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Journal of Molecular and Cellular... Jul 2020Genetic variants in SCN5A can result in channelopathies such as the long QT syndrome type 3 (LQT3), but the therapeutic response to Na channel blockers can vary. We...
BACKGROUND
Genetic variants in SCN5A can result in channelopathies such as the long QT syndrome type 3 (LQT3), but the therapeutic response to Na channel blockers can vary. We previously reported a case of an infant with malignant LQT3 and a missense Q1475P SCN5A variant, who was effectively treated with phenytoin, but only partially with mexiletine. Here, we functionally characterized this variant and investigated possible mechanisms for the differential drug actions.
METHODS
Wild-type or mutant Na1.5 cDNAs were examined in transfected HEK293 cells with patch clamping and biochemical assays. We used computational modeling to provide insights into altered channel kinetics and to predict effects on the action potential.
RESULTS
The Q1475P variant in Na1.5 reduced the current density and channel surface expression, characteristic of a trafficking defect. The variant also led to positive shifts in the voltage dependence of steady-state activation and inactivation, faster inactivation and recovery from inactivation, and increased the "late" Na current. Simulations of Na1.5 gating with a 9-state Markov model suggested that transitions from inactivated to closed states were accelerated in Q1475P channels, leading to accumulation of channels in non-inactivated closed states. Simulations with a human ventricular myocyte model predicted action potential prolongation with Q1475P, compared with wild type, channels. Patch clamp data showed that mexiletine and phenytoin similarly rescued some of the gating defects. Chronic incubation with mexiletine, but not phenytoin, rescued the Na1.5-Q1475P trafficking defect, thus increasing mutant channel expression.
CONCLUSIONS
The gain-of-function effects of Na1.5-Q1475P predominate to cause a malignant long QT phenotype. Phenytoin partially corrects the gating defect without restoring surface expression of the mutant channel, whereas mexiletine restores surface expression of the mutant channel, which may explain the lack of efficacy of mexiletine when compared to phenytoin. Our data makes a case for experimental studies before embarking on a one-for-all therapy of arrhythmias.
Topics: Action Potentials; Amino Acid Substitution; Anti-Arrhythmia Agents; Cardiac Conduction System Disease; Cells, Cultured; Disease Management; Disease Susceptibility; Gain of Function Mutation; HEK293 Cells; Humans; Ion Channel Gating; Long QT Syndrome; Models, Biological; Mutation, Missense; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Phenytoin; Voltage-Gated Sodium Channel Blockers
PubMed: 32339567
DOI: 10.1016/j.yjmcc.2020.04.027 -
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 -
Frontiers in Physiology 2022The voltage-gated sodium channel Na1.5 plays an essential role in the generation and propagation of action potential in cardiomyocytes. Mutations in Na1.5 have been...
The voltage-gated sodium channel Na1.5 plays an essential role in the generation and propagation of action potential in cardiomyocytes. Mutations in Na1.5 have been associated with LQT syndrome, Brugada syndrome, and sudden arrhythmia death syndrome. Genetic studies showed that Na1.5 mutations vary across race-ethnic groups. Here we investigated an Asian-specific mutation Na1.5-P1090L associated with LQT syndrome. We found that Na1.5-P1090L mutation perturbed the sodium channel function. It altered the gating process of the channel and exhibited an enhanced window current. Treatment with mexiletine reversed the depolarization shift of the steady-state inactivation produced by P1090L. Mexiletine also modified the recovery from steady-state inactivation and the development of inactivation of P1090L. It rescued the dysfunctional inactivation of P1090L and reduced the P1090L channel's availability.
PubMed: 35864896
DOI: 10.3389/fphys.2022.904664 -
Journal of Pain & Palliative Care... Jun 2020Lidocaine infusion for pain control has been used for years. While some centers transition from continuous infusion lidocaine to oral mexiletine, there are no published...
Lidocaine infusion for pain control has been used for years. While some centers transition from continuous infusion lidocaine to oral mexiletine, there are no published studies to guide this conversion in pain and palliative care settings. This is a retrospective case series of 10 cancer patients across four institutions, with attention to dosing of both agents, and subsequent decrease in morphine-equivalent daily dosing (MEDD). The mean age was 55 years (range 34-78). The mean bolus dose of lidocaine was 1.6 mg/kg, infused over an average of 24 minutes, followed by a mean continuous infusion rate of 1.1 mg/kg/hr, and the infusion was continued for an average of 14.1 hours (range of 0.2 - 28 hours). The mean starting daily mexiletine dose was 400 mg (in 2-3 divided doses) and final dosing averaged 500 mg/day. The mean MEDD prior to starting lidocaine was 1118 mg/24 hours, which, by the time of final mexiletine dosing, was 882 mg/24 hours, a 21% MEDD reduction. The average hospital length of stay was 14 days. There was no lidocaine-induced toxicity and no lidocaine levels were obtained. Two of the 10 patients stopped mexiletine early, one from confusion four days after initiation of mexiletine, and the other after six weeks due to dizziness and visual changes. For cancer patients with suboptimal pain control on large doses of opioid, lidocaine infusion followed by oral mexiletine was well tolerated and effective.
Topics: Administration, Oral; Adult; Aged; Anesthetics, Local; Cancer Pain; Female; Humans; Infusions, Intravenous; Lidocaine; Male; Mexiletine; Middle Aged; Pain, Intractable; Retrospective Studies
PubMed: 32091938
DOI: 10.1080/15360288.2019.1704339 -
Circulation. Arrhythmia and... Jan 2023Macroscopic T wave alternans (macro-TWA) often heralds the onset of Torsades de Pointes in patients with QT prolongation. However, the mechanisms underlying macro-TWA...
BACKGROUND
Macroscopic T wave alternans (macro-TWA) often heralds the onset of Torsades de Pointes in patients with QT prolongation. However, the mechanisms underlying macro-TWA remain unclear. We examined the cellular and ionic basis for macro-TWA in rabbits with left ventricular hypertrophy (LVH).
METHODS
The renovascular hypertension model was used to induce LVH in rabbits. Action potentials were simultaneously recorded from epicardium and endocardium together with a transmural ECG and isometric contractility in arterially perfused left ventricular wedges. Late sodium current (I) was recorded in single-isolated left ventricular myocytes with the whole cell patch-clamp technique.
RESULTS
Macro-TWA and accompanied mechanical alternans occurred spontaneously in 8 of 33 LVH rabbits (<0.05, versus 0/15 in controls) and were induced by an I enhancer ATX-II at 1 to 3 nM in additional 7. Macro-TWA and mechanical alternans occurred discordantly, that is, that longer QT interval and larger T wave were associated with weaker isometric contvractility. Alternating early afterdepolarizations in the endocardium caused macro-TWA in 12 of 15 LVH rabbits and, therefore, early afterdepolarization-dependent R-from-T extrasystoles and Torsades de Pointes always originated from the beats with longer QT and larger T wave during macro-TWA. I density was significantly larger in LVH myocytes than that of control myocytes. Macro-TWA, mechanical alternans, R-from-T extrasystoles, and Torsades de Pointes were all abolished by I blocker ranolazine or mexiletine.
CONCLUSIONS
LVH enhances I density and promotes alternating early afterdepolarizations in the left ventricular endocardium that manifest as macro-TWA with discordant mechanical alternans. I blockade abolishes macro-TWA, mechanical alternans, early afterdepolarization-dependent R-from-T extrasystoles, and Torsades de Pointes.
Topics: Animals; Rabbits; Torsades de Pointes; Bradycardia; Arrhythmias, Cardiac; Heart Ventricles; Long QT Syndrome; Cardiac Complexes, Premature; Electrocardiography; Action Potentials
PubMed: 36595630
DOI: 10.1161/CIRCEP.122.011453 -
Biomedicines Aug 2023The present study was designed to test the hypothesis that the selectivity of blocking the late Na current (I) over the peak Na current (I) is related to the fast offset...
The present study was designed to test the hypothesis that the selectivity of blocking the late Na current (I) over the peak Na current (I) is related to the fast offset kinetics of the Na channel inhibitor. Therefore, the effects of 1 µM GS967 (I inhibitor), 20 µM mexiletine (I/B antiarrhythmic) and 10 µM quinidine (I/A antiarrhythmic) on I and I were compared in canine ventricular myocardium. I was estimated as the maximum velocity of action potential upstroke (V). Equal amounts of I were dissected by the applied drug concentrations under APVC conditions. The inhibition of I by mexiletine and quinidine was comparable under a conventional voltage clamp, while both were smaller than the inhibitory effect of GS967. Under steady-state conditions, the V block at the physiological cycle length of 700 ms was 2.3% for GS967, 11.4% for mexiletine and 26.2% for quinidine. The respective offset time constants were 110 ± 6 ms, 456 ± 284 ms and 7.2 ± 0.9 s. These results reveal an inverse relationship between the offset time constant and the selectivity of I over I inhibition without any influence of the onset rate constant. It is concluded that the selective inhibition of I over I is related to the fast offset kinetics of the Na channel inhibitor.
PubMed: 37760824
DOI: 10.3390/biomedicines11092383 -
Neuromuscular Disorders : NMD Feb 2023Although mexiletine effectively treats myotonia, supply disruptions affected Europe between 2008-2018. MyoPath was a mixed-methods, cross-sectional, market research...
Although mexiletine effectively treats myotonia, supply disruptions affected Europe between 2008-2018. MyoPath was a mixed-methods, cross-sectional, market research survey conducted January-June 2018 to evaluate consequences of limited access to/awareness of mexiletine in people with myotonia. Part A: qualitative structured interviews (clinicians; advocates for adult patients); Part B: quantitative online questionnaire completed by people with self-reported history of myotonia. Part A: Interviews (clinicians, n=12; patient advocates, n=5; 12 countries) indicated poor mexiletine awareness among general neurologists. Patients chose between living with myotonia (other treatments were generally unsatisfactory) or importing mexiletine. Part B: Questionnaire respondents, myotonic dystrophy (DM)1, n=213; DM2, n=128; non-dystrophic myotonia (NDM), n=41; other n=8; (11 countries). Of the respondents, 76/390 (20%) people with awareness of/access to mexiletine described profound improvements in myotonia and health-related quality of life following treatment. Respondents with NDM had greatest mexiletine experience (n=28/41). Mexiletine was associated with fewer falls, less muscle stiffness, increased mobility. Treatment interruptions worsened myotonia and were associated with fatigue, pain, dysphagia, breathing difficulty, impaired digestion, poor sleep. However, 36/54 (67%) of currently treated people expressed anxiety about mexiletine's availability: this finding was expected (MyoPath was undertaken before mexiletine's approval in NDM). MyoPath provides the largest European exploration of patients' views regarding impact of mexiletine on myotonia. Anticipated effects of mexiletine differ between people with different myotonic disorders: myotonia is the main symptom in NDM but one of many potential symptoms affecting those with DM. Nevertheless, findings indicate substantial harm caused to people with myotonia when mexiletine awareness/access is limited.
Topics: Adult; Humans; Mexiletine; Myotonia; Quality of Life; Cross-Sectional Studies; Myotonic Dystrophy; Surveys and Questionnaires
PubMed: 36706619
DOI: 10.1016/j.nmd.2022.12.008 -
Frontiers in Cardiovascular Medicine 2022It is arduous to determine clinical solutions for Andersen-Tawil syndrome (ATS) in patients intolerant of β-blocker. Here, we present the case of a 7-year-old boy with...
It is arduous to determine clinical solutions for Andersen-Tawil syndrome (ATS) in patients intolerant of β-blocker. Here, we present the case of a 7-year-old boy with periodic paralysis and dysmorphic features who experienced syncope four times during exercise. His ECG revealed enlarged U waves and QU-prolongation associated with ATS-specific U wave patterns, frequent PVCs, and non-sustained bidirectional or polymorphic ventricular tachycardia. The genetic test showed a missense R218W mutation of . With the diagnosis of ATS and intolerance of β-blocker, the patient was prescribed oral medications of mexiletine 450 mg/day without severe adverse effects. The repeat ECG showed decreased PVC burden from 38 to 3% and absence of ventricular tachycardia. He remained symptom-free during over 2 years of outpatient follow-up. This case demonstrates a new anti-arrhythmic therapy with mexiletine for prevention of life-threatening cardiac events in patients with ATS who are intolerant of β-blocker treatment.
PubMed: 36093155
DOI: 10.3389/fcvm.2022.992185 -
Frontiers in Pharmacology 2020Re-entry is a basic mechanism of ventricular fibrillation, which can be elicited by extrasystolic activity, but the timing of an extrasystole can be critical. The action...
INTRODUCTION
Re-entry is a basic mechanism of ventricular fibrillation, which can be elicited by extrasystolic activity, but the timing of an extrasystole can be critical. The action potential duration (APD) of an extrasystole depends on the proximity of the preceding beat, and the relation between its timing and its APD is called electrical restitution. The aim of the present work was to study and compare the effect of several antiarrhythmic drugs on restitution in preparations from undiseased human ventricular muscle, and other mammalian species.
METHODS
Action potentials were recorded in preparations obtained from rat, guinea pig, rabbit, and dog hearts; and from undiseased human donor hearts using the conventional microelectrode technique. Preparations were stimulated with different basic cycle lengths (BCLs) ranging from 300 to 5,000 ms. To study restitution, single test pulses were applied at every 20th beat while the preparation was driven at 1,000 ms BCL.
RESULTS
Marked differences were found between the animal and human preparations regarding restitution and steady-state frequency dependent curves. In human ventricular muscle, restitution kinetics were slower in preparations with large phase 1 repolarization with shorter APDs at 1000 ms BCL compared to preparations with small phase 1. Preparations having APD longer than 300 ms at 1000 ms BCL had slower restitution kinetics than those having APD shorter than 250 ms. The selective I inhibitors E-4031 and sotalol increased overall APD and slowed the restitution kinetics, while I inhibition did not influence APD and electrical restitution. Mexiletine and nisoldipine shortened APD, but only mexiletine slowed restitution kinetics.
DISCUSSION
Frequency dependent APD changes, including electrical restitution, were partly determined by the APD at the BCL. Small phase 1 associated with slower restitution suggests a role of I in restitution. APD prolonging drugs slowed restitution, while mexiletine, a known inhibitor of I, shortened basic APD but also slowed restitution. These results indicate that although basic APD has an important role in restitution, other transmembrane currents, such as I or I, can also affect restitution kinetics. This raises the possibility that ion channel modifier drugs slowing restitution kinetics may have antiarrhythmic properties by altering restitution.
PubMed: 32425771
DOI: 10.3389/fphar.2020.00479 -
Cureus Jun 2022Bidirectional ventricular tachycardia (BVT) is a rare and unusual ventricular dysrhythmia that is characterized by a beat-to-beat alternation of the QRS axis. This can...
Bidirectional ventricular tachycardia (BVT) is a rare and unusual ventricular dysrhythmia that is characterized by a beat-to-beat alternation of the QRS axis. This can sometimes manifest as alternating left and right bundle branch blocks. To the best of our knowledge, there are two previous cases of BVT in the setting of type I myocardial infarction. Our case would be the third and showed a subtle change in the anterior-posterior axis that can be seen in lead V2. The coronary angiography of our patient demonstrated severe multivessel coronary artery disease with complete total occlusion of the proximal dominant right coronary artery, 100% in-stent restenosis of the ostial left circumflex, 40% stenosis of left main, and 90% stenosis of mid left anterior descending artery (LAD). The BVT resolved after two amiodarone boluses followed by a drip. We attempted to transition to oral mexiletine, however, the patient was unable to tolerate the medication due to intractable nausea and vomiting. The patient subsequently underwent high risk coronary artery bypass graft surgery with no further episodes of BVT following revascularization and was discharged after six weeks of hospitalization. Although rare, type I myocardial infarction is an important differential diagnosis of BVT.
PubMed: 35832750
DOI: 10.7759/cureus.25845