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EBioMedicine Sep 2023Brugada syndrome (BrS) is a cardiac channelopathy that can result in sudden cardiac death (SCD). SCN5A is the most frequent gene linked to BrS, but the...
BACKGROUND
Brugada syndrome (BrS) is a cardiac channelopathy that can result in sudden cardiac death (SCD). SCN5A is the most frequent gene linked to BrS, but the genotype-phenotype correlations are not completely matched. Clinical phenotypes of a particular SCN5A variant may range from asymptomatic to SCD. Here, we used comparison of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) derived from a SCN5A mutation-positive (D356Y) BrS family with severely affected proband, asymptomatic mutation carriers (AMCs) and healthy controls to investigate this variation.
METHODS
26 iPSC lines were generated from skin fibroblasts using nonintegrated Sendai virus. The generated iPSCs were differentiated into cardiomyocytes using a monolayer-based differentiation protocol.
FINDINGS
D356Y iPSC-CMs exhibited increased beat interval variability, slower depolarization, cardiac arrhythmias, defects of Na channel function and irregular Ca signaling, when compared to controls. Importantly, the phenotype severity observed in AMC iPSC-CMs was milder than that of proband iPSC-CMs, an observation exacerbated by flecainide. Interestingly, the iPSC-CMs of the proband exhibited markedly decreased Ca currents in comparison with control and AMC iPSC-CMs. CRISPR/Cas9-mediated genome editing to correct D356Y in proband iPSC-CMs effectively rescued the arrhythmic phenotype and restored Na and Ca currents. Moreover, drug screening using established BrS iPSC-CM models demonstrated that quinidine and sotalol possessed antiarrhythmic effects in an individual-dependent manner. Clinically, venous and oral administration of calcium partially reduced the malignant arrhythmic events of the proband in mid-term follow-up.
INTERPRETATION
Patient-specific and genome-edited iPSC-CMs can recapitulate the varying phenotypic severity of BrS. Our findings suggest that preservation of the Ca currents might be a compensatory mechanism to resist arrhythmogenesis in BrS AMCs.
FUNDING
National Key R&D Program of China (2017YFA0103700), National Natural Science Foundation of China (81922006, 81870175), Natural Science Foundation of Zhejiang Province (LD21H020001, LR15H020001), National Natural Science Foundation of China (81970269), Key Research and Development Program of Zhejiang Province (2019C03022) and Natural Science Foundation of Zhejiang Province (LY16H020002).
Topics: Humans; Brugada Syndrome; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Arrhythmias, Cardiac; Mutation; Death, Sudden, Cardiac
PubMed: 37544203
DOI: 10.1016/j.ebiom.2023.104741 -
Journal of the American College of... Aug 2019
Topics: Female; Flecainide; Humans; Pregnancy; Prenatal Care; Tachycardia, Supraventricular
PubMed: 31416532
DOI: 10.1016/j.jacc.2019.07.005 -
The Medical Letter on Drugs and... Sep 2019
Review
Topics: Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Calcium Channel Blockers; Clinical Trials as Topic; Dabigatran; Humans; Rivaroxaban
PubMed: 31599871
DOI: No ID Found -
Clinical Cardiology Oct 2023Beta-blockers (BB) or dihydropyridine calcium channel blockers (CCBs) are still the first choices in the treatment of idiopathic premature ventricular complexes (PVCs),...
BACKGROUND
Beta-blockers (BB) or dihydropyridine calcium channel blockers (CCBs) are still the first choices in the treatment of idiopathic premature ventricular complexes (PVCs), with low-modest efficacy. Antiarrhythmic drugs (AADs) of Ic class are moderate to highly efficient but the evidence on their benefits is still limited.
AIM
To compare effectiveness and safety of flecainide, propafenone, and sotalol in the treatment of symptomatic idiopathic PVCs.
METHODS
Our single-center retrospective study analyzed 104 consecutive patients with 130 medication episodes of frequent idiopathic PVCs treated with AADs flecainide, propafenone (Ic class) or sotalol (III class). The primary outcome was complete/near complete reduction of PVCs after medication episode (PVCs burden reduction >99%), and the secondary outcome was significant PVC burden reduction (≥80%).
RESULTS
The complete/near complete PVCs burden reduction occurred in 31% and was significant in 43% of treated patients. A reduction of PVC burden for >99% was achieved in 56% of patients on flecainide, in 11% of patients on propafenone (p = .002), and in 21% of patients receiving sotalol (p = .031). There was no difference between propafenone and sotalol (p = .174). A reduction of PVC burden for ≥80% was achieved in 64% of patients on flecainide, in 30% of patients on propafenone (p = .009), and 33% of patients on sotalol (p = .020). There was no difference between propafenone and sotalol (p = .661).
CONCLUSIONS
The efficacy of AADs class Ic and III in the treatment of idiopathic PVCs was modest. Flecainide was the most effective AAD in the achievement of complete/near complete or significant PVC burden reduction, compared to propafenone and sotalol.
Topics: Humans; Propafenone; Flecainide; Sotalol; Retrospective Studies; Electrocardiography; Anti-Arrhythmia Agents; Ventricular Premature Complexes
PubMed: 37533168
DOI: 10.1002/clc.24090 -
Pharmacology Research & Perspectives Aug 2019The aim of this study was to evaluate the pharmacokinetic variability of beta-adrenergic blocking agents used in cardiology by reviewing single-dose and steady-state... (Review)
Review
The aim of this study was to evaluate the pharmacokinetic variability of beta-adrenergic blocking agents used in cardiology by reviewing single-dose and steady-state pharmacokinetic studies from the literature. PubMed was searched for pharmacokinetic studies of beta-adrenergic blocking agents, both single-dose and steady-state studies. The studies included reported maximum plasma concentration (C) and/or area under the concentration curve (AUC). The coefficient of variation (CV%) was calculated for all studies, and a CV% <40% was considered low or moderate variability, and a CV% >40% was considered high variability. The C and AUC were reported a total of 672 times in 192 papers. Based on AUC, metoprolol, propranolol, carvedilol, and nebivolol showed high pharmacokinetic variability (highest first), whereas bisoprolol, atenolol, sotalol, labetalol, nadolol, and pindolol showed low to moderate variability (lowest first). We have shown a high interindividual pharmacokinetic variability that varies markedly in different beta-adrenergic blocking agents; the extreme being steady state ratios as high as 30 in metoprolol. A more personalized approach to the medical treatment of patients may be obtained by combining known pharmacokinetic information about variability, pharmaco-genetics and -dynamics, and patient characteristics, to avoid adverse events or lack of treatment effect.
Topics: Adrenergic beta-Antagonists; Area Under Curve; Biological Availability; Carvedilol; Healthy Volunteers; Humans; Male; Metoprolol; Propranolol
PubMed: 31338197
DOI: 10.1002/prp2.496 -
The Journal of Maternal-fetal &... Aug 2020Fetal arrhythmias are common, and they may resolve spontaneously in majority of the cases. Sustained fetal arrhythmias associated with major structural heart disorders,...
Fetal arrhythmias are common, and they may resolve spontaneously in majority of the cases. Sustained fetal arrhythmias associated with major structural heart disorders, hydrops fetalis, and fetal heart failure warrant intrauterine pharmaceutical conversion of heart rhythm or early pacemaker implant in order to avoid fetal demise. Fetal atrial flutter (AF) and supraventricular tachycardia (SVT) resemble in terms of the effects of intrauterine therapies. Digoxin is more suitable for rhythm conversion of fetal AF and SVT in fetuses free of hydrops fetalis, while sotalol shows better effects for those with hydrops fetalis. In fetal cases of atrioventricular blocks, an etiological treatment for the maternal antibody exposure by steroids could be an alternative remedy. In this article, the clinical diagnosis and treatment of fetal arrhythmias are presented, and advantages and disadvantages of antiarrhythmic agents for fetal arrhythmias are compared.
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Digoxin; Female; Humans; Hydrops Fetalis; Pregnancy; Sotalol; Tachycardia, Supraventricular
PubMed: 30879368
DOI: 10.1080/14767058.2018.1555804 -
Journal of the American Heart... May 2022Background There is limited information regarding the clinical use and effectiveness of IV sotalol in pediatric patients and patients with congenital heart disease,...
Background There is limited information regarding the clinical use and effectiveness of IV sotalol in pediatric patients and patients with congenital heart disease, including those with severe myocardial dysfunction. A multicenter registry study was designed to evaluate the safety, efficacy, and dosing of IV sotalol. Methods and Results A total of 85 patients (age 1 day-36 years) received IV sotalol, of whom 45 (53%) had additional congenital cardiac diagnoses and 4 (5%) were greater than 18 years of age. In 79 patients (93%), IV sotalol was used to treat supraventricular tachycardia and 4 (5%) received it to treat ventricular arrhythmias. Severely decreased cardiac function by echocardiography was seen before IV sotalol in 7 (9%). The average dose was 1 mg/kg (range 0.5-1.8 mg/kg/dose) over a median of 60 minutes (range 30-300 minutes). Successful arrhythmia termination occurred in 31 patients (49%, 95% CI [37%-62%]) with improvement in rhythm control defined as rate reduction permitting overdrive pacing in an additional 18 patients (30%, 95% CI [19%-41%]). Eleven patients (16%) had significant QTc prolongation to >465 milliseconds after the infusion, with 3 (4%) to >500 milliseconds. There were 2 patients (2%) for whom the infusion was terminated early. Conclusions IV sotalol was safe and effective for termination or improvement of tachyarrhythmias in 79% of pediatric patients and patients with congenital heart disease, including those with severely depressed cardiac function. The most common dose, for both acute and maintenance dosing, was 1 mg/kg over ~60 minutes with rare serious complications.
Topics: Arrhythmias, Cardiac; Child; Heart Defects, Congenital; Humans; Infant; Registries; Sotalol; Tachycardia, Supraventricular
PubMed: 35491986
DOI: 10.1161/JAHA.121.024375 -
Kardiologia Polska Jan 2021Sotalol is a class III antiarrhythmic drug commonly used in various arrhythmia treatments. However, due to its potent potassium channel inhibition, it can prolong the QT...
BACKGROUND
Sotalol is a class III antiarrhythmic drug commonly used in various arrhythmia treatments. However, due to its potent potassium channel inhibition, it can prolong the QT interval and lead to malignant arrhythmias. Empagliflozin is an inhibitor of sodium‑glucose cotransporter 2 (SGLT2) and has a positive effect on cardiovascular outcomes. Since the effect of empagliflozin on the activation of potassium channels is unknown, there is no recommendation regarding the coadministration of these drugs.
AIMS
The study aimed to evaluate the possible protective effects of empagliflozin on sotalol‑induced QT prolongation.
METHODS
We randomized 24 rats into 4 groups. The control group received only physiological saline, the EMPA group, empagliflozin; the SOT group, sotalol; and the EMPA+SOT group, empagliflozin and sotalol. PR and QT intervals and heart rates were measured under anesthesia at baseline and at 1, 2, and 3 hours in lead II.
RESULTS
In the SOT group, the QT and QTc intervals as well as T‑wave duration were statistically longer, whereas heart rates were lower than in the control group (P <0.001 for all parameters). Empagliflozin ameliorated sotalol‑induced QT and QTc prolongation in the EMPA+SOT group. The QT interval, T‑wave duration, and QTc interval were shorter, and the heart rate was greater than in the SOT group (P <0.001, P = 0.002, P <0.001, and P <0.001, respectively).
CONCLUSION
Empagliflozin significantly ameliorates sotalol‑induced QT prolongation and could be used safely with sotalol in clinical practice. Future clinical trials might recommend the routine use of empagliflozin to prevent QTc prolongation in diabetic patients receiving sotalol.
Topics: Animals; Anti-Arrhythmia Agents; Benzhydryl Compounds; Electrocardiography; Glucosides; Humans; Long QT Syndrome; Rats; Sotalol
PubMed: 33146500
DOI: 10.33963/KP.15666 -
Journal of Veterinary Cardiology : the... Jun 2023Atrioventricular accessory pathways are abnormal electrical connections between the atria and ventricles that predispose to ventricular pre-excitation (VPE) and...
OBJECTIVES
Atrioventricular accessory pathways are abnormal electrical connections between the atria and ventricles that predispose to ventricular pre-excitation (VPE) and tachycardias.
ANIMALS
Seventeen cats with VPE and 15 healthy matched-control cats.
MATERIAL AND METHODS
Multicenter case-control retrospective study. Clinical records were searched for cats with VPE, defined as preserved atrioventricular synchrony, reduced PQ interval, and increased QRS complex duration with a delta wave. Clinical, electrocardiography, echocardiographic, and outcome data were collated.
RESULTS
Most cats with VPE were male (16/17 cats), non-pedigree cats (11/17 cats). Median age and mean body weight were 5.4 years (0.3-11.9 years) and 4.6 ± 0.8 kg, respectively. Clinical signs at presentation included lethargy (10/17 cats), tachypnea (6/17 cats), and/or syncope (3/17 cats). In two cats, VPE was an incidental finding. Congestive heart failure was uncommon (3/17 cats). Nine (9/17) cats had tachyarrhythmias: 7/9 cats had narrow QRS complex tachycardia and 2/9 cats had wide QRS complex tachycardia. Four cats had ventricular arrhythmias. Cats with VPE had larger left (P < 0.001) and right (P < 0.001) atria and thicker interventricular septum (P = 0.019) and left ventricular free wall (P = 0.028) than controls. Three cats had hypertrophic cardiomyopathy. Treatment included different combinations of sotalol (5/17 cats), diltiazem (5/17 cats), atenolol (4/17 cats), furosemide (4/17 cats), and platelet inhibitors (4/17 cats). Five cats died, all from cardiac death (median survival time 1882 days [2-1882 days]).
CONCLUSIONS
Cats with VPE had a relatively long survival, albeit showing larger atria and thicker left ventricular walls than healthy cats.
Topics: Male; Cats; Animals; Female; Wolff-Parkinson-White Syndrome; Retrospective Studies; Pre-Excitation Syndromes; Tachycardia; Electrocardiography; Cat Diseases
PubMed: 37267820
DOI: 10.1016/j.jvc.2023.04.005 -
Journal of Cardiovascular... Jun 2023Various agents may be utilized to manage supraventricular tachycardia (SVT) in neonates and infants. Recently, sotalol has piqued interest given its reported success in...
INTRODUCTION
Various agents may be utilized to manage supraventricular tachycardia (SVT) in neonates and infants. Recently, sotalol has piqued interest given its reported success in managing neonates and infants with SVTs, especially with the intravenous formulation. While the manufacturer recommends using an age-related nomogram in neonates and young infants to guide doses, clinical reports describe various dosing based on weight (mg/kg) or on body surface area (BSA) in mg/m . Given the reported variation in clinical practice with regard to dosing in neonates, there is a gap in the literature and translation into clinical practice regarding applicability of the nomogram into clinical practice. The purpose of this study was to describe sotalol doses based on body weight and BSA in neonates for SVT.
METHODS
This is a single center retrospective study evaluating effective sotalol dosing from January 2011 and June 2021 (inclusive). Neonates who received intravenous (IV) or oral (PO) sotalol for SVT were eligible for inclusion. The primary outcome was to describe sotalol doses based on body weight and BSA. Secondary outcomes include comparison of doses to the manufacturer nomogram, description of dose titrations, reported adverse outcomes, and change in therapy. Two-sided Wilcoxon signed-rank tests were used to determine statistically significant differences.
RESULTS
Thirty-one eligible patients were included in this study. The median (range) age and weight were 16.5 (1-28) days and 3.2 (1.8-4.9) kg, respectively. The median initial dose was 7.3 (1.9-10.8) mg/kg or 114.3 (30.9-166.7) mg/m /day. Fourteen (45.2%) of patients required a dose increase for SVT control. The median dose required for rhythm control was 8.5 (2-14.8) mg/kg/day or 120.7 (30.9-225) mg/m /day. Of note, the median recommended dose per manufacturer nomogram for our patients would have been 51.3 (16.2-73.8) mg/m /day, which is significantly lower than both the initial dose (p < .001) and final doses (p < .001) utilized in our study. A total of 7 (22.9%) patients were uncontrolled on sotalol monotherapy using our dosing regimen. Two patients (6.5%) had reports of hypotension and one patient (3.3%) had a report of bradycardia requiring discontinuation of therapy. The average change in baseline QTC following sotalol initiation was 6.8%. Twenty-seven (87.1%), 3 (9.7%), 1 (3.3%) experienced prolongation, no change, or a decrease in QTc, respectively.
CONCLUSIONS
This study demonstrates that a sotalol strategy significantly higher than the manufacture dose recommendations are required for rhythm control in neonates with SVT. There were few adverse events reported with this dosing. Further prospective studies would be advantageous to confirm these findings.
Topics: Infant; Infant, Newborn; Humans; Sotalol; Anti-Arrhythmia Agents; Retrospective Studies; Prospective Studies; Arrhythmias, Cardiac; Tachycardia, Supraventricular; Body Weight
PubMed: 37210614
DOI: 10.1111/jce.15939