Citations

ABSTRACT Background Atrial fibrillation (AF) is prevalent in cardiac amyloidosis (CA) and is associated with adverse clinical outcomes. Catheter ablation is increasingly used for rhythm control in this population, yet its clinical outcomes remain uncertain. We performed a systematic review and meta‐analysis to evaluate arrhythmia recurrence and clinical outcomes following catheter ablation compared with medical therapy in patients with CA. Methods We systematically searched MEDLINE, Embase, and Scopus from inception through December 2025 for studies evaluating catheter ablation of atrial arrhythmias in CA. Cohort studies reporting arrhythmia recurrence and/or clinical outcomes were included. The primary outcome was freedom from atrial arrhythmia (AA) following ablation. Secondary outcomes included all‐cause mortality, heart failure hospitalization, and stroke. Random‐effects models were used to pool event rates and odds ratios (ORs). Results Thirteen observational studies comprising 797 patients with CA and AF were included. The pooled rate of freedom from AA following catheter ablation was approximately 50% (95% CI 37%–63%; I 2 = 71.7%). The all‐cause mortality analysis included 4 observational studies comprising 616 patients. Catheter ablation was associated with lower odds of all‐cause mortality (OR 0.26, 95% CI 0.11–0.60; I 2 = 18.4%); however, this association should be interpreted with caution given the retrospective design and risk of bias. No statistically significant differences were observed for heart failure hospitalization or stroke. Conclusions In patients with CA, catheter ablation was associated with modest arrhythmia‐free survival and lower odds of all‐cause mortality. However, all contributing studies were observational cohorts. Randomized studies are needed to confirm these findings.

Abstract Background Vagally mediated syncope and functional bradyarrhythmias can cause recurrent symptoms, injury and a need for permanent pacing, yet standard therapies do not address the underlying autonomic reflex. Cardioneuroablation (CNA) targets this mechanism, but adoption has been limited by uncertainty about patient selection, procedural endpoints and durable outcomes. Methods We studied 95 consecutive patients with vagally mediated syncope (n=78) or functional bradyarrhythmia (n=17) who underwent CNA at a single center by a single lead operator under a uniform, prospectively maintained protocol. Extracardiac vagal stimulation (ECVS) was performed before and after ablation to confirm vagally mediated sinus or atrioventricular (AV) nodal responses and to verify their attenuation. Outcomes through 1 year included clinical recurrence, quality of life, pacing burden and pacemaker extraction. Results Before ablation, ECVS provoked sinus pauses in 95.8% of patients and AV block in 91.6%; after ablation, sinus pauses were abolished in every patient and residual AV block was present in 4.2%. One-year freedom from recurrent syncope and from bradyarrhythmia-related events was 93.8% and 94.1%. Syncope burden fell from a median of 2.7 episodes per year to none, and disease-specific quality of life improved substantially (P<0.001). Among patients with pre-existing devices, atrial pacing burden fell from a median of 22% to 0%. There were no strokes, deaths or myocardial infarctions. Conclusions In this single-center cohort, physiology-guided CNA was associated with durable symptom control, improved quality of life and reduced pacing across vagally mediated bradyarrhythmia syndromes. Multicenter controlled studies are needed to confirm these findings.

9535 Background: MUM carries a poor prognosis with few effective treatments, especially for HLA-A*02:01-negative pts. While a subset of MUM pts responds to immune checkpoint inhibitors, the comparative efficacy of IPI+PD1 versus PD1 monotherapy is unclear. This study compares objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety between these regimens in MUM. Methods: MUM pts treated with PD1 or IPI+PD1 at 15 major melanoma centres (from Australia, Europe, United States and Israel) were included. Demographics, patient and disease characteristics, and clinical outcomes were examined. Univariate and multivariate (MVA) analyses were performed to identify clinical predictors of response and survival. Results: Of 412 MUM pts treated, 150 (36%) had PD1 and 262 (64%) received PD1+IPI. Compared to the PD1 group, PD1+IPI-treated pts were younger (64 vs. 70 years; p<0.001), had higher rate of elevated LDH (44% vs. 31%; p=0.037), and more frequently had prior treatment with tebentafusp (6.5% vs. 1.3%; p=0.031). Median follow-up from commencement of PD1+/-IPI was 4.9 years (95% CI 4.7 – 6.1). ORR was higher in IPI+PD1 group (18%) vs. PD1 (9%) (p=0.008), particularly in males (p=0.009), patients with liver metastases (p=0.018) and with lung metastases (p=0.011), with elevated LDH (p=0.047) and with no prior treatment with tebentafusp (p=0.007). PFS and OS at 1 and 2 years were numerically higher with IPI+PD1 (1- and 2-year PFS: 23% and 15%; 1- and 2-year OS: 63% and 39%) vs. PD1 (1- and 2-year PFS: 17% and 11%; 1- and 2-year OS: 54% and 36%), but these differences were not statistically significant (p>0.05). On MVA, adjusting for predefined variables (age, gender, ECOG PS, LDH, presence/absence of liver/lung metastases, prior treatment with tebentafusp), IPI+PD1 was associated with higher ORR (OR 2.71, 1.30 – 6.05; p=0.01) but not with PFS or OS compared to PD1. Presence of liver metastases (ORR [OR 0.28; 95% CI 0.13 - 0.64], PFS [HR 1.61; 95% CI 1.11 - 2.34], OS [HR 2.02; 95% CI 1.32 - 3.10]), ECOG PS≥2 (PFS [HR 1.82; 95% CI 1.07 - 3.10], OS [HR 2.24; 95% CI 1.25-4.01]), elevated LDH (PFS [HR 1.66; 95% CI 1.30 - 2.11], OS [HR 2.39; 95% CI 1.84-3.10]) and prior tebentafusp treatment (OS [HR 2.36; 95% CI 1.21-4.59]) were also independent predictors of response and/or survival. A higher percentage of pts experienced grade ≥3 immune-related adverse events (irAEs) in the IPI+PD1 group compared to the PD1 group (34% vs 13%, p<0.0001). Most pts ceased treatment due to progression (234, 57%), and more pts stopped due to toxicity in the IPI+PD1 vs. PD1 group (25% vs. 9%, p<0.0001). Conclusions: In pts with MUM, IPI+PD1 demonstrated a higher ORR but did not improve survival compared with PD1 alone. IPI+PD1 was more toxic, leading to early treatment discontinuation in one-quarter of pts. These findings may help guide treatment selection in MUM.

This cross-sectional study investigates the association between lipoprotein(a) levels and risk of ventricular arrhythmias among patients with heart failure with reduced ejection fraction receiving implantable cardioverter-defibrillator therapy.

Background Immune exclusion inhibits antitumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. In triple-negative breast cancer (TNBC), an aggressive and generally immune-rich subtype, an immune-cold microenvironment predicts poor prognosis due to a limited response to chemotherapy and immune checkpoint inhibitors. This study aimed to identify mechanisms regulating immune infiltration in TNBC. Methods We performed spatial transcriptomic analysis comparing immune-enriched versus immune-cold treatment-naïve TNBCs. Functional analyses, including loss-of-function and reconstitution experiments, were conducted to investigate the role of trophoblast cell-surface antigen 2 (TROP2), a key target of anticancer antibody drug conjugates (ADCs), in promoting TNBC progression. A humanized TROP2 syngeneic TNBC model was used to assess the effects of TROP2-targeting in combination with anti-programmed cell death protein 1 (PD-1) therapy. Additionally, data from patients treated with immune checkpoint blockade were used to test hypotheses from the preclinical findings. Results We reveal that TROP2 controls barrier-mediated immune exclusion in TNBC through claudin 7 association and tight junction regulation. TROP2 expression is inversely correlated with T-cell infiltration and predicts poor outcomes in TNBC. We demonstrate that TROP2 is sufficient to drive tumor progression in vivo in a CD8 T cell-dependent manner, while its loss deregulates expression and localization of multiple tight junction proteins, enabling T-cell infiltration. We show that TROP2 targeting via hRS7, the antibody component of the ADC sacituzumab govitecan, enhances the anti-PD-1 response and improves T-cell accessibility and effector function. Correspondingly, TROP2 expression is highly associated with lack of response to anti-PD-1 therapy in human breast cancer. Conclusions This study defines a new mechanism of barrier-mediated immune exclusion in cancer controlled by TROP2-dependent tight junctions. This mechanism drives tumor progression but can be targeted via TROP2-directed therapy to activate antitumor immunity and enhance immunotherapy response.

BACKGROUND: Catheter ablation for atrial fibrillation is a widely used rhythm-control strategy, yet its role in reducing thromboembolic risk and enabling oral anticoagulation (OAC) discontinuation remains uncertain. This meta-analysis aims to comprehensively synthesize and evaluate randomized controlled trial evidence supporting long-term antithrombotic strategies in patients with atrial fibrillation undergoing catheter ablation. METHODS: A systematic literature search was performed in MEDLINE/PubMed, Embase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials evaluating antithrombotic strategies after catheter ablation for atrial fibrillation. The primary outcome was ischemic stroke. A frequentist network meta-analysis comparing reported treatment arms, along with a pooled incidence meta-analysis for outcomes of interest, was conducted. RESULTS: Four randomized controlled trials, including 3924 patients, met the inclusion criteria. Three trials compared long-term OAC continuation versus OAC discontinuation, and 1 compared OAC continuation with left atrial appendage occlusion after catheter ablation. No significant differences in stroke incidence were observed when comparing OAC or left atrial appendage occlusion with no antithrombotic therapy (incidence rate ratio, 0.90 [95% CI, 0.02–33.85]; P =0.95; incidence rate ratio, 0.79 [95% CI, 0.00–241.01]; P =0.94, respectively). Among patients who discontinued antithrombotic therapy without undergoing left atrial appendage occlusion (n=1161), with 2864 cumulative person-years of follow-up, the pooled incidence of stroke was 0.23 events per 100 person-years (95% CI, 0.02–2.43; I 2 =0%). CONCLUSIONS: This analysis reinforces that, across randomized data, the incidence of thromboembolic events in patients who discontinued OAC after successful ablation remained low. However, the evaluation of net clinical benefit is limited by the low number of events across all treatment arms, underscoring the need for larger studies with prolonged follow-up to further validate the safety of this strategy, particularly in higher-risk populations.

Brugada Syndrome (BrS) is a rare but clinically significant inherited arrhythmia disorder characterized by a type 1 ECG pattern and an increased risk of sudden cardiac death (SCD). Since its first description in 1992, BrS has been the subject of intensive investigation, yet risk stratification remains one of its greatest challenges. While survivors of cardiac arrest and patients with documented ventricular fibrillation (VF) are clear candidates for implantable cardioverter-defibrillators (ICDs), predicting risk in asymptomatic or intermediate-risk individuals is less straightforward. Over the past two decades, multiple risk scores have been developed—including the Sieira, Shanghai, BRUGADA-RISK, and PAT—each integrating combinations of clinical, ECG, electrophysiological study (EPS), and genetic data. Performance metrics vary, with C-statistics ranging from 0.70 to 0.82 in derivation cohorts, but external validation has often been limited. Importantly, current ESC and AHA/ACC guidelines only endorse syncope and EPS inducibility as validated predictors, reflecting the cautious stance of expert panels in the face of heterogeneous data. Nonetheless, the emergence of structured risk models has improved our ability to stratify intermediate-risk patients and stimulated further innovation. Looking ahead, opportunities lie in integrating artificial intelligence applied to raw ECG waveforms, wearable technology for dynamic monitoring, advanced cardiac imaging biomarkers, and polygenic risk scores. Multinational collaboration and federated learning will be essential to overcome statistical fragility and ensure global applicability. Ultimately, BrS risk scores should be considered decision-support tools that enrich but do not replace clinical judgment. Shared decision-making remains central, particularly in asymptomatic patients where ICD implantation is not a clear-cut choice.

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide, and despite advances in treatment, immune suppression remains an obstacle to effective therapy. Effector CD4+ T cells (CD4+ Teff) are critical for antitumor immunity, but their function is often inhibited by regulatory T cells (Treg), which accumulate in lung tumors and mediate suppressive functions through multiple mechanisms. This suppression leads to tumor progression and poor patient outcomes. However, the mechanisms underlying Treg-mediated suppression are not fully understood. Herein, we identify the extracellular adenosine 5-triphosphate receptor P2RX7 as a key regulator of Treg function in lung tumors. In a murine lung cancer model induced by Lewis lung carcinoma cells, we found that P2RX7 enhanced the suppressive capacity of tumor-infiltrating Tregs, promoting tumor growth. In T cell–specific P2RX7-knockout (P2RX7-KO) mice, reduced Treg infiltration was accompanied by increased CD4+ Teff accumulation and improved tumor control. Treg-specific P2RX7-KO mice exhibited reduced tumor growth, confirming a Treg-intrinsic role of P2RX7. Suppression assays revealed that tumor-infiltrating wild-type Tregs had greater suppressive activity compared with P2RX7-KO Tregs, which failed to inhibit type 1 and follicular helper T–like responses. This was associated with increased tumor-specific IgG production by lung B cells in P2RX7-KO mice. We also observed that wild-type Tregs expressed higher levels of the immunosuppressive molecule CTLA-4 when compared with P2RX7-KO Tregs. Thus, we conclude that P2RX7 expression on Tregs is essential for their suppressive function in lung cancer and targeting P2RX7 may constitute a strategy to improve lung cancer treatment by alleviating Treg-mediated immune suppression.

BACKGROUND: Cavotricuspid isthmus (CTI) ablation is frequently performed either as a standalone procedure or in combination with pulmonary vein isolation. With the rapid adoption of pulsed field ablation for atrial fibrillation, it is essential to delineate the utility of this modality in treating CTI-dependent atrial flutter (AFL). This study aims to evaluate the procedural and clinical outcomes of CTI ablation using pulsed field energy. METHODS: We conducted a retrospective analysis of consecutive patients who underwent pulsed field ablation for CTI-dependent AFL between January 2024 and March 2025. The primary end points were acute procedural success, periprocedural complications, and CTI-dependent AFL recurrence during follow-up. RESULTS: A total of 132 patients underwent CTI nonthermal ablation. The median age was 69.5 years, and 27.3% were female. The Farawave catheter was used in 93.9% of cases, PulseSelect in 4.5%, and Sphere-9 in 1.5%. Acute block was achieved in 99.2% of patients, although 8 required adjunctive radiofrequency ablation to complete the line. Periprocedural complications included transient ST-segment elevation in 2 patients and transient conduction disturbances in 3. During a median follow-up of 114 days (n=131), 5 patients (3.8%) experienced recurrence of typical AFL. The 6-month typical AFL-free survival estimate was 93.6%. CONCLUSIONS: Pulsed field ablation appears to be a feasible and effective strategy for CTI-dependent AFL. However, anatomic variability may limit its universal applicability with current catheter designs. Although acute procedural success is high, the long-term durability of the CTI block and its comparative efficacy versus conventional thermal ablation remain areas requiring further investigation.