Bipolar catheter ablation with dedicated radiofrequency system for highly refractory ventricular arrhythmia-Does the rate of success depend on arrhythmia origin?

INTRODUCTION: Despite rapid technological progress, some arrhythmias are still resistant to standard unipolar ablation. These include arrhythmias arising from the base of the heart, cardiac crux, or epicardium. Bipolar radiofrequency ablation (B-RFA) may be useful in some cases, however, data on the efficacy of this approach in various arrhythmia localizations are scarce. The aim of this study was to assess the efficacy of B-RFA in patients with ventricular arrhythmias originating from various locations, occurring refractory to standard unipolar ablation approaches. METHODS: An observational, single center study was conducted over a 30-month period. B-RFA were performed using dedicated radio frequency (RF) generator and electroanatomic mapping system. RESULTS: Twenty-four procedures, in 23 patients with a median (range) of 1 (1-2) previously failed unipolar ablation procedures, were included in the final analysis. There were 12 ablations of ventricular arrhythmias originating from interventricular septum with an acute success rate of 75%, and 12 from left ventricular (LV) summit with an acute success rate of 58%. The midterm success rate (median interquartile range follow-up of 205 days [188-338]) was 66% and 50%, respectively. CONCLUSIONS: B-RFA is a promising method of catheter ablation for refractory cardiac arrhythmias. A higher success rate was observed in ablation for difficult ventricular arrhythmias originating from interventricular septal region than LV summit.

Cardioneuroablation for the treatment of reflex syncope and functional bradyarrhythmias. A Scientific Statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS) and the Latin American Heart Rhythm Society (LAHRS).

Cardioneuroablation has emerged as a potential alternative to cardiac pacing in selected cases with vasovagal reflex syncope, extrinsic vagally induced sinus bradycardia-arrest or atrioventricular block. The technique was first introduced decades ago, and its use has risen over the past decade. However, as with any intervention, proper patient selection and technique are a prerequisite for a safe and effective use of cardioneuroablation therapy. This document aims to review and interpret available scientific evidence and provide a summary position on the topic.

Procedural and Intermediate-term Results of the Electroanatomical-guided Cardioneuroablation for the Treatment of Supra-Hisian Second- or Advanced-degree Atrioventricular Block: the PIRECNA multicentre registry.

AIMS: Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute procedural characteristics and intermediate-term outcomes of electroanatomical-guided cardioneuroablation (EACNA) in patients with VAVB. METHODS AND RESULTS: This international multicentre retrospective registry included data collected from 20 centres. Patients presenting with symptomatic paroxysmal or persistent VAVB were included in the study. All patients underwent EACNA. Procedural success was defined by the acute reversal of atrioventricular blocks (AVBs) and complete abolition of atropine response. The primary outcome was occurrence of syncope and daytime second- or advanced-degree AVB on serial prolonged electrocardiogram monitoring during follow-up. A total of 130 patients underwent EACNA. Acute procedural success was achieved in 96.2% of the cases. During a median follow-up of 300 days (150, 496), the primary outcome occurred in 17/125 (14%) cases with acute procedural success (recurrence of AVB in 9 and new syncope in 8 cases). Operator experience and use of extracardiac vagal stimulation were similar for patients with and without primary outcomes. A history of atrial fibrillation, hypertension, and coronary artery disease was associated with a higher primary outcome occurrence. Only four patients with primary outcome required pacemaker placement during follow-up. CONCLUSION: This is the largest multicentre study demonstrating the feasibility of EACNA with encouraging intermediate-term outcomes in selected patients with VAVB. Studies investigating the effect on burden of daytime symptoms caused by the AVB are required to confirm these findings.

Procedural and Intermediate-term Results of the Electroanatomical-guided Cardioneuroablation for the Treatment of Supra-Hisian Second- or Advanced-degree Atrioventricular Block: the PIRECNA multicentre registry.

AIMS: Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute procedural characteristics and intermediate-term outcomes of electroanatomical-guided cardioneuroablation (EACNA) in patients with VAVB. METHODS AND RESULTS: This international multicentre retrospective registry included data collected from 20 centres. Patients presenting with symptomatic paroxysmal or persistent VAVB were included in the study. All patients underwent EACNA. Procedural success was defined by the acute reversal of atrioventricular blocks (AVBs) and complete abolition of atropine response. The primary outcome was occurrence of syncope and daytime second- or advanced-degree AVB on serial prolonged electrocardiogram monitoring during follow-up. A total of 130 patients underwent EACNA. Acute procedural success was achieved in 96.2% of the cases. During a median follow-up of 300 days (150, 496), the primary outcome occurred in 17/125 (14%) cases with acute procedural success (recurrence of AVB in 9 and new syncope in 8 cases). Operator experience and use of extracardiac vagal stimulation were similar for patients with and without primary outcomes. A history of atrial fibrillation, hypertension, and coronary artery disease was associated with a higher primary outcome occurrence. Only four patients with primary outcome required pacemaker placement during follow-up. CONCLUSION: This is the largest multicentre study demonstrating the feasibility of EACNA with encouraging intermediate-term outcomes in selected patients with VAVB. Studies investigating the effect on burden of daytime symptoms caused by the AVB are required to confirm these findings.

Bipolar ablation of therapy-refractory ventricular arrhythmias: application of a dedicated approach.

AIMS: Bipolar radiofrequency ablation (B-RFA) has been reported as a bail-out strategy for the treatment of therapy refractory ventricular arrhythmias (VA). Currently, existing setups have not been standardized for B-RFA, while the impact of conventional B-RFA approaches on lesion formation remains unclear. METHODS AND RESULTS: (i) In a multicentre observational study, patients undergoing B-RFA for previously therapy-refractory VA using a dedicated B-RFA setup were retrospectively analysed. (ii) Additionally, in an ex vivo model lesion formation during B-RFA was evaluated using porcine hearts. In a total of 26 procedures (24 patients), acute success was achieved in all 14 ventricular tachycardia (VT) procedures and 7/12 procedures with premature ventricular contractions (PVC), with major complications occurring in 1 procedure (atrioventricular block). During a median follow-up of 211 days in 21 patients, 6/11 patients (VT) and 5/10 patients (PVC) remained arrhythmia-free. Lesion formation in the ex vivo model during energy titration from 30 to 50 W led to similar lesion volumes compared with initial high-power 50 W B-RFA. Lesion size significantly increased when combining sequential unipolar and B-RFA (1429 mm3 vs. titration 501 mm3 vs. B-RFA 50 W 423 mm3, P < 0.001), an approach used in overall 58% of procedures and more frequently applied in procedures without VA recurrence (92% vs. 36%, P = 0.009). Adipose tissue severely limited lesion formation during B-RFA. CONCLUSION: Using a dedicated device for B-RFA for therapy-refractory VA appears feasible and safe. While some patients need repeat ablation, success rates were encouraging. Sequential unipolar and B-RFA may be favourable for lesion formation.

Cardioneuroablation - Induced shift in sinus node activation: A new parameter of vagal denervation?

Experimental studies demonstrated a shift in the leading pacemaker site based on parasympathetic or sympathetic dominance. Radiofrequency catheter ablation of ganglionated plexi (GP) might be used to overcome deleterious effects of enhanced parasympathetic tone. Herein, we present two patients who underwent GP ablation due to cardioinhibitory type reflex syncope and symptomatic bradycardia, respectively. In both cases complete vagal denervation was achieved and was associated with a cranial shift of sinus node activation area with corresponding changes in surface P wave morphology. This unique phenomenon needs to be confirmed in the larger prospective study.

Magnetic Core-Shell Molecularly Imprinted Nano-Conjugates for Extraction of Antazoline and Hydroxyantazoline from Human Plasma-Material Characterization, Theoretical Analysis and Pharmacokinetics.

The aim of this study was to develop magnetic molecularly imprinted nano-conjugate sorbent for effective dispersive solid phase extraction of antazoline (ANT) and its metabolite, hydroxyantazoline (ANT-OH) in analytical method employing liquid chromatography coupled with mass spectrometry method. The core-shell material was characterized in terms of adsorption properties, morphology and structure. The heterogeneous population of adsorption sites towards ANT-OH was characterized by two Kd and two Bmax values: Kd (1) = 0.319 µg L-1 and Bmax (1) = 0.240 µg g-1, and Kd (2) = 34.6 µg L-1 and Bmax (2) = 5.82 µg g-1. The elemental composition of magnetic sorbent was as follows: 17.55, 37.33, 9.14, 34.94 wt% for Si, C, Fe and O, respectively. The extraction protocol was optimized, and the obtained results were explained using theoretical analysis. Finally, the analytical method was validated prior to application to pharmacokinetic study in which the ANT was administrated intravenously to three healthy volunteers. The results prove that the novel sorbent could be useful in extraction of ANT and ANT-OH from human plasma and that the analytical strategy could be a versatile tool to explain a potential and pharmacological activity of ANT and ANT-OH.

Diagnostic value of implantable loop recorder in patients undergoing cryoballoon ablation of atrial fibrillation.

BACKGROUND: Due to limited data, implantable loop recorders (ILR) are not currently recommended by the guidelines to routinely monitor patients after atrial fibrillation (AF) ablation. AIMS: To validate the diagnostic value of ILR after AF ablation, modern generation ILRs (LINQ) were implanted in patients scheduled for cryoballoon ablation of AF (CBA). METHODS: We included 29 patients with frequent and symptomatic episodes of paroxysmal AF. ILR was implanted 3 months prior to CBA, and data were collected before and for 6 months after the procedure. The device was programmed to maximize sensitivity of AF/ atrial tachycardia (AT) detection. All EGM recordings were "manually" assessed and annotated as true AF, pseudo AF, unrecognized AF, and episodes with no EGM available. Duration and episode-based standard performance metrics were evaluated. RESULTS: A total number of 5,842 episodes were recorded. A total of 4,403 episodes were true AF, 453 episodes were pseudo AF, and 986 episodes had no EGM available. The device did not recognize 144 episodes of AF. Duration-based sensitivity was 95.2%, duration-based specificity 99.9%, duration-based PPV 99.2%, duration-based NPV 99.9%, episode-based sensitivity 98.0%, and episode-based PPV 91.0%. Misdiagnosis happened in 1 in 10 episodes. Total data review time was 166 hr. CONCLUSIONS: Implantable loop recorders is a valuable tool in evaluation of AF episodes in patients undergoing CBA. However, for high precision all recorded episodes need to be evaluated "manually." The memory storage space is too low for frequent AF episodes, resulting in overwriting of stored EGMs and data loss.

Characterization of In Vitro and In Vivo Metabolism of Antazoline Using Liquid Chromatography-Tandem Mass Spectrometry.

Antazoline (ANT) was recently shown to be an effective and safe antiarrhythmic drug in the termination of atrial fibrillation. However, the drug is still not listed in clinical guidelines. No data on ANT metabolism in humans is available. We used liquid chromatography coupled with tandem mass spectrometry to identify and characterize metabolites of ANT. We analyzed plasma of volunteers following a single intravenous administration of 100 mg of ANT mesylate and in in vitro cultures of human hepatocytes. We revealed that ANT was transformed into at least 15 metabolites and we investigated the role of cytochrome P450 isoforms. CYP2D6 was the main one involved in the fast metabolism of ANT. The biotransformation of ANT by CYP2C19 was much slower. The main Phase I metabolite was M1 formed by the removal of phenyl and metabolite M2 with hydroxyl in the para position of phenyl. Glucuronidation was the leading Phase II metabolism. Further study on pharmacokinetics of the metabolites would allow us to better understand the activity profile of ANT and to predict its potential clinical applications. Ultimately, further investigation of the activity profile of the new hydroxylated M2 metabolite of ANT might result in an active substance with a different pharmacological profile than the parent molecule, and potentially a new drug candidate.

Antazoline-insights into drug-induced electrocardiographic and hemodynamic effects: Results of the ELEPHANT II substudy.

BACKGROUND: Antazoline is an old antihistaminic and new antiarrhythmic agent with unknown mechanisms of action which recently has been shown to effectively terminate atrial fibrillation. The aim of study was to examine the effects of antazoline on hemodynamic and ECG parameters. METHODS: Antazoline was given intravenously in three 100 mg boluses to 10 healthy volunteers (four males, mean age 40 + 11 years). Hemodynamic and ECG parameters were measured using impedance cardiography [systolic (sBP), diastolic (dBP), mean (mBP) blood pressure, stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR) and heart rate (HR), P wave, PR interval, QRS complex, QT and corrected QT (QTcF) interval]. Plasma concentration of antazoline was also measured. RESULTS: Antazoline caused significant prolongation of P wave, QRS as well as QT and QTcF (101 ± 10 vs 110 ± 16 ms, p < .05, and 101 ± 12 vs 107 ± 12 ms, p < .05, 399 ± 27 vs 444 ± 23 ms, p < .05, and 403 ± 21 vs 448 ± 27 ms, p < .05, respectively). Also, a significant decrease in SV was noted (94.9 ± 21.8 vs 82.4 ± 19.6 ml, p < .05). A significant correlation between changes in plasma drug concentration and changes in CO, HR, and dBP was found. CONCLUSIONS: Antazoline impairs slightly hemodynamics, significantly reducing SV. Significant prolongation of P wave and QRS duration corresponds to drug-induced prolongation of conduction, whereas QT prolongation represents drug-induced prolongation of repolarization.

Cardioneuroablation for reflex asystolic syncope: Mid-term safety, efficacy, and patient's acceptance.

BACKGROUND: Cardioneuroablation (CNA) is a promising therapy for reflex asystolic syncope; however, convincing data on the mid-term safety and efficacy of this procedure are lacking. OBJECTIVE: The purpose of this study was to assess the mid-term safety, efficacy, and patient acceptance of CNA. METHODS: This prospective observational single-center study included 115 consecutive patients (mean age 39 ± 13 years; 58% female) treated between 2016 and 2022 who completed at least 1-year follow-up. RESULTS: No significant procedure-related acute complications occurred. During median follow-up of 28 months (range 12-75), 95 (83%) remained free from syncope. Of the 20 patients (17%) with syncope recurrence, syncope burden decreased from a mean 17 (median 6.5) to 3.75 (median 2.5) episodes (P = .015). In 9 of 10 patients, pacing system removal was possible. Repeated CNA was needed in 3 patients (3%), whereas pacemaker implantation was performed in 5 (4%). The most frequent mid-term complication of CNA was sinus rhythm acceleration (from 60 ± 14 bpm to 90 ± 16 bpm; P <.0001), which was symptomatic in 31 patients (27%); 8 patients (7%) required chronic beta-blocker and/or ivabradine. Sinus node modification was necessary in 1 patient. Other complaints included dyspnea, chronic chest pain, and decreased exercise capacity, which were mild and reported by 16 patients (14%). Patient acceptance of CNA was very high: 96% stated that it was worth undergoing the procedure. CONCLUSIONS: Mid-term efficacy of CNA exceeds 80%, and acute complications are absent. The most frequent mid-term chronic complication is inappropriate sinus tachycardia, which in 7% required chronic treatment. The procedure is well accepted by patients.

An extension of biorelevant fed-state dissolution tests to clinical pharmacokinetics - A study on gastrointestinal factors influencing rivaroxaban exposure and efficacy in atrial fibrillation patients.

A direct oral anticoagulant rivaroxaban fails to prevent stroke and systemic embolism in one-to-several percent of patients with nonvalvular atrial fibrillation (NVAF), but the reasons are unknown. The study used semi-mechanistic in vitro-in vivo prediction (IVIVP) modeling to explore the reasons for ineffective thrombosis prevention in NVAF patients. Steady-state drug concentrations in plasma were measured at 0 h (Ctrough), 3 h (C3h), and 12 h post-dosing in thirty-four patients treated with 20 mg rivaroxaban daily. The clinical data were compared against "virtual twins" generated with a novel IVIVP model that combined drug dissolution modeling, mechanistic description of gastric drug transit, and population pharmacokinetics defining the variability of drug disposition. The nonresponders had significantly lower C3h and Ctrough than the responders (p < 0.001) and the covariates included in the population pharmacokinetic submodel did not fully explain this difference. Simulations involving varied gastrointestinal parameters in the "virtual twins" revealed that lower small intestinal effective permeability (Peff), rather than a slower stomach emptying rate, could explain low rivaroxaban exposure in the nonresponders. IVIVP modeling was effectively used for exploring pharmacotherapy failure. Low Peff, found as a major determinant of ineffective rivaroxaban treatment, encourages further research to find (pato)physiological factors influencing suboptimal absorption.

Cardioneuroablation for Reflex Syncope: Efficacy and Effects on Autonomic Cardiac Regulation-A Prospective Randomized Trial.

BACKGROUND: Treatment of cardioinhibitory vasovagal syncope (VVS) is difficult. Recently, cardioneuroablation (CNA) has emerged as a new therapeutic option. OBJECTIVES: This study sought to assess the effects of CNA on syncope recurrences in patients with VVS. METHODS: This study was a prospective, open, randomized, controlled, investigator-initiated trial comparing CNA versus optimal nonpharmacologic therapy in patients with cardioinhibitory VVS. Patients were included if they had documented symptomatic cardioinhibitory or mixed VVS and positive atropine test. CNA was performed using radiofrequency ablation of the ganglionated plexi from the left and right atria. Follow-up lasted 2 years. Primary endpoint was time to first syncope recurrence. Secondary endpoints included changes in sinus rhythm and heart rate variability measured in Holter electrocardiography at baseline and 3, 12, and 24 months after CNA, as well as changes in quality of life at baseline and after completion of follow-up. RESULTS: A total of 48 patients (17 male, mean age 38 ± 10 years, 24 in CNA group, 24 in control group) entered the study. The primary endpoint occurred in 2 patients (8%) from the CNA group versus 13 control patients (54%) (P = 0.0004). After CNA the mean sinus rhythm at 24-hour Holter electrocardiography was significantly faster and heart rate variability parameters significantly changed toward parasympathetic withdrawal compared with baseline values. Quality of life significantly improved in the CNA group (30 ± 10 points vs 10 ± 7 points; P = 0.0001), whereas it remained stable in control patients (31 ± 10 points vs 30 ± 10 points; P = 0.5501). CONCLUSIONS: This is the first randomized study documenting efficacy of CNA in patients with cardioinhibitory VVS. Larger studies are needed to confirm these findings. (Cardioneuroablation for Reflex Syncope [ROMAN]; NCT03903744).

Variability of baroreceptor reflex assessed by tilt table test in a patient undergoing pulmonary vein isolation.

BACKGROUND: The autonomic nervous system (ANS) plays a significant role in atrial fibrillation (AF). Catheter ablation (CA) affects the ANS balance. The assessment of baroreceptor (BR) function is an established method to measure parasympathetic activity; however, it has been rarely used in patients undergoing CA of AF. AIMS: This study is to assess changes in BR function caused by CA and to compare these changes between two different types of CA: point-by-point radiofrequency (RF) versus cryoballoon (CB). METHODS: In this observational, prospective, single center study, 78 patients (25 females, mean age 58 ± 9) with paroxysmal AF and first CA were included: 39 patients (RF group) and 39 (CB group). The BR function was assessed non-invasively using tilt testing and three parameters: event count (BREC) depicting overall BR activity, slope mean depicting BR sensitivity (BRS), and BR effectiveness index (BEI). RESULTS: The groups did not differ in clinical or demographic data. Before CA, tilting caused a marked decrease in BR function parameters in the whole study group (BREC (29 ± 14.0-50.0 vs 28 ± 9.0-44.0, p < 0.068), BRS (10.2 ± 7.1-13.2 vs 5.8 ± 4.9-8.5; p < 0.001), and BEI (52.9 ± 39.9-65.5 vs 39.6 ± 23.6-52.1; p < 0.001), supine vs tilting, respectively). These changes were similar in the both groups. After CA, BR function decreased in the whole group (BREC 12.0 ± 3.0-22.0 vs 6.0 ± 3.0-18.0, p = 0.004; BRS 4.8 ± 3.6-6.8 vs 4.0 ± 3.0-5.8, p = 0.014; BEI 18.7 ± 8.3-27.4 vs 12.0 ± 5.1-21.0, p = 0.009). BREC was significantly more decreased in the CB vs RF. Similar trend was noted for BRS and BEI. CONCLUSIONS: CA significantly affects BR function. These changes were more pronounced following CB rather than RF CA.

Is catheter-tissue contact force value important for ablation of ventricular arrhythmias originating from the left ventricular papillary muscles?

Background: Good catheter-tissue contact is mandatory to create effective ablation lesions. The minimal contact force value for ablation of arrhythmias originating from the left ventricle is 8.0-10.0 grams but is not known for arrhythmias arising from papillary muscles. Purpose: To analyze contact force values during successful ablation procedures of arrhythmias originating from the left ventricular papillary muscles. Methods: 24 consecutive patients (mean age 57.9 ± 11.9 years, 16 males) underwent ablation of premature ventricular complexes originating from left ventricular papillary muscles with the use of CARTO electro-anatomical system and intracardiac echocardiography. Results: Acute complete abolition of ventricular ectopy was obtained in 23 (96%) patients. The fluoroscopy time was 3.9 ± 3.5 min and procedure duration - 114.8 ± 37.9 min. The mean contact force during successful ablations was 3.0 ± 1.1 grams and 3.18 ± 1.8 grams for antero-lateral and postero-medial papillary muscle, respectively (NS). The mean contact force during a single unsuccessful ablation was 3.0 grams. At control Holter ECG, the mean Ectopy Burden was Reduced in the Antero-Lateral Papillary Muscle Group from 18.0% ± 7.9% to 2.6% ± 2.9% (p = 0.005415) and in the Postero-Medial Papillary Muscle Group - from 34.8% ± 13.7%-1.7% ± 1.3% (p = 0.012694). During Median 27 (IQR: 17-34) Months of Follow-up There one Recurrence of Arrhythmia. Conclusion: The values of contact force for successful ablation of ventricular ectopy originating from the left ventricular papillary muscles may be much lower than those for ablation of other foci which questions the role of contact force measurement when ablating these arrhythmias.

Subclinical Dysfunction of Left Atrial Compliance after Cryoballoon versus Radiofrequency Ablation for Paroxysmal Atrial Fibrillation.

It has been suggested that cryoballoon (CB) ablation for paroxysmal atrial fibrillation (PAF) may lead to more extensive left atrial (LA) injury than radiofrequency (RF) ablation; however, results are conflicting. We sought to address this issue using modern echocardiographic techniques estimating the LA function after successful CB and RF ablation for PAF. A total of 90 patients (66% males, mean age 57 ± 10 years) successfully treated (no AF recurrences confirmed in serial 4-7 day ECG Holter monitoring) with RF (51%) or CB (49%) ablation for PAF were retrospectively studied. Echocardiography with speckle tracking (STE) was performed before and 12 months after the procedure. The peak longitudinal LA strain (LAS) and strain rate (LASR) during the reservoir (r), conduit (cd), and contraction (ct) phases were measured in sinus rhythm. Analysis of covariance was applied to compare changes in the echocardiographic parameters over time with the baseline measurements as covariance and the type of ablation as the factor. The parallelism of the slopes of the covariance was tested. The LA diameter decreased (38.3 ± 4.1 mm vs. 36.8 ± 3.6 mm, p < 0.001) in the whole study group at 12 months after ablation. The LASRr and LASRcd increased (1.1 ± 0.3 s-¹ vs. 1.3 ± 0.3 s-¹, p < 0.001 and 1.1 ± 0.3 s-¹ vs. 1.2 ± 0.3 s-¹, p < 0.001, respectively) whereas other LA strain parameters remained unchanged in the whole study group at 12 months after ablation. In the analysis of LA function at 12 months after the procedure regarding the mode of ablation, the worsening of parameters reflecting LA compliance was observed in patients with better pre-served baseline values in the CB ablation subgroup. For baseline LAScd >28%, the difference ΔCB - ΔRF was -7.6 (11.7; -3.4), p < 0.001, and for baseline LAScd >16%, ΔCB - ΔRF was -1.8 (-3.2; -0.4), p = 0.014. The traditional Doppler-derived parameter e' showed the same trend-for baseline e' ≥12 cm/s, ΔCB - ΔRF was -1.7 (-2.8; -0.6), p = 0.003. We conclude that worsening of parameters reflecting LA compliance was observed 12 months after CB ablation compared to RF ablation for PAF in patients who underwent a successful procedure and had better-preserved baseline LA function. This might suggest subclinical dysfunction of LA after the CB ablation procedure. The clinical significance of these findings warrants further investigations.

Development and Performance Verification of the PBPK Model for Antazoline and Its Metabolite and Its Utilization for Pharmacological Hypotheses Formulating.

Antazoline is an antihistaminic drug that is effective in the termination of paroxysmal atrial fibrillation. Despite its long presence in the market, antazoline's ADME parameters and pharmacokinetic effects in humans are poorly characterized. The objective of this study was to fill this gap by generation of in vitro and in vivo data and the development of a physiologically based pharmacokinetic model describing antazoline and its main metabolite disposition. A set of ADME parameters for the antazoline and its hydroxy metabolite is provided based on literature data, QSAR predictions, in vitro binding and metabolic stability assays. These can be used to feed PBPK models. In our current work, the developed PBPK model simulating simultaneously the pharmacokinetic profile of antazoline and its metabolite was successfully verified against the available clinical data and the presented capability to account for the clinically observed variability. When used to feed the PD model (e.g., simulating ECG), concentration-time profiles predicted by the model enable the assessment of antazoline's effect in various clinical scenarios with the possibility to account for population differences or CP mediated drug-drug interactions.

Ultrasound-guided extracardiac vagal stimulation-New approach for visualization of the vagus nerve during cardioneuroablation.

BACKGROUND: Fluoroscopy-guided extracardiac vagal stimulation (ECVS) from the internal right and left jugular veins (RIJV and LIJV) is routinely used to document vagal response (sinus arrest and/or atrioventricular block) during cardioneuroablation. Ultrasound-guided ECVS allows direct visualization and selective stimulation of the vagus nerve (VN). OBJECTIVES: The objectives of this study were to assess the feasibility of ultrasound-guided ECVS and to compare it with fluoroscopy-guided ECVS. METHODS: The study group consisted of 48 patients (25 men [52%]; mean age 38 ± 15 years) in whom fluoroscopy-guided ECVS and ultrasound-guided ECVS were performed. For fluoroscopy-guided ECVS, a pacing electrode was introduced into the RIJV and into the LIJV up to the level of the jugular foramen under fluoroscopic guidance. For ultrasound-guided ECVS, the VN and electrode were visualized using ultrasonography. Partial vagal response was defined as induction of sinus arrest or atrioventricular block, whereas full vagal response was defined as induction of both. RESULTS: ECVS was performed in all patients from the RIJV and in 45 from the LIJV. Visualization of the VN using ultrasound was possible in 44 patients (92%). During ECVS from the RIJV, partial vagal response was obtained in 39 (81%) using fluoroscopy-guided ECVS vs 45 (94%) using ultrasound-guided ECVS (not significant) whereas full vagal response was obtained in 27 patients (56%) using fluoroscopy-guided ECVS vs 40 (83%) using ultrasound-guided ECVS (P = .0071). For ECVS from the LIJV, partial vagal response was achieved in 40 (89%) vs 44 (98%) patients (not significant) whereas full vagal response was achieved in 30 (67%) vs 40 (89%) patients (P = .021) (fluoroscopy-guided ECVS vs ultrasound-guided ECVS, respectively). CONCLUSION: Ultrasound-guided ECVS is feasible and full vagal response is achieved significantly more frequently than using fluoroscopy-guided ECVS.