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Circulation Apr 2024Drug-induced QT prolongation (diLQT) is a feared side effect that could expose susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily...
BACKGROUND
Drug-induced QT prolongation (diLQT) is a feared side effect that could expose susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably the hERG (human ether-a-go-go-related gene) channels that generate the delayed-rectifier potassium current (I) and thereby regulate the late repolarization phase. There is an important interindividual susceptibility to develop diLQT, which is of unknown origin but can be reproduced in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs). We aimed to investigate the dynamics of hERG channels in response to sotalol and to identify regulators of the susceptibility to developing diLQT.
METHODS
We measured electrophysiological activity and cellular distribution of hERG channels after hERG blocker treatment in iPS-CMs derived from patients with highest sensitivity (HS) or lowest sensitivity (LS) to sotalol administration in vivo (ie, on the basis of the measure of the maximal change in QT interval 3 hours after administration). Specific small interfering RNAs and CAVIN1-T2A-GFP adenovirus were used to manipulate expression.
RESULTS
Whereas HS and LS iPS-CMs showed similar electrophysiological characteristics at baseline, the late repolarization phase was prolonged and I significantly decreased after exposure of HS iPS-CMs to low sotalol concentrations. I reduction was caused by a rapid translocation of hERG channel from the membrane to the cytoskeleton-associated fractions upon sotalol application. , essential for caveolae biogenesis, was 2× more highly expressed in HS iPS-CMs, and its knockdown by small interfering RNA reduced their sensitivity to sotalol. overexpression in LS iPS-CMs using adenovirus showed reciprocal effects. We found that treatment with sotalol promoted translocation of the hERG channel from the plasma membrane to the cytoskeleton fractions in a process dependent on CAVIN1 (caveolae associated protein 1) expression. silencing reduced the number of caveolae at the membrane and abrogated the translocation of hERG channel in sotalol-treated HS iPS-CMs. CAVIN1 also controlled cardiomyocyte responses to other hERG blockers, such as E4031, vandetanib, and clarithromycin.
CONCLUSIONS
Our study identifies unbridled turnover of the potassium channel hERG as a mechanism supporting the interindividual susceptibility underlying diLQT development and demonstrates how this phenomenon is finely tuned by CAVIN1.
PubMed: 38682330
DOI: 10.1161/CIRCULATIONAHA.123.063917 -
American Heart Journal Aug 2024Recurrent ventricular tachycardia (VT) in patients with prior myocardial infarction is associated with adverse quality of life and clinical outcomes, despite the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Recurrent ventricular tachycardia (VT) in patients with prior myocardial infarction is associated with adverse quality of life and clinical outcomes, despite the presence of implanted defibrillators (ICDs). Suppression of recurrent VT can be accomplished with antiarrhythmic drug therapy or catheter ablation. The Ventricular Tachycardia Antiarrhythmics or Ablation In Structural Heart Disease 2 (VANISH2) trial is designed to determine whether ablation is superior to antiarrhythmic drug therapy as first line therapy for patients with ischemic cardiomyopathy and VT.
METHODS
The VANISH2 trial enrolls patients with prior myocardial infarction and VT (with one of: ≥1 ICD shock; ≥3 episodes treated with antitachycardia pacing (ATP) and symptoms; ≥5 episodes treated with ATP regardless of symptoms; ≥3 episodes within 24 hours; or sustained VT treated with electrical cardioversion or pharmacologic conversion). Enrolled patients are classified as either sotalol-eligible, or amiodarone-eligible, and then are randomized to either catheter ablation or to that antiarrhythmic drug therapy, with randomization stratified by drug-eligibility group. Drug therapy, catheter ablation procedures and ICD programming are standardized. All patients will be followed until two years after randomization. The primary endpoint is a composite of mortality at any time, appropriate ICD shock after 14 days, VT storm after 14 days, and treated sustained VT below detection of the ICD after 14 days. The outcomes will be analyzed according to the intention-to-treat principle using survival analysis techniques RESULTS: The results of the VANISH2 trial are intended to provide data to support clinical decisions on how to suppress VT for patients with prior myocardial infarction.
CLINICALTRIALS
gov registration NCT02830360.
Topics: Humans; Tachycardia, Ventricular; Anti-Arrhythmia Agents; Catheter Ablation; Cardiomyopathies; Myocardial Ischemia; Male; Female; Defibrillators, Implantable; Middle Aged; Amiodarone; Treatment Outcome; Sotalol; Combined Modality Therapy
PubMed: 38649085
DOI: 10.1016/j.ahj.2024.04.009 -
Journal of Veterinary Cardiology : the... Jun 2024Studies on the use of amiodarone or sotalol are limited in dogs. Therefore, this study aimed to provide data on the efficacy and safety of these drugs in dogs with...
INTRODUCTION/OBJECTIVE
Studies on the use of amiodarone or sotalol are limited in dogs. Therefore, this study aimed to provide data on the efficacy and safety of these drugs in dogs with ventricular tachyarrhythmia (VT) and/or supraventricular tachyarrhythmia (SvT).
ANIMALS, MATERIALS, AND METHODS
Dogs with VT and/or SvT treated with amiodarone or sotalol as a first-line therapy were retrospectively evaluated. Signalment, clinical, diagnostic, therapeutic, and outcome data were retrieved. For VT, efficacy was demonstrated through a decrease of the Lown-Wolf grade to less than five or a reduction of at least 85% in the number of ventricular premature complexes observed on Holter monitoring. For SvT, efficacy was represented by cardioversion or a reduction in the mean heart rate on Holter monitoring ≤140 beats/min. Treatment-related side effects (TRSEs) were classified as clinically relevant and irrelevant. Statistical analysis was performed to compare data before and after antiarrhythmic prescription.
RESULTS
Sixty-four dogs were included. Amiodarone and sotalol were efficacious in treating both VT (85.7% and 90.0% of cases, respectively) and SvT (75% and 71.4% of cases, respectively). No significant differences were found when comparing their efficacy rates in dogs with VT and SvT (P=0.531 and 0.483, respectively). Clinically relevant TRSEs were rare with both amiodarone and sotalol (8.3% and 5% of cases, respectively), while clinically irrelevant TRSEs occurred more frequently with amiodarone (29.2%) than with sotalol (10%).
DISCUSSION
In dogs with tachyarrhythmias, amiodarone and sotalol are generally efficacious and safe, as clinically relevant TRSEs seem rare.
CONCLUSIONS
This study provides novel data on the effects of amiodarone and sotalol in dogs with tachyarrhythmias.
Topics: Animals; Dogs; Sotalol; Amiodarone; Anti-Arrhythmia Agents; Dog Diseases; Retrospective Studies; Male; Female; Treatment Outcome; Tachycardia, Ventricular; Tachycardia, Supraventricular
PubMed: 38608438
DOI: 10.1016/j.jvc.2024.03.002 -
Biomedicine & Pharmacotherapy =... May 2024Amiodarone is a benzofuran-based class III antiarrhythmic agent frequently used for the treatment of atrial and ventricular arrhythmias. The primary target of class III... (Review)
Review
Amiodarone is a benzofuran-based class III antiarrhythmic agent frequently used for the treatment of atrial and ventricular arrhythmias. The primary target of class III antiarrhythmic drugs is the cardiac human ether-a-go-go-related gene (hERG) encoded channel, KCNH2, commonly known as HERG, that conducts the rapidly activating delayed rectifier potassium current (I). Like other class III antiarrhythmic drugs, amiodarone exerts its physiologic effects mainly through I blockade, delaying the repolarization phase of the action potential and extending the effective refractory period. However, while many class III antiarrhythmics, including sotalol and dofetilide, can cause long QT syndrome (LQTS) that can progress to torsade de pointes, amiodarone displays less risk of inducing this fatal arrhythmia. This review article discusses the arrhythmogenesis in LQTS from the aspects of the development of early afterdepolarizations (EADs) associated with Ca current, transmural dispersion of repolarization (TDR), as well as reverse use dependence associated with class III antiarrhythmic drugs to highlight electropharmacological effects of amiodarone on the myocardium.
Topics: Amiodarone; Humans; Anti-Arrhythmia Agents; Animals; Action Potentials; Ion Channels; Myocardium; Electrophysiological Phenomena; Long QT Syndrome
PubMed: 38565056
DOI: 10.1016/j.biopha.2024.116513 -
European Heart Journal. Case Reports Mar 2024The treatment of cardiac sarcoidosis during pregnancy is inherently challenging owing to its impact on the foetus.
Multi-modal treatment in a pregnant woman with untreated cardiac sarcoidosis complicated by cardiac dysfunction and ventricular arrhythmias: a case report and literature review.
BACKGROUND
The treatment of cardiac sarcoidosis during pregnancy is inherently challenging owing to its impact on the foetus.
CASE SUMMARY
We report a case of a 30-year-old pregnant woman with untreated cardiac sarcoidosis. One year prior to admission, she underwent permanent pacemaker implantation for complete atrioventricular block. Left ventricular ejection fraction (EF) showed a declining trend, and ventricular tachycardia (VT) was documented. Following an extensive evaluation, the patient was diagnosed with active cardiac sarcoidosis, and the pregnancy was detected at the same time. Considering the high risk of mortality and cardiovascular complications in pregnant patients with decreased EF and VT, we meticulously discussed the optimal timing of multi-modal treatment, including bisoprolol, eplerenone, sotalol, and prednisolone and cardiac resynchronization therapy with a defibrillator, and its effect on the foetus. These interventions improved the EF to 49%, and the baby was successfully delivered without adverse events or neonatal complications developing. At 8 months' post-partum, the mother and the baby were doing well, and the EF was 45%.
DISCUSSION
Cardiac sarcoidosis can lead to adverse outcomes for both the mother and the foetus. However, with multi-modal treatment individually optimized and implemented by a multi-disciplinary team of specialists in each field, even pregnant women with untreated cardiac sarcoidosis who present with reduced EF and VT can achieve safe childbirth.
PubMed: 38454957
DOI: 10.1093/ehjcr/ytae108 -
Internal Medicine (Tokyo, Japan) 2024A 25-year-old woman with left ventricular (LV) dysfunction became pregnant during the diagnostic period. Decompensated heart failure with frequent ventricular...
A 25-year-old woman with left ventricular (LV) dysfunction became pregnant during the diagnostic period. Decompensated heart failure with frequent ventricular arrhythmias necessitated hospitalization in the 21st week of pregnancy. Under careful monitoring, diuretics and sotalol were added to her ongoing treatment of carvedilol and spironolactone due to the risk of hemodynamic collapse. An emergency cesarean section was performed in the 32nd week after the detection of rapid nonsustained ventricular tachycardia. Subsequent genetic testing revealed that the LV dysfunction was associated with Danon cardiomyopathy. This case highlights the importance of careful pregnancy management with LV dysfunction along with early genetic testing.
Topics: Female; Pregnancy; Humans; Adult; Cesarean Section; Cardiomyopathies; Heart Failure; Carvedilol; Ventricular Dysfunction, Left
PubMed: 38432893
DOI: 10.2169/internalmedicine.1673-23 -
Heart Rhythm Feb 2024Loading of oral sotalol for atrial fibrillation requires 3 days, frequently in the hospital, to achieve steady state. The Food and Drug Administration approved loading...
BACKGROUND
Loading of oral sotalol for atrial fibrillation requires 3 days, frequently in the hospital, to achieve steady state. The Food and Drug Administration approved loading with intravenous (IV) sotalol through model-informed development, without patient data.
OBJECTIVE
We present results of the first multicenter evaluation of this recent labeling for IV sotalol.
METHODS
The Prospective Evaluation Analysis and Kinetics of IV Sotalol (PEAKS) Registry was a multicenter observational registry of patients undergoing elective IV sotalol load for atrial arrhythmias. Outcomes, measured from hospital admission until first outpatient follow-up, included adverse arrhythmia events, efficacy, and length of stay.
RESULTS
Of 167 consecutively enrolled patients, 23% were female; the median age was 68 (interquartile range, 61-74) years, and the median CHADS-VASc score was 3 (interquartile range, 2-4). Overall, 99% were admitted for sotalol initiation (1% for dose escalation), with a target oral sotalol dose of either 80 mg twice daily (85 [51%]) or 120 mg twice daily (78 [47%]); 62 patients (37%) had an estimated creatinine clearance ≤90 mL/min. On presentation, 40% of patients were in sinus rhythm, whereas 26% underwent cardioversion before sotalol infusion. In 2 patients, sotalol infusion was stopped for bradycardia or hypotension. In 6 patients, sotalol was discontinued before discharge because of QTc prolongation (3), bradycardia (1), or recurrent atrial arrhythmia (2). The mean length of stay was 1.1 days, and 95% (n = 159) were discharged within 1 night.
CONCLUSION
IV sotalol loading is safe and feasible for atrial arrhythmias, with low rates of adverse events, and yields shorter hospitalizations. More data are needed on the minimal duration required for monitoring in the hospital.
PubMed: 38417598
DOI: 10.1016/j.hrthm.2024.02.046 -
Netherlands Heart Journal : Monthly... Apr 2024Postoperative atrial fibrillation (POAF) is a common phenomenon following cardiac surgery. In this study, we assessed current preventive strategies used by Dutch...
INTRODUCTION
Postoperative atrial fibrillation (POAF) is a common phenomenon following cardiac surgery. In this study, we assessed current preventive strategies used by Dutch cardiothoracic centres, identified common views on this matter and related these to international guidelines.
METHODS
We developed an online questionnaire and sent it to all cardiothoracic surgery centres in the Netherlands. The questionnaire concerned the management of POAF and the use of pharmaceutical therapies (beta-blockers and calcium antagonists) and non-pharmaceutical methods (posterior left pericardiotomy, pericardial flushing and epicardial botulinum toxin type A injections). Usage of electrical cardioversions, anticoagulants and left atrial appendage closure were also enquired.
RESULTS
Of the 15 centres, 14 (93%) responded to the survey and 13 reported a POAF incidence, ranging from 20 to 30%. Of these 14 centres, 6 prescribed preoperative AF prophylaxis to their patients, of which non-sotalol beta-blockers were prescribed most commonly (57%). Postoperative medication was administered by all centres and included non-sotalol beta-blockers (38%), sotalol (24%), digoxin (14%), calcium antagonists (13%) and amiodarone (10%). Only 2 centres used posterior left pericardiotomy or pericardial flushing as surgical manoeuvres to prevent POAF. Moreover, respondents expressed the need for guidance on anticoagulant use.
CONCLUSION
Despite the use of various preventive strategies, the reported incidence of POAF was similar in Dutch cardiothoracic centres. This study highlights limited use of prophylactic amiodarone and colchicine, despite recommendations by numerous guidelines, and restricted implementation of surgical strategies to prevent POAF.
PubMed: 38358408
DOI: 10.1007/s12471-023-01849-1 -
Molecules (Basel, Switzerland) Jan 2024In total, three related substances (RS) associated with sotalol hydrochloride (STHCl) were herein identified with a novel gradient high-performance liquid chromatography...
In total, three related substances (RS) associated with sotalol hydrochloride (STHCl) were herein identified with a novel gradient high-performance liquid chromatography (HPLC) protocol. Further characterization of these substances was then performed via liquid chromatography-mass spectroscopy (LC-MS/MS) and nuclear magnetic resonance (NMR) approaches. For these analyses, commercial STHCl samples were used for quantitative HPLC studies and the degradation of STHCl under acidic (1M HCl), alkaline (1M NaOH), oxidative (30% HO), photolytic (4500 Lx), and thermal stress conditions (100 °C) was assessed. This approach revealed this drug to be resistant to acidic, alkaline, and high-temperature conditions, whereas it was susceptible to light and oxidation as confirmed through long-term experiments. The putative mechanisms governing RS formation were also explored, revealing that RS3 was derived from the manufacturing process, whereas RS2 was generated via oxidation and RS1 was generated in response to light exposure. The cytotoxicity of these RS compounds was then assessed using MTT assays and acute toxicity test. Overall, this study provides details regarding the characterization, isolation, quantification, and toxicological evaluation of STHCl and associated RS compounds together with details regarding the precise, specific, and reliable novel HPLC technique, thus providing the requisite information necessary to ensure STHCl purity and safety.
Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Sotalol; Tandem Mass Spectrometry; Hydrogen Peroxide; Liquid Chromatography-Mass Spectrometry; Drug Stability; Hydrolysis; Oxidation-Reduction; Photolysis
PubMed: 38338332
DOI: 10.3390/molecules29030588