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Heart Rhythm Apr 2024Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable...
An international multicenter cohort study on implantable cardioverter-defibrillators for the treatment of symptomatic children with catecholaminergic polymorphic ventricular tachycardia.
BACKGROUND
Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable cardioverter-defibrillators (ICDs) are commonly advised. However, there is limited data on the outcomes of ICD use in children.
OBJECTIVE
The purpose of this study was to compare the risk of arrhythmic events in pediatric patients with CPVT with and without an ICD.
METHODS
We compared the risk of SCD in patients with RYR2 (ryanodine receptor 2) variants and phenotype-positive symptomatic CPVT patients with and without an ICD who were younger than 19 years and had no history of sudden cardiac arrest at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite end points of SCD, sudden cardiac arrest, or appropriate ICD shocks with or without arrhythmic syncope.
RESULTS
The study included 235 patients, 73 with an ICD (31.1%) and 162 without an ICD (68.9%). Over a median follow-up of 8.0 years (interquartile range 4.3-13.4 years), SCD occurred in 7 patients (3.0%), of whom 4 (57.1%) were noncompliant with medications and none had an ICD. Patients with ICD had a higher risk of both secondary composite outcomes (without syncope: hazard ratio 5.85; 95% confidence interval 3.40-10.09; P < .0001; with syncope: hazard ratio 2.55; 95% confidence interval 1.50-4.34; P = .0005). Thirty-one patients with ICD (42.5%) experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications.
CONCLUSION
SCD events occurred only in patients without an ICD and mostly in those not on optimal medical therapy. Patients with an ICD had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common, and risks vs benefits of ICDs need to be considered.
PubMed: 38588993
DOI: 10.1016/j.hrthm.2024.04.006 -
Medical Hypotheses Apr 2024Duchenne Muscular Dystrophy (DMD) is marked by genetic mutations occurring in the DMD gene, which is widely expressed in the cardiovascular system. In addition to...
Duchenne Muscular Dystrophy (DMD) is marked by genetic mutations occurring in the DMD gene, which is widely expressed in the cardiovascular system. In addition to developing cardiomyopathy, patients with DMD have been reported to be susceptible to the development of symptomatic hypotension, although the mechanisms are unclear. Analysis of single-cell RNA sequencing data has identified potassium voltage-gated channel subfamily Q member 5 (KCNQ5) and possibly ryanodine receptor 2 (RyR2) as potential candidate hypotension genes whose expression is significantly upregulated in the vascular smooth muscle cells of DMD mutant mice. We hypothesize that heightened KCNQ5 and RyR2 expression contributes to decreased arterial blood pressure in patients with DMD. Exploring pharmacological approaches to inhibit the KCNQ5 and RyR2 channels holds promise in managing the systemic hypotension observed in individuals with DMD. This avenue of investigation presents new prospects for improving clinical outcomes for these patients.
PubMed: 38585412
DOI: 10.1016/j.mehy.2024.111318 -
Stem Cell Research Jun 2024RYR1 variants are the most common genetic cause of congenital myopathies, and typically cause central core disease (CCD) and/or malignant hyperthermia (MH). Here, we...
Generation of two iPSC lines from patients with inherited central core disease and concurrent malignant hyperthermia caused by dominant missense variants in the RYR1 gene.
RYR1 variants are the most common genetic cause of congenital myopathies, and typically cause central core disease (CCD) and/or malignant hyperthermia (MH). Here, we generated iPSC lines from two patients with CCD and MH caused by dominant RYR1 variants within the central region of the protein (p.Val2168Met and p.Arg2508Cys). Both lines displayed typical iPSC morphology, uniform expression of pluripotency markers, trilineage differentiation potential, and had normal karyotypes. These are the first RYR1 iPSC lines from patients with both CCD and MH. As these are common CCD/MH variants, these lines should be useful to study these conditions and test therapeutics.
Topics: Humans; Ryanodine Receptor Calcium Release Channel; Malignant Hyperthermia; Induced Pluripotent Stem Cells; Mutation, Missense; Myopathy, Central Core; Male; Female; Cell Line; Cell Differentiation
PubMed: 38583293
DOI: 10.1016/j.scr.2024.103410 -
Seizure Apr 2024
Topics: Humans; Ryanodine Receptor Calcium Release Channel; Tachycardia, Ventricular; Epilepsy, Generalized; Male; Female; Mutation
PubMed: 38583245
DOI: 10.1016/j.seizure.2024.04.003 -
Stem Cell Research Jun 2024RYR1 variants are a common cause of congenital myopathies, including multi-minicore disease (MmD) and central core disease (CCD). Here, we generated iPSC lines from two...
RYR1 variants are a common cause of congenital myopathies, including multi-minicore disease (MmD) and central core disease (CCD). Here, we generated iPSC lines from two CCD patients with dominant RYR1 missense variants that affect the transmembrane (pore) and SPRY3 protein domains (p.His4813Tyr and p.Asn1346Lys, respectively). Both lines had typical iPSC morphology, expressed canonical pluripotency markers, exhibited trilineage differentiation potential, and had normal karyotypes. Together with existing RYR1 iPSC lines, these represent important tools to study and develop treatments for RYR1-related myopathies.
Topics: Humans; Ryanodine Receptor Calcium Release Channel; Induced Pluripotent Stem Cells; Mutation, Missense; Myopathy, Central Core; Adult; Cell Line; Male; Cell Differentiation; Female
PubMed: 38582058
DOI: 10.1016/j.scr.2024.103411 -
The Journal of Physiology Apr 2024
Topics: Calcium; Calcium Channels; Membrane Proteins; Calcium, Dietary; Stromal Interaction Molecule 1; TRPC Cation Channels; Calcium Signaling; ORAI1 Protein
PubMed: 38578234
DOI: 10.1113/JP286421 -
Heart Rhythm Apr 2024
PubMed: 38574788
DOI: 10.1016/j.hrthm.2024.03.1815 -
Journal of Electrocardiology 2024In this case report, we describe a 14-year-old patient with a novel RyR2 gene mutation (c.6577G > T/p.Val2193Leu), identified through a comprehensive review of medical...
In this case report, we describe a 14-year-old patient with a novel RyR2 gene mutation (c.6577G > T/p.Val2193Leu), identified through a comprehensive review of medical history, examination findings, and follow-up data. The pathogenic potential of this mutation, which results in the loss of some interatomic forces and compromises the closure of the RyR2 protein pore leading to calcium leakage, was analyzed using the I-TASSER Suite to predict the structural changes in the protein. This mutation manifested clinically as co-morbid catecholaminergic polymorphic ventricular tachycardia (CPVT) and benign epilepsy with centrotemporal spikes (BECTS), a combination not previously documented in the same patient. While seizures were successfully managed with levetiracetam, the patient's exercise-induced syncope episodes could not be controlled with metoprolol, highlighting the complexity and challenge in managing CPVT associated with this novel RyR2 variation.
Topics: Humans; Ryanodine Receptor Calcium Release Channel; Tachycardia, Ventricular; Adolescent; Male; Mutation; Epilepsy, Rolandic; Electrocardiography
PubMed: 38574633
DOI: 10.1016/j.jelectrocard.2024.03.013 -
Archives of Toxicology Jun 2024Aminoglycosides are commonly used antibiotics for treatment of gram-negative bacterial infections, however, they might act on inner ear, leading to hair-cell death and...
Aminoglycosides are commonly used antibiotics for treatment of gram-negative bacterial infections, however, they might act on inner ear, leading to hair-cell death and hearing loss. Currently, there is no targeted therapy for aminoglycoside ototoxicity, since the underlying mechanisms of aminoglycoside-induced hearing impairments are not fully defined. This study aimed to investigate whether the calcium channel blocker verapamil and changes in intracellular & extracellular calcium could ameliorate aminoglycoside-induced ototoxicity in zebrafish. The present findings showed that a significant decreased number of neuromasts in the lateral lines of zebrafish larvae at 5 days' post fertilization after neomycin (20 μM) and gentamicin (20 mg/mL) exposure, which was prevented by verapamil. Moreover, verapamil (10-100 μM) attenuated aminoglycoside-induced toxic response in different external calcium concentrations (33-3300 μM). The increasing extracellular calcium reduced hair cell loss from aminoglycoside exposure, while lower calcium facilitated hair cell death. In contrast, calcium channel activator Bay K8644 (20 μM) enhanced aminoglycoside-induced ototoxicity and reversed the protective action of higher external calcium on hair cell loss. However, neomycin-elicited hair cell death was not altered by caffeine, ryanodine receptor (RyR) agonist, and RyR antagonists, including thapsigargin, ryanodine, and ruthenium red. The uptake of neomycin into hair cells was attenuated by verapamil and under high external calcium concentration. Consistently, the production of reactive oxygen species (ROS) in neuromasts exposed to neomycin was also reduced by verapamil and high external calcium. Significantly, zebrafish larvae when exposed to neomycin exhibited decreased swimming distances in reaction to droplet stimulus when compared to the control group. Verapamil and elevated external calcium effectively protected the impaired swimming ability of zebrafish larvae induced by neomycin. These data imply that prevention of hair cell damage correlated with swimming behavior against aminoglycoside ototoxicity by verapamil and higher external calcium might be associated with inhibition of excessive ROS production and aminoglycoside uptake through cation channels. These findings indicate that calcium channel blocker and higher external calcium could be applied to protect aminoglycoside-induced listening impairments.
Topics: Animals; Zebrafish; Calcium Channel Blockers; Calcium; Verapamil; Neomycin; Hair Cells, Auditory; Gentamicins; Anti-Bacterial Agents; Reactive Oxygen Species; Ototoxicity; Aminoglycosides; Lateral Line System; Larva; Hearing Loss
PubMed: 38563869
DOI: 10.1007/s00204-024-03720-7 -
MedRxiv : the Preprint Server For... Mar 2024Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia caused by mutations in the ryanodine receptor type 2 (RyR2). Diagnosis of...
Location of ryanodine receptor type 2 mutation predicts age of onset of sudden death in catecholaminergic polymorphic ventricular tachycardia - A systematic review and meta-analysis of case-based literature.
BACKGROUND
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia caused by mutations in the ryanodine receptor type 2 (RyR2). Diagnosis of CPVT often occurs after a major cardiac event, thus posing a severe threat to the patient's health.
METHODS
Publication databases, including PubMed, Scopus, and Embase, were searched for articles on patients with RyR2-CPVT mutations and their associated clinical presentation. Articles were reviewed by two independent reviewers and mutations were analyzed for demographic information, mutation distribution, and therapeutics. The human RyR2 cryo-EM structure was used to model CPVT mutations and predict the diagnosis and outcomes of CPVT patients.
FINDINGS
We present a database of 1008 CPVT patients from 227 papers. Data analyses revealed that patients most often experienced exercise-induced syncope in their early teenage years but the diagnosis of CPVT took a decade. Mutations located near key regulatory sites in the channel were associated with earlier onset of CPVT symptoms including sudden cardiac death.
INTERPRETATION
The present study provides a road map for predicting clinical outcomes based on the location of RyR2 mutations in CPVT patients. The study was partially limited by the inconsistency in the depth of information provided in each article, but nevertheless is an important contribution to the understanding of the clinical and molecular basis of CPVT and suggests the need for early diagnosis and creative approaches to disease management.
FUNDING
The work was supported by grant NIH R01HL145473, P01 HL164319 R25HL156002, T32 HL120826.
PubMed: 38559077
DOI: 10.1101/2024.03.15.24304349