Catheter Ablation of Atrial Fibrillation in Patients With Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Coexistence of atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) is common, affecting morbidity and prognosis. This study evaluates outcome after cryoballoon ablation for AF in HFpEF compared with patients without heart failure. METHODS: A total of 102 AF patients with left ventricular ejection fraction ≥50% undergoing cryoballoon ablation were prospectively enrolled. Baseline evaluation included echocardiography, stress echocardiography, 6-minute walk test, biomarkers, and quality of life assessment (Short-Form-36). Procedural parameters and clinical, functional and echocardiographic end points at follow-up ≥12 months after AF ablation were compared between patients with and without HFpEF. RESULTS: Patients with HFpEF (n=24) were older (median, 74 years versus 65 years; P=0.001) more often female (83% versus 28%; P<0.001) and characterized by more pronounced AF-related symptoms (median European Heart Rhythm Association score 3 versus 2; P<0.001), higher left atrial pressures (median, 14 mm Hg versus 10 mm Hg; P=0.008), reduced left atrial-appendage velocity (median, 36 cm/s versus 59 cm/s; P<0.001), and reduced distance in the 6-minute walk test (median, 488 m versus 539 m; P<0.001). Patients with HFpEF more often experienced AF recurrence (57% versus 23%; P=0.003), repeat AF ablation (39% versus 14%; P=0.01) and AF-related rehospitalization (26% versus 7%; P=0.016). Heart failure symptoms and elevated cardiac biomarkers persisted, even in patients with HFpEF with successful rhythm control at follow-up. Echocardiographic follow-up showed progression of adverse left atrial remodeling and no relevant improvement in diastolic function in HFpEF. Quality of life improved in patients without HFpEF, whereas patients with HFpEF still exhibited a lower physical component summary score (median, 41.5 versus 53.4; P<0.004). CONCLUSIONS: Patients with HFpEF constitute a distinct subgroup with elevated risk for AF recurrence after cryoballon ablation. Functional hallmarks of HFpEF persist, irrespective of rhythm status at follow-up. Future research is needed to optimize treatment strategies in patients with HFpEF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04317911.

Expert-enhanced machine learning for cardiac arrhythmia classification.

We propose a new method for the classification task of distinguishing atrial fibrillation (AFib) from regular atrial tachycardias including atrial flutter (AFlu) based on a surface electrocardiogram (ECG). Recently, many approaches for an automatic classification of cardiac arrhythmia were proposed and to our knowledge none of them can distinguish between these two. We discuss reasons why deep learning may not yield satisfactory results for this task. We generate new and clinically interpretable features using mathematical optimization for subsequent use within a machine learning (ML) model. These features are generated from the same input data by solving an additional regression problem with complicated combinatorial substructures. The resultant can be seen as a novel machine learning model that incorporates expert knowledge on the pathophysiology of atrial flutter. Our approach achieves an unprecedented accuracy of 82.84% and an area under the receiver operating characteristic (ROC) curve of 0.9, which classifies as "excellent" according to the classification indicator of diagnostic tests. One additional advantage of our approach is the inherent interpretability of the classification results. Our features give insight into a possibly occurring multilevel atrioventricular blocking mechanism, which may improve treatment decisions beyond the classification itself. Our research ideally complements existing textbook cardiac arrhythmia classification methods, which cannot provide a classification for the important case of AFib↔AFlu. The main contribution is the successful use of a novel mathematical model for multilevel atrioventricular block and optimization-driven inverse simulation to enhance machine learning for classification of the arguably most difficult cases in cardiac arrhythmia. A tailored Branch-and-Bound algorithm was implemented for the domain knowledge part, while standard algorithms such as Adam could be used for training.

Recommendations regarding cardiac stereotactic body radiotherapy for treatment refractory ventricular tachycardia.

BACKGROUND: Ventricular tachycardia (VT) is a potentially lethal complication of structural heart disease. Despite optimal management, a subgroup of patients continue to suffer from recurrent VT. Recently, cardiac stereotactic body radiotherapy (CSBRT) has been introduced as a treatment option in patients with VT refractory to antiarrhythmic drugs and catheter ablation. OBJECTIVE: The purpose of this study was to establish an expert consensus regarding the conduct and use of CSBRT for refractory VT. METHODS: We conducted a modified Delphi process. Thirteen experts from institutions from Germany and Switzerland participated in the modified Delphi process. Statements regarding the following topics were generated: treatment setting, institutional expertise and technical requirements, patient selection, target volume definition, and monitoring during and after CSBRT. Agreement was rated on a 5-point Likert scale. The strength of agreement was classified as strong agreement (≥80%), moderate agreement (≥66%) or no agreement (<66%). RESULTS: There was strong agreement regarding the experimental status of the procedure and the preference for treatment in clinical trials. CSBRT should be conducted at specialized centers with a strong expertise in the management of patients with ventricular arrhythmias and in stereotactic body radiotherapy for moving targets. CSBRT should be restricted to patients with refractory VT with optimal antiarrhythmic medication who underwent prior catheter ablation or have contraindications. Target volume delineation for CSBRT is complex. Therefore, interdisciplinary processes that should include cardiology/electrophysiology and radiation oncology as well as medical physics, radiology, and nuclear medicine are needed. Optimal follow-up is required. CONCLUSION: Prospective trials and pooled registries are needed to gain further insight into this promising treatment option for patients with refractory VT.

Presence of contractile impairment appears crucial for structural remodeling in idiopathic left bundle-branch block.

BACKGROUND: To differentiate effects of ventricular asynchrony from an underlying hypocontractile cardiomyopathy this study aimed to enhance the understanding of functional impairment and structural remodeling in idiopathic left bundle-branch block (LBBB). We hypothesize, that functional asynchrony with septal flash volume effects alone might not entirely explain the degree of functional impairment. Hence, we suggest the presence of a superimposed contractile cardiomyopathy. METHODS: In this retrospective study, 53 patients with idiopathic LBBB were identified and matched to controls with and without cardiovascular risk factors. Cardiovascular magnetic resonance (CMR) was used to evaluate cardiac function, volumes and myocardial fibrosis using native T1 mapping and late gadolinium enhancement (LGE). Septal flash volume was assessed by CMR volumetric measurements and allowed to stratify patients with systolic dysfunction solely due to isolated ventricular asynchrony or superimposed contractile impairment. RESULTS: Reduced systolic LV-function, increased LV-volumes and septal myocardial fibrosis were found in patients with idiopathic LBBB compared to healthy controls. LV-volumes increased and systolic LV-function declined with prolonged QRS duration. Fibrosis was typically located at the right ventricular insertion points. Subgroups with superimposed contractile impairment appeared with pronounced LV dilation and increased fibrotic remodeling compared to individuals with isolated ventricular asynchrony. CONCLUSIONS: The presence of superimposed contractile impairment in idiopathic LBBB is crucial to identify patients with enhanced structural remodeling. This finding suggests an underlying cardiomyopathy. Future studies are needed to assess a possible prognostic impact of this entity and the development of heart failure. TRIAL REGISTRATION: This study was retrospectively registered.

Clinical results of fibroblast activation protein (FAP) specific PET for non-malignant indications: systematic review.

PURPOSE: Small molecules targeting fibroblast activation protein (FAP) have emerged as a new group of tracers for positron emission tomography (PET) in 2018. While most of the existing literature has been focussed on the application of FAP-specific PET in various kinds of cancers, some researchers have, both intentionally or unintentionally, used FAP-specific PET in patients with non-cancerous diseases. The purpose of this systematic review is therefore to summarize the available evidence of FAP-specific PET for non-malignant indications. METHODS: The MEDLINE database was searched for studies presenting the clinical use of FAP-specific PET, the records were screened according to PRISMA guidelines and articles containing patients suffering from non-malignant diseases were included. RESULTS: Sixteen studies with 303 patients were included. FAP-specific PET has been used in cardiac imaging, IgG4-related disease, benign tumors as well as various kinds of inflammation. Two prospective studies on FAP-specific PET for IgG4-related disease show its potential to differentiate inflammatory from fibrotic lesions, which could be used to determine the management of these patients. CONCLUSION: While publications on FAP-specific PET for non-malignant indications are mostly limited to case reports and incidental findings, the first retrospective and prospective studies present promising results for IgG4-related as well as cardiovascular disease that warrant further research. Several currently recruiting trials will add to the body evidence in the next few years.

Cryoballoon pulmonary vein isolation-mediated rise of sinus rate in patients with paroxysmal atrial fibrillation.

BACKGROUND: Modulation of the cardiac autonomic nervous system by pulmonary vein isolation (PVI) influences the sinoatrial nodal rate. Little is known about the causes, maintenance and prognostic value of this phenomenon. We set out to explore the effects of cryoballoon PVI (cryo-PVI) on sinus rate and its significance for clinical outcome. METHODS AND RESULTS: We evaluated 110 patients with paroxysmal atrial fibrillation (AF), who underwent PVI using a second-generation 28 mm cryoballoon by pre-, peri- and postprocedural heart rate acquisition and analysis of clinical outcome. Ninety-one patients could be included in postinterventional follow-up, indicating that cryo-PVI resulted in a significant rise of sinus rate by 16.5% (+ 9.8 ± 0.9 beats/min, p < 0.001) 1 day post procedure compared to preprocedural acquisition. This effect was more pronounced in patients with initial sinus bradycardia (< 60 beats/min.) compared to patients with faster heart rate. Increase of rate was primarily driven by ablation of the right superior pulmonary vein and for a subset of patients, in whom this could be assessed, persisted ≥ 1 year after the procedure. AF recurrence was neither predicted by the magnitude of the initial rate, nor by the extent of rate change, but postprocedural sinus bradycardia was associated with higher recurrence of AF in the year post PVI. CONCLUSIONS: Cryo-PVI causes a significant rise of sinus rate that is more pronounced in subjects with previous sinus bradycardia. Patient follow-up indicates persistence of this effect and suggests an increased risk of AF recurrence in patients with postprocedural bradycardia.

Spatial relationship between the pulmonary trunk and the left coronaries: Systematic risk assessment based on automated three-dimensional distance measurements.

BACKGROUND: Catheter ablation of right ventricular outflow tract ventricular arrhythmias from above the pulmonary valve is being increasingly reported. OBJECTIVE: The purpose of this study was to systematically analyze the spatial relationship between the pulmonary trunk and the left coronaries. METHODS: Contrast-enhanced computed tomographic scans from 58 patients were analyzed. After segmentation of the pulmonary trunk and the proximal left coronaries, 3-dimensional geometries were generated. Minimal distance between the pulmonary trunk and the coronaries was automatically determined using a newly developed mathematical algorithm. RESULTS: The minimal distance between the pulmonary trunk and the coronaries was 1.4 ± 0.11 mm. Closest relationship was detected 13.8 ± 0.87 mm above the pulmonary valve annulus. Considering a safety margin of 5 mm to render coronary damage unlikely, 84% of patients were found to be at potential risk within the bottom 10 mm of the left sinus cusp. In contrast, positions within or above the right and anterior cusps were less likely to exhibit a close relationship. We identified the anterior aspect of the left cusp as the most critical region. Positions 10-20 mm above the left cusp were found to be critical in 97% of patients. Clinical parameters such as gender, age, height, weight, and body mass index were not predictive of a close spatial relationship. CONCLUSION: Our data provide evidence for a close spatial relationship between the pulmonary trunk and coronary arteries. These results should be considered when performing catheter ablation from above the pulmonary valve.

Active-Scanned Protons and Carbon Ions in Cancer Treatment of Patients With Cardiac Implantable Electronic Devices: Experience of a Single Institution.

Background: Ionizing radiation was shown to be able to influence the function of cardiac implantable electronic devices (CIED's) leading to malfunctions with potentially severe consequences. Those effects presumably correlate with beam energy and neutron production. Thus, particle facilities are commonly cautious to treat patients with CIED's with particles, but substantial evidence is lacking. Methods and Materials: In total 31 patients were investigated, who have been treated at the Heidelberg Ion-Beam Therapy Center (HIT) from September 2012 to February 2019 with protons and carbon ions in active-scanning technique. All CIED's were checked after every single irradiation by the department of cardiology. The minimum distance between the CIED and the planning target volume (PTV), the 10% isodose and the single beam in Beam's Eye View (BEV) was analyzed for 12 patients. Results: In total, 31 patients received 32 courses of radiotherapy (RT). Twenty-two received treatment with carbon ion beam and ten with proton beam. The cumulative number of fractions was 582, the cumulative number of documented controls after RT was 504 (87%). Three patients had an implantable cardioverter-defibrillator (ICD) and 28 patients had a pacemaker at the time of treatment. Seven patients had a heart rate of ≤30/min. The majority of patients (69%) were treated for tumors of the head and neck. The median minimum distance between CIED and PTV, 10% isodose and the single beam on BEV was 13.4, 11.6, and 8.3 cm, respectively. There were no registered events associated with the treatment in this evaluation. Conclusion: Treatment of CIED-patients with protons and carbon ions applied with active raster scanning technique was safe without any incidents in our single center experience. Monitoring after almost every fraction provided systematic and extensive data. Further investigations are necessary in order to form reliable guidelines, which should consider different modes of beam application, as active scanning supposedly provides a greater level of safety from malfunctions for patients with CIED undergoing particle irradiation.

[Cardiac arrhythmias in oncological diseases, during radiotherapy, chemotherapy]. / Rhythmusstörungen bei malignen Erkrankungen, unter Bestrahlung und Chemotherapie.

Patients with oncological diseases frequently show cardiac arrhythmias. This is explained by an increased risk in this specific patient cohort and is frequently associated with specific oncological therapies. So far, it is unclear how to deal with the occurrence of arrhythmias diagnostically and therapeutically, since the current clinical data do not provide satisfying answers to these questions. Clinical care of high-risk patients in specialized teams with a focus on cardio-oncology is recommended. Based on the current clinical studies and the position papers of the European Society of Cardiology (ESC), we give a brief overview of arrhythmias in malignant diseases and their therapies.

Novel approach to discriminate left bundle branch block from nonspecific intraventricular conduction delay using pacing-induced functional left bundle branch block.

PURPOSE: Left bundle branch block (LBBB) has a predictive value for response to cardiac resynchronization therapy as reported by Zareba et al. (Circulation 123(10):1061-1072, 2011). However, based on ECG criteria, the discrimination between complete LBBB and nonspecific intraventricular conduction delay is challenging. We tested the hypothesis that discrimination can be performed using standard electrophysiological catheters and a simple stimulation protocol. METHODS: Fifty-nine patients were analyzed retrospectively. Patients were divided into groups of narrow QRS (n = 20), wide QRS of right bundle branch block (RBBB) morphology (n = 14), and wide QRS of LBBB morphology (n = 25). Using a diagnostic catheter placed in the coronary sinus, left ventricular activation was assessed during intrinsic conduction as well as during right ventricular (RV) stimulation. RESULTS: In patients with narrow QRS and RBBB, the Q-LV/QRS ratio was 0.43 ± 0.013 (n = 20) and 0.41 ± 0.026 (n = 14), respectively. In patients with LBBB morphology, the Q-LV/QRS split up into a group of patients with normal (0.43 ± 0.022, n = 7) and a group with delayed left ventricular activation (0.75 ± 0.016, n = 18). By direct comparison of the Q-LV/QRS ratio during intrinsic conduction with the Q-LV/QRS ratio during RV pacing leading to a functional LBBB, a clear distinction between a group of "true LBBB" and another group of "apparent LBBB"/nonspecific intraventricular conduction delay (NICD) could be generated. CONCLUSIONS: We present a novel and practical method that might facilitate discrimination between patients with apparent LBBB and true LBBB by comparing Q-LV/QRS ratios during intrinsic activation and during RV stimulation. Although this method can already be directly applied, validation by 3D electrical mapping and prospective correlation to cardiac resynchronization therapy (CRT) response will be required for further translation into clinical practice.

Use of the wearable cardioverter-defibrillator (WCD) and WCD-based remote rhythm monitoring in a real-life patient cohort.

The wearable cardioverter-defibrillator (WCD) was introduced to provide protection from sudden cardiac death (SCD) in patients with transiently elevated risk or during ongoing risk stratification. Benefits and clinical characteristics of routine WCD use remain to be assessed in larger patient populations. This study aims to identify determinants of WCD compliance, therapies, and inappropriate alarms in a real-life cohort. A total of 106 cases (68.9% male) were included between 11/2010 and 04/2016. WCD therapies, automatically recorded arrhythmia episodes, inappropriate WCD alarms, patient compliance, and outcome after WCD prescription were analyzed. Median duration of WCD use was 58.5 days. Average daily wearing time was 22.7 h. Compliance was reduced in patients ≤ 50 years. Three patients received WCD therapies (2.8%). In one case ventricular fibrillation (VF) was appropriately terminated with the first shock. Two patients received inappropriate WCD therapies due to WCD algorithm activation during ventricular pacemaker stimulation. One patient died of asystole while carrying a WCD (0.9%). Additional arrhythmias detected comprised self-terminating sustained ventricular tachycardia (VT; 2.8%), non-sustained VT (2.8%), and supraventricular arrhythmias (5.7%). Inappropriate WCD alarms due to over-/undersensing occurred in 77/106 patients (72.6%), of which 41 (38.7%) experienced ≥ 10 inappropriate WCD alarms during the prescription period. Thirteen patients (12.3%) displayed a mean of > 1 inappropriate alarms/day. WCD use was associated with high compliance and provided protection from VT/VF-related SCD. The majority of patients experienced inappropriate WCD alarms. Alterations in QRS morphology during pacemaker stimulation require consideration in WCD programming to prevent inappropriate alarms.

Fully digital data processing during cardiovascular implantable electronic device follow-up in a high-volume tertiary center.

BACKGROUND: Increasing numbers of patients with cardiovascular implantable electronic devices (CIEDs) and limited follow-up capacities highlight unmet challenges in clinical electrophysiology. Integrated software (MediConnect®) enabling fully digital processing of device interrogation data has been commercially developed to facilitate follow-up visits. We sought to assess feasibility of fully digital data processing (FDDP) during ambulatory device follow-up in a high-volume tertiary hospital to provide guidance for future users of FDDP software. METHODS: A total of 391 patients (mean age, 70 years) presenting to the outpatient department for routine device follow-up were analyzed (pacemaker, 44%; implantable cardioverter defibrillator, 39%; cardiac resynchronization therapy device, 16%). RESULTS: Quality of data transfer and follow-up duration were compared between digital (n = 265) and manual processing of device data (n = 126). Digital data import was successful, complete and correct in 82% of cases when early software versions were used. When using the most recent software version the rate of successful digital data import increased to 100%. Software-based import of interrogation data was complete and without failure in 97% of cases. The mean duration of a follow-up visit did not differ between the two groups (digital 18.7 min vs. manual data transfer 18.2 min). CONCLUSIONS: FDDP software was successfully implemented into the ambulatory follow-up of patients with implanted pacemakers and defibrillators. Digital data import into electronic patient management software was feasible and supported the physician's workflow. The total duration of follow-up visits comprising technical device interrogation and clinical actions was not affected in the present tertiary center outpatient cohort.

Inhibition of inwardly rectifying Kir2.x channels by the novel anti-cancer agent gambogic acid depends on both pore block and PIP2 interference.

The caged xanthone gambogic acid (GA) is a novel anti-cancer agent which exhibits anti-proliferative, anti-inflammatory and cytotoxic effects in many types of cancer tissues. In a recent phase IIa study, GA exhibits a favourable safety profile. However, limited data are available concerning its interaction with cardiac ion channels. Heteromeric assembly of Kir2.x channels underlies the cardiac inwardly rectifying IK1 current which is responsible for the stabilization of the diastolic resting membrane potential. Inhibition of the cardiac IK1 current may lead to ventricular arrhythmia due to delayed afterdepolarizations. Compared to Kv2.1, hERG and Kir1.1, a slow, delayed inhibition of Kir2.1 channels by GA in a mammalian cell line was reported before but no data exist in literature concerning action of GA on homomeric Kir2.2 and Kir2.3 and heteromeric Kir2.x channels. Therefore, the aim of this study was to provide comparative data on the effect of GA on homomeric and heteromeric Kir2.x channels. Homomeric and heteromeric Kir2.x channels were heterologously expressed in Xenopus oocytes, and the two-microelectrode voltage-clamp technique was used to record Kir2.x currents. To investigate the mechanism of the channel inhibition by GA, alanine-mutated Kir2.x channels with modifications in the channels pore region or at phosphatidylinositol 4,5-bisphosphate (PIP2)-binding sites were employed. GA caused a slow inhibition of homomeric and heteromeric Kir2.x channels at low micromolar concentrations (with IC50 Kir2.1/2.2 < Kir2.2 < Kir2.2/2.3 < Kir2.3 < Kir2.1 < Kir2.1/2.3). The effect did not reach saturation within 60 min and was not reversible upon washout for 30 min. The inhibition showed no strong voltage dependence. We provide evidence for a combination of direct channel pore blockade and a PIP2-dependent mechanism as a molecular basis for the observed effect. We conclude that Kir2.x channel inhibition by GA may be relevant in patients with pre-existing cardiac disorders such as chronic heart failure or certain rhythm disorders and recommend a close cardiac monitoring for those patients when treated with GA.

Role of plasma membrane-associated AKAPs for the regulation of cardiac IK1 current by protein kinase A.

The cardiac IK1 current stabilizes the resting membrane potential of cardiomyocytes. Protein kinase A (PKA) induces an inhibition of IK1 current which strongly promotes focal arrhythmogenesis. The molecular mechanisms underlying this regulation have only partially been elucidated yet. Furthermore, the role of A-kinase anchoring proteins (AKAPs) in this regulation has not been examined to date. The objective of this project was to elucidate the molecular mechanisms underlying the inhibition of IK1 by PKA and to identify novel molecular targets for antiarrhythmic therapy downstream ß-adrenoreceptors. Patch clamp and voltage clamp experiments were used to record currents and co-immunoprecipitation, and co-localization experiments were performed to show spatial and functional coupling. Activation of PKA inhibited IK1 current in rat cardiomyocytes. This regulation was markedly attenuated by disrupting PKA-binding to AKAPs with the peptide inhibitor AKAP-IS. We observed functional and spatial coupling of the plasma membrane-associated AKAP15 and AKAP79 to Kir2.1 and Kir2.2 channel subunits, but not to Kir2.3 channels. In contrast, AKAPyotiao had no functional effect on the PKA regulation of Kir channels. AKAP15 and AKAP79 co-immunoprecipitated with and co-localized to Kir2.1 and Kir2.2 channel subunits in ventricular cardiomyocytes. In this study, we provide evidence for coupling of cardiac Kir2.1 and Kir2.2 subunits with the plasma membrane-bound AKAPs 15 and 79. Cardiac membrane-associated AKAPs are a functionally essential part of the regulatory cascade determining IK1 current function and may be novel molecular targets for antiarrhythmic therapy downstream from ß-adrenoreceptors.

Novel algorithm for accelerated electroanatomic mapping and prediction of earliest activation of focal cardiac arrhythmias using mathematical optimization.

BACKGROUND: Premature beats (PBs) are a common finding in patients suffering from structural heart disease, but they can also be present in healthy individuals. Catheter ablation represents a suitable therapeutic approach. However, the exact localization of the origin can be challenging, especially in cases of low PB burden during the procedure. OBJECTIVE: The aim of this study was to develop an automated mapping algorithm on the basis of the hypothesis that mathematical optimization would significantly accelerate the localization of earliest activation. METHODS: The algorithm is based on iterative regression analyses. When acquiring local activation times (LATs) within a 3-dimensional anatomic map of the corresponding heart chamber, this algorithm is able to identify that exact position where a next LAT measurement adds maximum information about the predicted site of origin. Furthermore, on the basis of the acquired LAT measurements, the algorithm is able to predict earliest activation with high accuracy. RESULTS: A systematic retrospective analysis of the mapping performance comparing the operator with simulated search processes by the algorithm within 17 electroanatomic maps of focal spreading arrhythmias revealed a highly significant reduction of necessary LAT measurements from 55 ± 8.8 to 10 ± 0.51 (n = 17; P < .0001). CONCLUSION: On the basis of mathematical optimization, we developed an algorithm that is able to reduce the number of LAT measurements necessary to locate the site of earliest activation. This algorithm might significantly accelerate the mapping procedure by guiding the operator to the optimal position for the next LAT measurement. Furthermore, the algorithm would be able to predict the site of origin with high accuracy early during the mapping procedure.