Search

Aims Atrial fibrillation (AF) after heart transplantation (HTX) is associated with worse clinical outcomes. The current study aimed to analyse the association between AF before HTX and AF within 30 days after HTX. Methods and results This study included 639 adults who received HTX at Heidelberg Heart Center. Patients were subdivided into four groups depending on the status of AF before and after HTX. Analyses comprised recipient and donor data, medication, echocardiographic features, permanent pacemaker implantation, stroke, and mortality after HTX. Three hundred thirty‐two patients (52.0%) had neither AF before nor after HTX, 15 patients (2.3%) had no AF before HTX but showed AF after HTX, 219 patients (34.3%) showed AF before HTX but had no AF after HTX, and 73 patients (11.4%) had AF before and after HTX. Patients with AF before and after HTX had a higher 1 year post‐transplant mortality (39.7%) than patients without AF before or after HTX (18.1%, P

Aims Right bundle branch block (RBBB) after heart transplantation (HTX) is a common finding, but its impact on post‐transplant survival remains uncertain. This study investigated the post‐transplant outcomes of patients with complete RBBB (cRBBB) ≤ 30 days after HTX. Methods This registry study analysed 639 patients receiving HTX at Heidelberg Heart Center between 1989 and 2019. Patients were stratified by diagnosis of cRBBB ≤ 30 days after HTX. Analysis included recipient and donor data, medication, echocardiographic features, graft rejections, atrial fibrillation, heart rates, permanent pacemaker implantation and mortality after HTX including causes of death. Results One hundred thirty‐nine patients showed cRBBB ≤ 30 days after HTX (21.8%), 20 patients with pre‐existing cRBBB in the donor heart (3.2%) and 119 patients with newly acquired cRBBB (18.6%). Patients with newly acquired cRBBB had a worse 1‐year post‐transplant survival (36.1%, P

Background Non-paroxysmal (NPAF) forms of atrial fibrillation (AF) have been reported to be associated with an increased risk for systemic embolism or death. Methods Comparison of procedural details and long-term outcomes in patients (pts) with paroxysmal AF (PAF) against controls with NPAF in the prospective, multicentre observational registry of patients undergoing LAAC (LAARGE). Results A total of 638 pts (PAF 274 pts, NPAF 364 pts) were enrolled. In both groups, a history of PVI was rare (4.0% vs 1.6%, p = 0.066). The total CHA2DS2-VASc score was lower in the PAF group (4.4 ± 1.5 vs 4.6 ± 1.5, p = 0.033), while HAS-BLED score (3.8 ± 1.1 vs 3.9 ± 1.1, p = 0.40) was comparable. The rate of successful implantation was equally high (97.4% vs 97.8%, p = 0.77). In the three-month echo follow-up, LA thrombi (2.1% vs 7.3%, p = 0.12) and peridevice leak > 5 mm (0.0% vs 7.1%, p = 0.53) were numerically higher in the NPAF group. Overall, in-hospital complications occurred in 15.0% of the PAF cohort and 10.7% of the NPAF cohort (p = 0.12). In the one-year follow-up, unadjusted mortality (8.4% vs 14.0%, p = 0.039) and combined outcome of death, stroke and systemic embolism (8.8% vs 15.1%, p = 0.022) were significantly higher in the NPAF cohort. After adjusting for CHA2DS2-VASc and previous bleeding, NPAF was associated with increased death/stroke/systemic embolism (HR 1.67, 95% CI 1.02–2.72, p = 0.041). Conclusion Atrial fibrillation type did not impair periprocedural safety or in-hospital MACE patients undergoing LAAC. However, after one year, NPAF was associated with higher mortality. Graphic abstract

Ann-Kathrin Rahm,1– 3 Dominik Gramlich,1– 3 Teresa Wieder,1,2 Mara Elena Müller,1– 3 Axel Schoeffel,1,2 Fadwa A El Tahry,1 Patrick Most,1,2 Tanja Heimberger,1,3 Steffi Sandke,1,3 Tanja Weis,1,3 Nina D Ullrich,4 Thomas Korff,4,5 Patrick Lugenbiel,1– 3 Hugo A Katus,1– 3 Dierk Thomas1– 3 1Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, 69120, Germany; 2HCR (Heidelberg Center for Heart Rhythm Disorders), University Hospital Heidelberg, Heidelberg, 69120, Germany; 3DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, 69120, Germany; 4Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, Heidelberg, 69120, Germany; 5European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, GermanyCorrespondence: Dierk ThomasDepartment of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg, 69120, GermanyTel +49 6221 568855Fax +49 6221 565514Email dierk.thomas@med.uni-heidelberg.deAim: Effective antiarrhythmic treatment of atrial fibrillation (AF) constitutes a major challenge, in particular, when concomitant heart failure (HF) is present. HF-associated atrial arrhythmogenesis is distinctly characterized by prolonged atrial refractoriness. Small-conductance, calcium-activated K+ (KCa, SK, KCNN) channels contribute to cardiac action potential repolarization and are implicated in AF susceptibility and therapy. The mechanistic impact of AF/HF-related triggers on atrial KCa channels is not known. We hypothesized that tachycardia, stretch, β-adrenergic stimulation, and hypoxia differentially determine KCa 2.1– 2.3 channel remodeling in atrial cells.Methods: KCNN1-3 transcript levels were assessed in AF/HF patients and in a pig model of atrial tachypacing-induced AF with reduced left ventricular function. HL-1 atrial myocytes were subjected to proarrhythmic triggers to investigate the effects on Kcnn mRNA and KCa channel protein.Results: Atrial KCNN1-3 expression was reduced in AF/HF patients. KCNN2 and KCNN3 suppression was recapitulated in the corresponding pig model. In contrast to human AF, KCNN1 remained unchanged in pigs. Channel- and stressor-specific remodeling was revealed in vitro. Lower expression levels of KCNN1/KCa 2.1 were linked to stretch and β-adrenergic stimulation. Furthermore, KCNN3/KCa 2.3 expression was suppressed upon tachypacing and hypoxia. Finally, KCNN2/KCa 2.2 abundance was specifically enhanced by hypoxia.Conclusion: Reduction of KCa 2.1– 2.3 channel expression might contribute to the action potential prolongation in AF complicated by HF. Subtype-specific KCa 2 channel remodeling induced by tachypacing, stretch, β-adrenergic stimulation, or hypoxia is expected to differentially determine atrial remodeling, depending on patient-specific activation of each triggering factor. Stressor-dependent KCa 2 regulation in atrial myocytes provides a starting point for mechanism-based antiarrhythmic therapy.Keywords: atrial fibrillation, calcium, KCa channel, KCNN, remodeling, SK channel

Background The early recognition of paroxysmal atrial fibrillation (pAF) is a major clinical challenge for preventing thromboembolic events. In this prospective and multicentric study we evaluated prediction scores for the presence of pAF, calculated from non-invasive medical history and echocardiographic parameters, in patients with unknown AF status. Methods The 12-parameter score with parameters age, LA diameter, aortic root diameter, LV,ESD, TDI Aʹ, heart frequency, sleep apnea, hyperlipidemia, type II diabetes, smoker, ß-blocker, catheter ablation, and the 4-parameter score with parameters age, LA diameter, aortic root diameter and TDI A’ were tested. Presence of pAF was verified by continuous electrocardiogram (ECG) monitoring for up to 21 days in 305 patients. Results The 12-parameter score correctly predicted pAF in all 34 patients, in which pAF was newly detected by ECG monitoring. The 12- and 4-parameter scores showed sensitivities of 100% and 82% (95%-CI 65%, 93%), specificities of 75% (95%-CI 70%, 80%) and 67% (95%-CI 61%, 73%), and areas under the receiver operating characteristic (ROC) curves of 0.84 (95%-CI 0.80, 0.88) and 0.81 (95%-CI 0.74, 0.87). Furthermore, properties of AF episodes and durations of ECG monitoring necessary to detect pAF were analysed. Conclusions The prediction scores adequately detected pAF using variables readily available during routine cardiac assessment and echocardiography. The model scores, denoted as ECHO-AF scores, represent simple, highly sensitive and non-invasive tools for detecting pAF that can be easily implemented in the clinical practice and might serve as screening test to initiate further diagnostic investigations for validating the presence of pAF. Graphic abstract Prospective validation of a novel prediction model for paroxysmal atrial fibrillation based on echocardiography and medical history parameters by long-term Holter ECG

Background Pulmonary vein isolation is an established strategy for catheter ablation of atrial fibrillation (AF). However, in a significant number of patients, a repeat procedure is mandatory due to arrhythmia recurrence. In this study, we report safety data and procedural details of patients undergoing index ablation versus repeat ablation in a registry-based real-life setting. Methods Patients from the German Ablation Registry, a prospective, multicentre registry of patients undergoing ablation between January 2007 and January 2010 were included. Results A total of 4155 patients were enrolled in the study. Group I (index ablation) consisted of 3377/4155 (82.1%) and group II (repeat ablation) of 738/4155 (17.9%). Patients in group I had a significantly higher ratio of paroxysmal AF (69.3% vs 61.9%, p p p p 2 vs 3325 cGy × cm2, p = 0.001), and shorter study duration (181.2 min. vs 163.6 min., p p = 0.39), MACE (0.4% vs 0.3%, p = 0.58), MACCE (0.8% vs 0.6%, p = 0.47), composite safety endpoint (1.5% vs 1.4%, p = 0.76), and arrhythmia recurrence (43.8% vs 41.9%, p = 0.37) during 1-year follow-up. Both groups reported to have improved or no symptoms (80.4% vs 77.8%, p = 0.13). Conclusion Repeat catheter ablation is safe and provides a symptomatic relief comparable to index ablation. Repeat procedures are significantly shorter and use less fluoroscopy.

Aims Amiodarone and digitalis are frequently used drugs in patients with heart failure. Both have separately been linked to reduced post‐transplant survival, but their combined impact on mortality after HTX remains uncertain. This study investigated the effects of combined amiodarone and digitalis use before HTX on post‐transplant outcomes. Methods and results This registry study analysed 600 patients receiving HTX at Heidelberg Heart Center between 1989 and 2016. Patients were stratified by amiodarone and digitalis use before HTX. Analysis included patient characteristics, medication, echocardiographic features, heart rates, permanent pacemaker implantation, atrial fibrillation, and post‐transplant survival including causes of death. One hundred eighteen patients received amiodarone before HTX (19.7%), hereof 67 patients with digitalis (56.8%) and 51 patients without digitalis before HTX (43.2%). Patients with and without amiodarone before HTX showed a similar 1 year post‐transplant survival (72.0% vs. 78.4%, P = 0.11), but patients with combined amiodarone and digitalis before HTX had a worse 1 year post‐transplant survival (64.2%, P = 0.01), along with a higher percentage of death due to transplant failure (P = 0.03). Echocardiographic analysis of these patients showed a higher percentage of an enlarged right ventricle (P = 0.02), left atrium (P = 0.02), left ventricle (P = 0.03), and a higher rate of reduced left ventricular ejection fraction (P = 0.03). Multivariate analysis indicated combined amiodarone and digitalis use before HTX as a significant risk factor for 1 year mortality after HTX (hazard ratio: 1.69; 95% confidence interval: 1.02–2.77; P = 0.04). Conclusions Combined pre‐transplant amiodarone and digitalis therapy is associated with increased post‐transplant mortality.

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 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. Graphic abstract

Graphic abstract

Aims Severely elevated pre‐transplant pulmonary vascular resistance (PVR) has been linked to adverse effects after heart transplantation (HTX). The impact of a moderately increased PVR before HTX on post‐transplant outcomes remains uncertain. The aim of this study was to investigate the effects of an elevated pre‐transplant PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units) on outcomes after HTX. Methods and results This observational retrospective single‐centre study included 561 patients receiving HTX at Heidelberg Heart Center between 1989 and 2015. Patients were stratified by degree of pre‐transplant PVR. Analyses covered demographics, post‐transplant medication, mortality and causes of death after HTX, early post‐transplant atrial fibrillation (AF), and length of the initial hospital stay after HTX. Ninety‐four patients (16.8%) had a PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units). These patients had a higher rate of early post‐transplant AF [20.2 vs. 10.7%, difference: 9.5%, 95% confidence interval (CI): 0.9–18.1%, P = 0.01] and an increased 30 day post‐transplant mortality (25.5 vs. 6.4%, hazard ratio: 4.4, 95% CI: 2.6–7.6, P < 0.01), along with a higher percentage of death due to transplant failure (21.2 vs. 4.1%, difference: 17.1%, 95% CI: 8.7–25.5%, P < 0.01). Multivariate analysis revealed a PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units) as a significant risk factor for increased 30 day mortality after HTX (hazard ratio: 4.4, 95% CI: 2.5–7.6, P < 0.01). Kaplan–Meier estimator showed a lower 2 year survival after HTX (P < 0.01) in patients with a PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units). Conclusions Elevated pre‐transplant PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units) is associated with early post‐transplant AF and increased mortality after HTX.

In atrioventricular nodal reentrant tachycardia (AVNRT), catheter ablation is considered as first-line therapy. Despite high success rates, some patients present with arrhythmia recurrence or develop other types of arrhythmias over time. To assess the incidence of symptomatic arrhythmias after initially successful AVNRT ablation and to analyze their clinical implications in a real-world cohort. We included 2,795 patients from the German Ablation Registry undergoing first ablation of AVNRT between 01/2007 and 01/2010. In patients alive at long-term follow-up, patient-specific characteristics and long-term follow-up data were compared between patients with (group A) and without (group B) any symptomatic arrhythmia during follow-up. Symptomatic arrhythmias occurred in 17.2% of patients during a mean follow-up of 678 days after AVNRT ablation. The patients with symptomatic arrhythmias were more often female and suffered from structural heart disease. Arrhythmia occurrence was clinically relevant regarding symptoms and patient satisfaction. Serious adverse events including stroke, transient ischemic attack, pacemaker implantation, as well as continued use of antiarrhythmic medication occurred more often in group A. A second ablation procedure was performed in 26% of symptomatic patients to optimize the symptomatic outcome, whereas cardiovascular events or patient satisfaction were not further improved. During long-term follow-up, one out of six patients experienced symptomatic arrhythmias after AVNRT ablation, associated with an increase of serious adverse events. A subset of patients required medical or interventional antiarrhythmic therapy, possibly attributable to the co-existence of other arrhythmias. Screening for arrhythmic and cardiac co-morbidity before and after ablation may support comprehensive therapy planning and outcome.

Atrial fibrillation (AF) is the most frequent sustained arrhythmia and can lead to structural cardiac changes, known as tachycardia-induced cardiomyopathy (TIC). HCN4 is implicated in spontaneous excitation of the sinoatrial node, while channel dysfunction has been associated with sinus bradycardia, AF and structural heart disease. We here asked whether HCN4 mutations may contribute to the development of TIC, as well. Mutation scanning of HCN4 in 60 independent patients with AF and suspected TIC followed by panel sequencing in carriers of HCN4 variants identified the HCN4 variant P883R [minor allele frequency (MAF): 0,88%], together with the KCNE1 variant S38G (MAF: 65%) in three unrelated patients. Family histories revealed additional cases of AF, sudden cardiac death and cardiomyopathy. Patch-clamp recordings of HCN4-P883R channels expressed in HEK293 cells showed remarkable alterations of channel properties shifting the half-maximal activation voltage to more depolarized potentials, while channel deactivation was faster compared to wild-type (WT). Co-transfection of WT and mutant subunits, resembling the heterozygous cellular situation of our patients, revealed significantly higher current densities compared to WT. In conclusion HCN4-P883R may increase ectopic trigger and maintenance of AF by shifting the activation voltage of If to more positive potentials and producing higher current density. Together with the common KCNE1 variant S38G, previously proposed as a genetic modifier of AF, HCN4-P883R may provide a substrate for the development of AF and TIC.

Cardiac two-pore-domain potassium (K2P) channels have been proposed as novel antiarrhythmic targets. K2P13.1 (THIK-1) channels are expressed in the human heart, and atrial K2P13.1 levels are reduced in patients with atrial fibrillation (AF) or heart failure. The first objective of this study was to investigate acute effects of antiarrhythmic drugs on human K2P13.1 currents. Second, we assessed atrial K2P13.1 remodeling in AF pigs to validate the porcine model for future translational evaluation of K2P13.1-based antiarrhythmic concepts. K2P13.1 protein expression was studied in domestic pigs during AF induced by atrial burst pacing. AF was associated with 66% reduction of K2P13.1 levels in the right atrium at 21-day follow-up. Voltage clamp electrophysiology was employed to elucidate human K2P13.1 channel pharmacology in Xenopus oocytes. Propafenone (−26%; 100 μM), mexiletine (−75%; 1.5 mM), propranolol (−38%; 200 μM), and lidocaine (−59%; 100 μM) significantly inhibited K2P13.1 currents. By contrast, K2P13.1 channels were not markedly affected by quinidine, carvedilol, metoprolol, amiodarone and verapamil. Concentration-dependent K2P13.1 blockade by mexiletine occurred rapidly with membrane depolarization and was frequency-independent. Mexiletine reduced K2P13.1 open rectification properties and shifted current-voltage relationships towards more negative potentials. In conclusion, atrial expression and AF-associated downregulation of K2P13.1 channels in a porcine model resemble human findings and support a general role for K2P13.1 in AF pathophysiology. K2P13.1 current sensitivity to antiarrhythmic drugs provides a starting point for further development of an emerging antiarrhythmic paradigm.

HCN channels underlie the depolarizing funny current (If) that contributes importantly to cardiac pacemaking. If is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice (HCN4tg/wt) to assess functional consequences of HCN4 overexpression-mediated If increase in cardiomyocytes to levels observed in human heart failure. HCN4tg/wt animals exhibit a dilated cardiomyopathy phenotype with increased cellular arrhythmogenicity but unchanged heart rate and conduction parameters. If augmentation induces a diastolic Na+ influx shifting the Na+/Ca2+ exchanger equilibrium towards ‘reverse mode’ leading to increased [Ca2+]i. Changed Ca2+ homeostasis results in significantly higher systolic [Ca2+]i transients and stimulates apoptosis. Pharmacological inhibition of If prevents the rise of [Ca2+]i and protects from ventricular remodeling. Here we report that augmented myocardial If alters intracellular Ca2+ homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial If per se may constitute a therapeutic mechanism to prevent cardiomyopathy., The depolarizing funny current contributing to cardiac pacemaking is upregulated in the myocardium of failing and infarcted hearts, but whether the current is implied in disease mechanisms is unclear. Here the authors generate HCN4 transgenic mice and show that upregulation of funny current to the levels observed in human heart failure alters calcium homeostasis leading to cardiac remodelling and arrhythmia.

Aims Heart failure (HF) is linked to electrical remodeling that promotes ventricular arrhythmias. Underlying molecular signaling is insufficiently understood, in particular concerning patients with early disease stages. Previous observations suggest a key role for epigenetic mechanisms in cardiac remodeling processes. We hypothesized that histone deacetylases (HDACs) 1 and 2 contribute to cellular electrophysiological dysregulation in ventricular cardiomyocytes during HF development. Materials and methods HDAC and ion channel expression was quantified in a porcine model of early HF induced by short-term atrial tachypacing, resulting in atrial fibrillation with rapid ventricular rate response. Anti-Hdac1 and anti-Hdac2 siRNA treatment was employed in neonatal murine cardiomyocytes (NMCM) to study effects of HDACs on ion channel mRNA expression and action potential duration (APD). Key findings Early HF was characterized by mild reduction of left ventricular ejection fraction, prolonged QTc intervals, and increased ventricular effective refractory periods. Delayed repolarization was linked to significant downregulation of HDAC2 in left ventricular (LV) tissue. In addition, there was a tendency towards reduced transcript expression of KCNJ2/Kir2.1 K+ channels. In NMCM, knock-down of Hdac2 recapitulated AP prolongation. Finally, siRNA-mediated suppression of Hdac2 reduced Kcnh2/Kv11.1 K+ channel expression. Significance Suppression of HDAC2 is linked to ventricular electrical remodeling of APD and ion channel expression in early stages of heart failure. This previously unrecognized mechanism may serve as basis for future approaches to prevention and treatment of ventricular arrhythmias.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Stiftung für Herzinfarkforschung Background Non-paroxysmal (NPAF) forms of atrial fibrillation (AF) have been reported to be associated with an increased risk for systemic embolism or death compared with paroxysmal AF (PAF). This study investigates the procedural safety and long-term outcomes of left atrial appendage closure (LAAC) in patients with different forms of AF. Methods Comparison of procedural details and long-term outcomes in patients (pts) with PAF against controls with NPAF in the prospective, multicentre observational registry of patients undergoing LAAC in Germany (LAARGE). Results A total of 638 pts (PAF 274 pts, NPAF 364 pts) were enrolled. NPAF consisted of 31.6% patients with persistent AF and 68.4% with longstanding persistent AF or permanent AF. In both groups, a history of PVI was rare (4.0% vs 1.6%, p = 0.066). The PAF group had significantly less history of heart failure (19.0% vs 33.0%, p 5 mm (0.0% vs 7.1%, p= 0.53) were numerically higher in the NPAF group. Overall, in-hospital complications occurred in 15.0% of the PAF cohort and 10.7% of the NPAF cohort (p = 0.12). In the one-year follow-up, unadjusted mortality (8.4% vs 14.0%, p = 0.039) and combined outcome of death, stroke and systemic embolism (8.8% vs 15.1%, p = 0.022) were significantly higher in the NPAF cohort. After adjusting for CHA2DS2-VASc and previous bleeding, NPAF was associated with increased death/stroke/systemic embolism (HR 1.67, 95%-CI: 1.02-2.72). Conclusion Atrial fibrillation type did not impair periprocedural safety or in-hospital MACE of patients undergoing LAAC. However, after one year, NPAF was associated with higher mortality and combined outcome of death, stroke and systemic embolism.

CA extern - Weitere Nicht-UDE-Autoren sind nicht genannt. Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007. © 2020 Hellenic Society of Cardiology

Background: Cardiac manifestation of COVID-19 has been reported during the COVID pandemic. The role of cardiac arrhythmias in COVID-19 is insufficiently understood. This study assesses the incidence of cardiac arrhythmias and their prognostic implications in hospitalized COVID-19-patients. Methods: A total of 166 patients from eight centers who were hospitalized for COVID-19 from 03/2020&ndash, 06/2020 were included. Medical records were systematically analyzed for baseline characteristics, biomarkers, cardiac arrhythmias and clinical outcome parameters related to the index hospitalization. Predisposing risk factors for arrhythmias were identified. Furthermore, the influence of arrhythmia on the course of disease and related outcomes was assessed using univariate and multiple regression analyses. Results: Arrhythmias were detected in 20.5% of patients. Atrial fibrillation was the most common arrhythmia. Age and cardiovascular disease were predictors for new-onset arrhythmia. Arrhythmia was associated with a pronounced increase in cardiac biomarkers, prolonged hospitalization, and admission to intensive- or intermediate-care-units, mechanical ventilation and in-hospital mortality. In multiple regression analyses, incident arrhythmia was strongly associated with duration of hospitalization and mechanical ventilation. Cardiovascular disease was associated with increased mortality. Conclusions: Arrhythmia was the most common cardiac event in association with hospitalization for COVID-19. Older age and cardiovascular disease predisposed for arrhythmia during hospitalization. Whereas in-hospital mortality is affected by underlying cardiovascular conditions, arrhythmia during hospitalization for COVID-19 is independently associated with prolonged hospitalization and mechanical ventilation. Thus, incident arrhythmia may indicate a patient subgroup at risk for a severe course of disease.

Background: Hypertension (HTN) constitutes a risk factor for the development of atrial fibrillation (AF), as well as for thromboembolic and bleeding events. We analysed the outcome after catheter ablation of AF in HTN in a cohort from the prospective multicenter German Ablation Registry. Methods: Between 03/2008 and 01/2010, 626 patients undergoing AF-ablation were analysed. Patients diagnosed with HTN (n = 386) were compared with patients without HTN (n = 240) with respect to baseline, procedural and long-term outcome parameters. Results: Patients with HTN were older and more often presented with persistent forms of AF and cardiac comorbidities. Major and moderate in-hospital complications were low. At long-term follow-up, major cardiovascular events were rare in both groups. Rates of AF-recurrence, freedom from antiarrhythmic medication and repeat ablation were not statistically different between groups. Most patients reported improvement of symptoms and satisfaction with the treatment. However, patients with HTN more frequently complained of dyspnea of New York Heart Association (NYHA) class &ge, II and angina. They were more often rehospitalized, particularly when persistent AF had been diagnosed. Conclusion: Catheter ablation of AF is associated with low complication rates and favorable arrhythmia-related results in patients with HTN. Residual clinical symptoms may be due to cardiac comorbidities and require additional attention in this important subgroup of AF-patients.

Background The tandem of P domains in a weak inward rectifying K+ channel (TWIK)‐related acid‐sensitive K + channel (TASK‐1; hK 2P 3.1) two‐pore–domain potassium channel was recently shown to regulate the atrial action potential duration. In the human heart, TASK ‐1 channels are specifically expressed in the atria. Furthermore, upregulation of atrial TASK ‐1 currents was described in patients suffering from atrial fibrillation ( AF ). We therefore hypothesized that TASK ‐1 channels represent an ideal target for antiarrhythmic therapy of AF . In the present study, we tested the antiarrhythmic effects of the high‐affinity TASK ‐1 inhibitor A293 on cardioversion in a porcine model of paroxysmal AF . Methods and Results Heterologously expressed human and porcine TASK ‐1 channels are blocked by A293 to a similar extent. Patch clamp measurements from isolated human and porcine atrial cardiomyocytes showed comparable TASK ‐1 currents. Computational modeling was used to investigate the conditions under which A293 would be antiarrhythmic. German landrace pigs underwent electrophysiological studies under general anesthesia. Paroxysmal AF was induced by right atrial burst stimulation. After induction of AF episodes, intravenous administration of A293 restored sinus rhythm within cardioversion times of 177±63 seconds. Intravenous administration of A293 resulted in significant prolongation of the atrial effective refractory period, measured at cycle lengths of 300, 400 and 500 ms, whereas the surface ECG parameters and the ventricular effective refractory period lengths remained unchanged. Conclusions Pharmacological inhibition of atrial TASK ‐1 currents exerts antiarrhythmic effects in vivo as well as in silico , resulting in acute cardioversion of paroxysmal AF . Taken together, these experiments indicate the therapeutic potential of A293 for AF treatment.

Cardiac arrhythmias remain a common challenge and are associated with significant morbidity and mortality. Effective and safe rhythm control strategies are a primary, yet unmet need in everyday clinical practice. Despite significant pharmacological and technological advances, including catheter ablation and device-based therapies, the development of more effective alternatives is of significant interest to increase quality of life and to reduce symptom burden, hospitalizations and mortality. The mechanistic understanding of pathophysiological pathways underlying cardiac arrhythmias has advanced profoundly, opening up novel avenues for mechanism-based therapeutic approaches. Current management of arrhythmias, however, is primarily guided by clinical and demographic characteristics of patient groups as opposed to individual, patient-specific mechanisms and pheno-/genotyping. With this state-of-the-art paper, the Working Group on Cellular Electrophysiology of the German Cardiac Society aims to close the gap between advanced molecular understanding and clinical decision-making in cardiac electrophysiology. The significance of cellular electrophysiological findings for clinical arrhythmia management constitutes the main focus of this document. Clinically relevant knowledge of pathophysiological pathways of arrhythmias and cellular mechanisms of antiarrhythmic interventions are summarized. Furthermore, the specific molecular background for the initiation and perpetuation of atrial and ventricular arrhythmias and mechanism-based strategies for therapeutic interventions are highlighted. Current "hot topics" in atrial fibrillation are critically appraised. Finally, the establishment and support of cellular and translational electrophysiology programs in clinical rhythmology departments is called for to improve basic-science-guided patient management.

Robotic (RNS) or magnetic navigation systems (MNS) are available for remotely performed catheter ablation for atrial fibrillation (AF). The present study compares remotely assisted catheter navigation (RAN) to standard manual navigation (SMN) and both systems amongst each other. The analysis is based on a sub-cohort enrolled by five hospitals from the multicenter German ablation Registry. Out of 2442 patients receiving catheter ablation of AF, 267 (age 61.4 ± 10.4, 69.7% male) were treated using RAN (RNS n = 187, 7.7% vs. MNS n = 80, 3.3%). Fluoroscopy time [RNS median 17 (IQR 12–25) min vs. MNS 22 (16–32) min; p

Ventricular arrhythmias contribute significantly to morbidity and mortality in patients with heart failure (HF). Pathomechanisms underlying arrhythmogenicity in patients with structural heart disease and impaired cardiac function include myocardial fibrosis and the remodeling of ion channels, affecting electrophysiologic properties of ventricular cardiomyocytes. The dysregulation of ion channel expression has been associated with cardiomyopathy and with the development of arrhythmias. However, the underlying molecular signaling pathways are increasingly recognized. This review summarizes clinical and cellular electrophysiologic characteristics observed in dilated cardiomyopathy (DCM) with ionic and structural alterations at the ventricular level. Furthermore, potential translational strategies and therapeutic options are highlighted.

Patients after heart transplantation (HTX) present with sinus tachycardia due to graft denervation. As elevated heart rates negatively affect survival, the aim of this study was to analyze the effects of ivabradine vs metoprolol succinate on heart rate, left ventricular (LV) mass and survival following HTX. This observational retrospective single-center study assessed 84 patients continuously receiving either ivabradine (n = 40) or metoprolol succinate (n = 44) within 2 years after HTX. Patients with dual therapy (ivabradine and metoprolol succinate), other beta blockers, amiodarone, or digitalis were excluded. Patient characteristics, post-transplant medication, heart rates, LV mass, and survival were investigated. Analysis of patient characteristics, immunosuppressive drug regimen, and post-transplant medication showed no significant differences between groups except for ivabradine and metoprolol succinate. Baseline heart rates differed not significantly between patients treated with ivabradine [87.0 beats per minute (bpm)] and metoprolol succinate (86.2 bpm; P = 0.6395). At 2-year follow-up, patients with ivabradine (76.7 bpm) had a significantly lower heart rate compared to baseline (P

Two-pore-domain potassium (K 2P ) channels modulate cellular excitability. The significance of stretch-activated cardiac K 2P channels (K 2P 2.1, TREK-1, KCNK 2; K 2P 4.1, TRAAK, KCNK 4; K 2P 10.1, TREK-2, KCNK 10) in heart disease has not been elucidated in detail. The aim of this work was to assess expression and remodeling of mechanosensitive K 2P channels in atrial fibrillation (AF) and heart failure (HF) patients in comparison to murine models. Cardiac K 2P channel levels were quantified in atrial (A) and ventricular (V) tissue obtained from patients undergoing open heart surgery. In addition, control mice and mouse models of AF (cAMP-response element modulator (CREM)-IbΔC-X transgenic animals) or HF (cardiac dysfunction induced by transverse aortic constriction, TAC) were employed. Human and murine KCNK 2 displayed highest mRNA abundance among mechanosensitive members of the K 2P channel family (V > A). Disease-associated K 2P 2.1 remodeling was studied in detail. In patients with impaired left ventricular function, atrial KCNK 2 (K 2P 2.1) mRNA and protein expression was significantly reduced. In AF subjects, downregulation of atrial and ventricular KCNK 2 (K 2P 2.1) mRNA and protein levels was observed. AF-associated suppression of atrial Kcnk 2 (K 2P 2.1) mRNA and protein was recapitulated in CREM-transgenic mice. Ventricular Kcnk 2 expression was not significantly altered in mouse models of disease. In conclusion, mechanosensitive K 2P 2.1 and K 2P 10.1 K + channels are expressed throughout the heart. HF- and AF-associated downregulation of KCNK 2 (K 2P 2.1) mRNA and protein levels suggest a mechanistic contribution to cardiac arrhythmogenesis.

Aims Atrial fibrillation (AF) is associated with fibrosis that slows electrical conduction and causes perpetuation of the arrhythmia. The molecular characterization of AF pathophysiology may provide novel therapeutic options. This study was designed to elucidate profibrotic signaling and myofibroblast activation in a porcine model of atrial tachypacing-induced AF and reduced left ventricular function. Materials and methods Ten domestic pigs were randomized to sinus rhythm (SR) or AF groups. Prior to AF induction and on day 14 the animals underwent echocardiographic examinations. Profibrotic pathways were analyzed in right atrial tissue obtained from AF animals compared to SR controls using histology, immunofluorescence microscopy, Western blot, and real-time PCR. Key findings AF was associated with atrial dilation, increased atrial fibrosis, and enhanced expression of collagens I and V in right atrial tissue after 14 days follow-up. The fraction of α-smooth muscle actin (SMA)-producing activated myofibroblasts was elevated in AF, whereas the abundance of vimentin-expressing inactive fibroblasts was not affected. Profibrotic signaling involved upregulation of TGF-β 1 , Smad2/3, and CTGF. Significance The transformation of atrial fibroblasts into myofibroblasts through activation of TGF-β 1 and CTGF emerged as potential cellular trigger of fibrogenesis. Prevention of fibroblast-to-myofibroblast switching may serve as target for remodeling-based antiarrhythmic AF therapy.

Aims Atrial fibrillation (AF) prevalence increases with advanced stages of left ventricular (LV) dysfunction. Remote proarrhythmic effects of ventricular dysfunction on atrial electrophysiology remain incompletely understood. We hypothesized that repolarizing K(2P)3.1 K+ channels, previously implicated in AF pathophysiology, may contribute to shaping the atrial action potential (AP), forming a specific electrical substrate with LV dysfunction that might represent a target for personalized antiarrhythmic therapy.Methods and results A total of 175 patients exhibiting different stages of LV dysfunction were included. Ion channel expression was quantified by real-time polymerase chain reaction and Western blot. Membrane currents and APs were recorded from atrial cardiomyocytes using the patch-clamp technique. Severely reduced LV function was associated with decreased atrial K(2P)3.1 expression in sinus rhythm patients. In contrast, chronic (c) AF resulted in increased K(2P)3.1 levels, but paroxysmal (p) AF was not linked to significant K(2P)3.1 remodelling. LV dysfunction-related suppression of K(2P)3.1 currents prolonged atrial AP duration (APD) compared with patients with preserved LV function. In individuals with concomitant LV dysfunction and cAF, APD was determined by LV dysfunction-associated prolongation and by cAF-dependent shortening, respectively, consistent with changes in K(2P)3.1 abundance. K(2P)3.1 inhibition attenuated APD shortening in cAF patients irrespective of LV function, whereas in pAF subjects with severely reduced LV function, K(2P)3.1 blockade resulted in disproportionately high APD prolongation.Conclusion LV dysfunction is associated with reduction of atrial K(2P)3.1 channel expression, while cAF leads to increased K2P3.1 abundance. Differential remodelling of K(2P)3.1 and APD provides a basis for patient-tailored antiarrhythmic strategies.

Background Cardiac graft denervation causes inadequate sinus tachycardia in patients after heart transplantation (HTX) which is associated with reduced survival. This study investigated the 5-year results of heart rate control with ivabradine or metoprolol succinate in patients after HTX. Methods This registry study analyzed 104 patients receiving either ivabradine (n = 50) or metoprolol succinate (n = 54) within 5 years after HTX. Analysis included patient characteristics, medication, echocardiographic features, cardiac catheterization data, cardiac biomarkers, heart rates, and post-transplant survival including causes of death. Results Demographics and post-transplant medication revealed no significant differences except for ivabradine and metoprolol succinate use. At 5-year follow-up, patients with ivabradine had a significantly lower heart rate (73.3 bpm) compared to baseline (88.6 bpm; P P P P P P P P P Conclusion Patients receiving ivabradine showed a superior heart rate reduction and a better left ventricular diastolic function along with an improved 5-year survival after HTX.

Background TASK-1 (K2P3.1) is an atrial-specific two-pore domain potassium channel that is significantly upregulated in atrial fibrillation (AF) patients resulting in shortened atrial action potential duration (APD). Inhibition of TASK-1 in human atrial cardiomyocytes reverses AF-related APD shortening to values observed in patients with sinus rhythm (SR). By in silico-modelling and experimental characterization of drug binding sites, doxapram was identified as specific inhibitor of TASK-1. Purpose In this study, we investigated the antiarrhythmic efficacy of doxapram in a porcine model of AF to convert and suppress AF. Methods We established a new porcine model of persistent AF without induced tachymyopathy. AF was induced in domestic pigs by intermittent atrial burst stimulation using implanted pacemakers. During AF episodes, burst stimulation was inhibited by an integrated pacemaker biofeedback algorithm. AV-node ablation was performed to prevent AF-associated heart failure. All pigs underwent catheter-based electrophysiological investigations prior to and after 14 days doxapram treatment. Pigs in the treatment group received intravenous applications of doxapram twice per day. Rhythm status was continuously recorded by intracardiac long-term ECG monitors. The application of doxapram for cardioversion and long term suppression of AF in pigs with persistent AF was evaluated. Subsequent to the doxapram treatment, porcine cardiomyocytes were isolated from right and left atria and electrophysiologically investigated by patch-clamp and multi-electrode experiments. Atrial electrical remodeling was characterized by analyses of ion channel expression at mRNA and protein levels. Results TASK-1 mRNA, protein and transmembrane current were significantly increased in AF pigs compared to SR controls, resulting in shortened atrial APDs. In doxapram-treated AF pigs the AF burden was significantly reduced. After 14 days treatment with doxapram, TASK-1 currents and atrial APDs recorded in porcine cardiomyocytes were reduced and similar to values of SR animals. Doxapram could be successfully applied for cardioversion in pigs with persistent AF. On average, cardioversion was observed 3 minutes after doxapram application. Conclusion Doxapram significantly suppressed AF episodes and normalized cellular electrophysiological characteristics in a porcine model of AF through inhibition of the TASK-1 ion channel. Furthermore, doxapram rapidly converted AF into SR in pigs. Therefore, doxapram might serve as a new antiarrhythmic drug to treat AF in patients.

Stratification of patients with atrial fibrillation (AF) according to mechanistic and prognostic criteria may optimize the effectiveness and safety of catheter ablation. In women, AF is associated with more severe symptoms and worse prognosis.We sought to assess sex-related differences in catheter ablation procedures and outcome in a large cohort of patients with AF.A total of 3652 patients (1198 women [33%]; 2454 men [67%]) included in the German Ablation Registry were analyzed. Periprocedural parameters and outcome at 12-month follow-up were compared between male and female patients.Women were older at the time of ablation (women: 63.6 years; men: 59.1 years; P.0001) and exhibited a higher prevalence of paroxysmal AF (women: 72%; men: 61%; P.0001). They were less often affected by cardiovascular disease and reduced left ventricular function. Energy application duration and overall procedure duration were shorter in women. Conversely, the rate of major inhospital complications was increased in female patients (1.9% vs 0.8%; P = .023) and mainly driven by major bleeding events. At follow-up, women experienced higher AF recurrence rates (women: 50%; men: 45%; P = .017) and more often received oral medication for rhythm and rate control. In addition, the rate of pacemaker implantation was higher in the female cohort. Women more frequently reported femoral access site complications (women: 6%; men: 3%; P.001). Overall, male patients were more often free from AF-related symptoms and satisfied with the treatment.Catheter ablation of AF was associated with a distinct sex-related outcome and complication profile that requires consideration in clinical practice.

After careful evaluation of the case and genetic testing, the girl and her parents are informed about the diagnosis of Jervell-Lange-Nielsen syndrome and its potential risks. She receives a low-dose beta blocker for prevention of arrhythmias and avoidance of strenuous exercise, particularly swimming, is recommended. Her younger brother turned out to have developed a respiratory infection, which led to the episode of loss of consciousness but, apart from that, is entirely healthy.

Digitalis glycosides are employed for rate control of atrial fibrillation. Recent studies suggested potential harmful effects of digitalis monotherapy and combination with antiarrhythmic drugs. The aim of the present study was to assess the prevalence and potential impact of digitalis therapy on outcome in patients undergoing catheter ablation of supraventricular arrhythmias. The German Ablation Registry is a nationwide, prospective registry with a 1-year follow-up investigating 12,566 patients receiving catheter ablations of supraventricular arrhythmias in 52 German centres. The present analysis focussed on pharmacotherapy in 8608 patients undergoing catheter ablation of atrial tachycardia, atrial fibrillation, or atrial flutter. Patients receiving digitalis therapy (n = 417) were older and presented a significantly increased prevalence of comorbidities including coronary artery disease, heart failure, diabetes, and pulmonary disease. One-year mortality was significantly higher in digitalis-treated patients (4.7% vs. 1.3%, p

Heart failure (HF) is a complication of multiple cardiac diseases and is characterized by impaired contractile and electric function. Patients with HF are not only limited by reduced contractile function but are also prone to life-threatening ventricular arrhythmias. HF itself leads to remodeling of ion channels, gap junctions, and intracellular calcium handling abnormalities that in combination with structural remodeling, e.g., fibrosis, produce a substrate for an arrhythmogenic disorders. Not only ventricular life-threatening arrhythmias contribute to increased morbidity and mortality but also atrial arrhythmias, especially atrial fibrillation (AF), are common in HF patients and contribute to morbidity and mortality. The distinct ion channel remodeling processes in HF and in channelopathies associated with HF will be discussed. Further basic research and clinical studies are needed to identify underlying molecular pathways of HF pathophysiology to provide the basis for improved patient care and individualized therapy based on individualized ion channel composition and remodeling.

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. 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. 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. 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.

Background: Limb-Girdle muscular dystrophies (LGMD) are a heritable group of genetically determined disorders with a primary involvement of the pelvic or shoulder girdle musculature with partially cardiac manifestation, such as dilated cardiomyopathy (DCM) and life-threatening tachyarrhythmia. We report here that human induced pluripotent stem cell (hiPSC)–derived cardiomyocytes from a patient with LGMD2I and DCM associated with recurrent ventricular tachycardia displayed ion channel dysfunction and abnormality of calcium homeostasis. Methods: Dermal fibroblasts obtained from a patient with LGMD2I harboring a fukutin-related protein gene mutation (826C>A; Leu276Ile) and 3 healthy donors were reprogrammed to hiPSCs. The hiPSCs were differentiated into cardiomyocytes and used for biological and electrophysiological studies. Results: Compared with hiPSC cardiomyocytes from the healthy donors, the hiPSC cardiomyocytes from the patient exhibited abnormal action potentials characterized by reduced amplitude and upstroke velocity. The peak and late Na channel currents (I Na ) as well as the peak L-type calcium channel currents were significantly reduced. The expression of SCN5A and CACNA1C was reduced in DCM cardiomyocytes, consistent with reduction of I Na and L-type calcium channel currents. In addition, the rapidly activating delayed rectifier potassium current (I Kr ) was reduced, whereas the transient outward current (I to ) and slowly activating delayed rectifier potassium current (I Ks ) were similar in DCM and control cardiomyocytes. Finally, a significant reduction of systolic and diastolic intracellular Ca 2+ concentrations was detected in DCM cardiomyocytes. Conclusions: This study demonstrates that patient-specific hiPSC cardiomyocytes can recapitulate some phenotypic properties of LGMD2I with DCM and provide a platform for studies on the cardiac events in LGMD.

Background— Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanism-based approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K 2P 3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K + channel–related acid-sensitive K + channel-1]) 2-pore-domain K + (K 2P ) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic patients with AF is unknown. Methods and Results— Right and left atrial tissue was obtained from patients with paroxysmal or chronic AF and from control subjects in sinus rhythm. Ion channel expression was analyzed by quantitative real-time polymerase chain reaction and Western blot. Membrane currents and action potentials were recorded using voltage- and current-clamp techniques. K 2P 3.1 subunits exhibited predominantly atrial expression, and atrial K 2P 3.1 transcript levels were highest among functional K 2P channels. K 2P 3.1 mRNA and protein levels were increased in chronic AF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD 90 ) compared with patients in sinus rhythm. In contrast, K 2P 3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K 2P 3.1 inhibition prolonged APD 90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. Conclusions— Enhancement of atrium-selective K 2P 3.1 currents contributes to APD shortening in patients with chronic AF, and K 2P 3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K 2P 3.1 as a novel drug target for mechanism-based AF therapy.

Rasmus Rivinius,1 Matthias Helmschrott,1 Arjang Ruhparwar,2 Christian Erbel,1 Christian A Gleissner,1 Fabrice F Darche,1 Dierk Thomas,1 Tom Bruckner,3 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, Angiology and Pneumology, 2Department of Cardiac Surgery, Heidelberg University Hospital, 3Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany Purpose: Early posttransplant atrial fibrillation (AF) has been associated with worse clinical outcomes after heart transplantation (HTX). The type of surgical technique may constitute a relevant risk factor for AF. Patients and methods: This retrospective single-center study included 530 adult patients. Patients were stratified by surgical technique (biatrial, bicaval, or total orthotopic HTX) and early posttransplant heart rhythm (AF or sinus rhythm). Univariate and multivariate analyses were performed to evaluate risk factors for AF. Results: A total of 161 patients received biatrial HTX (30.4%), 115 bicaval HTX (21.7%), and 254 total orthotopic HTX (47.9%). Sixty-one of 530 patients developed early posttransplant AF (11.5%). Patients with AF showed a statistically inferior 5-year survival compared to those with sinus rhythm (P

Left ventricular noncompaction (LVNC) is a cardiomyopathy with hypertrabeculation of the LV, often complicated by heart failure, arrhythmia and thromboembolic events. The features of LVNC are still incompletely characterized due to its late recognition as clinically relevant condition. The aims of this study were to describe echocardiographic and electrophysiologic characteristics of LVNC patients and to assess the effects of chronic β-blocker treatment. Study patients (n = 20; 42.5 [36.3; 52.5] years; 12 men) exhibited reduced LV ejection fraction (median LVEF = 32 %) and an increased LV mass of 210 g. Sinus rhythm was present in 19 patients, whereas one patient was in atrial fibrillation. Baseline heart rate was 77.5 beats per minute. Left bundle branch block was detected in five cases. In a subgroup of patients receiving β-blocker therapy (n = 17), LV mass was reduced from 226 [178; 306] g to 220 [169; 254] g (p = 0.007) at 13 ± 6 months follow-up. By contrast, a subgroup of three patients that were not treated with an anti-β-adrenergic agent showed LV mass increase from 180 [169; 197] g to 199 [185; 213] g (p = 0.023). LVEF and electrocardiographic parameters were not significantly modulated during chronic β-blocker treatment. There was no sustained symptomatic ventricular tachyarrhythmia, thromboembolic event or death in either group. In conclusion, this study reveals reduction of LV mass among LVNC patients during β-blocker therapy. Effects of β-blocker treatment in LVNC require validation in prospective controlled studies.

A 57-year-old man presented with recurrent episodes of dizziness, weakness of legs, and presyncope. The electrocardiogram showed a sinus bradycardia and recurrent sinus pauses. Cardiac evaluation revealed a normal left ventricular ejection fraction without ischemic, structural, or valvular heart disease. Pronounced limb weakness prompted neurological consultation. Cranial magnetic resonance imaging showed a large right-sided intracranial tumor adjacent to the medial sphenoid wing. Surgical removal of the tumor was accomplished successfully after application of a transient cardiac pacemaker, while decision upon permanent pacemaker implantation was postponed. Histopathology provided evidence of a meningothelial meningioma. Postoperative assessment displayed the absence of sinus node dysfunction after tumor removal. Careful differential diagnostic assessment of patients with symptomatic bradycardias needs to rule out reversible causes before implantation of permanent devices.

The mixed ion channel blocker, vernakalant (RSD1235), is effective in rapid conversion of atrial fibrillation (AF) to sinus rhythm (SR). Suppression of cardiac two-pore-domain potassium (K2P) channels causes action potential prolongation and has recently been proposed as a novel antiarrhythmic strategy. The objective of this study was to investigate acute effects of vernakalant on human K2P2.1 (TREK-1) and K2P3.1 (TASK-1) channels to provide a more complete picture of its antiarrhythmic mechanism of action. The class IC antiarrhythmic drug flecainide was studied as a comparator agent. Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record K2P currents from Xenopus oocytes and Chinese hamster ovary (CHO) cells. Vernakalant inhibited cardiac K2P2.1 channels expressed in Xenopus oocytes and in CHO cells. The IC50 value obtained from mammalian cells (13.3 µM) was close to the range of vernakalant levels reported in patients (2-8 µM), indicating potential clinical significance of K2P2.1 blockade. Open rectification characteristics and current-voltage relationships of K2P2.1 currents were not affected by vernakalant. Vernakalant did not significantly reduce K2P3.1 currents. Finally, the class I antiarrhythmic drug flecainide had no effect on K2P2.1 or K2P3.1 channels. In conclusion, the recently developed antiarrhythmic drug vernakalant targets human K2P2.1 K(+) background channels. This previously unrecognized inhibitory property adds to the multichannel blocking profile of vernakalant and extends the mechanistic basis for its anti-fibrillatory effect.

Clinical research in cardiology 106(8), 582-589(2017). doi:10.1007/s00392-017-1090-5, Published by Springer, Berlin

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Concomitant heart failure (HF) poses a particular therapeutic challenge and is associated with prolonged atrial electrical refractoriness compared with non-failing hearts. We hypothesized that downregulation of atrial repolarizing TREK-1 (K2P2.1) K+ channels contributes to electrical remodeling during AF with HF, and that TREK-1 gene transfer would provide rhythm control via normalization of atrial effective refractory periods in this AF subset. In patients with chronic AF and HF, atrial TREK-1 mRNA levels were reduced by 82% (left atrium) and 81% (right atrium) compared with sinus rhythm (SR) subjects. Human findings were recapitulated in a porcine model of atrial tachypacing-induced AF and reduced left ventricular function. TREK-1 mRNA (-66%) and protein (-61%) was suppressed in AF animals at 14-day follow-up compared with SR controls. Downregulation of repolarizing TREK-1 channels was associated with prolongation of atrial effective refractory periods versus baseline conditions, consistent with prior observations in humans with HF. In a preclinical therapeutic approach, pigs were randomized to either atrial Ad-TREK-1 gene therapy or sham treatment. Gene transfer effectively increased TREK-1 protein levels and attenuated atrial effective refractory period prolongation in the porcine AF model. Ad-TREK-1 increased the SR prevalence to 62% during follow-up in AF animals, compared to 35% in the untreated AF group. In conclusion, TREK-1 downregulation and rhythm control by Ad-TREK-1 transfer suggest mechanistic and potential therapeutic significance of TREK-1 channels in a subgroup of AF patients with HF and prolonged atrial effective refractory periods. Functional correction of ionic remodeling through TREK-1 gene therapy represents a novel paradigm to optimize and specify AF management.

High-energy ion beams are successfully used in cancer therapy and precisely deliver high doses of ionizing radiation to small deep-seated target volumes. A similar noninvasive treatment modality for cardiac arrhythmias was tested here. This study used high-energy carbon ions for ablation of cardiac tissue in pigs. Doses of 25, 40, and 55 Gy were applied in forced-breath-hold to the atrioventricular junction, left atrial pulmonary vein junction, and freewall left ventricle of intact animals. Procedural success was tracked by (1.) in-beam positron-emission tomography (PET) imaging; (2.) intracardiac voltage mapping with visible lesion on ultrasound; (3.) lesion outcomes in pathohistolgy. High doses (40–55 Gy) caused slowing and interruption of cardiac impulse propagation. Target fibrosis was the main mediator of the ablation effect. In irradiated tissue, apoptosis was present after 3, but not 6 months. Our study shows feasibility to use high-energy ion beams for creation of cardiac lesions that chronically interrupt cardiac conduction.