RARE DISEASE
Catecholaminergic polymorphic ventricular tachycardia
Catecholaminergic polymorphic ventricular tachycardia
Catecholaminergic polymorphic ventricular tachycardia
Synonyms: Bidirectional ventricular tachycardia induced by catecholamine, CPVT, Malignant paroxysmal ventricular tachycardia, Polymorphic ventricular tachycardia induced by catecholamines
Synonyms: Bidirectional ventricular tachycardia induced by catecholamine, CPVT, Malignant paroxysmal ventricular tachycardia, Polymorphic ventricular tachycardia induced by catecholamines
Synonyms: Bidirectional ventricular tachycardia induced by catecholamine, CPVT, Malignant paroxysmal ventricular tachycardia, Polymorphic ventricular tachycardia induced by catecholamines
Drug discovery
5
drugs
With orphan designations
Overview
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia syndrome caused by dysregulated intracellular calcium handling (typically RYR2 or CASQ2 mutations). It manifests as bidirectional or polymorphic ventricular tachycardia triggered by exercise/emotional stress in structurally normal hearts. Untreated, it carries a 30–50% mortality by age 35. Diagnosis relies on exercise testing, clinical history, and genetic screening [1][2][6][14].
Therapies
First-line: Maximum-tolerated β-blockers (nadolol preferred) [3][14][19].
Add-on: Flecainide (2–3 mg/kg/day) for refractory arrhythmias [1][3][13].
Advanced: Left cardiac sympathetic denervation or ICD (cautiously, due to shock-induced storm risk) [1][3][14].
- Lifestyle: Avoid competitive sports/stress [1][3].
Categories: rare cardiac diseases, rare genetic diseases
Research Papers
785 drug discovery papers about Catecholaminergic polymorphic ventricular tachycardia, with 6 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
785 drug discovery papers about Catecholaminergic polymorphic ventricular tachycardia, with 6 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-22 | Calpain-Dependent Protein Degradation Contributes to CASQ2-R33Q CPVT.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease associated with cardiac arrest in children and young adults. The recessive form of CPVT is caused by loss-of-function mutations in the genes encoding CASQ2 and TRDN, which, together with JCTN, regulate the release of calcium ions from the sarcoplasmic reticulum through the RyR2 (ryanodine receptor). The CASQ2 R33Q mutation causes calcium mishandling and ventricular tachycardia through triggered activity. The homozygous mouse model Casq2R33Q/R33Q closely replicates the clinical phenotype of patients with CPVT. In this model, CASQ2 (calsequestrin 2), TRDN (triadin), and JCTN (junctin) levels are markedly reduced; however, the mechanisms underlying this reduction and their contribution to CPVT are incompletely understood. We used a combination of proteomics, animal models, and experimental methods to identify the molecular mechanisms responsible for the decrease of couplon proteins in Casq2R33Q/R33Q mice and to explore their functional contribution to the disease. Casq2R33Q/R33Q hearts showed activation of endoplasmic reticulum stress, the unfolded protein response, and alterations in major proteolytic pathways. Inhibition of the proteasome or autophagy in neonatal cardiomyocytes and adult mice partially restored CASQ2 but not TRDN levels, suggesting distinct degradation mechanisms. In contrast, calpain inhibition restored CASQ2 and TRDN protein levels, decreased triggered activity in isolated cardiomyocytes, and reduced ventricular tachycardia episodes in vivo in Casq2R33Q/R33Q mice. Biochemical assays showed that TRDN is a direct calpain substrate. TRDN degradation preceded CASQ2 loss, and TRDN overexpression using modified RNA in cardiomyocytes or an adeno-associated viral vector in vivo increased CASQ2 levels in mutant mice, supporting an upstream role for TRDN destabilization. Couplon protein loss in CPVT associated with CASQ2-R33Q is mediated by coordinated but distinct proteolytic pathways, with calpain-dependent TRDN degradation representing a key pathogenic event that promotes CASQ2 destabilization and arrhythmogenesis.
2026-09-21 | Beta-Blockers for the Treatment of Arrhythmias: Which Drug for Which Arrhythmia? A State-of-the-Art Narrative Review.
Beta-blockers are among the most widely prescribed drugs in the management of both supraventricular and ventricular arrhythmias, and they are frequently regarded as a homogeneous pharmacological class. They are not. The agents in current use differ substantially in beta1-receptor selectivity, lipophilicity, half-life, route of administration, intrinsic sympathomimetic activity, and ancillary properties, and arrhythmias themselves differ in mechanism, adrenergic dependence, anatomical origin, and structural substrate. This narrative review examines whether these pharmacological differences translate into clinically meaningful differences in efficacy and utility, asking not only whether a beta-blocker should be used but which one should be used. Evidence was drawn from a targeted search of PubMed, Web of Science, Scopus, Ovid, Embase, and the Cochrane Library, with priority given to randomized controlled trials, meta-analyses, large registries, and contemporary society guidelines, and was synthesized qualitatively by arrhythmia type. A class effect is apparent for many indications, particularly rate control in atrial fibrillation and atrial flutter, where metoprolol, bisoprolol, and carvedilol perform broadly similarly and the choice is driven mainly by comorbidity and tolerability. Drug-specific differences emerge in three settings. In adrenergically mediated inherited syndromes, namely catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, nonselective agents and especially nadolol are clearly superior to beta1-selective agents, and the same principle appears to extend to ventricular electrical storm, in which propranolol has outperformed metoprolol in a randomized comparison. In acute care, pharmacokinetics dominate, and the ultra-short-acting agents esmolol and landiolol permit a degree of titration that longer-acting drugs cannot match. In patients with heart failure and reduced ejection fraction, carvedilol, metoprolol succinate, and bisoprolol should be preferred irrespective of arrhythmia subtype because of their established mortality benefit. Conversely, beta1-selective agents, including the highly selective agent nebivolol, improve tolerability in bronchospastic disease, although this reflects respiratory tolerability rather than any demonstrated antiarrhythmic advantage, and beta-blockers have little role in Brugada syndrome or in bradycardia-dependent acquired torsades de pointes. Beta-blockers should therefore not be treated as interchangeable. Selection should integrate arrhythmic mechanism, structural substrate, and patient characteristics, and head-to-head trials remain conspicuously scarce.
2026-09-18 | Catecholaminergic polymorphic ventricular tachycardia with diagnostic difficulty differentiating seizures from syncope: a case report
Introduction Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially fatal inherited arrhythmia syndrome triggered by exercise or emotional stress that may mimic epileptic seizures, resulting in delayed diagnosis. Case presentation We report the case of a 6-year-old girl with recurrent transient loss of consciousness (T-LOC) who was initially misdiagnosed with epilepsy. She experienced three episodes of T-LOC between 4 and 6 years of age. The first two episodes occurred during or immediately post-exercise, whereas the third appeared non-exertional; however, retrospective review suggested fear-induced sympathetic activation as the trigger. During the second and third episodes, she exhibited eye opening, fixed gaze, and tonic posturing, closely resembling epileptic seizures. Interictal electroencephalography was normal, resting electrocardiography (ECG) showed sinus bradycardia without QT prolongation, and an initial Master's triple two-step exercise test increased the heart rate to only 74 beats per minute (bpm) without inducing arrhythmia. She was provisionally diagnosed with epilepsy, and a diagnostic trial of levetiracetam was initiated. Four months later, school-based ECG screening, prompted by her history of seizure-like episodes with impaired consciousness, led to further cardiac evaluation, which revealed bigeminal premature ventricular contractions. Subsequent treadmill exercise testing at a tertiary center induced bidirectional ventricular tachycardia at a heart rate of 144 bpm, confirming the diagnosis of CPVT. Genetic testing identified a pathogenic ryanodine receptor 2 ( RYR2) variant (c.11836G > A, p.Gly3946Ser). Treatment with nadolol and flecainide was initiated, levetiracetam was discontinued, and she has remained free of syncope and seizure-like episodes for >2 years. Conclusion This case highlights the diagnostic challenges of CPVT, and underscores the need for specialized evaluation, including repeat exercise testing under varying conditions, in children with exercise- or emotion-induced T-LOC suggestive of cardiac syncope.
2026-08-11 | Gain-of-function mutation of type 2 ryanodine receptor attenuates dopaminergic neuron development associated with Ca2+ overload-triggered oxidative damage in mitochondria.
Type 2 ryanodine receptor (RyR2), a Ca2+ release channel located in the endoplasmic reticulum (ER) membrane, expresses catecholamine-induced polymorphic ventricular tachycardia (CPVT), and is a potential risk factor of autism spectrum disorder (ASD). However, the pathological relationship between RyR2 mutation-induced Ca2+ dysregulation and ASD pathology remains unclear. This study examined the association between CPVT-related RyR2 mutations and ASD pathology to determine its dopaminergic pathological role in ASD. Patient-derived stem cells from human exfoliated deciduous teeth were obtained from a boy with comorbid CPVT and ASD, and differentiated to dopaminergic neurons (RyR2-DNs). Two heterozygous missense mutations were identified in RyR2: c.9910C > G, p.Q3304E in exon 69 and c.14222C > T, p.A4741V in exon 99 (RyR269/99). RyR2-DNs showed cytosolic and mitochondrial Ca2+ accumulation, and impaired neurite outgrowth, suggesting that RyR269/99 is a gain-of-function mutation that promotes Ca2+ release from the ER and attenuates neurite development. RyR2-DNs also exhibited increased mitochondrial reactive oxygen species along with impaired mitochondrial oxidative phosphorylation. These mitochondrial abnormalities and neurite outgrowth were managed by pharmacological intervention of mitochondrial Ca2+ accumulation. Thus, RyR2 hyper-activation-induced mitochondrial Ca2+ overload may cause oxidative stress-related mitochondrial dysfunction, impairing DN development and dopaminergic dysregulation in ASD.
2026-08-06 | Case Report: Overlap of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia in two Chinese children with CALM2-related calmodulinopathy.
Calmodulinopathy is a rare CALM-related hereditary channelopathy presenting with long QT syndrome (LQTS), less commonly with catecholaminergic polymorphic ventricular tachycardia (CPVT) or LQTS/CPVT overlap. It carries high mortality and limited data from Chinese population. We reviewed two Chinese children with CALM2 mutation-related LQTS/CPVT overlap. Clinical data, genetic findings, and treatments were collected; outcomes were obtained via telephone follow-up. A systematic literature review was also performed. Case 1 was a 13-year-old girl with seven exercise-induced syncopal episodes. Sinus rhythm QTc 0.55 s, with bidirectional/polymorphic premature ventricular contractions, and ventricular tachycardia during exercise. A de novo CALM2 p.E140Q mutation was found. She remained event-free on propranolol and propafenone for two years. Case 2 was a 15-year-old boy with onset at 4 years. He experienced > 10 syncopal episodes triggered by recurrent exercise or emotional stress. Initial Holter monitoring revealed sinus bradycardia with a mean heart rate of 70 bpm and a maximum QTc of 0.51 s. A de novo CALM2 p.N98S mutation was found. Despite treatment with propranolol plus mexiletine, syncopal episodes continued, with the QTc interval further prolonged to 0.62 s. The p.E140Q variant is novel, whereas p.N98S has been previously reported. Literature suggests that β-blockers combined with Class Ic drugs may be more effective, and implantable cardioverter defibrillator (ICD) implantation should be considered in cases who respond poorly to medical therapy or survivors of aborted cardiac arrest. Patients who experience recurrent syncope coexisting with significant sinus bradycardia may have more severe phenotypes with higher risk of malignant arrhythmias, warranting earlier or more aggressive evaluation for device therapy. Genetic testing is recommended for suspected pediatric channelopathies with phenotype-guided individualized treatment.
gene therapies
2026-08-31 | Evaluating the Therapeutic Potential of Gene Therapy for RyR2 and CASQ2 Gene Mutations in Catecholaminergic Polymorphic Ventricular Tachycardia
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a rare inherited cardiac arrhythmia characterized by adrenergically induced ventricular tachycardia and sudden cardiac death in structurally normal hearts.The current medical therapies, like non-cardioselective beta blockers, flecainide, calcium channel blockers, dantrolene, implantable cardioverter-defibrillators (ICDs), and left cardiac sympathetic denervation (LCSD), reduce risk but do not reliably prevent lifethreatening arrhythmic events.Breakthrough arrhythmias, device complications, and variable response to the medical therapies show the limitations of approaches that do not address the underlying molecular defect.This literature review combines preclinical and clinical literature on gene therapy strategies that directly target genetic defects that characterize CPVT.Experimental work in mouse and cell models demonstrates effective gene transfer, allele-specific silencing, CRISPR/Cas9-mediated editing, and CaMKII inhibition.These gene therapies normalize sarcoplasmic reticulum calcium handling and reduce ventricular arrhythmia burden.There have been some major breakthroughs, including SGT-501, a gene therapy designed to deliver a CASQ2 gene replacement to cardiomyocytes.These results support gene therapy as a mainline treatment rather than having a supporting role.These advancements represent a promising path towards a permanent gene therapy for CPVT, but careful assessment of the efficacy of treatments remains essential before widespread adoption.
2026-07-27 | Targeting the heart: CRISPR/Cas9-VPR mediated concurrent knockout and activation to treat cardiac diseases, exemplified by a gene therapy strategy for CPVT
Background: Cardiovascular diseases are the leading cause of death worldwide. Lifelong restrictions and often inadequate pharmacotherapeutic treatment put a heavy burden on patients and healthcare systems and leave many patients at constant risk of fatal cardiac events. In contrast, gene therapy offers potential cures for inherited or acquired cardiac diseases with currently nonexistent or limited treatment options, including heart failure, cardiomyopathies, and channelopathies, via a single application. Recombinant adeno-associated-virus (AAV) mediated in vivo transgene delivery is currently the gold standard for gene therapy. Yet, insufficient cardiac vector delivery, the small packaging capacity of 4.7 kb, and a lack of therapeutic approaches for diseases caused by gain-of-function mutations limit clinical applications. Thus, to date, no gene therapy for cardiac diseases has been approved, which illustrates the unmet need for further development of current approaches. Aims and methods: 1) AAV capsid engineering can be used to optimize cardiac transduction efficiency and specificity. Here, the tropism of four novel AAV9-based capsid variants carrying small peptide insertions was investigated in mice. 2) By initially implementing the recently developed dual rAAV-vector approach utilizing reconstitution via mRNA trans-splicing (REVeRT) in a heart context, we aimed to enable an efficient cardiac delivery of large transgenes. 3) Moreover, CRISPR/Cas9-VPR-mediated concurrent knockdown and activation (CONNACT) by single guide RNA multiplexing was evaluated as an innovative mutation-independent strategy to treat cardiac diseases with gain-of-function mutation origin. As such, catecholaminergic polymorphic ventricular tachycardia 1 (CPVT1), which is caused by gain-of-function mutations in the RYR2 gene, was addressed via a heart-specific knockout of Ryr2 and transactivation of Ryr1 via CONNACT as a novel gene therapeutical approach. Results: 1) The cardiac transduction efficacy of the novel AAV9 variants was comparable or inferior to that of the parental AAV9 capsid when administered intraperitoneally. 2) The dual REVeRT vector technology, combined with a cardiac-specific promoter, resulted in exceptional rates of up to 76% successfully targeted cardiomyocytes. 3) In the therapeutical approach, dual REVeRT vector-mediated delivery of CIRSPR/Cas9-VPR demonstrated a proof-of-concept for CONNACT in cardiac tissue. Ryr2 knockout could be linked to ER stress and SR disruption in mature cardiomyocytes, while Ryr1 activation showed no adverse effect. However, RYR1 could not functionally compensate for RYR2. Conclusion: This study demonstrates the power of REVeRT and CONNACT as valuable technologies for the development of cardiac gene therapies but indicates that the choice of analog proteins for functional compensation requires extensive preclinical work. Furthermore, our findings shed light on the impact of RYR2 depletion and RYR1 expression in mature cardiomyocytes.
2026-06-01 | Gene therapy for catecholaminergic polymorphic ventricular tachycardia (CPVT): IND-enabling data and design of the ARTEMIS Phase 1b clinical trial
Abstract Background CPVT is a rare, inherited disorder characterized by life-threatening ventricular arrhythmias triggered by exercise or emotional stress. Current treatments fail to address the underlying cause, are associated with significant side effects, and require strict compliance. CPVT is most commonly caused by mutations in the ryanodine receptor 2 (RYR2) gene, which regulates calcium (Ca2+) release from the sarcoplasmic reticulum (SR) during excitation–contraction coupling. Arrhythmias in CPVT occur due to diastolic leak of Ca2+ through RYR2 into the cytosol leading to delayed afterdepolarizations, which cause ventricular tachycardia (VT) or fibrillation. Calsequestrin 2 (CASQ2) is a closely associated protein in the SR that stabilizes the RYR2 channel in the closed state and increases buffering of Ca2+, thus preventing abnormal Ca2+ leak during diastole. We hypothesized that augmentation of CASQ2 levels may reduce diastolic Ca2+ flow through RYR2 and lead to a decrease in ventricular arrhythmias in a mouse model of CPVT as well as in CPVT patients with RYR2 mutations. Methods A gene therapy candidate (SGT-501) was developed using an AAV8 capsid to express human CASQ2 in cardiomyocytes (rAAV8-CASQ2). Cardiac efficacy was evaluated in RYR2 mutant mice (RYR2 R4496C/+) 3-months after a single IV infusion at a low, mid, or high dose. Long-term safety and biodistribution were assessed in non-human primates (NHPs) 6-months post-dosing. The planned first-in-human ARTEMIS trial aims to evaluate the safety, tolerability, and efficacy of a single IV dose of SGT-501 in patients with pathogenic or likely pathogenic mutations in RYR2 associated with CPVT. The primary objective will be to assess the incidence of treatment-emergent adverse events. Other objectives include measuring changes in the Ventricular Arrhythmia Score (VAS) during exercise. This multicenter open-label study will have 2 adult cohorts followed by a pediatric cohort. Results In RYR2 R4496C/+ mice, bioanalytical analysis demonstrated a clear dose-responsive impact on vector genomes, CASQ2 mRNA, and CASQ2 protein expression. Following a beta-adrenergic challenge (2mg/kg epinephrine and 120mg/kg caffeine), ECG analysis revealed an SGT-501 dose-dependent decrease in the incidence of VT. A significant decrease in VT incidence was observed at the mid dose (4/25, 16%) and high dose (1/28, 4%) compared to vehicle (13/25, 52%), with cardiac CASQ2 protein levels measured at 1.6-fold and 6-fold above vehicle levels, respectively. In NHPs, SGT-501 was well tolerated across all dose levels with no adverse observations. Conclusions A single administration of SGT-501 is effective in rescuing electrophysiological abnormalities in a mouse model of CPVT and is well-tolerated in NHPs. This is the basis of the ARTEMIS trial, a first- in- human clinical trial evaluating the safety, tolerability, and preliminary efficacy of SGT-501 in patients with CPVT.
2026-01-27 | Genetics of Sudden Cardiac Death.
Cardiomyopathies (DCM, HCM, and ACM) and primary arrhythmogenic disorders (BrS, LQTS, and CPVT) represent the most common causes of sudden cardiac death (SCD) in young individuals. Systematic genome-wide single-nucleotide polymorphism (SNP) analyses and genome-wide association studies (GWASs) have enabled the identification of numerous genetic variants associated with cardiovascular diseases. Body: Genetic testing for cardiomyopathies and inherited channelopathies primarily involves panel testing of genes with definitive and strong evidence of disease association; genes supported by moderate evidence may also be considered. Cardiomyocytes express a variety of proteins implicated in the pathogenesis of genetic cardiomyopathies, including sarcomeric, cytoskeletal, desmosomal, and nuclear envelope proteins. Inherited cardiac channelopathies result from mutations in genes encoding cellular components that influence calcium ion availability or affect membrane ion channels, including sodium, potassium, and calcium channels. Common variants associated with SCD are found in genes encoding cardiac ion channels (e.g., SCN5A, KCNQ1, and KCNH2), calmodulin (CALM2), sarcomeric proteins (MYH7, MYBPC3, TTN, and TNNI3), and desmosomal proteins (RyR2 and DES). This review demonstrates that specific genetic variants are significantly associated with an increased risk of SCD. The evidence underscores the importance of genetic screening and early intervention in individuals with a family history of SCD or other risk factors for inherited cardiac disorders predisposing to SCD. Future research should focus on gene-specific management strategies for familial cardiomyopathies and inherited channelopathies, with the goal of improving targeted genetic therapies and reducing the burden of sudden cardiac death.
2025-10-30 | Gene Therapy for Inherited Cardiac Arrhythmias.
Inherited cardiac arrhythmias are genetic disorders that impact the heart's electrical circuitry. These disorders are caused by inherited mutations and markedly increase the mortality risk of affected individuals. Conventional treatments, such as pharmacological agents for rate and rhythm control or surgical interventions, are often not efficacious and cause long-term complications. Gene therapy has recently emerged as a feasible and potentially curative approach for treating inherited cardiac arrhythmia syndromes. Advancements in elucidating the molecular mechanisms, pinpointing essential candidate genes, and improving gene delivery have rendered gene therapy as a feasible treatment alternative. This review examines recent studies on gene therapy applications in Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, familial atrial fibrillation, and arrhythmogenic cardiomyopathy. Additionally, we analyze current advancements in viral and non-viral gene delivery methods, highlighting their therapeutic potential and related challenges.
proteins
2026-05-07 | An RYR2-interacting fragment of MYBPC3 mitigates arrhythmia in human iPSC-CM and mouse models of CPVT.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia caused by pathogenic variants in RYR2 that increase its diastolic Ca2+ release. Current standard of care is insufficient to protect patients from ventricular tachycardia (VT) and sudden death. We identified RYR2 interaction with a subset of MYBPC3 in cardiomyocytes and validated this interaction by immunostaining, proximity ligation assay, and co-immunoprecipitation. Adeno-associated virus serotype 9 (AAV9)-mediated MYBPC3 overexpression reduced VT in Ryr2R176Q/+ mice, a model of CPVT. We identified a C-terminal fragment of MYBPC3, C6C10Δ, that is sufficient for RYR2 interaction and anti-arrhythmic activity. Recombinant C6C10Δ reduced the probability of open RYR2-R176Q channels in lipid bilayer single-channel recordings, and virally delivered C6C10Δ reduced VT inducibility and duration in the CPVT mouse model and in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) harboring several different CPVT-causing RYR2 variants. In wild-type mice, MyoAAV4E-C6C10Δ did not detectably affect cardiac morphology or systolic function. However, a proportion of MyoAAV4E-C6C10Δ-treated wild-type mice exhibited inducible VT, suggesting pro-arrhythmic potential that warrants further study. Together, these findings demonstrate that a subset of MYBPC3 interacts with RYR2 and that this interaction may be therapeutically exploited to develop CPVT gene therapy.
2026-03-28 | Structural and Functional Regulation of RyR2 in Cardiac Calcium Handling and Arrhythmogenesis.
Cardiac Ca2+ handling is critical for excitation-contraction coupling (ECC), with the ryanodine receptor type 2 (RyR2) serving as the key sarcoplasmic reticulum (SR) Ca2+ release channel in cardiomyocytes. The dysfunction of RyR2 is linked to fatal cardiac arrhythmias, including heart failure (HF) and catecholaminergic polymorphic ventricular tachycardia (CPVT). This review aims to elucidate the structural basis of RyR2, its core role in cardiac ECC and Ca2+ homeostasis, and the regulatory mechanisms of key modulators on its activity. By integrating recent high-resolution cryo-EM structural analyses with molecular and cellular studies on RyR2 regulation, as well as clinical evidence of RyR2 mutations in arrhythmogenic heart diseases, we provide a comprehensive overview of the field. Cryo-EM has unraveled RyR2's gating mechanisms, ligand-binding sites, and structural features. Functionally, RyR2 mediates calcium-induced calcium release (CICR) and maintains Ca2+ homeostasis through coordination with SERCA2a and NCX. Key modulators (CaM, FKBP12.6, and PKA/CaMKII) and disease-linked mutations regulate RyR2 activity through distinct pathways, with defective RyR2 leading to store-overload-induced Ca2+ release (SOICR) and arrhythmias. Furthermore, reactive oxygen species (ROS) can induce RyR2 oxidation, establishing a pathological Ca2+ leak-ROS cycle in heart disease. In conclusion, RyR2 is a pivotal sensor of myocardial function, with its structural and regulatory mechanisms now well-characterized by recent studies. However, the effects of numerous RyR2 mutations remain unclear, and deeper mechanistic insights will lay a key foundation for developing novel therapies against RyR2-related cardiac diseases.
2025-10-20 | Direct Therapeutic Modulation of RYR2 Activity by CMYA5.
A domain of CMYA5 (RID) is a novel RYR2 regulator. RID overexpression reduced arrhythmias in CPVT disease models.
2022-01-15 | CPVT-associated calmodulin variants N53I and A102V dysregulate Ca2+ signalling via different mechanisms
ABSTRACT Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited condition that can cause fatal cardiac arrhythmia. Human mutations in the Ca2+ sensor calmodulin (CaM) have been associated with CPVT susceptibility, suggesting that CaM dysfunction is a key driver of the disease. However, the detailed molecular mechanism remains unclear. Focusing on the interaction with the cardiac ryanodine receptor (RyR2), we determined the effect of CPVT-associated variants N53I and A102V on the structural characteristics of CaM and on Ca2+ fluxes in live cells. We provide novel data showing that interaction of both Ca2+/CaM-N53I and Ca2+/CaM-A102V with the RyR2 binding domain is decreased. Ca2+/CaM–RyR23583-3603 high-resolution crystal structures highlight subtle conformational changes for the N53I variant, with A102V being similar to wild type (WT). We show that co-expression of CaM-N53I or CaM-A102V with RyR2 in HEK293 cells significantly increased the duration of Ca2+ events; CaM-A102V exhibited a lower frequency of Ca2+ oscillations. In addition, we show that CaMKIIδ (also known as CAMK2D) phosphorylation activity is increased for A102V, compared to CaM-WT. This paper provides novel insight into the molecular mechanisms of CPVT-associated CaM variants and will facilitate the development of strategies for future therapies.
2021-10-20 | Computational Analysis of Binding Interactions between the Ryanodine Receptor Type 2 and Calmodulin.
Mutations in the cardiac ryanodine receptor type 2 (RyR2) have been linked to a variety of cardiac arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). RyR2 is regulated by calmodulin (CaM), and mutations that disrupt their interaction can cause aberrant calcium release, leading to an arrhythmia. It was recently shown that increasing the RyR2-CaM binding affinity could rescue a defective CPVT-related RyR2 channel to near wild-type behavior. However, the interactions that determine the binding affinity at the RyR2-CaM binding interface are not well understood. In this study, we identify the key domains and interactions, including several new interactions, involved in the binding of CaM to RyR2. Also, our comparison between the wild-type and V3599K mutant suggests how the RyR2-CaM binding affinity can be increased via a change in the central and N-terminal lobe binding contacts for CaM. This computational approach provides new insights into the effect of a mutation at the RyR2-CaM binding interface, and it may find utility in drug design for the future treatment of cardiac arrhythmias.
cell therapies
2026-03-12 | Bilateral Cardiac Sympathetic Denervation in Inherited Cardiac Arrhythmias
ABSTRACT Background Bilateral cardiac sympathetic denervation (BCSD) is infrequently used for long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), and its efficacy remains uncertain. Method We evaluated BCSD outcomes in these patients. Result Among three CPVT cases, none experienced preoperative syncope, fatal events, or appropriate ICD shocks after BCSD. In LQTS, syncope resolved in the LQT2/5 and LQT3 cases; the LQT3 patient with fetal‐onset ventricular fibrillation was discharged after mexiletine infusion, ICD implantation, and BCSD. Conclusion BCSD yielded meaningful only mild adverse effects in both CPVT and LQTS.
2026-03-10 | Paediatric inherited arrhythmia clinic: developing a new model of care.
To describe the development and utilisation of a paediatric inherited arrhythmia clinic (IAC) from 2014 to 2024, including service developments following the introduction of cardiac genetic coordinators (CGC). Retrospective cohort study. The IAC at Children's Hospital Westmead, New South Wales, Australia (approximately 8 million people). Children (aged 0-18 years) referred to the IAC. Clinical and genetic data were extracted and analysed. Description of the development and cohort of the clinic. A monthly clinic preceded by a team meeting (multidisciplinary team) led by a paediatric cardiologist and clinical geneticist was established. Attendees included a genetic counsellor, senior arrhythmia nurse and clinical psychologist.A total of 301 individuals aged 0-18 years were seen over 11 years: 32 in 2014 and 128 in 2024. 85 probands presented with cardiac arrest (37; 44%), syncope (23; 27%) and others (25; 29%). The most common diagnoses were Long QT syndrome 33 (38%), catecholaminergic polymorphic ventricular tachycardia 24 (28%) and Brugada syndrome 6 (7%). 226/301 children had genetic testing; pathogenic/likely pathogenic variants were found in 173/226 (77%), including 121 family members. The most common genes implicated were KCNQ1 (67), KCNH2 (39), SCN5A (28) and RyR2 (15).Dedicated allied health/nursing CGCs appointed in 2023 improved the collation of clinical/family data (particularly new referrals), links to adult cardiology, forensic and regional genetic and paediatric services. The multidisciplinary IAC achieves the phenotyping, genotyping and holistic care of large numbers of children, mostly with cardiac ion channelopathies. Dedicated coordinators provided an incremental improvement to the service.
2026-02-13 | [Cardiac arrhythmias-Cellular mechanisms, consequences and challenges in the diagnostics using human models].
Cardiac arrhythmias significantly contribute to morbidity and mortality in cardiovascular diseases. Hereditary ion channel disorders, including Brugada syndrome, long/short QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT), represent critical entities with elevated risk of malignant ventricular arrhythmias. Although beta-blockers, ion channel modulators and implantable cardioverter defibrillators (ICD) are available and the indications for them are increasingly based on genetic analyses, variants of uncertain significance (VUS) substantially impair the risk stratification. Atrial tachyarrhythmias, particular atrial fibrillation, can cause an often-reversible arrhythmia-induced cardiomyopathy (AIC). Pathophysiologically, the Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays an important role in atrial and ventricular arrhythmias. It can be activated by various pathological triggers, such as high heart rate, neuroendocrine activation and oxidative stress, the latter often resulting from mechano-energetic uncoupling. The development of effective treatment options for arrhythmia-associated cardiovascular diseases requires the use of human model systems in addition to animal experimental approaches, due to the genetic heterogeneity and systemic comorbidities. Patient-specific cardiac stem cell-models enable the classification of VUS and personalised drug testing. The integration of new methodological approaches into existing animal experimental approaches thus paves the way for functionally validated precision medicine and could fundamentally transform the treatment of both disease patterns.
2025-05-01 | Cardiac sympathetic denervation for different cardiovascular indications - the experience of two referral centers
Abstract Cardiac sympathetic denervation (CSD) reduces risk of ventricular tachyarrhythmias (VTA in long-QT syndrome, catecholaminergic polymorphic ventricular tachycardia and cardiomyopathies. CSD has also a theoretical potential to be alleviate symptoms in other disorders dependent on adrenergic input. The aim of this study was to assess efficacy and safety of bilateral CSD (BCSD) procedure performed for wide range of cardiovascular disorders. Apart form efficacy of CSD also physical and psychological consequences and patient satisfaction were studied. Methods and results Between 2018 - 2024 51 patients were qualified for BCSD in 2 centers in Poland. The median age of patients was 46,8 (range 17-78) years, 26 were males, 22 had prior ICD implants. In 4 cardioneuroablation was also performed. In 49 patients video- and in 2 robot-assisted BCSD ob T1-T4(5) chain was performed for recurrent VTA or electric storm in 41, coronary spam (5), Takotsubo cardiomyopathy (1), inappropriate sinus tachycardia (1) and Raynaud syndrome (9) . Several patients had multiple indications. In two patients with DCM VTA recurred within a week after CSD and also thereafter. There were 5 deaths on follow-up in the course of underlying disease, none was linked directly to BCSD. One death occurred in a patient in whom CSD was a last resort for refractory VT storm. Persistent neuropathic pain was the main adverse effect reported by patients. In the group of patients in whom both CSD and CNA wee performed no serious AE were observed. Conclusions BiCSD is an effective when performed for various cardiovascular indications such as recurrent ventricular tachyarrytmias, coronary spasm and Raynaud syndrome. BCSD is also well tolerated by majority of patients. The failure of antiarrhythmic effect shortly after the procedure in 2 patients with dilated cardiomyopathy and low EF needs to be elucidated in further studies.
2025-04-24 | Stellate Ganglia: A Key Therapeutic Target for Malignant Ventricular Arrhythmia in Heart Disease.
Malignant ventricular arrhythmias (VAs), such as ventricular tachycardia and ventricular fibrillation, are the cause of approximately half a million deaths per year in the United States, which is a common lethal event in heart disease, such as hypertension, catecholaminergic polymorphic ventricular tachycardia, takotsubo cardiomyopathy, long-QT syndrome, and progressing into advanced heart failure. A common characteristic of these heart diseases, and the subsequent development of VAs, is the overactivation of the sympathetic nervous system. Current treatments for VAs in these heart diseases, such as β-adrenergic receptor blockers and cardiac sympathetic ablation, aim at inhibiting cardiac sympathetic overactivation. However, these treatments do not translate into becoming efficacious as long-term suppressors of ventricular tachycardia/ventricular fibrillation events. As a key regulatory component in the heart, cardiac postganglionic sympathetic neurons residing in the stellate ganglia (SGs) release neurotransmitters (such as norepinephrine and NPY [neuropeptide Y]) to perform their regulatory role in dictating cardiac function. Growing evidence from animal experiments and clinical studies has demonstrated that the remodeling of the SG may be intimately involved in malignant arrhythmogenesis. This identifies the SG as a key potential therapeutic target for the treatment of malignant VAs in heart disease. Therefore, this review summarizes the role of SG in ventricular arrhythmogenesis and updates the novel targeting of SG for clinical treatment of VAs in heart disease.
other
2026-04-15 | Imaging and safety profiling of inhaled siRNA RyR2 in human respiratory models.
RNA therapeutics hold strong potential for treating genetic disease, yet progress is often limited by delivery, stability, and safety concerns. Here, we profile respiratory safety and cellular uptake of an inhaled siRNA targeting the cardiac RyR2 gene, which is responsible for catecholaminergic polymorphic ventricular tachycardia (CPVT), delivered via inhalation with calcium phosphate nanoparticles (CaP NPs). Barrier integrity, cytotoxicity, siRNA uptake, and immune activation, were assessed using a human 3D normal bronchial epithelial model (NHBE) under Air-Liquid Interphase (ALI) and dendritic cells (DCs), tested in monoculture and in co-culture. Barrier function, measured by transepithelial electrical resistance (TEER), remained stable after 48 h of exposure to 400 nM siRNA RyR2, scramble control, or CaP NPs, indicating preserved epithelial performance. Confocal imaging showed efficient internalization of Cy5-labeled siRNA in both mono- and co-cultures. Cytokine profiling revealed IL-8 release across all conditions in NHBE and NHBE + DC models, with IL-6 and TNF-α limited to immune-competent co-cultures; IFN-γ was below the limit of detection. No cytotoxicity was observed. Together, these data demonstrate that CaP NP-mediated delivery achieves robust siRNA uptake without compromising airway barrier integrity, while eliciting only modest, context-dependent immune responses (primarily IL-8 and TNF-α in the presence of DCs). This work supports the respiratory safety and translational potential of inhaled RyR2-targeting siRNA for CPVT.
2025-01-25 | A Novel Approach for In Vitro Testing and Hazard Evaluation of Nanoformulated RyR2-Targeting siRNA Drugs Using Human PBMCs.
Nucleic acid (NA)-based drugs are promising therapeutics agents. Beyond efficacy, addressing safety concerns-particularly those specific to this class of drugs-is crucial. Here, we propose an in vitro approach to screen for potential adverse off-target effects of NA-based drugs. Human peripheral blood mononuclear cells (PBMCs), purified from buffy coats of healthy donors, were used to investigate the ability of NA-drugs to trigger toxicity pathways and inappropriate immune stimulation. PBMCs were selected for their ability to represent potential human responses, given their likelihood of interacting with administered drugs. As proof of concept, a small interfering RNA (siRNA) targeting Ryanodine Receptor mRNA (RyR2) identified by the Italian National Center for Gene Therapy and Drugs based on RNA Technology as a potential therapeutic target for dominant catecholaminergic polymorphic ventricular tachycardia, was selected. This compound and its scramble were formulated within a calcium phosphate nanoparticle-based delivery system. Positive controls for four toxicity pathways were identified through literature review, each associated with a specific type of cellular stress: oxidative stress (tert-butyl hydroperoxide), mitochondrial stress (rotenone), endoplasmic reticulum stress (thapsigargin), and autophagy (rapamycin). These controls were used to define specific mRNA signatures triggered in PBMCs, which were subsequently used as indicators of off-target effects. To assess immune activation, the release of pro-inflammatory cytokines (interleukin-6, interleukin-8, tumor necrosis factor-α, and interferon-γ) was measured 24 h after exposure. The proposed approach provides a rapid and effective screening method for identifying potential unintended effects in a relevant human model, which also allows to address gender effects and variability in responses.
2022-04-25 | Benefits in cardiac function by CD38 suppression: Improvement in NAD+ levels, exercise capacity, heart rate variability and protection against catecholamine-induced ventricular arrhythmias.
CD38 enzymatic activity regulates NAD+ and cADPR levels in mammalian tissues, and therefore has a prominent role in cellular metabolism and calcium homeostasis. Consequently, it is reasonable to hypothesize about its involvement in cardiovascular physiology as well as in heart related pathological conditions. To investigate the role of CD38 in cardiovascular performance, and its involvement in cardiac electrophysiology and calcium-handling. When submitted to a treadmill exhaustion test, a way of evaluating cardiovascular performance, adult male CD38KO mice showed better exercise capacity. This benefit was also obtained in genetically modified mice with catalytically inactive (CI) CD38 and in WT mice treated with antibody 68 (Ab68) which blocks CD38 activity. Hearts from these 3 groups (CD38KO, CD38CI and Ab68) showed increased NAD+ levels. When CD38KO mice were treated with FK866 which inhibits NAD+ biosynthesis, exercise capacity as well as NAD+ in heart tissue decreased to WT levels. Electrocardiograms of conscious unrestrained CD38KO and CD38CI mice showed lower basal heart rates and higher heart rate variability than WT mice. Although inactivation of CD38 in mice resulted in increased SERCA2a expression in the heart, the frequency of spontaneous calcium release from the sarcoplasmic reticulum under stressful conditions (high extracellular calcium concentration) was lower in CD38KO ventricular myocytes. When mice were challenged with caffeine-epinephrine, CD38KO mice had a lower incidence of bidirectional ventricular tachycardia when compared to WT ones. CD38 inhibition improves exercise performance by regulating NAD+ homeostasis. CD38 is involved in cardiovascular function since its genetic ablation decreases basal heart rate, increases heart rate variability and alters calcium handling in a way that protects mice from developing catecholamine induced ventricular arrhythmias.
2022-02-08 | Impact of cascade screening for catecholaminergic polymorphic ventricular tachycardia type 1
Human cardiac ryanodine receptor 2 (RYR2) shows autosomal-dominant inheritance in catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1); however, de novo variants have been observed in sporadic cases. Here, we investigated CPVT1-related RYR2 variant inheritance and its clinical significance between familial and de novo cases.We enrolled 82 independent CPVT1 probands (median age: 10.0 (7.0-13.0) years; 45 male) carrying the RYR2 variants and whose biological origin could be confirmed by parental genetic analysis: assured familial inheritance (familial group: n=24) and de novo variants (de novo group: n=58). We examined the clinical characteristics of the probands and their family members carrying the RYR2 variants.In the de novo group, the RYR2 variants were more likely located in the C-terminus domain and less likely in the N-terminus domain than those in the familial group. The cumulative incidence of the first cardiac events (syncope and cardiac arrest (CA) or CA only) of the probands at the age of 5 and 10 years was higher in the de novo group than in the familial group. Nearly half of the probands in both groups experienced CA events before diagnosis. Only 37.5% of their genotype-positive parents had symptoms; however, at least 66.7% of the genotype-positive siblings were symptomatic.CPVT1 probands harbouring de novo RYR2 variants showed an earlier onset of symptoms than those with assured familial inheritance. Cascade screening may enable early diagnosis, risk stratification and prophylactic therapeutic intervention to prevent sudden cardiac death of probands and potential genotype-positive family members.
2021-03-15 | Genetic Loss of IK1 Causes Adrenergic-Induced Phase 3 Early Afterdepolariz ations and Polymorphic and Bidirectional Ventricular Tachycardia.
Arrhythmia syndromes associated with KCNJ2 mutations have been described clinically; however, little is known of the underlying arrhythmia mechanism. We create the first patient inspired KCNJ2 transgenic mouse and study effects of this mutation on cardiac function, IK1, and Ca2+ handling, to determine the underlying cellular arrhythmic pathogenesis. A cardiac-specific KCNJ2-R67Q mouse was generated and bred for heterozygosity (R67Q+/-). Echocardiography was performed at rest, under anesthesia. In vivo ECG recording and whole heart optical mapping of intact hearts was performed before and after adrenergic stimulation in wild-type (WT) littermate controls and R67Q+/- mice. IK1 measurements, action potential characterization, and intracellular Ca2+ imaging from isolated ventricular myocytes at baseline and after adrenergic stimulation were performed in WT and R67Q+/- mice. R67Q+/- mice (n=17) showed normal cardiac function, structure, and baseline electrical activity compared with WT (n=10). Following epinephrine and caffeine, only the R67Q+/- mice had bidirectional ventricular tachycardia, ventricular tachycardia, frequent ventricular ectopy, and/or bigeminy and optical mapping demonstrated high prevalence of spontaneous and sustained ventricular arrhythmia. Both R67Q+/- (n=8) and WT myocytes (n=9) demonstrated typical n-shaped IK1IV relationship; however, following isoproterenol, max outward IK1 increased by ≈20% in WT but decreased by ≈24% in R67Q+/- (P<0.01). R67Q+/- myocytes (n=5) demonstrated prolonged action potential duration at 90% repolarization and after 10 nmol/L isoproterenol compared with WT (n=7; P<0.05). Ca2+ transient amplitude, 50% decay rate, and sarcoplasmic reticulum Ca2+ content were not different between WT (n=18) and R67Q+/- (n=16) myocytes. R67Q+/- myocytes (n=10) under adrenergic stimulation showed frequent spontaneous development of early afterdepolarizations that occurred at phase 3 of action potential repolarization. KCNJ2 mutation R67Q+/- causes adrenergic-dependent loss of IK1 during terminal repolarization and vulnerability to phase 3 early afterdepolarizations. This model clarifies a heretofore unknown arrhythmia mechanism and extends our understanding of treatment implications for patients with KCNJ2 mutation.
small molecules
2026-09-22 | Calpain-Dependent Protein Degradation Contributes to CASQ2-R33Q CPVT.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease associated with cardiac arrest in children and young adults. The recessive form of CPVT is caused by loss-of-function mutations in the genes encoding CASQ2 and TRDN, which, together with JCTN, regulate the release of calcium ions from the sarcoplasmic reticulum through the RyR2 (ryanodine receptor). The CASQ2 R33Q mutation causes calcium mishandling and ventricular tachycardia through triggered activity. The homozygous mouse model Casq2R33Q/R33Q closely replicates the clinical phenotype of patients with CPVT. In this model, CASQ2 (calsequestrin 2), TRDN (triadin), and JCTN (junctin) levels are markedly reduced; however, the mechanisms underlying this reduction and their contribution to CPVT are incompletely understood. We used a combination of proteomics, animal models, and experimental methods to identify the molecular mechanisms responsible for the decrease of couplon proteins in Casq2R33Q/R33Q mice and to explore their functional contribution to the disease. Casq2R33Q/R33Q hearts showed activation of endoplasmic reticulum stress, the unfolded protein response, and alterations in major proteolytic pathways. Inhibition of the proteasome or autophagy in neonatal cardiomyocytes and adult mice partially restored CASQ2 but not TRDN levels, suggesting distinct degradation mechanisms. In contrast, calpain inhibition restored CASQ2 and TRDN protein levels, decreased triggered activity in isolated cardiomyocytes, and reduced ventricular tachycardia episodes in vivo in Casq2R33Q/R33Q mice. Biochemical assays showed that TRDN is a direct calpain substrate. TRDN degradation preceded CASQ2 loss, and TRDN overexpression using modified RNA in cardiomyocytes or an adeno-associated viral vector in vivo increased CASQ2 levels in mutant mice, supporting an upstream role for TRDN destabilization. Couplon protein loss in CPVT associated with CASQ2-R33Q is mediated by coordinated but distinct proteolytic pathways, with calpain-dependent TRDN degradation representing a key pathogenic event that promotes CASQ2 destabilization and arrhythmogenesis.
2026-09-21 | Beta-Blockers for the Treatment of Arrhythmias: Which Drug for Which Arrhythmia? A State-of-the-Art Narrative Review.
Beta-blockers are among the most widely prescribed drugs in the management of both supraventricular and ventricular arrhythmias, and they are frequently regarded as a homogeneous pharmacological class. They are not. The agents in current use differ substantially in beta1-receptor selectivity, lipophilicity, half-life, route of administration, intrinsic sympathomimetic activity, and ancillary properties, and arrhythmias themselves differ in mechanism, adrenergic dependence, anatomical origin, and structural substrate. This narrative review examines whether these pharmacological differences translate into clinically meaningful differences in efficacy and utility, asking not only whether a beta-blocker should be used but which one should be used. Evidence was drawn from a targeted search of PubMed, Web of Science, Scopus, Ovid, Embase, and the Cochrane Library, with priority given to randomized controlled trials, meta-analyses, large registries, and contemporary society guidelines, and was synthesized qualitatively by arrhythmia type. A class effect is apparent for many indications, particularly rate control in atrial fibrillation and atrial flutter, where metoprolol, bisoprolol, and carvedilol perform broadly similarly and the choice is driven mainly by comorbidity and tolerability. Drug-specific differences emerge in three settings. In adrenergically mediated inherited syndromes, namely catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, nonselective agents and especially nadolol are clearly superior to beta1-selective agents, and the same principle appears to extend to ventricular electrical storm, in which propranolol has outperformed metoprolol in a randomized comparison. In acute care, pharmacokinetics dominate, and the ultra-short-acting agents esmolol and landiolol permit a degree of titration that longer-acting drugs cannot match. In patients with heart failure and reduced ejection fraction, carvedilol, metoprolol succinate, and bisoprolol should be preferred irrespective of arrhythmia subtype because of their established mortality benefit. Conversely, beta1-selective agents, including the highly selective agent nebivolol, improve tolerability in bronchospastic disease, although this reflects respiratory tolerability rather than any demonstrated antiarrhythmic advantage, and beta-blockers have little role in Brugada syndrome or in bradycardia-dependent acquired torsades de pointes. Beta-blockers should therefore not be treated as interchangeable. Selection should integrate arrhythmic mechanism, structural substrate, and patient characteristics, and head-to-head trials remain conspicuously scarce.
2026-09-18 | Catecholaminergic polymorphic ventricular tachycardia with diagnostic difficulty differentiating seizures from syncope: a case report
Introduction Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially fatal inherited arrhythmia syndrome triggered by exercise or emotional stress that may mimic epileptic seizures, resulting in delayed diagnosis. Case presentation We report the case of a 6-year-old girl with recurrent transient loss of consciousness (T-LOC) who was initially misdiagnosed with epilepsy. She experienced three episodes of T-LOC between 4 and 6 years of age. The first two episodes occurred during or immediately post-exercise, whereas the third appeared non-exertional; however, retrospective review suggested fear-induced sympathetic activation as the trigger. During the second and third episodes, she exhibited eye opening, fixed gaze, and tonic posturing, closely resembling epileptic seizures. Interictal electroencephalography was normal, resting electrocardiography (ECG) showed sinus bradycardia without QT prolongation, and an initial Master's triple two-step exercise test increased the heart rate to only 74 beats per minute (bpm) without inducing arrhythmia. She was provisionally diagnosed with epilepsy, and a diagnostic trial of levetiracetam was initiated. Four months later, school-based ECG screening, prompted by her history of seizure-like episodes with impaired consciousness, led to further cardiac evaluation, which revealed bigeminal premature ventricular contractions. Subsequent treadmill exercise testing at a tertiary center induced bidirectional ventricular tachycardia at a heart rate of 144 bpm, confirming the diagnosis of CPVT. Genetic testing identified a pathogenic ryanodine receptor 2 ( RYR2) variant (c.11836G > A, p.Gly3946Ser). Treatment with nadolol and flecainide was initiated, levetiracetam was discontinued, and she has remained free of syncope and seizure-like episodes for >2 years. Conclusion This case highlights the diagnostic challenges of CPVT, and underscores the need for specialized evaluation, including repeat exercise testing under varying conditions, in children with exercise- or emotion-induced T-LOC suggestive of cardiac syncope.
2026-08-11 | Gain-of-function mutation of type 2 ryanodine receptor attenuates dopaminergic neuron development associated with Ca2+ overload-triggered oxidative damage in mitochondria.
Type 2 ryanodine receptor (RyR2), a Ca2+ release channel located in the endoplasmic reticulum (ER) membrane, expresses catecholamine-induced polymorphic ventricular tachycardia (CPVT), and is a potential risk factor of autism spectrum disorder (ASD). However, the pathological relationship between RyR2 mutation-induced Ca2+ dysregulation and ASD pathology remains unclear. This study examined the association between CPVT-related RyR2 mutations and ASD pathology to determine its dopaminergic pathological role in ASD. Patient-derived stem cells from human exfoliated deciduous teeth were obtained from a boy with comorbid CPVT and ASD, and differentiated to dopaminergic neurons (RyR2-DNs). Two heterozygous missense mutations were identified in RyR2: c.9910C > G, p.Q3304E in exon 69 and c.14222C > T, p.A4741V in exon 99 (RyR269/99). RyR2-DNs showed cytosolic and mitochondrial Ca2+ accumulation, and impaired neurite outgrowth, suggesting that RyR269/99 is a gain-of-function mutation that promotes Ca2+ release from the ER and attenuates neurite development. RyR2-DNs also exhibited increased mitochondrial reactive oxygen species along with impaired mitochondrial oxidative phosphorylation. These mitochondrial abnormalities and neurite outgrowth were managed by pharmacological intervention of mitochondrial Ca2+ accumulation. Thus, RyR2 hyper-activation-induced mitochondrial Ca2+ overload may cause oxidative stress-related mitochondrial dysfunction, impairing DN development and dopaminergic dysregulation in ASD.
2026-08-06 | Case Report: Overlap of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia in two Chinese children with CALM2-related calmodulinopathy.
Calmodulinopathy is a rare CALM-related hereditary channelopathy presenting with long QT syndrome (LQTS), less commonly with catecholaminergic polymorphic ventricular tachycardia (CPVT) or LQTS/CPVT overlap. It carries high mortality and limited data from Chinese population. We reviewed two Chinese children with CALM2 mutation-related LQTS/CPVT overlap. Clinical data, genetic findings, and treatments were collected; outcomes were obtained via telephone follow-up. A systematic literature review was also performed. Case 1 was a 13-year-old girl with seven exercise-induced syncopal episodes. Sinus rhythm QTc 0.55 s, with bidirectional/polymorphic premature ventricular contractions, and ventricular tachycardia during exercise. A de novo CALM2 p.E140Q mutation was found. She remained event-free on propranolol and propafenone for two years. Case 2 was a 15-year-old boy with onset at 4 years. He experienced > 10 syncopal episodes triggered by recurrent exercise or emotional stress. Initial Holter monitoring revealed sinus bradycardia with a mean heart rate of 70 bpm and a maximum QTc of 0.51 s. A de novo CALM2 p.N98S mutation was found. Despite treatment with propranolol plus mexiletine, syncopal episodes continued, with the QTc interval further prolonged to 0.62 s. The p.E140Q variant is novel, whereas p.N98S has been previously reported. Literature suggests that β-blockers combined with Class Ic drugs may be more effective, and implantable cardioverter defibrillator (ICD) implantation should be considered in cases who respond poorly to medical therapy or survivors of aborted cardiac arrest. Patients who experience recurrent syncope coexisting with significant sinus bradycardia may have more severe phenotypes with higher risk of malignant arrhythmias, warranting earlier or more aggressive evaluation for device therapy. Genetic testing is recommended for suspected pediatric channelopathies with phenotype-guided individualized treatment.
gene therapies
2026-08-31 | Evaluating the Therapeutic Potential of Gene Therapy for RyR2 and CASQ2 Gene Mutations in Catecholaminergic Polymorphic Ventricular Tachycardia
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a rare inherited cardiac arrhythmia characterized by adrenergically induced ventricular tachycardia and sudden cardiac death in structurally normal hearts.The current medical therapies, like non-cardioselective beta blockers, flecainide, calcium channel blockers, dantrolene, implantable cardioverter-defibrillators (ICDs), and left cardiac sympathetic denervation (LCSD), reduce risk but do not reliably prevent lifethreatening arrhythmic events.Breakthrough arrhythmias, device complications, and variable response to the medical therapies show the limitations of approaches that do not address the underlying molecular defect.This literature review combines preclinical and clinical literature on gene therapy strategies that directly target genetic defects that characterize CPVT.Experimental work in mouse and cell models demonstrates effective gene transfer, allele-specific silencing, CRISPR/Cas9-mediated editing, and CaMKII inhibition.These gene therapies normalize sarcoplasmic reticulum calcium handling and reduce ventricular arrhythmia burden.There have been some major breakthroughs, including SGT-501, a gene therapy designed to deliver a CASQ2 gene replacement to cardiomyocytes.These results support gene therapy as a mainline treatment rather than having a supporting role.These advancements represent a promising path towards a permanent gene therapy for CPVT, but careful assessment of the efficacy of treatments remains essential before widespread adoption.
2026-07-27 | Targeting the heart: CRISPR/Cas9-VPR mediated concurrent knockout and activation to treat cardiac diseases, exemplified by a gene therapy strategy for CPVT
Background: Cardiovascular diseases are the leading cause of death worldwide. Lifelong restrictions and often inadequate pharmacotherapeutic treatment put a heavy burden on patients and healthcare systems and leave many patients at constant risk of fatal cardiac events. In contrast, gene therapy offers potential cures for inherited or acquired cardiac diseases with currently nonexistent or limited treatment options, including heart failure, cardiomyopathies, and channelopathies, via a single application. Recombinant adeno-associated-virus (AAV) mediated in vivo transgene delivery is currently the gold standard for gene therapy. Yet, insufficient cardiac vector delivery, the small packaging capacity of 4.7 kb, and a lack of therapeutic approaches for diseases caused by gain-of-function mutations limit clinical applications. Thus, to date, no gene therapy for cardiac diseases has been approved, which illustrates the unmet need for further development of current approaches. Aims and methods: 1) AAV capsid engineering can be used to optimize cardiac transduction efficiency and specificity. Here, the tropism of four novel AAV9-based capsid variants carrying small peptide insertions was investigated in mice. 2) By initially implementing the recently developed dual rAAV-vector approach utilizing reconstitution via mRNA trans-splicing (REVeRT) in a heart context, we aimed to enable an efficient cardiac delivery of large transgenes. 3) Moreover, CRISPR/Cas9-VPR-mediated concurrent knockdown and activation (CONNACT) by single guide RNA multiplexing was evaluated as an innovative mutation-independent strategy to treat cardiac diseases with gain-of-function mutation origin. As such, catecholaminergic polymorphic ventricular tachycardia 1 (CPVT1), which is caused by gain-of-function mutations in the RYR2 gene, was addressed via a heart-specific knockout of Ryr2 and transactivation of Ryr1 via CONNACT as a novel gene therapeutical approach. Results: 1) The cardiac transduction efficacy of the novel AAV9 variants was comparable or inferior to that of the parental AAV9 capsid when administered intraperitoneally. 2) The dual REVeRT vector technology, combined with a cardiac-specific promoter, resulted in exceptional rates of up to 76% successfully targeted cardiomyocytes. 3) In the therapeutical approach, dual REVeRT vector-mediated delivery of CIRSPR/Cas9-VPR demonstrated a proof-of-concept for CONNACT in cardiac tissue. Ryr2 knockout could be linked to ER stress and SR disruption in mature cardiomyocytes, while Ryr1 activation showed no adverse effect. However, RYR1 could not functionally compensate for RYR2. Conclusion: This study demonstrates the power of REVeRT and CONNACT as valuable technologies for the development of cardiac gene therapies but indicates that the choice of analog proteins for functional compensation requires extensive preclinical work. Furthermore, our findings shed light on the impact of RYR2 depletion and RYR1 expression in mature cardiomyocytes.
2026-06-01 | Gene therapy for catecholaminergic polymorphic ventricular tachycardia (CPVT): IND-enabling data and design of the ARTEMIS Phase 1b clinical trial
Abstract Background CPVT is a rare, inherited disorder characterized by life-threatening ventricular arrhythmias triggered by exercise or emotional stress. Current treatments fail to address the underlying cause, are associated with significant side effects, and require strict compliance. CPVT is most commonly caused by mutations in the ryanodine receptor 2 (RYR2) gene, which regulates calcium (Ca2+) release from the sarcoplasmic reticulum (SR) during excitation–contraction coupling. Arrhythmias in CPVT occur due to diastolic leak of Ca2+ through RYR2 into the cytosol leading to delayed afterdepolarizations, which cause ventricular tachycardia (VT) or fibrillation. Calsequestrin 2 (CASQ2) is a closely associated protein in the SR that stabilizes the RYR2 channel in the closed state and increases buffering of Ca2+, thus preventing abnormal Ca2+ leak during diastole. We hypothesized that augmentation of CASQ2 levels may reduce diastolic Ca2+ flow through RYR2 and lead to a decrease in ventricular arrhythmias in a mouse model of CPVT as well as in CPVT patients with RYR2 mutations. Methods A gene therapy candidate (SGT-501) was developed using an AAV8 capsid to express human CASQ2 in cardiomyocytes (rAAV8-CASQ2). Cardiac efficacy was evaluated in RYR2 mutant mice (RYR2 R4496C/+) 3-months after a single IV infusion at a low, mid, or high dose. Long-term safety and biodistribution were assessed in non-human primates (NHPs) 6-months post-dosing. The planned first-in-human ARTEMIS trial aims to evaluate the safety, tolerability, and efficacy of a single IV dose of SGT-501 in patients with pathogenic or likely pathogenic mutations in RYR2 associated with CPVT. The primary objective will be to assess the incidence of treatment-emergent adverse events. Other objectives include measuring changes in the Ventricular Arrhythmia Score (VAS) during exercise. This multicenter open-label study will have 2 adult cohorts followed by a pediatric cohort. Results In RYR2 R4496C/+ mice, bioanalytical analysis demonstrated a clear dose-responsive impact on vector genomes, CASQ2 mRNA, and CASQ2 protein expression. Following a beta-adrenergic challenge (2mg/kg epinephrine and 120mg/kg caffeine), ECG analysis revealed an SGT-501 dose-dependent decrease in the incidence of VT. A significant decrease in VT incidence was observed at the mid dose (4/25, 16%) and high dose (1/28, 4%) compared to vehicle (13/25, 52%), with cardiac CASQ2 protein levels measured at 1.6-fold and 6-fold above vehicle levels, respectively. In NHPs, SGT-501 was well tolerated across all dose levels with no adverse observations. Conclusions A single administration of SGT-501 is effective in rescuing electrophysiological abnormalities in a mouse model of CPVT and is well-tolerated in NHPs. This is the basis of the ARTEMIS trial, a first- in- human clinical trial evaluating the safety, tolerability, and preliminary efficacy of SGT-501 in patients with CPVT.
2026-01-27 | Genetics of Sudden Cardiac Death.
Cardiomyopathies (DCM, HCM, and ACM) and primary arrhythmogenic disorders (BrS, LQTS, and CPVT) represent the most common causes of sudden cardiac death (SCD) in young individuals. Systematic genome-wide single-nucleotide polymorphism (SNP) analyses and genome-wide association studies (GWASs) have enabled the identification of numerous genetic variants associated with cardiovascular diseases. Body: Genetic testing for cardiomyopathies and inherited channelopathies primarily involves panel testing of genes with definitive and strong evidence of disease association; genes supported by moderate evidence may also be considered. Cardiomyocytes express a variety of proteins implicated in the pathogenesis of genetic cardiomyopathies, including sarcomeric, cytoskeletal, desmosomal, and nuclear envelope proteins. Inherited cardiac channelopathies result from mutations in genes encoding cellular components that influence calcium ion availability or affect membrane ion channels, including sodium, potassium, and calcium channels. Common variants associated with SCD are found in genes encoding cardiac ion channels (e.g., SCN5A, KCNQ1, and KCNH2), calmodulin (CALM2), sarcomeric proteins (MYH7, MYBPC3, TTN, and TNNI3), and desmosomal proteins (RyR2 and DES). This review demonstrates that specific genetic variants are significantly associated with an increased risk of SCD. The evidence underscores the importance of genetic screening and early intervention in individuals with a family history of SCD or other risk factors for inherited cardiac disorders predisposing to SCD. Future research should focus on gene-specific management strategies for familial cardiomyopathies and inherited channelopathies, with the goal of improving targeted genetic therapies and reducing the burden of sudden cardiac death.
2025-10-30 | Gene Therapy for Inherited Cardiac Arrhythmias.
Inherited cardiac arrhythmias are genetic disorders that impact the heart's electrical circuitry. These disorders are caused by inherited mutations and markedly increase the mortality risk of affected individuals. Conventional treatments, such as pharmacological agents for rate and rhythm control or surgical interventions, are often not efficacious and cause long-term complications. Gene therapy has recently emerged as a feasible and potentially curative approach for treating inherited cardiac arrhythmia syndromes. Advancements in elucidating the molecular mechanisms, pinpointing essential candidate genes, and improving gene delivery have rendered gene therapy as a feasible treatment alternative. This review examines recent studies on gene therapy applications in Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, familial atrial fibrillation, and arrhythmogenic cardiomyopathy. Additionally, we analyze current advancements in viral and non-viral gene delivery methods, highlighting their therapeutic potential and related challenges.
proteins
2026-05-07 | An RYR2-interacting fragment of MYBPC3 mitigates arrhythmia in human iPSC-CM and mouse models of CPVT.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia caused by pathogenic variants in RYR2 that increase its diastolic Ca2+ release. Current standard of care is insufficient to protect patients from ventricular tachycardia (VT) and sudden death. We identified RYR2 interaction with a subset of MYBPC3 in cardiomyocytes and validated this interaction by immunostaining, proximity ligation assay, and co-immunoprecipitation. Adeno-associated virus serotype 9 (AAV9)-mediated MYBPC3 overexpression reduced VT in Ryr2R176Q/+ mice, a model of CPVT. We identified a C-terminal fragment of MYBPC3, C6C10Δ, that is sufficient for RYR2 interaction and anti-arrhythmic activity. Recombinant C6C10Δ reduced the probability of open RYR2-R176Q channels in lipid bilayer single-channel recordings, and virally delivered C6C10Δ reduced VT inducibility and duration in the CPVT mouse model and in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) harboring several different CPVT-causing RYR2 variants. In wild-type mice, MyoAAV4E-C6C10Δ did not detectably affect cardiac morphology or systolic function. However, a proportion of MyoAAV4E-C6C10Δ-treated wild-type mice exhibited inducible VT, suggesting pro-arrhythmic potential that warrants further study. Together, these findings demonstrate that a subset of MYBPC3 interacts with RYR2 and that this interaction may be therapeutically exploited to develop CPVT gene therapy.
2026-03-28 | Structural and Functional Regulation of RyR2 in Cardiac Calcium Handling and Arrhythmogenesis.
Cardiac Ca2+ handling is critical for excitation-contraction coupling (ECC), with the ryanodine receptor type 2 (RyR2) serving as the key sarcoplasmic reticulum (SR) Ca2+ release channel in cardiomyocytes. The dysfunction of RyR2 is linked to fatal cardiac arrhythmias, including heart failure (HF) and catecholaminergic polymorphic ventricular tachycardia (CPVT). This review aims to elucidate the structural basis of RyR2, its core role in cardiac ECC and Ca2+ homeostasis, and the regulatory mechanisms of key modulators on its activity. By integrating recent high-resolution cryo-EM structural analyses with molecular and cellular studies on RyR2 regulation, as well as clinical evidence of RyR2 mutations in arrhythmogenic heart diseases, we provide a comprehensive overview of the field. Cryo-EM has unraveled RyR2's gating mechanisms, ligand-binding sites, and structural features. Functionally, RyR2 mediates calcium-induced calcium release (CICR) and maintains Ca2+ homeostasis through coordination with SERCA2a and NCX. Key modulators (CaM, FKBP12.6, and PKA/CaMKII) and disease-linked mutations regulate RyR2 activity through distinct pathways, with defective RyR2 leading to store-overload-induced Ca2+ release (SOICR) and arrhythmias. Furthermore, reactive oxygen species (ROS) can induce RyR2 oxidation, establishing a pathological Ca2+ leak-ROS cycle in heart disease. In conclusion, RyR2 is a pivotal sensor of myocardial function, with its structural and regulatory mechanisms now well-characterized by recent studies. However, the effects of numerous RyR2 mutations remain unclear, and deeper mechanistic insights will lay a key foundation for developing novel therapies against RyR2-related cardiac diseases.
2025-10-20 | Direct Therapeutic Modulation of RYR2 Activity by CMYA5.
A domain of CMYA5 (RID) is a novel RYR2 regulator. RID overexpression reduced arrhythmias in CPVT disease models.
2022-01-15 | CPVT-associated calmodulin variants N53I and A102V dysregulate Ca2+ signalling via different mechanisms
ABSTRACT Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited condition that can cause fatal cardiac arrhythmia. Human mutations in the Ca2+ sensor calmodulin (CaM) have been associated with CPVT susceptibility, suggesting that CaM dysfunction is a key driver of the disease. However, the detailed molecular mechanism remains unclear. Focusing on the interaction with the cardiac ryanodine receptor (RyR2), we determined the effect of CPVT-associated variants N53I and A102V on the structural characteristics of CaM and on Ca2+ fluxes in live cells. We provide novel data showing that interaction of both Ca2+/CaM-N53I and Ca2+/CaM-A102V with the RyR2 binding domain is decreased. Ca2+/CaM–RyR23583-3603 high-resolution crystal structures highlight subtle conformational changes for the N53I variant, with A102V being similar to wild type (WT). We show that co-expression of CaM-N53I or CaM-A102V with RyR2 in HEK293 cells significantly increased the duration of Ca2+ events; CaM-A102V exhibited a lower frequency of Ca2+ oscillations. In addition, we show that CaMKIIδ (also known as CAMK2D) phosphorylation activity is increased for A102V, compared to CaM-WT. This paper provides novel insight into the molecular mechanisms of CPVT-associated CaM variants and will facilitate the development of strategies for future therapies.
2021-10-20 | Computational Analysis of Binding Interactions between the Ryanodine Receptor Type 2 and Calmodulin.
Mutations in the cardiac ryanodine receptor type 2 (RyR2) have been linked to a variety of cardiac arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). RyR2 is regulated by calmodulin (CaM), and mutations that disrupt their interaction can cause aberrant calcium release, leading to an arrhythmia. It was recently shown that increasing the RyR2-CaM binding affinity could rescue a defective CPVT-related RyR2 channel to near wild-type behavior. However, the interactions that determine the binding affinity at the RyR2-CaM binding interface are not well understood. In this study, we identify the key domains and interactions, including several new interactions, involved in the binding of CaM to RyR2. Also, our comparison between the wild-type and V3599K mutant suggests how the RyR2-CaM binding affinity can be increased via a change in the central and N-terminal lobe binding contacts for CaM. This computational approach provides new insights into the effect of a mutation at the RyR2-CaM binding interface, and it may find utility in drug design for the future treatment of cardiac arrhythmias.
cell therapies
2026-03-12 | Bilateral Cardiac Sympathetic Denervation in Inherited Cardiac Arrhythmias
ABSTRACT Background Bilateral cardiac sympathetic denervation (BCSD) is infrequently used for long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), and its efficacy remains uncertain. Method We evaluated BCSD outcomes in these patients. Result Among three CPVT cases, none experienced preoperative syncope, fatal events, or appropriate ICD shocks after BCSD. In LQTS, syncope resolved in the LQT2/5 and LQT3 cases; the LQT3 patient with fetal‐onset ventricular fibrillation was discharged after mexiletine infusion, ICD implantation, and BCSD. Conclusion BCSD yielded meaningful only mild adverse effects in both CPVT and LQTS.
2026-03-10 | Paediatric inherited arrhythmia clinic: developing a new model of care.
To describe the development and utilisation of a paediatric inherited arrhythmia clinic (IAC) from 2014 to 2024, including service developments following the introduction of cardiac genetic coordinators (CGC). Retrospective cohort study. The IAC at Children's Hospital Westmead, New South Wales, Australia (approximately 8 million people). Children (aged 0-18 years) referred to the IAC. Clinical and genetic data were extracted and analysed. Description of the development and cohort of the clinic. A monthly clinic preceded by a team meeting (multidisciplinary team) led by a paediatric cardiologist and clinical geneticist was established. Attendees included a genetic counsellor, senior arrhythmia nurse and clinical psychologist.A total of 301 individuals aged 0-18 years were seen over 11 years: 32 in 2014 and 128 in 2024. 85 probands presented with cardiac arrest (37; 44%), syncope (23; 27%) and others (25; 29%). The most common diagnoses were Long QT syndrome 33 (38%), catecholaminergic polymorphic ventricular tachycardia 24 (28%) and Brugada syndrome 6 (7%). 226/301 children had genetic testing; pathogenic/likely pathogenic variants were found in 173/226 (77%), including 121 family members. The most common genes implicated were KCNQ1 (67), KCNH2 (39), SCN5A (28) and RyR2 (15).Dedicated allied health/nursing CGCs appointed in 2023 improved the collation of clinical/family data (particularly new referrals), links to adult cardiology, forensic and regional genetic and paediatric services. The multidisciplinary IAC achieves the phenotyping, genotyping and holistic care of large numbers of children, mostly with cardiac ion channelopathies. Dedicated coordinators provided an incremental improvement to the service.
2026-02-13 | [Cardiac arrhythmias-Cellular mechanisms, consequences and challenges in the diagnostics using human models].
Cardiac arrhythmias significantly contribute to morbidity and mortality in cardiovascular diseases. Hereditary ion channel disorders, including Brugada syndrome, long/short QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT), represent critical entities with elevated risk of malignant ventricular arrhythmias. Although beta-blockers, ion channel modulators and implantable cardioverter defibrillators (ICD) are available and the indications for them are increasingly based on genetic analyses, variants of uncertain significance (VUS) substantially impair the risk stratification. Atrial tachyarrhythmias, particular atrial fibrillation, can cause an often-reversible arrhythmia-induced cardiomyopathy (AIC). Pathophysiologically, the Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays an important role in atrial and ventricular arrhythmias. It can be activated by various pathological triggers, such as high heart rate, neuroendocrine activation and oxidative stress, the latter often resulting from mechano-energetic uncoupling. The development of effective treatment options for arrhythmia-associated cardiovascular diseases requires the use of human model systems in addition to animal experimental approaches, due to the genetic heterogeneity and systemic comorbidities. Patient-specific cardiac stem cell-models enable the classification of VUS and personalised drug testing. The integration of new methodological approaches into existing animal experimental approaches thus paves the way for functionally validated precision medicine and could fundamentally transform the treatment of both disease patterns.
2025-05-01 | Cardiac sympathetic denervation for different cardiovascular indications - the experience of two referral centers
Abstract Cardiac sympathetic denervation (CSD) reduces risk of ventricular tachyarrhythmias (VTA in long-QT syndrome, catecholaminergic polymorphic ventricular tachycardia and cardiomyopathies. CSD has also a theoretical potential to be alleviate symptoms in other disorders dependent on adrenergic input. The aim of this study was to assess efficacy and safety of bilateral CSD (BCSD) procedure performed for wide range of cardiovascular disorders. Apart form efficacy of CSD also physical and psychological consequences and patient satisfaction were studied. Methods and results Between 2018 - 2024 51 patients were qualified for BCSD in 2 centers in Poland. The median age of patients was 46,8 (range 17-78) years, 26 were males, 22 had prior ICD implants. In 4 cardioneuroablation was also performed. In 49 patients video- and in 2 robot-assisted BCSD ob T1-T4(5) chain was performed for recurrent VTA or electric storm in 41, coronary spam (5), Takotsubo cardiomyopathy (1), inappropriate sinus tachycardia (1) and Raynaud syndrome (9) . Several patients had multiple indications. In two patients with DCM VTA recurred within a week after CSD and also thereafter. There were 5 deaths on follow-up in the course of underlying disease, none was linked directly to BCSD. One death occurred in a patient in whom CSD was a last resort for refractory VT storm. Persistent neuropathic pain was the main adverse effect reported by patients. In the group of patients in whom both CSD and CNA wee performed no serious AE were observed. Conclusions BiCSD is an effective when performed for various cardiovascular indications such as recurrent ventricular tachyarrytmias, coronary spasm and Raynaud syndrome. BCSD is also well tolerated by majority of patients. The failure of antiarrhythmic effect shortly after the procedure in 2 patients with dilated cardiomyopathy and low EF needs to be elucidated in further studies.
2025-04-24 | Stellate Ganglia: A Key Therapeutic Target for Malignant Ventricular Arrhythmia in Heart Disease.
Malignant ventricular arrhythmias (VAs), such as ventricular tachycardia and ventricular fibrillation, are the cause of approximately half a million deaths per year in the United States, which is a common lethal event in heart disease, such as hypertension, catecholaminergic polymorphic ventricular tachycardia, takotsubo cardiomyopathy, long-QT syndrome, and progressing into advanced heart failure. A common characteristic of these heart diseases, and the subsequent development of VAs, is the overactivation of the sympathetic nervous system. Current treatments for VAs in these heart diseases, such as β-adrenergic receptor blockers and cardiac sympathetic ablation, aim at inhibiting cardiac sympathetic overactivation. However, these treatments do not translate into becoming efficacious as long-term suppressors of ventricular tachycardia/ventricular fibrillation events. As a key regulatory component in the heart, cardiac postganglionic sympathetic neurons residing in the stellate ganglia (SGs) release neurotransmitters (such as norepinephrine and NPY [neuropeptide Y]) to perform their regulatory role in dictating cardiac function. Growing evidence from animal experiments and clinical studies has demonstrated that the remodeling of the SG may be intimately involved in malignant arrhythmogenesis. This identifies the SG as a key potential therapeutic target for the treatment of malignant VAs in heart disease. Therefore, this review summarizes the role of SG in ventricular arrhythmogenesis and updates the novel targeting of SG for clinical treatment of VAs in heart disease.
other
2026-04-15 | Imaging and safety profiling of inhaled siRNA RyR2 in human respiratory models.
RNA therapeutics hold strong potential for treating genetic disease, yet progress is often limited by delivery, stability, and safety concerns. Here, we profile respiratory safety and cellular uptake of an inhaled siRNA targeting the cardiac RyR2 gene, which is responsible for catecholaminergic polymorphic ventricular tachycardia (CPVT), delivered via inhalation with calcium phosphate nanoparticles (CaP NPs). Barrier integrity, cytotoxicity, siRNA uptake, and immune activation, were assessed using a human 3D normal bronchial epithelial model (NHBE) under Air-Liquid Interphase (ALI) and dendritic cells (DCs), tested in monoculture and in co-culture. Barrier function, measured by transepithelial electrical resistance (TEER), remained stable after 48 h of exposure to 400 nM siRNA RyR2, scramble control, or CaP NPs, indicating preserved epithelial performance. Confocal imaging showed efficient internalization of Cy5-labeled siRNA in both mono- and co-cultures. Cytokine profiling revealed IL-8 release across all conditions in NHBE and NHBE + DC models, with IL-6 and TNF-α limited to immune-competent co-cultures; IFN-γ was below the limit of detection. No cytotoxicity was observed. Together, these data demonstrate that CaP NP-mediated delivery achieves robust siRNA uptake without compromising airway barrier integrity, while eliciting only modest, context-dependent immune responses (primarily IL-8 and TNF-α in the presence of DCs). This work supports the respiratory safety and translational potential of inhaled RyR2-targeting siRNA for CPVT.
2025-01-25 | A Novel Approach for In Vitro Testing and Hazard Evaluation of Nanoformulated RyR2-Targeting siRNA Drugs Using Human PBMCs.
Nucleic acid (NA)-based drugs are promising therapeutics agents. Beyond efficacy, addressing safety concerns-particularly those specific to this class of drugs-is crucial. Here, we propose an in vitro approach to screen for potential adverse off-target effects of NA-based drugs. Human peripheral blood mononuclear cells (PBMCs), purified from buffy coats of healthy donors, were used to investigate the ability of NA-drugs to trigger toxicity pathways and inappropriate immune stimulation. PBMCs were selected for their ability to represent potential human responses, given their likelihood of interacting with administered drugs. As proof of concept, a small interfering RNA (siRNA) targeting Ryanodine Receptor mRNA (RyR2) identified by the Italian National Center for Gene Therapy and Drugs based on RNA Technology as a potential therapeutic target for dominant catecholaminergic polymorphic ventricular tachycardia, was selected. This compound and its scramble were formulated within a calcium phosphate nanoparticle-based delivery system. Positive controls for four toxicity pathways were identified through literature review, each associated with a specific type of cellular stress: oxidative stress (tert-butyl hydroperoxide), mitochondrial stress (rotenone), endoplasmic reticulum stress (thapsigargin), and autophagy (rapamycin). These controls were used to define specific mRNA signatures triggered in PBMCs, which were subsequently used as indicators of off-target effects. To assess immune activation, the release of pro-inflammatory cytokines (interleukin-6, interleukin-8, tumor necrosis factor-α, and interferon-γ) was measured 24 h after exposure. The proposed approach provides a rapid and effective screening method for identifying potential unintended effects in a relevant human model, which also allows to address gender effects and variability in responses.
2022-04-25 | Benefits in cardiac function by CD38 suppression: Improvement in NAD+ levels, exercise capacity, heart rate variability and protection against catecholamine-induced ventricular arrhythmias.
CD38 enzymatic activity regulates NAD+ and cADPR levels in mammalian tissues, and therefore has a prominent role in cellular metabolism and calcium homeostasis. Consequently, it is reasonable to hypothesize about its involvement in cardiovascular physiology as well as in heart related pathological conditions. To investigate the role of CD38 in cardiovascular performance, and its involvement in cardiac electrophysiology and calcium-handling. When submitted to a treadmill exhaustion test, a way of evaluating cardiovascular performance, adult male CD38KO mice showed better exercise capacity. This benefit was also obtained in genetically modified mice with catalytically inactive (CI) CD38 and in WT mice treated with antibody 68 (Ab68) which blocks CD38 activity. Hearts from these 3 groups (CD38KO, CD38CI and Ab68) showed increased NAD+ levels. When CD38KO mice were treated with FK866 which inhibits NAD+ biosynthesis, exercise capacity as well as NAD+ in heart tissue decreased to WT levels. Electrocardiograms of conscious unrestrained CD38KO and CD38CI mice showed lower basal heart rates and higher heart rate variability than WT mice. Although inactivation of CD38 in mice resulted in increased SERCA2a expression in the heart, the frequency of spontaneous calcium release from the sarcoplasmic reticulum under stressful conditions (high extracellular calcium concentration) was lower in CD38KO ventricular myocytes. When mice were challenged with caffeine-epinephrine, CD38KO mice had a lower incidence of bidirectional ventricular tachycardia when compared to WT ones. CD38 inhibition improves exercise performance by regulating NAD+ homeostasis. CD38 is involved in cardiovascular function since its genetic ablation decreases basal heart rate, increases heart rate variability and alters calcium handling in a way that protects mice from developing catecholamine induced ventricular arrhythmias.
2022-02-08 | Impact of cascade screening for catecholaminergic polymorphic ventricular tachycardia type 1
Human cardiac ryanodine receptor 2 (RYR2) shows autosomal-dominant inheritance in catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1); however, de novo variants have been observed in sporadic cases. Here, we investigated CPVT1-related RYR2 variant inheritance and its clinical significance between familial and de novo cases.We enrolled 82 independent CPVT1 probands (median age: 10.0 (7.0-13.0) years; 45 male) carrying the RYR2 variants and whose biological origin could be confirmed by parental genetic analysis: assured familial inheritance (familial group: n=24) and de novo variants (de novo group: n=58). We examined the clinical characteristics of the probands and their family members carrying the RYR2 variants.In the de novo group, the RYR2 variants were more likely located in the C-terminus domain and less likely in the N-terminus domain than those in the familial group. The cumulative incidence of the first cardiac events (syncope and cardiac arrest (CA) or CA only) of the probands at the age of 5 and 10 years was higher in the de novo group than in the familial group. Nearly half of the probands in both groups experienced CA events before diagnosis. Only 37.5% of their genotype-positive parents had symptoms; however, at least 66.7% of the genotype-positive siblings were symptomatic.CPVT1 probands harbouring de novo RYR2 variants showed an earlier onset of symptoms than those with assured familial inheritance. Cascade screening may enable early diagnosis, risk stratification and prophylactic therapeutic intervention to prevent sudden cardiac death of probands and potential genotype-positive family members.
2021-03-15 | Genetic Loss of IK1 Causes Adrenergic-Induced Phase 3 Early Afterdepolariz ations and Polymorphic and Bidirectional Ventricular Tachycardia.
Arrhythmia syndromes associated with KCNJ2 mutations have been described clinically; however, little is known of the underlying arrhythmia mechanism. We create the first patient inspired KCNJ2 transgenic mouse and study effects of this mutation on cardiac function, IK1, and Ca2+ handling, to determine the underlying cellular arrhythmic pathogenesis. A cardiac-specific KCNJ2-R67Q mouse was generated and bred for heterozygosity (R67Q+/-). Echocardiography was performed at rest, under anesthesia. In vivo ECG recording and whole heart optical mapping of intact hearts was performed before and after adrenergic stimulation in wild-type (WT) littermate controls and R67Q+/- mice. IK1 measurements, action potential characterization, and intracellular Ca2+ imaging from isolated ventricular myocytes at baseline and after adrenergic stimulation were performed in WT and R67Q+/- mice. R67Q+/- mice (n=17) showed normal cardiac function, structure, and baseline electrical activity compared with WT (n=10). Following epinephrine and caffeine, only the R67Q+/- mice had bidirectional ventricular tachycardia, ventricular tachycardia, frequent ventricular ectopy, and/or bigeminy and optical mapping demonstrated high prevalence of spontaneous and sustained ventricular arrhythmia. Both R67Q+/- (n=8) and WT myocytes (n=9) demonstrated typical n-shaped IK1IV relationship; however, following isoproterenol, max outward IK1 increased by ≈20% in WT but decreased by ≈24% in R67Q+/- (P<0.01). R67Q+/- myocytes (n=5) demonstrated prolonged action potential duration at 90% repolarization and after 10 nmol/L isoproterenol compared with WT (n=7; P<0.05). Ca2+ transient amplitude, 50% decay rate, and sarcoplasmic reticulum Ca2+ content were not different between WT (n=18) and R67Q+/- (n=16) myocytes. R67Q+/- myocytes (n=10) under adrenergic stimulation showed frequent spontaneous development of early afterdepolarizations that occurred at phase 3 of action potential repolarization. KCNJ2 mutation R67Q+/- causes adrenergic-dependent loss of IK1 during terminal repolarization and vulnerability to phase 3 early afterdepolarizations. This model clarifies a heretofore unknown arrhythmia mechanism and extends our understanding of treatment implications for patients with KCNJ2 mutation.
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Drug Discovery Landscape
5 orphan drug designations for Catecholaminergic polymorphic ventricular tachycardia.
5 orphan drug designations for Catecholaminergic polymorphic ventricular tachycardia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Adeno-associated viral vector serotype 8 containing the human CASQ2 gene | gene therapies | EMA | — | Voisin Consulting Life Sciences |
(S)-(3-bromo-4-(trifluoromethyl)phenyl)(2-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)morpholino)methan-one | small molecules | FDA | Agiana Pharmaceuticals | |
4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl]benzoic acid, hemifumarate | small molecules | FDA | RyCarma Therapeutics, Inc. | |
adeno-associated viral vector serotype 8 containing the human cardiac calsequestrin gene | gene therapies | FDA | Solid Biosciences Inc. | |
Adeno-associated viral vector serotype 9 containing the human cardiac calsequestrin gene | gene therapies | EMA | — | Voisin Consulting Life Sciences |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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