Leadless Pacemaker Implantation, Focusing on Patients With Conduction System Disorders Post-Transcatheter Aortic Valve Replacement: A Retrospective Analysis.

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.

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.

Impact of ventricular tachycardia ablation in subcutaneous implantable cardioverter defibrillator carriers: a multicentre, international analysis from the iSUSI project.

AIMS: Catheter ablation (CA) of ventricular tachycardia (VT) has become an important tool to improve clinical outcomes in patients with appropriate transvenous implantable cardioverter defibrillator (ICD) shocks. The aim of our analysis was to test whether VT ablation (VTA) impacts long-term clinical outcomes even in subcutaneous ICD (S-ICD) carriers. METHODS AND RESULTS: International Subcutaneous Implantable Cardioverter Defibrillator (iSUSI) registry patients who experienced either an ICD shock or a hospitalization for monomorphic VT were included in this analysis. Based on an eventual VTA after the index event, patients were divided into VTA+ vs. VTA- cohorts. Primary outcome of the study was the occurrence of a combination of device-related appropriate shocks, monomorphic VTs, and cardiovascular mortality. Secondary outcomes were addressed individually. Among n = 1661 iSUSI patients, n = 211 were included: n = 177 experiencing ICD shocks and n = 34 hospitalized for VT. No significant differences in baseline characteristics were observed. Both the crude and the yearly event rate of the primary outcome (5/59 and 3.8% yearly event rate VTA+ vs. 41/152 and 16.4% yearly event rate in the VTA-; log-rank: P value = 0.0013) and the cardiovascular mortality (1/59 and 0.7% yearly event rate VTA+ vs. 13/152 and 4.7% yearly event rate VTA-; log-rank P = 0.043) were significantly lower in the VTA + cohort. At multivariate analysis, VTA was the only variable remaining associated with a lower incidence of the primary outcome [adjusted hazard ratio 0.262 (0.100-0.681), P = 0.006]. CONCLUSION: In a real-world registry of S-ICD carriers, the combined study endpoint of arrhythmic events and cardiovascular mortality was lower in the patient cohort undergoing VTA at long-term follow-up. CLINICALTRIALS.GOV IDENTIFIER: NCT0473876.

Characterization of spatial integrity with active and passive implants in a low-field magnetic resonance linear accelerator scanner.

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.

PBX/Knotted 1 homeobox-2 (PKNOX2) is a novel regulator of myocardial fibrosis.

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.

Electrocardiographic predictors of atrial mechanical sensing in leadless pacemakers.

BACKGROUND: Leadless pacemakers (LPs) capable of VDD pacing allow for atrioventricular synchrony through mechanical sensing of atrial contraction. However, mechanical sensing is less reliable and less predictable than electrical sensing. OBJECTIVE: The purpose of this study was to evaluate P-wave amplitude during sinus rhythm from preoperative 12-lead electrocardiograms (ECGs) as a predictor for atrial mechanical sensing in patients undergoing VDD LP implantation. METHODS: Consecutive patients undergoing VDD LP implantation were included in this 2-center prospective cohort study. ECG parameters were evaluated separately and in combination for association with the signal amplitude of atrial mechanical contraction (A4). RESULTS: Eighty patients (median age 82 years; female 55%; mean body mass index [BMI] 25.8 kg/m2) were included in the study and 61 patients in the A4 signal analysis (19 patients in VVI mode during follow-up). Absolute (aVL, aVF, V1, V2) and BMI-adjusted (I, II, aVL, aVF, aVR, V1, V2) P-wave amplitudes from baseline ECGs demonstrated a statistically significant positive correlation with A4 signal amplitude (all P <.05). A combined P-wave signal amplitude of at least 0.2 mV in V1 and aVL was predictive, with specificity of 83% (95% confidence interval 67%-100%) for A4 signal ≥1 m/s2. We found a significant correlation of A4 signal amplitude and overall atrioventricular synchrony (P = .013). CONCLUSION: P-wave amplitudes in ECG leads aVL and V1 can predict A4 signal amplitude in patients with VDD LP and therefore the probability of successful AV synchronous pacing.

Challenges and pitfalls during CRT implantation in patients with persistent left superior vena cava.

BACKGROUND: Persistent left superior vena cava (PLSVC) is a rare venous anomaly, affecting 0.3-0.5% of the general population. Cardiac resynchronization therapy (CRT) implantation in patients with PLSVC is challenging due to a complex anatomy. Moreover, data on CRT implantation in this patient population is scarce. Our aim was to report a series of patients with PLSVC and CRT implantation focusing on challenges and pitfalls. METHODS: Electronic medical databases on patients with CRT implantation at the University Heart Centers in Zurich, Switzerland, and Lübeck, Germany, were screened for individuals with a PLSVC. Clinical and demographic characteristics as well as procedural data were reported in all patients. RESULTS: This study presents six cases with a median age of 66 years. CRT implantation was successful in five patients, leading to a reduced QRS duration and improved left ventricular ejection fraction. Atrial fibrillation, ischemic cardiomyopathy, valvular heart disease, and dilated cardiomyopathy were observed in this group as underlying conditions. Specialized tools, such as active fixation left ventricular leads, were utilized. One patient experienced major complications. CONCLUSIONS: This case series shows that although challenging, conventional endovascular CRT implantation is feasible in PLSVC patients. Specialized tools for visualization and fixation may help. Our experiences highlight the importance of preprocedural evaluation of the anatomy and precise intervention planning.

Catheter Ablation for Ventricular Tachycardia in Patients With Desmoplakin Cardiomyopathy.

BACKGROUND: Desmoplakin (DSP) pathogenic/likely pathogenic (P/LP) variants are associated with malignant phenotypes of arrhythmogenic cardiomyopathy (DSP-ACM). Reports of outcomes after ventricular tachycardia (VT) ablation in DSP-ACM are scarce. OBJECTIVES: In this study, the authors sought to report on long-term outcomes of VT ablation in DSP-ACM. METHODS: Patients with P/LP DSP variants at 9 institutions undergoing VT ablation were included. Demographic, clinical, and instrumental data as well as all ventricular arrhythmia (VA) events were collected. Sustained VAs after the index procedure were the primary outcome. A per-patient before and after ablation comparison of rates of VA episodes per year was performed as well. RESULTS: Twenty-four DSP-ACM patients (39.3 ± 12.1 years of age, 62.5% male, median 6,116 [Q1-Q3: 3,362-7,760] premature ventricular complexes [PVCs] per 24 hours, median 4 [Q1-Q3: 2-11] previous VA episodes per patient at ablation) were included. Index procedure was most commonly endocardial/epicardial (19/24) The endocardium of the right ventricle (RV), the left ventricle (LV), or both ventricles were mapped in 8 (33.3%), 9 (37.5%), and 7 (29.2%) cases, respectively. Low voltage potentials were found in 10 of 15 patients in the RV and 11 of 16 in the LV. Endocardial ablation was performed in 18 patients (75.0%). Epicardial mapping in 19 patients (79.2%) identified low voltage potentials in 17, and 16 received epicardial ablation. Over the following 2.9 years (Q1-Q3: 1.8-5.5 years), 13 patients (54.2%) experienced VA recurrences. A significant reduction in per-patient event/year before and after ablation was observed (1.4 [Q1-Q3: 0.5-2.4] to 0.1 [Q1-Q3: 0.0-0.4]; P = 0.009). Two patients needed heart transplantation, and 4 died (3 of heart failure and 1 noncardiac death). CONCLUSIONS: VT ablation in DSP-ACM is effective in reducing the VA burden of the disease, but recurrences are common. Most VT circuits are epicardial, with both LV and RV low voltage abnormalities. Heart failure complicates clinical course and is an important cause of mortality.

Implantable cardioverter defibrillator use in arrhythmogenic right ventricular cardiomyopathy in North America and Europe.

BACKGROUND AND AIMS: Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. METHODS: This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. RESULTS: One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. CONCLUSIONS: North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies.

Inherited forms of arrhythmogenic and dilated cardiomyopathy (ACM and DCM) are characterized by variable disease expression and age-related penetrance. Calcium (Ca2+) is crucially important for proper cardiac function, and dysregulation of Ca2+ homeostasis seems to underly cardiomyopathy etiology. A polymorphism, c.286T>G p.(Ser96Ala), in the gene encoding the histidine-rich Ca2+ binding (HRC) protein, relevant for sarcoplasmic reticulum Ca2+ cycling, has previously been associated with a marked increased risk of life-threatening arrhythmias among idiopathic DCM patients. Following this finding, we investigated whether p.(Ser96Ala) affects major cardiac disease manifestations in carriers of the phospholamban (PLN) c.40_42delAGA; p.(Arg14del) pathogenic variant (cohort 1); patients diagnosed with, or predisposed to, ACM (cohort 2); and DCM patients (cohort 3). We found that the allele frequency of the p.(Ser96Ala) polymorphism was similar across the general European-American population (control cohort, 40.3-42.2%) and the different cardiomyopathy cohorts (cohorts 1-3, 40.9-43.9%). Furthermore, the p.(Ser96Ala) polymorphism was not associated with life-threatening arrhythmias or heart failure-related events across various patient cohorts. We therefore conclude that there is a lack of evidence supporting the important role of the HRC p.(Ser96Ala) polymorphism as a modifier in cardiomyopathy, refuting previous findings. Further research is required to identify bona fide genomic predictors for the stratification of cardiomyopathy patients and their risk for life-threatening outcomes.

Dose escalation for stereotactic arrhythmia radioablation of recurrent ventricular tachyarrhythmia - a phase II clinical trial.

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.

Dosimetric analysis of 17 cardiac Sub-structures, Toxicity, and survival in ultra central lung tumor patients treated with SBRT.

•Data on cardiac toxicity after SBRT for ultra-central lung tumors remains limited.•We analyzed the dose to 18 cardiac sub-structures and cardiovascular toxicity.•A SBRT regimen of 45 Gy in 8-10 fractions yields good local control and low toxicity.•The highest cardiac doses were observed in the pulmonary artery and left atrium.•Higher doses to the base of the heart seem to be associated with non-cancer deaths.

Recurrences of ventricular tachycardia after stereotactic arrhythmia radioablation arise outside the treated volume: analysis of the Swiss cohort.

AIMS: Stereotactic arrhythmia radioablation (STAR) has been recently introduced for the management of therapy-refractory ventricular tachycardia (VT). VT recurrences have been reported after STAR but the mechanisms remain largely unknown. We analysed recurrences in our patients after STAR. METHODS AND RESULTS: From 09.2017 to 01.2020, 20 patients (68 ± 8 y, LVEF 37 ± 15%) suffering from refractory VT were enrolled, 16/20 with a history of at least one electrical storm. Before STAR, an invasive electroanatomical mapping (Carto3) of the VT substrate was performed. A mean dose of 23 ± 2 Gy was delivered to the planning target volume (PTV). The median ablation volume was 26 mL (range 14-115) and involved the interventricular septum in 75% of patients. During the first 6 months after STAR, VT burden decreased by 92% (median value, from 108 to 10 VT/semester). After a median follow-up of 25 months, 12/20 (60%) developed a recurrence and underwent a redo ablation. VT recurrence was located in the proximity of the treated substrate in nine cases, remote from the PTV in three cases and involved a larger substrate over ≥3 LV segments in two cases. No recurrences occurred inside the PTV. Voltage measurements showed a significant decrease in both bipolar and unipolar signal amplitude after STAR. CONCLUSION: STAR is a new tool available for the treatment of VT, allowing for a significant reduction of VT burden. VT recurrences are common during follow-up, but no recurrences were observed inside the PTV. Local efficacy was supported by a significant decrease in both bipolar and unipolar signal amplitude.

Case report of long-term postural tachycardia syndrome in a patient after messenger RNA coronavirus disease-19 vaccination with mRNA-1273.

Background: Postural tachycardia syndrome (POTS) is characterized by orthostatic intolerance and heart rate increase in an upright position without orthostatic hypotension. It has been described after coronavirus disease-19 (COVID-19) as well as after COVID-19 vaccination. Case summary: A 54-year-old female patient presented with a 9-months history of severe orthostatic intolerance since COVID-19 vaccination with messenger RNA (mRNA)-1273 (Spikevax, Moderna). Except for diet-controlled coeliac disease, the patient was healthy, had no allergies, and did not take regular medication. Tilt table testing revealed a significant heart rate increase to 168 bpm without orthostatic hypotension accompanied by light-headedness, nausea, and syncope, findings consistent with POTS. Potential underlying causes including anaemia, thyroid dysfunction, adrenal insufficiency, pheochromocytoma, (auto)-immune disease, chronic inflammation as well as neurological causes were ruled out. Echocardiography and cardiac stress magnetic resonance imaging (MRI) did not detect structural or functional heart disease or myocardial ischaemia. Forty-eight-hour-electrocardiogram (ECG) showed no tachycardias other than sinus tachycardia. Finally, genomic analysis did not detect an inherited arrhythmia syndrome. Serologic analysis revealed adequate immune response to mRNA-1273 vaccination without signs of previous severe acute respiratory syndrome-coronavirus-2 infection. While ivabradine was not tolerated and metoprolol extended release only slightly improved symptoms, physical exercise reduced orthostatic intolerance moderately. At a 5-months follow-up, the patient remained dependant on assistance for activities of daily living. Discussion: The temporal association of POTS with the COVID-19 vaccination in a previously healthy patient and the lack of evidence of an alternative aetiology suggests COVID-19 vaccination is the potential cause of POTS in this patient. To our knowledge, this is the first case reporting severe, long-term, and treatment-refractory POTS following COVID-19 vaccination with mRNA1273.

A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients.

The presence of multiple pathogenic variants in desmosomal genes (DSC2, DSG2, DSP, JUP, and PKP2) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to a severe phenotype. However, the pathogenicity of variants is reclassified frequently, which may result in a changed clinical risk prediction. Here, we present the collection, reclassification, and clinical outcome correlation for the largest series of ARVC patients carrying multiple desmosomal pathogenic variants to date (n = 331). After reclassification, only 29% of patients remained carriers of two (likely) pathogenic variants. They reached the composite endpoint (ventricular arrhythmias, heart failure, and death) significantly earlier than patients with one or no remaining reclassified variant (hazard ratios of 1.9 and 1.8, respectively). Periodic reclassification of variants contributes to more accurate risk stratification and subsequent clinical management strategy. Graphical Abstract.

Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3.

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.

Peri-Procedural Management of Direct-Acting Oral Anticoagulants (DOACs) in Transcatheter Miniaturized Leadless Pacemaker Implantation.

INTRODUCTION: Data on peri-operative management of direct-acting oral anticoagulants (DOACs) during transcatheter pacing leadless system (TPS) implantations remain limited. This study aimed to evaluate a standardized DOAC management regime consisting of interruption of a single dose prior to implantation and reinitiation within 6-24 h; also, patient clinical characteristics associated with this approach were identified. METHOD: Consecutive patients undergoing standard TPS implantation procedures from two Swiss tertiary centers were included. DOAC peri-operative management included the standardized approach (Group 1A) or other approaches (Group 1B). RESULTS: Three hundred and ninety-two pts (mean age 81.4 ± 7.3 years, 66.3% male, left ventricular ejection fraction 55.5 ± 9.6%) underwent TPS implantation. Two hundred and eighty-two pts (71.9%) were under anticoagulation therapy; 192 pts were treated with DOAC; 90 pts were under vitamin-K antagonist. Patients treated with DOAC less often had structural heart disease, diabetes mellitus, and advanced renal failure. The rate of major peri-procedural complications did not differ between groups 1A (n = 115) and 1B (n = 77) (2.6% and 3.8%, p = 0.685). Compared to 1B, 1A patients were implanted with TPS for slow ventricular rate atrial fibrillation (AF) (p = 0.002), in a better overall clinical status, and implanted electively (<0.001). CONCLUSIONS: Standardized peri-procedural DOAC management was more often implemented for elective TPS procedures and did not seem to increase bleeding or thromboembolic adverse events.

Efficacy and Safety of Leadless Pacemaker Implantation in Octogenarians.

INTRODUCTION: Long-term complication rates in standard transvenous pacemakers are reported around 4-12% with a higher incidence in the elderly population. We report our experience in octogenarians undergoing leadless pacemaker implantation in two large-volume centers in Switzerland. METHODS: Consecutive patients undergoing leadless pacemaker implantation at two Swiss large volume centers (University Hospital Zurich, Zurich and Cardiocentro Ticino Institute, Lugano) between October 2015 and March 2020 were included in this retrospective analysis. Demographic information, clinical data, and procedural characteristics were recorded at the day of implantation and during follow-up. RESULTS: Two hundred and twenty patients (mean age 80.6 ± 7.7 years, male 66%) were included. The main indication for pacemaker implantation was slow ventricular rate atrial fibrillation (111 of 220 patients, 50.4%). Out of the 220 patients, 124 (56.3%) were ≥80 years. Overall successful implantation rate was 98.6%. In the octogenarian population, the median procedure time (45 ± 20.2 min vs. 40 ± 19.6 min, p = 0.03) and radiation duration (6.1 ± 8.2 min vs. 5.0 ± 7.2 min, p = 0.03) were longer compared to patients <80 years. Major complications (2.7%, n = 6) and device measurements during follow-up were similar between patients ≥80 and <80 years. CONCLUSION: Implantation of a leadless pacemaker device in octogenarians is safe and effective with a similarly low complication rate compared to non-octogenarians.