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PloS One 2024Drug-induced QT prolongation (diLQTS), and subsequent risk of torsade de pointes, is a major concern with use of many medications, including for non-cardiac conditions....
Drug-induced QT prolongation (diLQTS), and subsequent risk of torsade de pointes, is a major concern with use of many medications, including for non-cardiac conditions. The possibility that genetic risk, in the form of polygenic risk scores (PGS), could be integrated into prediction of risk of diLQTS has great potential, although it is unknown how genetic risk is related to clinical risk factors as might be applied in clinical decision-making. In this study, we examined the PGS for QT interval in 2500 subjects exposed to a known QT-prolonging drug on prolongation of the QT interval over 500ms on subsequent ECG using electronic health record data. We found that the normalized QT PGS was higher in cases than controls (0.212±0.954 vs. -0.0270±1.003, P = 0.0002), with an unadjusted odds ratio of 1.34 (95%CI 1.17-1.53, P<0.001) for association with diLQTS. When included with age and clinical predictors of QT prolongation, we found that the PGS for QT interval provided independent risk prediction for diLQTS, in which the interaction for high-risk diagnosis or with certain high-risk medications (amiodarone, sotalol, and dofetilide) was not significant, indicating that genetic risk did not modify the effect of other risk factors on risk of diLQTS. We found that a high-risk cutoff (QT PGS ≥ 2 standard deviations above mean), but not a low-risk cutoff, was associated with risk of diLQTS after adjustment for clinical factors, and provided one method of integration based on the decision-tree framework. In conclusion, we found that PGS for QT interval is an independent predictor of diLQTS, but that in contrast to existing theories about repolarization reserve as a mechanism of increasing risk, the effect is independent of other clinical risk factors. More work is needed for external validation in clinical decision-making, as well as defining the mechanism through which genes that increase QT interval are associated with risk of diLQTS.
Topics: Humans; Male; Female; Long QT Syndrome; Middle Aged; Electrocardiography; Multifactorial Inheritance; Risk Factors; Aged; Adult; Torsades de Pointes; Case-Control Studies; Phenethylamines; Genetic Risk Score; Sulfonamides
PubMed: 38885227
DOI: 10.1371/journal.pone.0303261 -
Journal of Chromatography. B,... Jun 2024Antiarrhythmic and antihypertensive drugs are frequently encountered in post mortem analysis, and the question may arise as to whether they were administered in...
Antiarrhythmic and antihypertensive drugs are frequently encountered in post mortem analysis, and the question may arise as to whether they were administered in therapeutic doses, and if they were taken in accidental, intentional, or suicidal overdose scenarios. Therefore, a novel analytical method was developed and validated for the quantification of 35 drugs with toxicological relevance, including antihypertensive and antiarrhythmic drugs (ajmaline, amlodipine, amiodarone, atenolol, bisoprolol, carvedilol, clonidine, desethylamiodarone, diltiazem, donepezil, doxazosin, dronedarone, esmolol, flecainide, lercanidipine, lidocaine, metoprolol, nebivolol, nimodipine, pindolol, prajmaline, propafenone, propranolol, sotalol, urapidil, and verapamil), as well as other medications commonly found in combination (sildenafil, tadalafil, atorvastatin, clopidogrel, dapoxetine, memantine, pentoxifylline, rivastigmine, and ivabradine). The method enables simultaneous identification and quantification in blood samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Validation exhibited excellent linearity across the concentration range for all analytes. Precision and accuracy were within acceptable limits, with bias and relative standard deviation (RSD) values consistently below 9 % and 10 %, respectively. Selectivity and specificity assessments confirmed the absence of any interference from contaminants or co-extracted drugs. The method demonstrated very high sensitivity, with limits of detection (LOD) as low as 0.01 ng/ml and limits of quantification (LOQ) as low as 0.04 ng/ml. Extraction recovery exceeded 57.5 % for all analytes except atenolol, and matrix effects were <17 % for all analytes except pindolol. Processed sample stability evaluations revealed consistent results with acceptable deviations for all analytes. In addition, the method was specifically tested for the use in post mortem analysis. The applicability of our method was demonstrated by the analysis of two authentic human autopsy blood samples.
PubMed: 38878710
DOI: 10.1016/j.jchromb.2024.124196 -
Ecotoxicology and Environmental Safety Jul 2024Microplastics and organic micropollutants are two emerging contaminants that interact with each other in environmental and engineered systems. Sorption of organic...
Microplastics and organic micropollutants are two emerging contaminants that interact with each other in environmental and engineered systems. Sorption of organic micropollutants, such as pharmaceuticals, pesticides and industrial compounds, to microplastics can modify their bioavailability and biodegradation. The present study investigated the capacity of ultra-high density polyethylene particles (125 µm in diameter), before and after aging, to sorb 21 organic micropollutants at different environmentally relevant concentration. Furthermore, the biodegradation of these organic micropollutants by a biofilm microbial community growing on the microplastic surface was compared with the biodegradation by a microbial community originating from activated sludge. Among all tested organic micropollutants, propranolol (70%), trimethoprim (25%) and sotalol (15%) were sorbed in the presence of polyethylene particles. Growth of a biofilm on the polyethylene particles had a beneficial effect on the sorption of bromoxynil, caffeine and chloridazon and on the biodegradation of irbesartan, atenolol and benzotriazole. On the other hand, the biofilm limited the sorption of trimethoprim, propranolol, sotalol and benzotriazole and the biodegradation of 2,4-D. These results showed that ultra-high density polyethylene particles can affect both in a positive and negative way for the abiotic and biotic removal of organic micropollutants in wastewater. This project highlights the need for further investigation regarding the interaction between microplastics and organic micropollutants in the aquatic environment.
Topics: Biofilms; Biodegradation, Environmental; Water Pollutants, Chemical; Polyethylene; Microplastics; Adsorption; Propranolol; Trimethoprim; Atenolol; Triazoles; Sewage
PubMed: 38810284
DOI: 10.1016/j.ecoenv.2024.116510 -
International Journal of Cardiology Aug 2024While current guidelines recommend amiodarone and dronedarone for rhythm control in patients with atrial fibrillation (AF) and coronary artery disease (CAD), there was...
BACKGROUND
While current guidelines recommend amiodarone and dronedarone for rhythm control in patients with atrial fibrillation (AF) and coronary artery disease (CAD), there was no comparative study of antiarrhythmic drugs (AADs) on the cardiovascular outcomes in general practice.
METHODS
This study included patients with AF and CAD who received their first prescription of amiodarone, class Ic AADs (flecainide, propafenone), dronedarone or sotalol between January 2016 and December 2020. The primary outcome was a composite of hospitalization for heart failure (HHF), stroke, acute myocardial infarction (AMI), and cardiovascular death. We used Cox proportional regression models, including with inverse probability of treatment weighting (IPTW), to estimate the relationship between AADs and cardiovascular outcomes.
RESULTS
Among the AF cohort consisting of 8752 patients, 1996 individuals had CAD, including 477 who took dronedarone and 1519 who took other AADs. After a median follow-up of 38 months, 46.3% of patients who took dronedarone and 54.4% of patients who took other AADs experienced cardiovascular events. Compared to dronedarone, the use of other AADs was associated with increased cardiovascular events after adjusting for covariates (hazard ratio [HR] 1.531, 95% confidence interval [CI] 1.112-2.141, p = 0.023) and IPTW (HR 1.491, 95% CI 1.174-1.992, p = 0.012). The secondary analysis showed that amiodarone and class Ic drugs were associated with an increased risk of HHF. The low number of subjects in the sotalol group limits data interpretation.
CONCLUSION
For patients with AF and CAD, dronedarone was associated with better cardiovascular outcomes than other AADs. Amiodarone and class Ic AADs were associated with a higher risk of cardiovascular events, particularly HHF.
Topics: Humans; Male; Atrial Fibrillation; Female; Anti-Arrhythmia Agents; Aged; Coronary Artery Disease; Middle Aged; Dronedarone; Follow-Up Studies; Amiodarone; Treatment Outcome; Retrospective Studies; Cohort Studies
PubMed: 38782070
DOI: 10.1016/j.ijcard.2024.132198 -
Texas Heart Institute Journal Apr 2024Atrial tachyarrhythmias are common and difficult to treat in adults with congenital heart disease. Dronedarone has proven effective in patients without congenital heart...
BACKGROUND
Atrial tachyarrhythmias are common and difficult to treat in adults with congenital heart disease. Dronedarone has proven effective in patients without congenital heart disease, but data are limited about its use in adults with congenital heart disease of moderate to great complexity.
METHODS
A single-center, retrospective chart review of 21 adults with congenital heart disease of moderate to great complexity who were treated with dronedarone for atrial tachyarrhythmias was performed.
RESULTS
The median (IQR) age at dronedarone initiation was 35 (27.5-39) years. Eleven patients (52%) were male. Ten patients (48%) had New York Heart Association class I disease, 10 (48%) had class II disease, and 1 (5%) had class III disease. Ejection fraction at initiation was greater than 55% in 11 patients (52%), 35% to 55% in 9 patients (43%), and less than 35% in 1 patient (5%). Prior treatments included β-blockers (71%), sotalol (38%), amiodarone (24%), digoxin (24%), and catheter ablation (38%). Rhythm control was complete in 5 patients (24%), partial in 6 (29%), and inadequate in 10 (48%). Two patients (10%) experienced adverse events, including nausea in 1 (5%) and cardiac arrest in 1 (5%), which occurred 48 months after initiation of treatment. There were no deaths during the follow-up period. The median (IQR) follow-up time for patients with complete or partial rhythm control was 20 (1-54) months.
CONCLUSION
Dronedarone can be effective for adult patients with congenital heart disease and atrial arrhythmias for whom more established therapies have failed, and with close monitoring it can be safely tolerated.
Topics: Humans; Dronedarone; Male; Retrospective Studies; Female; Adult; Heart Defects, Congenital; Anti-Arrhythmia Agents; Treatment Outcome; Heart Rate; Atrial Fibrillation; Amiodarone; Time Factors
PubMed: 38686681
DOI: 10.14503/THIJ-22-7993 -
Journal of Veterinary Cardiology : the... Mar 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.
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