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Purpose The second-generation multi-electrode catheter, PVAC Gold, was designed to improve the safe delivery of phased radiofrequency energy using a “single shot” approach for pulmonary vein isolation (PVI), while retaining efficacy. This large registry presents long-term performance in a daily practice setting. Methods A total of 1011 patients undergoing first time ablation for atrial fibrillation (AF) using PVAC Gold were included, 639 patients with PVI for paroxysmal AF (PAF PVI) and 372 patients with persistent or long-standing persistent AF, divided into 175 patients receiving PVI only (PersAF PVI) and 197 patients receiving PVI with additional substrate ablation (PersAF PVI +). Results At 24-month follow-up, single procedure freedom from atrial tachyarrhythmia (ATA) was 58% (368/639) in the PAF PVI group, 44% (77/175) in the PersAF PVI group, and 29% (57/197) in the PersAF PVI + group. Allowing one repeat procedure in 33% of patients, 76%, 65%, and 54% were free from ATA at 24 months, respectively. Pulmonary vein reconnection was observed in 98% of patients with recurrent arrhythmia after PVI. Conclusions Although phased RF ablation with PVAC Gold is quick and safe, the efficacy outcomes are modest compared to current mainstream ablation strategies.

Introduction: Over the past years, mapping and ablation techniques for the treatment of ventricular tachycardia (VT) have evolved rapidly. High Density (HD) substrate mapping is now routine and pre-procedural imaging is increasingly used. The additional value of these techniques for long-term VT-free survival is not clear. Methods: We compared baseline and procedural characteristics, procedural success, safety and outcome of mapping and ablation of ventricular tachycardia in patients with ischemic heart disease between two groups. (1) Low Density (LD) group: VT mapping and ablation with a 4 mm single tip catheter (2) HD group: HD substrate mapping with the Pentaray (Biosense Webster, USA) or HD Grid (Abbott, USA) catheter and ablation with a 4 mm single tip catheter. Results: VT ablation was performed in 133 patients (71 patients in LD group and 62 patients in HD group). The median follow-up was 5.0 years in LD group and 2.0 years in HD group. One-, two-, and five-year VT recurrence rates were 47%, 56%, and 65% in the LD group versus 39%, 50%, and 55% in the HD group (log-rank test for VT recurrence p =.70). One-, two-, and five-year ICD shock recurrence rates were 14%, 18%, and 24% in the LD group versus 8%, 15%, and 19% in the HD group (log-rank test for ICD-shock p =.79). All-cause mortality, cardiac (non-arrhythmic), and arrhythmic death, were similar in both groups. Severe procedural complications (tamponade, stroke, or procedural death) occurred in four patients (5%, 1 vascular, 3 tamponade) in the LD group versus two patients (3%, both tamponade) in the HD group (NS). In univariate and multivariable analysis, only a higher LVEF was significantly associated with VT-free survival. HD mapping was not significantly associated with VT-free survival. Anterior infarct location and age were significantly associated with ICD recurrent shock in both univariate and multivariable analyses. Conclusions: In patients with ischemic cardiomyopathy, a HD substrate mapping, and ablation strategy did not lead to higher VT-free survival and shock-free survival compared to a single tip mapping and ablation strategy. In this study, only LVF is an independent predictor for VT recurrence. Anterior infarct location and age predict recurrent ICD shocks.

Funding Acknowledgements Type of funding sources: None. Background Leadless pacemakers (LPs) were designed to circumvent pocket- and lead-related pacemaker complications. Up to two years after implantation, adequate real-world safety and efficacy have been demonstrated. Because the duration of pacemaker therapy is well over two years, longer-term data is warranted for the net clinical benefit of leadless pacing. Objective Our aim was to evaluate the safety and efficacy of LP therapy on the long-term in a real-world cohort. Methods In this retrospective cohort study, all consecutive patients were included with a first LP implantation (Nanostim LP or Micra VR LP) from December 21, 2012 to December 13, 2016 in 6 Dutch high-volume centers. The primary safety endpoint was the rate of procedure- or device-related major complications at 5-year follow-up. Analyses were performed with and without the Nanostim battery advisory-related complications. The efficacy is described as pacing threshold, impedance and R-wave amplitude over time; changes in these parameters were assessed using mixed models. Results 179 patients were included (117 [65%] male, mean age 79±9 years), of whom 93 (52%) with a Nanostim and 86 (48%) with a Micra LP. Mean follow-up duration was 45±25 months. A total of 46 major complications occurred, of which 8 not advisory-related. The 5-year major complication rate without advisory-related complications was 4.5% (Figure, A). Including advisory-related complications, the 5-year major complication rate was 30.5%. Not advisory-related complications included dislocations (n=3, of which 2 periprocedurally), pericardial effusion (n=1), groin bleeding (n=1), loss-of-capture (n=2) and pacemaker syndrome (n=1). Reinterventions were required in 7/8 (88%), only prolonged hospitalization in 1 (12%; the groin bleeding), and surgery in none. All 8 occurred within 90 days after implantation. Pacing threshold was stable over time (p=0.53), R-wave amplitude increased (p=0.002), and impedance decreased (p Conclusion The long-term major complication rate excluding advisory-related complications was low. Especially few complications occurred after the acute phase, which may be a specific benefit of LP therapy. The performance was adequate with a stable pacing threshold over time, whereas in transvenous pacemakers usually a gradually increasing threshold is seen. These findings confirm previous safety and efficacy results and are promising for longer-term data on leadless pacing.

Funding Acknowledgements Type of funding sources: None. Background Dielectric imaging is used by the KODEX-EPD system to provide information that can be used to guide catheter ablation of cardiac arrhythmia. This includes assessment of catheter-tissue contact (No touch, Touch, or High touch) and local atrial wall thickness (mm). Additionally, the system can detect changes in local dielectric tissue properties to assess the effect of a radiofrequency energy application. This assessment is used to classify ablation points into low or high dielectric response (LDR or HDR), which was designed to indicate the extent of lesion transmurality. Objectives To evaluate the relation between dielectric response and other ablation parameters. Methods The KODEX-EPD system was used to guide ablation in patients with prior pulmonary vein isolation. Ablation included re-isolation of the pulmonary veins and isolation of the superior vena cava if deemed necessary. We downloaded system data from all procedures that were performed with software that provided dielectric response (version 1.5.0, 1.5.0a, 1.5.1 and 1.5.1a) and analyzed the parameters of all individual ablation points. Results The cohort includes 55 patients, in which 135 pulmonary veins and 19 superior venae cavae were targeted. A total of 860 energy applications were applied, resulting in 1458 ablation points. The system classified 31% of ablation points as HDR and 19% as LDR. The system did not provide a dielectric response in 49%. The system’s ability to determine dielectric response was related to the software version(oldest version 71% no DR, newest version 18%) and duration of ablation. High dielectric response (versus LDR or no DR) was multivariably associated with longer energy applications, higher mean ablation power and lower local wall thickness (Table). Mean ablation temperature and impedance drop were not multivariably associated with dielectric response. Conclusion Dielectric response is independently associated with local wall thickness, ablation power and duration, but not with ablation temperature and impedance drop. Newer software versions have reduced the proportion of ablation points for which no dielectric response was provided.

Funding Acknowledgements Type of funding sources: None. Introduction Extravascular devices (EVD), such as the subcutaneous ICD (S-ICD) and leadless pacemaker (LP), have been developed to circumvent pocket- and lead-related device complications. Knowledge on trends in adoption of these devices among patient categories and hospital types is mainly derived from industry-initiated studies or selected populations. Purpose To assess the real-world nationwide trends in adoption of EVDs in the Netherlands. Methods Using real-world data registered at the Netherlands Heart Registration from 72 Dutch device-implanting hospitals, all consecutive patients were included with an EVD implantation (de novo or replacement) from 2012-2020. To describe the relative adoption of EVDs, all consecutive patients with a single-chamber conventional ICD or pacemaker were also included (pacemakers from 2014, the first LP registration). Trends in EVD adoption are described for different patient (age, gender, and BMI) and hospital (tertiles of device-implanting volume and implanting center [general , intervention, or thorax]) characteristics. Differences in adoption were tested using Chi-square and Fisher’s exact tests. Results From 2012-2020, 2862 S-ICDs and 15806 single-chamber conventional ICDs were implanted, while from 2014-2020, 785 LPs and 16530 single-chamber conventional pacemakers were implanted. S-ICD use among single-chamber ICD recipients increased from 7% to 22% and LP use among single-chamber pacemaker recipients increased from 1% to 8%, although utilization has levelled off in recent years (Fig. 1). The relative use of S-ICDs was largest in patients aged 10-30 years and declined with higher age (p Conclusions Although EVDs have been adopted early in the Netherlands, their utilization has levelled off in recent years, possibly driven by higher cost, battery issues, or the COVID-19 pandemic. Utilization of S-ICDs is highest among younger patients while utilization of LPs was not specifically high in certain age groups. The effects of gender and BMI were smaller. EVDs were mainly implanted in high-volume thorax centers.

Background Left atrial appendage occlusion (LAAO) may be a viable option for stroke prevention in patients with non-valvular atrial fibrillation and a contraindication for oral anticoagulation. No evidence evaluating the safety of this procedure in patients with a cardiac implantable electronic device (CIED) exists. The aim of this study was to evaluate whether CIED function is affected by LAAO and to explore LAAO procedural characteristics and complications in patients with a CIED. Methods This single-center cohort study included consecutive patients scheduled for percutaneous LAAO. Patients with a CIED prior to LAAO were selected and compared to the patients without CIED, concerning procedural characteristics and peri-procedural complications. In the group of patients with CIEDs, essential pacemaker integrity parameters were compared before and after the procedure to detect possible micro and macro lead displacements. Results Thirty-one patients with CIED were scheduled for LAAO (age 73.7 ± 5.4 years, 65% males, CHA2DS2-VASc 4.3 ± 1.5, and HAS-BLED 3.3 ± 1.0). The 245 patients without CIED were younger, and HAS-BLED-score was slightly lower (69.4 ± 8.2 years, p p = 0.022). Patients without CIED more frequently underwent LAAO combined with catheter ablation (p = 0.002). All other procedural characteristics were comparable between both groups. No visible lead displacement was observed on chest X-ray after LAAO. Additionally, no differences in impedance, threshold, or intracardiac sensing in various CIED lead locations were found prior versus post LAAO. Conclusion This study supports the feasibility and safety of LAAO in patients with a CIED.

Background Risk stratification for sudden cardiac death (SCD) in cardiac sarcoidosis (CS) is challenging in patients without overt cardiac symptoms. Objective This study reports the incidence of ventricular arrhythmias (VA) and mortality after long-term monitoring with cardiovascular implantable electronic devices (CIED) in CS patients identified after systematic screening in patients with extra-cardiac sarcoidosis (ECS). Methods A retrospective study was performed in 547 predominantly Caucasian patients with ECS screened for cardiac involvement. If CS was diagnosed, risk stratification (high- versus low-risk) for SCD was performed by a multidisciplinary team. The primary endpoint was defined as sustained VA, appropriate implantable cardioverter defibrillator (ICD) therapy or cardiac death. Results In total, 105 patients were included with a mean follow-up of 33±16 months. An ICD was implanted in 17 high-risk patients (16.2%), while 80 low-risk patients (76.1%) received an implantable loop recorder (ILR). Eight low-risk patients (7.6%) did not receive a device. The primary endpoint occurred in 4.8% (n=5) with an overall annualized event rate of 1.7%. The annualized event rate was 9.8% in high-risk patients and 0.4% in low-risk patients. Nine low-risk patients received an ICD during follow-up; in 7 patients due to ILR recordings. None of these patients required ICD therapy. Conclusion Overall, the annualized event rate of VA and cardiac death in CS patients without overt cardiac symptoms at initial presentation was 1.7%, but the event rate increased to 10% in high-risk patients. In low-risk patients, long-term arrhythmia monitoring enabled early detection of clinically important arrhythmias, without showing impact on prognosis.

Subcutaneous implantable cardioverter/defibrillators (S-ICDs) have been developed to offer ICD treatment to patients without venous access to the heart and to overcome complications associated with transvenous leads, particularly lead fracture/insulation defects and endocarditis. Several studies and registries have demonstrated the feasibility and safety of S‑ICD in different groups of patients. Further developments in S‑ICD technology involve the combination with devices that can provide anti-bradycardia and anti-tachycardia pacing if needed. The extravascular ICD (EV-ICD) is a new system that similarly offers ICD therapy without a transvenous lead but uses a substernal instead of a subcutaneous lead to facilitate detection of ventricular fibrillation and to provide anti-tachycardia and also temporary anti-bradycardia pacing. The first animal but also clinical data on EV-ICDs have been published. This review discusses the current state, potential advantages and limitations, and future research of both S‑ICD and EV-ICD.

Introduction The AcQMap High Resolution Imaging and Mapping System was recently introduced. This system provides 3D maps of electrical activation across an ultrasound-acquired atrial surface. Methods We evaluated the feasibility and the acute and short-term efficacy and safety of this novel system for ablation of persistent atrial fibrillation (AF) and atypical atrial flutter. Results A total of 21 consecutive patients (age (mean ± standard deviation) 62 ± 8 years, 23% female) underwent catheter ablation with the use of the AcQMap System. Fourteen patients (67%) were treated for persistent AF and 7 patients (33%) for atypical atrial flutter. Eighteen patients (86%) had undergone at least one prior ablation procedure. Acute success, defined as sinus rhythm without the ability to provoke the clinical arrhythmia, was achieved in 17 patients (81%). At 12 months, 4 patients treated for persistent AF (29%) and 4 patients treated for atypical flutter (57%) remained in sinus rhythm. Complications included hemiparesis, for which intra-arterial thrombolysis was given with subsequent good clinical outcome (n = 1), and complete atrioventricular block, for which a permanent pacemaker was implanted (n = 2). No major complications attributable to the mapping system occurred. Conclusion The AcQMap System is able to provide fast, high-resolution activation maps of persistent AF and atypical atrial flutter. Despite a high acute success rate, the recurrence rate of persistent AF was relatively high. This may be due to the selection of the patients with therapy-resistant arrhythmias and limited experience in the optimal use of this mapping system that is still under development.

Background Dielectric imaging systems can be used to guide catheter ablation for cardiac arrhythmia. Currently, the KODEX-EPD system can be used to acquire high-resolution anatomical data for electroanatomical mapping. Future software versions of this system enable tissue assessment utilizing local dielectric sensing. These dielectric-based tissue assessments (KODEX Vision) enable new features, including wall thickness measurement, catheter-tissue contact assessment, and ablation lesion assessment. Purpose To gain insight in the dielectric-based tissue assessment features. Methods The KODEX-EPD system was used to perform repeat ablations in patients with recurrent atrial fibrillation after pulmonary vein isolation. A primary system with the current software version (1.4.8) was used by the operator. Ablation was performed with a non-contact force-sensing irrigated radiofrequency catheter, with power set at 30–35W and aiming for ablation times of 30–60s. A secondary system was blinded for the operator and loaded with beta software (1.5.0) to enable the KODEX Vision features. Only successful local tissue assessments are presented in this abstract. All patients were enrolled in a prospective registry study which was approved by the local ethics committee. Results Electroanatomic mapping in 25 patients (age 65±8yr, male 84%, LAVI 31±9ml/m2) revealed electrical reconnection in 66 of 100 pulmonary veins. A total of 308 radiofrequency applications were used to re-isolate the veins and create additional lesions (superior vena cava isolation in 6, box lesion in 1). Wall thickness at the sites of ablation ranged from 1.3–3.9 mm. Tissue contact assessment at the start of RF applications indicated “touch” in 77%, while 17.5% and 5.5% of results indicated `no touch' or “high touch”. Tissue Response Viewer indicated low dielectric response in 18.5% and high dielectric response in 81.5% of results. High dielectric response was associated with lower wall thickness (OR: 0.86, 95% CI [0.76–0.97], p=0.014). Conclusion This preliminary evaluation underlines the potential of dielectric-based tissue assessment features. Wall thickness measurement, catheter-tissue contact, and ablation lesion assessment seem feasible with the beta software. Further evaluation of the feasibility, accuracy and clinical impact of the finalized software is warranted. Funding Acknowledgement Type of funding sources: None.

ObjectiveThe Rate Control versus Electrical Cardioversion Trial 7–Acute Cardioversion versus Wait and See trial compared early to delayed cardioversion for patients with recent-onset symptomatic atrial fibrillation (AF). This study aims to evaluate the adherence to a 4-week mobile health (mHealth) prescription to detect AF recurrences after an emergency department visit.MethodsAfter the emergency department visit, the 437 included patients, irrespective of randomisation arm (early or delayed cardioversion), were asked to record heart rate and rhythm for 1 min three times daily and in case of symptoms by an electrocardiography-based handheld device for 4 weeks (if available). Adherence was appraised as number of performed measurements per number of recordings asked from the patient and was evaluated for longitudinal adherence consistency. All patients who used the handheld device were included in this subanalysis.Results335 patients (58% males; median age 67 (IQR 11) years) were included. The median overall adherence of all patients was 83.3% (IQR 29.9%). The median number of monitoring days was 27 out of 27 (IQR 5), whereas the median number of full monitoring days was 16 out of 27 (IQR 14). Higher age and a previous paroxysm of AF were identified as multivariable adjusted factors associated with adherence.ConclusionsIn this randomised trial, a 4-week mHealth prescription to monitor for AF recurrences after an emergency department visit for recent-onset AF was feasible with 85.7% of patients consistently using the device with at least one measurement per day. Older patients were more adherent.Trial registration numberNCT02248753.

We describe a case of a boy with neurodevelopmental delay and a diffuse large B-cell lymphoma (DLBCL) in whom we discovered a germline de novo 2p16.3 deletion including MSH6 and part of the FBXO11 gene. A causative role for MSH6 in cancer development was excluded based on tumor characteristics. The constitutional FBXO11 deletion explains the neurodevelopmental delay in the patient. The FBXO11 protein is involved in BCL-6 ubiquitination and BCL-6 is required for the germinal center reaction resulting in B cell differentiation. Somatic loss of function alterations of FBXO11 result in BCL-6 overexpression which is a known driver in DLBCL. We therefore consider that a causative relationship between the germline FBXO11 deletion and the development of DLBCL in this boy is conceivable.

Fragile perinatal and fetal brains are the rule rather than the exception for developmental neuropathologists. Retrieving the fresh brain from the skull and examining early fetal, macerated or severely hydrocephalic brains after fixation can be a challenge. Textbooks on neurodevelopmental pathology mention these challenges to macroscopic examination of the developing central nervous system only in passing, but many perinatal pathologists recognize this diagnostic problem. We reviewed protocols and publications on the removal, fixation, slicing and sampling of these fetal- and perinatal brains. In addition, we describe a technique to facilitate the removal of severely hydrocephalic brains with very thin cerebral walls from the skull by replacing the intraventricular fluid with agar in-situ. Furthermore, we present a method for post-fixation pre-embedding in agar to facilitate slicing, macroscopic examination and sampling of fragile and macerated brains.

Purpose The second-generation multi-electrode catheter, pulmonary vein ablation catheter (PVAC) GOLD, was designed to improve the delivery of phased radiofrequency energy and reduce procedure times using a ‘single-shot’ approach for pulmonary vein isolation (PVI), while retaining efficacy and safety. This large registry presents acute success rates and safety outcomes in a daily practice setting. Methods A total of 1017 patients undergoing first-time ablation for atrial fibrillation (AF) using PVAC GOLD were included, 644 patients with paroxysmal AF and 373 patients with non-paroxysmal AF, divided into 175 patients receiving PVI only and 198 patients receiving PVI with additional substrate modification. Results High and comparable percentages of successful PVI could be achieved in all groups (98%, 95% and 99%; p = 0.108). The median total procedure time for all groups was 90 min [70–100]. As expected, the total procedure, ablation and fluoroscopy time were significantly longer in the PVI + substrate modification group compared with the PVI-only cases (all p p = 0.306, p = 0.088, p = 0.233, respectively). A total of 44 complications were observed in 43 patients (4.2%). Major complications were seen in 19 patients (1.87%) and non-major procedure–related complications were seen in 25 patients (2.46%). Complications leaving permanent sequelae were rare and occurred in only four patients (0.39%). Complications did not differ between groups (p = 0.199, p = 0.438, p = 0.240 and p = 0.465 respectively). Conclusion PVAC GOLD performs successful PVI, while reducing procedure times and retaining safety for paroxysmal, persistent and long-standing persistent AF. Safety was unaffected by additional substrate modification.

Ablation of atypical atrial flutter (AAFL) can be challenging. High-density (HD) mapping of ablation targets may potentially increase procedural success and freedom from recurrent AAFL. The objective of the present study was to explore whether employing HD mapping leads to a more favorable outcome in ablation of AAFL. We compared baseline and procedural characteristics, procedural success, safety and outcome of mapping and ablation of atypical flutter in three groups. (1) HD Grid catheter + the high-density electroanatomical mapping (EAM) system EnSite Precision; (2) standard 10-pole circular mapping catheter (CMC) + EnSite Precision; (3) CMC + the low-density EnSite Velocity EAM. Voltage and propagation maps were constructed. Mapping of 142 AAFL in 82 patients was performed. Acute ablation success was 78%, 68%, and 51% in groups 1, 2, and 3 (p = 0.037 between group 1 and 3, non-significant between groups otherwise). Moreover, 8%, 27%, and 36% of flutters were unmappable in groups 1, 2, and 3, respectively (p < 0.05 between group 1 and both groups 2 and 3). AAFL recurrence at 1-year FU was 26%, 36%, and 62% in groups 1, 2, and 3 (p = 0.007 between groups 1 and 3, p = 0.05 between groups 2 and 3). AAFL-free survival was significantly higher in patients mapped with Precision than with Velocity (p = 0.011). No strokes or mortality occurred within 30 days. Acute procedural success of ablation of atypical atrial flutter is higher and the number of unmappable flutters is lower using the HD Grid mapping catheter in combination with the high-density EnSite Precision system, as compared to a decapolar circular mapping catheter and the low-density EnSite Velocity EAM system. This may lead to increased freedom from recurrent AAFL at 1 year. HD mapping is safe.

The completely subcutaneous implantable cardioverter defibrillator (S-ICD) is rapidly evolving to become a complete alternative for the transvenous ICD (TV-ICD) leaving the heart and vasculature untouched. Newer trials and registries in cohorts that are similar to real-world ICD patient populations confirm the initial data on safety and efficacy. Technical improvements have resulted in reduced inappropriate shock rates, although more data are warranted, and new developments such as substernal lead positioning, communication between the S-ICD and a leadless cardiac pacemaker and remote monitoring options have evolved to overcome the shortcomings of S-ICD therapy. With these continuing developments, it is expected that within the next years the S-ICD will continue to evolve to a treatment option for ventricular arrhythmia as effective as the TV-ICD overcoming the shortcomings of transvenous leads as well as the drawbacks of the initial system, providing effective shock therapy, pacing capabilities, low complication and inappropriate therapy rates, and automated remote monitoring.

Introduction: Atrial fibrillation (AF) is associated with an increased risk of stroke. Stroke prevention with oral anticoagulation (OAC) is recommended in AF patients at increased risk of stroke. The left atrial appendage (LAA) is the main source of thrombus formation in AF patients. The WATCHMAN percutaneous LAA closure (LAAC) device may serve as an alternative to OAC overcoming disadvantages including the risk of (major) bleeding. Areas covered: This review will focus on LAAC with the Watchman device for stroke prevention in AF patients. Current status, available literature, clinical safety and efficacy will be summarized. Furthermore, the future perspectives of Watchman will be discussed. Expert opinion: LAAC with Watchman appears a promising, safe, and effective alternative to OAC. Ongoing and future studies to consolidate the position of Watchman should focus on comparative safety and efficacy of different LAAC devices, patient selection, various post-procedural antithrombotic regimens, head-to-head comparisons with NOAC, better understanding of device-related thrombus, and the role of the LAA in the propagation of non-valvular AF. This research may attribute to a paradigm shift in which LAAC no longer serves as a ’last resort’ treatment for AF patients ineligible for OAC but may serve as a second-line or even first-line treatment option for AF patients.

Introduction In patients with a prior myocardial infarction (MI) but preserved left ventricular (LV) function, sustained ventricular arrhythmias (VAs) may arise in the setting of an acute coronary syndrome (ACS). It is unknown whether an implantable cardioverter-defibrillator (ICD) is mandatory in these patients as VA might be triggered by a reversible cause. The purpose of this study is to analyze the benefit of ICD therapy in this patient population. Methods We conducted a retrospective observational study in ICD recipients implanted from 2008 to 2011. The study group consisted of patients with sustained VA in the setting of an ACS, with a history of MI, but with left ventricular ejection fraction (LVEF) greater than 35 (group A). The two control groups consisted of patients admitted with VA with a history of MI, but without ACS at presentation, either with LVEF greater than 35% (group B) or ≤35% (group C). The primary endpoint was the number of patients with appropriate ICD therapy (antitachycardia pacing or shock). Results A total of 291 patients were included with a mean follow-up of 5.3 years. Appropriate ICD therapy occurred in 45.6% of the patients in group A vs 51.6% and 60.4% in groups B and C (P = .11). In group A, 31.1% received an appropriate ICD shock vs 34.7% and 44.3% in control groups B and C (P = .12). Conclusion On the basis of these data, ICD implantation seems warranted in patients with history of MI presenting with VA in the setting of an ACS, despite preserved LV function and adequate revascularization. Further trials, preferably randomizes, should be performed to address these findings.

Aims In patients with atrial fibrillation (AF) and heart failure (HF), strict and regular rate control with atrioventricular junction ablation and biventricular pacemaker (Ablation + CRT) has been shown to be superior to pharmacological rate control in reducing HF hospitalizations. However, whether it also improves survival is unknown. Methods and results In this international, open-label, blinded outcome trial, we randomly assigned patients with severely symptomatic permanent AF >6 months, narrow QRS (≤110 ms) and at least one HF hospitalization in the previous year to Ablation + CRT or to pharmacological rate control. We hypothesized that Ablation + CRT is superior in reducing the primary endpoint of all-cause mortality. A total of 133 patients were randomized. The mean age was 73 ± 10 years, and 62 (47%) were females. The trial was stopped for efficacy at interim analysis after a median of 29 months of follow-up per patient. The primary endpoint occurred in 7 patients (11%) in the Ablation + CRT arm and in 20 patients (29%) in the Drug arm [hazard ratio (HR) 0.26, 95% confidence interval (CI) 0.10–0.65; P = 0.004]. The estimated death rates at 2 years were 5% and 21%, respectively; at 4 years, 14% and 41%. The benefit of Ablation + CRT of all-cause mortality was similar in patients with ejection fraction (EF) ≤35% and in those with >35%. The secondary endpoint combining all-cause mortality or HF hospitalization was significantly lower in the Ablation + CRT arm [18 (29%) vs. 36 (51%); HR 0.40, 95% CI 0.22–0.73; P = 0.002]. Conclusions Ablation + CRT was superior to pharmacological therapy in reducing mortality in patients with permanent AF and narrow QRS who were hospitalized for HF, irrespective of their baseline EF. Study registration ClinicalTrials.gov Identifier: NCT02137187.

Rho kinase activity in hepatic stellate cells (HSCs) is associated with activation, transformation and contraction of these cells, leading to extracellular matrix production and portal hypertension in liver cirrhosis. Inhibition of rho kinase activity can reduce these activities, but may also lead to side effects, for instance systemic hypotension. This can be circumvented by liver-specific delivery of a rho kinase inhibitor to effector cells. Therefore, we targeted the rho kinase inhibitor Y27632 to the key pathogenic cells in liver fibrosis, i.e. myofibroblasts including activated HSCs that highly express the PDGF beta-receptor, using the drug carrier pPB-MSA. This carrier consists of mouse serum albumin (MSA) covalently coupled to several PDGF beta-recognizing moieties (pPB). We aimed to create a prolonged release system of such a targeted construct, by encapsulating pPB-MSA-Y27632 in biodegradable polymeric microspheres, thereby reducing short-lasting peak concentrations and the need for frequent administrations. Firstly, we confirmed the vasodilating potency of PDGF beta-receptor targeted Y27632 in vitro in a contraction assay using HSCs seeded on a collagen gel. We subsequently demonstrated the in vivo antifibrotic efficacy of pPB-MSA-Y27632-loaded microspheres in the Mdr2 - / - mouse model of progressive biliary liver fibrosis. A single subcutaneous microsphere administration followed by organ harvest one week later clearly attenuated liver fibrosis progression and significantly suppressed the expression of fibrosis related genes, such as several collagens, profibrotic cytokines and matrix metalloproteinases. In conclusion, we demonstrate that polymeric microspheres are suitable as drug delivery system for the sustained systemic delivery of targeted protein constructs with antifibrotic potential, such as pPB-MSA-Y27632. This formulation appears suitable for the sustained treatment of liver fibrosis and possibly other chronic diseases.

Automated detection of cancer metastases in lymph nodes has the potential to improve the assessment of prognosis for patients. To enable fair comparison between the algorithms for this purpose, we set up the CAMELYON17 challenge in conjunction with the IEEE International Symposium on Biomedical Imaging 2017 Conference in Melbourne. Over 300 participants registered on the challenge website, of which 23 teams submitted a total of 37 algorithms before the initial deadline. Participants were provided with 899 whole-slide images (WSIs) for developing their algorithms. The developed algorithms were evaluated based on the test set encompassing 100 patients and 500 WSIs. The evaluation metric used was a quadratic weighted Cohen's kappa. We discuss the algorithmic details of the 10 best pre-conference and two post-conference submissions. All these participants used convolutional neural networks in combination with pre- and postprocessing steps. Algorithms differed mostly in neural network architecture, training strategy, and pre- and postprocessing methodology. Overall, the kappa metric ranged from 0.89 to -0.13 across all submissions. The best results were obtained with pre-trained architectures such as ResNet. Confusion matrix analysis revealed that all participants struggled with reliably identifying isolated tumor cells, the smallest type of metastasis, with detection rates below 40%. Qualitative inspection of the results of the top participants showed categories of false positives, such as nerves or contamination, which could be targeted for further optimization. Last, we show that simple combinations of the top algorithms result in higher kappa metric values than any algorithm individually, with 0.93 for the best combination.

Aims Pulmonary vein isolation (PVI) for atrial fibrillation (AF) has become increasingly safe and effective with the evolution of single-tip ablation catheters aided by contact force sensing (ST-CF) and single-shot devices such as the second-generation pulmonary vein ablation catheter (PVAC) Gold multi-electrode array. The multicentre randomized GOLD FORCE trial was conducted to evaluate non-inferiority of safety and efficacy of PVAC Gold PVI compared to ST-CF ablation for paroxysmal AF. Methods and results The primary efficacy endpoint documented AF recurrence ≥30 s was assessed by time-to-first-event analysis after a 90-day blanking period using repeated 7-day Holters. Secondary endpoints include acute success and procedural characteristics. Safety endpoints included procedural complications, stroke/transient ischaemic attack (TIA), tamponade, bleeding, and access site complications. Two hundred and eight patients underwent randomization and PVI (103 assigned to PVAC Gold, 105 to ST-CF). Acute success rates were 95% and 97% for PVAC Gold and ST-CF, respectively. At 12 months, AF recurrence was observed in 46.6% of the PVAC Gold group and in 26.2% of the ST-CF group [absolute efficacy difference 20.4% (95% confidence interval, CI 7.5–33.2%), hazard ratio 2.05 (95% CI 1.28–3.29), P = 0.003]. PVAC Gold had significantly shorter procedure and ablation times. Complication rates were 5.7% and 4.9% for PVAC Gold and ST-CF, respectively (P = 0.782). Conclusion In this multicentre randomized clinical trial, ablation with ST-CF and PVAC Gold ablation catheters non-inferiority for efficacy was not met. AF recurrence was significantly more frequent in the PVAC Gold group compared to single-tip contact force group. Both groups had similarly low rates of adverse events. PVAC Gold ablation had significantly shorter procedure and ablation times.

Synthetic textiles shed fibers that accumulate indoors and this results in continuous exposure when indoors. High exposure to microplastic fibers in nylon flock workers has been linked to the development of airway and interstitial lung disease, but the exact health effects of microplastic fibers on the lungs are unknown. Here we determined effects of polyester and nylon textile microplastic fibers on airway and alveolar epithelial cells using human and murine lung organoids. We observed that particularly nylon microfibers had a negative impact on the growth and development of airway organoids. We demonstrated that this effect was mediated by components leaking from nylon. Moreover, our data suggested that microplastic textile fibers may especially harm the developing airways or airways undergoing repair. Our results call for a need to assess exposure and inhalation levels in indoor environments to accurately determine the actual risk of these fibers to human health.TeaserAirborne fibers shed from synthetic textiles, in particular nylon, can inhibit repair of the cells coating the airways

At a time when self-sufficiency and health are becoming increasingly important in society, the chances of intoxications with wild plants are increasing. Foxglove contains poisonous cardiac glycosides such as digoxin, digitoxin and gitoxin. The levels vary greatly and depend on the season and the location of the plants. The "non-digoxin" cardiac glycosides show a limited cross-reaction with the digoxin assay. This means that a low or therapeutic digoxin level does not rule out a severe foxglove intoxication. Due to the long half-life of the different cardiac glycosides, toxic symptoms can be persistent.A 43-year-old woman arrived at the Emergency Department with persistent vomiting and specific ECG-abnormalities. The day before, she drunk a smoothie made from wild plants picked in the woods. Patient appeared to have mistaken foxglove for common sorrel.In case of persistent gastrointestinal complaints with specific ECG abnormalities after ingestion of plant material, clinicians should be aware of a foxglove intoxication.

We exhibit the generation of soliton microcombs with 1.48-THz line spacing over 8.8 THz around 1575 nm by using the self-injection locking of a III-V DFB laser butt-coupled to a Si3N4 microresonator.

Ablation of atypical atrial flutter (AAFL) can be challenging. High-density (HD) mapping of ablation targets may potentially increase procedural success and freedom from recurrent AAFL. The objective of the present study was to explore whether employing HD mapping leads to a more favorable outcome in ablation of AAFL.We compared baseline and procedural characteristics, procedural success, safety and outcome of mapping and ablation of atypical flutter in three groups. (1) HD Grid catheter + the high-density electroanatomical mapping (EAM) system EnSite Precision; (2) standard 10-pole circular mapping catheter (CMC) + EnSite Precision; (3) CMC + the low-density EnSite Velocity EAM. Voltage and propagation maps were constructed.Mapping of 142 AAFL in 82 patients was performed. Acute ablation success was 78%, 68%, and 51% in groups 1, 2, and 3 (p = 0.037 between group 1 and 3, non-significant between groups otherwise). Moreover, 8%, 27%, and 36% of flutters were unmappable in groups 1, 2, and 3, respectively (p0.05 between group 1 and both groups 2 and 3). AAFL recurrence at 1-year FU was 26%, 36%, and 62% in groups 1, 2, and 3 (p = 0.007 between groups 1 and 3, p = 0.05 between groups 2 and 3). AAFL-free survival was significantly higher in patients mapped with Precision than with Velocity (p = 0.011). No strokes or mortality occurred within 30 days.Acute procedural success of ablation of atypical atrial flutter is higher and the number of unmappable flutters is lower using the HD Grid mapping catheter in combination with the high-density EnSite Precision system, as compared to a decapolar circular mapping catheter and the low-density EnSite Velocity EAM system. This may lead to increased freedom from recurrent AAFL at 1 year. HD mapping is safe.

Introduction: Treatment infections is challenging in pacemaker (PM) dependent patients. We proposed a novel implantation strategy for this group of patients. Methods: Patients who were PM dependent and were admitted with a PM infection received a combined procedure of left ventricular (LV) epicardial implantation of a PM lead and subsequent extraction of the infected system. No temporary pacing wire was used and the PM generator was placed in the left flank. Results: Between 2012 and 2015 we treated 16 patients who were PM dependent and with a PM infection. The majority of patients were male (81% [13/16]) and the median age was 71 years (50–91). The cause of infection was valvular endocarditis in 38% (6/16), lead infection in 25% (4/16), and isolated pocket infection in 38% (6/16). All patients underwent epicardial implantation of a LV lead (1084T bipolar lead; St. Jude Medical Myodex, St. Paul, MN, USA) and extraction of the infected device. There was no occurrence of periprocedural mortality and no postprocedural tamponades. There was one complication in the form of a hemorrhage at the infected device extraction site. In the median follow-up period of 17 months there were four of 16 deaths, none of which were attributable to epicardial LV implantation. LV-lead threshold was 1.1V (±0.7V) upon implantation that increased to 1.2V (±0.6V) at 0.4-ms pulse duration. There were no reinfections of the epicardial lead or device. Conclusion: Epicardial left ventricle PM implantation and subsequent extraction of an infected PM in PM-dependent patients is feasible and safe with good long-term outcome.

Injectable sustained release drug delivery systems are an attractive alternative for the intravenous delivery of therapeutic proteins. In particular, for chronic diseases such as fibrosis, this approach could improve therapy by reducing the administration frequency while avoiding large variations in plasma levels. In fibrotic tissues the platelet-derived growth factor receptor beta (PDGFβR) is highly upregulated, which provides a target for site-specific delivery of drugs. Our aim was to develop an injectable sustained release formulation for the subcutaneous delivery of the PDGFβR-targeted drug carrier protein pPB-HSA, which is composed of multiple PDGFβR-recognizing moieties (pPB) attached to human serum albumin (HSA). We used blends of biodegradable multi-block copolymers with different swelling degree to optimize the release rate using the model protein HSA from microspheres produced via a water-in-oil-in-water double emulsion evaporation process. The optimized formulation containing pPB-HSA, showed complete release in vitro within 14 days. After subcutaneous administration to mice suffering from renal fibrosis pPB-HSA was released from the microspheres and distributed into plasma for at least 7days after administration. Furthermore, we demonstrated an enhanced accumulation of pPB-HSA in the fibrotic kidney. Altogether, we show that subcutaneously administered polymeric microspheres present a suitable sustained release drug delivery system for the controlled systemic delivery for proteins such as pPB-HSA.

Introduction Optimal left ventricular (LV) lead position in patients undergoing cardiac resynchronization therapy(CRT) is crucial to achieve an optimal effect on hemodynamics. Due to various difficulties, up to 30% of transvenous LV lead placements fail, or a suboptimal position is achieved. Surgical epicardial LV lead placement could be performed at a position anticipated to be the optimal site. This could have a more favorable effect, which may be expressed by increased improvement in left ventricular ejection fraction(LVEF) and cardiac perfusion. The objective of this trial is to compare transvenous versus epicardial LV lead placement in CRT in a randomized fashion Methods and results : 52 patients were randomized to either epicardial or transvenous approach. All patients received an ICD with CRT. Patients were followed for 6 months after device implant. Primary endpoint was the degree of change in cardiac perfusion measured by myocardial perfusion scintigraphy. LVEF equally improved in both groups, from 24% to 36% in the transvenous group versus 25% to 35% in the epicardial group (p = 0.797). Cardiac perfusion, expressed as summed stress score(SSS), improved in both groups without a significant difference as well (p = 0.727). Complication rate was similar, respectively 6 and 7 patients had any complication. Admission time was significantly longer in the epicardial group with 2 (2-7) versus 3 (2-32) days (p

Introduction Modern pacemakers are designed to allow patients to undergo magnetic resonance imaging (MRI) under a set of specific conditions. Aim of this study is to provide confirmatory evidence of safety and performance of a new pacing system (ImageReady™, Boston Scientific) in patients undergoing 1.5 and 3T MRI. Methods and results Two prospective, nonrandomized, single-arm studies were designed to provide confirmatory data of no impact of MRI on device function, lead parameters, and patient conditions in subjects implanted with the system undergoing a clinically non-indicated 1.5T and 3T MRI, respectively. Device measurements were done within 1 hour before and after the scan and at 1 month follow-up. Thirty-two subjects underwent MRI visit (17 subjects with 1.5T MRI and 15 subjects with 3T MRI). There were no unanticipated adverse effects related to the pacemaker. Device measurements taken pre- and post-MRI scan did not show any clinical relevant change that could indicate an effect of the MRI on the device or at the lead-tissue interface (RV threshold change: 0.01 ± 0.13 V, P = 0.60; RA threshold change: 0.01 ± 0.11 V, P = 0.53; R wave change: -0.44 ± 1.73 mV, P = 0.36; R wave change: 0.12 ± 1.67 mV, P = 0.73), with data confirmed at 1-month follow-up visit. Conclusion The study documented safety of the pacing system in the 1.5T and 3T MRI environment by showing no adverse events related to device or MRI scan. Additional data are required to cover the more complex scenarios involving different diagnostic needs, conditions of use, clinical conditions, and new emerging technologies.

Non-invasive prenatal testing (NIPT) of cell-free DNA in maternal plasma, which is a mixture of maternal DNA and a low percentage of fetal DNA, can detect fetal aneuploidies using massively parallel sequencing. Because of the low percentage of fetal DNA, methods with high sensitivity and precision are required. However, sequencing variation lowers sensitivity and hampers detection of trisomy samples. Therefore, we have developed three algorithms to improve sensitivity and specificity: the chi-squared-based variation reduction (χ2VR), the regression-based Z-score (RBZ) and the Match QC score. The χ2VR reduces variability in sequence read counts per chromosome between samples, the RBZ allows for more precise trisomy prediction, and the Match QC score shows if the control group used is representative for a specific sample. We compared the performance of χ2VR to that of existing variation reduction algorithms (peak and GC correction) and that of RBZ to trisomy prediction algorithms (standard Z-score, normalized chromosome value and median-absolute-deviation-based Z-score). χ2VR and the RBZ both reduce variability more than existing methods, and thereby increase the sensitivity of the NIPT analysis. We found the optimal combination of algorithms was to use both GC correction and χ2VR for pre-processing and to use RBZ as the trisomy prediction method.

Introduction The latest European Society of Cardiology Guidelines recommend consideration of a wearable cardioverter-defibrillator (WCD) for patients with a poor left ventricular ejection fraction (LVEF) who are at risk of sudden arrhythmic death but are not eligible for an implantable defibrillator. For these patients a WCD can be an alternative to long-term hospitalisation. Purpose To evaluate the use of WCD therapy in these patient groups in two Dutch centres. Methods All consecutive patients treated with the WCD between 2009 and 2016 were included from two centres in the Netherlands. Data on events and compliance were collected retrospectively through home monitoring systems and adjudicated by the investigators. Results A total of 79 patients were treated with a WCD. Common indications were newly diagnosed cardiomyopathy without optimal medical treatment in 46 patients (58.2%) and bridge to implantable cardioverter-defibrillator (ICD) implant in 33 patients (41.8%). Bridge to implant indications consisted of contraindications for immediate implantation such as infections (e. g. previous device-related infections) and radiotherapy. Compliance was over 97% per day (median 23.3 h, 22.6–23.7), during a median of 79 days (50.0–109.8.0). Two patients (2.6%) received an appropriate shock (annual rate 13.6%), there was 1 (1.3%) inappropriate shock (annual rate 6.7%). In 24 patients (52.2%) without optimal medical treatment, the LVEF was sufficiently improved and ICD implant was avoided. Eight (10.1%) patients did not receive an ICD. In 45 patients an ICD was implanted (57.0%). Conclusion WCD therapy provides a safe and effective treatment in outpatient setting for patients at high risk for sudden cardiac death and reduces the number of ICDs implanted.

International audience; The goal of this work is to increase the power emitted at E-band by a photomixing antenna array on PCB technology. The antenna architecture has been tailored to obtain a scalable design and a high radiation efficiency, while featuring a relative bandwidth larger than 10%. Our first prototype, with a 3-dB gain bandwidth of 12 GHz and one active photodiode, has been used in a wireless link. This preliminary demonstration has yielded a 2.15 Gb/s error-free data rate transmission for a 25 cm distance.

This article reports the development of 200-mW 1.55-μm DFB laser module with RIN below -162 dB/Hz which are well suited for microwave photonics or free space optical communication applications. Specific design has allowed reaching high power (>300 mW), low noise and high spectral purity laser chip. The chip has been packaged in Butterfly module optimized for reducing the module power consumption. DFB laser module system validations have been done on three laboratory test-beds representative of target applications, namely high-frequency optical LO distribution, photonic RF frequency conversion, and free space optical communication links.

This paper analyzes integrated components for ultra-broadband millimeter-wave wireless transmitters enabling the 5 G objective to increase the wireless data rates 10x to 100x . We have pursued the photonic-based approach to generate the millimeter-wave carrier (approximate to 97GHz in this paper) through photomixing. We have achieved up to 10 Gb s(-1) data rate using an OOK modulation format (to reduce latency) and either direct detection (DD) or coherent detection. We show that coherent detection enables a sensitivity improvement of 17 dB over DD. We also demonstrate in this work that such improvement can be achieved using as the transmitter a novel integrated antenna array-the self-complementary chessboard array. This avoids the use of complex coherent schemes at the receiver, enabling simple DD for ultra-broadband links. The authors acknowledge Dr David Gonzalez Ovejero for fruitful discussions on antenna simulation. This work has been financially supported by Ministerio de Economia, Industria y Competitividad iTWIT Proyect with references TEC2016-76 997-C3-2-R and TEC2016-76 997-C3-3-R. Authors also acknowledge Ayuda Fundacion BBVA a Investigadores y Creadores Culturales 2016' and 'Estancias de movilidad de profesores PRX16/00 021'.