Antiarrhythmic Efficacy Research Articles

Bayesian Network Meta-analysis of Randomized Controlled Trials on the Efficacy of Antiarrhythmics in the Pharmacological Cardioversion of Paroxysmal Atrial Fibrillation.

Since atrial fibrillation (AF) is one of the major arrhythmias managed in hospitals worldwide, it has a major impact on public health. The guidelines agree on the desirability of cardioverting paroxysmal AF episodes. This meta-analysis aims to answer the question of which antiarrhythmic agent is most effective in cardioverting a paroxysmal AF. A systematic review and Bayesian network meta-analysis, searching MEDLINE, Embase, and CINAHL, were performed, including randomized controlled trials (RCTs) enrolling a population of unselected adult patients with a paroxysmal AF that compared at least two pharmacological regimes to restore the sinus rhythm or a cardioversion agent against a placebo. The main outcome was efficacy in restoring sinus rhythm. Sixty-one RCTs (7988 patients) were included in the quantitative analysis [deviance information criterion (DIC) 272.57; I2 = 3%]. Compared with the placebo, the association verapamil-quinidine shows the highest SUCRA rank score (87%), followed by antazoline (86%), vernakalant (85%), tedisamil at high dose (i.e., 0.6 mg/kg; 80%), amiodarone-ranolazine (80%), lidocaine (78%), dofetilide (77%), and intravenous flecainide (71%). Taking into account the degree of evidence of each individual comparison between pharmacological agents, we have drawn up a ranking of pharmacological agents from the most effective to the least effective. In comparing the antiarrhythmic agents used to restore sinus rhythm in the case of paroxysmal AF, vernakalant, amiodarone-ranolazine, flecainide, and ibutilide are the most effective medications. The verapamil-quinidine combination seems promising, though few RCTs have studied it. The incidence of side effects must be taken into account in the choice of antiarrhythmic in clinical practice. PROSPERO: International prospective register of systematic reviews, 2022, CRD42022369433 (Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022369433 ).

Management of Ventricular Arrhythmias in Heart Failure.

Despite substantial progress in medical and device-based heart failure (HF) therapy, ventricular arrhythmias (VA) and sudden cardiac death (SCD) remain a major challenge. Here we review contemporary management of VA in the context of HF with one particular focus on recent advances in imaging and catheter ablation. Besides limited efficacy of antiarrhythmic drugs (AADs), their potentially life-threatening side effects are increasingly acknowledged. On the other hand, with tremendous advances in catheter technology, electroanatomical mapping, imaging, and understanding of arrhythmia mechanisms, catheter ablation has evolved into a safe, efficacious therapy. In fact, recent randomized trials support early catheter ablation, demonstrating superiority over AAD. Importantly, CMR imaging with gadolinium contrast has emerged as a central tool for the management of VA complicating HF: CMR is not only essential for an accurate diagnosis of the underlying entity and subsequent treatment decisions, but also improves risk stratification for SCD prevention and patient selection for ICD therapy. Finally, 3-dimensional characterization of arrhythmogenic substrate by CMR and imaging-guided ablation approaches substantially enhance procedural safety and efficacy. VA management in HF patients is highly complex and should be addressed in a multidisciplinary approach, preferably at specialized centers. While recent evidence supports early catheter ablation of VA, an impact on mortality remains to be demonstrated. Moreover, risk stratification for ICD therapy may have to be reconsidered, taking into account imaging, genetic testing, and other parameters beyond left ventricular function.

Arrhythmia Profile in Children Presenting at a Tertiary Care Centre in India - From Fetal Life to Fifteen Years of Age Prabhu Shakuntala, Prabhshara

Many of the arrhythmias tend to be asymptomatic and detected incidentally, while some others may be picked up too late after a catastrophic presentation. The goal of this study was to document the arrhythmia profile in children presenting to our tertiary care hospital in India. We also reviewed the early and late outcomes of arrhythmias in these patients (including in isolated and post cardiac surgical patients). Amongst 100 patients with arrhythmias, 35% were detected incidentally for presentations like breathlessness (29%) and refusal to feed. A majority of patients (70%) did not have any underlying structural defect and had no cardiomegaly on chest X-Ray. Of those with structural defects, 90% were congenital with the majority being acyanotic (58%) and would have gone clinically undetected. 19 children (20%) presented with heart failure. Tachyarrhythmias (61%) were more common, and all the immediate deaths were from this group. Bradyarrhythmias were mostly complete heart blocks. Almost half the patients required emergency antiarrhythmics. Holter study was done to check for antiarrhythmic efficacy and to decide regarding pacing. In 48% cases, clinical management was changed based on the Holter report. Almost half the patients required emergency antiarrhythmics (adenosine, isoprenaline, amiodarone). The long-term outcomes were favorable with 50% of the patients not requiring long term antiarrhythmics and most remained asymptomatic. The need for interventional therapy like pacemaker insertion and radiofrequency ablation was less than 2%. Arrythmias in children have varied symptoms and pediatricians need to be aware about this. With optimal management, long term outcomes for these children are usually favorable.

Comparison the efficacy of amiodarone and lidocaine for cardiac arrest: A network meta-analysis.

There is no evidence that antiarrhythmic drugs can improve long-term survival or survival with favorable neurological outcomes in cardiac arrest patients. We did this network meta-analysis to comprehensively compare the efficacy of various antiarrhythmic drugs for cardiac arrest patients. We searched studies from inception until Nov 11, 2022 through PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP Database, and Wanfang database. All studies comparing different antiarrhythmic drugs for cardiac arrest were included in this meta-analysis. Outcomes were survival to hospital discharge in cardiac arrest, survival to hospital admission/24 h and favorable neurological outcome. This network meta-analysis was performed by R software. Finally, a total of 9 studies (10,980 patients) were finally included in this network meta-analysis. Amiodarone (odd ratio [OR] 2.28, 95% credibility interval [CrI] 1.61-3.27) and lidocaine (OR 1.53, 95% CrI 1.05-2.25) was superior than placebo in terms of the survival to hospital admission/24 h with statistically significant. Amiodarone (OR 2.19, 95% CrI 1.54-3.14) and lidocaine (OR 1.58, 95% CrI 1.09-2.32) was superior than placebo in terms of the survival to hospital discharge with statistically significant. Amiodarone (OR 2.43, 95% CrI 1.61-3.68) and lidocaine (OR 1.62, 95% CrI 1.04-2.53) was superior than placebo in terms of the favorable neurological outcome with statistically significant. The surface under the cumulative ranking (SUCRA) shows that amiodarone ranked first (SUCRA, 99.6%), lidocaine ranked second (SUCRA, 49.6%), placebo ranked the last (SUCRA, 0.86%). Inverted funnel plot is essentially symmetrical, it is possible that this study has a small sample effect or a small publication bias. Amiodarone had the best effect on both survival to hospital admission, discharge and more favorable neurological outcome. Thus, amiodarone should be listed as first line drug for cardiac arrest. However, the quality of available evidence limits the formation of powerful conclusions regarding the comparative efficacy or safety of amiodarone or lidocaine used to treat cardiac arrest. Higher-quality randomized controlled trials are required for further research in future.

Class IC Antiarrhythmic Drugs: Informed Choice

Abstract The article presents data on the most commonly used antiarrhythmic drugs of subclass IC: propafenone, flecainide, and a drug manufactured in Latvia — ethacizine. The features and priority areas of each drug use were identified. The author conducted a critical analysis of the results of Cardiac Arrhythmia Suppression Trials (CAST)-I and CAST-II and suggested ways to further study of subclass IC antiarrhythmic drugs in the context of current treatment strategies. The results of CAST-I and CAST-II should be interpreted in view of the heterogeneity of the subclass IC antiarrhythmic drugs and the fact that among the drugs of this subclass that are currently registered and approved for use in Ukraine, only flecainide was studied in CAST-I, and none of these drugs — in CAST-II. Ethacizine has a special position as a promising drug, especially effective in the treatment of vagus-induced heart rhythm disorders, with a small number of contraindications and drug interactions compared with propafenone and flecainide. Despite many years of use in several countries, this drug remains “invisible” to researchers around the world due to a limited number of international studies. The author draws attention to the need to re-evaluate antiarrhythmic drugs with an outdated evidence, in some cases quite limited, and to plan new experimental studies to clarify the possibility of subclass IC drugs to influence new pharmacological targets in arrhythmology, as well as large-scale well-planned studies of the safety and efficacy of subclass IC antiarrhythmic drugs in real present-day clinical practice.

In Vivo Pharmacokinetic and Pharmacodynamic Properties of the Antiarrhythmic Molecule ent-Verticilide.

The unnatural verticilide enantiomer (ent-verticilide) is a selective and potent inhibitor of cardiac ryanodine receptor (RyR2) calcium release channels and exhibits antiarrhythmic activity in a murine model of catecholaminergic polymorphic ventricular tachycardia (CPVT). To determine verticilide's pharmacokinetic and pharmacodynamic properties in vivo, we developed a bioassay to measure nat- and ent-verticilide in murine plasma and correlated plasma concentrations with antiarrhythmic efficacy in a mouse model of CPVT. nat-Verticilide rapidly degraded in plasma in vitro, showing >95% degradation within 5 minutes, whereas ent-verticilide showed <1% degradation over 6 hours. Plasma was collected from mice following intraperitoneal administration of ent-verticilide at two doses (3 mg/kg, 30 mg/kg). Peak C max and area under the plasma-concentration time curve (AUC) scaled proportionally to dose, and the half-life was 6.9 hours for the 3-mg/kg dose and 6.4 hours for the 30-mg/kg dose. Antiarrhythmic efficacy was examined using a catecholamine challenge protocol at time points ranging from 5 to 1440 minutes after intraperitoneal dosing. ent-Verticilide inhibited ventricular arrhythmias as early as 7 minutes after administration in a concentration-dependent manner, with an estimated potency (IC50) of 266 ng/ml (312 nM) and an estimated maximum inhibitory effect of 93.5%. Unlike the US Food and Drug Administration-approved pan-RyR blocker dantrolene, the RyR2-selective blocker ent-verticilide (30 mg/kg) did not reduce skeletal muscle strength in vivo. We conclude that ent-verticilide has favorable pharmacokinetic properties and reduces ventricular arrhythmias with an estimated potency in the nanomolar range, warranting further drug development. SIGNIFICANCE STATEMENT: ent-Verticilide has therapeutic potential to treat cardiac arrhythmias, but little is known about its pharmacological profile in vivo. The primary purpose of this study is to determine the systemic exposure and pharmacokinetics of ent-verticilide in mice and estimate its efficacy and potency in vivo. The current work suggests ent-verticilide has favorable pharmacokinetic properties and reduces ventricular arrhythmias with an estimated potency in the nanomolar range, warranting further drug development.

Medical therapy with flecainide and propafenone in atrial fibrillation: Long-term clinical experience in the tertiary care setting.

Flecainide and propafenone are Class Ic antiarrhythmic drugs that block the cardiac fast inwards Na+ current and are used for rhythm control in patients with atrial fibrillation (AF). However, data on long-term clinical efficacy and safety of these drugs in a real-world setting are scarce. Patients with AF who received chronic flecainide or propafenone therapy were retrospectively studied from the database of a tertiary care center. The primary outcome of the study was clinical efficacy of Class Ic antiarrhythmics, which was assessed based on the improvement of arrhythmia-related symptoms at the time of last follow-up. Among the 361 patients (261 males, 72.3%) with a mean age of 56 ± 12 years, 287 (79.5%) were using long-term flecainide, and 74 (20.5%) patients propafenone. The majority of the patients had paroxysmal AF (n = 331, 91.7%) and had an atrioventricular-nodal blocking co-medication (n = 287, 79.5%). A total of 117 (32%) patients discontinued therapy after a median of 210 days (interquartile range 62-855 days). Clinical efficacy was observed in 188 (52%) patients. The most common reason for therapy discontinuation was adverse drug effects, particularly proarrhythmic effects (48% for flecainide and 33% for propafenone). Patients who did not clinically benefit from Class Ic antiarrhythmics more often underwent pulmonary vein isolation (p = 0.02). Long-term therapy with Class Ic antiarrhythmics showed clinical efficacy in approximately half of the patients with paroxysmal or persistent AF. However, these drugs were also associated with a relatively high rate of adverse events, and in particular proarrhythmic effects, which often resulted in therapy discontinuation rendering appropriate patient selection and therapy surveillance essential.

Modeling incomplete penetrance in long QT syndrome type 3 (LQT3) through ion channel heterogeneity: An in silico population study.

Many cardiac diseases are characterized by an increased late sodium current, including heart failure, hypertrophic cardiomyopathy, and inherited long QT syndrome type 3 (LQT3). The late sodium current in LQT3 is caused by a gain-of-function mutation in the voltage-gated sodium channel Nav1.5. Despite a well-defined genetic cause of LQT3, treatment remains inconsistent due to incomplete penetrance of the mutation and variability of anti-arrhythmic efficacy. Here, we investigate the relationship between LQT3-associated mutation incomplete penetrance and variability in ion channel expression, simulating a population of 1,000 single-cell “individuals” using the O’Hara-Rudy model of the human ventricular myocyte. We first simulate healthy electrical activity (i.e., in the absence of a mutation), then incorporate heterozygous expression for three LQT3-associated mutations (Y1795C, I1768V, and ∆KPQ), to directly compare the effects of each mutation on individuals across a diverse population. For all mutations, we find that susceptibility, defined either by the presence of an early after depolarization (EAD) or prolonged action potential duration (APD), primarily depends on the balance between the conductance of IKr and INa, for which individuals with a higher IKr-INa ratio are less susceptible. Further, we find distinct differences across the population, observing individuals susceptible to zero, one, two, or all three mutations. Individuals tend to be less susceptible with an appropriate balance of repolarizing currents, typically via increased IKs or IK1. Interestingly, the more critical repolarizing current is mutation specific. We conclude that balance between key currents plays a significant role in mutant-specific presentation of the disease phenotype in LQT3.

The Effectiveness of Catheter Ablation in the Management of Ventricular Tachycardia in Comparison With Antiarrhythmic Drugs in Patients With Structural Heart Disease: A Meta-Analysis.

The aim of this meta-analysis is to compare the safety and efficacy of catheter ablation versus antiarrhythmic drugs (AADs) in the management of ventricular tachycardia (VT) in patients with structural heart diseases. Two independent investigators searched electronic databases including PubMed, Cochrane, and Excerpta Medica database (EMBASE) using keywordcombinations (Medical Subject Headings (MeSH) terms and free terms)such as "catheter ablation," "ventricular tachycardia," "escalation," and "antiarrhythmic drugs" from inception to November 30, 2022. The primary efficacy outcomes included recurrence of VT at follow-up, all-cause mortality, and cardiovascular mortality. The secondary efficacy outcomes assessed in the current meta-analysis included implantable cardioverter-defibrillator (ICD) shock and hospitalization due to cardiac reasons. Safety outcomes included treatment-related adverse events and serious adverse events. A total of three studies were included in this meta-analysis. Therewas no significant difference in the risk of recurrence of VT (RR: 0.94, 95% CI: 0.72-1.24, p-value: 0.67), all-cause mortality (RR: 0.99, 95% CI: 0.67, 1.46, p-value: 0.98), cardiovascular mortality (risk ratio (RR): 0.90, 95% confidence interval (CI): 0.56-1.45, p-value: 0.67),incidence of ICD shocks (RR: 0.99, 95% CI: 0.76-1.29, p-value: 0.93, I-square: 0%), and hospitalization due to cardiac reasons in follow-up (RR: 0.77, 95% CI: 0.55-1.07, p-value: 0.12) between the catheter ablation group and the antiarrhythmic druggroup. However, the risk of treatment-related adverse events was lower in the ablation group compared to the antiarrhythmic medicine (AAM) group (RR: 0.44, 95% CI: 0.29-0.67, p-value: 0.0001). In this meta-analysis of three randomized controlled trials (RCTs) among patients with structural heart disease who had ventricular tachycardia, the incidence of the recurrence of VT, all-cause mortality, cardiovascular mortality, and ICD shock was not significantly different between patients who received catheter ablation and antiarrhythmic drugs. However, regarding safety, catheter ablation is a safe procedure with a low risk of treatment-related events compared to antiarrhythmic drugs.

Defining Anti-arrhythmic Efficacy in the Setting of Evolving Concepts About Atrial Fibrillation.

Defining Anti-arrhythmic Efficacy in the Setting of Evolving Concepts About Atrial Fibrillation.

Comparison of radiofrequency ablation and antiarrhythmic drug for the treatment of atrial fibrillation: A protocol for systematic review and meta-analysis

Antiarrhythmic drugs and radiofrequency ablation are first-line treatments of atrial fibrillation, however, there exists a paucity of data regarding the potential benefit of different catheter ablation technologies versus antiarrhythmic drugs as an early rhythm strategy. We performed a protocol for systematic review and meta-analysis to compare the efficacy and safety of radiofrequency ablation and antiarrhythmic drugs for the treatment of atrial fibrillation. This review protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42022375095). Additionally, this review will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols 2015 Statement. A computerized literature search will be performed in the following electronic databases from their inceptions to November 2022: PubMed, EMBASE, MEDLINE, Cochrane Central Register of Controlled Clinical Trials, China Knowledge Resource Integrated Database, Wanfang Data Information, and Weipu Database for Chinese Technical Periodicals. The risk of bias will be assessed independently by 2 authors using the Cochrane tool of risk of bias. All statistical analyses will be conducted using the software program Review Manager version 5.3. The results of this systematic review will be published in a peer-reviewed journal. This study provides evidence of the comparison of radiofrequency ablation and antiarrhythmic drugs for the treatment of atrial fibrillation.

In silico assessment of pharmacotherapy for carbon monoxide induced arrhythmias in healthy and failing human hearts.

Background: Carbon monoxide (CO) is gaining increased attention in air pollution-induced arrhythmias. The severe cardiotoxic consequences of CO urgently require effective pharmacotherapy to treat it. However, existing evidence demonstrates that CO can induce arrhythmias by directly affecting multiple ion channels, which is a pathway distinct from heart ischemia and has received less concern in clinical treatment. Objective: To evaluate the efficacy of some common clinical antiarrhythmic drugs for CO-induced arrhythmias, and to propose a potential pharmacotherapy for CO-induced arrhythmias through the virtual pathological cell and tissue models. Methods: Two pathological models describing CO effects on healthy and failing hearts were constructed as control baseline models. After this, we first assessed the efficacy of some common antiarrhythmic drugs like ranolazine, amiodarone, nifedipine, etc., by incorporating their ion channel-level effects into the cell model. Cellular biomarkers like action potential duration and tissue-level biomarkers such as the QT interval from pseudo-ECGs were obtained to assess the drug efficacy. In addition, we also evaluated multiple specific I Kr activators in a similar way to multi-channel blocking drugs, as the I Kr activator showed great potency in dealing with CO-induced pathological changes. Results: Simulation results showed that the tested seven antiarrhythmic drugs failed to rescue the heart from CO-induced arrhythmias in terms of the action potential and the ECG manifestation. Some of them even worsened the condition of arrhythmogenesis. In contrast, I Kr activators like HW-0168 effectively alleviated the proarrhythmic effects of CO. Conclusion: Current antiarrhythmic drugs including the ranolazine suggested in previous studies did not achieve therapeutic effects for the cardiotoxicity of CO, and we showed that the specific I Kr activator is a promising pharmacotherapy for the treatment of CO-induced arrhythmias.

Abstract 12148: A New Perspective in the Management of Paroxysmal Atrial Fibrillation: Dual Anti-Arrhythmic Medications

Introduction: Atrial fibrillation is the most common disorder of cardiac rhythm, which is often associated with a high risk of morbidity and mortality. Antiarrhythmic medications (AAMs) continue to be the mainstay in the treatment of paroxysmal atrial fibrillation. However, the use of these medications has been limited by their modest anti-arrhythmic efficacy. Hypothesis: We hypothesized that dual AAMs (sodium/potassium channels blockers) improve the chance of maintaining sinus rhythm and decrease the need for catheter ablation when compared to single AAM. Methods: We conducted a retrospective observational study; we reviewed medical records of 150 patients with paroxysmal atrial fibrillation over five years at our hospital in New York. We collected the following data: age, sex, comorbidities, electrocardiogram findings, ejection fraction by echocardiography, classes of AAMs, duration and response to treatments. A successful response was defined as the absence of symptoms and the presence of sinus rhythm on electrocardiogram. A failed response was defined as persistence of symptoms and/or atrial fibrillation on electrocardiogram and the subsequent need for catheter ablation. Results: 86 patients met the inclusion criteria in our analysis. The average age of the patinets was 71.06 years. 45 patients were given the dual AAMs of either amiodarone+flecainide or dronedarone+flecainide, and were treated for an average of 15.4 months. 41 patients received a single AAM then catheter ablation if needed. A chi-square test was performed. X 2 =18.9429, p&lt;.0001. Patients taking dual AAMs were very likely to maintain sinus rhythm and less likely to need catheter ablation (Figure). Conclusions: Our preliminary results demonstrate that patients who receive dual AAMs are significantly less likely to need catheter ablation than those who receive single AAM. Well-designed prospective studies are needed to further explore the use of dual AAM therapy and its clinical impact.

The effect of ionizing radiation through cardiac stereotactic body radiation therapy on myocardial tissue for refractory ventricular arrhythmias: A review.

Cardiac stereotactic body radiation therapy (cSBRT) is a non-invasive treatment modality that has been recently reported as an effective treatment for ventricular arrhythmias refractory to medical therapy and catheter ablation. The approach leverages tools developed and refined in radiation oncology, where experience has been accumulated in the treatment of a wide variety of malignant conditions. However, important differences exist between rapidly dividing malignant tumor cells and fully differentiated myocytes in pathologically remodeled ventricular myocardium, which represent the respective radiation targets. Despite its initial success, little is known about the radiobiology of the anti-arrhythmic effect cSBRT. Pre-clinical data indicates a late fibrotic effect of that appears between 3 and 4 months following cSBRT, which may result in conduction slowing and block. However, there is clear clinical evidence of an anti-arrhythmic effect of cSBRT that precedes the appearance of radiation induced fibrosis for which the mechanism is unclear. In addition, the data to date suggests that even the late anti-arrhythmic effect of cSBRT is not fully attributable to radiation.-induced fibrosis. Pre-clinical data has identified upregulation of proteins expected to result in both increased cell-to-cell coupling and excitability in the early post cSBRT period and demonstrated an associated increase in myocardial conduction velocity. These observations indicate a complex response to radiotherapy and highlight the lack of clarity regarding the different stages of the anti-arrhythmic mechanism of cSBRT. It may be speculated that in the future cSBRT therapy could be planned to deliver both early and late radiation effects titrated to optimize the combined anti-arrhythmic efficacy of the treatment. In addition to these outstanding mechanistic questions, the optimal patient selection, radiation modality, radiation dose and treatment planning strategy are currently being investigated. In this review, we consider the structural and functional effect of radiation on myocardium and the possible anti-arrhythmic mechanisms of cSBRT. Review of the published data highlights the exciting prospects for the development of knowledge and understanding in this area in which so many outstanding questions exist.

Common Structural Pattern for Flecainide Binding in Atrial-Selective Kv1.5 and Nav1.5 Channels: A Computational Approach.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Its treatment includes antiarrhythmic drugs (AADs) to modulate the function of cardiac ion channels. However, AADs have been limited by proarrhythmic effects, non-cardiovascular toxicities as well as often modest antiarrhythmic efficacy. Theoretical models showed that a combined blockade of Nav1.5 (and its current, INa) and Kv1.5 (and its current, IKur) ion channels yield a synergistic anti-arrhythmic effect without alterations in ventricles. We focused on Kv1.5 and Nav1.5 to search for structural similarities in their binding site (BS) for flecainide (a common blocker and widely prescribed AAD) as a first step for prospective rational multi-target directed ligand (MTDL) design strategies. We present a computational workflow for a flecainide BS comparison in a flecainide-Kv1.5 docking model and a solved structure of the flecainide-Nav1.5 complex. The workflow includes docking, molecular dynamics, BS characterization and pattern matching. We identified a common structural pattern in flecainide BS for these channels. The latter belongs to the central cavity and consists of a hydrophobic patch and a polar region, involving residues from the S6 helix and P-loop. Since the rational MTDL design for AF is still incipient, our findings could advance multi-target atrial-selective strategies for AF treatment.

Efficacy and Safety of Catheter Ablation vs Antiarrhythmic Drugs as Initial Therapy for Management of Symptomatic Paroxysmal Atrial Fibrillation: A Meta-Analysis.

Catheter ablation is an effective treatment for atrial fibrillation (AF), primarily performed in patients who fail antiarrhythmic drugs. Whether early catheter ablation, as first-line therapy, is associated with improved clinical outcomes remains unclear. Electronic databases (PubMed, Scopus, Embase) were searched until March 28th, 2021. Randomized controlled trials (RCTs) compared catheter ablation vs antiarrhythmic drug therapy as first-line therapy were included. The primary outcome of interest was the first documented recurrence of any atrial tachyarrhythmia (symptomatic or asymptomatic; AF, atrial flutter, and atrial tachycardia). Secondary outcomes included symptomatic atrial tachyarrhythmia (AF, atrial flutter, and atrial tachycardia) and serious adverse events. Unadjusted risk ratios (RR) were calculated from dichotomous data using Mantel Haenszel (M-H) random-effects with statistical significance considered if the confidence interval (CI) excludes one and p < 0.05. A total of six RCTs with 1212 patients (Ablation n = 609; Antiarrhythmic n = 603) were included. Follow- up period ranged from 1-2 years. Patients who underwent ablation were less likely to experience any recurrent atrial tachyarrhythmia when compared to patients receiving antiarrhythmic drugs (RR 0.63; 95% CI 0.55-0.73; p < 0.00001). Symptomatic atrial tachyarrhythmia was also lower in the ablation arm (RR 0.53; 95% CI 0.32-0.87; p = 0.01). No statistically significant differences were noted for overall any type of adverse events (RR 0.93; 95% CI 0.68-1.27; p = 0.64) and cardiovascular adverse events (RR 0.90; 95% CI 0.56-1.44; p = 0.65) respectively. Catheter ablation, as first-line therapy, was associated with a significantly lower rate of tachyarrhythmia recurrence compared to conventional antiarrhythmic drugs, with a similar adverse effect risk profile. These findings support a catheter ablation strategy as first-line therapy among patients with symptomatic paroxysmal atrial fibrillation.

Sotalol versus amiodarone for postoperative junctional tachycardia after congenital heart surgery.

Junctional ectopic tachycardia (JET) is a common arrhythmia after congenital heart disease surgery. There is variability in the choice of antiarrhythmic therapy, with amiodarone used commonly. Intravenous (IV) sotalol is a newly available agent that may be useful for JET. The purpose of this study was to evaluate the safety and efficacy of IV sotalol for postoperative JET and compare outcomes with IV amiodarone. This is a retrospective single-center study of all patients who received IV sotalol or IV amiodarone for postoperative JET at Texas Children's Hospital from December 15, 2015, to December 15, 2020. Data included antiarrhythmic efficacy, hemodynamics, and adverse effects. Successful JET control was defined as a decrease in JET rate to <170 beats/min (or decrease by >20%), or conversion to sinus rhythm, with persistent control over 24 hours without requiring alternative antiarrhythmics or mechanical support. A total of 32 patients (median age 71 days; interquartile range 17-221 days) received IV amiodarone (n = 20 [62%]) or IV sotalol (n = 12 [38%]) for postoperative JET. Amiodarone was successful in treating JET in 75% of cases; sotalol was successful in 83%. The JET rate decreased faster over the first 90 minutes after a sotalol bolus (25 beats/min per hour) than after an amiodarone bolus (8 beats/min per hour) (P < .01); no heart rate difference was seen after 24 hours. Amiodarone infusion was discontinued early because of hypotension/bradycardia in 2 patients; this was not required in any patients receiving sotalol. For children with postoperative JET, both IV sotalol and amiodarone are safe and efficacious. IV sotalol may lead to a faster improvement in heart rate.

Mechanisms Underlying Antiarrhythmic Properties of Cardioprotective Agents Impacting Inflammation and Oxidative Stress.

The prevention of cardiac life-threatening ventricular fibrillation and stroke-provoking atrial fibrillation remains a serious global clinical issue, with ongoing need for novel approaches. Numerous experimental and clinical studies suggest that oxidative stress and inflammation are deleterious to cardiovascular health, and can increase heart susceptibility to arrhythmias. It is quite interesting, however, that various cardio-protective compounds with antiarrhythmic properties are potent anti-oxidative and anti-inflammatory agents. These most likely target the pro-arrhythmia primary mechanisms. This review and literature-based analysis presents a realistic view of antiarrhythmic efficacy and the molecular mechanisms of current pharmaceuticals in clinical use. These include the sodium-glucose cotransporter-2 inhibitors used in diabetes treatment, statins in dyslipidemia and naturally protective omega-3 fatty acids. This approach supports the hypothesis that prevention or attenuation of oxidative and inflammatory stress can abolish pro-arrhythmic factors and the development of an arrhythmia substrate. This could prove a powerful tool of reducing cardiac arrhythmia burden.

Intraosseous infusion of liposome-encapsulated hemoglobin (HbV) acutely prevents hemorrhagic anemia-induced lethal arrhythmias, and its efficacy persists with preventing proarrhythmic side effects in the subacute phase of severe hemodilution model.

Artificial oxygen carriers (HbV) can treat hemorrhagic shock with lethal arrhythmias (VT/VF). No reports exist on subacute HbV's effects. Acute and subacute resuscitation effects with anti-arrhythmogenesis of HbV were studied in 85% blood exchange rat model (85%-Model). Lethal 85%-Model was created by bone marrow transfusion and femoral artery bleeding in 80 SD rats in HbV-administered group (HbV-group), washed erythrocyte-administered group (wRBC-group), and 5% albumin-administered group (ALB-group). Survival rates, anti-arrhythmic efficacy by optical mapping system (OMP) with electrophysiological study (EPS) in Langendorff heart, cardiac autonomic activity by heart rate variability (HRV) and ventricular arrhythmias by 24-h electrocardiogram telemetry monitoring (24h-ECG) in awake, and left ventricular function by echocardiography (left ventricular ejection fraction [LVEF]) were measured. All rats in HbV- and wRBC-groups survived for 4 weeks, whereas no rats in ALB-group. HbV and wRBC acutely suppressed VT/VF in Langendorff heart through ameliorating action potential duration dispersion (APDd) analyzed by OMP with EPS. For subacute analysis, 50% blood exchange by 5% albumin was used (ALB-group 50). Subacute salutary effect on APDd and VT/VF inducibility was confirmed in HbV- and wRBC-groups. 24h-ECG showed that HbV and wRBC suppressed none-sustained ventricular tachycardia (NSVT) and sympathetic component of HRV (LF/HF) with preserved LVEF (HbV-group, wRBC-group vs. ALB-group 50; NSVT numbers/days, 0.5±0.3, 0.4±0.3 vs. 3.9±1.2*; LF/HF, 1.1±0.2, 0.8±0.2 vs. 3.5±1.0*; LVEF, 84±5, 83±4, vs. 77±4%*; *p<0.05). Collectively, HbV has sustained antiarrhythmic effect in subacute 85%-Model by ameliorating electrical remodeling and improving arrhythmogenic modifying factors (HRV and LVEF). These findings are useful in now continuing clinical trials of HbV.

Abstract 12129: Vascular Endothelial Barrier Protection May Prevent Arrhythmias in Atrial Fibrillation and Myocardial Infarction

Vascular leak is a major sequela of inflammation, which is associated with arrhythmic pathologies such as atrial fibrillation (AF) and myocardial infarction (MI). We recently demonstrated that the vascular leak-inducing cytokine vascular endothelial growth factor (VEGF; 90-580 pg/ml - levels found in AF patients) induces acute remodeling (30-60 minutes) of sodium channel (Na V 1.5) -rich intercalated disk (ID) nanodomains, disrupting their ultrastructure and prompting translocation of Na V 1.5 from these sites. This in turn disrupted impulse propagation and promoted arrhythmias in murine atria. Here, we tested the hypotheses that i) similar acute pro-arrhythmic remodeling occurs in the ventricles of MI patients, and ii) protecting the vascular barrier may prevent arrhythmias following an acute inflammatory insult. First, we examined myocardial samples from five human MI patients. VEGF was overexpressed in both cardiomyocytes and vascular endothelium in the border zone surrounding &lt;6 month-old infarcts. Notably, co-localization analysis showed significantly reduced Na V 1.5 near both connexin43 and N-cadherin within the border zone in 1-, 3-, and 9-day-old infarcts, paralleling our observations in mouse atria. Next, we returned to our murine model of AF induced by acute inflammatory insult (100 pg/ml VEGF for 60 minutes) to test the antiarrhythmic efficacy of protecting the vascular endothelial barrier. Overall, median in vivo arrhythmia burden was higher in VEGF-treated mice relative to vehicle controls (7.5±11 vs. 0±6 s/hr). We tested two strategies shown to prevent vascular barrier breakdown: Blocking connexin43 hemichannels (αCT11 peptide) decreased in vivo arrhythmia burden to 0 ± 6.07 s/hr. Panx1-IL2 (a peptide inhibitor of Panx1 channels) treatment decreased also in vivo arrhythmia burden (0 ± 15.57 s/hr with 1.6 μM Panx1-IL2). Similar antiarrhythmic efficacy was also achieved with small molecule inhibitors of Cx43 and Panx1. These results highlight VEGF-induced vascular leak as a novel mechanism for acute arrhythmias both in the early stage AF and following MI. Indeed, this mechanism may contribute to post-MI AF. Importantly, vascular-barrier protection may be a viable strategy to prevent these arrhythmias.