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Introduction: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) arises from amyloidogenic aggregates of destabilized TTR protein in variant (ATTRv-CM) or acquired wild-type TTR (ATTRwt-CM). The p.V142I (V122I) variant is the most common pathogenic TTR allele in the USA and has higher mortality vs wild type. Acoramidis, an oral TTR stabilizer achieving ≥90% stabilization, is approved in USA, UK, Europe, and Japan for treating ATTR-CM in adults. In ATTRibute-CM (NCT03860935), acoramidis showed a reduction in all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) vs placebo (PBO), with consistent benefit in ATTRwt-CM and ATTRv-CM (all variants). We report clinical outcomes in participants with p.V142I ATTRv-CM. Research Question: What was the efficacy of acoramidis for clinical outcomes (ACM, CVH) in participants with p.V142I ATTRv-CM in ATTRibute-CM? Methods: In ATTRibute-CM, 632 participants were randomized 2:1 to receive acoramidis HCl 800 mg or PBO twice daily for 30 months. All participants enrolled in open-label extension (OLE) received acoramidis only. Exploratory post hoc analyses were done in the p.V142I ATTRv-CM subgroup. Time-to-event analyses used a stratified Cox proportional hazards model using treatment group as an explanatory factor and baseline 6MWD as a covariate, stratified by randomization factors: serum NT-proBNP and eGFR. ACM was analyzed at Month 42 (ATTRibute-CM 30 months + 12 months OLE). Results: Of the 59 patients with ATTRv-CM reported at randomization, 35 (59.3%) had p.V142I (23 acoramidis, 12 PBO) with comparable baseline characteristics; 4 were homozygous for p.V142I (1 acoramidis, 3 PBO). Through Month 30, ACM/first CVH occurred in 43.5% (10/23) of acoramidis vs 83.3% (10/12) in PBO (HR 0.311; 95% CI 0.120–0.805; Figure 1 ). Through Month 42, ACM occurred in 26.1% (6/23) of continuous acoramidis vs 66.7% (8/12) in PBO to acoramidis (HR 0.307; 95% CI 0.097–0.973; Figure 2 ). Conclusions: In participants with p.V142I ATTRv-CM, acoramidis use was associated with 69% risk reduction in ACM/first CVH through Month 30 and ACM through Month 42 vs PBO. This is the first report of clinical benefit of this magnitude observed in this high-risk population. These findings have biologic plausibility and may reflect the near-complete stabilization observed experimentally with acoramidis in p.V142I ATTR fibrils. These observations require confirmation in larger cohort studies.

Background: Cardiac fibrosis is a critical and independent driver of heart failure (HF), characterized by excessive extracellular matrix (ECM) deposition. Decreased CDCP1 (CUB domain-containing protein 1) expression has been associated with myocardial recovery in human genome wide association studies by attenuating PDGF-BB driven cardiac fibroblast proliferation with no effect on canonical TGF-beta mediated transdifferentiation in-vitro. In-vivo, Cdcp1 deletion significantly reduced cardiac fibrosis and dysfunction in an angiotensin II/phenylephrine-induced pressure overload mouse model. However, its upstream regulators and its downstream effects on molecular signaling pathways that modulate ECM remodeling are unknown. Hypothesis: CDCP1 promotes human cardiac fibroblast mediated ECM remodeling in the HF microenvironment. Methods: Human ventricular fibroblasts (HVF) were treated with PDGF-BB (20 ng/ml), TGF-β (10 ng/ml), or Angiotensin II (100 ng/ml) for 48 hours. CDCP1 knockdown (KD) was achieved through siRNA transfection. Gene expression analysis was performed using qRT-PCR and protein quantification by Western blot. Both intact HVF and decellularized ECM were immunostained for collagen 1 to evaluate for ECM compositional changes. Results: Individual and combination treatments with fibrotic stimuli significantly increased CDCP1 expression (Figure 1A-1B). CDCP1 KD resulted in reduction of key ECM markers COL1A1, CTGF, and LOX (Figure 1C) across all fibrotic stimuli . Immunostaining of HVF after treatment with fibrotic stimuli showed reduced collagen 1 production with CDCP1 KD (Figure 1D). Western blot analysis showed increased phosphorylation of Src (tyr416) with 6h of treatment with fibrotic stimuli which was nullified by silencing of CDCP1 (Figure 1E). Conclusion: Our findings demonstrate that CDCP1 is necessary for ECM synthesis and Src signaling across multiple profibrotic pathways. Selective targeting of CDCP1 to modulate Src signaling pathways could provide novel therapeutic avenues for HF and fibrosis treatment.

Background: Impella 5.5 is a temporary MCS device FDA-approved for use up to 14 days. Limited data suggest it may be safe beyond this. We aim assess outcomes based on the duration of Impella 5.5 support in heart failure cardiogenic shock (HFCS) patients at our institution. Methods: We retrospectively reviewed all HFCS patients supported with Impella 5.5 at our institution between 2020-2024. Patients supported for >14 days were compared with those supported for ≤14 days. Categorical variables were analyzed with chi-square tests, continuous variables with t-tests or Mann-Whitney U. Logistic regression identified factors linked to clinical outcomes. Results: 154 patients were included: 38 (25%) with support ≤14 days, 116 (75%) with >14 days. Median support duration was 10 (6–12) vs 31 (22–45) days, respectively. Median support duration was 10 (6-12) days for the ≤14 cohort and 31 days (22-45) days for the >14 cohort. Baseline characteristics, comorbidities, LVEF 18% (15-23) and hemodynamics show no statistical differences. Patients supported for >14 days were more likely to undergo heart transplant compared to those supported ≤14 days (91% vs 74%, p=0.009). In contrast, myocardial recovery was more likely in the ≤14 day cohort (8% vs 1%, p=0.018). One patient suffered stroke post-transplant in the ≤14 day group and two had brachial plexus injuries in the >14 days group. Mortality during the impella-supported period was slightly higher in the ≤14 day group (8% vs 5%, p=0.535) but comparable overall, 13% in both groups, p=0.971. Support >14 days was associated with transplant outcome (OR 3.41, 95% CI 1.32–8.84, p=0.012), and remained significant after adjusting for age, gender, GFR, and EF (OR 4.05, 95% CI 1.31–12.54, p=0.015). Support duration <14 days was associated with recovery or LVAD outcomes (OR 5.01, 95% CI 1.49–16.89, p=0.009), and remained significant after adjustment (OR 5.43, 95% CI 1.11–26.45, p=0.036). No association was observed between duration of support and LVAD/mortality outcomes or with EcPella use. Conclusion: Shorter Impella support duration was independently associated with early myocardial recovery or LVAD candidacy, likely reflecting rapid clinical decision-making. Prolonged Impella support was associated with increased likelihood of transitioning to heart transplantation, likely reflecting clinical stabilization over time. Our multidisciplinary, single-center data suggests Impella 5.5 can be used beyond FDA-approved 14 days in HFCS patients.

Introduction: Patients with variant transthyretin (TTR) amyloid cardiomyopathy (ATTRv-CM) experience early onset disease, rapid progression, and poor outcomes due to amyloid aggregated from destabilized tetrameric TTR. Acoramidis, a highly selective, oral TTR stabilizer, achieves ≥90% TTR stabilization and is approved in the USA, EU, Japan, and UK for adults with wild-type (ATTRwt-CM) or ATTRv-CM. In the phase 3 ATTRibute-CM study and its open-label extension (OLE), acoramidis reduced both the risk of all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) through Month 30 and risk of ACM through Month 42 by 36%. Research Question: Is acoramidis efficacy in ATTRv-CM consistent with that observed in the overall ATTRibute-CM population? Methods: In ATTRibute-CM, participants with ATTR-CM were randomized 2:1 to acoramidis HCl 800 mg or PBO, twice daily (BID) for 30 months. After Month 30, all participants enrolled in the OLE received acoramidis HCl 800 mg BID. Genotype (ATTRwt-CM or ATTRv-CM) was captured at randomization; efficacy was analyzed separately in ATTRv-CM. Time-to-event analyses used a stratified Cox model with terms for treatment, baseline 6MWT, genotype, genotype×treatment interaction, stratified by randomization NT-proBNP and eGFR levels. ACM was analyzed at Month 42 (ATTRibute-CM 30 months + OLE 12 months). Results: The ATTRv-CM group comprised 59 patients (39 acoramidis, 20 PBO). Baseline characteristics were mostly similar in both groups ( Table ). The three most common variants reported were p.V142I (n=35), p.I88L (n=7), and p.T80A (n=5). Compared with PBO, acoramidis reduced the risk of ACM/first CVH through Month 30 by 59% (acoramidis, 46.2%; PBO, 75.0%; HR 0.41; 95% CI 0.21–0.81; P =0.011; Fig 1 ) and ACM through Month 42 by 59% (continuous acoramidis, 30.8%; PBO to acoramidis, 60.0%; HR 0.41; 95% CI 0.19–0.93; P =0.032; Fig 2 ) , with Kaplan–Meier curves separating at Months 5 and 10, respectively. Conclusions: In ATTRibute-CM, acoramidis use was associated with clinical benefit in the ATTRv-CM group as demonstrated by a 59% risk reduction in both ACM/first CVH at Month 30, and ACM at Month 42 compared to PBO. These previously unreported findings support the hypothesis that near complete TTR stabilization observed experimentally with acoramidis across multiple TTR mutations translates into improvement in long-term outcomes. Further validation by individual TTR variant is warranted.

Background: Patients with cardiac implantable electronic devices (CIEDs) undergoing radiation therapy face potential risks of device malfunction. Proton beam therapy (PBT), with its reduced neutron scatter, has emerged as a potentially safer alternative, yet real-world safety data remain scarce. Methods: We conducted a retrospective cohort study of 100 patients with CIEDs (76 pacemakers, 24 ICDs) who underwent PBT from 2016 to 2023 at a quaternary center. Baseline and serial device interrogations were performed before, during, and after treatment to assess lead impedance, capture thresholds, battery function, and arrhythmic events. Patients were stratified by pacemaker dependence and monitored accordingly. Primary outcomes included device malfunction and new-onset arrhythmias during treatment. Secondary outcomes included device parameter changes, one-year arrhythmia incidence, and cardiac-related hospitalizations. Results: No treatment-related deaths or major device failures occurred. Device malfunction was rare (2 pacemaker patients, 2.6%), with no malfunctions in ICD recipients. Transient, non-clinically significant changes in lead impedance and capture thresholds were observed. Arrhythmias during treatment occurred in 26% of pacemaker and 25% of ICD patients, but only 4% developed new arrhythmias. At one year, device-related complications and cardiac outcomes remained comparable across groups. Independent predictors of arrhythmias during treatment included a higher radiation dose per fraction (OR 1.45; p=0.001), a longer treatment duration (OR 1.12; p=0.04), and a higher number of fractions (OR 1.20; p=0.01). Conclusion: Proton beam therapy appears safe in patients with CIEDs, with a low incidence of clinically significant device malfunctions or arrhythmias. These findings support the integration of PBT into routine practice for this population and underscore the importance of structured monitoring protocols and prospective guideline refinement.

Background: The prevalence of cardiac implantable electronic devices (CIED) is increasing, with over 300,000 new implants annually in the U.S. Stress cardiac magnetic resonance (CMR) has proven as a powerful modality for myocardial characterization, enabling accurate diagnosis of different cardiac conditions. In patients without devices, CMR findings have also demonstrated prognostic value for major adverse cardiovascular events (MACE) and guide clinical decision-making. However, its use in CIED patients has historically been limited due to safety and image quality concerns. Hypothesis: We aimed to evaluate the prognostic value of CMR imaging using wideband sequences in CIED patients. Methods: CIED patients referred for clinical CMR were included prospectively and retrospectively between January 2020 and February 2025. All patients underwent a stress CMR protocol, which included cine, wideband late gadolinium enhancement (LGE), wideband T1 mapping, and wideband stress/rest perfusion imaging. Clinical follow-up is ongoing. The primary endpoint was the occurrence of MACE, defined as the composite of myocardial infarction, heart failure hospitalization, implantable cardioverter defibrillator (ICD) therapy, cardiac death, revascularization, or heart transplant. Results: A total of 89 patients were included (median age 69.0 [58.0–75.5] years; 62.9% male). Device types included pacemakers (33.7%), ICDs (48.3%), and cardiac resynchronization therapy devices (16.9%). Over a median of follow-up of 613 days [355-991], 21 patients experienced a MACE. In unadjusted models, higher left ventricular ejection fraction (LVEF) (per 5%) was significantly associated with a lower risk of MACE (odds ratio [OR] 0.80, 95% confidence interval [CI] 0.65–0.95; p=0.016), as was higher stress myocardial blood flow (MBF) (per 0.25 mL/g/min increase: OR 0.78, 95% CI 0.60–0.98; p=0.05). In contrast, greater LV myocardial mass (per 10 g) was significantly associated with a higher risk of MACE (OR 1.27, 95% CI 1.08–1.52; p = 0.006), figure 1. Conclusion: The use of wideband sequences enabled the assessment of prognostic imaging value in CIED patients. LVEF remains a strong and consistent predictor of MACE in this population and LV mass was significantly associated with higher rates of MACE reflecting the influence of underlying cardiomyopathy. While stress perfusion CMR imaging showed promising trends, further studies with longer follow-up are needed to clarify its prognostic value in this population.

Background: Critical congenital heart disease (CCHD) screening algorithms based on pulse oximetry have up to 27% false positive rate at high altitudes (>2500 m) despite altitude-specific cutoff changes. We examined the added value of an adult-based AI model applied to phonocardiography (AI-PCG) in the digital stethoscope EKO Core 500 in these settings. Research Question: What is the diagnostic performance of AI-PCG model compared to pulse oximetry in detecting neonatal CCHD across different altitudes in Latin America? Methods: This observational, prospective, case-control study included newborns born at different altitudes from 0 to 4380 meters in Peru, Mexico, Colombia and Bolivia. All underwent preductal and postductal oximetry at least 18 hours after birth, electrocardiography and PCG with the digital stethoscope. All CCHD cases were confirmed by echocardiography. Non-CCHD cases were defined by echocardiography or clinically if they were alive for 1 month and had 1) negative pulse oximetry, 2) no hospitalization due to cardiac or pulmonary causes and 3) no cyanosis or pneumonia. Those with abnormal pulse oximetry, genetic syndromes or murmur detection underwent echocardiography. Diagnostic performance metrics [area under the receiving operating characteristic curve (AUROC), sensitivity, specificity and false positive rate] were evaluated per modality. Results: A total of 1152 newborns were enrolled, 725 at <2500 m [13 (1.8%) with CCHD] and 427 at >2500 m [6 (1.4%) with CCHD]. Out of 19 CCHD cases, 17 had positive pulse oximetry and 9 had a positive AI-PCG model. One newborn with severe coarctation of the aorta and atrial septal defect had negative pulse oximetry and AI-PCG model. Pulse oximetry showed superior AUROC (0.932 vs 0.664), sensitivity (89.5% vs 47.4%), specificity (97% vs 85.5%) and lower false positive rate (3% vs 14.5%) compared to the AI-PCG model across altitudes. Diagnostic accuracy varied with altitude (Figure): at <2500 m, pulse oximetry showed higher AUROC (0.999 vs 0.612) and lower false positive rate (0.1% vs 16%) than AI-PCG model, but at >2500 m, pulse oximetry had similar AUROC (0.794 vs 0.774) and lower false positive rate (7.8% vs 11.9%) than the AI-PCG model. Conclusion: Pulse oximetry has superior diagnostic performance than an adult-based AI-PCG model when screening for neonatal CCHD at <2500 m, but similar performance is found >2500 m.

Purpose: Melatonin can protect against oxidative damage and ischemia-induced cell death. 17β-Estradiol (E2) has neuroprotective effects, and its receptors are expressed in the retina. The protective effects of melatonin and E2 against hypoxic stress induced by cobalt chloride (CoCl 2 ) were investigated using human retinal cell lines. Materials and Methods: Human retinal pigment epithelial cells (ARPE-19) and Müller glial cells (MIO-M1) were pretreated for 6 h with either melatonin (200, 400, and 800 µM) or E2 (20, 40, and 80 µM) and then stressed for 48 h with CoCl 2 . Cultures were analyzed for cell metabolism (MTT assay), reactive oxygen species (ROS/H2DCFDA assay), and mitochondrial membrane potential (MMP/JC-1 assay). Results: Melatonin pretreatment significantly increased (i) the cell metabolism in ARPE-19 cells (400 µM, P = 0.0352; 800 µM, P = 0.0016) and MIO-M1 cells (200 µM, P = 0.0341; 400 µM, P = 0.0009) and (ii) mitochondrial membrane potential in ARPE-19 (400 µM, P = 0.0131; 800 µM, P = 0.0096) and also the MIO-M1 cells (800 µM, P = 0.0082) after CoCl 2 hypoxic stress. Pretreatment with E2 improved cell metabolism in ARPE-19 cells (20 µM, P = 0.0076). MIO-M1 cells showed improved metabolism at all E2 concentrations studied and higher mitochondrial membrane potential with E2 40 µM pretreatment ( P = 0.0152). ROS levels were not improved with melatonin or E2 pretreatments. Conclusions: In response to CoCl 2 -induced hypoxic stress, pretreatment with melatonin and E2 can significantly improve the cellular metabolism and mitochondrial membrane potential in human RPE and Müller glial cell lines. Translational Relevance: Our study investigates the protective effects of melatonin and 17β-estradiol against ischemic stress in vitro with the overall goal to improve cellular homeostasis and decrease retinal degeneration.

Abstract Artificial intelligence (AI) encompasses the development of systems that can perform human‐like tasks, such as treatment guidance, decision‐making, pattern recognition and understanding language. Within AI, machine learning and deep learning play pivotal roles in diagnosis and outcome prediction, while natural language processing aids in synthesising large datasets from the electronic medical record. In orthopaedics, AI has demonstrated success in various areas, including image evaluation, surgical planning, outcome prediction, cohort identification and administrative tasks. The purpose of this manuscript was to provide an overview of the benefits of AI implementation within the field of orthopaedics. An additional goal was to address the challenges associated with producing high quality AI‐based research in a rapidly developing field. Level of Evidence Level IV.

Abstract Aims Heart failure with preserved ejection fraction (HFpEF) is one of the most common forms of heart failure with no effective treatment. While chronic systemic inflammation, triggered by comorbidities, is a critical factor of HFpEF pathophysiology and a relevant target for therapy, mechanisms underlying inflammation remain poorly understood. Here, we aim to understand the upstream mechanisms driving inflammation, including immune dysregulation and cellular senescence. Methods and results ZSF1-Obese rats, a cardiometabolic model of HFpEF, were used to investigate systemic and cardiac inflammation, and to characterise the senescent program in immune, circulating endothelial and cardiac cells, before disease onset and onward. Using patient samples, we further evaluated the association between cellular senescence and diagnostic and prognostic markers of HFpEF. Finally, we administered a senolytic - Navitoclax - at two time-points, before and after the appearance of HFpEF. Conclusion ZSF1-Obese rats had increased immune and endothelial senescent cells in their peripheral blood and myocardium, together with exacerbated systemic inflammation and endothelial damage, compared to control ZSF1-Lean rats. Moreover, increased circulating senescent leucocytes were associated with markers of disease severity in patients with HFpEF. Senescent cell clearance decreased circulating B-type natriuretic peptide levels and attenuated inflammation, vascular remodelling, and cardiac fibrosis. Additionally, it improved renal function and reduced pulmonary oedema. Our findings suggest that senotherapeutics may improve the treatment for HFpEF by attenuating systemic effects of the disease whilst reducing cardiac fibrosis and endothelial rarefaction.