bluuebunny/crossref_metadata_2025 huggingface dataset:
Leadless left bundle branch pacing: feasibility in an animal model
Authors: Vergara P , Taloni ST , Shute AS , Lee ML
Published: May 2022

Funding Acknowledgements

Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): EBR Systems Inc.

Introduction

Epicardial cardiac resynchronization therapy (CRT) is an established treatment for heart failure; left bundle branch (LBB) pacing has been proposed to overcome epicardial CRT limitations. In this study, we report on the first implants of a leadless electrode for endocardial pacing of the LBB in a porcine model.

Methods

The implant of the leadless, left ventricular endocardial pacing system (WiSE-CRT System) was attempted by transeptal approach in two porcines. Fluoroscopic and transoesophageal echocardiographic guidance were used to navigate the Delivery Sheath to the LBB area; the targeted implant site was selected by analysis of the electrograms from the implanting Electrode. At the end of the procedure, the animals were sacrificed and the hearts were isolated and analysed.

Results

In both animals, the Delivery System was successfully navigated to the LV septum. The target sites showed LBB electrograms preceding the far field ventricular electrogram by 15ms. The Electrode was successfully implanted on both animals with pacing threshold <2.0V @ 0.5ms. The implant of the pacing electrode was associated with minimal, multifocal haemorrhage; Purkinje fibers components of the LBB were observed in the on both sides of the site of implantation site. The lesion was 1.7 mm large and 2 mm deep.

Conclusions

This study supports the feasibility of leadless LBB pacing. Anatomical evaluation showed a close relationship between the Electrode and the LBB, with absence of significant damage to the conduction system from the implanted Electrode.
Real-time image-guided lead placement in cardiac resynchronisation therapy: feasibility and outcome in a multicentre setting
Authors: Wouters PC , Van Slochteren FJ , Tuinenburg AE , Doevendans PAFM , Cramer MJM , Delnoy PPHM , Van Dijk VF , Meine M
Published: May 2022

Funding Acknowledgements

Type of funding sources: None.

Introduction

Image-guidance to assist left ventricular (LV) lead placement may improve outcome after cardiac resynchronisation therapy (CRT). Because previous approaches and results varied greatly, the optimal strategy remains unknown. To date, only a few studies investigated ‘real-time’ guidance, and feasibility in a multicentre setting is lacking altogether.

Methods

In 30 patients from three hospitals, cardiac magnetic resonance imaging (MRI) was performed to identify myocardial scar and late mechanical activation (LMA). LMA was determined using radial strain, plotted over time. Segments without scar but clear LMA were classified as optimal, according to an accurate 36-segment model. LV-lead deployment was guided, in real-time, using live image-overlay with fluoroscopy. After 6 months, volumetric response was defined as ≥15% reduction in LV end-systolic volume (∆LVESV). Reduction in log-transformed N-terminal pro-brain natriuretic peptide (NT-proBNP) was assessed at 2 months.

Results

Real-time image-guidance was successful performed in all CRT patients (age 66±10 years; 59% male, 72% non-ischemic cardiomyopathy; 69% left bundle branch block). LV-leads were deployed as follows: within (24%), adjacent (52%), or remote (24%) from the pre-defined target. According to the traditional 18-segment model, a remote position occurred only once. On average, 86% of patients demonstrated a volumetric response (mean ∆LVESV 36±29%). In addition, lead placement was association with reduction in log-transformed NT-proBNP (Figure 1).

Conclusion

Real-time image-guidance towards a pre-defined target for LV-lead placement was feasible in a multicentre setting, and has promising clinical results. Efficacy will be further investigated in the randomised controlled ‘Advanced Image Supported Lead Placement in Cardiac Resynchronization Therapy’ trial.
Anatomical variations in coronary venous drainage: challenges and solutions in delivering cardiac resynchronisation therapy
Authors: Akhtar Z , Sohal M , Kontogiannis C , Leung LWM , Harding I , Zuberi Z , Bajpai A , Norman M , Pearse S , Beeton I , Gallagher MM
Published: May 2022

Funding Acknowledgements

Type of funding sources: None.

Background

Cardiac resynchronisation therapy (CRT) is the cornerstone of heart failure management. Delivery of a left ventricular lead can occur in a small proportion of patients undermining the benefits of this treatment. Abnormal coronary venous anatomy is a contributing factor to this failure. Although epicardial lead placement is available, this patient cohort requiring CRT is subject to higher peri-operative morbidity and mortality than the general population; a transvenous approach is preferable.

Purpose

To investigate the abnormalities of the coronary venous system in candidates for cardiac resynchronization therapy (CRT) and describe methods for circumventing the resulting difficulties.

Methods

From 4 implanting institutes, data of all CRT implants between October 2008-October 2020 were screened for abnormal cardiac venous anatomy, defined as an anatomical variation not conforming to the accepted ‘normal’ anatomy. Patient demographics, procedural detail and subsequent left ventricle (LV) lead pacing indices were collected.

Results

From a total of 3548 CRT implants, 15 (0.42%) patients (80% male) of 72.2±10.6 years in age with a LV ejection fraction of 34±10.3% were identified to have had an abnormal cardiac venous anatomy over the study period. There were 13 cases of persistent left side superior vena cava (pLSVC), 5 of which had coronary sinus ostium atresia (CSOA) including 2 with an ‘unroofed’ coronary sinus (CS); 1 patient had a unique anomalous origin of the CS and 1 patient had an isolated CSOA. In total 14 patients (60% repeat attempt) had successful percutaneous implant under general anaesthesia (46.7%) via the cephalic vein (59.1%), using the femoral approach (53.3%) for levophase venography and/or pull-through, including 1 case of endocardial LV implant. Pacing follow-up over 37.64±37.6 months demonstrated LV lead threshold between 0.62-2.9 volts (pulsewidth 0.4-1.5 milliseconds) in all cases; 5 patients died within 2.92±1.6 years of successful implant.

Conclusion

CRT devices can be implanted percutaneously even in the presence of substantial abnormalities of coronary venous anatomy. Alternative routes of venous access may be required.
The acute haemodynamic response with endocardial biventricular pacing: comparing RV paced and LBBB patients
Authors: Cantor E , Butcher C , Chow JJ , Sohaib S M A , Valli H , Shun-Shin M , Shi R , Boyalla V , O’connor M , Chen Z , Haldar S , Mason M , Lane R , Francis D , Wong T
Published: May 2022

Funding Acknowledgements

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

Background

A third of patients that receive cardiac resynchronisation (CRT) are non-responders. Predictors of positive response include broader QRS duration, non-ischaemic aetiology and sinus rhythm, but it is still unclear whether lead placement site determines a positive responder.

Purpose

We assessed the acute haemodynamic response of endocardial biventricular pacing in patients with intrinsic left bundle brunch block (LBBB) versus LBBB due to pre-existing right ventricular pacing (RVP).

Methods

Patients who fulfilled standard criteria for CRT implantation but had failed conventional (coronary sinus) left ventricular (LV) lead placement (primary or revision) or were deemed clinical ‘non-responders after > 6 months of conventional CRT were enrolled. The acute haemodynamic response during endocardial biventricular pacing was assessed with a roving LV lead at 9 different locations (basal and mid: septal, anterior, posterior and lateral walls and apex). Acute changes in beat-to-beat systolic blood pressure (SBP) in the left ventricle were recorded and analysed.

Results

We recruited 23 patients across 10 UK centres: 14 intrinsic LBBB and 9 dependent on RVP. Patient characteristics were comparable: age (mean 67 + 10.6 years vs. 62 + 15.4 years), ischaemic (63% vs 50%), QRS (160 + 18ms vs. 190 + 36ms, p =0.07). Of the RVP group 5/9 had septal RV leads (the remainder apically positioned).

There was no difference in the SBP improvement between the groups: change in SBP ranged from -5.25 – 19.91mmHg (median 3mmHg) in RVP patients vs -5.92 – 23.03mmHg (median 3mmHg) for intrinsic LBBB. However, the improvement in SBP was more consistent across the different segments in the patients with RVP (group A), as compared to intrinsic LBBB (group B), where the lateral wall and then non-septal walls provided the greatest haemodynamic improvement.

Figure 1: depicts SBP improvement (in mmHg) during endocardial biventricular pacing in different positions within the LV for patients with RVP (A) vs underlying intrinsic LBBB (B): 9 segment model of the LV: Ant (anterior wall), Lat (lateral wall), Post (posterior wall), Sept (septum). Outer ring represents the four basal LV locations, middle ring the mid LV locations and centre ring the apex. Scale depicts mmHg improvement in SBP.

Conclusion

When implanting an LV lead for patients who are RV pacing dependent any position within the LV provides an acute haemodynamic improvement, compared with those with intrinsic LBBB, where a targeted lateral wall approach is more important. This finding corroborates the key differences in LV activation patterns for induced versus intrinsic LBBB.
Novel multi-site, multi-point biventricular pacing configuration: acute haemodynamic benefit
Authors: Kautzner J , Kukla J , Necasova L , Kryze L , Wunschova H , Sramko M
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Supported by the research grant of the AZV (Ministry of Health of the Czech Republic)

Background

Biventricular pacing (BVP) using multiple left ventricular (LV) sites may augment the hemodynamic effect of cardiac resynchronisation therapy (CRT) by engaging a greater mass of the myocardium.

Purpose

To evaluate the acute hemodynamic effect of a novel multi-site, multi-point BVP configuration.

Methods

The study investigated 18 patients with idiopathic dilated cardiomyopathy and left bundle-branch block during implantation of a BVP device (age: 59 ± 14 years, female gender: 7 [39%], LVEF: 27 ± 6%, native QRS: 171 ± 16 ms). Conventional leads were placed in the right atrium (RA) and ventricle (RV), one quadripolar LV lead (Quartet, Abbott, Abbott Park, IL, USA) was positioned in the posterolateral and another one in lateral or anterolateral coronary vein. Individual bipoles of all leads were connected through a splitter to separate external cardiac stimulators. Hemodynamics was evaluated using a micromanometer-tipped catheter (Micro-Cath, Millar, Tx, USA) located in the LV during RA pacing above sinus rate and five atrio-ventricular sequential pacing configurations at the same rate: 1.) RA+RV, 2.) RA + RV + distal bipole of the LV lead with greater dP/dT („conventional BVP"), 3.) RA + RV + distal and proximal bipoles of the LV lead with greater dP/dT („single-lead multi-point BVP"), 4.) RA + RV + distal bipoles of both LV leads („two-lead multi-site BVP"), and 5.) sequentional pacing RA + RV + all bipoles of both LV leads interconnected to a mesh („maximum BVP").

Results

Compared to RA pacing, LV dP/dT was significantly greater during all BVP pacing configurations (RA pacing: 1940 ± 507 mmHg/s vs. conventional BVP: 2431 ± 855 mmHg/s, single-lead multi-point BVP: 2539 ± 740 mmHg/s, two-lead multisite BVP: 2517 ± 836 mmHg/s, and "maximum BVP": 2685 ± 893 mmHg/s, all p<0.001, Figure 1), but not during RA-RV pacing (2014 ± 721 mmHg/s, p=0.12). In addition, dP/dT was significantly greater during "maximum BVP" compared to conventional BVP (p=0.05).

Conclusion

Compared to RA pacing and conventional BVP, the greatest increase in LV contractility was achieved with a novel multi-site, multi-point "maximum BVP" configuration. These preliminary findings provide a rationale for designing new approaches to CRT.
CTR-D without the left lead vs single/dual chamber ICD implantation: a cost saving strategy to avoid future upgrading of the latter?
Authors: Franco Fernandez I , Aroca Peinado A , Merino Llorens JL , Al-Razzo O
Published: May 2022

Funding Acknowledgements

Type of funding sources: None.

Introduction/Background: Implantation of cardioverter defibrillators (ICD) to prevent sudden death is common in patients with left ventricular dysfunction (LVD) (1).However, these devices are expensive and there is increasing controversy about their cost benefit ratio. More agreement is present about the benefits of cardiac resynchronization therapy (CRT) in patients with LVD and concurrent heart failure (HF) and left bundle branch block (LBB) (2). Nevertheless, LVD often presents without one these two conditions which may only develop at follow up. This makes unclear the benefits of CRT at the time of ICD implantation (CRT-D) in these patients. Some have advocated implanting a CRT-D without the left ventricle lead instead of a conventional single/dual chamber ICD which would give the possibility to add CRT pacing without replacing the device generator at follow-up. However, this practice has been never evaluated and it is unclear its potential impact on cost.

Methods

This study included all CRT devices implanted in our institution since 2005. Patients with LVD but just heart failure (HF) or left bundle branch block (LBB) were considered for CRT-D implantation without the left lead. The number of patients who needed implantation of a LV lead at follow-up was analyzed. Only patients who needed device replacement due to battery depletion were included in the final analysis

Results

A total of 913 CRT devices were implanted of which 115 (12.59%) were implanted without a left ventricular lead. The left ventricular lead was not implanted due to technical reasons in 46 cases (5%) and electively in the remaining. CRT device replacement (due to Elective Replacement Indicator (ERI) activation) was necessary in 38 patients of the latter and a LV lead had been never implanted in 32 (84.21%) of them during follow-up (7 +/- 2 years). In patients who needed a LV lead added, device replacement (because of battery depletion) was necessary during left ventricular lead implant procedure in 2 (6.25%). Using the average cost of these devices in our institution (22,000 euros), around 384,000 euros could have been saved if the CRT-D had not been implanted until left ventricular lead was.

Conclusions

Implantation of a CRT-D without the left ventricle lead instead of a conventional single/dual chamber ICD in patient with border line indication for CRT is not cost effective and does not result is significant savings in ICD generators.
Association between atrial fibrillation and cardiac implantable defibrillator detected heart failure status
Authors: Vitali F , Tavoletta V , Giano A , Calo L , Santini L , Savarese G , Dello Russo A , Santobuono VE , Mattera A , Lavalle C , Amellone C , Pecora D , Bertini M
Published: May 2022

Funding Acknowledgements

Type of funding sources: None.

Background

In heart failure (HF) patients, atrial fibrillation (AF) is a common comorbidity and is associated with a worse prognosis. Implantable defibrillator (ICD) diagnostics allow continuous monitoring of atrial high-rate events (AHRE), as a surrogate of AF, and are equipped with algorithms for HF monitoring. We evaluated the association between the values of the multisensor HF HeartLogic Index and the incidence of AF, and assessed the performance of the Index in detecting follow-up periods of significantly increased AF risk.

Methods

The HeartLogic feature was activated in 568 ICD patients. The median follow-up was 25 months [25th–75th percentile: 15-35]. The HeartLogic algorithm calculates a daily HF index and identifies periods IN the alert state on the basis of a configurable threshold. The endpoints were: daily AF burden of ≥5 minutes, ≥6 hours and ≥23 hours.

Results

The HeartLogic index crossed the threshold value 1200 times (0.71 alerts/patient-year). The time IN the alert state was 13% of the total observation period. During the observation period, an AF burden of ≥5 minutes/day was documented in 183 (32%) patients, ≥6 hours/day in 118 (21%) patients, and ≥23 hours/day in 89 (16%). On using a time-dependent Cox model, the weekly time IN the alert state was independently associated with an AF burden of ≥5 minutes/day (HR:1.95, 95%CI:1.22-3.13, p=0.005), ≥6 hours/day (HR:2.66, 95%CI:1.60-4.44, p<0.001), and ≥23 hours/day (HR:3.32, 95%CI:1.83-6.02, p<0.001), after correction for baseline confounders. Comparison of the episode rates in the IN-alert state with those in the OUT-of-alert state yielded HRs ranging from 1.57 to 3.11 for AF burden from ≥5 minutes to ≥23 hours.

Conclusions

The HeartLogic alert state was independently associated with AF occurrence. The intervals of time defined by the algorithm as periods of increased risk of HF allow risk stratification of AF according to various thresholds of daily burden.
External cardioversion of atrial fibrillation and flutter in patients with cardiac implantable electrical devices
Authors: Elgaard AF , Dinesen PT , Riahi S , Hansen J , Lundbye-Christensen S , Thoegersen AM , Larsen JM
Published: May 2022

Funding Acknowledgements

Type of funding sources: None.

Introduction

Atrial tachyarrhythmias are often treated with external cardioversion (ECV) with direct current shocks in patients with potentially electrically sensitive cardiovascular implantable electronic devices (CIED). Long-term follow-up data on contemporary pacemakers and implantable cardioverter defibrillators (ICD) undergoing ECV is sparsely described. This study investigated shock-related complications and impact on CIEDs.

Methods

All ECV procedures of atrial fibrillation and flutter from 2010 to 2020 in patients with CIED performed at a tertiary hospital (Denmark) were identified in the Danish National Patient Registry. Data on device interrogation before and after ECV and procedure-related complications were retrieved retrospectively by review of medical records.

Results

We analysed 664 ECV-events performed in 362 CIEDs, median implant time 1.5 year. Mean age of patients at first ECV-event were 69.4±9.7 years and 72.2% were men. We identified two cases of major programming changes and two cases of premature battery depletion (≤3 years after generator implant) following ECV. Minor shock-related device changes were found for impedances, atrial sensing values and pacing thresholds of right ventricle lead. In two cases increased pacing threshold of right ventricle leads following ECV triggered exit-blocks after few months. No patients died due to shock-related device dysfunctions.

Conclusion

Following external cardioversion with transthoracic direct current shocks, sporadic (<1%) but potentially critical changes in device function were identified in patients with contemporary pacemakers and implantable cardioverter-defibrillators. The present study suggests that routine post-cardioversion device interrogation is imperative for patient safety.
Remote device monitoring for implantable cardioverter defibrillators during the COVID-19 pandemic
Authors: Kolk MZH , Tjong FVY , Knops RE
Published: May 2022

Funding Acknowledgements

Type of funding sources: None.

Background

Remote monitoring (RM) for implantable cardioverter defibrillators (ICDs) is recommended as the standard of care in clinical guidelines. Presumably, the restrictions on face-to-face visits that were imposed during the coronavirus (COVID-19) pandemic have further accelerated the adoption of RM. However, quantitative real-world data on the uptake of RM during the COVID-19 pandemic is lacking.

Purpose

To assess the uptake of RM during the COVID-19 pandemic to a pre-COVID-19 period, and compare the arrhythmic burden between the two groups.

Methods

This is a substudy of the retrospective, observational single-center DISTANT-study. For this substudy, data from patients who were enrolled in the RM program after de novo ICD implantation (single- and dual chamber, biventricular or subcutaneous ICDs) were analysed. The time until RM was initiated per patient was calculated for patient implanted during the COVID-19 pandemic (March 2020-January 2021) and compared to a similar 10-month period pre-COVID-19 (May 2019-March 2020). ICD therapy (shock and/or anti-tachycardia pacing), non-sustained ventricular tachycardia (NSVT), supraventricular tachycardia (SVT) and mortality were registered for each patient. Patients <18 years old at implantation and patients with a follow-up of <6 months were excluded from this analysis.

Results

A total of 134 patients (72.4 % male, mean age 57.3 ±14.9 years) were eligible for this substudy, of which 61 patients in the COVID-19 group and 73 patients in the pre-COVID-19 group. In both groups there was a similar percentage of primary prevention ICD implantations (COVID-19: 43%, pre-COVID: 44%; p=0.888). During COVID-19, RM was initiated more promptly following ICD implantation compared to pre-COVID-19 (respectively 63 days vs. 131 days; p=0.007). Second, in the COVID-19 group 60.7% patients were enrolled in RM within 30 days following implantation compared to 39.7% in the pre-COVID-19 group (p=0.016). In terms of arrhythmic burden, no differences in the occurrence of ICD therapy (p=0.759), NSVT (p=0.267) and SVT (p=0.454) were observed.

Conclusion

During the COVID-19 pandemic RM was initiated more promptly following ICD implantation compared to before the pandemic, however, no differences in arrhythmic burden between groups were observed.
Patient motivation and adherence to an on-demand app-based heart rate and rhythm monitoring infrastructure for atrial fibrillation management through teleconsultation. TeleCheck-AF project results
Authors: Gawalko M , Hermans ANL , Van Der Velden RMJ , Betz K , Verhaert DVM , Pluymaekers NAHA , Vernooy K , Sultan A , Pison L , Manninger M , Duncker D , Evans S , Sohaib A , Linz D , Hendriks JM
Published: May 2022

Funding Acknowledgements

Type of funding sources: None.

Background

TeleCheck-AF is a mobile health (mHealth) infrastructure developed to provide remote management and comprehensive care to patients with atrial fibrillation (AF) during the Covid disease-19 pandemic lockdown within cardiology centers in Europe. TeleCheck-AF integrates an on-demand photoplethysmography-based heart rate/rhythm monitoring application supported a scheduled teleconsultation.

Purpose

The current sub-study of the TeleCheck-AF project aimed to provide the first real-world dataset on patient adherence and motivation to a standardized mHealth application integrated in remote AF management.

Methods

Patients were instructed to perform 60-second app-based heart rate/rhythm recordings three times daily and in case of symptoms for seven consecutive days prior to teleconsultation. Motivation was defined as number of days in which the expected number of measurements (≥three/day) were performed per number of days over the entire prescription period. Adherence was defined as number of performed measurements per number of expected measurements over the entire prescription period.

Results

Data from 990 consecutive patients with diagnosed AF (median age 64 [57-71] years, 39% female) from 10 centers that included the highest number of patients (≥25) were analyzed. Patients with both optimal motivation (100%) and adherence (≥100%) constituted 28% of the study population and had a lower percentage of recordings in sinus rhythm (90 [53-100%] vs 100 [64-100%], P<0.001) compared to others. Age and diabetes were predictors of both optimal motivation and adherence (odds ratio [OR] 1.02, 95% coincidence interval [95% CI] 1.01-1.04, P<0.001 and OR, 0.49, 95% CI 0.28-0.86, P=0.013, respectively). Patients with 100% motivation also had ≥100% adherence. Independent predictors for optimal adherence alone were age (OR 1.02, 95% CI 1.00-1.04, P=0.014), female sex (OR 1.70, 95% CI 1.29-2.23, P<0.001), previous AF ablation (OR 1.35, 95%CI 1.03-1.07, P=0.028).

Conclusion

In the TeleCheck-AF project, older age and diabetes were predictors of optimal patient motivation and adherence to app-based heart rate/rhythm monitoring. Therefore, physicians, nurses and allied health specialists involved in the management and care for patients with AF should not be discouraged to provide a mHealth infrastructure to elderly patients. Patient engagement improves mHealth adherence/motivation, hence, it is crucial to tailor the mHelath intervention to the needs and preferences of the patient.
Determining the role of uremic toxins on cardiac electrophysiology and pro-arrhythmia during chronic kidney disease
Authors: Van Ham WB , Bossu A , Houtman MJC , Cornelissen CM , Vos MA , Van Veen TAB
Published: May 2022

Funding Acknowledgements

Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Young Talent Programme, CVON

Introduction

Chronic kidney disease (CKD) is represented by a diminished filtration capacity of the kidneys. End stage renal disease patients need dialysis treatment to remove waste and toxins from the circulation. However, endogenously produced uremic toxins (UTs) cannot always be filtered during dialysis. UTs are one of the CKD-related factors already linked to maladaptive and pathophysiological remodeling of the heart. Importantly, 50% of the deaths in dialysis patients is cardiovascular related, with sudden cardiac death predominating. However, the mechanisms responsible still remain poorly understood.

Purpose

To assess the potentially increased pro-arrhythmic risk of pre-identified UTs at clinically relevant concentrations: 1) acutely in isolated adult dog ventricular cardiomyocytes (ADCMs) and human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), 2) chronically in iPSC-CMs and 3) both conditions in human embryonic kidney (HEK) cells transfected with constructs that generate different ion channels, using optical and manual electrophysiological in vitro approaches.

Methods and results

Using the voltage sensitive membrane dye FluoVolt and manual patch clamp, action potential duration (APD) prolongation, considered as a pro-arrhythmic parameter, was assessed in ADCMs and iPSC-CMs. Acute exposure of indoxyl sulfate (IS), kynurenine (KYN) or kynurenic acid (KYNA) induced no alterations in APD in ADCMs and iPSC-CMs. iPSC-CMs, although having rather immature electrophysiological characteristics, showed significant APD prolongation when exposed chronically (48h) to those UTs.

Manual patch clamp on HEK293 cells was performed to investigate individual ion currents to reveal underlying mechanisms. The repolarizing current IKr, often most sensitive and responsible for APD alterations, was not acutely affected by IS, KYN, or KYNA. However, chronic exposure (48h) to IS or KYNA significantly decreased IKr at clinically relevant concentrations.

Finally, the protein level of the ion channel conducting IKr was determined in HEK293 cells, to further unveil the mechanism behind the effects of UTs on channels conducting IKr. Chronic exposure (48-72h) of the three UTs decreased total ion channel expression at pathological concentrations, which could be responsible for the decreased IKr and prolonged APD.

Conclusion

The results show the proof of concept to identify potentially pro-arrhythmogenic UTs and their mode of action, allowing the provision of a clinically relevant overview of (patho)physiological concentrations of UTs in both acute and chronic exposure.
Subthreshold delayed afterdepolarizations mediated by reduced tissue conductivity form a substrate for unidirectional block and reentry within the infarcted heart
Authors: Campos F , Shiferaw Y , Whitaker J , O’neill M , Razavi R , Plank G , Bishop MJ
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): British Heart Foundation, Wellcome Trust

Background

Delayed afterdepolarizations (DADs) due to spontaneous calcium release (SCR) events at the subcellular scale have been associated with arrhythmia formation in the border zone (BZ) of infarcted hearts. DADs may not only summate to form ectopic focal sources but may also inactivate sodium channels forming a substrate for unidirectional conduction block and reentry. The role played by infarct anatomy and altered intracellular coupling in facilitating this phenomenon is not fully understood.

Purpose

To use computational modelling to investigate the role of anatomical properties of the infarct BZ in creating a substrate for DAD-mediated conduction block and reentry.

Methods

MRI data from a porcine post-infarction heart was used to build the computational model. A phenomenological model was used to simulate SCRs in the BZ. Arrhythmia susceptibility was quantified by pacing the model followed by a pause, to see whether DADs would occur, and an extra S2 beat with different coupling intervals (CIs). Tissue conductivity in the BZ was decreased to investigate the effect of uncoupling on DAD-mediated conduction block.

Results

Subthreshold DADs occurring within the infarct BZ inactivated the fast sodium channels which resulted in block of S2 beats. This occurred most readily in narrow isthmuses where electrotonic load was attenuated by the non-conducting scar. DADs rendered the entire isthmus area refractory establishing a substrate for unidirectional block and reentry (see Fig. A). Reduced tissue conductivity in the BZ reduced electrotonic load on cells undergoing DADs. This led to more local tissue depolarization (Vm) as uncoupling prevented current from flowing to neighboring cells at rest (Fig. B-C). Reduced tissue conductivity also enhanced DAD-mediated block by increasing the vulnerable window for reentry initiation (700ms < S2 CI < 900ms as shown in Fig. D).

Conclusion

Subthreshold DADs provide a substrate for arrhythmogenesis in the infarct BZ. Tissue uncoupling enhanced the arrhythmogenic risk by increasing the time window of unidirectional block.
Selective intracardiac sympathetic denervation acutely modulates left ventricular control
Authors: Kahle AK , Klatt N , Jungen C , Dietenberger A , Kuklik P , Muenkler P , Willems S , Nikolaev V , Scherschel K , Meyer C
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Centre for Cardiovascular Research (DZHK)

Background

The sympathetic nervous system plays an integral role in cardiac physiology. Neuromodulation is emerging as a treatment option for ventricular arrhythmias, but selective intracardiac approaches are rare. Sympathetic nerve fibers innervating the left ventricle have been demonstrated to be amenable to transvenous catheter stimulation along the coronary sinus (CS).

Purpose

The aim of the present study was to modulate left ventricular control by selective sympathetic denervation using epicardial or standard catheter ablation for intracardiac axotomy at the level of the CS.

Methods

First, the impact of epicardial CS ablation on cardiac electrophysiology was studied in a Langendorff model of murine hearts (n=10 each, ablation and control). Second, the impact of transvenous, anatomically-driven axotomy by catheter-based radiofrequency ablation along the CS was evaluated in a healthy ovine in vivo model (n=8) before and during left stellate ganglion stimulation (LSGS).

Results

CS ablation for intracardiac sympathetic axotomy prolonged epicardial ventricular refractory period (VRP) without (41.8±8.4 ms vs. 53.0±13.5 ms; P=0.0487) and with beta1-2-adrenergic receptor blockade (47.8±2.8 ms vs. 73.1±5.0 ms; P=0.0009) and enhanced the increasing effect of beta1-2-adrenergic receptor blockade on epicardial VRP (∆VRP 6.3±7.0 ms vs. 20.0±7.5 ms; P=0.0045) in mice (Figure, A). Mean epicardial wave propagation velocity in the left ventricle was faster in ablated hearts than in controls (1.13±0.05 m/s vs. 1.00±0.02 m/s; P=0.0463), but did not differ in the right ventricle (1.15±0.05 m/s vs. 1.20±0.08 m/s; P=0.7938). Transvenous catheter ablation of the CS reduced systolic (SBP, 57.7±5.0 mmHg vs. 46.9±3.6 mmHg; P=0.0428) and diastolic blood pressure (DBP, 35.5±3.0 mmHg vs. 26.7±1.8 mmHg; P=0.0106) and diminished the blood pressure increase during LSGS in sheep (∆SBP 21.9±3.8 mmHg vs. 10.5±4.2 mmHg; P=0.0234; ∆DBP 9.0±1.9 mmHg vs. 3.0±1.2 mmHg; P=0.0391) (Figure, B, C). Cycle length remained unchanged by LSGS, both before (baseline 653.2±20.6 ms vs. LSGS 627.8±27.5 ms; P=0.2309) and after CS ablation (baseline 734.8±24.2 ms vs. LSGS 746.2±37.3 ms; P=0.7145).

Conclusions

Anatomically-driven axotomy targeting nerve fibers along the CS enables selective intracardiac sympathetic denervation resulting in acute modulation of left ventricular control.
Novel biomarkers predict ablation outcomes in long stranding persistent atrial fibrillation
Authors: Boyalla V , Bodinier B , Kralj-Hans I , Haldar S , Khan HR , Shi R , Cantor E , Hussain W , Jones DG , Jarman JWE , Markides V , Chadeau-Hyam M , Harding SE , Cleland JGF , Wong T
Published: May 2022

Funding Acknowledgements

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

Background

Ablation of long-standing persistent atrial fibrillation (LSPAF) is not always successful. The arrhythmia burden was reduced by 75% by 12 months in majority (72%) of patients with LSPAF who underwent surgical or percutaneous ablation in the CASA-AF trial. We hypothesised that biomarker(s) improve prediction of clinical success and offer insights into mechanisms.

Objective

To identify biomarkers that predict success (75% arrhythmia burden reduction) after ablation for LSPAF at 12-months.

Methods

Amongst patients participating in the CASA-AF RCT (ISRCTN18250790), pre-ablation serum samples were selected for 20 patients who met criteria for ablation-success at 12 months, and 20 who did not. Olink ProteomicsTM (Sweden) provided analyses using three biomarker panels [inflammation (INFL), cardiovascular III (CVD III), and cell cytology (CELL)] each containing 92 biomarkers. Univariate and multivariable analyses were adjusted for age, sex, BMI, LA diameter and CRP. ROC analysis was undertaken to assess the diagnostic accuracy of the biomarkers. To counter the false discovery rate, Benjamini-Hochberg correction was utilised.

Results

When patients with ablation-success and -failure were compared, no differences in demographics or cardiac function were found. On univariate analysis, several biomarkers in each panel were associated with ablation-success. Multivariable analysis narrowed the range of biomarkers and identified those that were jointly predictive of outcome: INFL (MCP1 + CD8A + CD40, Figure 1), CVD III (FAS + CPB1) and CELL (GCG + ENTPD6 + IL17RB). These joint biomarkers were analysed using ROC (Figure 2), which showed that increases of biomarkers on the INFL panel (MCP1 + CD8A + CD40) were associated with a greater risk of failure and achieved the highest AUC for prediction of outcome [0.82 (0.75-0.87)].

Conclusion

The increase in the serum concentration of markers of inflammation (MCP1 + CD8A + CD40) might be used to identify patients less likely to have sustained benefit from LSPAF ablation. Further studies are required to confirm their prognostic value as pre-procedural biomarkers.
Atrial fibrillation and age synergistically increase clotting potential and promote atrial structural remodeling in goats
Authors: D’ Alessandro E , Scaf B , Sobota V , Van Hunnik A , Kuiper M , Winters J , Van Oerle R , Spronk HMH , Van Nieuwenhoven FA , Ten Cate H , Verheule S , Schotten U
Published: May 2022

Funding Acknowledgements

Type of funding sources: Other. Main funding source(s): Netherlands Heart Foundation, European Union

Background

Age is a risk factor for atrial fibrillation (AF) as well as for stroke in patients with AF. However, the effect of ageing on AF mechanisms and on coagulation activity is not well understood.

Purpose

To evaluate the effect of age and AF on coagulation activity, AF characteristics, and atrial structural remodeling.

Methods

Four groups of female goats were investigated: Young sham (Y-Sh: sinus rhythm, <3 years old, n=9), Young AF (Y-AF: 4 weeks of AF, <3 years old, n=7), Old sham (O-Sh: sinus rhythm, >8 years old, n=6), and Old AF (O-AF, 4 weeks of AF, >8 years old, n=8). Groups were matched for body weight. AF was maintained using implantable pacemakers in both AF groups. Clotting potential, expressed as the ability of activated plasma to generate thrombin, was measured using tissue factor-induced thrombin generation assays at baseline and 4 weeks (final). A terminal experiment was performed with atrial contact mapping to study electrophysiological AF properties and to collect atrial tissue for histological analysis.

Results

Thrombin generation analysis showed that 4 weeks of AF induced a significant increase in clotting potential in old, but not in young goats. AF complexity and hemodynamics were not affected by age alone. AF, however, significantly increased the right atrial pressure in old (O-Sh: 6.4±1.9 vs. O-AF: 11.4±3.1 mmHg, p=0.02), but not in young goats. AF induced atrial myocyte hypertrophy and left atrial epicardial endomysial fibrosis in old goats, while this was not the case in young goats.

Conclusion

Four weeks of AF and advanced age synergistically enhanced coagulation potential and promoted atrial structural remodeling in goats. Complexity of atrial conduction was affected by AF, but not by age.
Implementing Just Culture to Improve Patient Safety
Authors: Murray John S , Clifford Joan , Larson Stacey , Lee Jonathan K , Sculli Gary L
Published: May 2022

Introduction

The number of deaths in the United States related to medical errors remains unacceptably high. Further complicating this situation is the problem of underreporting due to the fear of the consequences. In fact, the most commonly reported cause of underreporting worldwide is the fear of the negative consequences associated with reporting. As health care organizations along the journey to high-reliability strive to improve patient safety, a concerted effort needs to be focused on changing how medical errors are addressed. A paradigm shift is needed from immediately assigning blame and punishing individuals to one that is trusting and just. Staff must trust that when errors occur, organizations will respond in a manner that is fair and appropriate.

Materials and Methods

An extensive review of the literature from 2017 until January 2022 was conducted for the most current evidence describing the principles and practices of “just culture” in health care organizations. Additionally, recommendations were sought on how health care organizations can go about implementing “just culture” principles.

Results

Twenty sources of evidence on “just culture’ were retrieved and reviewed. The evidence was used to describe the concept and principles of “just culture” in health care organizations. Furthermore, five strategies for implementing “just culture” principles were identified.

Conclusions

Improving patient safety requires that high-reliability organizations strive to ensure that the culture of the organization is trusting and just. In a trusting and just culture, adverse events are recognized as valuable opportunities to understand contributing factors and learn rather than immediately assign blame. Moving away from a blame culture is a paradigm shift for many health care organizations yet critically important for improving patient safety.
The “Politics”
Authors: Walker Michael L.
Published: May 2022

In this chapter, the problem of race as an organizing principle in Golden County jails is explored. The chapter describes a set of racialized principles known as “the politics” and explains how adherence to the politics varied from one housing unit to the next and from one type of temporary holding place to the next. In so doing, the chapter reveals cleavages in the logic of racial classification and the purported conflict said to be inherent to race relations in penal organizations. Equally important, this chapter introduces the term “flat hierarchy” and covers the many ways that race was used to distribute resources across the three racialized groups of penal residents. Finally, the author explains how deputies increased (rather than decreased) the likelihood of violence in the housing units by supporting and exploiting the politics for their own interests.
The Science of Describing
Authors: Nassar Dalia
Published: May 2022

This chapter offers a detailed explication of the kind of science that Herder and Goethe pursued—a science that aims to describe and elucidate, rather than to derive. It sheds light on differences between Kant’s aims and those of Herder and Goethe, and explains how Herder’s and Goethe’s “science of describing” challenges us to think differently about both the meaning of “explanation” and the meaning of “necessity.” It offers a first articulation of the crucial notion of the Hauptform, explicates its place within the science of describing, elaborates how it adapted and used by Goethe, and shows how this distinctive notion allows us to “remain” with the phenomenon.
Miné Okubo
Authors: Hathaway Heather
Published: May 2022

This chapter compares Okubo’s contributions to TREK to renderings of similar scenes in Citizen 13660 to explain how and why they differed, politically and aesthetically. It argues that a strategic bilingualism shaped both bodies of work in that they convey one message to those who experienced the incarceration and a different message to those who did not. This analysis is set within the context of Okubo’s work with the leftist muralist, Diego Rivera, on the 1939 Golden Gate Exposition and with Chiura Obata, who established the Tanforan and Topaz art schools. The chapter also addresses the complex position in which Okubo found herself, immediately upon her release from Topaz, as a result of the War Relocation Authority’s endorsement and partial co-optation of Citizen 13660 when it was published in 1946.
The Pulse of Granada/Amache
Authors: Hathaway Heather
Published: May 2022

This chapter reads the Pulse, the literary magazine published at Granada/Amache, alongside contemporaneous and subsequent writing by the detainees Yamato Ichihashi, Lily Yuriko Nakai Havey, and Lawson Fusao Inada, to highlight unique characteristics of this camp. It argues that, owing to the liberal views of the reports officer Joseph McLelland and of the camp director James Lindley, inmates contributing to the Pulse experienced among the highest levels of freedom of speech during the incarceration. Through the writing of the Stanford professor Ichihashi, the chapter compares Tule Lake and Granada/Amache to another in terms of inmate tension and strife. Numerous contributions to the Pulse focus on the brutal weather at Granada/Amache, and the chapter explains how this wore down the prisoners physically and emotionally. The chapter also examines the complex relationship that developed between local Indigenous Americans and incarcerated Japanese Americans who were linked by their shared oppression.
Jerome’s Magnet
Authors: Hathaway Heather
Published: May 2022

This chapter argues that the Jerome camp in southeast Arkansas differed considerably in climate and culture from the other prisons because of its location on southern swampland. It examines the literary magazine published at Jerome, the Denson Magnet, to highlight distinctive features of Jerome, paying particular attention to how wood cutting governed daily life. Wood served as the primary fuel source, compared to coal used elsewhere, so felling trees and chopping wood was required labor for male prisoners. Their inexperience with forestry also caused major injuries. Women and children were responsible for gathering wood to heat their quarters, and these activities are illustrated in the artwork of Henry Sugimoto, a Jerome prisoner. Nisei leaving Jerome as part the National Japanese Student Relocation Council (NJSRC) program and as soldiers headed for training at Camp Shelby in Mississippi or Camp Robinson in Little Rock is also discussed.
Early Kush
Authors: Emberling Geoff , Minor Elizabeth
Published: May 2022

The kingdom of Kerma was an African state located along the Nile River south of Egypt, on the edge of the ancient Middle Eastern world-system. It had complex and well-documented relations with Egypt—trade partner, military adversary, source of immigrants—from the late Old Kingdom (ca. 2300 BC) until its conquest by Egyptian armies at the beginning of the New Kingdom (ca. 1500 BC). The kingdom of Kerma also developed trade relations with regions further to the south and west, although these are much less well documented, and it mediated the exchange of products from inner Africa to Egypt and the broader Mediterranean and Middle East. This chapter summarizes the growth of the city of Kerma and the regional expansion of its culture and political control until its conquest by New Kingdom Egypt.
Elam in the Late Bronze Age
Authors: Mofidi-Nasrabadi Behzad
Published: May 2022

From the emergence of the first urban forms of society in the fourth millennium BC to the Achaemenid era, the kingdom of Elam in southwestern Iran played a significant role in the political and cultural landscape of the Middle East. After a period of political dominance of Mesopotamia over Elam in the Ur III period, the country developed into one of the wider region’s most important political and economic powers in the course of the second millennium BC. This development reached its climax in the Late Bronze Age during the so-called Middle Elamite period, when Elam’s political and economic expansion transformed the regional power structures. Such change is characterized by the concentration of power in the person of the king, whose office combined the highest secular position with religious authority. The king’s access and control over resources is reflected by the significant increase in construction activities and the foundation of new settlements, while the demand for further resources resulted in increasing military activities and wars of expansion, which led to the conquest of Mesopotamia in the last phase of the Middle Elamite period. This chapter discusses the current state of understanding of Elam’s chronology and history based on archaeological data and written sources and discusses key aspects of society, state administration, and religious practices.
Introduction
Authors: Kjær Anne Lise , Lam Joanna
Published: May 2022

The linguistic turn in twentieth century’s philosophy, as well as pragmatist trends in contemporary linguistic research, have significantly changed the theory of legal interpretation. The emergence of new streams within social and cultural studies, pointing to the importance of the context of any interpretive event, has also significantly influenced the approaches, methods, and imagery of legal interpretation. This chapter examines how the linguistic turn has in recent years affected the theory and practice of international law and international courts and tribunals, in particular in terms of a departure from the predominantly positivist interpretive tradition. This gradual change is associated with new types of challenges for adjudicators that the intensifying globalization processes in law have created. Besides the judicial activism and the dynamic interpretation style that have turned international adjudicators into writers rather than readers of the law, globalization has also affected the practice of legal interpretation in other ways. This chapter demonstrates how acting across a multiplicity of languages and legal traditions, comparative law, legal translation, and multilingual interpretation have become necessary elements in the interpretive practice of international courts and tribunals.