bluuebunny/crossref_metadata_2025 huggingface dataset:
Major procedure-related complications in a real-world cohort of patients undergoing transvenous lead extraction
Authors: Doring M , Lucas J , Bode K , Nedios S , Hilbert S , Ebert M , Moscoso Luduena C , Hindricks G , Richter S
Published: May 2022

Funding Acknowledgements

Type of funding sources: None.

Background

Transvenous lead extraction (TLE) is the mainstay therapy for device-related infections. Though TLE procedures are associated with low complication and high success rates, risk factors for major procedure-related complications remain not well defined.

Purpose

To evaluate the safety and efficacy of TLE in a large single centre cohort and to identify risk factors for major complications.

Methods

All consecutive patients undergoing TLE in our department between May 2012 and December 2021 were included in a prospective registry. Our protocol for TLE followed a stepwise approach according to lead dwell time and estimated complexity of the procedure: use of simple traction ± locking stylet (LS) ± mechanical and/or powered sheaths ± snare technique via a femoral or jugular access. Patient characteristics, procedural data and complications were gathered and analysed. Logistic regression analysis was applied to identify risk factors for major procedure related complications.

Results

A total of 2218 leads (25.7% ICD leads) were targeted for TLE in 1060 patients (67.7 ± 14.8 years; 74% male). The mean lead dwell time was 82 ± 62 months. The leading indication for TLE was cardiac device related infection (CDRI) in 695 patients (65.6%), 373 (35.2%) had systemic and 322 (30.4%) localized infection. Leads were extracted by simple traction in 30%, traction with LS in 3.7%, dilator sheaths with LS in 47.7%, and additional use of powered mechanical sheaths in 14.6%. The snare technique was used in 3.9%, with additional venous entry from femoral in 3.5% and jugular in 1.0% of all targeted leads. TLE was completely successful in 92.6%, partially successful with lead fragments <4cm in 4.2%, and failed in 3.1% of all patients, which translated to a clinical success rate of 96.9%.

Twenty-nine patients (2.7%) experienced minor and 18 patients (1.7%) had major procedure-related complications (cardiac tamponade/perforation) including 2 intraprocedural deaths (0.2%). Presence of abandoned leads (HR 8.41, 95% CI 3.21–22.02; p<0.001), lead-years-per-patient (HR 1.063, 95% CI 1.037–1.090; p<0.001), dwelling time of the oldest lead (HR 1.011, 95% CI 1.006–1.016; p<0.001), and a right-sided implantation (HR 2.68, 95% CI 1.05–6.83; p=0.04) were significant predictors of major complications in logistic regression analysis.

Conclusion

TLE is feasible, effective and safe in our large single centre experience. Overall complication and failure rates are low. Following our TLE protocol, the presence of abandoned leads, a right-sided implantation and dwelling time of the extracted leads were associated with major procedure-related complications.
External validation study of the 2014 European Society of Cardiology Guidelines in relation to 2020 ACC/AHA guidelines on sudden cardiac death prevention in hypertrophic cardiomyopathy
Authors: Frochaux A , Maurizi N , Porretta AP , Nana Davies S , Pascale P , Janreaud X , Pruvot E , Monney P
Published: May 2022

Funding Acknowledgements

Type of funding sources: None.

Background

Strategies for reliable selection of high-risk hypertrophic cardiomyopathy (HCM) patients for prevention of sudden cardiac death (SCD) with implantable cardioverter-defibrillators (ICDs) are still debated.

Purpose

Assess the sensitivity of sudden death risk strategies (2014 ESC SCD 5-year risk score and 2020 ACC/AHA risk factor strategy) in predicting lethal arrhythmic events (LAE), appropriate ICD shocks, SCD or out of hospital cardiac arrest among a cohort of HCM patients

Methods

Sixty-five patients (42±17 y) with a clinical diagnosis of HCM were enrolled in our institution from 1990 to 2021. Among them, 28 patients (43%) underwent a genetic test and a pathogenic/likely pathogenic sarcomeric variant was detected in 23 cases (82%). Patients were managed according to the best available treatment strategy for HCM in the different clinical eras.

Results

Of the 65 patients, 28 cases (43%) received an ICD, including 23 for primary and 5 for secondary prevention. During a follow-up period of 15 years (median, 15 [6, 21], range 1 to 33 years, 1014 patients/year), a total of 10 LAE were observed (0.98%/year). According to ESC SCD 5-year Risk Score, 7 (10%) were at high risk, 14 (22%) at intermediate to high risk, and 44 (68%) at low risk. Median SCD 5-year risk score of 3.5% ± 2.1. ACC/AHA risk factors categorized patients as 35 (54%) at high risk, 24 (37%) at intermediate to high risk, and 6 (9%) at low risk. A total of 4 (2.8%) patients experiencing SCD events were misclassified as low-risk patients by the ESC SCD Risk Score, whereas none by the ACC/AHA model. Of the 7 patients categorized as high risk by the ESC SCD Risk Score, 2 (29%) experienced a LAE, whereas of the 35 patients at high risk by the ACC/AHA, 9 (26%) suffered a LAE. No difference in the area under the curve was showed for the 2020 ACC/AHA SCD risk stratification strategies with respect to 2014 ESC SCD 5-year-risk score (0.72; 95% CI 0.60–0.83, 0.66; 95% CI 0.49–0.84, p =0.55).

Conclusions

In this HCM cohort followed up over an extended period of more than 15 years, LAE remained relatively low (0.98%/year). SCD risk stratification recommended by the 2014 ESC SCD 5 year risk score did not showed a better discrimination than that of 2020 ACC/AHA stratifications, despite the latter proved to be more sensible in the identification of the low risk patients. More than half of our cohort was classified with a recommendation by the 2020 ACC/AHA for an ICD implantation. A larger multicenter, independent, and prospective study with long-term follow-up is warranted to better elucidate these results.
ECG descriptors of ventricular repolarization are associated with cardiac events in a gene-specific manner in long QT syndrome patients
Authors: Morgat C , Denjoy I , Fressart V , Badilini F , Vaglio M , Messali A , Maison-Blanche P , Leenhardt A , Extramiana F
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public hospital(s). Main funding source(s): Assistance Publiques Hôpitaux de Paris (APHP)

Background

Congenital long QT syndrome (LQTS) is still associated with syncope and a risk of sudden cardiac death despite the dramatic reduction in mortality associated with beta-blocker therapy. Current risk stratification tools are imperfect.

Objective

To assess the contribution of automated scalar ECG descriptors of ventricular repolarization for arrrhythmic risk stratification in genotyped LQTS patients.

Methods

Patients with genotyped type 1, 2 or 3 LQTS with at least 1 digital ECG recording have been included in the study. History at diagnosis, and follow-up data were collected. Cardiac events included syncope, aborted cardiac arrest, appropriate implantable cardioverter-defibrillator therapy in VF zone, and sudden death.

ECG were analyzed using the BRAVO algorithm embedded in the CalECG software, version 4.1.0. QT interval duration was manually checked but ECG descriptors of Ventricular Repolarization were fully automatic.

Multivariate cox regression analysis were performed to identify parameters associated with cardiac events.

Results

467 patients (58% female, median age at diagnosis=25, LQT1,2,3 54%, 39%, 7%) were followed-up during 15.2±9.2 years. Rate of cardiac event was 1.2/100 patients-year before diagnosis and 0.9/100 patients-year during follow-up.

QTc duration was associated with the occurrence of cardiac events in the whole study population (HR=1.01 95%CI 1.0-1.01, p=0.03). Ventricular repolarization parameters associated with cardiac events were different according to LQTS type. Cardiac events were associated with increased time to accumulate 50% of T-wave energy (HR=1.53 95%CI 1.04-2.26, p=0.03) in LQT1 but with a decrease in T-wave slopes (ascending slope HR=0.63 95%CI 0.17-0.75, p<0.01) in type 2 LQTS patients. QTc duration was not independently associated with cardiac events in genotype specific multivariate models.

Conclusions

T-wave morphology parameters are associated with cardiac events in a gene-specific manner. Change in T-wave symmetry and T-wave flattening are associated with cardiac events in type 1 and type 2 LQTS respectively. The descriptors of ventricular repolarization are promising parameters or risk stratification beyond QTc duration in LQTS patients.
A positive toxicology screen is a rare finding in sports-related sudden cardiac deaths
Authors: Hansen CJ , Svane J , Isbister J , Ben-Haim Y , Morentin B , Molina P , Behr E , Lucena J , Semsarian C , Sheppard MN , Tfelt-Hansen J
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public Institution(s). Main funding source(s): University of Copenhagen

Introduction

Sports-related sudden cardiac deaths (SrSCD) are rare events often occurring in healthy individuals. An underlying cardiac disease may, in combination with strenuous exercise, trigger lethal arrhythmias. Intake of drugs (legal and illicit) increases the risk of sudden cardiac death (SCD), but knowledge on toxicological findings in SrSCD remains sparse.

Purpose

This study aimed to characterize the SrSCD population in an international consortium by investigating the epidemiology and autopsy findings in SrSCD.

Methods

Participating centers of the consortium (Denmark, Australia, England, Spain) provided data on all forensically autopsied SCDs aged 12—49 years in their respective cohorts, spanning from 2000—2019. Demographics, autopsy findings, and toxicology screen were assessed. A toxicology screen was considered positive if any drug was detected, except drugs related to resuscitation.

Results

Of all 5,029 SCDs, we identified 435 (9%) SrSCD. The majority (88%) died during sports while the remaining 12% died within one hour from exercise. SrSCD occurred more often in males (91% vs 71%, p<0.001) who were younger (32 vs 36 years). In SrSCD, the autopsy more frequently revealed an underlying structural cardiac cause of death (64% vs 54%, p<0.001); the most frequent causes of death among SrSCDs were sudden unexpected death (SUD), ischemic heart disease (IHD), and arrhythmogenic cardiomyopathy (ACM). Toxicological screens were performed in approx. 90% of cases, regardless of relation to sport. Among SrSCD cases, the rate of a positive toxicology was less than half compared to other SCDs (18% vs 44%, p<0.001). The most frequent toxicological findings among SrSCDs were ethanol, central stimulants, cannabinoids, and non-opioid analgesics.

Conclusions

Sports-related SCD accounted for 9% of all SCDs in our population aged 12—49 years. The majority of sports-related deaths (88%) occurred during exercise activity. SrSCDs more often had an underlying structural cardiac disease, mainly IHD and ACM. Positive toxicology screens were half as frequent in SrSCDs compared with non-SrSCDs.
Prediction of thrombosis in atrial fibrillation with compact atrial shape representation
Authors: Harrison J , Lorenzi M , Legghe B , Iriart X , Cochet H , Sermesant M
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – EU funding. Main funding source(s): IHU LIRYC ANR-10-IAHU-04

ERACoSysMed PARIS Project

Background

The impact of LA shape on clot formation in AF is yet to be understood

Purpose

To analyze the impact of LA, PVs and LAA orientations on clot formation

Methods

Pts with history of AF and an indication for LAA closure underwent pre-operative cardiac CT. Those with either a prior history of embolism or a clot detected on arterial and venous-enhanced CT images were categorized as clot positive. On CT images, the LA was segmented and meshed. Automated labelling of PVs and LAA was employed to build a compact skeleton representation of the LA (by registering labels from a template to all cases, and by connecting the center of mass of each labels). LA skeletons were used to train a novel Neural Network model for joint classification of heterogeneous data, such as images taken at different phases of the cardiac cycle. Such model consists of one encoder per dataset followed by a common classifier, enforcing a joint representation of all datasets in the same latent space. This is made possible by writing the task as a variational problem to optimise, we call this model a multi-channel variational classifier. The model was trained to predict clot positive patients and its generalizability was assessed on a test population.

Results

237 pts were included (age 74±8, 70% males, CHADS-VASc 4.3±1.2). CTs were acquired during systole in 117 and diastole in 120. 100 (42%) patients were considered clot positive. Segmentation, labeling and skeletization was successfully achieved in all pts. The model was trained using a 10-Fold cross validation. We compared the results after training on diastole and systole cases independently and by jointly training on both datasets. At testing, our model reached a 0.72 overall accuracy for the prediction of LAA clots (0.83 for systole and 0.61 for diastole), while training separately on systole and diastole was prone to strong overfitting and mode collapse with 0.52 and 0.48 accuracy, respectively.

Conclusion

While LA shape, LA size, PV and LAA orientations alone may not be sufficient for robust clot prediction, we introduce a compressed representation of the global anatomy that closely relates to LAA thrombosis, possibly identifying global features related to adverse hemodynamics. The method is reproducible and introduces a novel approach to accommodate heterogeneous diastole and systole datasets.
Use of a novel multi-disciplinary meeting to aid decision making for cardiac implantable electronic devices and the management of patients with arrhythmias
Authors: Esmonde S , Mckeag N
Published: May 2022

Funding Acknowledgements

Type of funding sources: None.

Background

Heart team meetings are well established for the management of coronary artery disease. We recently developed a novel weekly multi-disciplinary meeting (MDM) to aid decision making in the selection of patients suitable for treatment with cardiac implantable electronic devices (CIEDs) and the management of patients with arrhythmias. In this study, we present the results of an audit of the service.

Purpose

To illustrate the workload, range of conditions and decisions, and electronic communication used in the MDM.

Methods

Patients from all of Northern Ireland can be listed for discussion at the meeting using the Northern Ireland Electronic Clinical Record (NIECR). The same electronic record is used to log the result of the discussion (Figure 1). These records were analyzed for all patients discussed at the meeting from August 2019 to March 2021. Demographic and outcome (decision and mortality) data were recorded.

Results

A total of 614 patients were discussed (median age 63.0 years, 68.2% male). The mean weekly number of patients discussed was 7.5 per week. A total of 621 decision outcomes were made. 37 patients (6.0%) had died at the time of data collection. A summary of the major disease for discussion and outcome from discussion is shown in Figure 2.

Conclusion

A wide variety of patients, diseases and issues were discussed over this period. Conduction system disease was the most common disease, highlighting the challenges in treating this population. Furthermore, the most common outcome from discussion was conservative management. This may reflect the fact that arrhythmias are now frequently detected in asymptomatic patients without structural heart disease. This small study clearly demonstrates that there is interest in such a meeting to help in the management of these complex patients.
Current practices and expectations to reduce Electrophysiology catheters environmental impact: a large EHRA/LIRYC European survey
Authors: Boussuge-Roze J , Boveda S , Anic A , Conte J , Chun JKR , Marijon E , Legentil X , Mekongo V , Sacher F , Jais P
Published: May 2022

Funding Acknowledgements

Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Boston Scientific

Background

Despite aiming at improving patients’ health, healthcare consumes a large amount of resources and contributes to 4.6% of the global GHG/carbon emissions, 71% of the footprint being due the supply chain. It also produces millions of tons of complex waste per year. Yet, sustainability in EP remains a complex challenge as the performance and safety for patients are critical.

Objective

To set the ground to reduce electrophysiology (EP) catheters’ environmental impact.

Methods

A survey was conducted to poll European EP centers on 24 questions on sustainability practices and expectations.

Results

278, mostly EP doctors (84%, 76% male, 43yo), working in a public environment (89%, >100 procedures/year in 53% and > 500 in 36%) participated. A majority of EP doctors uses 2 to 4 more catheters/sheath per paroxysmal AF ablation procedure. MAPPING/ABLATION catheters are discarded after the procedure (73&78%), with partial re-cycling (electrodes) in 23&26 %. Local/external sterilization is rarely used (12% & 9%).

Catheters’ packaging are discarded in medical or general waste (38 & 31%) while it is recycled in only 19%.

EP Healthcare professionals are highly motivated in being environment friendly in their personal (82%) and in EP practice (62%). They identify a lack of interest from their hospital in 59% (only 16% having an executive in charge). Other barriers are the complexity of sustainability processes (48%), the effort required to change practice (47%), infectious risk (41%), lack of training (37%) and cost (33%). EP Healthcare professionals would favor sustainable mapping /ablation catheters if performances were preserved (60 & 50%). They consider re-use as the most relevant solution (60%) while being currently illegal in some European countries. Packaging should be reduced in size or made reusable. Finally, they consider that regulatory (31%), education (19%) and recommendations by companies (19%) would encourage the field to transition to more environmentally friendly practices. Interestingly, age, gender, type of practice, country or experience did not impact the results.

Conclusion

EP Healthcare professionals demonstrate a willingness to adopt sustainable practices. They consider re-use as the most relevant approach as of today. 60/50 % would favour sustainable mapping/ablation catheters providing preserved performances. Leaping to the next level of sustainability will request development of new sustainable solutions, models and technologies. Reaching this urgent goal will require governments, industry, hospitals and doctors to work closely in a coordinated approach.
Use of a neural network to generate a whole atrium 3D reconstruction of electrographic flow and basket catheter geometry from biosignals alone
Authors: Gagyi R , Szili-Torok T , Grund A , Ahapov K , Ruppersberg P , Kong M , Haeusser P
Published: May 2022

Funding Acknowledgements

Type of funding sources: None.

Background

Electrographic flow (EGF) mapping detects and quantifies patterns of electrical wavefront propagation in the atrial myocardium from basket catheter recordings. However, no single catheter can map the entire endocardial surface simultaneously. Creating panoramic maps of the whole atrium may be possible by reconstructing multiple basket positions obtained within a few minutes of each other.

Purpose

Present a method of 3D reconstruction of EGF maps generated from individual basket recordings using QRS morphologies and CT anatomies.

Methods

EGF maps were generated from unipolar signals recorded over 1 minute from 64-pole basket catheters. QRS morphologies recorded by each individual electrode were used to train a neural network (NN) on the reconstruction of the basket geometries in 3D. The NN uses the similarities between QRS morphologies to represent multiple recordings in one coherent 3D space and spatially integrate phenomena across multiple recordings without any external navigation system.

Results

A basket catheter was placed in the superior vena cava of a chronic AF canine model. The catheter was manually pulled back in steps of 5mm under fluoroscopic supervision. After reconstruction of the 3D electrode positions, a successive displacement of 3.5±1.2mm per step was reproduced. We applied the proposed method on recordings of 18 patients where an EGF source was identified. Independently, an expert determined the source locations on a 3rd party navigation system, based on 10 predefined regions in the left atrium. In 83% of the cases, the proposed method projected the sources in the same or adjacent region.

Conclusion

Novel 3D reconstruction from QRS signatures enables integration of EGF maps from multiple basket recordings that can be aligned with CT anatomy. Due to the real-time EGF map acquisition, synthesizing maps from more than 1 basket position provides a more panoramic visualization of complex atrial flow patterns.
Comparison of systemic inflammation activity and patients immune status in patients with various forms of atrial fibrillation and flutter
Authors: Ilchyshyna O YA
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public Institution(s). Main funding source(s): National Scientific Centre "M. D. Strazhesko Institute of Cardiology"

Aims

The inflammatory theory of atrial fibrillation and flutter arrhythmogenesis has attracted researcher`s attention in recent years, so the aim of our work is to compare the immune status of patients and systemic inflammation in paroxysmal and persistent atrial fibrillation and flutter in hypertensive people.

Materials and methods

The study involved 103 patients with hypertension and arrhythmias, who were divided into three main groups: group 1 (n = 35) - with paroxysmal atrial fibrillation (AF), group 2 (n = 38) - with persistent form of AF, group 3 (n = 30) - with persistent form of atrial flutter (AFl). For comparison, 2 control groups were formed: 4 (n = 23) - patients with hypertension, but without a history of arrhythmias and 5 (n = 21) - almost healthy people. The immune status of these patients was assessed by determining the level of monocytes (Mc), lymphocytes subpopulations and T-regulatory cells (T-reg) in the peripheral blood using flow cytometry. The activity of systemic inflammation was determined by serum highly specific C-reactive protein (CRP) level.

Results

It was noted that he number of classical CD14++CD16- and intermediate CD14++CD16+ Mc was significantly higher in patients with persistent AF and AFl comparing with patients without arrhythmias and healthy people (p<0.005). This fraction of Mc is able to produce proinflammatory cytokines and activate the local renin-angiotensin system, thus triggering the processes of fibrosis in the myocardium. Amount of non-classical CD14+CD16++ Mc was significantly lower in the second group both quantitatively and in percentage (p<0.005). The count of T cells with natural killer (TNK) activity was higher in all groups comparing to normal value, so statistical significance was observed only in comparison with the fifth group. The highest quantity of T-reg cells was found in healthy people comparing to other groups and a strong mathematical significance was obtained in all cases (p <0.005), both comparing the values in percentage and in μl. Patients with cardiac arrhythmias had signs of active systemic inflammation, such as high level of highly specific CRP. The highest one was in 2 group and exceeded the normal level by 6.7 times (8.31 ± 0.42) versus 1.25 ± 0.01) mg per l (p <0.001).

Conclusions

Patients with AF and AFl on the hypertension background comparing to hypertensive patients without arrhythmias or healthy people have a higher intensity of systemic inflammation because of higher levels of highly specific CRP, increased activity of proinflammatory subpopulation of monocytes, higher amount of T-cells with natural killer activity and reduced T-regulatory cells, whose main function is to control the immune response.
Understanding the contribution of stretch-activated ion channels to cardiac arrhythmogenesis using computational modelling
Authors: Buonocunto M , Lyon A , Delhaas T , Heijman J , Lumens J
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch heart foundation, ERA-CVD

Introduction

Cardiac electrophysiology and mechanics are strongly interconnected. Among other things, their interaction is mediated by cardiac mechano-electric feedback through stretch-activated ion-channels (SACs). These channels are also thought to contribute to the development of arrhythmias, but their precise role remains unclear.

Purpose

To elucidate the contribution of SACs to arrhythmias using a novel computational model of cardiac electromechanics.

Methods

We implemented two types of SACs in the O’Hara-Rudy model (ORd) of human ventricular electrophysiology: potassium-selective SACs and non-selective SACs (conducting sodium and potassium). The model was calibrated based on experimental human and rodent data of cardiomyocytes undergoing stretch. The calibration also considered inter-species differences, age, and upregulation of SACs under disease conditions. Subsequently, we varied the amplitude, duration, and timing of the simulated stretch to investigate their effects on action potential (AP).

Results

The model reproduced APs measured experimentally. Early afterdepolarizations, delayed afterdepolarizations, and ectopic beats were observed when applying stretch with short duration (e.g. 20ms) and high amplitude (e.g. 40%). When varying the time of application, stretch applied closer to the subsequent beat (cycle length: 1000ms) also shortened the following AP duration (APD) (shortening of 30ms with stretch at t=600ms, 130ms at t=800ms). Higher sensitivity to stretch was observed when simulating disease-related remodelling of SACs. Milder effects (no APD shortening with stretch at t=600ms and t=800ms) were seen with a lower stretch amplitude (e.g. 10% with SACs disease-related remodelling, 15% without). Failure of repolarization only occurred when sustained stretch (1000ms duration) of more than 10% (with SACs disease-related remodelling) or 15% (without) was applied.

Conclusions

Using a novel human electromechanical computational model, we quantified the contribution of SACs to cardiac AP changes. We showed that both disease-related SAC remodelling and variations of amplitude, timing, and duration of cardiomyocyte stretch modulated the effects on cardiac electrophysiology. We also showed that SACs may lead to afterdepolarizations and shorten the subsequent AP duration, factors which may potentially contribute to the generation of arrhythmias.
Defining refractoriness in single atrial beats using autoencoder neural networks
Authors: Ruiperez-Campillo S , Deb B , Feng R , Ganesan P , Clopton P , Rogers AJ , Narayan SM
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NIH

Background

Mapping atrial fibrillation (AF) is complicated by signals which may be local or far-field, but which cannot currently be separated. This could be clarified by a knowledge of atrial refractory periods, yet these are difficult to define from monophasic action potentials (MAP) in patients. We hypothesized that transfer learning using an autoencoder neural network (ANN), first trained with less-noisy ventricular signals, can be applied to de-noise and classify atrial MAPs.

Methods

We first developed an ANN to encode MAPs in 5706 ventricular MAPs from N=42 patients (age 65±13y) during pacing (fig1. A-B). This created a latent feature space. We now tuned the ANN to classify atrial MAPs in a different cohort of patients with AF. We used a statistical loss function based on mathematical optimization to evaluate the accuracy of final representations of the MAP and classify the different signals.

Results

The autoencoder ANN reconstructed ventricular MAPs with an average similarity of 0.85 (range 0-1) (an example is shown in fig 1.B). We tested on 3000 atrial MAPs in AF patients (N=21; 67±5y, 13 women). Atrial MAPs were accurately represented (fig 1.E-F) with similarity indices that were higher than those obtained by a panel of 3 experts. Fig. 1 shows the reconstruction of different signals: ventricular MAP (fig 1.A-B), ventricular MAP with pacing artifact (fig. 1.C-D), atrial MAP (transfer learning is assumed in here; fig 1.E-F) and noise or signals with morphologies of no interest (fig 1.G-H). Fig. 2 shows the classification of signals according to the similarity metric that allows distinguishing among the different types of signals without manual annotation (p<0.05 between groups).

Conclusion

Atrial refractory periods can be defined in single beats in AF patients using autoencoder neural networks and transfer learning. This approach can separate atrial beats from far-field ventricular beats and other sources of noise. Future work can study if this approach can be used to improve AF mapping or define novel physiological phenotypes.
Pharmacological inhibition of SK-channels with AP14145 prevents atrial arrhythmogenic changes in a porcine model for obstructive respiratory events
Authors: Linz B , Hesselkilde EM , Skarsfeldt MA , Hertel JN , Sattler SM , Yan Y , Tfelt-Hansen J , Diness JG , Bentzen BH , Linz D , Jespersen T
Published: May 2022

Funding Acknowledgements

Type of funding sources: Foundation. Main funding source(s): This work was supported by the Novo Nordisk Foundation (Tandem Programme; #31634).

Background

Obstructive sleep apnea (OSA) creates a complex substrate for atrial fibrillation (AF), which is refractory to many clinically available pharmacological interventions.

Purpose

To investigate atrial antiarrhythmogenic properties and ventricular electrophysiological safety of small-conductance Ca2+ -activated K+ (SK)- channel inhibition in a porcine model for obstructive respiratory events.

Methods

In spontaneously breathing pigs, obstructive respiratory events were simulated by intermittent negative upper airway pressure (INAP) applied via a pressure device connected to the intubation tube. INAP was applied for 75 seconds, every 10 minutes, three times before and three times during infusion of the SK-channel inhibitor AP14145. Atrial effective refractory periods (AERP) were acquired before (Pre-INAP), during (INAP) and after (Post-) INAP. AF-inducibility was determined by a S1S2 atrial pacing protocol. For the purpose of drug safety, ventricular arrhythmicity was evaluated by heart rate adjusted QT-interval duration (QT-paced) and electromechanical window (EMW) calculation.

Results

During vehicle infusion, INAP transiently shortened AERP (Pre-INAP: 135±10 ms vs. Post-INAP 101±11 ms; p=0.008) and increased AF-inducibility. QT-paced prolonged during INAP (Pre-INAP 270±7 ms vs. INAP 275±7 ms; p=0.04) and EMW shortened progressively throughout INAP and Post-INAP (Pre-INAP 80±4 ms; INAP 59±6 ms, Post-INAP 46±10 ms). AP14145 prolonged baseline AERP, partially prevented INAP-induced AERP-shortening and reduced AF-susceptibility. AP14145 did neither alter QT-paced (Pre-AP14145 270±7 ms vs. AP14145 268±6 ms, p=0.83) nor INAP-induced QT-paced prolongation, but blunted Post-INAP associated EMW-shortening.

Conclusion

In a pig model for obstructive respiratory events, the SK-channel-inhibitor AP14145 prevented INAP-associated AERP-shortening and AF-susceptibility without impairing ventricular electrophysiology. Hence, SK-channels may represent a promising target for OSA-related AF.
Differential effects of positive and negative upper airway pressure application on atrial electrophysiology: implications for CPAP-therapy in OSA-patients
Authors: Linz B , Hertel JN , Tfelt-Hansen J , Jespersen T , Linz D
Published: May 2022

Funding Acknowledgements

Type of funding sources: Foundation. Main funding source(s): Novo nordisk foundation

Background

Obstructive sleep apnea (OSA) is closely associated with atrial fibrillation (AF) and OSA-treatment by continuous positive airway pressure (CPAP) is believed to reduce the AF burden in OSA-patients. While negative upper airway pressure during obstructive respiratory events have been shown to increase AF susceptibility, atrial electrophysiological effects of positive upper airway pressure during CPAP-therapy are unknown.

Purpose

In pigs, we investigated differential atrial electrophysiological effects of increasing levels of CPAP-applications compared to obstructive respiratory events.

Methods

In sedated and spontaneously breathing pigs, obstructive respiratory events were simulated by intermittent negative upper airway pressure (INAP) applied via a pressure device connected to the intubation tube. INAP was applied for 75 seconds with a 10 minute resting period in-between. After four INAP-applications, during which atrial electrophysiological responses to INAP were recorded, continuous positive airway pressure was applied in increasing pressure stages for a duration of 20 minutes for each pressure level (4, 8, 12 and 16 mbar). Atrial effective refractory periods (AERP) were recorded at the free wall of the right atrium (RA) and in the distal area of the coronary sinus (CS) before (Pre-INAP), during (INAP) and after (Post-) INAP and every 10 minutes throughout the stepwise increase of CPAP.

Results

AERP shortened due to INAP application in the RA (Pre-INAP 134±7ms vs. INAP 95±7ms; p=0.008, Fig.1.), but not in the CS (Pre-INAP 132±8ms vs. INAP 110±9ms; p=0.144, Fig.2). Stepwise increases of CPAP-application up until 12 mbar did neither result in changes of RA- nor CS-AERP. Only CPAP-application at 16 mbar (CPAP16) resulted in transiently shortened CS-AERP (CPAP-baseline 140±6ms versus CPAP16 115±10ms; p=0.0081, Fig.2.), but not RA-AERPs (p=0.31, Fig.1.).

Conclusion

While simulation of obstructive respiratory events by INAP were reproducibly associated with a predominantly right atrial shortening of refractoriness, high-pressure CPAP-application of 16 mbar was associated with an isolated moderate shortening of left atrial refractoriness. These findings may have important implications for CPAP treatment in patients with AF, which should be considered in the design of future clinical studies.
Consortin: a potential modulator of ventricular conduction
Authors: Marsman EMJ , Offerhaus JA , Bosada FM , Beekman L , Christoffels VM , Boukens BJ , Remme CA , Bezzina CR
Published: May 2022

Funding Acknowledgements

Type of funding sources: None.

Background

Consortin, encoded by the CNST gene, is a ubiquitously expressed protein putatively involved in trafficking of connexins to the plasma membrane. In the heart, connexins form gap junctions, which are essential for cardiac conduction. Reduced levels and abnormal cellular distribution of connexins have been found in patients with heart failure, atrial fibrillation, arrhythmogenic cardiomyopathy and Brugada syndrome.

Purpose

To decipher the role of Consortin in cardiac electrophysiology.

Methods

Homozygous Cnst knockout mice (Cnst-/-) were generated using CRISPR-Cas9 technology. Consortin expression was assessed by Western blot analysis. Cardiac conduction parameters were recorded by electrocardiography in anesthetized wild-type (WT) and Cnst-/- male and female littermates aged 3-6 months. Conduction velocity (CV) was determined in Langendorff-perfused hearts by optical mapping of the right ventricle (RV) at a pacing cycle length of 120 ms. Data were analyzed by Student’s t­-test and P values < 0.05 were considered significant.

Results

Western blot analysis confirmed the presence of Consortin in WT mouse hearts, and its absence in Cnst-/- hearts. Heart rate, P-wave duration and PR-interval did not differ between groups, whereas QRS interval was significantly prolonged in Cnst-/- (mean±SEM 8.7±1.3 ms, n=13) compared to WT mice (7.9±1.1ms, n=13; (p=0.0009)). Hearts were structurally normal, and heart weight:body weight ratio was similar between groups. Preliminary optical mapping at the RV of Langendorff-perfused hearts demonstrated a lower, although not significantly different, transversal CV in Cnst-/- (56±4.3 cm/s, n=6) compared to WT (65±7.1 cm/s; n=3; p=0.31), whereas longitudinal CV was similar between groups (Cnst-/- 80±4.2 cm/s versus WT 83±9.1 cm/s; p=0.74). No differences were observed in RV effective refractory period (p=0.59).

Conclusion

These preliminary findings support a modulatory role of Consortin in ventricular conduction.

Current efforts are aimed at elucidating the underlying electrophysiological and molecular mechanisms, including the impact of Consortin on cardiac connexins.
Neuronal nitric oxide synthase inhibition exacerbates atrial electrical remodeling via small-conductance Ca2+-activated K+ channel activation
Authors: Koya T , Watanabe M , Natsui H , Kadosaka T , Koizumi T , Nakao M , Hagiwara H , Kamada R , Temma T , Anazai T
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public Institution(s). Main funding source(s): The Japan Society for the Promotion of Science KAKENHI

Background

The presence of atrial fibrillation (AF) is associated with electrical remodeling processes that promote a substrate for the maintenance of AF itself. Small conductance Ca2+-activated K+ (SK) channels; K+-selective and voltage-independent ion channels are key factors in the atrial electrical remodeling (2, 3). However, the mechanism of its activation remains unclear. A recent study showed that neuronal nitric oxide synthase (nNOS) expression and activity are reduced in AF patients and that nNOS depletion causes the abbreviation of action potential duration (APD), leading to increased AF inducibility in animal experiments (4). Decreased NO production, especially driven by nNOS inhibition, might play a key role in the atrial electrical remodeling, and the downstream alteration of SK channels might result from this process.

Purpose

We aimed to evaluate the potential of SK channel blocking to mitigate abnormal electrophysiological properties and the inducibility of atrial tachyarrhythmia (ATA) which was induced by nNOS depletion, and to describe the related mechanism.

Methods

Atrial tachyarrhythmia induction and optical mapping were performed in perfused rat hearts. nNOS was pharmacologically inhibited by S-methylthiocitrulline (SMTC, 100 nM). The influence of the SK channel was examined by a specific channel inhibitor, apamin (100 nM). APD, conduction velocity, and calcium transient (CaT) parameters (CaTD, rise time, time to 50% decay, and tau) were evaluated by voltage and calcium dual optical mapping. Dominant frequency was evaluated to analyze the wave dynamics of AF.

Results

SMTC increased the inducibility of ATA and apamin mitigated the nNOS inhibition-induced arrhythmogenicity (0% [0/7] vs 62% [8/13] vs 15% [2/13] in control, SMTC and SMTC + apamin). SMTC caused the abbreviation and enhanced spatial dispersion of APD, which were reversed by apamin. In contrast, conduction velocity was not affected by SMTC or apamin. Moreover, apamin reduced the dominant frequency of SMTC-induced ATA. In voltage and calcium optical mapping, STMC and apamin did not alter the parameters associated with CaT, however, SMTC caused the abbreviation of APD, which was reversed by apamin (APD80: 48.4 ± 2.7 msec in control group, 30.8 ± 1.5 msec in SMTC group, p <0.0001 vs. control, 41.8 ± 1.5 msec in SMTC + apamin, p = 0.01 vs. SMTC by One-way ANOVA and Tukey’s multiple-comparison test) (Figure A-C).

Conclusion

Acute nNOS inhibition abbreviated APD via activating SK channels. A specific SK channel blocker mitigated APD abbreviation without the alteration of CaT, implying an underlying mechanism of post translational modification of SK channels.
A comprehensive review on classifying fast-acting and slow-acting antimalarial agents based on time of action and target organelle of Plasmodium sp
Authors: Mariebernard Monika , Mohanty Abhinab , Rajendran Vinoth
Published: May 2022

The clinical resistance towards malarial parasites has rendered many antimalarials ineffective, likely due to a lack of understanding of time of action and stage specificity of all life stages. Therefore, to tackle this problem a more incisive comprehensive analysis of the fast- and slow-acting profile of antimalarial agents relating to parasite time–kill kinetics and the target organelle on the progression of blood-stage parasites was carried out. It is evident from numerous findings that drugs targeting food vacuole, nuclear components, and endoplasmic reticulum mainly exhibit a fast-killing phenotype within 24 h affecting first-cycle activity. Whereas drugs targeting mitochondria, apicoplast, microtubules, parasite invasion, and egress exhibit a largely slow-killing phenotype within 96–120 h, affecting second-cycle activity with few exemptions as moderately fast-killing. It is essential to understand the susceptibility of drugs on rings, trophozoites, schizonts, merozoites, and the appearance of organelle at each stage of the 48-h intraerythrocytic parasite cycle. Therefore, these parameters may facilitate the paradigm for understanding the timing of antimalarials action in deciphering its precise mechanism linked with time. Thus, classifying drugs based on the time of killing may promote designing new combination regimens against varied strains of Plasmodium falciparum and evaluating potential clinical resistance.
Selling the Responsibility to Protect: The False Novelty but Real Impact of a Norm
Authors: Staunton Eglantine , Glanville Luke
Published: May 2022

The responsibility to protect (R2P) is often referred to as a new concept on the basis that it provides both states and the international community responsibilities, rather than merely rights, to protect populations from mass atrocities. As this article argues, this claim of novelty is overstated. And yet, R2P has comprised an important development in human protection over the past two decades: it has helped to generate a degree of consensus on how to prevent and address atrocity situations. If R2P is not as novel as is often suggested, why has it had such an impact on international discourse? After demonstrating R2P's overstated novelty, this article advances four key factors that help explain its meaningful international impact: the importance of previous and contiguous normative developments, the role played by norm entrepreneurs, the emphasis placed on prevention over intervention, and the concept's constructive mix of clarity and ambiguity. By doing so, it provides a stronger understanding of the norm.
The risks associated with percutaneous native kidney biopsies: a prospective study
Authors: Andrulli Simeone , Rossini Michele , Gigliotti Giuseppe , La Manna Gaetano , Feriozzi Sandro , Aucella Filippo , Granata Antonio , Moggia Elisabetta , Santoro Domenico , Manenti Lucio , Infante Barbara , Ferrantelli Angelo , Cianci Rosario , Giordano Mario , Giannese Domenico , Seminara Giuseppe , Di Luca Marina , Bonomini Mario , Spatola Leonardo , Bruno Francesca , Baraldi Olga , Micarelli David , Piemontese Matteo , Distefano Giulio , Mattozzi Francesca , De Giovanni Paola , Penna Davide , Garozzo Maurizio , Vernaglione Luigi , Abaterusso Cataldo , Zanchelli Fulvia , Brugnano Rachele , Gintoli Enrica , Sottini Laura , Quaglia Marco , Cavoli Gioacchino Li , De Fabritiis Marco , Conte Maria Maddalena , Manes Massimo , Battaglia Yuri , Fontana Francesco , Gesualdo Loreto ,   ITA-KID-BIO-Group
Published: May 2022

Background

The known risks and benefits of native kidney biopsies are mainly based on the findings of retrospective studies. The aim of this multicentre prospective study was to evaluate the safety of percutaneous renal biopsies and quantify biopsy-related complication rates in Italy.

Methods

The study examined the results of native kidney biopsies performed in 54 Italian nephrology centres between 2012 and 2020. The primary outcome was the rate of major complications 1 day after the procedure, or for longer if it was necessary to evaluate the evolution of a complication. Centre and patient risk predictors were analysed using multivariate logistic regression.

Results

Analysis of 5304 biopsies of patients with a median age of 53.2 years revealed 400 major complication events in 273 patients (5.1%): the most frequent was a ≥2 g/dL decrease in haemoglobin levels (2.2%), followed by macrohaematuria (1.2%), blood transfusion (1.1%), gross haematoma (0.9%), artero-venous fistula (0.7%), invasive intervention (0.5%), pain (0.5%), symptomatic hypotension (0.3%), a rapid increase in serum creatinine levels (0.1%) and death (0.02%). The risk factors for major complications were higher plasma creatinine levels [odds ratio (OR) 1.12 for each mg/dL increase, 95% confidence interval (95% CI) 1.08–1.17], liver disease (OR 2.27, 95% CI 1.21–4.25) and a higher number of needle passes (OR for each pass 1.22, 95% CI 1.07–1.39), whereas higher proteinuria levels (OR for each g/day increase 0.95, 95% CI 0.92–0.99) were protective.

Conclusions

This is the first multicentre prospective study showing that percutaneous native kidney biopsies are associated with a 5% risk of a major post-biopsy complication. Predictors of increased risk include higher plasma creatinine levels, liver disease and a higher number of needle passes.
Nightmares and Respite
Authors: Walker Michael L.
Published: May 2022

Rarely is the relationship between sleep hygiene and punishment explored; however, this chapter does just that. The author argues that dreams are not wholly individual experiences, but social ones shaped to one extent or another by shared social circumstances. It is not that people have the same dreams, but that they are more likely to have the same kinds of dreams. Chapter 8 explores the sociology of dreaming, but it is also an investigation of the inherent weaknesses of offering mental health treatment to penal residents who are hungry and sleep-deprived—especially mental health care that is so woefully underresourced. Still, residents learned to use trips to mental health for their nightmares and other sleep-related problems as endurance strategies of another kind: friendship and care among each other, access to a phone, and respite from the problems associated with the politics.
It Is What It Is
Authors: Walker Michael L.
Published: May 2022

In this chapter, the author explores two main philosophies of life that residents adopted as endurance strategies to make sense of their time in jail. Residents could situate the punishment they experienced as being outside of their hands, a philosophy best summarized as it is what it is. Or they could situate the punishment as being well within the hands of a divine personality who had a plan for their lives, which is best summarized as it is as it should be. Commensurate with organic ethnography, the author describes his own emotional stance to the study.
The Hittite Empire
Authors: Weeden Mark
Published: May 2022

From the mid-seventeenth to the early twelfth centuries BC, Central Anatolia saw the development and expansion of the Hittite state whose influence came to spread beyond the Taurus mountains into Syria and which was seen at the time as one of the Great Powers of the Late Bronze Age. Commonly interpreted as a territorial state in its first phase and an empire in its second phase, this state’s center was situated in the mountainous city of Hattusa (modern Boğazköy), which was its enduring but not continual capital. The chapter focuses on how the Hittite state negotiated the exercise of authority over a highly fragmented landscape. Persistent fragility of dominion, internal dynastic squabbles and external conflicts, all rooted in deep-seated problems of achieving and capitalizing on territorial unity, brought forth innovative responses to the delegation of power, which manifested themselves in the development of a complex system of treaties as well as coordinated interventions in landscape management. The chapter also addresses questions resulting from the sources and the significant disconnect between material culture and archaeological evidence, on the one hand, and narratives owed to the copious textual material preserved on cuneiform tablets from the Hittite capital, on the other hand.