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Frontiers in Pharmacology 2023We studied time course of pathological remodeling occurring in the cynomolgus monkey hearts against persistent atrioventricular block condition ( = 10). The...
We studied time course of pathological remodeling occurring in the cynomolgus monkey hearts against persistent atrioventricular block condition ( = 10). The atrioventricular block induced the ventricular and atrial dilation followed by the ventricular hypertrophy. Interstitial fibrosis in the ventricle was also observed along with gradual increases in the plasma angiotensin II and aldosterone concentrations. These adaptations were associated with the changes in gene expression profiling reflecting fibrosis and hypertrophy. Atrioventricular block reduced the ventricular rate and cardiac output, but the ejection fraction and stroke volume increased, whereas the cardiac output was gradually restored to its basal level. Systolic/diastolic blood pressure after the atrioventricular block was kept equal to or lower than that before the block, according with lack of increase in the plasma catecholamine levels. Chronic atrioventricular block gradually prolonged the QRS width and JT interval, leading to the QT interval prolongation in conscious state. 10 mg/kg of -sotalol hydrochloride induced torsade de pointes (TdP) in 6 out of 10 animals by 15 months. Animals showing longer QTcF under anesthesia after the atrioventricular block developed -sotalol-induced TdP earlier. No marked difference was observed in pharmacokinetics of -sotalol between 1 and 7 months after the atrioventricular block. Each TdP spontaneously terminated, reflecting a monkey's relatively small "effective size of the heart (=∛(left ventricular weight)/wavelength of reentry)". These fundamental knowledge will help better utilize the chronic atrioventricular block monkeys as an proarrhythmia model for detecting drug-induced TdP.
PubMed: 36744259
DOI: 10.3389/fphar.2023.1055031 -
JMIR Cardio Jan 2023Drug-induced prolongation of the corrected QT interval (QTc) increases the risk for Torsades de Pointes (TdP) and sudden cardiac death. Medication effects on the QTc...
BACKGROUND
Drug-induced prolongation of the corrected QT interval (QTc) increases the risk for Torsades de Pointes (TdP) and sudden cardiac death. Medication effects on the QTc have been studied in controlled settings but may not be well evaluated in real-world settings where medication effects may be modulated by patient demographics and comorbidities as well as the usage of other concomitant medications.
OBJECTIVE
We demonstrate a new, high-throughput method leveraging electronic health records (EHRs) and the Surescripts pharmacy database to monitor real-world QTc-prolonging medication and potential interacting effects from demographics and comorbidities.
METHODS
We included all outpatient electrocardiograms (ECGs) from September 2008 to December 2019 at a large academic medical system, which were in sinus rhythm with a heart rate of 40-100 beats per minute, QRS duration of <120 milliseconds, and QTc of 300-700 milliseconds, determined using the Bazett formula. We used prescription information from the Surescripts pharmacy database and EHR medication lists to classify whether a patient was on a medication during an ECG. Negative control ECGs were obtained from patients not currently on the medication but who had been or would be on that medication within 1 year. We calculated the difference in mean QTc between ECGs of patients who are on and those who are off a medication and made comparisons to known medication TdP risks per the CredibleMeds.org database. Using linear regression analysis, we studied the interaction of patient-level demographics or comorbidities on medication-related QTc prolongation.
RESULTS
We analyzed the effects of 272 medications on 310,335 ECGs from 159,397 individuals. Medications associated with the greatest QTc prolongation were dofetilide (mean QTc difference 21.52, 95% CI 10.58-32.70 milliseconds), mexiletine (mean QTc difference 18.56, 95% CI 7.70-29.27 milliseconds), amiodarone (mean QTc difference 14.96, 95% CI 13.52-16.33 milliseconds), rifaximin (mean QTc difference 14.50, 95% CI 12.12-17.13 milliseconds), and sotalol (mean QTc difference 10.73, 95% CI 7.09-14.37 milliseconds). Several top QT prolonging medications such as rifaximin, lactulose, cinacalcet, and lenalidomide were not previously known but have plausible mechanistic explanations. Significant interactions were observed between demographics or comorbidities and QTc prolongation with many medications, such as coronary disease and amiodarone.
CONCLUSIONS
We demonstrate a new, high-throughput technique for monitoring real-world effects of QTc-prolonging medications from readily accessible clinical data. Using this approach, we confirmed known medications for QTc prolongation and identified potential new associations and demographic or comorbidity interactions that could supplement findings in curated databases. Our single-center results would benefit from additional verification in future multisite studies that incorporate larger numbers of patients and ECGs along with more precise medication adherence and comorbidity data.
PubMed: 36662566
DOI: 10.2196/41055 -
Journal of Cardiovascular... Mar 2023Oral sotalol initiation requires a multiple-day, inpatient admission to monitor for QT prolongation during loading. A 1-day intravenous (IV) sotalol loading protocol was...
INTRODUCTION
Oral sotalol initiation requires a multiple-day, inpatient admission to monitor for QT prolongation during loading. A 1-day intravenous (IV) sotalol loading protocol was approved by the United States Food and Drug Administration in March 2020, but limited data on clinical use and administration currently exists. This study describes implementation of an IV sotalol protocol within an integrated health system, provides initial efficacy and safety outcomes, and examines length of stay (LOS) compared with oral sotalol initiation.
METHODS
IV sotalol was administered according to a prespecified initiation protocol to adult patients with refractory atrial or ventricular arrhythmias. Baseline characteristics, safety and feasibility outcomes, and LOS were compared with patients receiving oral sotalol over a similar time period.
RESULTS
From January 2021 to June 2022, a total of 29 patients (average age 66.0 ± 8.6 years, 27.6% women) underwent IV sotalol load and 20 patients (average age 60.4 ± 13.9 years, 65.0% women) underwent oral sotalol load. The load was successfully completed in 22/29 (75.9%) patients receiving IV sotalol and 20/20 (100%) of patients receiving oral sotalol, although 7/20 of the oral sotalol patients (35.0%) required dose reduction. Adverse events interrupting IV sotalol infusion included bradycardia (seven patients, 24.1%) and QT prolongation (three patients, 10.3%). No patients receiving IV or oral sotalol developed sustained ventricular arrhythmias before discharge. LOS for patients completing IV load was 2.6 days shorter (mean 1.0 vs. 3.6, p < .001) compared with LOS with oral load.
CONCLUSION
IV sotalol loading has a safety profile that is similar to oral sotalol. It significantly shortens hospital LOS, potentially leading to large cost savings.
Topics: Adult; Female; Humans; Middle Aged; Aged; Male; Sotalol; Anti-Arrhythmia Agents; Length of Stay; Feasibility Studies; Arrhythmias, Cardiac; Long QT Syndrome
PubMed: 36640424
DOI: 10.1111/jce.15819 -
Methodist DeBakey Cardiovascular Journal 2022Antiarrhythmic drug therapy has traditionally been centered in modulating the generation or propagation of the cardiac action potential by drugs acting on membrane ion... (Review)
Review
Antiarrhythmic drug therapy has traditionally been centered in modulating the generation or propagation of the cardiac action potential by drugs acting on membrane ion channels. The history of this approach has been disappointing, marked by catastrophic failures such as those of sodium channel blockers or sotalol to treat ventricular arrhythmias in the setting of structural cardiomyopathies, which led to increased mortality, and by modest clinical efficacy in paroxysmal atrial fibrillation. As catheter ablation has become an established effective therapy for most tachyarrhythmias, membrane-acting drugs have been relegated to symptomatic control of benign arrhythmias in normal hearts or to adjunctive treatments of ventricular tachycardia (combined with catheter ablation and cardiac defibrillators) in the setting of cardiomyopathies. Novel targets of biological modulation of arrhythmia substrates beyond the membrane potential appear promising and could represent future opportunities for arrhythmia pharmacotherapy.
Topics: Humans; Anti-Arrhythmia Agents; Atrial Fibrillation; Sotalol; Tachycardia, Ventricular; Catheter Ablation
PubMed: 36561081
DOI: 10.14797/mdcvj.1185 -
Turkish Journal of Obstetrics and... Dec 2022Fetal arrhythmias complicate 1-2% of all pregnancies. Ultrasound evaluation and Doppler technology are indispensable in both diagnosis and management. Digoxin, sotalol,...
OBJECTIVE
Fetal arrhythmias complicate 1-2% of all pregnancies. Ultrasound evaluation and Doppler technology are indispensable in both diagnosis and management. Digoxin, sotalol, flecainide and amiodarone are widely accepted antiarrhythmic agents that are frequently. We reviewed the maternal and fetal outcomes in cases with fetal arrhythmia in a tertiary care center in the last decade.
MATERIALS AND METHODS
Fetal arrhythmias were classified under three main groups: Irregular rhythms, tachyarrhythmia and bradyarrhythmia. Detailed anatomical evaluation and fetal echocardiography were performed in all cases to determine whether a structural cardiac and extracardiac anomaly accompanied fetal arrhythmia and the type of fetal arrhythmia. Digoxin was started primarily as first-line therapy in patients with persistent fetal tachyarrhythmia. In cases, not responding to digoxin, other antiarrhythmic agents (sotalol, flecainide) were combined with treatment without discontinuing digoxin.
RESULTS
Fetal arrhythmia was detected in 36 cases during the study period. 50% (n=18/36) of the cases had supraventricular tachycardia, whereas 28% (n=10/36) of them were fetal bradyarrhythmia and 22% (n=8/36) of them were with various irregular rhythms. Transplacental therapy was initiated in 13 patients with persistent supraventricular tachycardia and atrial flutter regardless of the presence of hydrops. The success rate in transplacental therapy was 77% (n=10/13).
CONCLUSION
Successful transplacental therapy was achieved in approximately 80% of cases and delivery could be postponed to advanced gestational weeks, confirming the crucial role of this treatment for the management of tachyarrhythmia.
PubMed: 36511630
DOI: 10.4274/tjod.galenos.2022.61818 -
Journal of Pharmacological and... 2022ICH S7B recommends screening for hERG channel block using patch clamp recordings to assess a drug's proarrhythmic risk. Block of the hERG channel has been associated...
ICH S7B recommends screening for hERG channel block using patch clamp recordings to assess a drug's proarrhythmic risk. Block of the hERG channel has been associated with clinical QT prolongation as well as the rare, but potentially fatal ventricular tachyarrhythmia Torsade de Pointes (TdP). During recording, drug concentrations perfused to the cells can deviate from nominal concentrations due to molecule-specific properties (such as non-specific binding), thereby introducing error when assessing drug potency. To account for this potential source of error, both the original ICH S7B and the newly released ICH E14/S7B Q&As guidelines call for verifying drug solutions' concentrations. Dofetilide, cisapride, terfenadine, sotalol and E-4031 are hERG blockers commonly used as positive controls to illustrate hERG assay sensitivity. The first four compounds are also clinical drugs associated with high TdP risk; therefore, their safety margins may be useful comparators to better understand an investigational product's TdP risk. Having analytical methods to quantify these five compounds in the hERG external solution that will be used for patch clamp recordings is important from a regulatory science research perspective. However, a literature search revealed no analytical methods or stability information for these molecules in the high salt, serum-free matrix that constitutes the hERG external solution. This study was conducted to develop and validate LC-MS/MS methods to quantify these 5 molecules in hERG external solution. The bioanalytical methods for these positive controls were validated as per the FDA's bioanalytical method validation guidance along with various stabilities.
Topics: Humans; Chromatography, Liquid; Tandem Mass Spectrometry; Torsades de Pointes; Long QT Syndrome; DNA-Binding Proteins; Ether-A-Go-Go Potassium Channels
PubMed: 36334898
DOI: 10.1016/j.vascn.2022.107229 -
NPJ Systems Biology and Applications Nov 2022Short QT syndrome (SQTS) is a rare but dangerous genetic disease. In this research, we conducted a comprehensive in silico investigation into the arrhythmogenesis in...
Short QT syndrome (SQTS) is a rare but dangerous genetic disease. In this research, we conducted a comprehensive in silico investigation into the arrhythmogenesis in KCNH2 T618I-associated SQTS using a multi-scale human ventricle model. A Markov chain model of I was developed firstly to reproduce the experimental observations. It was then incorporated into cell, tissue, and organ models to explore how the mutation provided substrates for ventricular arrhythmias. Using this T618I Markov model, we explicitly revealed the subcellular level functional alterations by T618I mutation, particularly the changes of ion channel states that are difficult to demonstrate in wet experiments. The following tissue and organ models also successfully reproduced the changed dynamics of reentrant spiral waves and impaired rate adaptions in hearts of T618I mutation. In terms of pharmacotherapy, we replicated the different effects of a drug under various conditions using identical mathematical descriptions for drugs. This study not only simulated the actions of an effective drug (quinidine) at various physiological levels, but also elucidated why the I inhibitor sotalol failed in SQT1 patients through profoundly analyzing its mutation-dependent actions.
Topics: Humans; Quinidine; Sotalol; Anti-Arrhythmia Agents; Action Potentials; Mutation; ERG1 Potassium Channel
PubMed: 36333337
DOI: 10.1038/s41540-022-00254-5 -
Frontiers in Physiology 2022Cardiac fibrosis has been identified as a major factor in conduction alterations leading to atrial arrhythmias and modification of drug treatment response. To perform...
Cardiac fibrosis has been identified as a major factor in conduction alterations leading to atrial arrhythmias and modification of drug treatment response. To perform an proof-of-concept study of Artificial Intelligence (AI) ability to identify susceptibility for conduction blocks in simulations on a population of models with diffused fibrotic atrial tissue and anti-arrhythmic drugs. Activity in 2D cardiac tissue planes were simulated on a population of variable electrophysiological and anatomical profiles using the Koivumaki model for the atrial cardiomyocytes and the Maleckar model for the diffused fibroblasts (0%, 5% and 10% fibrosis area). Tissue sheets were of 2 cm side and the effect of amiodarone, dofetilide and sotalol was simulated to assess the conduction of the electrical impulse across the planes. Four different AI algorithms (Quadratic Support Vector Machine, QSVM, Cubic Support Vector Machine, CSVM, decision trees, DT, and K-Nearest Neighbors, KNN) were evaluated in predicting conduction of a stimulated electrical impulse. Overall, fibrosis implementation lowered conduction velocity (CV) for the conducting profiles (0% fibrosis: 67.52 ± 7.3 cm/s; 5%: 58.81 ± 14.04 cm/s; 10%: 57.56 ± 14.78 cm/s; < 0.001) in combination with a reduced 90% action potential duration (0% fibrosis: 187.77 ± 37.62 ms; 5%: 93.29 ± 82.69 ms; 10%: 106.37 ± 85.15 ms; < 0.001) and peak membrane potential (0% fibrosis: 89.16 ± 16.01 mV; 5%: 70.06 ± 17.08 mV; 10%: 82.21 ± 19.90 mV; < 0.001). When the antiarrhythmic drugs were present, a total block was observed in most of the profiles. In those profiles in which electrical conduction was preserved, a decrease in CV was observed when simulations were performed in the 0% fibrosis tissue patch (Amiodarone ΔCV: -3.59 ± 1.52 cm/s; Dofetilide ΔCV: -13.43 ± 4.07 cm/s; Sotalol ΔCV: -0.023 ± 0.24 cm/s). This effect was preserved for amiodarone in the 5% fibrosis patch (Amiodarone ΔCV: -4.96 ± 2.15 cm/s; Dofetilide ΔCV: 0.14 ± 1.87 cm/s; Sotalol ΔCV: 0.30 ± 4.69 cm/s). 10% fibrosis simulations showed that part of the profiles increased CV while others showed a decrease in this variable (Amiodarone ΔCV: 0.62 ± 9.56 cm/s; Dofetilide ΔCV: 0.05 ± 1.16 cm/s; Sotalol ΔCV: 0.22 ± 1.39 cm/s). Finally, when the AI algorithms were tested for predicting conduction on input of variables from the population of modelled, Cubic SVM showed the best performance with AUC = 0.95. proof-of-concept study demonstrates that fibrosis can alter the expected behavior of antiarrhythmic drugs in a minority of atrial population models and AI can assist in revealing the profiles that will respond differently.
PubMed: 36311248
DOI: 10.3389/fphys.2022.1025430 -
Frontiers in Toxicology 2022The preclinical identification of drug-induced cardiotoxicity and its translation into human risk are still major challenges in pharmaceutical drug discovery. The ICH...
The preclinical identification of drug-induced cardiotoxicity and its translation into human risk are still major challenges in pharmaceutical drug discovery. The ICH S7B Guideline and Q&A on Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential promotes human drug trials as a novel tool for proarrhythmia risk assessment. To facilitate the use of data in regulatory submissions, explanatory control compounds should be tested and documented to demonstrate consistency between predictions and the historic validation data. This study aims to quantify drug-induced electrophysiological effects on cardiac human Purkinje cells, to compare them with existing rabbit data, and to assess their accuracy for clinical pro-arrhythmic risk predictions. The effects of 14 reference compounds were quantified in simulations with a population of human cardiac Purkinje models. For each drug dose, five electrophysiological biomarkers were quantified at three pacing frequencies, and results compared with available experiments and clinical proarrhythmia reports. Three key results were obtained: 1) repolarization abnormalities in human Purkinje simulations predicted drug-induced arrhythmia for all risky compounds, showing higher predicted accuracy than rabbit experiments; 2) Drug-induced electrophysiological changes observed in human-based simulations showed a high degree of consistency with rabbit recordings at all pacing frequencies, and depolarization velocity and action potential duration were the most consistent biomarkers; 3) discrepancies observed for dofetilide, sotalol and terfenadine are mainly caused by species differences between humans and rabbit. Taken together, this study demonstrates higher accuracy of methods compared to animal models for pro-arrhythmic risk prediction, as well as a high degree of consistency with experiments commonly used in safety pharmacology, supporting the potential for industrial and regulatory adoption of trials for proarrhythmia prediction.
PubMed: 36278026
DOI: 10.3389/ftox.2022.992650 -
Europace : European Pacing,... Feb 2023Utilizing real-world UK data, we aimed to understand: (i) whether anti-arrhythmic drugs and catheter ablation are effective in improving the survival of atrial...
Impact of anti-arrhythmic drugs and catheter ablation on the survival of patients with atrial fibrillation: a population study based on 199 433 new-onset atrial fibrillation patients in the UK.
AIMS
Utilizing real-world UK data, we aimed to understand: (i) whether anti-arrhythmic drugs and catheter ablation are effective in improving the survival of atrial fibrillation (AF) patients and (ii) which rhythm control option produces better results for the whole AF population and for specific groups of patients, stratified by age, sex, and history of heart failure.
METHODS AND RESULTS
We identified 199 433 individuals (mean age at diagnosis 75.7 ± 12.7 years; 50.2% women) with new-onset AF diagnosis in nationwide electronic health records linking primary care consultation with hospital data and death registry data from 1998 to 2016. We investigated the survival and causes of death of new-onset AF patients receiving vs. not-receiving rhythm control therapies. During a median follow-up of 2.7 (0.7-6.0) years, we observed a significantly lower mortality in patients receiving rhythm control [multivariate-adjusted hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.84-0.88]. Pulmonary vein isolation was associated with a two-third significant mortality reduction compared with no rhythm control (HR = 0.36, 95% CI 0.28-0.48), flecainide with 50% reduction (HR = 0.52, 95% CI 0.48-0.57), and propafenone and sotalol with reduction by a third (HR = 0.63, 95% CI 0.50-0.81, 0.71, 95% CI 0.68-0.74, respectively). Amiodarone showed no survival benefit in individuals <70 years (HR = 0.99, 95% CI 0.97-1.02). Otherwise, the effect of rhythm control on survival did not differ by age, sex, nor history of heart failure.
CONCLUSION
Among individuals with new-onset AF, favourable survival was observed for patients receiving rhythm control treatment. Among different rhythm control strategies, pulmonary vein isolation showed the most pronounced survival benefit.
Topics: Humans; Female; Middle Aged; Aged; Aged, 80 and over; Male; Atrial Fibrillation; Anti-Arrhythmia Agents; Heart Failure; Catheter Ablation; United Kingdom; Treatment Outcome
PubMed: 36106534
DOI: 10.1093/europace/euac155