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Journal of Cardiothoracic Surgery Jun 2024Long QT Syndrome (LQTS) and Beckwith-Wiedemann Syndrome (BWS) are complex disorders with unclear origins, underscoring the need for in-depth molecular investigations...
BACKGROUND
Long QT Syndrome (LQTS) and Beckwith-Wiedemann Syndrome (BWS) are complex disorders with unclear origins, underscoring the need for in-depth molecular investigations into their mechanisms. The main aim of this study is to identify the shared key genes between LQTS and BWS, shedding light on potential common molecular pathways underlying these syndromes.
METHODS
The LQTS and BWS datasets are available for download from the GEO database. Differential expression genes (DEGs) were identified. Weighted gene co-expression network analysis (WGCNA) was used to detect significant modules and central genes. Gene enrichment analysis was performed. CIBERSORT was used for immune cell infiltration analysis. The predictive protein interaction (PPI) network of core genes was constructed using STRING, and miRNAs regulating central genes were screened using TargetScan.
RESULTS
Five hundred DEGs associated with Long QT Syndrome and Beckwith-Wiedemann Syndrome were identified. GSEA analysis revealed enrichment in pathways such as T cell receptor signaling, MAPK signaling, and adrenergic signaling in cardiac myocytes. Immune cell infiltration indicated higher levels of memory B cells and naive CD4 T cells. Four core genes (CD8A, ICOS, CTLA4, LCK) were identified, with CD8A and ICOS showing low expression in the syndromes and high expression in normal samples, suggesting potential inverse regulatory roles.
CONCLUSION
The expression of CD8A and ICOS is low in long QT syndrome and Beckwith-Wiedemann syndrome, indicating their potential as key genes in the pathogenesis of these syndromes. The identification of shared key genes between LQTS and BWS provides insights into common molecular mechanisms underlying these disorders, potentially facilitating the development of targeted therapeutic strategies.
Topics: Humans; Long QT Syndrome; Beckwith-Wiedemann Syndrome; Inducible T-Cell Co-Stimulator Protein; CD8 Antigens; Gene Expression Profiling
PubMed: 38845009
DOI: 10.1186/s13019-024-02804-w -
Journal of Clinical Research in... Jun 2024Central precocious puberty is treated with long-acting GnRH analogues. Some adult patients undergoing GnRHa treatment experienced prolonged QT syndrome, which is...
INTRODUCTION
Central precocious puberty is treated with long-acting GnRH analogues. Some adult patients undergoing GnRHa treatment experienced prolonged QT syndrome, which is associated with an increased risk of serious cardiac events such as myocardial infarction, stroke, arrhythmias, and sudden cardiac death.
METHOD
Seventy-four patients, aged between 5 and 11 years and diagnosed with central precocious puberty but with no other concomitant disease or medication use, underwent electrocardiogram assessment. They had been receiving 3.75 mg leuprolide acetate (Lucrin® Depot) injections every 28 days for at least three months.
RESULTS
The electrocardiograms of all patients showed a QTc interval within normal limits, consistent with the data of healthy Turkish children of the same age and gender. No other pathological physical examination or ECG findings were observed. Furthermore, there was no significant difference in QTc interval in relation to age, anthropometric data, or the duration or cumulative dose of the treatment.
CONCLUSION
The study found no correlation between QTc interval values and age, treatment duration, total cumulative dose, and anthropometric data. The findings suggest that cardiovascular adverse events associated with GnRHa may be related to age and other underlying physiopathological conditions rather than the drug.
PubMed: 38828891
DOI: 10.4274/jcrpe.galenos.2024.2024-2-8 -
MedRxiv : the Preprint Server For... May 2024Timothy syndrome (OMIM #601005) is a rare disease caused by variants in the gene . Timothy syndrome patients were first identified as having a cardiac presentation of...
Timothy syndrome (OMIM #601005) is a rare disease caused by variants in the gene . Timothy syndrome patients were first identified as having a cardiac presentation of Long QT and syndactyly of the fingers and/or toes, and an identical variant in , Gly406Arg. However, since this original identification, more individuals harboring diverse variants in have been identified and have presented with various cardiac and extra-cardiac symptoms. Furthermore, it has remained underexplored whether individuals harboring canonical Gly406Arg variants in mutually exclusive exon 8A (Timothy syndrome 1) or exon 8 (Timothy syndrome 2) have additional symptoms. Here, we describe the first Natural History Study for Timothy syndrome, providing a thorough resource describing the current understanding of disease manifestation in Timothy syndrome patients. Parents of Timothy syndrome children were queried regarding a wide-ranging set of symptoms and features via a survey. Importantly, we find that in addition to cardiac concerns, Timothy syndrome patients commonly share extra-cardiac features including neurodevelopmental impairments, hypoglycemia, and respiratory problems. Our work expands the current understanding of the disorder to better inform the care of Timothy syndrome patients.
PubMed: 38826393
DOI: 10.1101/2024.05.20.24307583 -
Europace : European Pacing,... Jun 2024KCNQ1 mutations cause QTc prolongation increasing life-threatening arrhythmias risks. Heterozygous mutations [type 1 long QT syndrome (LQT1)] are common. Homozygous...
AIMS
KCNQ1 mutations cause QTc prolongation increasing life-threatening arrhythmias risks. Heterozygous mutations [type 1 long QT syndrome (LQT1)] are common. Homozygous KCNQ1 mutations cause type 1 Jervell and Lange-Nielsen syndrome (JLNS) with deafness and higher sudden cardiac death risk. KCNQ1 variants causing JLNS or LQT1 might have distinct phenotypic expressions in heterozygous patients. The aim of this study is to evaluate QTc duration and incidence of long QT syndrome-related cardiac events according to genetic presentation.
METHODS AND RESULTS
We enrolled LQT1 or JLNS patients with class IV/V KCNQ1 variants from our inherited arrhythmia clinic (September 1993 to January 2023). Medical history, ECG, and follow-up were collected. Additionally, we conducted a thorough literature review for JLNS variants. Survival curves were compared between groups, and multivariate Cox regression models identified genetic and clinical risk factors. Among the 789 KCNQ1 variant carriers, 3 groups were identified: 30 JLNS, 161 heterozygous carriers of JLNS variants (HTZ-JLNS), and 550 LQT1 heterozygous carriers of non-JLNS variants (HTZ-Non-JLNS). At diagnosis, mean age was 3.4 ± 4.7 years for JLNS, 26.7 ± 21 years for HTZ-JLNS, and 26 ± 21 years for HTZ-non-JLNS; 55.3% were female; and the mean QTc was 551 ± 54 ms for JLNS, 441 ± 32 ms for HTZ-JLNS, and 467 ± 36 ms for HTZ-Non-JLNS. Patients with heterozygous JLNS mutations (HTZ-JLNS) represented 22% of heterozygous KCNQ1 variant carriers and had a lower risk of cardiac events than heterozygous non-JLNS variant carriers (HTZ-Non-JLNS) [hazard ratio (HR) = 0.34 (0.22-0.54); P < 0.01]. After multivariate analysis, four genetic parameters were independently associated with events: haploinsufficiency [HR = 0.60 (0.37-0.97); P = 0.04], pore localization [HR = 1.61 (1.14-1.2.26); P < 0.01], C-terminal localization [HR = 0.67 (0.46-0.98); P = 0.04], and group [HR = 0.43 (0.27-0.69); P < 0.01].
CONCLUSION
Heterozygous carriers of JLNS variants have a lower risk of cardiac arrhythmic events than other LQT1 patients.
Topics: Humans; KCNQ1 Potassium Channel; Female; Male; Risk Assessment; Romano-Ward Syndrome; Risk Factors; Child; Electrocardiography; Child, Preschool; Heterozygote; Mutation; Jervell-Lange Nielsen Syndrome; Genetic Predisposition to Disease; Infant; Adult; Adolescent; Phenotype; Retrospective Studies; Death, Sudden, Cardiac; Young Adult; Incidence
PubMed: 38825991
DOI: 10.1093/europace/euae136 -
International Heart Journal 2024Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Conversely, RyR2 loss-of-function...
Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Conversely, RyR2 loss-of-function mutations cause a new disease entity, termed calcium release deficiency syndrome (CRDS), which may include RYR2-related long QT syndrome (LQTS). Importantly, unlike CPVT, patients with CRDS do not always exhibit exercise- or epinephrine-induced ventricular arrhythmias, which precludes a diagnosis of CRDS. Here we report a boy and his father, who both experienced exercise-induced cardiac events and harbor the same RYR2 E4107A variant. In the boy, an exercise stress test (EST) and epinephrine provocation test (EPT) did not induce any ventricular arrhythmias. QTc was slightly prolonged (QTc: 474 ms), and an EPT induced QTc prolongation (QTc-baseline: 466 ms, peak: 532 ms, steady-state: 527 ms). In contrast, in his father, QTc was not prolonged (QTc: 417 ms), and neither an EST nor EPT induced QTc prolongation. However, an EST induced multifocal premature ventricular contraction (PVC) bigeminy and bidirectional PVC couplets. Thus, they exhibited distinct clinical phenotypes: the boy exhibited LQTS (or CRDS) phenotype, whereas his father exhibited CPVT phenotype. These findings suggest that, in addition to the altered RyR2 function, other unidentified factors, such as other genetic, epigenetic, and environmental factors, and aging, may be involved in the diverse phenotypic manifestations. Considering that a single RYR2 variant can cause both CPVT and LQTS (or CRDS) phenotypes, in cascade screening of patients with CPVT and CRDS, an EST and EPT are not sufficient and genetic analysis is required to identify individuals who are at increased risk for life-threatening arrhythmias.
Topics: Humans; Ryanodine Receptor Calcium Release Channel; Male; Long QT Syndrome; Phenotype; Tachycardia, Ventricular; Electrocardiography; Pedigree; Adult; Exercise Test; Mutation
PubMed: 38825499
DOI: 10.1536/ihj.23-652 -
Genome Medicine May 2024KCNE1 encodes a 129-residue cardiac potassium channel (I) subunit. KCNE1 variants are associated with long QT syndrome and atrial fibrillation. However, most variants...
BACKGROUND
KCNE1 encodes a 129-residue cardiac potassium channel (I) subunit. KCNE1 variants are associated with long QT syndrome and atrial fibrillation. However, most variants have insufficient evidence of clinical consequences and thus limited clinical utility.
METHODS
In this study, we leveraged the power of variant effect mapping, which couples saturation mutagenesis with high-throughput sequencing, to ascertain the function of thousands of protein-coding KCNE1 variants.
RESULTS
We comprehensively assayed KCNE1 variant cell surface expression (2554/2709 possible single-amino-acid variants) and function (2534 variants). Our study identified 470 loss- or partial loss-of-surface expression and 574 loss- or partial loss-of-function variants. Of the 574 loss- or partial loss-of-function variants, 152 (26.5%) had reduced cell surface expression, indicating that most functionally deleterious variants affect channel gating. Nonsense variants at residues 56-104 generally had WT-like trafficking scores but decreased functional scores, indicating that the latter half of the protein is dispensable for protein trafficking but essential for channel function. 22 of the 30 KCNE1 residues (73%) highly intolerant of variation (with > 70% loss-of-function variants) were in predicted close contact with binding partners KCNQ1 or calmodulin. Our functional assay data were consistent with gold standard electrophysiological data (ρ = - 0.64), population and patient cohorts (32/38 presumed benign or pathogenic variants with consistent scores), and computational predictors (ρ = - 0.62). Our data provide moderate-strength evidence for the American College of Medical Genetics/Association of Molecular Pathology functional criteria for benign and pathogenic variants.
CONCLUSIONS
Comprehensive variant effect maps of KCNE1 can both provide insight into I channel biology and help reclassify variants of uncertain significance.
Topics: Potassium Channels, Voltage-Gated; Humans; Calmodulin; Arrhythmias, Cardiac; High-Throughput Nucleotide Sequencing; Genetic Variation; Protein Transport; HEK293 Cells
PubMed: 38816749
DOI: 10.1186/s13073-024-01340-5 -
Heart Rhythm Jun 2024
Review
Topics: Long QT Syndrome; Humans; Electrocardiography; Anti-Arrhythmia Agents
PubMed: 38816146
DOI: 10.1016/j.hrthm.2024.02.007 -
CPT: Pharmacometrics & Systems... Jun 2024Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in... (Randomized Controlled Trial)
Randomized Controlled Trial
Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in adults. The cardiovascular safety of zavegepant nasal spray was assessed in both single-ascending dose (SAD) and multiple-ascending dose (MAD) studies in healthy participants. The SAD study included 72 participants (54 active/18 placebo) who received 0.1-40 mg zavegepant or placebo. The MAD study included 72 participants (56 active/16 placebo) who received 5-40 mg zavegepant or placebo for 1-14 days. Plasma zavegepant pharmacokinetics and electrocardiographic (ECG) parameters (Fridericia-corrected QT interval [QTcF], heart rate, PR interval, ventricular depolarization [QRS], T-wave morphology, and U-wave presence) were analyzed pre- and post-zavegepant administration. Using pooled data from the SAD and MAD studies, the relationship between time-matched plasma zavegepant concentrations and QTc interval was assessed using a linear mixed-effects model to evaluate the potential for QTc interval prolongation. Results showed that single and multiple doses of zavegepant had no significant impact on ECG parameters versus placebo, and there was no concentration-dependent effect on QTcF interval. The estimated slope of the plasma zavegepant concentration-QTcF model was -0.053 ms per ng/mL with a 90% confidence interval of -0.0955 to -0.0110 (p = 0.0415), which is not considered clinically meaningful. At doses up to four times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.
Topics: Humans; Male; Electrocardiography; Adult; Female; Healthy Volunteers; Nasal Sprays; Heart Rate; Double-Blind Method; Young Adult; Dose-Response Relationship, Drug; Middle Aged; Azepines; Administration, Intranasal; Long QT Syndrome; Adolescent
PubMed: 38812357
DOI: 10.1002/psp4.13140 -
The Journal of Innovations in Cardiac... May 2024We report the case of a 7-year-old boy who presented with post-viral myositis, rhabdomyolysis, and hepatitis, who was later readmitted due to a seizure-like activity and...
We report the case of a 7-year-old boy who presented with post-viral myositis, rhabdomyolysis, and hepatitis, who was later readmitted due to a seizure-like activity and ultimately found to have episodes of recalcitrant polymorphic ventricular tachycardia secondary to simultaneous QT prolongation and severe hypothyroidism. Temporary transvenous atrial pacing was successful at controlling the ventricular arrhythmias in the intensive care unit. With levothyroxine therapy and cessation of QT-prolonging medications, the corrected QT (QTc) normalized. A comprehensive arrhythmia panel identified a pathogenic mutation in , consistent with long QT syndrome (LQTS) type 1. After the patient experienced progressive neurodegeneration and seizures, he was referred to a genetics clinic to rule out genetic epilepsy. On the epilepsy panel of genetic testing, he was found to have two pathogenic variants in . deficiency explains the initial presentation of myositis, rhabdomyolysis, hypothyroidism, and life-threatening arrhythmias surrounding a viral illness more so than the initial diagnosis of mere LQTS. However, the gene is not included in most comprehensive arrhythmia and cardiomyopathy panels. deficiency is a rare condition that often presents with arrhythmias but may be unfamiliar to many cardiologists and electrophysiologists. This case describes management strategies and caveats, which could aid in the successful diagnosis and treatment of deficiency at the time of presentation.
PubMed: 38808169
DOI: 10.19102/icrm.2024.15054 -
Journal of Clinical Medicine May 2024Patients with neuromuscular diseases are particularly vulnerable in the perioperative period to the development of pulmonary and cardiac complications, or medication... (Review)
Review
Patients with neuromuscular diseases are particularly vulnerable in the perioperative period to the development of pulmonary and cardiac complications, or medication side effects. These risks could include hypoventilation, aspiration pneumonia, exacerbation of underlying cardiomyopathy, arrhythmias, adrenal insufficiency, prolonged neuromuscular blockade, issues related to thermoregulation, rhabdomyolysis, malignant hyperthermia, or prolonged mechanical ventilation. Interventions at each of the perioperative stages can be implemented to mitigate these risks. A careful pre-operative evaluation may help identify risk factors so that appropriate interventions are initiated, including cardiology consultation, pulmonary function tests, initiation of noninvasive ventilation, or implementation of preventive measures. Important intraoperative issues include positioning, airway and anesthetic management, and adequate ventilation. The postoperative period may require correction of electrolyte abnormalities, control of secretions with medications, manual or mechanical cough assistance, avoiding the risk of reintubation, judicious pain control, and appropriate medication management. The aim of this review is to increase awareness of the particular surgical challenges in this vulnerable population, and guide the clinician on the various evaluations and interventions that may result in a favorable surgical outcome.
PubMed: 38792504
DOI: 10.3390/jcm13102963