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Even though the relationship between antiarrhythmic drug usage and subsequent prostate cancer （PCa） risk has recently been highlighted, relevant findings in the previous literature are still inconsistent. In addition, very few studies have attempted to investigate the association between sodium channel blockers or potassium channel blockers for arrhythmia and the subsequent PCa risk. Therefore, this cohort study aimed to find the relationship between antiarrhythmic drug usage and the subsequent PCa risk using a population-based dataset. The data used in this study were derived from the Longitudinal Health Insurance Database 2005, Taiwan, China. We respectively identified 9988 sodium channel blocker users, 3663 potassium channel blocker users, 65 966 beta-blocker users, 23 366 calcium channel blockers users, and 7031 digoxin users as the study cohorts. The matched comparison cohorts （one comparison subject for each antiarrhythmic drug user） were selected from the same dataset. Each patient was tracked for a 5-year period to define those who were subsequently diagnosed with PCa. After adjusting for sociodemographic characteristics, comorbidities, and age, Cox proportional hazard regressions found that the hazard ratio （HR） of subsequent PCa for sodium channel blocker users was 1.12 （95% confidence interval [CI]： 0.84-1.50）, for potassium channel blocker users was 0.89 （95% CI. 0.59-1.34）, for beta-blocker users was 1.08 （95% Ch 0.96-1.22）, for calcium channel blocker users was 1.14 （95% Ch 0.95-1.36）, and for digoxin users was 0.89 （95% Ch 0.67-1.18）, compared to their matched nonusers. We concluded that there were no statistical associations between different types of antiarrhvthmic drug usage and subsequent PCa risk.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly arrhythmogenic syndrome triggered by stress, primarily linked to gain-of-function point mutations in the cardiac ryanodine receptor (RyR2). Flecainide, as an effective therapy for CPVT, is a known blocker of the surface-membrane Na[sup.+] channel, also affecting the intracellular RyR2 channel. The therapeutic relevance of the flecainide-RyR2 interaction remains controversial, as flecainide blocks only the RyR2 current flowing in the opposite direction to the physiological Ca[sup.2+] release from the sarcoplasmic reticulum (SR). However, it has been proposed that charge-compensating countercurrent from the cytosol to SR lumen plays a critical role, and its reduction may indeed suppress excessive diastolic SR Ca[sup.2+] release through RyR2 channels in CPVT. Monitoring single-channel properties, we examined whether flecainide can target intracellular pathways for charge-balancing currents carried by RyR2 and SR Cl[sup.−] channels under cell-like conditions. Particularly, the Tris[sup.+] countercurrent flowed through the RyR2 channel simultaneously with a dominant reverse Ca[sup.2+]/Ba[sup.2+] current. We demonstrate that flecainide blocked the RyR2-mediated countercurrent without affecting channel activity. In contrast, the SR Cl[sup.−] channel was completely resistant to flecainide. Based on these findings, it is reasonable to propose that the primary intracellular target of flecainide in vivo is the RyR2-mediated countercurrent.

Since the clinical use of digitalis as the first pharmacological therapy for atrial fibrillation (AF) 235 years ago in 1785, antiarrhythmic drug therapy has advanced considerably and become a cornerstone of AF clinical management. Yet, a preventive or curative panacea for sustained AF does not exist despite the rise of AF global prevalence to epidemiological proportions. While multiple elevated risk factors for AF have been established, the natural history and etiology of AF remain incompletely understood. In the present article, the first section selectively highlights some disappointing shortcomings and current efforts in antiarrhythmic drug therapy to uncover reasons why AF is such a clinical challenge. The second section discusses some modern takes on the natural history of AF as a relentless, progressive fibro-inflammatory \"atriomyopathy.\" The final section emphasizes the need to redefine therapeutic strategies on par with new insights of AF pathophysiology.

Reflecting both the worldwide importance of AF, as well as the worldwide performance of AF ablation, this document is the result of a joint partnership between the HRS, EHRA, ECAS, the Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Society of Cardiac Stimulation and Electrophysiology (Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología [SOLAECE]). The purpose of this 2017 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a writing group, convened by these five international societies. The writing group is composed of 60 experts representing 11 organizations: HRS, EHRA, ECAS, APHRS, SOLAECE, STS, ACC, American Heart Association (AHA), Canadian Heart Rhythm Society (CHRS), Japanese Heart Rhythm Society (JHRS), and Brazilian Society of Cardiac Arrhythmias (Sociedade Brasileira de Arritmias Cardíacas [SOBRAC]). Rather, the ultimate judgment regarding care of a particular patient must be made by the health care provider and the patient in light of all the circumstances presented by that patient.

The human voltage-gated sodium channel, hNaV1.5, is responsible for the rapid upstroke of the cardiac action potential and is target for antiarrhythmic therapy. Despite the clinical relevance of hNaV1.5-targeting drugs, structure-based molecular mechanisms of promising or problematic drugs have not been investigated at atomic scale to inform drug design. Here, we used Rosetta structural modeling and docking as well as molecular dynamics simulations to study the interactions of antiarrhythmic and local anesthetic drugs with hNaV1.5. These calculations revealed several key drug binding sites formed within the pore lumen that can simultaneously accommodate up to two drug molecules. Molecular dynamics simulations identified a hydrophilic access pathway through the intracellular gate and a hydrophobic access pathway through a fenestration between DIII and DIV. Our results advance the understanding of molecular mechanisms of antiarrhythmic and local anesthetic drug interactions with hNaV1.5 and will be useful for rational design of novel therapeutics.

Purpose The therapeutic index (TI) is the range of doses at which a medication is effective without unacceptable adverse events. Drugs with a narrow TI (NTIDs) have a narrow window between their effective doses and those at which they produce adverse toxic effects. Generic drugs may be substituted for brand-name drugs provided that they meet the recommended bioequivalence (BE) limits. However, an appropriate range of BE for NTIDs is essential to define due to the potential for ineffectiveness or adverse events. Flecainide is an antiarrhythmic agent that has the potential to be considered an NTID. This review aims to evaluate the literature surrounding guidelines on generic substitution for NTIDs and to evaluate the evidence for flecainide to be considered an NTID. Methods A review of recommendations from various regulatory authorities regarding BE and NTIDs, and publications regarding the NTID characteristics of flecainide, was carried out. Results Regulatory authorities generally recommend reduced BE limits for NTIDs. Some, but not all, regulatory authorities specify flecainide as an NTID. The literature review demonstrated that flecainide displays NTID characteristics including a steep drug dose–response relationship for safety and efficacy, a need for therapeutic drug monitoring of pharmacokinetic (PK) or pharmacodynamics measures and intra-subject variability in its PK properties. Conclusions There is much evidence for flecainide to be considered an NTID based on both preclinical and clinical data. A clear understanding of the potential of proarrhythmic effects or lack of efficacy, careful patient selection and regular monitoring are essential for the safe and rational administration of flecainide.

Potency of drug action is usually determined by binding to a specific receptor site on target proteins. In contrast to this conventional paradigm, we show here that potency of local anesthetics (LAs) and antiarrhythmic drugs (AADs) that block sodium channels is controlled by fenestrations that allow drug access to the receptor site directly from the membrane phase. Voltage-gated sodium channels initiate action potentials in nerve and cardiac muscle, where their hyperactivity causes pain and cardiac arrhythmia, respectively. LAs and AADs selectively block sodium channels in rapidly firing nerve and muscle cells to relieve these conditions. The structure of the ancestral bacterial sodium channel NaVAb, which is also blocked by LAs and AADs, revealed fenestrations connecting the lipid phase of the membrane to the central cavity of the pore. We cocrystallized lidocaine and flecainide with NavAb, which revealed strong drug-dependent electron density in the central cavity of the pore. Mutation of the contact residue T206 greatly reduced drug potency, confirming this site as the receptor for LAs and AADs. Strikingly, mutations of the fenestration cap residue F203 changed fenestration size and had graded effects on resting-state block by flecainide, lidocaine, and benzocaine, the potencies of which were altered from 51- to 2.6-fold in order of their molecular size. These results show that conserved fenestrations in the pores of sodium channels are crucial pharmacologically and determine the level of resting-state block by widely used drugs. Fine-tuning drug access through fenestrations provides an unexpected avenue for structure-based design of ion-channel–blocking drugs.

•Dronedarone was a cost-effective AAD compared to amiodarone or sotalol for patients with paroxysmal or persistent AF in China.•The incremental cost associated with dronedarone was effectively offset by cumulative benefits in life expectancy and QALY in the long-term rhythm control.•Cost-effectiveness results highlighting the economic value of adopting dronedarone as an alternative first-line AAD option. Antiarrhythmic drug (AAD) therapies are foundational in the long-term management of atrial fibrillation (AF), yet there remains uncertainty in clinical and reimbursement decisions in China. This study aimed to estimate the cost-effectiveness of dronedarone compare to amiodarone and sotalol for the treatment of paroxysmal or persistent AF in China from the health system perspective. A Markov decision model was developed to compare the lifetime clinical efficacy and costs of three AAD therapies associated with AF recurrence, congestive heart failure, strokes, and deaths due to AF or AF related complications. Model inputs were derived from the ATHENA trial results, real-world database, published literature, and supplemented from expert opinion. Cost-effectiveness was measured by the incremental cost-effectiveness ratio (ICER), defined as the incremental cost per quality-adjusted life year (QALY) gained among groups. One-way sensitivity, probabilistic sensitivity, and scenario analyses were performed to explore the uncertainty of the model. This study used a simulated cohort with baseline characteristics of patients from the CCC-AF project. In the base case, compared to amiodarone and sotalol, dronedarone was expected to gain additional 1.28 QALYs (5.15 vs 3.87) and 1.78 QALYs (5.15 vs 3.37), with higher costs of $6632 ($11,025 vs $4393) and $6278 ($11,025 vs $4748) over a lifetime horizon, leading to ICERs of $5166 and $3524 per QALY, respectively. One-way sensitivity analysis revealed that the results were most sensitive to the relative risk of cardiovascular mortality, the discount rate of QALYs, and the utility for sinus rhythm. The probabilistic sensitivity analyses indicated that the probability of cost-effectiveness for dronedarone ranged from 97.0% to 99.4% at the threshold of one to three times China’s per capita gross domestic product in 2023, whereas the probability for amiodarone ranged from 3.0% to <1%, and for sotalol was always <1%. Scenario analyses confirmed that the base-case results were sufficiently reliable. Our analysis suggests that dronedarone is a cost-effective AAD compared to amiodarone and sotalol for patients with paroxysmal or persistent AF in China, offering improvements in life expectancy and QALY in the long-term rhythm control.

Based on recent findings, an increased late sodium current (I ) plays an important pathophysiological role in cardiac diseases, including rhythm disorders. The article first describes what is I and how it functions under physiological circumstances. Next, it shows the wide range of cellular mechanisms that can contribute to an increased I in heart diseases, and also discusses how the upregulated I can play a role in the generation of cardiac arrhythmias. The last part of the article is about I inhibiting drugs as potential antiarrhythmic agents, based on experimental and preclinical data as well as in the light of clinical trials.

Objective: This study aimed to identify the different associations between antiarrhythmic drugs (AADs) and arrhythmias, and to determine whether pharmacokinetic drug interactions involving AADs increase the risk of AAD-related arrhythmias compared to using AADs alone. Materials and methods: The disproportionality analysis of AAD-associated cardiac arrhythmias, including AAD monotherapies and concomitant use of pharmacokinetic interacting agents involving AADs, was conducted by using reporting odds ratio (ROR) and information component (IC) as detection of potential safety signals based on FAERS data from January 2016 to June 2022. We compared the clinical features of patients reported with AAD–associated arrhythmias between fatal and non-fatal groups, and further investigated the onset time (TTO) following different AAD regimens. Results: A total of 11754 AAD–associated cardiac arrhythmias reports were identified, which was more likely to occur in the elderly (52.17%). Significant signals were detected between cardiac arrhythmia and all AAD monotherapies, with ROR ranging from 4.86 with mexiletine to 11.07 with flecainide. Regarding four specific arrhythmias in High Level Term (HLT) level, the AAD monotherapies with the highest ROR were flecainide in cardiac conduction disorders (ROR025 = 21.18), propafenone in rate and rhythm disorders (ROR025 = 10.36), dofetilide in supraventricular arrhythmias (ROR025 = 17.61), and ibutilide in ventricular arrhythmias (ROR025 = 4.91). Dofetilide/ibutilide, ibutilide, mexiletine/ibutilide and dronedarone presented no signal in the above four specific arrhythmias respectively. Compared with amiodarone monotherapy, sofosbuvir plus amiodarone detected the most significantly increased ROR in arrhythmias. Conclusion: The investigation showed the spectrum and risk of AAD–associated cardiac arrhythmias varied among different AAD therapies. The early identification and management of AAD-associated arrhythmias are of great importance in clinical practice.