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International Journal of Obesity (2005) Apr 2021Atrial fibrillation (AF) is the most common sustained arrhythmia, with growing evidence identifying obesity as an important risk factor for the development of AF....
Phospho-ablation of cardiac sodium channel Na1.5 mitigates susceptibility to atrial fibrillation and improves glucose homeostasis under conditions of diet-induced obesity.
BACKGROUND
Atrial fibrillation (AF) is the most common sustained arrhythmia, with growing evidence identifying obesity as an important risk factor for the development of AF. Although defective atrial myocyte excitability due to stress-induced remodeling of ion channels is commonly observed in the setting of AF, little is known about the mechanistic link between obesity and AF. Recent studies have identified increased cardiac late sodium current (I) downstream of calmodulin-dependent kinase II (CaMKII) activation as an important driver of AF susceptibility.
METHODS
Here, we investigated a possible role for CaMKII-dependent I in obesity-induced AF using wild-type (WT) and whole-body knock-in mice that ablates phosphorylation of the Na1.5 sodium channel and prevents augmentation of the late sodium current (S571A; SA mice).
RESULTS
A high-fat diet (HFD) increased susceptibility to arrhythmias in WT mice, while SA mice were protected from this effect. Unexpectedly, SA mice had improved glucose homeostasis and decreased body weight compared to WT mice. However, SA mice also had reduced food consumption compared to WT mice. Controlling for food consumption through pair feeding of WT and SA mice abrogated differences in weight gain and AF inducibility, but not atrial fibrosis, premature atrial contractions or metabolic capacity.
CONCLUSIONS
These data demonstrate a novel role for CaMKII-dependent regulation of Na1.5 in mediating susceptibility to arrhythmias and whole-body metabolism under conditions of diet-induced obesity.
Topics: Animals; Atrial Fibrillation; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Diet, High-Fat; Gene Knock-In Techniques; Glucose; Homeostasis; Male; Mexiletine; Mice; Mice, Inbred C57BL; NAV1.5 Voltage-Gated Sodium Channel; Obesity; Phosphorylation
PubMed: 33500550
DOI: 10.1038/s41366-021-00742-4 -
Annals of Noninvasive Electrocardiology... May 2021SCN5A-related Brugada syndrome (BrS) can be caused by multiple mechanisms including trafficking defects and altered channel gating properties. Most SCN5A mutations at...
BACKGROUND
SCN5A-related Brugada syndrome (BrS) can be caused by multiple mechanisms including trafficking defects and altered channel gating properties. Most SCN5A mutations at pore region cause trafficking defects, and some of them can be rescued by mexiletine (MEX).
OBJECTIVE
We recently encountered symptomatic siblings with BrS and sought to identify a responsible mutation and reveal its biophysical defects.
METHODS
Target panel sequencing was performed. Wild-type (WT) or identified mutant SCN5A was transfected into tsA201 cells. After incubation of transfected cells with or without 0.1 mM MEX for 24-36 hr, whole-cell sodium currents (I ) were recorded using patch-clamp techniques.
RESULTS
The proband was 29-year-old male who experienced cardiopulmonary arrest. Later, his 36-year-old sister, who had been suffering from recurrent episodes of syncope since 12 years, was diagnosed with BrS. An SCN5A W374G mutation, located at pore region of domain 1 (D1 pore), was identified in both. The peak density of W374G-I was markedly reduced (WT: 521 ± 38 pA/pF, W374G: 60 ± 10 pA/pF, p < .01), and steady-state activation (SSA) was shifted to depolarizing potentials compared with WT-I (V -WT: -39.1 ± 0.8 mV, W374G: -30.9 ± 1.1 mV, p < .01). Incubation of W374G-transfected cells with MEX (W374G-MEX) increased I density, but it was still reduced compared with WT-I (W374G-MEX: 174 ± 19 pA/pF, p < .01 versus W374G, p < .01 versus WT). The SSA of W374G-MEX-I was comparable to W374G-I (V -W374G-MEX: -31.6 ± 0.7 mV, P = NS).
CONCLUSIONS
Reduced current density, possibly due to a trafficking defect, and depolarizing shift in activation of SCN5A W374G are underlying biophysical defects in this severe form of BrS. Trafficking defects of SCN5A mutations at D1 pore may be commonly rescued by MEX.
Topics: Adult; Anti-Arrhythmia Agents; Brugada Syndrome; Electrocardiography; Female; Humans; Male; Mexiletine; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Patient Acuity
PubMed: 33463855
DOI: 10.1111/anec.12828 -
Clinical and Translational Science May 2021The risk of fatal arrhythmias is the major concern for using chloroquine (CQ) or hydroxychloroquine (HCQ) to treat coronavirus disease 2019 (COVID-19), but the reported...
The risk of fatal arrhythmias is the major concern for using chloroquine (CQ) or hydroxychloroquine (HCQ) to treat coronavirus disease 2019 (COVID-19), but the reported number of life-threatening arrhythmic events or deaths is relatively small. The objective of this study was to assess the arrhythmogenic risk of these two drugs using a multiscale heart simulation, which allows testing even at high concentrations, including those that cause fatal arrhythmias. We measured the inhibitory action of CQ, HCQ, and HCQ with 30 μM azithromycin (AZ) on six ion currents (fast [INa] and late [INa,L] components of the sodium current, L-type calcium current [ICa,L], rapid [IKr/hERG], and slow [IKs] components of delayed rectifier potassium, and inward rectifier potassium [IK1]) over a wide range of concentrations using the automated patch-clamp system. Using the concentration-inhibition relationship that was thus obtained, we simulated the drug effects while increasing the concentration until the life-threatening arrhythmia, torsade de pointes (TdP), was observed. The obtained threshold concentrations for TdP were 12.5, 35, and 22.5 μM for CQ, HCQ, and HCQ with AZ, respectively. Adding therapeutic concentrations of mexiletine or verapamil successfully prevented the occurrence of TdP, and verapamil was more effective. CQ, HCQ, and HCQ with AZ thresholds for TdP were larger than both antiviral concentrations that were reported by in vitro experiments and free plasma concentrations that were attained by the clinically used dosage. The current simulation data provided a safety margin to the currently used clinical dose for CQ and HCQ/AZ. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Despite the potent in vitro antiviral effect, clinical trials have failed to show the therapeutic effects of chloroquine (CQ) and hydroxychloroquine (HCQ)/azithromycin (AZ) to treat coronavirus disease 2019. Torsadogenic potentials may limit the dosage of these drugs, but the reported incidence of fatal arrhythmias is rare. WHAT QUESTION DID THIS STUDY ADDRESS? Our objective was to assess the arrhythmogenicity of CQ and HCQ/AZ over a wide range of drug concentrations using a multiscale heart simulation. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our study showed that CQ and HCQ/AZ do not induce fatal arrhythmias even at concentrations much higher than in vitro antiviral half-maximal effective concentration (EC ) values at which QT prolongation exceeds 150 ms. We also found that estimated free plasma concentrations of CQ and HCQ/AZ achieved by currently used dosing protocols are lower than the antiviral EC for these drugs. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Our simulation data provided a safety margin to the currently used clinical dose for CQ and HCQ/AZ.
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chloroquine; Computer Simulation; Electrocardiography; Humans; Hydroxychloroquine; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33404133
DOI: 10.1111/cts.12976 -
Journal of Neurology, Neurosurgery, and... Mar 2021The management of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform... (Comparative Study)
Comparative Study Meta-Analysis
INTRODUCTION
The management of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) remains challenging in view of the paucity of data and evidence-based treatment recommendations are missing.
METHODS
In this single-centre, non-randomised, prospective open-label study, we evaluated and compared the efficacy of oral and parenteral treatments for SUNCT and SUNA in a real-world setting. Additionally, single-arm meta-analyses of the available reports of SUNCT and SUNA treatments were conducted.
RESULTS
The study cohort comprised 161 patients. Most patients responded to lamotrigine (56%), followed by oxcarbazepine (46%), duloxetine (30%), carbamazepine (26%), topiramate (25%), pregabalin and gabapentin (10%). Mexiletine and lacosamide were effective in a meaningful proportion of patients but poorly tolerated. Intravenous lidocaine given for 7-10 days led to improvement in 90% of patients, whereas only 27% of patients responded to a greater occipital nerve block. No statistically significant differences in responders were observed between SUNCT and SUNA. In the meta-analysis of the pooled data, topiramate was found to be significantly more effective in SUNCT than SUNA patients. However, a higher proportion of SUNA than SUNCT was considered refractory to medications at the time of the topiramate trial, possibly explaining this isolated difference.
CONCLUSIONS
We propose a treatment algorithm for SUNCT and SUNA for clinical practice. The response to sodium channel blockers indicates a therapeutic overlap with trigeminal neuralgia, suggesting that sodium channels dysfunction may be a key pathophysiological hallmark in these disorders. Furthermore, the therapeutic similarities between SUNCT and SUNA further support the hypothesis that these conditions are variants of the same disorder.
Topics: Administration, Oral; Adolescent; Adult; Aged; Analgesics; Anesthetics, Local; Anticonvulsants; Female; Humans; Infusions, Parenteral; Male; Middle Aged; Prospective Studies; SUNCT Syndrome; Young Adult
PubMed: 33361408
DOI: 10.1136/jnnp-2020-323999 -
Muscle & Nerve Mar 2021To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial.
METHODS
Twenty ALS subjects were randomized to placebo and mexiletine 300 or 600 mg daily for 4 wk and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT).
RESULTS
RMT was unchanged with 4 wk of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (P = .039). Reductions of motor evoked potential (MEP) amplitude (P = .013) and accommodation half-time (P = .002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 wk on mexiletine.
CONCLUSIONS
The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half-time supports the reduction of cortical and axonal hyperexcitability with mexiletine.
Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Axons; Cortical Excitability; Double-Blind Method; Electrodiagnosis; Electromyography; Evoked Potentials, Motor; Female; Humans; Male; Median Nerve; Mexiletine; Middle Aged; Neural Conduction; Preliminary Data; Transcranial Magnetic Stimulation; Voltage-Gated Sodium Channel Blockers
PubMed: 33340120
DOI: 10.1002/mus.27146 -
Journal of Neuromuscular Diseases 2021Skeletal muscle ion channelopathies include non-dystrophic myotonias (NDM), periodic paralyses (PP), congenital myasthenic syndrome, and recently identified congenital...
BACKGROUND
Skeletal muscle ion channelopathies include non-dystrophic myotonias (NDM), periodic paralyses (PP), congenital myasthenic syndrome, and recently identified congenital myopathies. The treatment of these diseases is mainly symptomatic, aimed at reducing muscle excitability in NDM or modifying triggers of attacks in PP.
OBJECTIVE
This systematic review collected the evidences regarding effects of pharmacological treatment on muscle ion channelopathies, focusing on the possible link between treatments and genetic background.
METHODS
We searched databases for randomized clinical trials (RCT) and other human studies reporting pharmacological treatments. Preclinical studies were considered to gain further information regarding mutation-dependent drug effects. All steps were performed by two independent investigators, while two others critically reviewed the entire process.
RESULTS
For NMD, RCT showed therapeutic benefits of mexiletine and lamotrigine, while other human studies suggest some efficacy of various sodium channel blockers and of the carbonic anhydrase inhibitor (CAI) acetazolamide. Preclinical studies suggest that mutations may alter sensitivity of the channel to sodium channel blockers in vitro, which has been translated to humans in some cases. For hyperkalemic and hypokalemic PP, RCT showed efficacy of the CAI dichlorphenamide in preventing paralysis. However, hypokalemic PP patients carrying sodium channel mutations may have fewer benefits from CAI compared to those carrying calcium channel mutations. Few data are available for treatment of congenital myopathies.
CONCLUSIONS
These studies provided limited information about the response to treatments of individual mutations or groups of mutations. A major effort is needed to perform human studies for designing a mutation-driven precision medicine in muscle ion channelopathies.
Topics: Channelopathies; Humans; Hypokalemic Periodic Paralysis; Lamotrigine; Mexiletine; Muscle, Skeletal; Mutation; Myasthenic Syndromes, Congenital; Myotonic Disorders; Precision Medicine; Randomized Controlled Trials as Topic; Sodium Channel Blockers
PubMed: 33325393
DOI: 10.3233/JND-200582 -
Pharmaceutics Dec 2020Physiologically-based pharmacokinetic (PBPK) modeling is a well-recognized method for quantitatively predicting the effect of intrinsic/extrinsic factors on drug...
A Physiologically-Based Pharmacokinetic (PBPK) Model Network for the Prediction of CYP1A2 and CYP2C19 Drug-Drug-Gene Interactions with Fluvoxamine, Omeprazole, S-mephenytoin, Moclobemide, Tizanidine, Mexiletine, Ethinylestradiol, and Caffeine.
Physiologically-based pharmacokinetic (PBPK) modeling is a well-recognized method for quantitatively predicting the effect of intrinsic/extrinsic factors on drug exposure. However, there are only few verified, freely accessible, modifiable, and comprehensive drug-drug interaction (DDI) PBPK models. We developed a qualified whole-body PBPK DDI network for cytochrome P450 (CYP) CYP2C19 and CYP1A2 interactions. Template PBPK models were developed for interactions between fluvoxamine, S-mephenytoin, moclobemide, omeprazole, mexiletine, tizanidine, and ethinylestradiol as the perpetrators or victims. Predicted concentration-time profiles accurately described a validation dataset, including data from patients with genetic polymorphisms, demonstrating that the models characterized the CYP2C19 and CYP1A2 network over the whole range of DDI studies investigated. The models are provided on GitHub (GitHub Inc., San Francisco, CA, USA), expanding the library of publicly available qualified whole-body PBPK models for DDI predictions, and they are thereby available to support potential recommendations for dose adaptations, support labeling, inform the design of clinical DDI trials, and potentially waive those.
PubMed: 33302490
DOI: 10.3390/pharmaceutics12121191 -
Journal of Neurology May 2021Non-dystrophic myotonias (NDM) are heterogeneous diseases caused by mutations in CLCN1 and SCN4A. The study aimed to describe the clinical and genetic spectrum of NDM in...
INTRODUCTION
Non-dystrophic myotonias (NDM) are heterogeneous diseases caused by mutations in CLCN1 and SCN4A. The study aimed to describe the clinical and genetic spectrum of NDM in a large German cohort.
METHODS
We retrospectively identified all patients with genetically confirmed NDM diagnosed in our center. The following data were analyzed: demographics, family history, muscular features, cardiac involvement, CK, EMG, genotype, other tested genes, treatment perceived efficacy.
RESULTS
70 patients (age 40.2 years ± 14.9; 52.8% males) were included in our study (48 NDM-CLCN1, 22 NDM-SCN4A). The most frequent presenting symptoms were myotonia (NDM-CLCN1 83.3%, NDM-SCN4A 72.2%) and myalgia (NDM-CLCN1 57.4%, NDM-SCN4A 52.6%). Besides a more prominent facial involvement in NDM-SCN4A and cold-sensitivity in NDM-CLCN1, no other significant differences were observed between groups. Cardiac arrhythmia or conduction defects were documented in sixNDM-CLCN1 patients (three of them requiring a pacemaker) and one patient with NDM-SCN4A. CK was normal in 40% of patients. Myotonic runs in EMG were detected in 89.1% of CLCN1 and 78.9% of SCN4A. 50% of NDM-CLCN1 patients had the classic c.2680C>T (p.Arg894*) mutation. 12 new genetic variants are reported. About 50% of patients were not taking any anti-myotonic drug at the last follow-up. The anti-myotonic drugs with the best patient's perceived efficacy were mexiletine and lamotrigine.
CONCLUSION
This study highlights the relevant clinical overlap between NDM-CLCN1 and NDM-SCN4A patients and warrants the use of early and broad genetic investigation for the precise identification of the NDM subtype. Besides the clinical and genetic heterogeneity, the limited response to current anti-myotonic drugs constitutes a continuing challenge.
Topics: Adult; Chloride Channels; Female; Humans; Male; Mutation; Myotonia; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Retrospective Studies
PubMed: 33263785
DOI: 10.1007/s00415-020-10328-1 -
Journal of Cardiology Cases Nov 2020Congenital long-QT syndrome type 3 (LQT3) with -V411M mutation has been reported as a malignant case of LQT3 with highest risk for sudden cardiac death (SCD). Here, we...
Congenital long-QT syndrome type 3 (LQT3) with -V411M mutation has been reported as a malignant case of LQT3 with highest risk for sudden cardiac death (SCD). Here, we present two cases of LQT3 with -V411M who had been implanted with subcutaneous (S-) or transvenous (TV-) implantable cardioverter defibrillators (ICD). Case 1, a 2-year-old boy, although he had no symptoms, was diagnosed as having LQT3 (V411M-) due to family history. The QTc interval was still longer than 500 ms during follow-up even under oral mexiletine. Case 2 (his aunt) diagnosed as LQT3 suffered from syncope caused by ventricular fibrillation at 35-years-old despite taking mexiletine. Furthermore, case 1's father and half-brother, both had the V411M mutation with LQT3, had suddenly died. Thus, case 1 was recommended S-ICD when he was 15-years-old for primary prevention of SCD but not necessary for pacing therapy, while, case 2 had been implanted TV-ICD for secondary prevention of SCD. They had no event after ICD implantation, however, case 2 had to have added an extra ICD-lead due to lead failure when she was 44-years-old. The S-ICD may be a potent therapeutic option for high-risk LQTS when patients are younger and do not need pacing therapy. < In congenital long-QT syndrome (LQTS) type 3, some of the first events are lethal, particularly, LQT3 with V411M- mutation is the highest risk for sudden cardiac death (SCD). Which implantable cardioverter defibrillator (ICD), transvenous (TV-ICD) or subcutaneous (S-ICD) is better for primary prevention of SCD in LQTS is still controversial. The S-ICD rather than TV-ICD may have a potent benefit for high-risk LQTS when patients are younger and do not need pacing therapy.>.
PubMed: 33133318
DOI: 10.1016/j.jccase.2020.07.007 -
ESC Heart Failure Dec 2020SCN5A gene mutations are described in 2% of patients with dilated cardiomyopathy (DCM) and different rhythm disturbances, including multifocal ectopic Purkinje-related...
SCN5A gene mutations are described in 2% of patients with dilated cardiomyopathy (DCM) and different rhythm disturbances, including multifocal ectopic Purkinje-related premature contractions. Recent data indicate that sodium channel blockers are particularly effective monotherapy in carriers of the R222Q SCN5A variant. Our purpose is to describe the effectiveness of antiarrhythmic treatment in a family with genetically determined arrhythmogenic DCM associated with the R814W variant in the SCN5A gene. We examined a family with arrhythmogenic DCM (multifocal ectopic Purkinje-related premature contractions phenotype, atrial tachyarrhythmias, automatism, and conduction disorders) and described antiarrhythmic treatment efficacy in heart failure symptoms reduction and myocardial function improvement. We found a heterozygotic mutation R814W in SCN5A by whole exome sequencing in the proband and confirmed its presence in all affected subjects. There were two sudden cardiac deaths and one heart transplantation among first-degree relatives. The 58-year-old father and his 37-year-old daughter had full spectrum of symptoms associated with R814W SCN5A mutation. Both had implanted cardioverter defibrillator. In the father, adding mexiletine to quinidine therapy reduced ventricular arrhythmia (50-60% → 6-8% of whole rhythm) and reverted long-standing atrial fibrillation to sinus rhythm. In the daughter, mexiletine and overdrive pacing were effective in ventricular arrhythmia reduction (25% → 0.01%). Because of a growing number of atrial fibrillation recurrences, a reduced dose of quinidine (subsequently flecainide) was added, resulting in arrhythmia significant reduction. In both cases, antiarrhythmic effectiveness correlated with clinical improvement. In SCN5A R814W-associated DCM, a combination of Class I antiarrhythmics and overdrive pacing is an effective treatment of severe ventricular and atrial arrhythmias.
PubMed: 33084224
DOI: 10.1002/ehf2.12993