Sex differences among subcutaneous implantable cardioverter-defibrillator recipients: a propensity-matched, multicentre, international analysis from the i-SUSI project.

AIMS: Women have been historically underrepresented in implantable cardioverter-defibrillator (ICD) trials. No data on sex differences regarding subcutaneous ICDs (S-ICD) carriers have been described. Aim of our study was to investigate sex-related differences among unselected S-ICD recipients. METHODS AND RESULTS: Consecutive patients enrolled in the multicentre, international i-SUSI registry were analysed. Comparisons between sexes were performed using a 1:1 propensity matching adjusted analysis for age, body mass index (BMI), left ventricular function, and substrate. The primary outcome was the rate of appropriate shocks during follow-up. Inappropriate shocks and other device-related complications were deemed secondary outcomes. A total of 1698 patients were extracted from the i-SUSI registry; 399 (23.5%) were females. After propensity matching, two cohorts of 374 patients presenting similar baseline characteristics were analysed. Despite similar periprocedural characteristics and a matched BMI, women resulted at lower risk of conversion failure as per PRAETORIAN score (73.4% vs. 81.3%, P = 0.049). Over a median follow-up time of 26.5 [12.7-42.5] months, appropriate shocks were more common in the male cohort (rate/year 3.4% vs. 1.7%; log-rank P = 0.049), while no significant differences in device-related complications (rate/year: 6.3% vs. 5.8%; log-rank P = 0.595) and inappropriate shocks (rate/year: 4.3% vs. 3.1%; log-rank P = 0.375) were observed. After controlling for confounders, sex remained significantly associated with the primary outcome (aHR 1.648; CI 0.999-2.655, P = 0.048), while not resulting predictor of inappropriate shocks and device-related complications. CONCLUSION: In a propensity-matched cohort of S-ICD recipients, women are less likely to experience appropriate ICD therapy, while not showing higher risk of device-related complications. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0473876.

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.

Early Clinical Outcomes and Advantages of a Novel-Size Adjustable Second-Generation Cryoballoon: A Proof-of-Concept Study.

(1) Background/Objective Balloon-guided catheter ablation (CA) has emerged as an alternative option for atrial fibrillation (AF) management. The recent introduction of a novel-size adjustable second-generation cryoballoon (CB) system offers innovations, but clinical outcomes remain unexplored. This study aims to assess the acute performance of the POLARx FIT™ CB system in AFCA. (2) Methods: Consecutive patients undergoing AF ablation with the POLARx FIT™ CB system in our center were included. The primary outcome was the rate of 31 mm balloon-size utilization, with secondary outcomes including acute pulmonary vein isolation (PVI) rate, periprocedural complications, and in-hospital AF recurrences. (3) Results: Twenty-four patients with a mean age of 59.5 years, predominantly male (87.5%), and exhibiting paroxysmal AF (91.7%) were enrolled. Procedural characteristics demonstrated a high acute success rate (100% PV isolation) with a favorable safety profile. Notably, the 31 mm CB configuration was utilized in 51% of applications, showcasing its adaptability in challenging anatomies. No major complications occurred, with two patients experiencing in-hospital self-limiting AF recurrences. (4) Conclusions: This study represents the first comprehensive assessment of the POLARx FIT™ CB system in AF ablation. While acknowledging the study's limitations, this novel CB emerges as a promising tool, warranting further exploration in larger studies with extended follow-up periods.

Pulsed field ablation technology for pulmonary vein and left atrial posterior wall isolation in patients with persistent atrial fibrillation.

INTRODUCTION: Limited data exist on pulsed-field ablation (PFA) in patients with persistent atrial fibrillation (PeAF) undergoing left atrial posterior wall isolation (LAPWI). METHODS: The Advanced TecHnologies For SuccEssful AblatioN of AF in Clinical Practice (ATHENA) prospective registry included consecutive patients referred for PeAF catheter ablation at 9 Italian centers, treated with the FARAPULSETM-PFA system. The primary efficacy and safety study endpoints were the acute LAPWI rate, freedom from arrhythmic recurrences and the incidence of major periprocedural complications. Patients undergoing pulmonary vein isolation (PVI) alone, PWI + LAPWI and redo procedures were compared. RESULTS: Among 249 patients, 21.7% had long-standing PeAF, 79.5% were male; mean age was 63 ± 9 years. LAPWI was performed in 57.6% of cases, with 15.3% being redo procedures. Median skin-to-skin times (PVI-only 68 [60-90] vs. PVI + LAPWI 70 [59-88] mins) did not differ between groups. 45.8% LAPWI cases were approached with a 3D-mapping system, and 37.3% with intracardiac echocardiography. LAPWI was achieved in all patients by means of PFA alone, in 88.8% cases at first pass. LAPWI was validated either by an Ultrahigh-density mapping system or by recording electrical activity + pacing maneuvers. No major complications occurred, while 2.4% minor complications were detected. During a median follow-up of 273 [191-379] days, 41 patients (16.5%) experienced an arrhythmic recurrence after the 90-day blanking period, with a mean time to recurrence of 223 ± 100 days and no differences among ablation strategies. CONCLUSION: LAPWI with PFA demonstrates feasibility, rapidity, and safety in real-world practice, offering a viable alternative for PeAF patients. LAPWI is achievable even with a fluoroscopy-only method and does not significantly extend overall procedural times.

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.

Enhanced pro-apoptotic activity of rituximab through IBTK silencing in non-Hodgkin lymphoma B-cells.

Rituximab is a commonly used chemotherapeutic drug for patients with aggressive lymphomas, such as non-Hodgkin's lymphoma (NHL). Currently, the combination of Rituximab and chemotherapy (R-CHOP) stands as the most prevalent first-line therapy for NHL. Nevertheless, the development of new therapeutic approaches remains imperative. An increasing body of evidence highlights a novel role for IBTK in tumorigenesis and cancer growth. In this study, we aim to broaden our understanding of IBTK's function in B-lymphoma, with a particular focus on its impact on the expression of the oncogene MYC. Here, we assessed the effects of combining Rituximab with IBTK silencing on cell viability through cell cycle analysis and Annexin V assays in vitro. Furthermore, we leveraged the transplantability of Eµ-myc lymphomas to investigate whether the inhibition of IBTK could elicit anti-tumor effects in the treatment of lymphomas in vivo. Our data suggests that IBTK silencing may serve as an effective anti-tumor agent for aggressive B-Lymphomas, underscoring its role in promoting apoptosis when used in combination with Rituximab, both in in vitro and in vivo settings.

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.

Differences in underlying cardiac substrate among S-ICD recipients and its impact on long-term device-related outcomes: Real-world insights from the iSUSI registry.

BACKGROUND: Outcome comparisons among subcutaneous implantable cardioverter-defibrillator (S-ICD) recipients with nonischemic cardiomyopathies are scarce. OBJECTIVE: The aim of this study was to evaluate differences in device-related outcomes among S-ICD recipients with different structural substrates. METHODS: Patients enrolled in the i-SUSI (International SUbcutaneouS Implantable cardioverter defibrillator registry) project were grouped according to the underlying substrate (ischemic vs nonischemic) and subgrouped into dilated cardiomyopathy, hypertrophic cardiomyopathy, Brugada syndrome (BrS), arrhythmogenic right ventricular cardiomyopathy (ARVC). The main outcome of our study was to compare the rates of appropriate and inappropriate shocks and device-related complications. RESULTS: Among 1698 patients, the most common underlying substrate was ischemic (31.7%), followed by dilated cardiomyopathy (20.5%), BrS (10.8%), hypertrophic cardiomyopathy (8.5%), and ARVC (4.4%). S-ICD for primary prevention was more common in the nonischemic cohort (70.9% vs 65.4%; P = .037). Over a median (interquartile range) follow-up of 26.5 (12.6-42.8) months, no differences were observed in appropriate shocks between ischemic and nonischemic patients (4.8%/y vs 3.9%/y; log-rank, P = .282). ARVC (9.0%/y; hazard ratio [HR] 2.492; P = .001) and BrS (1.8%/y; HR 0.396; P = .008) constituted the groups with the highest and lowest rates of appropriate shocks, respectively. Device-related complications did not differ between groups (ischemic: 6.4%/y vs nonischemic: 6.1%/y; log-rank, P = .666), nor among underlying substrates (log-rank, P = .089). Nonischemic patients experienced higher rates of inappropriate shocks than did ischemic S-ICD recipients (4.4%/y vs 3.0%/y; log-rank, P = .043), with patients with ARVC (9.9%/y; P = .001) having the highest risk, even after controlling for confounders (adjusted HR 2.243; confidence interval 1.338-4.267; P = .002). CONCLUSION: Most S-ICD recipients were primary prevention nonischemic cardiomyopathy patients. Among those, patients with ARVC tend to receive the most frequent appropriate and inappropriate shocks and patients with BrS the least frequent appropriate shocks.

Left ventricular assist device in the presence of subcutaneous implantable cardioverter defibrillator: Data from a multicenter experience.

BACKGROUND: Left ventricular assist devices (LVADs) are an increasingly used strategy for the management of patients with advanced heart failure (HF). Subcutaneous implantable cardioverter defibrillator (S-ICD) might be a viable alternative to conventional ICDs with a lower risk of short- and long-term of device-related complications and infections.The aim of this multicenter study was to evaluate the outcomes and management of S-ICD recipients who underwent LVAD implantation. METHODS: The study population included patients with a preexisting S-ICD who underwent LVAD implantation for advanced HF despite optimal medical therapy. RESULTS: The study population included 30 patients (25 male; median age 45 [38-52] years).The HeartMate III was the most common LVAD type. Median follow-up in the setting of concomitant use of S-ICDs and LVADs was 7 months (1-20).There were no reports of inability to interrogate S-ICD systems in this population. Electromagnetic interference (EMI) occurred in 21 (70%) patients. The primary sensing vector was the one most significantly involved in determining EMI. Twenty-seven patients (90%) remained eligible for S-ICD implantation with at least one optimal sensing vector. The remaining 3 patients (10%) were ineligible for S-ICD after attempts of reprogramming of sensing vectors. Six patients (20%) experienced inappropriate shocks (IS) due to EMI. Six patients (20%) experienced appropriate shocks. No S-ICD extraction because of need for antitachycardia pacing, ineffective therapy or infection was reported. CONCLUSIONS: Concomitant use of LVAD and S-ICD is feasible in most patients. However, the potential risk of EMI oversensing, IS and undersensing in the post-operative period following LVAD implantation should be considered. Careful screening for EMI should be performed in all sensing vectors after LVAD implantation.

Intracardiac echocardiography-guided pulsed-field ablation for successful ablation of atrial fibrillation: a propensity-matched analysis from a large nationwide multicenter experience.

BACKGROUND: Intracardiac echocardiography (ICE) is increasingly employed in atrial fibrillation (AF) ablation procedures, with the potential to enhance procedural efficacy. Nevertheless, there is currently a lack of evidence assessing the impact of ICE on the efficiency, effectiveness, and safety outcomes in the context of novel pulsed-field ablation (PFA) for AF. PURPOSE: We aimed to assess whether the use of ICE could improve procedural parameters in a large population undergoing AF ablation with FARAPULSE™ catheter. METHODS: Consecutive patients who had undergone PFA of AF from nine Italian centers were included. In procedures where the ICE catheter was employed for guidance (ICE-guided group), it was used to maneuver the PFA catheter within the left atrium to achieve optimal contact with atrial structures. RESULTS: We analyzed 556 patients: 357 (66%) with paroxysmal AF, 499 (89.7%) de novo PVI. ICE-guided procedures (n = 138) were propensity matched with patients with a standard approach (n = 138), and their outcomes were compared. During ICE-guided procedures, no improvement in procedural metrics was recorded (ICE vs Standard, 23 ± 6 min vs 18.5 ± 9 min for time to PVI, p < 0.0001; 38.8 ± 7 vs 32.5 ± 5 number of PFA deliveries to achieve PVI, p < 0.0001; 68.8 ± 19 min vs 71.8 ± 29 min for primary operator time, p = 0.5301; 16.1 ± 8 min vs 18.2 ± 10 min for fluoroscopy time, p = 0.5476) except for support time (76.8 ± 26 min vs 91.4 ± 37 min, p = 0.0046). No major procedure-related adverse events were reported. CONCLUSION: Our findings confirmed that PFA could be consistently performed in a rapid, safe, and efficacious manner. The use of ICE to guide PFA was not associated with an improvement in procedural metrics.

Safety and Efficacy of Uninterrupted Oral Anticoagulation in Patients Undergoing Catheter Ablation for Atrial Fibrillation with Different Techniques.

BACKGROUND: The safety and efficacy of an uninterrupted direct anticoagulation (DOAC) strategy during catheter ablation (CA) for atrial fibrillation (AF) has not been fully investigated with different ablation techniques. METHODS: We evaluated consecutive AF patients undergoing catheter ablation with three different techniques. All patients were managed with an uninterrupted DOAC strategy. The primary endpoint was the rate of periprocedural thromboembolic and bleeding events. The secondary endpoints of the study were the rate of MACE and bleeding events at one-year follow-up. RESULTS: In total, 162 patients were enrolled. Overall, 53 were female and the median age was 60 [55.5-69.5] years. The median CHA2DS2-VASc and HAS-BLED scores were 2 [1-4] and 2 [1-2], respectively. In total, 16 patients had a past stroke or TIA while 11 had a predisposition or a history of bleeding. The CA procedure was performed with different techniques: RF 43%, cryoballoon 37%, or laser-balloon 20%. Overall, 35.8% were on rivaroxaban, 20.4% were on edoxaban, 6.8% were on apixaban, and 3.7% were on dabigatran. All other patients were all naïve to DOACs; the first anticoagulant dose was given before the ablation procedure. As for periprocedural complications, we found three groin hematomas not requiring interventions, one ischemic stroke, and one systemic air embolism (the last two likely due to several catheter changes through the transeptal sheath). Five patients reached the secondary endpoints: one patient for a myocardial infarction while four patients experienced minor bleeding during 1-year follow-up. CONCLUSIONS: Our results corroborate the safety and the efficacy of uninterrupted DOAC strategy in patients undergoing CA for AF, regardless of the ablation technique.

Atrial fibrillation recurrences during the blanking period after catheter ablation with the laser balloon technique.

INTRODUCTION: Regardless of the catheter ablation (CA) for atrial fibrillation (AF) strategy, the role of early recurrences during the blanking period (BP) is still unclear. Our aim was to evaluate atrial tachyarrhythmias (ATAs) recurrences during the BP after CA with the laser-balloon (LB) technique. METHODS: Consecutive patients undergoing LBCA were enrolled. Primary outcome of the study was the overall crude ATA recurrence rate during the BP. ATA recurrences after the BP and in-hospital readmissions during the BP were deemed secondary outcomes. RESULTS: Two hundred and twenty-four patients underwent CA with the LB. Median age was 63.0 (55.5-69.5) years and 74.1% were males. 28.6% were persistent AF patients, and 34.8% of patients were followed up with a loop recorder. 15.6% of patients experienced at least an ATA recurrence during the BP. Male sex, chronic heart failure, persistent AF, and recurrences during the BP were found to be associated with long-term ATA recurrences. Recurrences during the BP remained associated with the outcome of interest at multivariate analysis (hazard ratio [HR] = 12.393, 95% confidence interval [95% CI] = 3.699-41.865, p < .001). An association over time was found between early and late recurrences, with 73.7%, 45.5%, and 10.8% of patients presenting with recurrences at 1-, 2-, and 3-month follow-up being free from recurrences after the BP, respectively. 8.0% of patients were readmitted during the BP: 4.5% for AF electrical cardioversion, and 1.8% for CA of other atrial arrhythmias; no redo CA was performed. CONCLUSION: After adjusting for confounders, ATA recurrences during the BP represent the most significant predictor of ATA recurrences after the BP, regardless of AF pattern.

A novel in-frame deletion in MYOT causes an early adult onset distal myopathy.

Missense mutations in MYOT encoding the sarcomeric Z-disk protein myotilin cause three main myopathic phenotypes including proximal limb-girdle muscular dystrophy, spheroid body myopathy, and late-onset distal myopathy. We describe a family carrying a heterozygous MYOT deletion (Tyr4_His9del) that clinically was characterized by an early-adult onset distal muscle weakness and pathologically by a myofibrillar myopathy (MFM). Molecular modeling of the full-length myotilin protein revealed that the 4-YERPKH-9 amino acids are involved in local interactions within the N-terminal portion of myotilin. Injection of in vitro synthetized mutated human MYOT RNA or of plasmid carrying its cDNA sequence in zebrafish embryos led to muscle defects characterized by sarcomeric disorganization of muscle fibers and widening of the I-band, and severe motor impairments. We identify MYOT novel Tyr4_His9 deletion as the cause of an early-onset MFM with a distal myopathy phenotype and provide data supporting the importance of the amino acid sequence for the structural role of myotilin in the sarcomeric organization of myofibers.

Determinants of acute irreversible electroporation lesion characteristics after pulsed field ablation: the role of voltage, contact, and adipose interference.

AIMS: Pulsed field ablation (PFA) is a non-thermal ablative approach in which cardiomyocyte death is obtained through irreversible electroporation (IRE). Data correlating the biophysical characteristics of IRE and lesion characteristics are limited. The aim of this study was to assess the effect of different procedural parameters [voltage, number of cycles (NoCs), and contact] on lesion characteristics in a vegetal and animal model for IRE. METHODS AND RESULTS: Two hundred and four Russet potatoes were used. Pulsed field ablation lesions were delivered on 3 cm cored potato specimens using a multi-electrode circular catheter with its dedicated IRE generator. Different voltage (from 300 to 1200 V) and NoC (from 1 to 5×) protocols were used. The impact of 0.5 and 1 mm catheter-to-specimen distances was tested. A swine animal model was then used to validate the results observed in the vegetable model. The association between voltage, the NoCs, distance, and lesion depth was assessed through linear regression. An almost perfect linear association between lesion depth and voltage was observed (R2 = 0.95; P < 0.001). A similarly linear relationship was observed between the NoCs and the lesion depth (R2 = 0.73; P < 0.001). Compared with controls at full contact, a significant dampening on lesion depth was observed at 0.5 mm distance (1000 V 2×: 2.11 ± 0.12 vs. 0.36 ± 0.04, P < 0.001; 2.63 ± 0.10 vs. 0.43 ± 0.08, P < 0.001). No lesions were observed at 1.0 mm distance. CONCLUSION: In a vegetal and animal model for IRE assessment, PFA lesion characteristics were found to be strongly dependent on voltage settings and the NoCs, with a quasi-linear relationship. The lack of catheter contact was associated with a dampening in lesion depth.

Human Mutated MYOT and CRYAB Genes Cause a Myopathic Phenotype in Zebrafish.

Myofibrillar myopathies (MFMs) are a group of hereditary neuromuscular disorders sharing common histological features, such as myofibrillar derangement, Z-disk disintegration, and the accumulation of degradation products into protein aggregates. They are caused by mutations in several genes that encode either structural proteins or molecular chaperones. Nevertheless, the mechanisms by which mutated genes result in protein aggregation are still unknown. To unveil the role of myotilin and αB-crystallin in the pathogenesis of MFM, we injected zebrafish fertilized eggs at the one-cell stage with expression plasmids harboring cDNA sequences of human wildtype or mutated MYOT (p.Ser95Ile) and human wildtype or mutated CRYAB (p.Gly154Ser). We evaluated the effects on fish survival, motor behavior, muscle structure and development. We found that transgenic zebrafish showed morphological defects that were more severe in those overexpressing mutant genes. which developed a myopathic phenotype consistent with that of human myofibrillar myopathy, including the formation of protein aggregates. Results indicate that pathogenic mutations in myotilin and αB-crystallin genes associated with MFM cause a structural and functional impairment of the skeletal muscle in zebrafish, thereby making this non-mammalian organism a powerful model to dissect disease pathogenesis and find possible druggable targets.

Sex differences in leadless pacemaker implantation: A propensity-matched analysis from the i-LEAPER registry.

BACKGROUND: The impact of sex in clinical and procedural outcomes in leadless pacemaker (LPM) patients has not yet been investigated. OBJECTIVE: The purpose of this study was to investigate sex-related differences in patients undergoing LPM implantation. METHODS: Consecutive patients enrolled in the i-LEAPER registry were analyzed. Comparisons between sexes were performed within the overall cohort using an adjusted analysis with 1:1 propensity matching for age and comorbidities. The primary outcome was the comparison of major complication rates. Sex-related differences regarding electrical performance and all-cause mortality during follow-up were deemed secondary outcomes. RESULTS: In the overall population (n = 1179 patients; median age 80 years), 64.3% were men. After propensity matching, 738 patients with no significant baseline differences among groups were identified. During median follow-up of 25 [interquartile range 24-39] months, female sex was not associated with LPM-related major complications (hazard ratio [HR] 2.03; 95% confidence interval [CI] 0.70-5.84; P = .190) or all-cause mortality (HR 0.98; 95% CI 0.40-2.42; P = .960). LPM electrical performance results were comparable between groups, except for a higher pacing impedance in women at implant and during follow-up (24 months: 670 [550-800] Ω vs 616 [530-770] Ω; P = .014) that remained within normal limits. CONCLUSION: In a real-world setting, we found differences in sex-related referral patterns for LPM implantation with an underrepresentation of women, although major complication rate and LPM performance were comparable between sexes. Female patients showed higher impedance values, which had no impact on overall device performance. Electrical parameters remained within normal limits in both groups during the entire follow-up.