AIMS:Loss-of-function (LOF) variants in SCN5A are associated with Brugada syndrome (BrS), progressive conduction slowing, and other arrhythmias. While the prognosis of SCN5A carriers with a positive sodium channel blocker challenge (SCBC) is established, data on those with negative SCBC are limited. OBJECTIVE:To assess the clinical presentation and prognosis of SCN5A variant carriers with negative SCBC, and compare them to relatives with positive SCBC. METHODS AND RESULTS:We retrospectively included patients from five university hospitals (2000-2024) carrying a pathogenic or likely pathogenic SCN5A variant and negative SCBC. Relatives with the same variant and positive SCBC were also analysed. Patients with spontaneous type 1 ECG, gain-of-function variants, double variants, or ACMG class 1-3 variants were excluded. Clinical, ECG, genetic, and follow-up data were collected. Conduction slowing was evaluated using the PR interval and QRS duration. The cohort included 162 patients from 43 families (median age 37 ± 19 years, 46% male), of whom 69 (43%) had negative SCBC. Among these 69 patients, 25 (36%) had baseline intraventricular conduction defects, and 19 (28%) had first-degree AV block. After a median follow-up of 75 [40-168] months, 52% of patients developed progressive conduction slowing. Negative SCBC patients had fewer conduction defects (36% vs. 70%, p = 0.002) and ICD implantations (1% vs. 23%, P < 0.001). Non-missense variants were associated with more conduction slowing (71% vs. 42%, P = 0.04). CONCLUSION:This multicentre study provides the largest analysis of SCN5A carriers with negative SCBC, showing excellent arrhythmic prognosis despite frequent progressive conduction slowing.
Importance:Anterior acute myocardial infarction is associated with increased risk of left ventricular (LV) thrombus. The benefit and risk of adding an oral anticoagulant to dual antiplatelet therapy (DAPT) in preventing LV thrombus remain uncertain. Objective:To determine whether the addition of low-dose rivaroxaban to DAPT reduces the incidence of LV thrombus at 1 month in patients with anterior ST-segment elevation myocardial infarction (STEMI). Design, Setting, and Participants:This multicenter, open-label, blinded-end point randomized clinical trial was performed in 29 centers in France. The trial was nested in the ongoing FRENCHIE (French Cohort of Myocardial Infarction Evaluation) registry. Between October 2021 and January 2023, patients with anterior STEMI were enrolled. The last date of participant follow-up was in March 2023. Data analysis was performed from September 2024 to July 2025. Interventions:Patients were randomized to receive either DAPT plus rivaroxaban, 2.5 mg, twice daily for 4 weeks (n = 283) or DAPT alone (aspirin ≤100 mg per day and either clopidogrel, 75 mg per day, or ticagrelor, 90 mg twice a day [n = 277]), as soon as possible following completion of the initial percutaneous coronary intervention or angiography procedure. Main Outcomes and Measures:The primary end point was presence of LV thrombus on contrast-enhanced cardiac magnetic resonance imaging at 1 month. Results:Among 560 patients with anterior STEMI enrolled (mean [SD] age, 61.1 [11.6] years; 121 female patients [21.6%]), LV thrombus was detected in 38 patients (13.7%) receiving rivaroxaban and 47 patients (16.6%) with DAPT alone (difference, -2.9%; 95% CI, -8.9% to 3.2%; P = .34). No difference was observed between the 2 groups regarding the largest diameter of LV thrombus or the incidence of major adverse cardiovascular events. The incidence of major bleeding events (Bleeding Academic Research Consortium [BARC] ≥type 2) was also comparable (4 [1.5%] with DAPT plus rivaroxaban vs 2 [0.7%] with DAPT alone; difference, 0.7%; 95% CI, -1.3% to 3.1%), whereas minor bleeding events (BARC type 1) occurred more frequently in the DAPT plus rivaroxaban group (45 [16.4%] vs 20 [7.2%]; difference, 9.3%; 95% CI, 3.6%-14.8%). Conclusions and Relevance:In this multicenter randomized clinical trial among patients with anterior STEMI, the addition of low-dose rivaroxaban to DAPT did not demonstrate a statistically significant reduction in LV thrombus formation at 1 month but did increase minor bleeding. Given the limited power of the study, these findings should be interpreted with caution, as a modest effect cannot be excluded. Trial Registration:ClinicalTrials.gov Identifier: NCT05077683.
Background: Although several risk-stratification models have been developed for patients with refractory cardiogenic shock requiring temporary mechanical circulatory support, most primarily predict short- and long-term mortality and do not reliably identify patients who can be successfully weaned from support. Cardiac troponin is routinely measured during the acute phase of myocardial infarction. Cumulative troponin exposure, quantified by the troponin area under the concentration–time curve (T-AUC), correlates with the extent of myocardial necrosis. The objective of this study was to evaluate whether T-AUC could improve prediction of temporary mechanical circulatory support weaning failure. Methods: We conducted a single-centre retrospective cohort study including consecutive adults admitted to our cardiac intensive care unit between January 2014 and September 2025 with acute myocardial infarction-related cardiogenic shock requiring temporary mechanical circulatory support. From serial daily troponin I measurements, cumulative troponin exposure was reconstructed as T-AUC. The primary endpoint was temporary mechanical circulatory support weaning failure, defined as death, durable mechanical circulatory support, or heart transplantation during support or within 30 days after explantation. Results: Among the 159 included patients, 97 (61.0%) reached the primary endpoint. In the adjusted time-dependent Cox model, higher cumulative troponin exposure was independently associated with temporary mechanical circulatory support weaning failure (hazard ratio [HR] 1.40 per 1,000,000 ng/L·day increase, 95% confidence interval [CI] 1.19–1.65; p < 0.0001). Restoration of TIMI 3 flow after revascularisation was associated with a significantly lower risk of failure (HR 0.50, 95% CI 0.31–0.80; p = 0.004). Addition of day-5 T-AUC to the clinical model provided the greatest improvement in discrimination (AUC 0.862, 95% CI 0.797–0.926), followed by peak troponin (AUC 0.848, 95% CI 0.779–0.918). Conclusions: In patients with acute myocardial infarction-related cardiogenic shock requiring temporary mechanical circulatory support, cumulative troponin exposure, quantified by T-AUC, was independently associated with failure to wean from support and provided incremental predictive value beyond established clinical risk factors.
e16441 Background: Pancreatic ductal adenocarcinoma is one of the most lethal malignancies with a 5-year survival rate under 5%. Locally advanced pancreatic ductal adenocarcinoma (LAP) represents 30-40% of cases at the diagnosis, with an overall survival around 15 months. Optimizing chemotherapy in LAP is still a huge challenge. A concomitant inhibition of epithelial mesenchymal transition (EMT) process may potentiate chemotherapy efficacy and decrease the development of resistances. Netrin-1 is upregulated in many metastatic cancers including 60% of pancreatic cancer and promotes tumor invasiveness and metastases development through EMT induction. NP137, a first-in-class anti-Netrin-1 monoclonal antibody, has shown in phase I study the ability to inhibit EMT, potentially overcoming resistance (Cassier et al., Nature, 2023). The goal of LAP-NET1 (NCT05546853) is to evaluate the safety and efficacy of the combination of modified FOLFIRINOX with anti-Netrin-1 targeting (NP137). Methods: LAP-NET1 is a phase 1b multicentric trial studying the combination of modified FOLFIRINOX with NP-137 every 2 weeks for 12 cycles in patients naive of systemic treatment with LAP according to National Comprehensive Cancer Network criteria. A safety lead-in phase will initially enroll 3-12 patients to confirm the recommended dose of NP137 (14 or 9 mg/kg) according to a 3+3 de-escalation protocol, followed by an expansion phase of 40 patients. The primary endpoint is the proportion of patients experiencing adverse events (AEs) of any grade and grade 3/4 AEs (CTCAE v 5.0) related to the experimental treatment at 6 months. Secondary endpoints are best overall objective response according to RECIST 1.1, 12-month progression-free survival (PFS-12m), 12-month overall survival (OS-12m), surgical resection rate, quality of life (EORTC QLQ-C30), time to deterioration and ancillary outcomes based on spatial transcriptomic and classic bulk RNA sequencing. Clinical trial information: NCT05546853 .
BACKGROUND:Advances in medical and surgical care have improved survival in patients with transposition of the great arteries (TGA), shifting focus toward quality of life (QoL). In this study we evaluate QoL in adults with TGA, including congenitally corrected TGA (ccTGA) and patients with dextro-TGA (d-TGA), by comparing patients with a systemic right ventricle (sRV) and systemic left ventricle (sLV), while identifying mediating factors. METHODS:This cross-sectional study, part of the APPROACH-IS II trial, included 798 adults with TGA from 42 centres worldwide. QoL was assessed using a linear analogue scale (0-100). Regression models identified variables associated with QoL, and mediation analysis assessed the effect of sRV on QoL. RESULTS:Among participants (median age 34 years, 44.9% women), 504 (63.2%) had an sRV (ccTGA or d-TGA with atrial switch) and 294 (36.8%) had an sLV (ccTGA with double-switch operation or Rastelli and d-TGA with arterial switch or Rastelli). Patients with an sRV reported lower QoL (median 75, interquartile range 60-85) compared with those with an sLV (median 80, interquartile range 70-90; P < 0.001). The negative effect of sRV on QoL was mediated for 59% of patients by ventricular dysfunction (B = -2.37, 95% confidence interval -3.38 to -1.21; P < 0.001). Poorer QoL was independently associated with Asian race, employment status (job seeking, unemployed, or disabled), less social support, New York Heart Association functional class ≥ II, ventricular dysfunction, more interventional catheterizations, and depression/anxiety. CONCLUSIONS:TGA patients with an sRV experience a lower QoL than those with an sLV, mediated mainly by ventricular dysfunction. CLINICAL TRIAL REGISTRATION:NCT04902768.
