulation ruled out CPVT and unmasked wide complex tachycardia as varying aberrant conduction of focal atrial tachycardia (FAT). 3D-navigated mapping of FAT revealed a direct parahisian origin. Due to significantly increased risk of atrio-ventricular (AV) block during ablation, the patient refused ablation and preferred medical antiarrhythmic therapy. Discussion Given the consequences of both, delayed diagnosis and misdiagnosis of CPVT, thorough workup is fundamental. In case of doubt regarding potential aberrant AV conduction in the context of wide complex tachycardia, an invasive EP study may easily and safely prove or rule out aberrancy. [ABSTRACT FROM AUTHOR]

Aims Calmodulinopathy due to mutations in any of the three CALM genes (CALM1–3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. Methods and results The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM -positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5–19]), 97 index cases and 43 family members. CALM -LQTS and CALM -CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P =.001) and sudden death (9% vs. 27%; P =.008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM -LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. Conclusion Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter–defibrillator. [ABSTRACT FROM AUTHOR]

Calcium release deficiency syndrome (CRDS) is a newly described form of inherited arrhythmia caused by damaging loss-of-function variants in the cardiac ryanodine receptor (RyR2). Unlike the prototypical RyR2 gain-of-function channelopathy, known as catecholaminergic polymorphic ventricular tachycardia, patients with CRDS are predisposed to sudden death usually in the absence of any electrical abnormalities at rest or during stress electrocardiography. This makes diagnosis incredibly challenging, however, an invasive electrophysiologic test appears to be effective in unmasking the phenotype, called the long-burst, long-pause, short-coupled ventricular extra-stimulus protocol. Optimal therapies for patients with CRDS remain unestablished, although flecainide appears to be a promising candidate drug. [ABSTRACT FROM AUTHOR]

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by bidirectional or polymorphic ventricular arrhythmia provoked by exercise or emotion. Most cases are caused by pathogenic variants in the gene encoding the cardiac ryanodine receptor (RYR2). The options for treating patients with CPVT have increased during the years, and evidence suggests that these have led to lower arrhythmic event rates. In addition, numerous potential new therapies are being investigated. In this review, we summarize the state of knowledge on both established and potential future treatment strategies for patients with CPVT and describe our approach to their management. [ABSTRACT FROM AUTHOR]

Abstract Cardiac ion channelopathies encompass a set of inherited or acquired conditions that are due to dysfunction in ion channels or their associated proteins, typically in the presence of structurally normal hearts. They are associated with the development of ventricular arrhythmias and sudden cardiac death. The aim of this review is to provide a historical perspective and recent advances in the research of the cardiac ion channelopathies, Brugada syndrome, long QT syndrome and catecholaminergic polymorphic ventricular tachycardia, in Hong Kong, China. In particular, recent works on the development of novel predictive models incorporating machine learning techniques to improve risk stratification are outlined. The availability of linked records of affected patients with good longitudinal data in the public sector, together with multidisciplinary collaborations, implies that ion channelopathy research efforts have advanced significantly.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited cardiac ion channelopathy where the initial disease presentation is during childhood or adolescent stages, leading to increased risks of sudden cardiac death. Despite advances in medical science and technology, several gaps remain in the understanding of the molecular mechanisms, risk prediction, and therapeutic management of patients with CPVT. Recent studies have identified and validated seven sets of genes responsible for various CPVT phenotypes, including RyR2, CASQ-2, TRDN, CALM1, 2, and 3, and TECRL, providing novel insights into the molecular mechanisms. However, more data on atypical CPVT genotypes are required to investigate the underlying mechanisms further. The complexities of the underlying genetics contribute to challenges in risk stratification as well as the uncertainty surrounding nongenetic modifiers. Therapeutically, although medical management involving beta-blockers and flecainide, or insertion of an implantable cardioverter defibrillator remains the mainstay of treatment, animal and stem cell studies on gene therapy for CPVT have shown promising results. However, its clinical applicability remains unclear. Current gene therapy studies have primarily focused on the RyR2 and CASQ-2 variants, which constitute 75% of all CPVT cases. Alternative approaches that target a broader population, such as CaMKII inhibition, could be more feasible for clinical implementation. Together, this review provides an update on recent research on CPVT, highlighting the need for further investigation of the molecular mechanisms, risk stratification, and therapeutic management of this potentially lethal condition.

The 3 most common inherited arrhythmia syndromes—Brugada syndrome, congenital long QT syndrome and catecholaminergic polymorphic ventricular tachycardia—were initially described in the previous century. Since then, research has evolved, which has enabled us to identify patients prior to the onset of potentially life-threatening symptoms. However, there are significant gaps in knowledge that complicate clinical management of these patients today. With this review paper, we aim to highlight the most important knowledge gaps in clinical research of these inherited arrhythmia syndromes. [ABSTRACT FROM AUTHOR]

Over the last three decades, the genetic basis of various inherited arrhythmia syndromes has been elucidated, providing key insights into cardiomyocyte biology and various regulatory pathways associated with cellular excitation, contraction, and repolarisation. As varying techniques to manipulate genetic sequence, gene expression, and different cellular pathways have become increasingly defined and understood, the potential to apply various gene-based therapies to inherited arrhythmia has been explored. The promise of gene therapy has generated significant interest in the medical and lay press, providing hope for sufferers of seemingly incurable disorders to imagine a future without repeated medical intervention, and, in the case of various cardiac disorders, without the risk of sudden death. In this review, we focus on catecholaminergic polymorphic ventricular tachycardia (CPVT), discussing the clinical manifestations, genetic basis, and molecular biology, together with current avenues of research related to gene therapy. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder in which catecholamine release during exercise or emotional stress cause fatal tachyarrhythmias. In this paper, we discuss methods to minimize the sympathetic stimulation that can occur during the perioperative period in patients undergoing left cardiac sympathetic denervation to surgically treat CPVT. [ABSTRACT FROM AUTHOR]

Aims The ryanodine receptor 2 (RyR2) is essential for cardiac muscle excitation–contraction coupling; dysfunctional RyR2 participates in the development of inherited arrhythmogenic cardiac disease. In this study, a novel RyR2 mutation A690E is identified from a patient with family inheritance of sudden cardiac death, and we aimed to investigate the pathogenic basis of the mutation. Methods and results We generated a mouse model that carried the A690E mutation. Mice were characterized by adrenergic-induced ventricular arrhythmias similar to clinical manifestation of the patient. Optical mapping studies revealed that isolated A690E hearts were prone to arrhythmogenesis and displayed frequency-dependence calcium transient alternans. Upon β-adrenoceptor challenge, the concordant alternans was shifted towards discordant alternans that favour triggering ectopic beats and Ca2+ re-entry; similar phenomenon was also found in the A690E cardiomyocytes. In addition, we found that A690E cardiomyocytes manifested abnormal Ca2+ release and electrophysiological disorders, including an increased sensitivity to cytosolic Ca2+, an elevated diastolic RyR2-mediated Ca2+ leak, and an imbalance between Ca2+ leak and reuptake. Structural analyses reveal that the mutation directly impacts RyR2–FK506 binding protein interaction. Conclusion In this study, we have identified a novel mutation in RyR2 that is associated with sudden cardiac death. By characterizing the function defects of mutant RyR2 in animal, whole heat, and cardiomyocytes, we demonstrated the pathogenic basis of the disease-causing mutation and provided a deeper mechanistic understanding of a life-threatening cardiac arrhythmia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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BackgroundGenetic variants in calsequestrin-2 (CASQ2) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2-CPVT was sought through an international multicenter collaboration.MethodsGenotype-phenotype segregation in CASQ2-CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure.ResultsA total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6-11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; P=0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; P

This article reviews progress in the field of cardiac genome editing, in particular, its potential utility in treating cardiac arrhythmias. First, we discuss genome editing methods by which DNA can be disrupted, inserted, deleted, or corrected in cardiomyocytes. Second, we provide an overview of in vivo genome editing in preclinical models of heritable and acquired arrhythmias. Third, we discuss recent advancements in cardiac gene transfer, including delivery methods, gene expression optimization, and potential adverse effects associated with therapeutic somatic genome editing. While genome editing for cardiac arrhythmias is still in its infancy, this approach holds great promise, especially for inherited arrhythmia syndromes with a defined genetic defect. [ABSTRACT FROM AUTHOR]

Key Clinical Message Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder in which catecholamine release during exercise or emotional stress cause fatal tachyarrhythmias. In this paper, we discuss methods to minimize the sympathetic stimulation that can occur during the perioperative period in patients undergoing left cardiac sympathetic denervation to surgically treat CPVT.

Ahmed Almarzuqi,1 Shane Kimber,1 Kenneth Quadros,1 Janek Senaratne1,2 1Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada; 2Department of Critical Care Medicine, University of Alberta, Edmonton, CanadaCorrespondence: Janek Senaratne, Tel +1 (780) 463-2184, Fax +1 (780) 450-8359, Email janeks@ualberta.caAbstract: Bidirectional ventricular tachycardia (BiVT) is a rare form of ventricular tachycardia that manifests on surface electrocardiogram by dual QRS morphologies alternating on a beat-to-beat basis. It was first reported in the 1920s as a complication of digoxin, and since then, it has been reported in other conditions including fulminant myocarditis, sarcoidosis, catecholaminergic polymorphic ventricular tachycardia, and Andersen-Tawil syndrome. The mechanism for BiVT is not as well known as other forms of ventricular tachycardia but appears to include typical mechanisms including triggered activity from afterdepolarizations, abnormal automaticity, or reentry. This review will go beyond the definition, surface electrocardiogram, mechanisms, causes, and treatment of BiVT as per our current understanding.Keywords: bidirectional ventricular tachycardia, dual reentry, ventricular arrhythmia, digoxin toxicity, catecholaminergic polymorphic ventricular tachycardia

Calcium (Ca2+) is the major mediator of cardiac contractile function. It plays a key role in regulating excitation–contraction coupling and modulating the systolic and diastolic phases. Defective handling of intracellular Ca2+ can cause different types of cardiac dysfunction. Thus, the remodeling of Ca2+ handling has been proposed to be a part of the pathological mechanism leading to electrical and structural heart diseases. Indeed, to ensure appropriate electrical cardiac conduction and contraction, Ca2+ levels are regulated by several Ca2+-related proteins. This review focuses on the genetic etiology of cardiac diseases related to calcium mishandling. We will approach the subject by focalizing on two clinical entities: catecholaminergic polymorphic ventricular tachycardia (CPVT) as a cardiac channelopathy and hypertrophic cardiomyopathy (HCM) as a primary cardiomyopathy. Further, this review will illustrate the fact that despite the genetic and allelic heterogeneity of cardiac defects, calcium-handling perturbations are the common pathophysiological mechanism. The newly identified calcium-related genes and the genetic overlap between the associated heart diseases are also discussed in this review. [ABSTRACT FROM AUTHOR]