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BACKGROUND: Ventricular fibrillation (VF) remains a leading cause of sudden cardiac death with an incompletely characterized electrophysiological substrate. Traditional large-animal VF models are limited by hemodynamic collapse and myocardial ischemia. This study establishes a reproducible swine model using dual mechanical circulatory devices to enable high-density electroanatomic mapping under nonischemic conditions. METHODS: Five Yorkshire swine (55–65 kg) underwent sustained VF supported by venoarterial extracorporeal membrane oxygenation (2.5–3.0 L/min) and percutaneous left ventricular unloading (Impella CP, P-2–P-4). High-density electroanatomic mapping using CARTO 7 was performed at baseline and after defibrillation. Bipolar voltage was acquired from 7 predefined ventricular regions (21 measurements per animal per time point; n=210 paired observations). Unipolar voltage mapping and continuous surface ECG monitoring were used to assess acute ischemic injury. Systemic perfusion was maintained at systolic arterial pressure ≥80 mm Hg. Linear mixed-effects modeling was used to analyze voltage changes from pre-VF to post-VF. RESULTS: Sustained VF (10±1 minutes) was reproducibly induced and maintained with consistent hemodynamics (systolic arterial pressure, 90±5 mm Hg; extracorporeal membrane oxygenation flow, 2.5±0.5 L/min). All animals were successfully defibrillated. High-density mapping was feasible in all experiments (1000±300 points per chamber). Bipolar voltage showed no change from pre-VF (5.86±2.56 mV) to post-VF (6.53±2.22 mV; mean difference, 0.67 mV [95% CI, –0.31 to 1.65]; P =0.15). Both left ( P =0.17) and right ventricles ( P =0.08) demonstrated voltage preservation. Regional analysis showed no significant changes (all P >0.05); post-VF voltages remained above viability thresholds (>1.5 mV). Unipolar voltage maps recovered toward baseline, with no ECG injury pattern identified after defibrillation. CONCLUSIONS: Dual mechanical circulatory support with venoarterial extracorporeal membrane oxygenation and Impella CP enables reproducible, high-fidelity electroanatomic mapping and preserves myocardial substrate after sustained VF in a large-animal model. This platform overcomes key technical barriers in VF research, providing a nonischemic foundation for future mechanistic and translational studies.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

ABSTRACT Introduction Right ventricular pacing (RVP) has long been the standard therapy for bradyarrhythmias but may induce ventricular dyssynchrony and adverse cardiac remodeling. Physiologic pacing strategies that preserve the native conduction system, particularly left bundle branch area pacing (LBBAP), have emerged as promising alternatives. This study aimed to evaluate the comparative efficacy and safety of LBBAP versus RVP through an updated meta‐analysis. Methods Following PRISMA guidelines, we systematically searched PubMed, Cochrane CENTRAL, and ClinicalTrials.gov for relevant studies published through June 2025. Studies comparing LBBAP and RVP in patients undergoing pacemaker implantation were included. Pooled estimates were calculated using random‐effects models. Results A total of 40 studies comprising 8290 patients were included. LBBAP was associated with significantly shorter QRS duration compared with RVP (30 studies, n = 5510; MD −35.56 ms, 95% CI −41.88 to −29.24; p < 0.0001). Structural remodeling also favored LBBAP, with greater improvement in left ventricular ejection fraction (16 studies, n = 1693; MD +3.77%, 95% CI 2.43–5.12; p < 0.0001) and greater reduction in left ventricular end‐diastolic diameter (13 studies, n = 1666; MD −2.33 mm, 95% CI −3.59 to −1.07; p < 0.0001). Clinically, LBBAP was associated with lower heart failure hospitalization (RR 0.38, 95% CI 0.29–0.52; p < 0.0001) and reduced all‐cause mortality (RR 0.55, 95% CI 0.41–0.72; p < 0.0001), along with greater reduction in NT‐proBNP levels. Conclusion LBBAP provides superior electrical synchrony, improved cardiac remodeling, and favorable clinical outcomes compared with RVP, while maintaining a comparable procedural safety profile.

ABSTRACT Background Factor XI/XIa inhibitors are emerging anticoagulants with potential to reduce bleeding complications in atrial fibrillation (AF) patients. This meta‐analysis evaluated their efficacy and safety compared to direct oral anticoagulants (DOACs) and explored dose optimization. Methods A systematic search of PubMed, Cochrane, and Embase was conducted through March 2025 following PRISMA guidelines. Randomized controlled trials (RCTs) comparing Factor XI/XIa inhibitors with DOACs in AF patients were included. Outcomes assessed were major bleeding, stroke, systemic embolism, all‐cause and cardiovascular mortality and serious adverse events. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using a Mantel‐Haenszel random‐effects model. Heterogeneity was evaluated with the I² statistic, and evidence certainty assessed by the GRADE approach. Trial Sequential Analysis (TSA) was performed. Results Three RCTs including 16,772 patients (mean age 73 years, CHA₂DS₂‐VASc 3.9–5) were analyzed. Factor XI/XIa inhibitors significantly reduced major bleeding (RR: 0.41, 95% CI: 0.36–0.46, I² = 0%) compared to DOACs. However, stroke risk was increased (RR: 3.42, 95% CI: 2.62–4.46), particularly with asundexian 50 mg (RR: 4.02). No significant differences were observed in all‐cause mortality (RR: 0.82) or cardiovascular death (RR: 1.05). Systemic embolism risk was higher (RR: 4.26), while serious adverse events were comparable (RR: 0.95). TSA indicated encouraging safety outcomes but highlighted the need for further large‐scale studies. Conclusion Factor XI/XIa inhibitors lower major bleeding risk in AF patients but increase stroke and systemic embolism rates without impacting mortality.

Abstract Background The extravascular implantable cardioverter defibrillator (EV-ICD) was designed to avoid lead-related complications associated with transvenous systems and deliver features such as anti-tachycardia pacing (ATP) and reduced generator size that provide an advantage over a subcutaneous ICD (S-ICD). As such, the EV-ICD is an attractive alternative for younger patients with genetic heart diseases (GHDs) who are not in need of permanent pacing. Objective To examine the indications, complications, and the clinical outcomes of patients with GHDs who received an EV-ICD. Methods A retrospective review of the electronic record was done for all GHD patients evaluated in genetic heart rhythm and/or cardiomyopathy clinics who had an EV-ICD implanted between 1/2021 and 2/2025. Basic demographic, ICD indications, complications, and therapy data were then extracted for all study patients. Results Overall, 23 patients (35% female; mean age 39 ± 16 years; 61% with a disease-causative genetic variant; mean LVEF 57%) with an underlying GHD (hypertrophic cardiomyopathy in 9, arrhythmogenic cardiomyopathy in 8, idiopathic ventricular fibrillation in 3, dilated cardiomyopathy in 2, and long QT syndrome in 1) had an EV-ICD implanted. For the majority, an EV-ICD was implanted for primary prevention (15/23; 65%) and represented their first ICD system (21/23; 91%). The success rate of the procedure was 96% with only one abandoned procedure because of poor R-wave sensing. Inadvertent intraprocedural lead placement in the pericardial space occurred in 1 patient with previous thoracotomy and surgically placed epicardial lead without sequelae or need for revision. Over a mean follow-up of 8±9 months, the rate of complications was low (1/23; 4%) with one electrode displacement and this patient underwent defibrillation threshold testing (DFT), the device properly detected VF and emitted a successful shock 30 J. Thus far, 2 patients have received appropriate VT/VF-terminating therapies (3 ICD shocks, 0 ATP) with successful conversion to sinus rhythm. One patient died following an electrical storm. One patient had 3 inappropriate ICD shock for sinus tachycardia while exercising followed by 1 successful shock for VF. Conclusion In this early experience, EV-ICDs appear to be safe and effective in younger patients with genetic arrhythmogenic and hypertrophic cardiomyopathies. Future studies are needed to better understand the utility of EV-ICDs in patients with cardiac channelopathies and advantages of EV-ICDs over transvenous and S-ICD systems in patients with an array of sudden death-predisposing GHDs.

ABSTRACT Background Pulsed‐field ablation (PFA) offers myocardial selectivity with minimal thermal injury, but depth for ventricular lesions may be insufficient or heterogeneous at clinically tolerable field strengths. Calcium electroporation—local calcium chloride (CaCl₂) infusion after PFA—may amplify electroporation‐mediated cell death while maintaining low energy settings. Objective To determine whether immediate post‐PFA CaCl₂ infusion enhances acute and chronic ventricular lesion formation in vivo. Methods Nine swine underwent focal ventricular PFA (750–1000 V, biphasic, 20 μs × 50 pulses, 200 ms interpulse) via an irrigated focal catheter and benchtop electroporator. Immediately post‐PFA, lesions were randomized to saline, 0.2 g Ca, or 0.4 g Ca infused locally through the catheter tip. Acute hearts were explanted for TTC analysis; surviving animals were studied at 7 days for chronic lesion geometry. Results Among 41 acute lesions (17 control, 12 Ca 0.2 g, 12 Ca 0.4 g), Ca 0.4 g increased dark‐zone depth (3.5 ± 1.4 vs. 2.3 ± 0.8 mm; p = 0.038) and pale‐zone depth (2.6 ± 1.3 vs. 1.3 ± 0.8 mm; p = 0.011) versus control. At 7 days ( n = 33 lesions), Ca 0.4 g produced larger scars than control (width 11.6 ± 2.1 vs. 10.0 ± 1.9 mm; p = 0.027; depth 4.2 ± 1 vs. 3.0 ± 0.8 mm; p < 0.001; volume 193.6.4 ± 82.3 vs. 109.4 ± 48.2 mm³; p = 0.001). Conclusions Local CaCl₂ infusion after ventricular PFA significantly augments acute electroporation effect and chronic lesion size at low output, supporting facilitated PFA as a strategy for deeper, more durable ventricular ablation.

ABSTRACT Background Ventricular tachycardia (VT) is a life‐threatening arrhythmia frequently observed in structural heart diseases, including LMNA‐related cardiomyopathy, a genetic disorder associated with high risk of sudden cardiac death and progressive systolic dysfunction. While catheter ablation is an established therapeutic option for VT, its efficacy in cardiac laminopathy remains poorly defined. Objectives To synthesize available evidence on the role and outcomes of VT ablation in patients with cardiac laminopathy. Methods A systematic review and single‐arm meta‐analysis was performed in accordance with PRISMA guidelines. PubMed, Embase, and Cochrane databases were searched for studies reporting VT ablation outcomes in LMNA‐related cardiomyopathy. An inverse variance random‐effects model was applied for meta‐analysis of proportions. Results Seven studies (six cohorts, one abstract) comprising 62 patients (mean age 53.2 ± 9.7 years; 85% male; 88% with implantable cardioverter‐defibrillator) were included. An endocardial/endo‐epicardial approach was used in 93% of cases. Acute procedural success was achieved in 37% (95% CI: 14%–63%; I² = 27.4%), and 28% required multiple procedures. Over a median follow‐up of 26 (9–35) months, VT recurrence occurred in 91% (95% CI: 76%–100%; I² = 37.2%). All‐cause mortality was 54% (95% CI: 39%–70%; I² = 28%), predominantly from cardiac causes (51%, 95% CI: 25%–76%; I² = 53%), and 14% (95% CI: 1%–34%; I² = 42%) underwent heart transplantation. Conclusions In LMNA‐related cardiomyopathy, catheter ablation is associated with high VT recurrence, limited long‐term success, and substantial cardiovascular mortality and transplantation rates, underscoring the importance of ICD implantation and the need for alternative strategies, including variant‐specific and molecularly targeted therapies.