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Herzschrittmachertherapie &... Jun 2023In general, asymptomatic patients with channelopathies are at increased risk of sudden cardiac death (SCD), due to pathogenic variants in genes encoding ion channels... (Review)
Review
In general, asymptomatic patients with channelopathies are at increased risk of sudden cardiac death (SCD), due to pathogenic variants in genes encoding ion channels that result in pathological ion currents. Channelopathies include long-QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and short-QT syndrome (SQTS). In addition to the patient's clinical presentation, history and clinical tests, the main diagnostic tools are electrocardiography and genetic testing to identify known gene mutations. Early and correct diagnosis as well as further risk stratification of affected individuals and their relatives are paramount for prognosis. The recent availability of risk score calculators for LQTS and BrS allows SCD risk to be accurately estimated. The extent to which these improve patient selection for treatment with an implantable cardioverter-defibrillator (ICD) system is currently unknown. In most cases, initiation of basic therapy in asymptomatic patients in the form of avoidance of triggers, which are usually medication or stressful situations, is sufficient and contributes to risk reduction. In addition, there are other risk-reducing prophylactic measures, such as permanent medication with nonselective β‑ blockers (for LQTS and CPVT) or mexiletine for LQTS3. Patients and their family members should be referred to specialized outpatient clinics for individual risk stratification in the sense of primary prophylaxis.
Topics: Humans; Channelopathies; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Long QT Syndrome; Brugada Syndrome; Tachycardia, Ventricular; Adrenergic beta-Antagonists; Risk Assessment
PubMed: 37103573
DOI: 10.1007/s00399-023-00937-4 -
The Korean Journal of Physiology &... May 2023Cardiotoxicity, particularly drug-induced Torsades de Pointes (TdP), is a concern in drug safety assessment. The recent establishment of human induced pluripotent stem...
Cardiotoxicity, particularly drug-induced Torsades de Pointes (TdP), is a concern in drug safety assessment. The recent establishment of human induced pluripotent stem cell-derived cardiomyocytes (human iPSC-CMs) has become an attractive human-based platform for predicting cardiotoxicity. Moreover, electrophysiological assessment of multiple cardiac ion channel blocks is emerging as an important parameter to recapitulate proarrhythmic cardiotoxicity. Therefore, we aimed to establish a novel multiple cardiac ion channel screening-based method using human iPSC-CMs to predict the drug-induced arrhythmogenic risk. To explain the cellular mechanisms underlying the cardiotoxicity of three representative TdP high- (sotalol), intermediate- (chlorpromazine), and low-risk (mexiletine) drugs, and their effects on the cardiac action potential (AP) waveform and voltage-gated ion channels were explored using human iPSC-CMs. In a proof-of-principle experiment, we investigated the effects of cardioactive channel inhibitors on the electrophysiological profile of human iPSC-CMs before evaluating the cardiotoxicity of these drugs. In human iPSC-CMs, sotalol prolonged the AP duration and reduced the total amplitude (TA) selective inhibition of I and I currents, which are associated with an increased risk of ventricular tachycardia TdP. In contrast, chlorpromazine did not affect the TA; however, it slightly increased AP duration balanced inhibition of I and I currents. Moreover, mexiletine did not affect the TA, yet slightly reduced the AP duration dominant inhibition of I currents, which are associated with a decreased risk of ventricular tachycardia TdP. Based on these results, we suggest that human iPSC-CMs can be extended to other preclinical protocols and can supplement drug safety assessments.
PubMed: 37078300
DOI: 10.4196/kjpp.2023.27.3.267 -
Crystal Growth & Design Apr 2023A porous, nonsolvated polymorph of the voltage-gated sodium channel blocker mexiletine hydrochloride absorbs iodine vapor to give a pharmaceutical cocrystal...
A porous, nonsolvated polymorph of the voltage-gated sodium channel blocker mexiletine hydrochloride absorbs iodine vapor to give a pharmaceutical cocrystal incorporating an ICl anion that forms a halogen-π interaction with the mexiletine cations. The most thermodynamically stable form of the compound does not absorb iodine. This example shows that vapor sorption is a potentially useful and underused tool for bringing about changes in pharmaceutical solid form as part of a solid form screening protocol.
PubMed: 37038401
DOI: 10.1021/acs.cgd.2c01464 -
Circulation. Genomic and Precision... Jun 2023
Topics: Humans; Autistic Disorder; Calcium Channels, L-Type; Long QT Syndrome; Syndactyly; Child
PubMed: 37009738
DOI: 10.1161/CIRCGEN.122.004010 -
World Journal of Clinical Cases Mar 2023The R-on-T phenomenon is a malignant arrhythmia associated with potentially catastrophic consequences. It may initiate ventricular tachycardia or ventricular...
BACKGROUND
The R-on-T phenomenon is a malignant arrhythmia associated with potentially catastrophic consequences. It may initiate ventricular tachycardia or ventricular fibrillation, which can result in syncope or sudden cardiac death. This manifestation poses a great challenge for anesthesiologists. However, it is rarely encountered in the perioperative setting.
CASE SUMMARY
We herein present a case in which the R-on-T phenomenon was incidentally revealed by 24-h Holter monitoring in a patient diagnosed with sigmoid colon cancer. Careful evaluation and treatment with mexiletine were carried out preoperatively under consultation with a cardiovascular specialist, and surgery was uneventfully performed under general anesthesia after thorough preparation.
CONCLUSION
Physicians should be vigilant about this infrequent but potentially fatal arrhythmia. Our experience suggests that the anesthetic process can be greatly optimized with careful preparation.
PubMed: 36998950
DOI: 10.12998/wjcc.v11.i9.2098 -
Pediatrics International : Official... Jan 2023
Topics: Humans; Mexiletine; Flecainide; Cardiac Conduction System Disease; Long QT Syndrome; Anti-Arrhythmia Agents; Electrocardiography
PubMed: 36847291
DOI: 10.1111/ped.15517 -
Muscle & Nerve May 2023Myotonic dystrophy (DM) is a systemic disease with multiple organ complications, making the standardization of medical care a challenge. We analyzed data from Japan's...
INTRODUCTION/AIMS
Myotonic dystrophy (DM) is a systemic disease with multiple organ complications, making the standardization of medical care a challenge. We analyzed data from Japan's national registry to clarify the current treatment patterns and demographic features of Japanese DM patients.
METHODS
Using the Japanese National Registry of Muscular Dystrophy (Remudy), we analyzed medical care practice for the multisystemic issues associated with adult DM type 1 patients, excluding congenital DM.
RESULTS
We included 809 patients with a median age of 44.2 years. Among these patients, 15.8% used ventilators; 31.7% met the index considered at risk for sudden death due to cardiac conduction defects (PR interval over 240 milliseconds or QRS duration over 120 milliseconds) and 2.8% had implanted cardiac devices. Medication for heart failure was prescribed to 9.6% of patients. Overall, 21.2% of patients had abnormal glucose metabolism, of whom 42.9% were treated with oral medications. Among the oral medications, dipeptidyl peptidase-4 inhibitors were the most common. Cancers were observed in 3.7% of the patients, and endometrial and breast cancers were dominant. Mexiletine was prescribed for myotonia in 1.9% of the patients, and only 1% of the patients received medication for daytime sleepiness.
DISCUSSION
This study shows difference in treatment patterns for DM1 in Japan compared with other countries, such as lower rates of use of implantable cardiac devices and higher rates of ventilator use. These data may be useful in discussions aimed at standardizing medical care for patients with DM.
Topics: Adult; Humans; Myotonic Dystrophy; Japan; Muscular Dystrophies; Myotonia; Registries
PubMed: 36762492
DOI: 10.1002/mus.27799 -
International Journal of Biological... Apr 2023SARS-CoV-2 Main protease (M) is a well-known drug target against SARS-CoV-2 infection. Identification of M inhibitors is vigorously pursued due to its crucial role in...
SARS-CoV-2 Main protease (M) is a well-known drug target against SARS-CoV-2 infection. Identification of M inhibitors is vigorously pursued due to its crucial role in viral replication. The present study was aimed to identify M inhibitors via repurposing of US-FDA approved drugs by STD-NMR spectroscopy. In this study, 156 drugs and natural compounds were evaluated against M. Among them, 10 drugs were found to be interacting with M, including diltiazem HCl (1), mefenamic acid (2), losartan potassium (3), mexiletine HCl (4), glaucine HBr (5), trimebutine maleate (6), flurbiprofen (7), amantadine HCl (8), dextromethorphan (9), and lobeline HCl (10) in STD-NMR spectroscopy. Their interactions were compared with three standards (Repurposed anti-viral drugs), dexamethasone, chloroquine phosphate, and remdesivir. Thermal stability of M and dissociation constant (K) of six interacting drugs were also determined using DSF. RMSD plots in MD simulation studies showed the formation of stable protein-ligand complexes. They were further examined for their antiviral activity by plaque reduction assay against SARS-CoV-2, which showed 55-100% reduction in viral plaques. This study demonstrates the importance of drug repurposing against emerging and neglected diseases. This study also exhibits successful application of STD-NMR spectroscopy combined with plaque reduction assay in rapid identification of potential anti-viral agents.
Topics: Humans; Antiviral Agents; COVID-19; SARS-CoV-2; Drug Repositioning; Protease Inhibitors; Molecular Docking Simulation; Molecular Dynamics Simulation
PubMed: 36740128
DOI: 10.1016/j.ijbiomac.2023.123540 -
Heart Rhythm May 2023Pathogenic variants in the SCN5A-encoded Nav1.5 sodium channel cause type 3 long QT syndrome (LQT3). We present the case of an infant with severe LQT3 who was refractory...
Functional characterization and identification of a therapeutic for a novel SCN5A-F1760C variant causing type 3 long QT syndrome refractory to all guideline-directed therapies.
BACKGROUND
Pathogenic variants in the SCN5A-encoded Nav1.5 sodium channel cause type 3 long QT syndrome (LQT3). We present the case of an infant with severe LQT3 who was refractory to multiple pharmacologic therapies as well as bilateral stellate ganglionectomy. The patient's novel variant, p.F1760C-SCN5A, involves a critical residue of the Nav1.5's local anesthetic binding domain.
OBJECTIVE
The purpose of this study was to characterize functionally the p.F1760C-SCN5A variant using TSA-201 and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
METHODS
Whole-cell patch clamp was used to assess p.F1760C-SCN5A associated sodium currents with/without lidocaine (Lido), flecainide, and phenytoin (PHT) in TSA-201 cells. p.F1760C-SCN5A and CRISPR-Cas9 variant-corrected isogenic control (IC) iPSC-CMs were generated. FluoVolt voltage dye was used to measure the action potential duration (APD) with/without mexiletine or PHT.
RESULTS
V of inactivation was right-shifted significantly in F1760C cells (-72.2 ± 0.7 mV) compared to wild-type (WT) cells (-86.3 ± 0.9 mV; P <.0001) resulting in a marked increase in window current. F1760C increased sodium late current 2-fold from 0.18% ± 0.04% of peak in WT to 0.49% ± 0.07% of peak in F1760C (P = .0005). Baseline APD to 90% repolarization (APD) was increased markedly in F1760C iPSC-CMs (601 ± 4 ms) compared to IC iPSC-CMs (423 ± 15 ms; P <.0001). However, 4-hour treatment with 10 μM mexiletine failed to shorten APD, and treatment with 5μM PHT significantly decreased APD of F1760C iPSC-CMs (453 ± 6 ms; P <.0001).
CONCLUSION
PHT rescued electrophysiological phenotype and APD of a novel p.F1760C-SCN5A variant. The antiepileptic drug PHT may be an effective alternative therapeutic for the treatment of LQT3, especially for variants that disrupt the Lido/mexiletine binding site.
Topics: Humans; Infant; Anti-Arrhythmia Agents; Lidocaine; Long QT Syndrome; Mexiletine; NAV1.5 Voltage-Gated Sodium Channel
PubMed: 36731785
DOI: 10.1016/j.hrthm.2023.01.032 -
Experimental Neurology Apr 2023Non-dystrophic myotonias include several entities with possible clinical overlap, i.e. myotonia congenita caused by CLCN1 gene mutations, as well as paramyotonia...
Non-dystrophic myotonias include several entities with possible clinical overlap, i.e. myotonia congenita caused by CLCN1 gene mutations, as well as paramyotonia congenita and sodium channel myotonia caused by SCN4A gene mutations. Herein, we describe the clinical features of five relatives affected by clinical and neurophysiological myotonia, with an aspecific and mixed phenotype. Next-generation sequencing identified the novel p.K1302R variant in SCN4A and the p.H838P variant in CLCN1. Segregation of the two mutations with the disease was confirmed by genotyping affected and non-affected family members. Patch-clamp experiments showed that sodium currents generated by p.K1302R and WT hNav1.4 were very similar. Mutant channel showed a small negative shift (5 mV) in the voltage-dependence of activation, which increased the likelihood of the channel to open at more negative voltages. The p.H838P mutation caused a reduction in chloride current density and a small voltage-dependence shift towards less negative potentials, in agreement with its position into the CBS2 domain of the C-terminus. Our results demonstrated that the mild functional alterations induced by p.K1302R and p.H838P in combination may be responsible for the mixed myotonic phenotypes. The K1302R mutant was sensitive to mexiletine and lamotrigine, suggesting that both drugs might be useful for the K1302R carriers.
Topics: Humans; NAV1.4 Voltage-Gated Sodium Channel; Mutation; Myotonia; Myotonia Congenita; Phenotype; Chloride Channels
PubMed: 36720299
DOI: 10.1016/j.expneurol.2023.114342