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Heart Rhythm Nov 2023Use of d,l-sotalol for rhythm control in patients with atrial fibrillation (AF) has raised safety concerns. Previous randomized studies are few and not designed for...
BACKGROUND
Use of d,l-sotalol for rhythm control in patients with atrial fibrillation (AF) has raised safety concerns. Previous randomized studies are few and not designed for mortality outcome.
OBJECTIVE
The purpose of this study was to compare the incidences of mortality and ventricular arrhythmias in AF patients treated with d,l-sotalol for rhythm control vs matched control patients treated with cardioselective beta-blockers.
METHODS
This population-based cohort study included AF patients from the Swedish National Patient Registry (2006-2017) who underwent rhythm control after a second cardioversion. Incidence rates (IRs) and adjusted hazard ratios (aHRs) for mortality and a composite endpoint of cardiac arrest/death and ventricular arrhythmias were calculated for the overall cohort and a 1:1 propensity score matched cohort of d,l-sotalol vs beta-blocker treatment.
RESULTS
Among patient treated with d,l-sotalol (n = 4987) and beta-blocker (n = 27,078) (mean follow-up 458 days), all-cause mortality was lower in patients treated with d,l-sotalol: IR 1.21; 95% confidence interval 0.95-1.52 vs 2.42 (2.26-2.60) deaths per 100 patient-years; aHR 0.66 (0.52-0.83). The difference in mortality persisted in the propensity score matched comparison (n = 4953 in each group): aHR 0.63 (0.48-0.86). No differences were observed in the composite outcome: IR in propensity cohorts 2.13 (1.78-2.52) vs 2.07 (1.73-2.53) events per 100 years; aHR 1.01 (0.78-1.29).
CONCLUSION
There was no excess mortality with d,l-sotalol compared with cardioselective beta-blockers in patients undergoing rhythm control treatment for AF after a second cardioversion. Our results indicate that the risk associated with d,l-sotalol treatment for AF can be mitigated by careful patient selection and strict adherence to follow-up protocols.
Topics: Humans; Sotalol; Atrial Fibrillation; Anti-Arrhythmia Agents; Cohort Studies; Adrenergic beta-Antagonists
PubMed: 37598987
DOI: 10.1016/j.hrthm.2023.08.019 -
Utilizing human induced pluripotent stem cells to study atrial arrhythmias in the short QT syndrome.Journal of Molecular and Cellular... Oct 2023Among the monogenic inherited causes of atrial fibrillation is the short QT syndrome (SQTS), a rare channelopathy causing atrial and ventricular arrhythmias. One of the...
BACKGROUND
Among the monogenic inherited causes of atrial fibrillation is the short QT syndrome (SQTS), a rare channelopathy causing atrial and ventricular arrhythmias. One of the limitations in studying the mechanisms and optimizing treatment of SQTS-related atrial arrhythmias has been the lack of relevant human atrial tissues models.
OBJECTIVE
To generate a unique model to study SQTS-related atrial arrhythmias by combining the use of patient-specific human induced pluripotent stem cells (hiPSCs), atrial-specific differentiation schemes, two-dimensional tissue modeling, optical mapping, and drug testing.
METHODS AND RESULTS
SQTS (N588K KCNH2 mutation), isogenic-control, and healthy-control hiPSCs were coaxed to differentiate into atrial cardiomyocytes using a retinoic-acid based differentiation protocol. The atrial identity of the cells was confirmed by a distinctive pattern of MLC2v downregulation, connexin 40 upregulation, shorter and triangular-shaped action potentials (APs), and expression of the atrial-specific acetylcholine-sensitive potassium current. In comparison to the healthy- and isogenic control cells, the SQTS-hiPSC atrial cardiomyocytes displayed abbreviated APs and refractory periods along with an augmented rapidly activating delayed-rectifier potassium current (I). Optical mapping of a hiPSC-based atrial tissue model of the SQTS displayed shortened APD and altered biophysical properties of spiral waves induced in this model, manifested by accelerated spiral-wave frequency and increased rotor curvature. Both AP shortening and arrhythmia irregularities were reversed by quinidine and vernakalant treatment, but not by sotalol.
CONCLUSIONS
Patient-specific hiPSC-based atrial cellular and tissue models of the SQTS were established, which provide examples on how this type of modeling can shed light on the pathogenesis and pharmacological treatment of inherited atrial arrhythmias.
Topics: Humans; Induced Pluripotent Stem Cells; Atrial Fibrillation; Myocytes, Cardiac; Potassium; Action Potentials
PubMed: 37579942
DOI: 10.1016/j.yjmcc.2023.08.003 -
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 -
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 -
Journal of Veterinary Cardiology : the... Oct 2023A two-year and four-month, male German Shepherd was referred for exercise intolerance and panting. Irregular heart auscultation (250 beats per minute (bpm)) and pulse...
A two-year and four-month, male German Shepherd was referred for exercise intolerance and panting. Irregular heart auscultation (250 beats per minute (bpm)) and pulse deficits were noted on physical exam. Electrocardiogram (ECG) showed irregular, narrow-QRS tachycardia without P waves compatible with coarse atrial fibrillation (AF). A 24-h ECG showed sustained AF (mean ventricular response rate 92 bpm). Echocardiography showed no structural abnormalities. Given the young age and presence of AF-related symptoms, rhythm control was preferred. Transthoracic electrical cardioversion was successfully performed six weeks later but AF recurred within 24-h. Sotalol was started but discontinued due to poor tolerance and AF persisted. Seven months after AF diagnosis, radiofrequency catheter ablation (RFCA) aiming for pulmonary vein isolation was performed under general anaesthesia. After transseptal puncture, three-dimensional electroanatomical mapping of the left atrium was performed. Point-by-point pulmonary vein isolation was achieved by RFCA. Seventy-eight RFCA lesions were placed in the left atrium encircling the three pulmonary vein ostia followed by electrical cardioversion. No complications occurred and the dog was discharged with amiodarone. In the immediate post-operative phase, there was recurrence of persistent AF requiring electrical cardioversion. Furthermore, at one month after the ablation, the dog experienced a single and transient paroxysm of AF. Since then, stable sinus rhythm (SR) was retained on daily ECG monitoring at home and confirmed by 24-h ECG three months post-operatively. Amiodarone was stopped subsequently. At the time of writing (one year post-operative), the dog remains in SR with normal exercise tolerance.
Topics: Male; Dogs; Animals; Atrial Fibrillation; Treatment Outcome; Pulmonary Veins; Heart Atria; Amiodarone; Catheter Ablation; Dog Diseases
PubMed: 37517098
DOI: 10.1016/j.jvc.2023.07.001 -
Pharmaceuticals (Basel, Switzerland) Jul 2023We focused on the first demonstration that antiarrhythmics, particularly class II and class III antiarrhythmic and beta-blocker sotalol can induce severe...
We focused on the first demonstration that antiarrhythmics, particularly class II and class III antiarrhythmic and beta-blocker sotalol can induce severe occlusion/occlusion-like syndrome in rats. In this syndrome, as in similar syndromes with permanent occlusion of major vessels, peripheral and central, and other similar noxious procedures that severely disable endothelium function, the stable gastric pentadecapeptide BPC 157-collateral pathways activation, was a resolving therapy. After a high dose of sotalol (80 mg/kg intragastrically) in 180 min study, there were cause-consequence lesions in the brain (swelling, intracerebral hemorrhage), congestion in the heart, lung, liver, kidney, and gastrointestinal tract, severe bradycardia, and intracranial (superior sagittal sinus), portal and caval hypertension, and aortal hypotension, and widespread thrombosis, peripherally and centrally. Major vessels failed (congested inferior caval and superior mesenteric vein, collapsed azygos vein). BPC 157 therapy (10 µg, 10 ng/kg given intragastrically at 5 min or 90 min sotalol-time) effectively counteracted sotalol-occlusion/occlusion-like syndrome. In particular, eliminated were heart dilatation, and myocardial congestion affecting coronary veins and arteries, as well as myocardial vessels; eliminated were portal and caval hypertension, lung parenchyma congestion, venous and arterial thrombosis, attenuated aortal hypotension, and centrally, attenuated intracranial (superior sagittal sinus) hypertension, brain lesions and pronounced intracerebral hemorrhage. Further, BPC 157 eliminated and/or markedly attenuated liver, kidney, and gastrointestinal tract congestion and major veins congestion. Therefore, azygos vein activation and direct blood delivery were essential for particular BPC 157 effects. Thus, preventing such and similar events, and responding adequately when that event is at risk, strongly advocates for further BPC 157 therapy.
PubMed: 37513889
DOI: 10.3390/ph16070977 -
Birth Defects Research Oct 2023Fetal atrial flutter (AF), accounting for 30% of all fetal tachyarrhythmias, predominantly (over 80%) manifests as a 2:1 atrioventricular conduction. Swift referral and...
BACKGROUND
Fetal atrial flutter (AF), accounting for 30% of all fetal tachyarrhythmias, predominantly (over 80%) manifests as a 2:1 atrioventricular conduction. Swift referral and timely intervention become imperative in instances of severe persistent arrhythmia.
CASE PRESENTATION
We discuss the case of a 32-year-old multiparous Chinese woman, at 30 weeks of gestation, wherein an ultrasonographic examination revealed persistent fetal AF (atrial rate ranging from 219 to 445 beats/min and ventricular rate from 219 to 228 beats/min, with a 2:1 or 1:1 down transmission) and minor ascites. Despite the maternal ingestion of digoxin and sotalol, the fetal heart rhythm remained uncorrected. Following this, at 32 weeks of gestation, an intramuscular injection of cedilanid, guided by ultrasound, was administered to the fetus. Postoperatively, the fetal ventricular rate demonstrated a decline after 6 days, and the ascites resolved. Subsequently, at 33 weeks, a cesarean section was necessitated due to maternal intolerance to the medication, resulting in the delivery of the infant. Remarkably, the infant's cardiac rhythm spontaneously converted to sinus rhythm within 5 min of birth. A follow-up conducted 1 year postpartum revealed no recurrence of AF.
CONCLUSIONS
This case illustrates that in the event of transplacental drug treatment failure, intrauterine therapeutic intervention should be considered. Moreover, it highlights the encouraging prognosis associated with fetal AF, as the cardiac rhythm spontaneously reverted to sinus rhythm postbirth in this instance.
Topics: Pregnancy; Humans; Female; Adult; Atrial Flutter; Anti-Arrhythmia Agents; Cesarean Section; Ascites; Fetal Diseases; Arrhythmias, Cardiac; Fetus
PubMed: 37491874
DOI: 10.1002/bdr2.2220 -
Circulation. Arrhythmia and... Aug 2023Sotalol and dronedarone are both used for maintenance of sinus rhythm for patients with atrial fibrillation. However, while sotalol requires initial monitoring for QT...
BACKGROUND
Sotalol and dronedarone are both used for maintenance of sinus rhythm for patients with atrial fibrillation. However, while sotalol requires initial monitoring for QT prolongation and proarrhythmia, dronedarone does not. These treatments can be used in comparable patients, but their safety and effectiveness have not been compared head to head. Therefore, we retrospectively evaluated the effectiveness and safety using data from a large health care system.
METHODS
Using Veterans Health Administration data, we identified 11 296 antiarrhythmic drug-naive patients with atrial fibrillation prescribed dronedarone or sotalol in 2012 or later. We excluded patients with prior conduction disease, pacemakers or implantable cardioverter-defibrillators, ventricular arrhythmia, cancer, renal failure, liver disease, or heart failure. We used natural language processing to identify and compare baseline left ventricular ejection fraction between treatment arms. We used 1:1 propensity score matching, based on patient demographics, comorbidities, and medications, and Cox regression to compare strategies. To evaluate residual confounding, we performed falsification analysis with nonplausible outcomes.
RESULTS
The matched cohort comprised 6212 patients (3106 dronedarone and 3106 sotalol; mean [±SD] age, 71±10 years; 2.5% female; mean [±SD] CHADS-VASC, 2±1.3). The mean (±SD) left ventricular ejection fraction was 55±11 and 58±10 for dronedarone and sotalol users, correspondingly. Dronedarone, compared with sotalol, did not demonstrate a significant association with risk of cardiovascular hospitalization (hazard ratio, 1.03 [95% CI, 0.88-1.21]) or all-cause mortality (hazard ratio, 0.89 [95% CI, 0.68-1.16]). However, dronedarone was associated with significantly lower risk of ventricular proarrhythmic events (hazard ratio, 0.53 [95% CI, 0.38-0.74]) and symptomatic bradycardia (hazard ratio, 0.56 [95% CI, 0.37-0.87]). The primary findings were stable across sensitivity analyses. Falsification analyses were not significant.
CONCLUSIONS
Dronedarone, compared with sotalol, was associated with a lower risk of ventricular proarrhythmic events and conduction disorders while having no difference in risk of incident cardiovascular hospitalization and mortality. These observational data provide the basis for prospective efficacy and safety trials.
Topics: Female; Humans; Middle Aged; Aged; Aged, 80 and over; Male; Anti-Arrhythmia Agents; Dronedarone; Sotalol; Atrial Fibrillation; Retrospective Studies; Prospective Studies; Stroke Volume; Veterans; Ventricular Function, Left; Amiodarone
PubMed: 37485722
DOI: 10.1161/CIRCEP.123.011893 -
Communications Medicine Jul 2023Professional society practice guidelines conflict regarding their recommendations of dofetilide (DOF) and sotalol (STL) for treatment of arrhythmias in hypertrophic...
BACKGROUND
Professional society practice guidelines conflict regarding their recommendations of dofetilide (DOF) and sotalol (STL) for treatment of arrhythmias in hypertrophic cardiomyopathy (HCM), and supporting data is sparse. We aim to assess safety and efficacy of DOF and STL on arrhythmias in HCM.
METHODS
This was an observational study of HCM patients treated with DOF or STL for atrial fibrillation (AF) and ventricular arrhythmias (VA). Outcomes of drug discontinuation and arrhythmia recurrence were compared at 1 year and latest follow-up by Kaplan-Meier analysis. Predictors of drug failure were studied using uni- and multi-variable analyses. Drug-related adverse events were quantitated.
RESULTS
Here we show that of our cohort of 72 patients (54 ± 14 years old, 75% male), 21 were prescribed DOF for AF, 52 STL for AF, and 18 STL for VA. At 1 year, discontinuation and recurrence rates were similar for DOF-AF (38% and 43%) and STL-AF (29% and 44%) groups. Efficacy data was similar at long-term follow-up of 1603 (IQR 994-4131) days, and for STL-VA. Drug inefficacy was the most common reason for discontinuation (28%) followed by side-effects (13%). Incidences of heart failure hospitalization (5%) and mortality (3%) were low. One STL-AF patient developed non-sustained torsades de pointes in the setting of severe pneumonia and acute kidney injury, but there were no other drug-related serious adverse events.
CONCLUSIONS
DOF and STL demonstrate modest efficacy and satisfactory safety when used for AF and VA in HCM patients.
PubMed: 37468544
DOI: 10.1038/s43856-023-00315-8 -
Journal of Pharmacological and... 2023Pharmacological blockade of the I channel (hERG) by diverse drugs in clinical use is associated with the Long QT Syndrome that can lead to life threatening arrhythmia....
Pharmacological blockade of the I channel (hERG) by diverse drugs in clinical use is associated with the Long QT Syndrome that can lead to life threatening arrhythmia. Various computational tools including machine learning models (MLM) for the prediction of hERG inhibition have been developed to facilitate the throughput screening of drugs in development and optimise thus the prediction of hERG liabilities. The use of MLM relies on large libraries of training compounds for the quantitative structure-activity relationship (QSAR) modelling of hERG inhibition. The focus on inhibition omits potential effects of hERG channel agonist molecules and their associated QT shortening risk. It is instructive, therefore, to consider how known hERG agonists are handled by MLM. Here, two highly developed online computational tools for the prediction of hERG liability, Pred-hERG and HergSPred were probed for their ability to detect hERG activator drug molecules as hERG interactors. In total, 73 hERG blockers were tested with both computational tools giving overall good predictions for hERG blockers with reported ICs below Pred-hERG and HergSPred cut-off threshold for hERG inhibition. However, for compounds with reported ICs above this threshold such as disopyramide or sotalol discrepancies were observed. HergSPred identified all 20 hERG agonists selected as interacting with the hERG channel. Further studies are warranted to improve online MLM prediction of hERG related cardiotoxicity, by explicitly taking into account channel agonism as well as inhibition.
Topics: Humans; Potassium Channel Blockers; Ether-A-Go-Go Potassium Channels; Arrhythmias, Cardiac; Machine Learning; Internet
PubMed: 37468081
DOI: 10.1016/j.vascn.2023.107293