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Inflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 next to basement membrane compounds. Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell-states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we found an expansion of pro-inflammatory Ly6Chighmacrophages in HFpEF, and we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNFɑ. Finally, a marker of murine HFpEF fibroblast activation, Angiopoietin-like 4, was elevated in plasma samples of HFpEF patients and associated with disease severity. Taken together, our study provides a comprehensive characterization of molecular fibroblast and macrophage activation patterns in murine HFpEF, as well as the identification of a novel biomarker for disease progression in patients.

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 P P =0.008), reduced left atrial-appendage velocity (median, 36 cm/s versus 59 cm/s; P P 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 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.

The wearable cardioverter defibrillator (WCD) can protect patients against sudden cardiac death during temporarily increased or unknown risk of ventricular arrhythmias or in the situation of implantable cardioverter-defibrillator (ICD) explantation due to infection. In unusual cases, misinterpretation of the ECG by the tachycardia detection and discrimination algorithm of the WCD can occur which can lead to inappropriate acoustic alerts or inappropriate WCD therapy. We explain the mechanisms of inappropriate WCD therapy in two cases from daily clinical practice together with potential strategies to avoid such events in this special group of patients.Die tragbare Defibrillatorweste („wearable cardioverter defibrillator“, WCD) kann bei passager erhöhtem oder unklarem Risiko für ventrikuläre Arrhythmien oder bei Notwendigkeit einer infektionsbedingten ICD-Explantation einen temporären Schutz vor plötzlichem Herztod bieten. In besonderen Fällen kann es zu einer EKG-Fehlinterpretation durch den WCD-Detektionsalgorithmus kommen, welche zu inadäquaten akustischen Alarmtonabgaben oder inadäquaten WCD-Therapien führen kann. Dargestellt werden der Hintergrund von inadäquaten WCD-Schockabgaben anhand zweier Fälle aus dem klinischen Alltag sowie mögliche Strategien zur Vermeidung derartiger Ereignisse in diesem besonderen Kollektiv.

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.

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.

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.

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.

The dentate gyrus is the main hippocampal input structure receiving strong excitatory cortical afferents via the perforant path. Therefore, inhibition at this 'hippocampal gate' is important, particularly during postnatal development, when the hippocampal network is prone to seizures. The present study describes the development of tonic GABAergic inhibition in mouse dentate gyrus. A prominent tonic GABAergic component was already present at early postnatal stages (postnatal day 3), in contrast to the slowly developing phasic postsynaptic GABAergic currents. Tonic currents were mediated by GABA(A) receptors containing α(5)- and δ-subunits, which are sensitive to low ambient GABA concentrations. The extracellular GABA level was determined by synaptic GABA release and GABA uptake via the GABA transporter 1. The contribution of these main regulatory components was surprisingly stable during postnatal granule cell maturation. Throughout postnatal development, tonic GABAergic signals were inhibitory. They increased the action potential threshold of granule cells and reduced network excitability, starting as early as postnatal day 3. Thus, tonic inhibition is already functional at early developmental stages and plays a key role in regulating the excitation/inhibition balance of both the adult and the maturing dentate gyrus.

Aims This investigation addresses procedural characteristics of catheter ablation in patients with atrial fibrillation (AF) and sinus bradycardia. Methods From the prospective, multi-center German Ablation Registry 1073 patients with sinus rhythm at the time of AF ablation were divided into two groups according to heart rate at start of procedure (A, Results Acute procedural success was high (≥ 98%) and similar between groups. Procedure duration and energy application time were increased in group A (180 min vs. 155 min and 2561 s vs. 1879 s, respectively). Major complications were more frequent in group A (2.2% vs. 0.5%), and a greater proportion of these patients was discharged under antiarrhythmic medication (64% vs. 52%). Conclusion Catheter ablation of AF with concomitant sinus bradycardia is associated with high procedural efficacy, longer procedure- and energy application durations, and a slightly elevated complication rate.

The dentate gyrus is the main hippocampal input structure receiving strong excitatory cortical afferents via the perforant path. Therefore, inhibition at this 'hippocampal gate' is important, particularly during postnatal development, when the hippocampal network is prone to seizures. The present study describes the development of tonic GABAergic inhibition in mouse dentate gyrus. A prominent tonic GABAergic component was already present at early postnatal stages (postnatal day 3), in contrast to the slowly developing phasic postsynaptic GABAergic currents. Tonic currents were mediated by GABA(A) receptors containing α(5)- and δ-subunits, which are sensitive to low ambient GABA concentrations. The extracellular GABA level was determined by synaptic GABA release and GABA uptake via the GABA transporter 1. The contribution of these main regulatory components was surprisingly stable during postnatal granule cell maturation. Throughout postnatal development, tonic GABAergic signals were inhibitory. They increased the action potential threshold of granule cells and reduced network excitability, starting as early as postnatal day 3. Thus, tonic inhibition is already functional at early developmental stages and plays a key role in regulating the excitation/inhibition balance of both the adult and the maturing dentate gyrus.

The mammalian hippocampus expresses several types of network oscillations which entrain neurons into transiently stable assemblies. These groups of co-active neurons are believed to support the formation, consolidation and recall of context-dependent memories. Formation of new assemblies occurs during theta- and gamma-oscillations under conditions of high cholinergic activity. Memory consolidation is linked to sharp wave-ripple oscillations (SPW-R) during decreased cholinergic tone. We hypothesized that increased cholinergic tone supports plastic changes of assemblies while low cholinergic tone favors their stability. Coherent spatiotemporal network patterns were measured during SPW-R activity in mouse hippocampal slices. We compared neuronal activity within the oscillating assemblies before and after a transient phase of carbachol-induced gamma oscillations. Single units maintained their coupling to SPW-R throughout the experiment and could be re-identified after the transient phase of gamma oscillations. However, the frequency of SPW-R-related unit firing was enhanced after muscarinic stimulation. At the network level, these changes resulted in altered patterns of extracellularly recorded SPW-R waveforms. In contrast, recording of ongoing SPW-R activity without intermittent cholinergic stimulation revealed remarkably stable repetitive activation of assemblies. These results show that activation of cholinergic receptors induces plasticity at the level of oscillating hippocampal assemblies, in line with the different role of gamma- and SPW-R network activity for memory formation and -consolidation, respectively.