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Acta Biomaterialia Jun 2024Potassium ion transport across myocardial cell membrane is essential for type 2 long QT syndrome (LQT2). However, the dysfunction of potassium ion transport due to...
Potassium ion transport across myocardial cell membrane is essential for type 2 long QT syndrome (LQT2). However, the dysfunction of potassium ion transport due to genetic mutations limits the therapeutic effect in treating LQT2. Biomimetic ion channels that selectively and efficiently transport potassium ions across the cellular membranes are promising for the treatment of LQT2. To corroborate this, we synthesized a series of foldamer-based ion channels with different side chains, and found a biomimetic ion channel of K (BIC) with the highest transport activity among them. The selected BIC can restore potassium ion transport and increase transmembrane potassium ion current, thus shortening phase 3 of action potential (AP) repolarization and QT interval in LQT2. Moreover, BIC does not affect heart rate and cardiac rhythm in treating LQT2 model induced by E4031 in isolated heart as well as in guinea pigs. By restoring ion transmembrane transport tactic, biomimetic ion channels, such as BIC, will show great potential in treating diseases related to ion transport blockade. STATEMENT OF SIGNIFICANCE: Type 2 long QT syndrome (LQT2) is a disease caused by K transport disorder, which can cause malignant arrhythmia and even death. There is currently no radical cure, so it is critical to explore ways to improve K transmembrane transport. In this study, we report that a small-molecule biomimetic ion channel BIC can efficiently simulate natural K channel proteins on the cardiomyocyte and cure E4031-induced LQT2 in guinea pig by restoring K transport function for the first time. This study found that the potassium transmembrane transport by BIC significantly reduced the QT interval, which provides a conceptually new strategy for the treatment of LQT2 disease.
Topics: Long QT Syndrome; Animals; Potassium; Guinea Pigs; Humans; Action Potentials; Ion Transport; Male; Biomimetic Materials; Potassium Channels; Myocytes, Cardiac; Heart Rate
PubMed: 38704114
DOI: 10.1016/j.actbio.2024.04.046 -
Clinical and Translational Science May 2024Sitravatinib (MGCD516) is an orally available, small molecule, tyrosine kinase inhibitor that has been evaluated in patients with advanced solid tumors....
Sitravatinib (MGCD516) is an orally available, small molecule, tyrosine kinase inhibitor that has been evaluated in patients with advanced solid tumors. Concentration-corrected QT interval (QTc; C-QTc) modeling was undertaken, using 767 matched concentration-ECG observations from 187 patients across two clinical studies in patients with advanced solid malignancies, across a dose range of 10-200 mg, via a linear mixed-effects (LME) model. The effect on heart rate (HR)-corrected QT interval via Fridericia's correction method (QTcF) at the steady-state maximum concentration (C) for the sitravatinib proposed therapeutic dosing regimen (100 mg malate once daily [q.d.]) without and with relevant intrinsic and extrinsic factors were predicted. No significant changes in HR from baseline were observed. Hysteresis between sitravatinib plasma concentration and change in QTcF from baseline (ΔQTcF) was not observed. There was no significant relationship between sitravatinib plasma concentration and ΔQTcF. The final C-QTc model predicted a mean (90% confidence interval [CI]) ΔQTcF of 3.92 (1.95-5.89) ms and 2.94 (0.23-6.10) ms at the proposed therapeutic dosing regimen in patients with normal organ function (best case scenario) and patients with hepatic impairment (worst-case scenario), respectively. The upper bounds of the 90% CIs were below the regulatory threshold of concern of 10 ms. The results of the described C-QTc analysis, along with corroborating results from nonclinical safety pharmacology studies, indicate that sitravatinib has a low risk of QTc interval prolongation at the proposed therapeutic dose of 100 mg malate q.d.
Topics: Humans; Neoplasms; Heart Rate; Male; Female; Electrocardiography; Middle Aged; Aged; Adult; Dose-Response Relationship, Drug; Long QT Syndrome; Models, Biological; Aged, 80 and over; Protein Kinase Inhibitors; Young Adult; Antineoplastic Agents
PubMed: 38700272
DOI: 10.1111/cts.13808 -
PloS One 2024Inherited cardiovascular diseases are rare diseases that are difficult to diagnose by non-expert professionals. Genetic analyses play a key role in the diagnosis of...
Inherited cardiovascular diseases are rare diseases that are difficult to diagnose by non-expert professionals. Genetic analyses play a key role in the diagnosis of these diseases, in which the identification of a pathogenic genetic variant is often a diagnostic criterion. Therefore, genetic variant classification and routine reinterpretation as data become available represent one of the main challenges associated with genetic analyses. Using the genetic variants identified in an inherited cardiovascular diseases unit during a 10-year period, the objectives of this study were: 1) to evaluate the impact of genetic variant reinterpretation, 2) to compare the reclassification rates between different cohorts of cardiac channelopathies and cardiomyopathies, and 3) to establish the most appropriate periodicity for genetic variant reinterpretation. All the evaluated cohorts (full cohort of inherited cardiovascular diseases, cardiomyopathies, cardiac channelopathies, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, Brugada syndrome, long QT syndrome and catecholaminergic polymorphic ventricular tachycardia) showed reclassification rates above 25%, showing even higher reclassification rates when there is definitive evidence of the association between the gene and the disease in the cardiac channelopathies. Evaluation of genetic variant reclassification rates based on the year of the initial classification showed that the most appropriate frequency for the reinterpretation would be 2 years, with the possibility of a more frequent reinterpretation if deemed convenient. To keep genetic variant classifications up to date, genetic counsellors play a critical role in the reinterpretation process, providing clinical evidence that genetic diagnostic laboratories often do not have at their disposal and communicating changes in classification and the potential implications of these reclassifications to patients and relatives.
Topics: Humans; Cardiovascular Diseases; Channelopathies; Genetic Testing; Genetic Variation; Cardiomyopathies; Long QT Syndrome; Brugada Syndrome
PubMed: 38691546
DOI: 10.1371/journal.pone.0297914 -
JAMA Network Open Apr 2024Individuals with dialysis-dependent kidney failure have numerous risk factors for medication-related adverse events, including receipt of care by multiple clinicians and...
IMPORTANCE
Individuals with dialysis-dependent kidney failure have numerous risk factors for medication-related adverse events, including receipt of care by multiple clinicians and initiation of some QT-prolonging medications with known risk of torsades de pointes (TdP), which is associated with higher risk of sudden cardiac death. Little is known about the prescription and dispensation patterns of QT-prolonging medications among people receiving dialysis, hindering efforts to reduce drug-related harm from these and other medications in this high-risk population.
OBJECTIVE
To examine prescription and dispensation patterns of QT-prolonging medications with known TdP risk and selected interacting medications prescribed to individuals receiving hemodialysis.
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional study included patients 60 years or older who were enrolled in Medicare Parts A, B, and D receiving in-center hemodialysis from January 1 to December 31, 2019. Analyses were conducted from October 20, 2022, to June 16, 2023.
EXPOSURES
New-user prescriptions for the 7 most frequently filled QT-prolonging medications characterized by the timing of the new prescription relative to acute care encounters, the type of prescribing clinician and pharmacy that dispensed the medication, and concomitant use of selected medications known to interact with the 7 most frequently filled QT-prolonging medications with known TdP risk.
MAIN OUTCOMES AND MEASURES
The main outcomes were the frequencies of the most commonly filled and new-use episodes of QT-prolonging medications; the timing of medication fills relative to acute care events; prescribers and dispensing pharmacy characteristics for new use of medications; and the frequency and types of new-use episodes with concurrent use of potentially interacting medications.
RESULTS
Of 20 761 individuals receiving hemodialysis in 2019 (mean [SD] age, 74 [7] years; 51.1% male), 10 992 (52.9%) filled a study drug prescription. Approximately 80% (from 78.6% for odansetron to 93.9% for escitalopram) of study drug new-use prescriptions occurred outside of an acute care event. Between 36.8% and 61.0% of individual prescriptions originated from general medicine clinicians. Between 16.4% and 26.2% of these prescriptions occurred with the use of another QT-prolonging medication. Most potentially interacting drugs were prescribed by different clinicians (46.3%-65.5%).
CONCLUSIONS AND RELEVANCE
In this cross-sectional study, QT-prolonging medications for individuals with dialysis-dependent kidney failure were commonly prescribed by nonnephrology clinicians and from nonacute settings. Prescriptions for potentially interacting medications often originated from different prescribers. Strategies aimed at minimizing high-risk medication-prescribing practices in the population undergoing dialysis are needed.
Topics: Humans; Renal Dialysis; Male; Cross-Sectional Studies; Female; Aged; Middle Aged; United States; Torsades de Pointes; Long QT Syndrome; Aged, 80 and over; Drug Prescriptions; Kidney Failure, Chronic
PubMed: 38687480
DOI: 10.1001/jamanetworkopen.2024.8732 -
International Journal of Molecular... Apr 2024The accurate prediction of adverse drug reactions (ADRs) is essential for comprehensive drug safety evaluation. Pre-trained deep chemical language models have emerged as...
The accurate prediction of adverse drug reactions (ADRs) is essential for comprehensive drug safety evaluation. Pre-trained deep chemical language models have emerged as powerful tools capable of automatically learning molecular structural features from large-scale datasets, showing promising capabilities for the downstream prediction of molecular properties. However, the performance of pre-trained chemical language models in predicting ADRs, especially idiosyncratic ADRs induced by marketed drugs, remains largely unexplored. In this study, we propose MoLFormer-XL, a pre-trained model for encoding molecular features from canonical SMILES, in conjunction with a CNN-based model to predict drug-induced QT interval prolongation (DIQT), drug-induced teratogenicity (DIT), and drug-induced rhabdomyolysis (DIR). Our results demonstrate that the proposed model outperforms conventional models applied in previous studies for predicting DIQT, DIT, and DIR. Notably, an analysis of the learned linear attention maps highlights amines, alcohol, ethers, and aromatic halogen compounds as strongly associated with the three types of ADRs. These findings hold promise for enhancing drug discovery pipelines and reducing the drug attrition rate due to safety concerns.
Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Deep Learning; Models, Chemical; Rhabdomyolysis; Long QT Syndrome
PubMed: 38674100
DOI: 10.3390/ijms25084516 -
Journal of Clinical Medicine Apr 2024Ventricular fibrillation (VF) is a common cause of sudden cardiac death in patients with channelopathies, particularly in the young population. Although pharmacological... (Review)
Review
Ventricular fibrillation (VF) is a common cause of sudden cardiac death in patients with channelopathies, particularly in the young population. Although pharmacological treatment, cardiac sympathectomy, and implantable cardioverter defibrillators (ICD) have been the mainstay in the management of VF in patients with channelopathies, they are associated with significant adverse effects and complications, leading to poor quality of life. Given these drawbacks, catheter ablation has been proposed as a therapeutic option for patients with channelopathies. Advances in imaging techniques and modern mapping technologies have enabled increased precision in identifying arrhythmia triggers and substrate modification. This has aided our understanding of the underlying pathophysiology of ventricular arrhythmias in channelopathies, highlighting the roles of the Purkinje network and the epicardial right ventricular outflow tract in arrhythmogenesis. This review explores the role of catheter ablation in managing the most common channelopathies (Brugada syndrome, congenital long QT syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia). While the initial results for ablation in Brugada syndrome are promising, the long-term efficacy and durability of ablation in different channelopathies require further investigation. Given the genetic and phenotypic heterogeneity of channelopathies, future studies are needed to show whether catheter ablation in patients with channelopathies is associated with a reduction in VF, and psychological distress stemming from recurrent ICD shocks, particularly relative to other available therapeutic options (e.g., quinidine in high-risk Brugada patients).
PubMed: 38673656
DOI: 10.3390/jcm13082384 -
Biomolecules Apr 2024Andersen-Tawil syndrome (ATS) is a multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias, prolonged QT interval, and facial dysmorphisms...
Andersen-Tawil syndrome (ATS) is a multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias, prolonged QT interval, and facial dysmorphisms occurring in the first/second decade of life. High phenotypic variability and incomplete penetrance of the genes causing the disease make its diagnosis still a challenge. We describe a three-generation family with six living individuals affected by ATS. The proband is a 37-year-old woman presenting since age 16, with episodes of muscle weakness and cramps in the pre-menstrual period. The father, two brothers, one paternal uncle and one cousin also complained of cramps, muscle stiffness, and weakness. Despite normal serum potassium concentration, treatment with potassium, magnesium, and acetazolamide alleviated paralysis attacks suggesting a dyskalemic syndrome. Dysmorphic features were noted in the proband, only later. On the ECG, all but one had normal QT intervals. The affected males developed metabolic syndrome or obesity. The father had two myocardial infarctions and was implanted with an intracardiac cardioverter defibrillator (ICD). A genetic investigation by WES analysis detected the heterozygous pathogenic variant (NM_000891.2: c.652C>T, p. Arg218Trp) in the gene related to ATS, confirmed by segregation studies in all affected members. Furthermore, we performed a review of cases with the same mutation in the literature, looking for similarities and divergences with our family case.
Topics: Adult; Female; Humans; Male; Alleles; Andersen Syndrome; Mutation; Pedigree; Phenotype; Potassium Channels, Inwardly Rectifying
PubMed: 38672523
DOI: 10.3390/biom14040507 -
Journal of Cardiovascular Development... Mar 2024Guidelines are important tools to guide the diagnosis and treatment of patients to improve the decision-making process of health professionals. They are periodically... (Review)
Review
Guidelines are important tools to guide the diagnosis and treatment of patients to improve the decision-making process of health professionals. They are periodically updated according to new evidence. Four new Guidelines in 2021, 2022 and 2023 referred to pediatric pacing and defibrillation. There are some relevant changes in permanent pacing. In patients with atrioventricular block, the heart rate limit in which pacemaker implantation is recommended was decreased to reduce too-early device implantation. However, it was underlined that the heart rate criterion is not absolute, as signs or symptoms of hemodynamically not tolerated bradycardia may even occur at higher rates. In sinus node dysfunction, symptomatic bradycardia is the most relevant recommendation for pacing. Physiological pacing is increasingly used and recommended when the amount of ventricular pacing is presumed to be high. New recommendations suggest that loop recorders may guide the management of inherited arrhythmia syndromes and may be useful for severe but not frequent palpitations. Regarding defibrillator implantation, the main changes are in primary prevention recommendations. In hypertrophic cardiomyopathy, pediatric risk calculators have been included in the Guidelines. In dilated cardiomyopathy, due to the rarity of sudden cardiac death in pediatric age, low ejection fraction criteria were demoted to class II. In long QT syndrome, new criteria included severely prolonged QTc with different limits according to genotype, and some specific mutations. In arrhythmogenic cardiomyopathy, hemodynamically tolerated ventricular tachycardia and arrhythmic syncope were downgraded to class II recommendation. In conclusion, these new Guidelines aim to assess all aspects of cardiac implantable electronic devices and improve treatment strategies.
PubMed: 38667717
DOI: 10.3390/jcdd11040099 -
Nature Apr 2024Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions. TS type 1 (TS1) is...
Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.
Topics: Animals; Female; Humans; Male; Mice; Alternative Splicing; Autistic Disorder; Calcium; Calcium Channels, L-Type; Cell Movement; Dendrites; Exons; Long QT Syndrome; Neurons; Oligonucleotides, Antisense; Organoids; Prosencephalon; Syndactyly; Interneurons
PubMed: 38658687
DOI: 10.1038/s41586-024-07310-6 -
EBioMedicine May 2024The clinical significance of optimal pharmacotherapy for inherited arrhythmias such as short QT syndrome (SQTS) and long QT syndrome (LQTS) has been increasingly... (Review)
Review
The clinical significance of optimal pharmacotherapy for inherited arrhythmias such as short QT syndrome (SQTS) and long QT syndrome (LQTS) has been increasingly recognised. The advancement of gene technology has opened up new possibilities for identifying genetic variations and investigating the pathophysiological roles and mechanisms of genetic arrhythmias. Numerous variants in various genes have been proven to be causative in genetic arrhythmias. Studies have demonstrated that the effectiveness of certain drugs is specific to the patient or genotype, indicating the important role of gene-variants in drug response. This review aims to summarize the reported data on the impact of different gene-variants on drug response in SQTS and LQTS, as well as discuss the potential mechanisms by which gene-variants alter drug response. These findings may provide valuable information for future studies on the influence of gene variants on drug efficacy and the development of genotype-guided or precision treatment for these diseases.
Topics: Humans; Long QT Syndrome; Genotype; Genetic Variation; Arrhythmias, Cardiac; Genetic Predisposition to Disease; Anti-Arrhythmia Agents; Treatment Outcome; Pharmacogenomic Variants
PubMed: 38653189
DOI: 10.1016/j.ebiom.2024.105108