tbuckley/cabot-search huggingface dataset:
Abstract 16686: A Novel Co-Culture 3D Cardiac Organoid Models Early Heart Development
Authors: YINGJUAN LIU, Honglin Xu, Bernard D Keavney
Journal: Circulation (2023)

Introduction: Embryoid body-derived cardiac organoids (CO), incorporating complex chamber-like structures, have been reported since 2021. By contrast, co-culture COs described so far, which have been assembled from primary or hESC derived-cardiomyocytes, endothelial and fibroblast cells, lack complex structures. Cells of the endocardial lineage have a critical role in heart septation and chamber formation in vivo , but their potential role in engineering complex COs is hitherto unreported. We present a co-culture CO method incorporating endocardial lineage cells, showing these cells' critical contribution in forming chambered and vascularised COs suitable to model heart development and congenital heart disease (CHD). Methods: hESC-cardiomyocytes (CM, Day12), hESC-endothelial cell (EC, Day16), hESC-cardiac fibroblasts (Fb, Day16), and hESC-endocardial like cells (ECC, Day12) are differentiated with 2D protocols. COs are formed by co-culturing cells (1-2x10 ^ 4 cells/organoid) in ultra low attachment plates. Mature COs contain CMs, ECs and Fbs (3:1:1). Developing COs contain CMs, ECs, and ECCs (2:1:2). After four weeks, COs are characterised by immunostaining and optical mapping. Results: Mature and Developing COs form in three days of co-culture, with beating activities restoring during 2-7 days. Fig1A shows that both mature COs and developing COs beat regularly. Mature COs show evenly distributed cell populations (Fig1B). Developing COs form chamber-like cavities with surrounding vascular lumens (Fig1C). The inside chamber is layered by endocardial cells (Fig1C); vascular lumens form networks (Fig1C) within the middle compartment of CMs (Fig1D). Fibroblasts mainly specify the outside layer of developing COs (Fig1D). Conclusions: Endocardial lineage is critical in forming chamber-like structures in COs. This lineage-controllable developing CO can apply to drug screening and model early heart development and CHDs.
Abstract 15060: Inhibition of Endoplasmic Reticulum Stress and YAP/TAZ Signaling Protects Endothelial Function in Diabetes
Authors: Yan Zhou, Wai San Cheang
Journal: Circulation (2023)

Introduction: Previous studies have demonstrated the role of Hippo pathway with its major effectors, Yes-associated protein (YAP) and transcription activator with PDZ binding motif (TAZ) in atherosclerosis. However, the involvement of YAP/TAZ signaling in diabetes-associated endothelial dysfunction remains unexplored. Hypothesis: We hypothesized that activation of YAP/TAZ signaling links with endoplasmic reticulum (ER) stress and contributes to endothelial dysfunction. Methods: Male C57BL/6 mice were fed with high-fat diet, 45% kcal% fat for 15 weeks to induce obesity and diabetes. ER stress alleviator 4-phenylbutyric acid was orally administered for 4 weeks at 100 mg/kg/day. Vascular reactivity of mouse aortas was assessed by wire myograph. Human umbilical vein endothelial cells (HUVECs) were cultured with risk factors such as high glucose and ER stress inducer tunicamycin. Western blot and immunofluorescent staining were performed to evaluate the expressions of protein targets. Results: YAP/TAZ signaling was activated accomplished with ER stress in aortas from obese diabetic mice and in endothelial cells treated with risk factors. Chronic treatment with 4-phenylbutyric acid ameliorated endothelium-dependent relaxations as well as inhibited ER stress, YAP/TAZ signaling and oxidative stress in aortas. Phosphorylation of YAP at Ser127 was reduced in mouse aortic arch which was downregulated by ER stress alleviator. In HUVECs, ER stress alleviators significantly inhibited YAP/TAZ signaling and increased NO bioavailability but YAP inhibitor did not suppress ER stress. Conclusions: ER stress activates YAP/TAZ signaling, resulting in endothelial dysfunction in diabetes. Inhibition of YAP/TAZ is vasoprotective and exhibits therapeutic potential against diabetic vascular complication.
Abstract 17069: Efficacy and Safety of Pulsed Field Ablation For Atrial Fibrillation: A Systematic Review and Meta-Analysis
Authors: Usama Qamar, Siddharth Agarwal, Satyam Krishan, Zain Ul Abideen Asad
Journal: Circulation (2023)

Introduction: Pulsed-field ablation (PFA) is a novel ablation modality to treat atrial fibrillation (AF) with high tissue selectivity and thereby potentially lesser complications compared to thermal ablation. Hypothesis: We aimed to analyze the efficacy and safety of PFA in the treatment of AF. Methods: A systematic search of Embase, Medline, Scopus, and Web of Science was conducted from inception till May 2023 to identify all the studies that included patients undergoing pulsed field ablation for the treatment of AF. We pooled outcomes using a random-effects model. All analyses was performed using the OpenMetaAnalyst software. Results: A total of 24 studies including 2,256 patients met our inclusion criteria. Acute isolation of all pulmonary veins was achieved in 99.7% of all patients (95% confidence interval (CI): 99.4%-99.9%; I 2 : 0%). The average total procedure time was 81 (95% CI: 69-93; I 2 : 99%) minutes, and the average fluoroscopy time was 14 (95% CI: 12-16; I 2 : 98%) minutes. The overall complication rate was 2.9% (95% CI: 1.4%-4.0%; I 2 : 71%). At a mean follow-up of 6.6 months, the overall rate of arrhythmia recurrence after the blanking period of 90 days was 17% (95% CI: 11%-24%; I 2 : 94%). Conclusion: PFA has a high procedural success with low complication and recurrence rates. Further randomized controlled trials are needed to compare its long-term efficacy and safety against conventional ablation techniques.
Abstract 15837: Anomalous Bronchial Artery Origin- The Canary in the Coal Mine- For the Diagnosis of Chronic Thromboembolic Pulmonary Hypertension
Authors: Devi Parvathy Jyothi Ramachandran Nair, Shilla Zachariah, DAVID SACKS, Michael Koslow, Rittu Hingorani
Journal: Circulation (2023)

Introduction- Anomalous bronchial artery origin is seen in 8.3% to 35% of cases with most originating from the aortic arch, internal mammary artery, and subclavian artery. Origin of this vessel from a coronary artery is extremely rare. Case presentation- A 49-year-old male with history of unprovoked pulmonary embolisms (PE) in the setting of triple antibody positive Antiphospholipid antibody syndrome on lifelong anticoagulation presented with left sided chest pain and dyspnea. Initial lab work showed a troponin of 5.46 ng/mL, BNP of 602 pg/mL and D-dimer of 0.62 ug/mL. EKG showed normal sinus rhythm with non-specific ST segment changes in anterior leads. Computed Tomography Angiography (CTA) was positive for a PE. There was concern for a false positive result due to previous history of multiple PEs while on therapeutic levels of warfarin and near normal D-dimer. Echocardiogram showed ejection fraction of 38% with akinesis of anteroapical and inferoapical segments and no evidence of shunt on bubble study. Cardiac catheterization showed non-obstructive coronaries. From the ostium of the right coronary artery there appeared a fistula like structure extending into the pulmonary vasculature. Pulmonary angiogram was performed and showed chronic occlusion in branches of right pulmonary artery (RPA), pulmonary hypertension (PH) with mean pulmonary artery pressure of 36 mmHg and no evidence of acute thrombus. There was aberrant origin of the right bronchial artery from the right coronary artery that was hypertrophied as it supplied collateral flow to the area of the occluded RPA. The patient was started on guideline directed medical therapy for heart failure and follow up was arranged for further outpatient management of PH. Discussion- A rare congenital anomaly was used to guide the diagnosis of a potentially devastating and treatable medical condition. It shows the limitations of a CTA in the setting of chronic PE.
Abstract 15264: Impact of 2018 Change in UNOS Heart Transplant Policy on Wait List Outcomes
Authors: Het Patel
Journal: Circulation (2023)

Introduction: In October 2018, the updated Heart transplant (HT) policy by United network of Organ Sharing (UNOS) gave priority to critically ill heart failure patients. It has made significant improvement in long term survival of ECMO bridged HT recipients. However, there are limited reports on wait list mortality following change in this policy. Hypothesis: Review of waitlist mortality following 2018 change in guideline Methods: This is a retrospective cohort study including all adult heart failure patients listed for HT alone between 2015 and 2022 in the UNOS data. Cohort was stratified on the basis of year of listing, those who listed between 2015 &amp; 2018 and those who listed between 2019 &amp; 2022. The categorical and continuous variables were compared using chi2 and Kruskal Wallis test, respectively. Time to death analysis between both the group was evaluated using Kaplan Meier curve and log rank test. Results: Total 33,908 patients were included, of them 16,281 were listed between 2015 &amp; 2018 and remaining 17,627 were listed between 2019 &amp; 2022. The rate of HT did not change between both the time period (10,660 (65.5%) &amp; 11,660 (66.1%), p=0.19)), respectively. There was no difference in age, gender and BMI between both the groups. The use of Intra-aortic balloon pump, ventilator, Inotropes and other parameters indicating severity of illness were frequently noted among patients listed between 2019 &amp; 2022. The overall wait list mortality has reduced from 1250/16,281(7.7%) to 764/17,627 (4.0%) during later time period, p&lt;0.001 (Figure 1). Similarly, patients’ dropouts due to illness severity has reduced from 1321/16821 (8.1%) to 764/17,627 (4.3%), p&lt;0.001, respectively. There is significant reduction in disease etiology specific mortality following 2018 change. Conclusions: The change in HT policy in 2018 has significantly reduced the wait list mortality and dropouts during study periods. In addition, sicker patients were listed for transplant following 2018 change.
Abstract 15203: Periprocedural Oral Anticoagulation for Ventricular Tachycardia Ablation and Postprocedural Stroke - Analysis of a Japanese Nationwide Inpatient Database
Authors: Hisaki Makimoto, Hayato Yamana, Toshiaki Isogai, Hiroki Matsui, Hideo Yasunaga, Takahide Kohro
Journal: Circulation (2023)

Introduction: The effectiveness and the safety of periprocedural anticoagulation for ventricular tachycardia (VT) ablation remain to be clarified. Hypothesis: Periprocedural anticoagulation reduces the incidence of ischemic stroke after VT ablation without increasing intracranial hemorrhage. Methods: Using the Japanese Diagnosis Procedure Combination database, we identified patients aged ≥18 years who underwent VT ablation from July 2010 to March 2021. The endpoints were ischemic stroke and intracranial hemorrhage which occurred during the hospitalization of the index VT ablation or led to re-admissions within three months. We performed weighted analyses using inverse probability of treatment based on propensity-score to adjust for confounding factors. We also conducted analyses stratified by antiplatelet use. Results: We identified 18,894 patients from 750 hospitals who underwent VT ablation (12,918 males [68%], 60.5 ± 15.7 years). Postprocedural ischemic stroke and intracranial hemorrhage were documented in 84 (0.44%) and 15 (0.08%) cases, respectively. Anticoagulants and antiplatelets were administered in 4352 (23.0%) and 5319 (28.2%) patients, respectively. Propensity score-weighted analysis demonstrated no significant association between anticoagulant use and postprocedural ischemic stroke (odds ratio, 0.91; 95% confidence interval [CI], 0.51-1.63; P=0.76). Anticoagulation was also not associated with intracranial hemorrhage (odds ratio, 2.15; 95% CI, 0.65-7.15; P=0.21). In the stratified analysis, anticoagulation was associated with an increased risk of intracranial hemorrhage in patients with antiplatelets (odds ratio, 6.30; 95% CI, 1.26-31.5; P=0.025) but not in those without. Conclusions: Our analysis of Japanese patients who underwent VT ablation suggests that periprocedural administration of anticoagulants may not result in a reduction of ischemic strokes and that adding anticoagulants to antiplatelet therapy may increase the risk of intracranial hemorrhage. Further studies are warranted to investigate the clinical efficacy of periprocedural anticoagulation strategy after VT ablation.
Abstract 15469: Projected Heart Failure Incidence in US Adults From 2018-2050
Authors: Susan Hennessy, Joanne Penko, Pamela Coxson, Ross Boylan, Brandon K Bellows, Andrew E Moran, Yiyi Zhang, Kirsten Bibbins-Domingo, Alexis Beatty, Dhruv S Kazi
Journal: Circulation (2023)

Background Heart failure (HF) currently affects 6.7 million people in the US accounting for $40 billion in annual healthcare costs. Projecting future trends in the clinical burden of HF may guide strategic investments in prevention and treatment as well as workforce planning. This study projects the incidence of heart failure in the US population through 2050. Methods: The Cardiovascular Disease (CVD) Policy Model is an established computer-simulation, state-transition model for the US population ages 35-94 years. Age- and sex- specific HF incidence rates were derived from NHLBI pooled cohort studies; the probability of HF hospitalizations associated with coronary heart disease (CHD) or stroke were derived from the National Inpatient Sample and published literature. We applied age- and sex-specific risk factor distributions, incidence, and event rates from 2018 to population projections through 2050 from the US Census. The model estimated absolute number of incident HF cases in subpopulations with CHD (ischemic HF) and without CHD (non-ischemic HF). Results: In 2018, 11% of the US population without HF was aged &gt;=75 years, which compares with 16% projected in 2050. The estimated HF incidence rate was higher in males. The annual incidence of HF in US adults aged 35 to 94 years is projected to increase by 39% from 836,000 in 2018 to 1.2 million by 2050 (Table 1). Most incident HF is estimated to occur in the population without CHD, accounting for three quarters of HF in women and over half in men. Among those with HF, the proportion of the population aged &gt;=75 years was projected to increase from 42% in 2018 to 54% in 2050. Conclusion A large increase in incident HF is expected in coming years, primarily due to an aging population. Most incident HF is estimated to be non-ischemic. Primary prevention, specifically controlling risk factors associated with non-ischemic HF, may offer the greatest opportunity to reduce HF incidence.
Abstract 14275: Allosteric Inhibition Restricts Motion of the SMURF1 Glycine Hinge and Reverses Experimental Pulmonary Arterial Hypertension
Authors: Alex M Rothman, Amir Florentin, Catherine Quigley, Florence Zink, Olivier Bonneau, Rene Hemming, Amanda Hachey, Tomas Rejtar, Maulik Thaker, Rishi Jain, Ji-Hu Zhang, Simona Cotesta, Johannes Ottl, Alina Kordinsky, Reut Avishid, Thomas Troxler, Sarah K Binmahfooz, Nicholas W Morrell, Marc Humbert, Jennifer Cobb, Nils Osterman, John Tallerico, Duncan Shaw, Sabine Guth-Gundel, Gali Prag, David J Rowlands
Journal: Circulation (2023)

Background: Reduced expression of bone morphogenetic protein receptor 2 (BMPR2) predisposes to pulmonary vascular remodelling and the development of pulmonary arterial hypertension (PAH). The HECT E3 ligase SMURF1 is a key negative regulator of this pathway that is overexpressed in the pulmonary vasculature of patients with PAH. However, the absence of an active-site pocket renders E3s undruggable. Hypothesis: We hypothesized that a large, unbiased screen would be needed to identify SMURF1 inhibitors and that a SMURF1 inhibition would augment BMP signaling and treat experimental PAH. Aims: We aimed to: identify SMURF1 inhibitors through a large, unbiased screen; determine mechanism of action; examine the effects on BMP signalling, cell phenotype and experimental models of PAH. Methods: We constructed a time-resolved fluorescence resonance energy transfer-based assay reporting SMURF1 self-ubiquitylation and undertook a 1.1 million compound screen. Primary hits were rationalised based on biochemical selectivity and cell-based assays designed to prioritize and optimize molecules for specific inhibition of SMURF1. Crystal structure of SMURF1 and SMURF2 were determined in the bound and unbound state at 2.05-2.75 Å. Target interaction was examined in a split-CAT based system. The effect on signaling and phenotype was examined in primary pulmonary artery endothelial and smooth muscle cells, and in rats with PAH induced by monocrotaline and sugen hypoxia. Results: Screening identified lead compounds that selectively inhibited SMURF1. Structures reveal that inhibitor binding induces an α-helix elongation over an invariant glycine-containing hinge, limiting a motion mandatory for catalytic activity. We affirmed this structure-based model with mutants engineered to resist inhibition and demonstrated that inhibition prevents direct BMPR2 ubiquitylation, normalized BMP signaling and restored homeostasis in pulmonary vascular cells from patients with PAH. Finally, we demonstrated that SMURF1 inhibition reverses established, experimental PAH. Conclusions: Our structural understanding enables design of HECT and other glycine-hinge protein inhibitors opening a new druggable space.
Abstract 13918: Improvement of Pulmonary Arterial Hypertension (PAH) Risk Assessment Model Using Cardiac Magnetic Resonance Imaging Variables
Authors: Priscilla Correa-Jaque, Yeming Lin, Shili Lin, Yongqi Liu, Charles Fauvel, Rebecca Vanderpool, Manreet Kanwar, Jidapa Kraisangka, Adam Perer, Allen D Everett, Samer Alabed, Andew Swift, David G Kiely, Raymond L Benza
Journal: Circulation (2023)

Introduction: PAH is a deadly disease without cure. Formalized risk stratification allows therapeutic adjustments that optimize drug utilization. Risk scores, like REVEAL 2.0 recommended by PAH guidelines only offer good discrimination. Our goal was to create risk models with excellent discrimination (C-Index over 0.8), using modern statistical techniques and expanded variable pools including imaging and genomics. The AIM of this study was to demonstrate the improved performance with the addition of cardiac MRI variables. Methods: PAH patients from the ASPIRE cardiac MRI database were analyzed. Imaging variable (IMV) selection was performed using three machine learning methods: logistic regression, Lasso, and Random Forest. Rankings of the IMVs from these sources were aggregated to arrive at a consensus list. The selected IMVs were added to the set of variables for deriving the REVEAL 2.0 composite score. Bayesian networks (BN) were then built to predict 1-year survival based on the Tree-Augmented naïve Bayes (TAN) algorithm. Five-fold cross-validation was performed to assess the improvement in survival prediction from adding the selected imaging variables. Results: A total of 343 PAH previously diagnosed subjects were included in this analysis. The rank aggregation algorithm identified several IMV, including LVSVI, RVCO, LVEDVI, and RVESVI, that were predictive of survival but not the REVEAL 2.0 composite score. Adding these IMV to the REVEAL 2.0 variables, we built a BN model that depicts the non-linear relationships among the predictors and one-year survival (Fig 1). We obtained an average AUC of 0.83 over the five cross-validation test sets, an improvement over the AUC of 0.78 using only the REVEAL 2.0 variables. A Mann-Whitney non-parametric test shows the improvement is statistically significant at the 0.1 level. Conclusion: Advanced statistical models that include cardiac IMVs improve performance of PAH risk assessment models.
Abstract 15017: Chromatin Regulators as Potential Players in Atrial Fibrillation: Locus Analysis and Regulatory Role Investigation
Authors: Yichao Xiao, Yunong Bao, Qiming Liu, Shenghua Zhou
Journal: Circulation (2023)

Background: Atrial fibrillation (AF), a prevalent cardiac arrhythmia, has multiple biomarkers identified, yet their roles remain partially understood. Research Questions and Aims: The study sought to investigate the expression and prognostic value of Chromatin Regulators (CRs) in AF, their correlation with the immune microenvironment, and to identify potential prognostic markers, therapeutic drugs, and miRNAs. Methods: We filtered three GEO database datasets containing AF and normal samples, identifying 23 differentially expressed CRs. Sequence analysis and protein-protein interaction (PPI) network construction led to the identification of 10 AF prognosis-related CRs. The biological roles and potential pathways of these CRs were analyzed through Gene Ontology (GO) and ssGSEA algorithm. Moreover, we examined the correlation between hub genes and immune cells/immune function, identifying the top 5 immunity-relevant CRs. Results: Ten CRs linked to AF prognosis were identified, achieving an AUC of 0.901997 in a nomogram model. GO analysis demonstrated the involvement of these CRs in processes associated with cardiovascular diseases. The ssGSEA algorithm showed a connection between the identified CRs and immune infiltration. The study also identified the top 5 immunity-related CRs, and potential drugs and miRNAs for AF therapy. Conclusions: This study elucidates the role of specific CRs in AF, presenting a promising risk model and potential therapeutic targets. Further validation and evaluation of potential therapeutic targets' efficacy and safety are required. This underscores CRs as potential biomarkers and therapeutic targets for AF.
Abstract 16543: New-Onset Infective Endocarditis in Diabetic Patients Receiving SGLT2I and DPP4I: A Population-Based Cohort Study
Authors: Oscar Hou In Chou, Tianyu Guo, Cheuk To T Chung, Fengshi Jing, Jeffrey S Chan, Danish Iltaf Satti, Ronald T Pang, Sharen Lee, Wing Tak Jack Wong, bernard cheung, Gary Tse, Jiandong Zhou
Journal: Circulation (2023)

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2I) have been suggested to have beneficial effects against infection. However, the comparative risks of new onset infective endocarditis between SGLT2Is and dipeptidyl peptidase-4 inhibitors (DPP4Is) remain unknown. Objective: This real-world study aims to compare the risks of infective endocarditis upon exposure to SGLT2I and dipeptidyl peptidase-4 inhibitors (DPP4I). Methods: This was a retrospective population-based cohort study of patients with type-2 diabetes mellitus (T2DM) on either SGLT2I or DPP4I between 1st January 2015 and 31st December 2020 using a territory-wide registry in Hong Kong. The primary outcome was new-onset infective endocarditis. The secondary outcome was cardiovascular-related mortality. Propensity score matching (1:1 ratio) using the nearest neighbour search was performed. Multivariable Cox regression was applied to identify significant associations. Results: This cohort included 75638 T2DM patients (median age: 62.3 years old [SD: 12.8]; 55.79 % males). The SGLT2I and DPP4I groups consisted of 28774 patients and 46864 patients, respectively. After matching, 104 and 161 endocarditis events in the SGLT2I and DPP4I groups occurred over a follow-up of 5.6 years. SGLT2I use was associated with lower risks of infective endocarditis (Hazard ratio [HR]: 0.58; 95% Confidence Interval [CI]: 0.41-0.81; p=0.0016) and cardiovascular mortality (HR: 0.49; 95% CI: 0.33-0.72; p=0.0002) compared to DPP4I use after adjustments for demographics, comorbidities, medications, renal function and HbA1c levels. Similar associations were observed in subgroup analyses by gender, hypertension, arrhythmia, or renal disease, competing risk and sensitivity analyses. Conclusions: SGLT2I use is associated with lower risks of new-onset infective endocarditis compared to DPP4I.