Electrophysiological and genetic insights into atrial fibrillation

In this PhD thesis we evaluated the role of the autonomic nervous system (ANS) and the genetic background on atrial substrates required for the initiation and perpetuation of atrial fibrillation (AF), one of the most common arrhythmia. It was shown that dispersion of refractoriness, an electrophysiological substrate for the initiation and perpetuation of AF, is not influenced by the electrical remodeling during AF and it is mainly enhanced in the left atrium (LA) of patients with idiopathic AF. The influence of the ANS on dispersion of refractoriness is rather limited and dependent on the degree of electrical remodeling and the atrial site. In patients with early remodeling dispersion of refractoriness is not influenced by autonomic blockade (AB); while in patients with advanced remodeling due to long-lasting AF, dispersion of refractoriness after AB is only decreased in the right atrium (RA). However, the influence of ANS on complex fractionated electrograms (CFAEs) is greater. Areas of CFAEs can represent critical regions for maintaining AF sites, since they can be related to anatomic and electrical changes of the atrial myocardium. CFAEs are influenced by systemic blockade of the ANS. Such blockade reduced the prevalence of CFAEs in the atria of patients with long-lasting AF, and prevented the time-dependant rise of CFAEs in patients with a new episode of AF and thus in the early- phase of AF. The presence of CFAEs is thus, at least partly, influenced by the status of the ANS. The detection of CFAEs, however, has been controversial among studies. The most accurate technique to identify these areas is unipolar recordings with subtraction of remote ventricular activity (gold standard). With the bipolar technique, some areas with CFAEs may be missed while other areas may be erroneously identified as presenting CFAEs. CFAEs derived from activation times in unipolar recordings without QRS subtraction and a catheter placed perpendicular to the endocardial atrial wall come closest to the gold standard. In this thesis we also studied the role of Cx40 protein in AF. Based on literature it was concluded that heterogeneous distribution of Cx40 protein in the atria during AF can contribute to the stabilization of AF and altered expression of Cx40 protein in the myocardial sleeves of the thoracic veins may be the substrate for the firing foci that can trigger AF. However, Cx40 polymorphism was not present in a big cohort of patients with unexplained ischemic cerebrovascular events and it could not be used as a genetic marker in order to predict idiopathic AF in this population. Additionally it was shown that patients bearing this polymorphism had a reduced expression of Cx40 protein in their atria. However, the presence of this polymorphism was not associated with the prevalence of post-operative AF after cardiothoracic surgery

3D-electroanatomical mapping of the left atrium and catheter-based pulmonary vein isolation in pigs: A practical guide

AimTo propose a standardized workflow for 3D-electroanatomical mapping guided pulmonary vein isolation in pigs.Materials and methodsDanish female landrace pigs were anaesthetized. Ultrasound-guided puncture of both femoral veins was performed and arterial access for blood pressure measurement established. Fluoroscopy- and intracardiac ultrasound-guided passage of the patent foramen ovale or transseptal puncture was performed. Then, 3D-electroanatomical mapping of the left atrium was conducted using a high-density mapping catheter. After mapping all pulmonary veins, an irrigated radiofrequency ablation catheter was used to perform ostial ablation to achieve electrical pulmonary vein isolation. Entrance- and exit-block were confirmed and re-assessed after a 20-min waiting period. Lastly, animals were sacrificed to perform left atrial anatomical gross examination.ResultsWe present data from 11 consecutive pigs undergoing pulmonary vein isolation. Passage of the fossa ovalis or transseptal puncture was uneventful and successful in all animals. Within the inferior pulmonary trunk 2–4 individual veins as well as 1–2 additional left and right pulmonary veins could be cannulated. Electrical isolation by point-by-point ablation of all targeted veins was successful. However, pitfalls including phrenic nerve capture during ablation, ventricular arrhythmias during antral isolation close to the mitral valve annulus and difficulties in accessing right pulmonary veins were encountered.ConclusionFluoroscopy- and intracardiac ultrasound-guided transseptal puncture, high-density electroanatomical mapping of all pulmonary veins and complete electrical pulmonary vein isolation can be achieved reproducibly and safely in pigs when using current technologies and a step-by-step approach.</p

The great deceiver: a case series of 'double fire' atrioventricular nodal response.

BACKGROUND: The 'double fire' (DF) atrioventricular (AV) nodal response is a rare mechanism of two ventricular electrical activations following a single atrial beat due to dual AV node physiology. DF AV nodal response is often misdiagnosed and may lead to unnecessary invasive procedures. CASE SUMMARY: We describe a series of three cases with distinct clinical manifestations of DF AV nodal response: Patient 1 remained symptomatic after slow pathway modification for common AV nodal re-entry tachycardia. Patient 2 was misdiagnosed as having junctional bigeminy and developed heart failure with reduced left ventricle ejection fraction. Patient 3 was misdiagnosed as having atrial fibrillation (AF) and underwent two pulmonary vein isolation (PVI) procedures, without clinical improvement. All patients underwent an electrophysiological study (EPS) during which DF AV nodal response was confirmed and treated with radiofrequency ablation of the slow pathway. All patients were afterwards relieved from their symptoms. DISCUSSION AND CONCLUSION: DF AV nodal response is a rare electrophysiological phenomenon which can be clinically misinterpreted as other common arrhythmias, such as premature junctional bigeminy or AF and can contribute to tachycardia induced cardiomyopathy. Typical electrocardiogram- and EPS-derived findings can be indicative for DF AV nodal response. DF AV nodal response can be easily and effectively treated by slow pathway ablation

Acute success and safety of the second-generation PVAC GOLD phased RF ablation catheter for atrial fibrillation

Purpose The second-generation multi-electrode catheter, pulmonary vein ablation catheter (PVAC) GOLD, was designed to improve the delivery of phased radiofrequency energy and reduce procedure times using a 'single-shot' approach for pulmonary vein isolation (PVI), while retaining efficacy and safety. This large registry presents acute success rates and safety outcomes in a daily practice setting. Methods A total of 1017 patients undergoing first-time ablation for atrial fibrillation (AF) using PVAC GOLD were included, 644 patients with paroxysmal AF and 373 patients with non-paroxysmal AF, divided into 175 patients receiving PVI only and 198 patients receiving PVI with additional substrate modification. Results High and comparable percentages of successful PVI could be achieved in all groups (98%, 95% and 99%; p = 0.108). The median total procedure time for all groups was 90 min [70-100]. As expected, the total procedure, ablation and fluoroscopy time were significantly longer in the PVI + substrate modification group compared with the PVI-only cases (all p < 0.001), but not between the PVI-only groups (p = 0.306, p = 0.088, p = 0.233, respectively). A total of 44 complications were observed in 43 patients (4.2%). Major complications were seen in 19 patients (1.87%) and non-major procedure-related complications were seen in 25 patients (2.46%). Complications leaving permanent sequelae were rare and occurred in only four patients (0.39%). Complications did not differ between groups (p = 0.199, p = 0.438, p = 0.240 and p = 0.465 respectively). Conclusion PVAC GOLD performs successful PVI, while reducing procedure times and retaining safety for paroxysmal, persistent and long-standing persistent AF. Safety was unaffected by additional substrate modification

A VIRTUAL Sleep Apnoea management pathway For the work-up of Atrial fibrillation patients in a digital Remote Infrastructure: VIRTUAL-SAFARI

AIMS: In atrial fibrillation (AF) patients, untreated sleep-disordered breathing (SDB) is associated with lower success rates of rhythm control strategies and as such structured SDB testing is recommended. Herein, we describe the implementation of a virtual SDB management pathway in an AF outpatient clinic and examine the utility and feasibility of this new approach. METHODS AND RESULTS: Prospectively, consecutive AF patients accepted for AF catheter ablation procedures without previous diagnosis of SDB were digitally referred to a virtual SDB management pathway and instructed to use WatchPAT-ONE (ITAMAR) for one night. Results were automatically transferred to a virtual sleep laboratory, upon which a teleconsultation with a sleep physician was planned. Patient experience was measured using surveys. SDB testing was performed in 119 consecutive patients scheduled for AF catheter ablation procedures. The median time from digital referral to finalization of the sleep study report was 18 [11-24] days. In total, 65 patients (55%) were diagnosed with moderate-to-severe SDB. Patients with SDB were prescribed more cardiovascular drugs and had higher body mass indices (BMI, 29 ± 3.3 vs. 27 ± 4.4kg/m2, P < 0.01). Patients agreed that WatchPAT-ONE was easy to use (91%) and recommended future use of this virtual pathway in AF outpatient clinics (86%). Based on this remote SDB testing, SDB treatment was recommended in the majority of patients. CONCLUSION: This novel virtual AF management pathway allowed remote SDB testing in AF outpatient clinics with a short time to diagnosis and high patient satisfaction. Structured SDB testing results in a high detection of previously unknown SDB in AF patients scheduled for AF ablation

Atrial fibrillation-specific refinement of the STOP-Bang sleep apnoea screening questionnaire: insights from the Virtual-SAFARI study

Background Sleep-disordered breathing (SDB) is prevalent in up to 50% of patients referred for atrial fibrillation (AF) catheter ablation (CA). Currently, it remains unclear how to improve pre-selection for SDB screening in patients with AF.Aim We aimed to (1) assess the accuracy of the STOP-Bang screening questionnaire for detection of SDB within an AF population referred for CA; (2) derive a refined, AF-specific SDB score to improve pre-selection.Methods Consecutive AF patients referred for CA without a history of SDB and/or SDB screening were included. Patients were digitally referred to the previously implemented Virtual-SAFARI SDB screening and management pathway including a home sleep test. An apnoea-hypopnoea index (AHI) of >= 15 was interpreted as moderate-to-severe SDB. Logistic regression analysis was used to assess characteristics associated with moderate-to-severe SDB to refine pre-selection for SDB screening.Results Of 206 included patients, 51% were diagnosed with moderate-to-severe SDB. The STOP-Bang questionnaire performed poorly in detecting SDB, with an area under the receiver operating characteristic curve (AUROC) of 0.647 (95% Confidence-Interval (CI) 0.573-0.721). AF-specific refinement resulted in the BOSS-GAP score. Therein, BMI with cut-off point >= 27 kg/m(2) and previous stroke or transient ischaemic attack (TIA) were added, while tiredness and neck circumference were removed. The BOSS-GAP score performed better with an AUROC of 0.738 (95% CI 0.672-0.805) in the overall population.Conclusion AF-specific refinement of the STOP-Bang questionnaire moderately improved detection of SDB in AF patients referred for CA. Whether questionnaires bring benefits for pre-selection of SDB compared to structural screening in patients with AF requires further studies

Rationale and Design of the ISOLATION Study:: A Multicenter Prospective Cohort Study Identifying Predictors for Successful Atrial Fibrillation Ablation in an Integrated Clinical Care and Research Pathway

Introduction: Continuous progress in atrial fibrillation (AF) ablation techniques has led to an increasing number of procedures with improved outcome. However, about 30-50% of patients still experience recurrences within 1 year after their ablation. Comprehensive translational research approaches integrated in clinical care pathways may improve our understanding of the complex pathophysiology of AF and improve patient selection for AF ablation. Objectives: Within the "IntenSive mOlecular and eLectropathological chAracterization of patienTs undergoIng atrial fibrillatiOn ablatioN " (ISOLATION) study, we aim to identify predictors of successful AF ablation in the following domains: (1) clinical factors, (2) AF patterns, (3) anatomical characteristics, (4) electrophysiological characteristics, (5) circulating biomarkers, and (6) genetic background. Herein, the design of the ISOLATION study and the integration of all study procedures into a standardized pathway for patients undergoing AF ablation are described. Methods: ISOLATION (NCT04342312) is a two-center prospective cohort study including 650 patients undergoing AF ablation. Clinical characteristics and routine clinical test results will be collected, as well as results from the following additional diagnostics: determination of body composition, pre-procedural rhythm monitoring, extended surface electrocardiogram, biomarker testing, genetic analysis, and questionnaires. A multimodality model including a combination of established predictors and novel techniques will be developed to predict ablation success. Discussion: In this study, several domains will be examined to identify predictors of successful AF ablation. The results may be used to improve patient selection for invasive AF management and to tailor treatment decisions to individual patient

Rationale and Design of the ISOLATION Study::A Multicenter Prospective Cohort Study Identifying Predictors for Successful Atrial Fibrillation Ablation in an Integrated Clinical Care and Research Pathway

INTRODUCTION: Continuous progress in atrial fibrillation (AF) ablation techniques has led to an increasing number of procedures with improved outcome. However, about 30-50% of patients still experience recurrences within 1 year after their ablation. Comprehensive translational research approaches integrated in clinical care pathways may improve our understanding of the complex pathophysiology of AF and improve patient selection for AF ablation. OBJECTIVES: Within the "IntenSive mOlecular and eLectropathological chAracterization of patienTs undergoIng atrial fibrillatiOn ablatioN" (ISOLATION) study, we aim to identify predictors of successful AF ablation in the following domains: (1) clinical factors, (2) AF patterns, (3) anatomical characteristics, (4) electrophysiological characteristics, (5) circulating biomarkers, and (6) genetic background. Herein, the design of the ISOLATION study and the integration of all study procedures into a standardized pathway for patients undergoing AF ablation are described. METHODS: ISOLATION (NCT04342312) is a two-center prospective cohort study including 650 patients undergoing AF ablation. Clinical characteristics and routine clinical test results will be collected, as well as results from the following additional diagnostics: determination of body composition, pre-procedural rhythm monitoring, extended surface electrocardiogram, biomarker testing, genetic analysis, and questionnaires. A multimodality model including a combination of established predictors and novel techniques will be developed to predict ablation success. DISCUSSION: In this study, several domains will be examined to identify predictors of successful AF ablation. The results may be used to improve patient selection for invasive AF management and to tailor treatment decisions to individual patients