Citations

Abstract Enhancer is a critical epigenetic feature in head and neck squamous cell carcinoma (HNSCC), yet the functional roles of individual enhancers remain poorly understood. Here, we conducted an integrative multi-omics analysis based on publicly available ATAC-seq, H3K27ac ChIP-seq, transcriptomic profiling, and genetic association datasets to systematically map HNSCC-associated enhancers and their target genes. Integrating ATAC-seq and H3K27ac ChIP-seq, we identified 20,362 enhancers and 18,040 enhancer-associated genes, highlighting widespread regulatory complexity. Functional characterization of the TERT -associated enhancer GH05J001312 (GRCh38/hg38: chr5:1312099-1317743) revealed strong transcriptional activity in HNSCC. CRISPR-mediated deletion of a core sequence significantly reduced TERT expression, impaired cellular proliferation in vitro , and suppressed tumor growth in vivo , confirming its role as a key cis-regulatory element. RNA-seq analysis of enhancer-edited cells uncovered 742 differentially expressed genes enriched in cancer-related pathways, including MAPK and IL-17 signaling, indicating a broad transcriptional impact. Collectively, our findings establish GH05J001312 as a functional enhancer driving oncogenic programs in HNSCC and suggest enhancer-targeted strategies as a potential therapeutic avenue.

Abstract Background Coronary Computed Tomography Angiography (CCTA) is the first-line diagnostic tool for suspected stable Coronary Artery Disease (CAD) to rule out obstructive CAD and is recommended for risk stratification. Both obstructive CAD and total plaque burden on CCTA predict cardiovascular (CV) risk. Prior studies demonstrated that type 2 diabetes (T2D) patients exhibit greater plaque burden and higher CV event risk. Purpose This study evaluates whether T2D patients undergoing CCTA for stable CAD symptoms, when matched for traditional cardiovascular risk factors, have a higher prevalence of CAD and greater atherosclerotic plaque burden. Methods A total of 568 patients were included: 284 T2D patients were 1:1 propensity-matched to 284 non-T2D patients based on age, sex, and CV risk factors. All underwent diagnostic CCTA between January 2022 and November 2023. CCTA parameters included CAD-Reporting and Data System (RADS) classification, segment involvement score (SIS), coronary artery calcium (CAC) score, and plaque composition. SIS was defined as the number of segments with at least mild plaque. Coronary segmentation followed the 16-segment model (SCCT). Plaque burden was classified as P1 (mild), P2 (moderate), P3 (severe), and P4 (extensive) per CAD-RADS 2.0, based on SIS, CAC score, and the number and severity of affected vessels. Results The mean age was 60.8 ± 9.97 years (T2D) vs. 61.2 ± 9.80 years (non-T2D), with similar gender distribution (48.6% vs. 48.9% female). BMI was significantly higher in T2D patients (29.2 vs. 26.5, p < 0.05). Smoking was less frequent in T2D patients (56.0% vs. 60.9%, p = 0.03). Other CV risk factors were similar. T2D patients were more likely to use antiplatelet and lipid-lowering agents. CAD prevalence was higher in T2D patients (83.1% vs. 76.4%, p < 0.05), while obstructive CAD was not significantly higher in T2D (33.5% vs. 27.5%, p = 0.13). No significant differences were observed in 1-, 2-, or 3-vessel disease. The SIS was significantly higher in T2D patients (3.85 vs. 3.37, p = 0.03). CAC scores were higher in T2D patients (median 60 [6–369] vs. 31 [0–224]), though not statistically significant. For plaque burden classification, P2 (moderate plaque burden) was more common in non-T2D patients (23.6% vs. 15.5%, p = 0.02), while P4 (extensive plaque burden) was significantly higher in T2D patients (21.1% vs. 14.1%, p = 0.03). Conclusion When matched for cardiovascular risk factors, T2D patients more frequently exhibited CAD on CCTA, with higher SIS scores and a greater prevalence of extensive plaque burden (P4 classification). Despite greater use of preventive medication and a lower smoking prevalence in the T2D group, plaque burden remained higher in these patients. These findings emphasize the need for improved risk stratification and preventive strategies in individuals with T2D.

Abstract Background Ischemic mitral regurgitation (IMR) is a common complication of coronary artery disease (CAD), often occurring after myocardial infarction (MI). Even when moderate in severity, IMR is associated with adverse outcomes, including a twofold increase in mortality rates. Aim To assess the functional correlates of resting IMR during stress echocardiography (SE) in patients with CAD. Methods This prospective multicenter study included 192 patients with CAD (143 males; mean age 65 ± 10 years) from eight cardiology institutions. Exclusion criteria included a history of coronary artery bypass surgery, more than moderate IMR, and other significant valvular diseases. Patients were divided into two groups based on semiquantitative- quantitative assessment at rest based on EACVI-ASE criteria: Group 1: Patients with moderate IMR, Group 2: Patients without IMR or with trivial IMR. All patients underwent stress echocardiography (SE) using the ABCE protocol. Patients underwent exercise tests, if execise echocardiography was not possible, dobutamine stress tests were performed. At rest and peak SE, we assessed: Left atrial volume index (LAVi), Left ventricular end-diastolic (LV EDV) and end-systolic volumes (LV ESV), ejection fraction (EF), wall motion score index (WMSI), global longitudinal strain (GLS), B-lines (4-site simplified scan), tricuspid annular plane systolic excursion (TAPSE), systolic pulmonary artery pressure (SPAP), LV contractile reserve (LVCR) and heart rate reserve (HRR). Results Despite similar EF at rest, Group 1 patients showed more pronounced functional impairment at rest, which increased during stress. Stress-induced functional worsening affected indices of MR (more frequently becoming severe), ischemic burden (WMSI), diastolic function (LAVI and LVEDV dilation), LV systolic function (LVCR), pulmonary congestion (B-lines), cardiac sympathetic reserve (reduced HRR) and right ventricular/pulmonary artery coupling (reduced TAPSE/SPAP): table 1. Conclusion Compared to CAD patients with absent-to-trivial resting IMR, patients with moderate IMR at rest show a constellation of functional vulnerabilities during SE involving more frequent exercise-induced worsening of MR, blunted LV diastolic and systolic reserve, more pulmonary congestion, impaired cardiac autonomic reserve, and worse right ventricular-pulmonary artery coupling. The individual patient's functional response heterogeneity can be identified with comprehensive exercise SE, possibly a roadmap to personalized and targeted therapeutic interventions.

Abstract Introduction High-power short-duration (HPSD) ablation has emerged as a promising alternative to conventional power delivery (CPD) for pulmonary vein isolation (PVI) among patients with atrial fibrillation (AF). However, its efficacy, procedural efficiency, and safety profile remain uncertain. Methods PubMed, Embase, Cochrane Library and ClinicalTrials.Gov databases were systematically searched for randomized controlled trials (RCTs) comparing HPSD with CPD ablation for PVI in patients with AF. Random-effects models were used to pool hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals (CI). Results Seven RCTs with 1,006 patients (514 HPSD, 489 CPD) were included. No significant differences were found in freedom from arrhythmia during the follow-up period (HR 0.77; 95% CI 0.41–1.45; p=0.424). AF recurrence did not differ (RR 0.94; 95% CI 0.65–1.36; p=0.733) between groups. HPSD had a significantly shorter procedural (MD -22.61 min; 95% CI -33.18, -12.04; p<0.001) and RF ablation (MD -15.70 min; 95% CI -20.86, -10.55; p<0.001) times, with comparable fluoroscopy time (MD 0 min; 95% CI -0.44, 0.45; p=0.99) between groups. Conclusion In patients with AF undergoing PVI, HPSD did not increase freedom from arrhythmia as compared with CPD ablation, however it was associated with shorter procedure and RF ablation times. These findings suggest that HPSD may be a more efficient approach without compromising clinical outcomes.

Abstract Background/Introduction Acute coronary syndrome (ACS) is common among elderly patients and is associated with a high risk of complications. Managing ACS, particularly dual antiplatelet therapy (DAPT), poses challenges due to the increased risk of recurrent hemorrhagic and ischemic events in this population. Purpose This study evaluated cardiovascular outcomes in patients ≥75 years that were initiated on DAPT with aspirin (ASA) plus either ticagrelor or clopidogrel following an acute myocardial infarction (AMI). Methods We used the TriNetX repository to identify adult patients (≥75 years) diagnosed with AMI between January 1, 2011, and December 31, 2021, who subsequently initiated DAPT and were not on anticoagulation. Patients were stratified into two cohorts: ASA + ticagrelor and ASA + clopidogrel. Outcomes assessed included major bleeding, repeat coronary intervention, all-cause mortality, all-cause hospitalizations, stroke, new-onset atrial fibrillation, and pacemaker implantation. Follow-up time was restricted to one year. A 1:1 propensity score matching algorithm was applied using the greedy nearest-neighbor method with a caliper of 0.1 pooled standard deviations to ensure balance (i.e., comorbidities, medications, laboratory values) between the two cohorts. Logistic regression models were used to calculate adjusted odds ratios (aOR), and Cox proportional hazards models estimated hazard ratios (HR). Results Before propensity score matching (PSM), 19,859 patients were in the ASA + ticagrelor cohort, and 47,032 were in the ASA + clopidogrel cohort. Post-PSM, 19,746 patients remained in each cohort, with a mean age of 82.2 years and a mean follow-up duration of 298.77 days for the ASA + ticagrelor cohort and 297.59 days for the ASA + clopidogrel cohort. The ASA + ticagrelor cohort had a higher incidence of major bleeding (aOR 1.19 [95% CI, 1.08–1.31]) and pacemaker implantation (aOR 1.14 [95% CI, 1.02–1.29]) compared to the ASA + clopidogrel cohort. Event-free survival analysis showed lower survival rates for major bleeding (HR 1.18 [95% CI, 1.07–1.30]) and pacemaker implantation (HR 1.14 [95% CI, 1.01–1.28]). No significant differences were observed between cohorts in repeat coronary interventions (aOR 0.95 [95% CI, 0.88–1.03]), atrial fibrillation (aOR 1.03 [95% CI, 0.97–1.08]), all-cause mortality (aOR 1.03 [95% CI, 0.96–1.12]), all-cause hospitalization (aOR 1.01 [95% CI, 0.97–1.05]), or stroke (aOR 0.95 [95% CI, 0.86–1.04]). Conclusions In elderly patients, DAPT with ASA + ticagrelor was associated with higher rates of major bleeding and need for pacemaker compared to ASA + clopidogrel. Given the similar risks of recurrent coronary intervention and mortality between the two regimens, these findings highlight the need for careful consideration when selecting ticagrelor over clopidogrel in this population.

Abstract Background Vascular Ehlers-Danlos syndrome (VEDS) and Marfan’s syndrome are associated with cardiovascular complications, including arrhythmias. However, ventricular tachycardia (VT) risk in these populations has not been frequently reported. Purpose This study aims to assess the VT risk in VEDS and Marfan's syndrome patients through an international database. Methods The TriNetX database was used to pull patients with a diagnosis of VEDS and Marfan's Syndrome. Baseline characteristics (e.g., demographics, cardiovascular comorbidities, etc.) were collected, and propensity score matching was performed to balance the cohorts. Risk analysis and Kaplan-Meier survival were used to assess outcomes. Results A total of 1,114 and 23,172 patients had VEDS and Marfan’s syndrome, respectively. After propensity score matching, each cohort included 1,091 balanced patients regarding demographics and clinical characteristics. The cohorts were balanced with a mean age of 37.7 ± 16.0 years in both groups. 68.7% and 68.8% were females in the VEDS and Marfan cohorts, the majority being White (82.2% in VEDS, 82.9% in Marfan’s). VT Incidence was lower in VEDS (0.9%) compared to Marfan’s syndrome (2.6%), with a risk difference of -0.016 (p = 0.003). Kaplan-Meier survival showed higher survival in VEDS (99.44%) vs. Marfan’s (94.04%, log-rank p = 0.002). The risk ratio for VT in VEDS was 0.357 (95% CI: 0.174, 0.732). Conclusion VEDS patients have a significantly lower VT risk compared to those with Marfan’s syndrome. These findings suggest significant differences in the arrhythmic burden between these connective tissue disorders, which can direct future risk stratification and management strategies.

Abstract Intro Energy harvesters that convert biomechanical energy into electrical power could be used for implantable devices, providing a near infinite energy solution. While various energy harvesters with piezoelectric or triboelectric elements have been designed and applied to the cardiac environment, none have been successfully integrated into leadless pacemakers due to their size constraints or insufficient energy generation. Purpose This study aimed to develop a proprietary inertial piezoelectric energy harvester (PEH) capable of generating the energy required for a self-sustaining leadless pacemaker from the beating of the heart. Method Human heart dynamics were tested using ultra-fast MRI scans of 20 patients, which were analyzed for displacement of the right ventricular (RV) apex, mid- to low septum, and the right atrial (RA) walls. The data was used to design the PEH, which was evaluated in thirteen (13) male swine. In addition, epicardial MEMS-based sensors recorded the acceleration, angular positions, and gravity in 3 directions. The sensors were placed at the apex of the RV, LV Apex, LV free wall, and the RA using adhesive means. The data collected from the animals was used to calculate the power produced by the PEH in the different regions of interests and to create a bench model to optimize the PEH design further. The PEH was then tested in-vivo in an ovine model. Results The heart contractility creates harmonic acceleration in the heart tissue, transmitting this vibration into the PEH, resulting in the harvester acceleration of 0.75 g (±0.25g). When the PEH is subject to vibrations, the PEH oscillates using kinetic forces exerted on the piezoelectric beam through a proof mass, transforming these mechanical forces into electric energy. The electrical energy produced using this PEH is 6µW (± 2µW), which is sufficient to power a leadless pacemaker, providing pacing therapy of 100% pacing, at 60 BPM, with heart impedance of 600 (±200), and a pacing voltage reaching 2V, with sufficient excess energy to maintain charge of a secondary battery used for communication and advanced pacemaker functions. This was then tested in a pre-clinical setup, using an ovine model (results to be presented in the future). Conclusion This work demonstrates that a proprietary inertial PEH can use the contraction energy of the heart to generate electrical energy. The design of the PEH was based on the analysis of human heart kinetics using MRI scans and in-vivo recordings from pigs’ hearts. This design of an effective energy harvester can produce enough energy to power a leadless pacemaker. The design can fit in a small capsule that can be used in a leadless pacemaker that will be implanted in the RV providing sensing and pacing as well as daily communication enabling advanced pacemaker functions. The PEH is currently being tested in an ovine model, demonstrating its safety and performance.

Abstract Background Coronary computed tomography angiography (CCTA) and myocardial perfusion imaging (MPI) are guideline-recommended to assist in clinical decision-making in patients with prior coronary artery bypass grafting (CABG). However, the value of combining CCTA and MPI for guiding revascularization decision-making in post-CABG patients with recurrent ischemic symptoms remains unexplored. In this study, we compared Heart Team strategies for revascularization based on CCTA and MPI as standalone and hybrid CCTA/MPI imaging, to strategies guided by invasive coronary angiography (ICA). Methods We included symptomatic patients with prior CABG who underwent CCTA and MPI (single-photon emission computed tomography, positron emission tomography or stress perfusion cardiac magnetic resonance imaging) preceding ICA. Simulated Heart Teams, blinded to other Heart teams and outcomes, performed revascularization decision-making based on conventional CCTA, MPI and a hybrid CCTA/MPI strategy (non-invasive Heart Team) or based on ICA (invasive Heart Team). The primary outcome was the Cohen’s kappa agreement (κ) between non-invasive and invasive Heart Teams. Results A total of 115 patients (mean age 73±7 years; 99 [86%] male) were included. Revascularization was recommended in 96 patients (83.5%) by CCTA, 92 patients (80.0%) by MPI, 80 patients (69.6%) by hybrid CCTA/MPI and 76 patients (66.1%) by ICA. The agreements were significant but low for CCTA (κ: 0.25 [95% confidence interval (CI): 0.07-0.42], P=0.003) and MPI (κ: 0.27 [95% CI: 0.09-0.48], P=0.002) compared to ICA, with only a modest increase when using the hybrid non-invasive imaging strategy (κ: 0.32 [95% CI: 0.14-0.51], P<0.001). Conclusions In patients with recurrent ischemic symptoms after CABG, Heart Team assessment of conventional CCTA and MPI yielded similarly poor agreements with revascularization strategies based on ICA, with only a modest improvement observed when using a hybrid CCTA/MPI approach. Overall, non-invasive imaging alone appears insufficient to accurately guide treatment strategies in patients with prior CABG, and their use as gatekeeping for ICA in these patients should be questioned.

Autism is a heritable neurodevelopmental condition marked by impaired social interaction, repetitive behavior, and co-occurring conditions. Sleep disturbances are common in autism. This study uses low-cost wearable devices to compare sleep, physical activity, and circadian behavior in autistic adults and their non-autistic relatives. We recruited 318 autistic individuals and 130 family members, collecting accelerometer data over 3 weeks (8249 days). Using a data-driven approach, we identified actimetry-derived features associated with autism. We examined 308 traits using the elastic net algorithm and linear mixed effects regressions. We identified 52 actimetry measures associated with autism (area under the curve: 0.812; confidence interval: 0.761–0.862), validated in a test set (area under the curve: 0.756; confidence interval: 0.700–0.813). Both mean and day-to-day variability in several measures (e.g., time spent sedentary, total light physical activity) were associated with autism. In autistic individuals, reduced physical activity during wake was more strongly associated with shorter sleep time than in non-autistic relatives (likelihood ratio: 41.6; p = 1.13e−10). Reduced physical activity in autistic individuals was linked to increased social impairment, as measured by the Social Responsiveness Scale. Long inactivity periods and lower physical activity levels were associated with autism, correlating with less sleep and later sleep onset. Interventional studies are needed to explore if improving sleep and physical activity can improve the quality of life for autistic individuals. Lay Abstract Autistic individuals frequently report problems with their sleep, though what aspects of sleep are most affected is not well understood. In this study, we recruited 318 adult autistic participants without intellectual disability and 130 of their non-autistic family members to measure their sleep, physical activity, and daily routines. Study participants wore accelerometer-based wrist-worn devices over 3 consecutive weeks to record their movement and activity. In total, 154 distinct physical activity, sleep, and behavioral traits were identified from the recordings, 52 of which were found to associate with autism. Many of these traits were related to physical activity, where autistic individuals were more likely to be less active for longer periods and have lower overall physical activity levels. Long periods of inactivity also associated with less sleep, with a stronger association in those with autism. For example, for every hour of inactivity, autistic participants had on average ~23 min less of sleep compared to ~17 min in their family members. Autistic individuals with lower levels of physical activity showed higher social impairment as measured by the Social Responsiveness Scale. Overall, lower physical activity may impair sleep and worsen the core features of autism. Interventional studies aimed to increase physical activity may improve the quality of life of autistic individuals.

Abstract Glioblastoma (GBM) remains the most aggressive primary adult brain cancer with limited therapeutic options. Our prior research demonstrated that androgen receptor antagonists (ARAs) enhance survival in GBM mouse models by preferentially suppressing glioma stem cells. This study investigates the potential of ARAs as radiosensitizers in combination with radiotherapy (RT). Combined effects of ARAs and RT were evaluated using an orthotopic GBM mouse model. RNA-Seq and TCGA analyses delineated AR-associated regulatory networks, while integrated cellular and molecular approaches utilizing human and mouse GBM cell lines, as well as in patient-derived primary high-grade glioma cultures, interrogated signaling and immune paradigms. ARA treatment induced G2/M cell cycle arrest, apoptosis, and downregulated DNA repair genes, with AR expression correlating with the DNA repair and TGF-β pathway. In both immortalized GBM cell lines and primary high-grade glioma cultured cells, ARAs in combination with RT showed only a modest enhancement of radiosensitivity. However, in an orthotopic GBM mouse model, ARA + RT demonstrated a strong synergy, achieving 100% long-term survival, compared to less than 50% with ARA alone and 0% with RT alone. Mechanistically, ARA modulated the TGF-β pathway, durably switching from Smad3 linker to c-terminal phosphorylation (pSmad3C) and inhibiting LIF/STAT3 axis. Distinct TGF-βs ligand expression patterns were observed in ARA-treated GBM cells. A protein–protein interaction noted between AR and Smad3, which was disrupted following ARA treatment, leading to elevated protein levels and nuclear localization of pSmad3C (S423/425), indicating normalization/activation of the TGF-β/pSmad3C-dependent anti-tumorigenic cascade. Comprehensive analyses in GBM cell lines and mouse model tissues demonstrated pathway reprogramming characterized by elevated TGF-β2 and increased pSmad3C. Tissue analysis revealed immune activation in the tumor microenvironment, while peripheral blood and spleen showed systemic immune responses following ARA + RT. Our study provides novel insights into how ARAs enhance RT efficacy through immunomodulation involving TGF-β/pSmad3C cascade, offering therapeutic implications in GBM.