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Frontiers in Pharmacology 2023The human ether-a-go-go-related gene (hERG) not only encodes a potassium-selective voltage-gated ion channel essential for normal electrical activity in the heart but is...
The human ether-a-go-go-related gene (hERG) not only encodes a potassium-selective voltage-gated ion channel essential for normal electrical activity in the heart but is also a major drug anti-target. Genetic hERG mutations and blockage of the channel pore by drugs can cause long QT syndrome, which predisposes individuals to potentially deadly arrhythmias. However, not all hERG-blocking drugs are proarrhythmic, and their differential affinities to discrete channel conformational states have been suggested to contribute to arrhythmogenicity. We used Rosetta electron density refinement and homology modeling to build structural models of open-state hERG channel wild-type and mutant variants (Y652A, F656A, and Y652A/F656 A) and a closed-state wild-type channel based on cryo-electron microscopy structures of hERG and EAG1 channels. These models were used as protein targets for molecular docking of charged and neutral forms of amiodarone, nifekalant, dofetilide, d/l-sotalol, flecainide, and moxifloxacin. We selected these drugs based on their different arrhythmogenic potentials and abilities to facilitate hERG current. Our docking studies and clustering provided atomistic structural insights into state-dependent drug-channel interactions that play a key role in differentiating safe and harmful hERG blockers and can explain hERG channel facilitation through drug interactions with its open-state hydrophobic pockets.
PubMed: 38035013
DOI: 10.3389/fphar.2023.1244166 -
The Journal of Pediatric Pharmacology... 2023We present a case of bidirectional ventricular tachycardia in a 15-year-old boy asymptomatic for arrhythmias, whose major complaint was muscle weakness. At our first...
We present a case of bidirectional ventricular tachycardia in a 15-year-old boy asymptomatic for arrhythmias, whose major complaint was muscle weakness. At our first evaluation he was receiving sotalol for his ventricular arrhythmias. In addition to bidirectional tachycardia, electrocardiogram during sinus rhythm showed prominent U waves and prolonged QT-U interval. These electrocardiographic signs, along with the evidence of clinodactyly and mild hypertelorism, led us to the diagnosis of Andersen-Tawil syndrome, confirmed by genetic analysis that revealed a "" missense mutation of KCNJ2 gene. Monotherapy with flecainide was rapidly effective and almost eliminated ventricular arrhythmias. After a 4-year follow-up there were no adverse events, flecainide has been well tolerated without significant modification of the QRS or repolarization, and ventricular arrhythmias have not been relapsed to date. The case highlights the importance of a correct clinical diagnosis, which is crucial for the optimal selection of the most appropriate drug therapy, which is expected not to be harmful, before being beneficial.
PubMed: 38025154
DOI: 10.5863/1551-6776-28.7.662 -
Circulation Nov 2023Atrial fibrillation (AF) is the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM) with clinical and subclinical episodes occurring in nearly one-half... (Review)
Review
Atrial fibrillation (AF) is the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM) with clinical and subclinical episodes occurring in nearly one-half of patients. AF in HCM historically has been characterized as a decisive disease complication associated with substantial risk for thromboembolic stroke and increased morbidity and mortality. However, there have been many advances in treatment strategy resulting in improved outcomes for this patient group. For example, stroke risk in HCM has been greatly reduced by using systemic oral anticoagulation initiated after the first clinical (symptomatic) AF episode, usually with preference given to direct anticoagulants over warfarin. In contrast, stroke risk scoring systems (such as CHADS-VASc score) are not informative in HCM given the substantial potential for stroke events in patients with low scores, and therefore should not be used for anticoagulation decisions in this disease. A novel risk score specifically designed for HCM (HCM-AF score) can reliably identify most patients with HCM at risk for future AF. Although a strategy focused on controlling ventricular rate is effective in asymptomatic (or minimally symptomatic) patients with AF, restoring and maintaining sinus rhythm is required for most patients with marked AF symptom burden and impaired quality of life. Several antiarrhythmic drugs such as sotalol, disopyramide, and amiodarone, can be effective in suppressing AF episodes; albeit safe, long-term efficacy is supported by only limited data. Catheter AF ablation has emerged as an important treatment option for some patients, although freedom from AF after a single ablation is relatively low (35% at 3 years), multiple ablations and the concomitant use of antiarrhythmic drugs can control AF with more than two-thirds of patients maintaining sinus rhythm at 5 years. Surgical AF ablation with biatrial Cox-Maze IV performed as an adjunctive procedure during myectomy can reduce symptomatic AF episodes (70% of patients free from AF at 5 years). For the vast majority of patients who have HCM with AF, the implementation of contemporary therapies has allowed for improved quality of life and low HCM-related mortality.
Topics: Humans; Atrial Fibrillation; Anti-Arrhythmia Agents; Quality of Life; Risk Factors; Anticoagulants; Stroke; Cardiomyopathy, Hypertrophic; Catheter Ablation; Treatment Outcome
PubMed: 38011245
DOI: 10.1161/CIRCULATIONAHA.123.065037 -
Pharmacology Research & Perspectives Dec 2023Beta-blocker usage is inconsistently associated with increased fall risk in the literature. However, due to age-related changes and interindividual heterogeneity in...
Beta-blocker usage is inconsistently associated with increased fall risk in the literature. However, due to age-related changes and interindividual heterogeneity in pharmacokinetics and dynamics, it is difficult to predict which older adults are more at risk for falls. Therefore, we wanted to explore whether elevated plasma concentrations of selective and nonselective beta-blockers are associated with an increased risk of falls in older beta-blocker users. To answer our research question, we analyzed samples of selective (metoprolol, n = 316) and nonselective beta-blockers (sotalol, timolol, propranolol, and carvedilol, n = 179) users from the B-PROOF cohort. The associations between the beta-blocker concentration and time to first fall were assessed using Cox proportional hazard models. Change of concentration over time in relation to fall risk was assessed with logistic regression models. Models were adjusted for potential confounders. Our results showed that above the median concentration of metoprolol was associated with an increased fall risk (HR 1.55 [1.11-2.16], p = .01). No association was found for nonselective beta-blocker concentrations. Also, changes in concentration over time were not associated with increased fall risk. To conclude, metoprolol plasma concentrations were associated with an increased risk of falls in metoprolol users while no associations were found for nonselective beta-blockers users. This might be caused by a decreased β1-selectivity in high plasma concentrations. In the future, beta-blocker concentrations could potentially help clinicians estimate fall risk in older beta-blockers users and personalize treatment.
Topics: Humans; Aged; Aged, 80 and over; Metoprolol; Adrenergic beta-Antagonists; Carvedilol
PubMed: 37885367
DOI: 10.1002/prp2.1126 -
Cureus Sep 2023Catheter ablation has become an important treatment strategy for the management of atrial fibrillation (AF) in symptomatic patients. Pulmonary vein isolation (PVI) is...
Catheter ablation has become an important treatment strategy for the management of atrial fibrillation (AF) in symptomatic patients. Pulmonary vein isolation (PVI) is increasingly used to restore rhythm in patients with AF and flutter. The serious procedural complication rate has significantly reduced over time and most patients undergo PVI without any adverse events. We present the case of a 70-year-old man with symptomatic AF who underwent elective PVI that was complicated by large pericardial effusion from left atrial appendage (LAA) perforation resulting in cardiac tamponade requiring emergency pericardiocentesis followed by sternotomy to suture the LAA. The perforated LAA was sutured and the LAA was closed surgically through sternotomy by using AtriClip and a large amount of blood was evacuated achieving good cardiac output and hemodynamic stability. A surgical PVI was performed twice restoring normal sinus rhythm. The patient was discharged home, however, he returned to the hospital a few days later with atrial flutter with a rapid ventricular response. He underwent direct current cardioversion (DCCV) and remained in sinus rhythm during the rest of his admission. His bisoprolol was switched to Sotalol to maintain normal sinus rhythm and he was discharged home with outpatient follow-up.
PubMed: 37829980
DOI: 10.7759/cureus.44989 -
Journal of the American Heart... Oct 2023
PubMed: 37815124
DOI: 10.1161/JAHA.120.027739 -
The American Journal of Cardiology Oct 2023This chapter discusses the American College of Cardiology/American Heart Association/ Heart Rhythm Society (AHA/ACC/HRS) and European Society of Cardiology (ESC)...
This chapter discusses the American College of Cardiology/American Heart Association/ Heart Rhythm Society (AHA/ACC/HRS) and European Society of Cardiology (ESC) guidelines for atrial fibrillation (AF) management with particular focus on antiarrhythmic drug (AAD) selection and the identification of individuals for whom AAD treatment is appropriate. Discussion includes AAD indications, when to start an AAD, choosing among AADs, how to minimize proarrhythmic risk, how to determine efficacy, and the use of adjuvant interventions. The indications for all AADs are based on safety; the current AHA/ACC/HRS and ESC guidelines state that the choice of AAD is based on the presence or absence of structural heart disease (SHD), coronary artery disease, or heart failure (HF), with further recommendations in the ESC guidelines based on HF type (e.g., HF with reduced ejection fraction [HFrEF] versus HF with preserved ejection fraction [HFpEF]). The chapter closes with a discussion of the lack of consistent use of guideline-directed care, with a review of supportive data from the recently reported AIM-AF survey-a multinational survey on AF management that involved both cardiologists and electrophysiologists. In AIM-AF, inappropriate drug selection in terms of suitable candidate selection and drug choice occurred with all types of drugs and in most patient groups. Most notable was the overuse of amiodarone in patients without SHD, and the widespread use of sotalol, including its use in patients with HFrEF. Chapter 5 is summarized as follows.
Topics: Humans; Anti-Arrhythmia Agents; Atrial Fibrillation; Heart Failure; Sotalol; Stroke Volume; United States
PubMed: 37777295
DOI: 10.1016/j.amjcard.2023.08.029 -
Chemical Research in Toxicology Sep 2023Epidemiological studies aim to assess associations between diseases and risk factors. Such investigations involve a large sample size and require powerful analytical...
Epidemiological studies aim to assess associations between diseases and risk factors. Such investigations involve a large sample size and require powerful analytical methods to measure the effects of risk factors, resulting in a long analysis time. In this study, chemical exposure markers were detected as the main variables strongly affecting two components coming from a principal component analysis (PCA) exploration of the metabolomic data generated from urinary samples collected on a cohort of about 500 individuals using direct introduction coupled with a Fourier-transform ion cyclotron resonance instrument. The assignment of their chemical identity was first achieved based on their isotopic fine structures detected at very high resolution ( > 900,000). Their identification as dimethylbiguanide and sotalol was obtained at level 1, thanks to the available authentic chemical standards, tandem mass spectrometry (MS/MS) experiments, and collision cross section measurements. Epidemiological data confirmed that the subjects discriminated by PCA had declared to be prescribed these drugs for either type II diabetes or cardiac arrhythmia. Concentrations of these drugs in urine samples of interest were also estimated by rapid quantification using an external standard calibration method, direct introduction, and MS/MS experiments. Regression analyses showed a good correlation between the estimated drug concentrations and the scores of individuals distributed on these specific PCs. The detection of these chemical exposure markers proved the potential of the proposed high-throughput approach without any prior drug exposure knowledge as a powerful emerging tool for rapid and large-scale phenotyping of subjects enrolled in epidemiological studies to rapidly characterize the chemical exposome and adherence to medical prescriptions.
PubMed: 37729183
DOI: 10.1021/acs.chemrestox.3c00158 -
Journal of Cardiovascular... Mar 2024Premature ventricular complexes (PVCs) are the most common ventricular arrhythmia that are encountered in the clinical practice. Recent data suggests that high PVC... (Review)
Review
INTRODUCTION
Premature ventricular complexes (PVCs) are the most common ventricular arrhythmia that are encountered in the clinical practice. Recent data suggests that high PVC burden may lead to the development of PVC-induced cardiomyopathy (PVC-CM) even in patients without structural heart disease. Treatment for effective suppression of PVCs, can reverse PVC-CM. Both antiarrhythmic drugs (AADs) and catheter ablation (CA) are recognized treatment modalities for any cardiac arrhythmias. However, with increasing preference of CA, the role of AADs needs further defining regarding their efficacy, safety, indications and patient selection to treat PVC-CM.
METHODS
To ascertain the role of AADs to treat PVC-CM; whether they are indicated to treat PVC-CM, and if so, when, we interrogated PubMed and other search engines for English language publications with key words premature ventricular complexes (PVCs), cardiomyopathy, anti-arrhythmic drugs, catheter ablation, and pharmacological agents. All publications were carefully reviewed and scrutinized by the authors for their inclusion in the review paper. For illustration of cases, ethical standard was observed as per the 1975 Declaration of Helsinki, and the patient was treated as per the prevailing standard of care. Informed consent was obtained from the patient for conducting the ablation procedure.
RESULTS
Our literature search specifically the pharmacological treatment of PVC-CM with AADs revealed significant paradigm shift in treatment approach for PVCs and PVC-induced cardiomyopathy. No major large, randomized control trials of AADs versus CA for PVC-CM were found. We found that beta-blockers and calcium channel blockers are particularly effective in the treatment of PVCs originating from right ventricular outflow tract. For Class Ic AADs - flecainide and propafenone, small clinical studies showed Class Ic AADs to be effective in PVC suppression, but their usage was not recommended in patients with significant coronary artery disease. Mexiletine was found to have modest effect on PVC suppression. Studies showed sotalol to significantly reduce PVCs frequency in patients receiving both low and high doses. Studies also showed amiodarone to have higher successful PVC suppression, but not recommended as a first-line treatment for patients with idiopathic PVCs in the absence of symptoms and left ventricular dysfunction. For dronedarone, no major clinical data were available.
CONCLUSIONS
Based on the available data in the literature, we conclude that AADs play important role in the treatment of PVC-induced cardiomyopathy. However, appropriate patient selection criteria are vitally important, and in general terms AADs are indicated or polymorphic PVCs, epicardial PVCs; and when CA procedure is contraindicated, or not feasible or failed.
Topics: Humans; Anti-Arrhythmia Agents; Ventricular Premature Complexes; Stroke Volume; Ventricular Dysfunction, Left; Cardiomyopathies; Catheter Ablation
PubMed: 37676022
DOI: 10.1111/jce.16055 -
Cureus Aug 2023Fetal tachyarrhythmia and aortic stenosis (AS) both disrupt fetal hemodynamics, leading to congestive heart failure, hydrops, and intrauterine demise. Traditional...
Fetal tachyarrhythmia and aortic stenosis (AS) both disrupt fetal hemodynamics, leading to congestive heart failure, hydrops, and intrauterine demise. Traditional transplacental treatments for fetal supraventricular tachycardia (SVT) include digoxin, flecainide, and sotalol. However, the treatment of fetal SVT in the setting of AS has not been described, particularly in cases of refractory SVT. We present a case of a 27-year-old nulliparous female carrying a fetus with fetal AS diagnosed at 25 weeks of gestational age (GA). The patient was not a candidate for in utero valvuloplasty. During ultrasound monitoring at 32 and 6/7 weeks of gestation, fetal SVT with a heart rate of 230-260 beats per minute (bpm) was diagnosed. Maternal digoxin was initiated, and sotalol was subsequently added. Due to persistent fetal SVT and a worsening cardiac function, the patient was treated with direct adenosine administration via cordocentesis successfully terminating the fetal arrhythmia. Despite continued transplacental treatment with digoxin and sotalol throughout the course of pregnancy, the fetal SVT recurred at 35 and 5/7 weeks of gestation prompting delivery. Our case illustrates the use of direct intrauterine adenosine as a novel treatment for refractory fetal SVT in the setting of congenital aortic stenosis and concern about progression to fetal hydrops and fetal demise.
PubMed: 37667701
DOI: 10.7759/cureus.42931