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IntroductionIn recent years, high-density microelectrode arrays (HD-MEAs) have emerged as a valuable tool in preclinical research for characterizing the electrophysiology of human induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs). HD-MEAs enable the capturing of both extracellular and intracellular signals on a large scale, while minimizing potential damage to the cell. However, despite technological advancements of HD-MEAs, there is a lack of effective data-analysis platforms that are capable of processing and analyzing the data, particularly in the context of cardiac arrhythmias and drug testing.MethodsTo address this need, we introduce CardioMEA, a comprehensive data-analysis platform designed specifically for HD-MEA data that have been obtained from iPSCCMs. CardioMEA features scalable data processing pipelines and an interactive web-based dashboard for advanced visualization and analysis. In addition to its core functionalities, CardioMEA incorporates modules designed to discern crucial electrophysiological features between diseased and healthy iPSC-CMs. Notably, CardioMEA has the unique capability to analyze both extracellular and intracellular signals, thereby facilitating customized analyses for specific research tasks.Results and discussionWe demonstrate the practical application of CardioMEA by analyzing electrophysiological signals from iPSC-CM cultures exposed to seven antiarrhythmic drugs. CardioMEA holds great potential as an intuitive, userfriendly platform for studying cardiac diseases and assessing drug effects.

Background: Leadless pacing has been established as an alternative approach to transvenous devices for selected patients. Often, leadless pacemaker (LP) implantation is a de novo procedure, but in an increasing number of patients, an LP is used after previous implantation of a conventional pacing system (CPS). Methods: A retrospective analysis was conducted of the efficacy and safety of LP implantation in the context of a previously implanted CPS, from 2 large Swiss centres. Results: A total of 257 consecutive patients undergoing LP implantation were included. They were divided into 2 groups: group 1 consisted of 233 patients who did not have a previous CPS, and group 2 consisted of 24 patients with an in situ CPS. In group 2, a total of 20 patients (83%) required transvenous lead extraction due to infection, malfunction, or other reasons. In 3 patients with device-related infection, lead extraction and LP implantation was performed as a single procedure, whereas in the remaining 11 cases, a time window occurred between the 2 procedures (median: 11.5 days; range: 2-186 days). Electrical device parameters at implantation and during follow-up did not differ between the 2 groups (mean: 12.5 ± 9.3 months). Eight major periprocedural complications (3.1%) were encountered (4 pericardial effusions, 3 instances of femoral bleeding, and 1 instance of intra-abdominal bleeding) in the entire cohort within a 30-day period. No complications occurred in the group with a previous device. No infections were registered, even when complete extraction of an infected CPS was performed prior to LP implantation. Conclusions: Implantation of an LP in patients with a prior CPS (with or without extraction of the previous system) was effective and safe in our population of patients. RÉsumÉ: Contexte: La stimulation cardiaque sans fil a été établie comme une solution de substitution aux dispositifs transveineux chez certains patients. L’implantation d’un stimulateur cardiaque sans fil est souvent une intervention de novo, mais chez un nombre croissant de patients, ce type de stimulateur est utilisé après l’implantation d’un stimulateur classique. Méthodologie: Une analyse rétrospective de l’efficacité et de l’innocuité de la stimulation cardiaque sans fil dans le contexte de l’implantation d’un stimulateur classique a été réalisée dans deux grands centres suisses. Résultats: Un total de 257 patients consécutifs ayant subi l’implantation d’un stimulateur cardiaque sans fil ont été inclus. Les patients étaient répartis dans deux groupes; le groupe 1 était composé de 233 patients non porteurs d’un stimulateur classique, et le groupe 2, de 24 patients porteurs d’un stimulateur classique in situ. Dans le groupe 2, 20 patients au total (83 %) ont eu besoin d’une extraction de la sonde transveineuse en raison d’une infection, d’un défaut de fonctionnement, ou pour d’autres motifs. Chez 3 patients présentant une infection liée au stimulateur, l’extraction de la sonde et l’implantation d’un stimulateur cardiaque sans fil ont été réalisées simultanément, tandis que dans les 11 autres cas, il s’est écoulé un temps médian de 11,5 jours entre les deux interventions (min.-max. : 2-186 jours). Les paramètres relatifs au dispositif électrique au moment de l’implantation et pendant le suivi n’étaient pas différents entre les deux groupes (moyenne : 12,5 ± 9,3 mois). Huit complications périopératoires importantes (3,1 %) sont survenues (4 cas d’épanchement péricardique, 3 cas d’hémorragie fémorale et 1 cas d’hémorragie intra-abdominale) dans l’ensemble de la cohorte au cours d’une période de 30 jours. Aucune complication ne s’est produite dans le groupe de patients porteurs d’un stimulateur classique. On n’a enregistré aucun cas d’infection, même lorsque l’extraction complète du stimulateur classique infecté a été effectuée avant l’implantation du stimulateur cardiaque sans fil. Conclusions: L’implantation d’un stimulateur cardiaque sans fil chez les patients porteurs d’un stimulateur classique (avec ou sans extraction de ce stimulateur) était une intervention efficace et sûre dans cette population de patients.

ABSTRACT Much effort has been made to uncover the cellular heterogeneities of human hearts by single-nucleus RNA sequencing. However, the cardiac transcriptional regulation networks have not been systematically described because of the limitations in detecting transcription factors. In this study, we optimized a pipeline for isolating nuclei and conducting single-nucleus RNA sequencing targeted to detect a higher number of cell signal genes and an optimal number of transcription factors. With this unbiased protocol, we characterized the cellular composition of healthy human hearts and investigated the transcriptional regulation networks involved in determining the cellular identities and functions of the main cardiac cell subtypes. Particularly in fibroblasts, a novel regulator, PKNOX2, was identified as being associated with physiological fibroblast activation in healthy hearts. To validate the roles of these transcription factors in maintaining homeostasis, we used single-nucleus RNA-sequencing analysis of transplanted failing hearts focusing on fibroblast remodelling. The trajectory analysis suggested that PKNOX2 was abnormally decreased from fibroblast activation to pathological myofibroblast formation. Both gain- and loss-of-function in vitro experiments demonstrated the inhibitory role of PKNOX2 in pathological fibrosis remodelling. Moreover, fibroblast-specific overexpression and knockout of PKNOX2 in a heart failure mouse model induced by transverse aortic constriction surgery significantly improved and aggravated myocardial fibrosis, respectively. In summary, this study established a high-quality pipeline for single-nucleus RNA-sequencing analysis of heart muscle. With this optimized protocol, we described the transcriptional regulation networks of the main cardiac cell subtypes and identified PKNOX2 as a novel regulator in suppressing fibrosis and a potential therapeutic target for future translational studies.

Background: Impairment of the conduction system is a common complication of transcatheter aortic valve replacement (TAVR), which is typically performed in elderly patients. A leadless pacemaker (LP) may be a suitable option in this frail population, but the available scientific data concerning the efficacy and safety of leadless pacing after TAVR are sparse. The purpose of this analysis was to evaluate the efficacy and safety of LP implantation in patients with relevant bradycardias after TAVR, compared to other indications. Methods: Consecutive patients were retrospectively enrolled. Demographics, background heart diseases, interventional parameters, and follow-up data were collected. Results: A total of 257 consecutive patients who underwent LP implantation were included. In 26 patients, the device was implanted due to bradycardias after TAVR (TAVR group), whereas the remaining 231 patients were in the population without previous TAVR (non-TAVR group). The mean implantation duration (56 ± 22 minutes in the TAVR group vs 48 ± 20 minutes in the non-TAVR group; P = not significant [NS]) and the implantation success rate (100% in the TAVR group vs 98.7% in the non-TAVR group; P = NS) were similar in the 2 cohorts. No significant differences occurred in pacing parameters (sensing, impedance, and threshold, respectively) between the 2 groups, either at implantation or during follow-up. A total of 8 major periprocedural complications (3.1% of patients in total; 3.8% in the TAVR group vs 3.0% in the non-TAVR group; P = NS) occurred within 30 days, without significant difference between the 2 groups. Conclusions: LP implantation appears to be safe and effective in patients after TAVR, and therefore, this procedure is a suitable option for this often old and frail population. Résumé: Contexte: L’atteinte du système de conduction cardiaque est une complication courante du remplacement valvulaire aortique par cathéter (RVAC), une intervention habituellement pratiquée chez les patients âgés. Un stimulateur cardiaque sans sonde peut être une option convenable pour cette population fragile, mais les données scientifiques actuelles concernant l’efficacité et l’innocuité de la stimulation sans sonde après un RVAC sont fragmentaires. Cette analyse visait à évaluer l’efficacité et l’innocuité de l’implantation d’un stimulateur cardiaque sans sonde chez des patients atteints de bradycardies pertinentes après un RVAC, comparativement à d’autres indications. Méthodologie: Des patients consécutifs ont été recrutés de manière rétrospective. Les données démographiques, les maladies cardiaques sous-jacentes, les paramètres interventionnels et les données de suivi ont été colligés. Résultats: Un total de 257 patients consécutifs qui se sont fait implanter un stimulateur cardiaque sans sonde ont été inclus. Chez 26 patients, le dispositif a été implanté en raison d’une bradycardie après un RVAC (groupe RVAC), alors que les 231 autres patients formaient la population sans RVAC antérieur (groupe sans RVAC). La durée moyenne de l’intervention d’implantation (56 ± 22 minutes dans le groupe RVAC vs 48 ± 20 minutes dans le groupe sans RVAC; p = non significatif [NS]) et le taux de réussite de l’implantation (100 % dans le groupe RVAC vs 98,7 % dans le groupe sans RVAC; p = NS) étaient similaires dans les deux cohortes. Aucune différence significative n’a été observée dans les paramètres de stimulation (sensibilité, impédance et seuil, respectivement) entre les 2 groupes, que ce soit au moment de l’implantation ou pendant le suivi. Un total de 8 complications périopératoires majeures (3,1 % de l’ensemble des patients; 3,8 % dans le groupe RVAC vs 3,0 % dans le groupe sans RVAC; p = NS) sont survenues dans les 30 jours, sans différence notable entre les 2 groupes. Conclusions: L’implantation d’un stimulateur cardiaque sans sonde semble sûre et efficace après un RVAC; par conséquent, cette intervention représente une option convenable pour cette population souvent âgée et fragile.

Background and Purpose: Standard imaging protocols can guarantee the spatial integrity of magnetic resonance (MR) images utilized in radiotherapy. However, the presence of metallic implants can significantly compromise this integrity. Our proposed method aims at characterizing the geometric distortions induced by both passive and active implants commonly encountered in planning images obtained from a low-field 0.35 T MR-linear accelerator (LINAC). Materials and Methods: We designed a spatial integrity phantom defining 1276 control points and covering a field of view of 20x20x20 cm3. This phantom was scanned in a water tank with and without different implants used in hip and shoulder arthroplasty procedures as well as with active cardiac stimulators. The images were acquired with the clinical planning sequence (balanced steady-state free-precession, resolution 1.5x1.5x1.5 mm3). Spatial integrity was assessed by the Euclidian distance between the control point detected on the image and their theoretical locations. A first plane free of artefact (FPFA) was defined to evaluate the spatial integrity beyond the larger banding artefact. Results: In the region extending up to 20 mm from the largest banding artefacts, the tested passive and active implants could cause distortions up to 2 mm and 3 mm, respectively. Beyond this region the spatial integrity was recovered and the image could be considered as unaffected by the implants. Conclusions: We characterized the impact of common implants on a low field MR-LINAC planning sequence. These measurements could support the creation of extra margin while contouring organs at risk and target volumes in the vicinity of implants.

Abstract Background Stereotactic arrhythmia radioablation (STAR) is delivered with a planning target volume (PTV) prescription dose of 25 Gy, mostly to the surrounding 75–85% isodose line. This means that the average and maximum dose received by the target is less than 35 Gy, which is the minimum threshold required to create a homogenous transmural fibrosis. Similar to catheter ablation, the primary objective of STAR should be transmural fibrosis to prevent heterogenous intracardiac conduction velocities and the occurrence of sustained ventricular arrhythmias (sVA) caused by reentry. We hypothesize that the current dose prescription used in STAR is inadequate for the long-term prevention of sVA and that a significant increase in dose is necessary to induce transmural scar formation. Objective A single arm, multi-center, phase II, dose escalation prospective clinical trial employing the i3 + 3 design is being conducted to examine the safety of a radiation dose-escalation strategy aimed at inducing transmural scar formation. The ultimate objective of this trial is to decrease the likelihood of sVA recurrence in patients at risk. Methods Patients with ischemic or non-ischemic cardiomyopathy and recurrent sVA, with an ICD and history of ≥ 1 catheter ablation for sVA will be included. This is a prospective, multicenter, one-arm, dose-escalation trial utilizing the i3 + 3 design, a modified 3 + 3 specifically created to overcome limitations in traditional dose-finding studies. A total of 15 patients will be recruited. The trial aims to escalate the ITV dose from 27.0 Gy to an ITV prescription dose-equivalent level of maximum 35.1 Gy by keeping the PTV prescription dose constant at 25 Gy while increasing the dose to the target (i.e. the VT substrate without PTV margin) by step-wise reduction of the prescribing isodose line (85% down to 65%). The primary outcome of this trial is safety measured by registered radiation associated adverse events (AE) up to 90 days after study intervention including radiation associated serious adverse events graded as at least 4 or 5 according to CTCAE v5, radiation pneumonitis or pericarditis requiring hospitalization and decrease in LVEF ≥ 10% as assessed by echocardiography or cardiac MRI at 90 days after STAR. The sample size was determined assuming an acceptable primary outcome event rate of 20%. Secondary outcomes include sVA burden at 6 months after STAR, time to first sVA recurrence, reduction in appropriate ICD therapies, the need for escalation of antiarrhythmic drugs, non-radiation associated safety and patient reported outcome measures such as SF-36 and EQ5D. Discussion DEFT-STAR is an innovative prospective phase II trial that aims to evaluate the optimal radiation dose for STAR in patients with therapy-refractory sVA. The trial has obtained IRB approval and focuses on determining the safe and effective radiation dose to be employed in the STAR procedure. Trial registration NCT05594368.

Abstract Severe forms of dilated cardiomyopathy (DCM) are associated with point mutations in the alternative splicing regulator RBM20 that are frequently located in the arginine/serine-rich domain (RS-domain). Such mutations can cause defective splicing and cytoplasmic mislocalization, which leads to the formation of detrimental cytoplasmic granules. Successful development of personalized therapies requires identifying the direct mechanisms of pathogenic RBM20 variants. Here, we decipher the molecular mechanism of RBM20 mislocalization and its specific role in DCM pathogenesis. We demonstrate that mislocalized RBM20 RS-domain variants retain their splice regulatory activity, which reveals that aberrant cellular localization is the main driver of their pathological phenotype. A genome-wide CRISPR knockout screen combined with image-enabled cell sorting identified Transportin-3 (TNPO3) as the main nuclear importer of RBM20. We show that the direct RBM20-TNPO3 interaction involves the RS-domain, and is disrupted by pathogenic variants. Relocalization of pathogenic RBM20 variants to the nucleus restores alternative splicing and dissolves cytoplasmic granules in cell culture and animal models. These findings provide proof-of-principle for developing therapeutic strategies to restore RBM20’s nuclear localization in RBM20-DCM patients.

Introduction Patients suffering from arrhythmogenic right ventricular cardiomyopathy (ARVC) should avoid intense endurance exercise to reduce the risk of adverse cardiac events and disease progression. On the other hand, an active lifestyle might be preferable to a sedentary one, which also brings a host of complications. Evidence for safe levels of physical activity in ARVC, however, is scarce. This is study aimed to describe the ventricular arrhythmia burden - estimated as the prevalence of premature ventricular contractions (PVC) - of different exercise modalities and intensities on ARVC patients. Methods The pilot analysis includes four (1F, 33 ± 12 yrs, BMI 24 ± 4 kg/m2) ARVC patients harboring a pathogenic plakophilin-2 variant and carrying an implantable cardioverter-defibrillator performed different exercises while monitored via 12-lead ECG. The order of modalities was randomized and participants instructed to stop when surpassing perceived exertion of 15 on the Borg 6-20 scale. Resistance exercises included two-legged squats and single arm biceps curls (each with 20 repetitions and 2 min duration) while endurance exercise included 5 min of treadmill walking, 3 min cycling bouts at heart rate (HR) of 80, 100 and 120 bpm as well as cycling at 120 bpm with 2 additional min of active cool down. Blood lactate concentration was assessed at the end of the cycling bouts. Results No adverse cardiac event were noted and no exercise was terminated for medical reasons. During walking HR was 76 ± 8 bpm, whereas PVC burden was 11 ± 6% (range 4-18%). Cycling at 82 ± 4 bpm induced a PVC burden of 7 ± 5% (range 3- 14%), which increased to 13 ± 8% (range 3- 21%) at 93 ± 2 bpm and further to 16 ± 16% (range 7-37%) at 105 ± 3 bpm. In all three modalities the PVC burden was higher in the first 3 min of recovery than during the activity itself. Adding a 2 min active cool down increased the PVC burden to 25 ± 16% (range 6-45%). 2-legged squats performed at 101 ± 15 bpm had a PVC burden of 9 ± 12%, which increased to 19 ± 14% at recovery. One arm biceps curls at 75 ± 13 bpm had a PVC burden of 4 ± 3% during the activity and 9 ± 5% during recovery. Perception of effort varied widely when cycling at 80 bpm (range 6-12) or 100 bpm (range 8-14), but less so at 120 bpm (range 13-15). Blood lactate concentration when cycling at 120 bpm ranged between 2.2 and 3.5 mmol/L, typically associated with exercise in the “heavy” intensity domain. Discussion/Conclusion ARVC patients present a high, intensity-dependent PVC burden during exercise and short-term recovery. However, we observed widely different PVC burdens and perceived exertion at a given HR during different exercise modalities, which calls for personalized recommendations on physical activity. Exercises with small muscle mass seem to minimize the PVC burden and training the different muscles separately could be an interesting avenue to maintain physical fitness in ARVC patients.

Abstract Atrial cardiomyopathy refers to structural and electrical remodelling of the atria, which can lead to impaired mechanical function. While historical studies have implicated atrial fibrillation as the leading cause of cardioembolic stroke, atrial cardiomyopathy may be an important, underestimated contributor. To date, the relationship between atrial cardiomyopathy, atrial fibrillation, and cardioembolic stroke remains obscure. This review summarizes the pathogenesis of atrial cardiomyopathy, with a special focus on neurohormonal and inflammatory mechanisms, as well as the role of adipose tissue, especially epicardial fat in atrial remodelling. It reviews the current evidence implicating atrial cardiomyopathy as a cause of embolic stroke, with atrial fibrillation as a lagging marker of an increased thrombogenic atrial substrate. Finally, it discusses the potential of antithrombotic therapy in embolic stroke with undetermined source and appraises the available diagnostic techniques for atrial cardiomyopathy, including imaging techniques such as echocardiography, computed tomography, and magnetic resonance imaging as well as electroanatomic mapping, electrocardiogram, biomarkers, and genetic testing. More prospective studies are needed to define the relationship between atrial cardiomyopathy, atrial fibrillation, and embolic stroke and to establish a prompt diagnosis and specific treatment strategies in these patients with atrial cardiomyopathy for the secondary and even primary prevention of embolic stroke.

Abstract The pathophysiological mechanisms underlying the development of the athlete’s heart are still poorly understood. To characterize the intracavitary blood flows in the right ventricle (RV) and right-ventricular outflow tract (RVOT) in 2 healthy probands, patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and 2 endurance athletes, we performed 4D-MRI flow measurements to assess differences in kinetic energy and shear stresses. Time evolution of velocity magnitude, mean kinetic energy (MKE), turbulent kinetic energy (TKE) and viscous shear stress (VSS) were measured both along the whole RV and in the RVOT. RVOT regions had higher kinetic energy values and higher shear stresses levels compared to the global averaging over RV among all subjects. Endurance athletes had relatively lower kinetic energy and shear stresses in the RVOT regions compared to both healthy probands and ARVC patients. The athlete’s heart is characterized by lower kinetic energy and shear stresses in the RVOT, which might be explained by a higher diastolic compliance of the RV.

AimTo investigate the clinical significance of right atrial mapping prior to cavotricuspid isthmus (CTI) ablation in patients with typical atrial flutter (AFL).MethodsClinical and ablation parameters were retrospectively assessed and compared in patients undergoing CTI ablation with or without a first-step right atrial mapping (FRAM) by using the CARTO 3D mapping system.ResultsCTI block by radiofrequency ablation (RFA) was achieved in all 143 patients. In the FRAM group there was a shorter ablation duration and fluoroscopy exposure compared with the non-FRAM group. CHA2DS2-VASc score was associated with higher ablation durations, more ablation applications and increased fluoroscopy exposure. Body mass index (BMI) was associated with longer ablation duration and more ablation applications. Furthermore, patients with reduced left ventricular ejection fraction (LVEF) had longer ablation durations and more fluoroscopy exposure. One patient in the non-FRAM group developed cardiac effusion after ablation. None of the patients had recurrence after 6 months of follow-up.ConclusionsPatients with high BMI, high CHA2DS2-VASc score and reduced LVEF may benefit from the FRAM approach by reducing ablation duration, number of ablation applications and fluoroscopy exposure.

BackgroundArrhythmogenic cardiomyopathy can be caused by genetic variants in desmosomal cadherins. Since cardiac desmosomal cadherins are crucial for cell-cell-adhesion, their correct localization at the plasma membrane is essential.MethodsNine desmocollin-2 variants at five positions from various public genetic databases (p.D30N, p.V52A/I, p.G77V/D/S, p.V79G, p.I96V/T) and three additional conserved positions (p.C32, p.C57, p.F71) within the prodomain were investigated in vitro using confocal microscopy. Model variants (p.C32A/S, p.V52G/L, p.C57A/S, p.F71Y/A/S, p.V79A/I/L, p.I96l/A) were generated to investigate the impact of specific amino acids.ResultsWe revealed that all analyzed positions in the prodomain are critical for the intracellular transport. However, the variants p.D30N, p.V52A/I and p.I96V listed in genetic databases do not disturb the intracellular transport revealing that the loss of these canonical sequences may be compensated.ConclusionAs disease-related homozygous truncating desmocollin-2 variants lacking the transmembrane domain are not localized at the plasma membrane, we predict that some of the investigated prodomain variants may be relevant in the context of arrhythmogenic cardiomyopathy due to disturbed intracellular transport.

Introduction: In recent years, high-density microelectrode arrays (HD-MEAs) have emerged as a valuable tool in preclinical research for characterizing the electrophysiology of human induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs). HD-MEAs enable the capturing of both extracellular and intracellular signals on a large scale, while minimizing potential damage to the cell. However, despite technological advancements of HD-MEAs, there is a lack of effective data-analysis platforms that are capable of processing and analyzing the data, particularly in the context of cardiac arrhythmias and drug testing. Methods: To address this need, we introduce CardioMEA, a comprehensive data-analysis platform designed specifically for HD-MEA data that have been obtained from iPSCCMs. CardioMEA features scalable data processing pipelines and an interactive web-based dashboard for advanced visualization and analysis. In addition to its core functionalities, CardioMEA incorporates modules designed to discern crucial electrophysiological features between diseased and healthy iPSC-CMs. Notably, CardioMEA has the unique capability to analyze both extracellular and intracellular signals, thereby facilitating customized analyses for specific research tasks. Results and discussion: We demonstrate the practical application of CardioMEA by analyzing electrophysiological signals from iPSC-CM cultures exposed to seven antiarrhythmic drugs. CardioMEA holds great potential as an intuitive, userfriendly platform for studying cardiac diseases and assessing drug effects. [ABSTRACT FROM AUTHOR]

A novel quality assurance process for electroanatomical mapping (EAM)-to-radiotherapy planning imaging (RTPI) target transport was assessed within the multi-center multi-platform framework of the RAdiosurgery for VENtricular TAchycardia (RAVENTA) trial. A stand-alone software (CARDIO-RT) was developed to enable platform independent registration of EAM and RTPI of the left ventricle (LV), based on pre-generated radiotherapy contours (RTC). LV-RTC were automatically segmented into the American-Heart-Association 17-segment-model and a manual 3D-3D method based on EAM 3D-geometry data and a semi-automated 2D-3D method based on EAM screenshot projections were developed. The quality of substrate transfer was evaluated in five clinical cases and the structural analyses showed substantial differences between manual target transfer and target transport using CARDIO-RT.