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Circulation Journal : Official Journal... Nov 2023Cardiac calmodulinopathy, characterized by a life-threatening arrhythmia and sudden death in the young, is extremely rare and caused by genes encoding calmodulin, namely...
BACKGROUND
Cardiac calmodulinopathy, characterized by a life-threatening arrhythmia and sudden death in the young, is extremely rare and caused by genes encoding calmodulin, namely calmodulin 1 (CALM1), CALM2, and CALM3.Methods and Results: We screened 195 symptomatic children (age 0-12 years) who were suspected of inherited arrhythmias for 48 candidate genes, using a next-generation sequencer. Ten probands were identified as carrying variants in any of CALM1-3 (5%; median age 5 years), who were initially diagnosed with long QT syndrome (LQTS; n=5), catecholaminergic polymorphic ventricular tachycardia (CPVT; n=3), and overlap syndrome (n=2). Two probands harbored a CALM1 variant and 8 probands harbored 6 CALM2 variants. There were 4 clinical phenotypes: (1) documented lethal arrhythmic events (LAEs): 4 carriers of N98S in CALM1 or CALM2; (2) suspected LAEs: CALM2 p.D96G and D132G carriers experienced syncope and transient cardiopulmonary arrest under emotional stimulation; (3) critical cardiac complication: CALM2 p.D96V and p.E141K carriers showed severe cardiac dysfunction with QTc prolongation; and (4) neurological and developmental disorders: 2 carriers of CALM2 p.E46K showed cardiac phenotypes of CPVT. Beta-blocker therapy was effective in all cases except cardiac dysfunction, especially in combination with flecainide (CPVT-like phenotype) and mexiletine (LQTS-like).
CONCLUSIONS
Calmodulinopathy patients presented severe cardiac features, and their onset of LAEs was earlier in life, requiring diagnosis and treatment at the earliest age possible.
Topics: Child; Child, Preschool; Humans; Infant; Infant, Newborn; Arrhythmias, Cardiac; Calmodulin; East Asian People; Long QT Syndrome; Phenotype; Tachycardia, Ventricular; Death, Sudden, Cardiac
PubMed: 37380439
DOI: 10.1253/circj.CJ-23-0195 -
Europace : European Pacing,... Jun 2023SCN5A mutations are associated with various cardiac phenotypes, including long QT syndrome type 3 (LQT3), Brugada syndrome (BrS), and cardiac conduction disease (CCD)....
AIMS
SCN5A mutations are associated with various cardiac phenotypes, including long QT syndrome type 3 (LQT3), Brugada syndrome (BrS), and cardiac conduction disease (CCD). Certain mutations, such as SCN5A-1795insD, lead to an overlap syndrome, with patients exhibiting both features of BrS/CCD [decreased sodium current (INa)] and LQT3 (increased late INa). The sodium channel blocker mexiletine may acutely decrease LQT3-associated late INa and chronically increase peak INa associated with SCN5A loss-of-function mutations. However, most studies have so far employed heterologous expression systems and high mexiletine concentrations. We here investigated the effects of a therapeutic dose of mexiletine on the mixed phenotype associated with the SCN5A-1795insD mutation in HEK293A cells and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
METHODS AND RESULTS
To assess only the chronic effects on trafficking, HEK293A cells transfected with wild-type (WT) SCN5A or SCN5A-1795insD were incubated for 48 h with 10 µm mexiletine followed by wash-out, which resulted in an increased peak INa for both SCN5A-WT and SCN5A-1795insD and an increased late INa for SCN5A-1795insD. Acute re-exposure of HEK293A cells to 10 µm mexiletine did not impact on peak INa but significantly decreased SCN5A-1795insD late INa. Chronic incubation of SCN5A-1795insD hiPSC-CMs with mexiletine followed by wash-out increased peak INa, action potential (AP) upstroke velocity, and AP duration. Acute re-exposure did not impact on peak INa or AP upstroke velocity, but significantly decreased AP duration.
CONCLUSION
These findings demonstrate for the first time the therapeutic benefit of mexiletine in a human cardiomyocyte model of SCN5A overlap syndrome.
Topics: Humans; Mexiletine; Cardiac Conduction System Disease; NAV1.5 Voltage-Gated Sodium Channel; Long QT Syndrome; Brugada Syndrome; Action Potentials; Myocytes, Cardiac
PubMed: 37369559
DOI: 10.1093/europace/euad154 -
Journal of Neuromuscular Diseases 2023Myotonia congenita is the most common form of nondystrophic myotonia and is caused by Mendelian inherited mutations in the CLCN1 gene encoding the voltage-gated chloride...
BACKGROUND
Myotonia congenita is the most common form of nondystrophic myotonia and is caused by Mendelian inherited mutations in the CLCN1 gene encoding the voltage-gated chloride channel of skeletal muscle.
OBJECTIVE
The study aimed to describe the clinical and genetic spectrum of Myotonia congenita in a large pediatric cohort.
METHODS
Demographic, genetic, and clinical data of the patients aged under 18 years at time of first clinical attendance from 11 centers in different geographical regions of Türkiye were retrospectively investigated.
RESULTS
Fifty-four patients (mean age:15.2 years (±5.5), 76% males, with 85% Becker, 15% Thomsen form) from 40 families were included. Consanguineous marriage rate was 67%. 70.5% of patients had a family member with Myotonia congenita. The mean age of disease onset was 5.7 (±4.9) years. Overall 23 different mutations (2/23 were novel) were detected in 52 patients, and large exon deletions were identified in two siblings. Thomsen and Becker forms were observed concomitantly in one family. Carbamazepine (46.3%), mexiletine (27.8%), phenytoin (9.3%) were preferred for treatment.
CONCLUSIONS
The clinical and genetic heterogeneity, as well as the limited response to current treatment options, constitutes an ongoing challenge. In our cohort, recessive Myotonia congenita was more frequent and novel mutations will contribute to the literature.
Topics: Male; Humans; Child; Adolescent; Aged; Infant; Child, Preschool; Female; Myotonia Congenita; Retrospective Studies; Chloride Channels; Mutation; Muscle, Skeletal
PubMed: 37355912
DOI: 10.3233/JND-230046 -
Perioperative Medicine (London, England) Jun 2023The present study aimed to compare the effects of the combined administration of two adjuvants, dopamine and phenylephrine, on the cutaneous analgesic effect and...
BACKGROUND
The present study aimed to compare the effects of the combined administration of two adjuvants, dopamine and phenylephrine, on the cutaneous analgesic effect and duration of mexiletine in rats.
METHODS
Nociceptive blockage was evaluated by the inhibition of response to skin pinpricks in rats via the cutaneous trunci muscle reflex (CTMR). After subcutaneous injection, the analgesic activities of mexiletine in the absence and presence of either dopamine or phenylephrine were assessed. Each injection was standardized into 0.6 ml with a mixture of drugs and saline.
RESULTS
Subcutaneous injections of mexiletine successfully induced dose-dependent cutaneous analgesia in rats. The results revealed that rats injected with 1.8 μmol mexiletine exhibited 43.75% blockage (%MPE), while rats injected with 6.0 μmol mexiletine showed 100% blockage. Co-application of mexiletine (1.8 or 6.0 μmol) with dopamine (0.06, 0.60, or 6.00 μmol) elicited full sensory block (%MPE). Sensory blockage ranged from 81.25% to 95.83% in rats injected with mexiletine (1.8 μmol) and phenylephrine (0.0059 or 0.0295 μmol), and complete subcutaneous analgesia was observed in rats injected with mexiletine (1.8 μmol) and a higher concentration of phenylephrine (0.1473 μmol). Furthermore, mexiletine at 6.0 μmol completely blocked nociception when combined with any concentration of phenylephrine, while 0.1473 μmol phenylephrine alone exhibited 35.417% subcutaneous analgesia. The combined application of dopamine (0.06/0.6/6 μmol) and mexiletine (1.8/6 μmol) resulted in increased %MPE, complete block time, full recovery time, and AUCs compared to the combined application of phenylephrine (0.0059 and 0.1473 μmol) and mexiletine (1.8/6 μmol) (p < 0.001).
CONCLUSION
Dopamine is superior to phenylephrine in improving sensory blockage and enhancing the duration of nociceptive blockage by mexiletine.
PubMed: 37312135
DOI: 10.1186/s13741-023-00314-2 -
Expert Opinion on Pharmacotherapy 2023Mexiletine is a class IB sodium-channel blocker. Unlike class IA or IC antiarrhythmic drugs, mexiletine rather shortens than prolongs action potential duration;...
INTRODUCTION
Mexiletine is a class IB sodium-channel blocker. Unlike class IA or IC antiarrhythmic drugs, mexiletine rather shortens than prolongs action potential duration; therefore, it is less associated with proarrhythmic effects.
AREAS COVERED
Recently, new European Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death were published, including a reappraisal of some established older antiarrhythmic drugs.
EXPERT OPINION
Mexiletine offers a first-line, genotype-specific treatment strategy for LQT3 patients as emphasized by the most recent guidelines. Besides this recommendation, current study reports suggest that in therapy-refractory ventricular tachyarrhythmias and electrical storms adjunctive mexiletine treatment may offer the possibility of stabilizing patients with or without concomitant interventional therapy such as catheter ablation.
Topics: Humans; Mexiletine; Anti-Arrhythmia Agents; Sodium Channel Blockers; Tachycardia, Ventricular; Arrhythmias, Cardiac
PubMed: 37306465
DOI: 10.1080/14656566.2023.2223964 -
Frontiers in Pharmacology 2023This study aimed to identify the different associations between antiarrhythmic drugs (AADs) and arrhythmias, and to determine whether pharmacokinetic drug interactions...
This study aimed to identify the different associations between antiarrhythmic drugs (AADs) and arrhythmias, and to determine whether pharmacokinetic drug interactions involving AADs increase the risk of AAD-related arrhythmias compared to using AADs alone. The disproportionality analysis of AAD-associated cardiac arrhythmias, including AAD monotherapies and concomitant use of pharmacokinetic interacting agents involving AADs, was conducted by using reporting odds ratio (ROR) and information component (IC) as detection of potential safety signals based on FAERS data from January 2016 to June 2022. We compared the clinical features of patients reported with AAD-associated arrhythmias between fatal and non-fatal groups, and further investigated the onset time (TTO) following different AAD regimens. A total of 11754 AAD-associated cardiac arrhythmias reports were identified, which was more likely to occur in the elderly (52.17%). Significant signals were detected between cardiac arrhythmia and all AAD monotherapies, with ROR ranging from 4.86 with mexiletine to 11.07 with flecainide. Regarding four specific arrhythmias in High Level Term (HLT) level, the AAD monotherapies with the highest ROR were flecainide in cardiac conduction disorders (ROR025 = 21.18), propafenone in rate and rhythm disorders (ROR025 = 10.36), dofetilide in supraventricular arrhythmias (ROR025 = 17.61), and ibutilide in ventricular arrhythmias (ROR025 = 4.91). Dofetilide/ibutilide, ibutilide, mexiletine/ibutilide and dronedarone presented no signal in the above four specific arrhythmias respectively. Compared with amiodarone monotherapy, sofosbuvir plus amiodarone detected the most significantly increased ROR in arrhythmias. The investigation showed the spectrum and risk of AAD-associated cardiac arrhythmias varied among different AAD therapies. The early identification and management of AAD-associated arrhythmias are of great importance in clinical practice.
PubMed: 37251345
DOI: 10.3389/fphar.2023.1170039 -
Breastfeeding Medicine : the Official... Jun 2023Mexiletine is a class 1B antiarrhythmic agent, used to treat ventricular arrhythmias, and noncardiac-related problems such as myotonia. Limited safety data are...
Mexiletine is a class 1B antiarrhythmic agent, used to treat ventricular arrhythmias, and noncardiac-related problems such as myotonia. Limited safety data are available on the transfer of this drug into breast milk. We report the case of a woman diagnosed with myotonia congenita who breastfed two children after two consecutive pregnancies. During the breastfeeding of the first and the second infant, she collected, respectively, five and seven samples at 0, 2, 4, 6, and 8 hours and 0, 1, 2, 3, 4, 6, and 8 hours after taking 200 mg of mexiletine thrice daily for seven doses. One week after the collection, samples were analyzed with a validated liquid chromatography tandem mass spectrometry method. No side effect was observed in either child according to the mother. Using the mean milk concentrations, it is estimated that an exclusively breastfed infant would receive a maximum of 5.14% of the initial pediatric mexiletine dosage. We calculated a maximum of 2.67% for the first infant in our case, considering a nonexclusive breastfeeding. Maximal concentrations were observed 1-2 hours after the dose of mexiletine. Results seem to be in accordance with the two cases previously published. Mexiletine transfers into breast milk in low levels. However, results are obtained from only one woman. Therefore, caution should be used when mexiletine is prescribed to breastfeeding women. More cases are needed to evaluate the interindividual variability and to guide women regarding breastfeeding with mexiletine.
Topics: Infant; Pregnancy; Female; Child; Humans; Milk, Human; Breast Feeding; Mexiletine; Mothers
PubMed: 37184533
DOI: 10.1089/bfm.2023.0042 -
Heart Rhythm O2 Apr 2023Long QT syndrome (LQTS) stems from pathogenic variants in (LQT1), (LQT2), or (LQT3) and is characterized by action potential duration (APD) prolongation. Inhibition...
BACKGROUND
Long QT syndrome (LQTS) stems from pathogenic variants in (LQT1), (LQT2), or (LQT3) and is characterized by action potential duration (APD) prolongation. Inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) is proposed as a novel therapeutic for LQTS.
OBJECTIVE
The study sought to test the efficacy of novel, selective SGK1 inhibitors in induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) models of LQTS.
METHODS
The mexiletine (MEX)-sensitive SCN5A-P1332L iPSC-CMs were tested initially compared with a CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 SCN5A-P1332L variant-corrected isogenic control (IC). The SGK1-I1 therapeutic efficacy, compared with MEX, was tested for APD at 90% repolarization (APD90) shortening in SCN5A-P1332L, SCN5A-R1623Q, KCNH2-G604S, and KCNQ1-V254M iPSC-CMs using FluoVolt.
RESULTS
The APD90 was prolonged in SCN5A-P1332L iPSC-CMs compared with its IC (646 ± 7 ms vs 482 ± 23 ms; < .0001). MEX shortened the APD90 to 560 ± 7 ms (52% attenuation, < .0001). SGK1-I1 shortened the APD90 to 518 ± 5 ms (78% attenuation, < .0001) but did not shorten the APD90 in the IC. SGK1-I1 shortened the APD90 of the SCN5A-R1623Q iPSC-CMs (753 ± 8 ms to 475 ± 19 ms compared with 558 ± 19 ms with MEX), the KCNH2-G604S iPSC-CMs (666 ± 10 ms to 574 ± 18 ms vs 538 ± 15 ms after MEX), and the KCNQ1-V254M iPSC-CMs (544 ± 10 ms to 475 ± 11ms; = .0004).
CONCLUSIONS
Therapeutically inhibiting SGK1 effectively shortens the APD in human iPSC-CM models of the 3 major LQTS genotypes. These preclinical data support development of SGK1 inhibitors as novel, first-in-class therapy for patients with congenital LQTS.
PubMed: 37124559
DOI: 10.1016/j.hroo.2023.02.003