Do extra-pulmonary triggers or autonomic neural activity affect rhythm control by anti-arrhythmic drugs in patients with post-ablation atrial fibrillation recurrence?

Background: The role of anti-arrhythmic drugs (AADs) in recurrent atrial fibrillation (AF) after catheter ablation (CA) is not fully understood. The aim of this study was to explore the effects of AADs in patients who recurred after AFCA depending on extra-pulmonary vein triggers (ExPVTs) and post-ablation heart rate variability (HRV) parameters. Methods: We analyzed 2,036 patients who underwent de-novo AFCA and 486 patients with post-AFCA recurrence who underwent rhythm control with AADs. We investigated the effects of ExPVTs and 3rd month HRV parameters on the post-AFCA recurrence and subsequent AAD responsiveness. Results: A total of 486 out of 2,036 patients developed clinical recurrence of AF and subsequently underwent rhythm control with AADs. 486 out of 310 patients (63.8%) remained free of second recurrence at 1-year. Post-AFCA recurrence was significantly higher in patients with ExPVT [Log-rank p < 0.001, HR 1.45 (1.16-1.83), p = 0.001] or higher 3rd month root mean square of the differences between successive RR intervals (rMSSD) [Log-rank p < 0.001, HR 1.36 (1.11-1.65), p = 0.003] than their counterparts. Patients with ExPVTs during the de-novo procedure had significantly higher 3rd month rMSSD (15.0 [11.0-23.0] vs. 17.0 [11.0-28.0], p = 0.022). Patients with high 3rd month rMSSD had higher rate of ExPVTs during the repeat procedure (n = 160, 41.0% vs. 22.2%, p = 0.019). Among patients with recurrent AF after AFCA, post-AAD recurrence did not differ depending on the presence of ExPVT [Log-rank p = 0.455, HR 1.12 (0.78-1.69), p = 0.436] or 3rd month rMSSD [Log-rank p = 0.457, HR 1.16 (0.87-1.55), p = 0.300]. Post-AAD recurrence did not differ between class IC and III AADs (p for interaction = 0.311). Conclusions: ExPVT and post-procedural high rMSSD are independent risk factors for post-AFCA recurrence but not for AAD response in patients with recurrent AF. AADs may suppress ExPVTs and modulate cardiac autonomic activity after post-AFCA recurrence.

Effectiveness of a Triple Antiarrhythmic Drug Strategy for Arrhythmia Recurrence after Persistent Atrial Fibrillation Ablation.

BACKGROUND AND OBJECTIVE: Treating recurrent atrial arrhythmias after persistent atrial fibrillation (PeAF) ablation is often challenging. This single-center, prospective study aimed to observe the effectiveness of different combinations of oral antiarrhythmic drugs (AADs) in reverting to sinus rhythm (SR) in patients with recurrent atrial arrhythmias after PeAF ablation. METHODS: Forty-five patients who experienced recurrent atrial arrhythmias after PeAF ablation were included. Based on their medication regimens, patients were divided into two groups, with the study group being a triple-drug group (digoxin combined with amiodarone/ propafenone and ß-blocker), and the control group being a non-triple-drug group. RESULTS: The rate of reversion to SR was significantly higher in the study group (n = 29) than in the control group (n = 16) at 3 weeks (34.48% vs. 0%, p < 0.01) and 1 month (44.84% vs. 6.25%, p = 0.02) after initiating AADs. No patients with asymptomatic bradycardia were observed in either group. CONCLUSIONS: For patients with recurrent atrial arrhythmias after PeAF ablation, a regimen of low-dose digoxin combined with amiodarone/propafenone and ß-blocker may effectively improve short-term reversion rates.

Promising tools for future drug discovery and development in antiarrhythmic therapy.

Arrhythmia refers to irregularities in the rate and rhythm of the heart, with symptoms spanning from mild palpitations to life-threatening arrhythmias and sudden cardiac death (SCD). The complex molecular nature of arrhythmias complicates the selection of appropriate treatment. Current therapies involve the use of antiarrhythmic drugs (class I-IV) with limited efficacy and dangerous side effects and implantable pacemakers and cardioverter-defibrillators with hardware-related complications and inappropriate shocks. The number of novel antiarrhythmic drug in the development pipeline has decreased substantially during the last decade and underscores uncertainties regarding future developments in this field. Consequently, arrhythmia treatment poses significant challenges, prompting the need for alternative approaches. Remarkably, innovative drug discovery and development technologies show promise in helping advance antiarrhythmic therapies. Here, we review unique characteristics and the transformative potential of emerging technologies that offer unprecedented opportunities for transitioning from traditional antiarrhythmics to next-generation therapies. We assess stem cell technology, emphasizing the utility of innovative cell profiling using multi-omics, high-throughput screening, and advanced computational modeling in developing treatments tailored precisely to individual genetic and physiological profiles. We offer insights into gene therapy, peptide and peptibody approaches for drug delivery. We finally discuss potential strengths and weaknesses of such techniques in reducing adverse effects and enhancing overall treatment outcomes, leading to more effective, specific, and safer therapies. Altogether, this comprehensive overview introduces innovative avenues for personalized rhythm therapy, with particular emphasis on drug discovery, aiming to advance the arrhythmia treatment landscape and the prevention of SCD. Significance Statement Arrhythmias and sudden cardiac death account for 15-20% of deaths worldwide. However, current antiarrhythmic therapies are ineffective and with dangerous side effects. Here, we review the field of arrhythmia treatment underscoring the slow progress in advancing the cardiac rhythm therapy pipeline and the uncertainties regarding evolution of this field. We provide information on how emerging technological and experimental tools can help accelerate progress and address the limitations of antiarrhythmic drug discovery.

SARS-CoV-2 ORF 3a-mediated currents are inhibited by antiarrhythmic drugs.

AIMS: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been linked to cardiovascular complications, notably cardiac arrhythmias. The open reading frame (ORF) 3a of the coronavirus genome encodes for a transmembrane protein that can function as an ion channel. The aim of this study was to investigate the role of the SARS-CoV-2 ORF 3a protein in COVID-19-associated arrhythmias and its potential as a pharmacological target. METHODS AND RESULTS: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and cultured human fibroblasts were infected with SARS-CoV-2. Subsequent immunoblotting assays revealed the expression of ORF 3a protein in hiPSC-CM but not in fibroblasts. After intracytoplasmic injection of RNA encoding ORF 3a proteins into Xenopus laevis oocytes, macroscopic outward currents could be measured. While class I, II, and IV antiarrhythmic drugs showed minor effects on ORF 3a-mediated currents, a robust inhibition was detected after application of class III antiarrhythmics. The strongest effects were observed with dofetilide and amiodarone. Finally, molecular docking simulations and mutagenesis studies identified key amino acid residues involved in drug binding. CONCLUSION: Class III antiarrhythmic drugs are potential inhibitors of ORF 3a-mediated currents, offering new options for the treatment of COVID-19-related cardiac complications.

Sex- and age-specific differences in the use of antiarrhythmic therapies among atrial fibrillation patients: a nationwide cohort study.

AIMS: Atrial fibrillation (AF) patients frequently require active rhythm control therapy to maintain sinus rhythm and reduce symptom burden. Our study assessed whether antiarrhythmic therapies (AATs) are used disproportionately between men and women after new-onset AF. METHODS AND RESULTS: The nationwide Finnish anticoagulation in AF registry-based linkage study covers all patients with new-onset AF in Finland during 2007-2018. Study outcomes included initiation of AATs in the form of antiarrhythmic drugs (AADs), cardioversion, or catheter ablation. The study population constituted of 229 565 patients (50% females). Women were older than men (76.6 ± 11.8 vs. 68.9 ± 13.4 years) and had higher prevalence of hypertension or hyperthyroidism, but lower prevalence of vascular disease, diabetes, renal disease, and cardiomyopathies than men. Overall, 17.6% of women and 25.1% of men were treated with any AAT. Women were treated with AADs more often than men in all age groups [adjusted subdistribution hazard ratio (aSHR) 1.223, 95% confidence interval (CI) 1.187-1.261]. Cardioversions were also performed less often on women than on men aged <65 years (aSHR 0.722, 95% CI 0.695-0.749), more often in patients ≥ 75 years (aSHR 1.166, 95% CI 1.108-1.227), while no difference between the sexes existed in patients aged 65-74 years. Ablations were performed less often in women aged <65 years (aSHR 0.908, 95% CI 0.826-0.998) and ≥75 years (aSHR 0.521, 95% CI 0.354-0.766), whereas there was no difference in patients aged 65-74 years. CONCLUSION: Women used more AAD than men in all age groups but underwent fewer cardioversion and ablation procedures when aged <65 years.

Safety observation of antiarrhythmic drug use in a patient with sinus bradycardia following atrial fibrillation radiofrequency ablation combined with cardiac neural ablation: a case report.

This study assessed the safety of Antiarrhythmic Drug (AAD) administration in a patient experiencing sinus bradycardia following radiofrequency ablation for Atrial Fibrillation (AF), followed by cardiac ganglion ablation. Post-AF radiofrequency ablation, the employment of AADs is a prevalent clinical practice; however, these drugs may exacerbate bradycardia, leading to increased patient discomfort and treatment complexity. The decision to employ AADs in patients with sinus bradycardia post-AF ablation poses a significant clinical challenge. This investigation aimed to ascertain the safety of AADs in such patients. The study encompassed a single case, wherein a patient with pre- and post-procedure sinus bradycardia was treated with AADs following AF radiofrequency ablation and cardiac ganglion ablation, with a subsequent safety assessment. The findings indicate that AADs can be safely administered to patients with sinus bradycardia after these procedures, offering valuable insights for clinical decision-making. This case report underscores the intricacies of post-AF ablation management in patients with sinus bradycardia and advocates for personalized therapeutic strategies. The results enhance the clinical knowledge regarding the safety of AADs in this patient subset and may guide future treatment protocols. Nonetheless, the study's conclusions are drawn from a single case, and further research with larger cohorts is essential to substantiate these findings and elucidate the long-term safety and efficacy of this therapeutic approach.

AN INTERNATIONAL PHYSICIAN SURVEY OF CURRENT ABLATION PRACTICES IN ATRIAL FIBRILLATION: AN AIM-AF SUBSTUDY.

BACKGROUND: Practice guidelines recommend Ablation (ABL) in atrial fibrillation (AF) for rhythm control; guidance for antiarrhythmic drugs (AADs) post-ablation is limited. OBJECTIVE: To understand AAD and ABL practices in USA and Europe. METHODS: An online survey of experienced cardiologists (CDs, n=360) and interventional electrophysiologists (EPs, n=269) was conducted. AAD and ABL related survey questions and responses were analyzed. RESULTS: ABL was preferred more often as first-line AF therapy (Rx) by US CDs/EPs (p<.001). ABL was selected to avoid AAD Rx by 46% (50% CDs, 40% EPs), prevent AF progression by 41% (36% CDs, 47% EPs) and for superior efficacy by 28% (27% CDs, 30% EPs), ABL was employed by 9% in asymptomatic AF (9% CDs, 10% EPs), by 14% in subclinical AF (13% CDs, 14% EPs), by 17% for first AF event (15% CDs, 18% EPs). Primary ABL was preferred in heart failure by 38%. Co-morbidities, age and left atrial size were limitations for ABL by 48%, 40% and 38%, respectively. AADs were used after ABL for AF/ atrial tachycardia (AT) prophylaxis by 34% for 3-6 months and 29% for 1-2 months. AADs were given for a single AF recurrence by 34%, bridging to re-ablation by 32%, and long-term Rx by 34%. AF/AT post-ABL was most often managed with amiodarone (42-48%). CONCLUSION: ABL was frequently preferred over AADs in symptomatic AF but was notably also used for asymptomatic and subclinical AF. Post-ABL AAD Rx for AF prophylaxis or recurrence was frequent with empiric amiodarone being the most often selected AAD.

Long-term health-related quality of life and rhythm outcomes of catheter ablation versus antiarrhythmic drugs in patients with atrial fibrillation.

BACKGROUND: Data on long-term effects of catheter ablation vs antiarrhythmic drugs (AADs) on health-related quality of life (HRQoL) and atrial fibrillation (AF) burden are limited. OBJECTIVE: The study aimed to assess long-term HRQoL and rhythm data in patients with symptomatic AF. METHODS: The 75 patients who underwent ablation and 74 receiving AADs in the Catheter Ablation compared with Pharmacological Therapy for Atrial Fibrillation (CAPTAF) trial were followed for 48 months. The General Health subscale of the 36-Item Short-Form Health Survey, time to first AF episode ≥1 hour, and AF burden, recorded by implantable cardiac monitors, were compared. RESULTS: One hundred forty-seven patients completed follow-up, with 7 crossovers in the ablation group and 34 crossovers in the AAD group. General Health improved by ablation from a median of 62 points at baseline to 79.2 points at follow-up (P < .001) and by AADfrom a median of 67 to 77 points (P < .001), without treatment differences (P = .77). Time to first AF episode ≥1 hour was longer (median 257 days in the ablation group vs 180 days in the AAD group; P = .025). The cumulative AF burden during follow-up was lower in the ablation group (median 0.3%; interquartile range [IQR] 0%-1.4%) than in the AAD group (1.6%; IQR 0.1%-11.0%); P = .01. The cumulative reduction in AF burden compared with baseline was greater in the ablation group (median -89.5%; IQR -98.4% to -51.3%) than in the AAD group (-52.7%; IQR -92.6% to 263.6%); P < .001. CONCLUSION: HRQoL improvement in long-term did not differ between ablation and AAD groups despite a larger reduction in AF burden after ablation. The results should be interpreted in the light of a high crossover rate in the AAD group.

The Properties of the Transient Outward, Inward Rectifier and Acetylcholine-Sensitive Potassium Currents in Atrial Myocytes from Dogs in Sinus Rhythm and Experimentally Induced Atrial Fibrillation Dog Models.

AIMS: Atrial fibrillation (AF) is the most common chronic/recurrent arrhythmia, which significantly impairs quality of life and increases cardiovascular morbidity and mortality. Therefore, the aim of the present study was to investigate the properties of three repolarizing potassium currents which were shown to contribute to AF-induced electrical remodeling, i.e., the transient outward (Ito), inward rectifier (IK1) and acetylcholine-sensitive (IK,ACh) potassium currents in isolated atrial myocytes obtained from dogs either with sinus rhythm (SR) or following chronic atrial tachypacing (400/min)-induced AF. METHODS: Atrial remodeling and AF were induced by chronic (4-6 weeks of) right atrial tachypacing (400/min) in dogs. Transmembrane ionic currents were measured by applying the whole-cell patch-clamp technique at 37 °C. RESULTS: The Ito current was slightly downregulated in AF cells when compared with that recorded in SR cells. This downregulation was also associated with slowed inactivation kinetics. The IK1 current was found to be larger in AF cells; however, this upregulation was not statistically significant in the voltage range corresponding with atrial action potential (-80 mV to 0 mV). IK,ACh was activated by the cholinergic agonist carbachol (CCh; 2 µM). In SR, CCh activated a large current either in inward or outward directions. The selective IK,ACh inhibitor tertiapin (10 nM) blocked the outward CCh-induced current by 61%. In atrial cardiomyocytes isolated from dogs with AF, the presence of a constitutively active IK,ACh was observed, blocked by 59% with 10 nM tertiapin. However, in "AF atrial myocytes", CCh activated an additional, significant ligand-dependent and tertiapin-sensitive IK,ACh current. CONCLUSIONS: In our dog AF model, Ito unlike in humans was downregulated only in a slight manner. Due to its slow inactivation kinetics, it seems that Ito may play a more significant role in atrial repolarization than in ventricular working muscle myocytes. The presence of the constitutively active IK,ACh in atrial myocytes from AF dogs shows that electrical remodeling truly developed in this model. The IK,ACh current (both ligand-dependent and constitutively active) seems to play a significant role in canine atrial electrical remodeling and may be a promising atrial selective drug target for suppressing AF.

Exploring the interplay between extracellular pH and Dronedarone's pharmacological effects on cardiac function.

Dronedarone (DRN) is a clinically used drug to mitigate arrhythmias with multichannel block properties, including the sodium channel Nav1.5. Extracellular acidification is known to change the pharmacological properties of several antiarrhythmic drugs. Here, we explore how modification in extracellular pH (pHe) shapes the pharmacological profile of DRN upon Nav1.5 sodium current (INa) and in the ex vivo heart preparation. Embryonic human kidney cells (HEK293T/17) were used to transiently express the human isoform of Nav1.5 α-subunit. Patch-Clamp technique was employed to study INa. Neurotoxin-II (ATX-II) was used to induce the late sodium current (INaLate). Additionally, ex vivo Wistar male rat preparations in the Langendorff system were utilized to study electrocardiogram (ECG) waves. DRN preferentially binds to the closed state inactivation mode of Nav1.5 at pHe 7.0. The recovery from INa inactivation was delayed in the presence of DRN in both pHe 7.0 and 7.4, and the use-dependent properties were distinct at pHe 7.0 and 7.4. However, the potency of DRN upon the peak INa, the voltage dependence for activation, and the steady-state inactivation curves were not altered in both pHe tested. Also, the pHe did not change the ability of DRN to block INaLate. Lastly, DRN in a concentration and pH dependent manner modulated the QRS complex, QT and RR interval in clinically relevant concentration. Thus, the pharmacological properties of DRN upon Nav1.5 and ex vivo heart preparation partially depend on the pHe. The pHe changed the biological effect of DRN in the heart electrical function in relevant clinical concentration.

Cardiac Arrhythmias and Their Management: An In-Depth Review of Current Practices and Emerging Therapies.

Cardiac arrhythmias encompass a range of conditions characterized by abnormal heart rhythms, affecting millions globally and significantly contributing to morbidity and mortality. This review provides a comprehensive analysis of the current practices and emerging therapies in managing cardiac arrhythmias, covering their definition, classification, epidemiology, and the critical importance of effective management. It explores the pathophysiology underlying various arrhythmias, including the mechanisms of arrhythmogenesis, such as re-entry, automaticity, and triggered activity. The review details the latest diagnostic tools, including ECG, Holter monitoring, and electrophysiological studies, and discusses the clinical presentation of different arrhythmias, from supraventricular to ventricular types and bradyarrhythmias. We examine current pharmacological and non-pharmacological treatment strategies, such as antiarrhythmic drugs, catheter ablation, and device therapy, highlighting their efficacy and limitations. Furthermore, the review delves into emerging therapies, including advanced catheter ablation techniques, novel antiarrhythmic agents, gene therapy, and innovative device technologies like leadless pacemakers and subcutaneous implantable cardioverter-defibrillators (ICDs). Special considerations for managing arrhythmias in diverse populations, including pediatrics, the elderly, and pregnant women, are discussed. Additionally, the review explores future directions in arrhythmia management, emphasizing personalized medicine, artificial intelligence applications, and the integration of advanced technologies in diagnosis and treatment. By synthesizing current knowledge and prospects, this review aims to enhance understanding and promote advancements in the field, ultimately improving patient outcomes with cardiac arrhythmias.

Efficacy of prescribing Inderal for polymorphic ventricular tachycardia in a young patient with the normal QT interval: A case report study.

Polymorphic ventricular tachycardia (PVT) is a group of life-threatening heart rhythm disorders. These arrhythmias share similar electrocardiographic characteristics but require different modes of therapy for effective treatment. It is important to note that the medications that are considered the first-line treatment for one type of PVT may not be appropriate for another type, and may worsen the condition. Therefore, it is crucial to accurately diagnose the type of PVT before initiating treatment to provide the most effective therapy for the patient. A 42-year-old man was admitted to the emergency department with dyspnea, Levine sign, and severe chest pain. His electrocardiogram showed ST elevation, and the QT interval was normal. The patient was sent to the cath lab based on the treatment protocols. According to the results of angiography, three coronary arteries were severely obstructed. His coronary arteries did not open during percutaneous coronary intervention; thus, the healthcare team decided on open heart surgery. He suffered from recurrent PVT following open heart surgery and did not respond to any of the drugs suitable for this type of tachycardia. Inderal prevented the recurrence of ventricular tachycardia (VT) in a patient with polymorphic VT without QT prolongation, contrary to the healthcare team's expectations. Inderal was used as the last line of treatment because this patient's arrhythmia was polymorphic VT without QT prolongation. Inderal is typically used for treating VT in patients with long QT syndromes and heart structural disorders. This case report aims to highlight the impact of Inderal on polymorphic tachycardia, specifically in cases where the QT interval is not elongated. In this particular case, the standard treatment approaches were ineffective in preventing reversibility, but Inderal proved to be successful. Therefore, we feel it is important to document and share this case.

Ketamine Terminating Persistent Ventricular Tachycardia.

Ventricular tachycardia (VT) is an arrhythmia associated with sudden cardiac death. VT storm is a complication of persistent VT requiring immediate antiarrhythmic therapy. In refractory cases, adjunctive therapy includes sedation/mechanical ventilation or catheter ablation. This case highlights a patient with ischemic cardiomyopathy in refractory VT storm terminated by administration of ketamine.

Safety of different therapies for atrial fibrillation: a network meta-analysis.

OBJECTIVE: Most published studies have aimed to compare the effectiveness of different treatment strategies for atrial fibrillation (AF), while few articles have comprehensively compared the safety of therapeutic measures.The aim of the article was to assess the safety of different therapeutic measures (different ablation techniques, antiarrhythmic drugs and surgery) in patients with AF. METHOD: A comprehensive and systematic search was undertaken across various databases, namely PubMed, Embase, Cochrane Library, and Web of Science, with the aim of identifying pertinent randomized controlled trials (RCTs) that delve into the safety aspects of diverse atrial fibrillation treatment strategies. The search was conducted up until December 1st, 2023. R4.2.3 software gemtc package was used for data analysis, Review Manager 5.3 was used for quality assessment of included studies, and stata15.0 was used for publication bias.Safety is defined as the adverse outcomes that occur in different treatment strategies for atrial fibrillation, with specific adverse events as described below. RESULT: 22 RCTs (involving 5073 subjects) with interventions including cryoballoon ablation (CA), radiofrequency ablation (RF), laser balloon ablation (LB), pulmonary vein ablation catheter (PVAC), antiarrhythmic drugs (AADS), and surgery (SA) were included in this study. In this article, medication and surgery were combined into the same intervention (non-traditional treatment measure, UT). UT was not associated with pericardial effusion (OR:4.27e-10, 95%CI:4.91e-30-0.0663), infections (OR:0.248, 95%CI:0.0584-0.89), arrhythmias (OR:0.609,95%CI:0.393-0.936), pseudoaneurysms (OR:5.57e-10, 95%CI:1.16e-31-0.934) and pulmonary vein stenosis (OR:1.16e-09, 95%CI:6.56e-24-0.194). Complications of the procedure were mainly mechanical injuries. Among the various ablation strategies, radiofrequency ablation had a lower incidence of phrenic nerve palsy and pain (OR:4.01e-06, 95%CI:1.18e-17-0.710) than cryoballoon ablation, which was superior to radiofrequency ablation in terms of infection rates. Finally, there were no significant differences between the various ablation techniques in terms of other complication rates. CONCLUSION: Because the interventions in the UT group were predominantly AADS and antiarrhythmic drug therapy didn't have some of the common aggressive complications of ablation strategies, the UT group had a low rate of complications such as pericardial effusion, postprocedural arrhythmia, pseudoaneurysm, and pulmonary vein stenosis compared with various catheter ablation strategies. Additionally, we also discovered between the various ablation technology groups, there was no significant difference in the incidence of major adverse events. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registry number:CRD42024566530.

Atrial Fibrillation and Heart Failure With Reduced Ejection Fraction: New Assessment of an Old Problem.

Atrial fibrillation (AF) and heart failure (HF)-specifically, heart failure with reduced ejection fraction (HFrEF)-often coexist, and each contributes to the propagation of the other. This relationship extends from the mechanistic and physiological to clinical syndromes, quality of life, and long-term cardiovascular outcomes. The risk factors for AF and HF overlap and create a critical opportunity to prevent adverse outcomes among patients at greatest risk for either condition. Increasing recognition of the linkages between AF and HF have led to widespread interest in designing diagnostic, predictive, and interventional strategies targeting all aspects of disease, from identifying genetic predisposition to addressing social determinants of health. Advances across this spectrum culminated in updated multisociety guidelines for management of AF, which includes specific consideration of comorbid AF and HF. This review expands on these guidelines by further highlighting relevant clinical trial findings and providing additional context for the evolving recommendations for management in this important and growing population.

A Comparative Study of the Rapid (IKr) and Slow (IKs) Delayed Rectifier Potassium Currents in Undiseased Human, Dog, Rabbit, and Guinea Pig Cardiac Ventricular Preparations.

To understand the large inter-species variations in drug effects on repolarization, the properties of the rapid (IKr) and the slow (IKs) components of the delayed rectifier potassium currents were compared in myocytes isolated from undiseased human donor (HM), dog (DM), rabbit (RM) and guinea pig (GM) ventricles by applying the patch clamp and conventional microelectrode techniques at 37 °C. The amplitude of the E-4031-sensitive IKr tail current measured at -40 mV after a 1 s long test pulse of 20 mV, which was very similar in HM and DM but significant larger in RM and GM. The L-735,821-sensitive IKs tail current was considerably larger in GM than in RM. In HM, the IKs tail was even smaller than in DM. At 30 mV, the IKr component was activated extremely rapidly and monoexponentially in each studied species. The deactivation of the IKr component in HM, DM, and RM measured at -40 mV. After a 30 mV pulse, it was slow and biexponential, while in GM, the IKr tail current was best fitted triexponentially. At 30 mV, the IKs component activated slowly and had an apparent monoxponential time course in HM, DM, and RM. In contrast, in GM, the activation was clearly biexponential. In HM, DM, and RM, IKs component deactivation measured at -40 mV was fast and monoexponential, while in GM, in addition to the fast component, another slower component was also revealed. These results suggest that the IK in HM resembles that measured in DM and RM and considerably differs from that observed in GM. These findings suggest that the dog and rabbit are more appropriate species than the guinea pig for preclinical evaluation of new potential drugs expected to affect cardiac repolarization.

Investigative agents for atrial fibrillation: agonists and stimulants, progress and expectations.

INTRODUCTION: Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. Its prevalence has increased due to worldwide populations that are aging in combination with the growing incidence of risk factors associated. Recent advances in our understanding of AF pathophysiology and the identification of nodal players involved in AF-promoting atrial remodeling highlights potential opportunities for new therapeutic approaches. AREAS COVERED: This detailed review summarizes recent developments in the field antiarrhythmic drugs in the field AF. EXPERT OPINION: The current situation is far than optimal. Despite clear unmet needs in drug development in the field of AF treatment, the current development of new drugs is absent. The need for a molecule with absence of cardiac and non-cardiac toxicity in the short and long term is a limitation in the field. Improvement in the understanding of AF genetics, pathophysiology, molecular alterations, big data and artificial intelligence with the objective to provide a personalized AF treatment will be the cornerstone of AF treatment in the coming years.

Analysis of drug-induced and spontaneous cardioversions reveals similar patterns leading to termination of atrial fibrillation.

Introduction: The mechanisms leading to the conversion of atrial fibrillation (AF) to sinus rhythm are poorly understood. This study describes the dynamic behavior of electrophysiological parameters and conduction patterns leading to spontaneous and pharmacological AF termination. Methods: Five independent groups of goats were investigated: (1) spontaneous termination of AF, and drug-induced terminations of AF by various potassium channel inhibitors: (2) AP14145, (3) PA-6, (4) XAF-1407, and (5) vernakalant. Bi-atrial contact mapping was performed during an open chest surgery and intervals with continuous and discrete atrial activity were determined. AF cycle length (AFCL), conduction velocity and path length were calculated for each interval, and the final conduction pattern preceding AF termination was evaluated. Results: AF termination was preceded by a sudden episode of discrete activity both in the presence and absence of an antiarrhythmic drug. This episode was accompanied by substantial increases in AFCL and conduction velocity, resulting in prolongation of path length. In 77% ± 4% of all terminations the conduction pattern preceding AF termination involved medial to lateral conduction along Bachmann's bundle into both atria, followed by anterior to posterior conduction. This finding suggests conduction block in the interatrial septum and/or pulmonary vein area as final step of AF termination. Conclusion: AF termination is preceded by an increased organization of fibrillatory conduction. The termination itself is a sudden process with a critical role for the interplay between spatiotemporal organization and anatomical structure.