tbuckley/cabot-search huggingface dataset:
Abstract 4139014: Building Nucleic Acid-Based Hirudins：Potent, Selective, and Reversible Protease Inhibitors
Authors: Haixiang Yu, Amy Yan, George Pitoc, Susannah Garber, Jeffrey Clancy, Bruce Sullenger
Journal: Circulation (2024)

Background: Unfractionated heparin (UFH), the main anticoagulant used in heart surgeries, is associated with adverse effects such as bleeding and heparin-induced thrombocytopenia. Anticoagulant aptamers targeting coagulation proteases have advantages such as low immunogenicity, low bleeding risk, and reversibility by complementary oligonucleotides. However, the potency of aptamers is often limited as they do not directly inhibit the catalytic sites on their targeted proteases. The natural anticoagulant hirudin achieves potent activity by inhibiting both thrombin’s exosite and active site. We hypothesize that hirudin-like protease inhibitors can be generated de novo by linking EXosite-binding aptamers with small molecule ACTive site inhibitors to create EXACT inhibitors that are much more potent than the small molecule inhibitors or aptamers alone. Methods: Protease inhibition by EXACT inhibitors were characterized by fluorogenic substrate cleavage assays. The anticoagulation activity of EXACT inhibitors was assessed in normal pooled plasma or whole blood using the standard clinical clotting assays: prothrombin time (PT), activated partial thromboplastin time (aPTT), and active clotting time (ACT). The clinical potential of the EXACT inhibitor was evaluated in an ex vivo Extracorporeal Membrane Oxygenation (ECMO) circuit that mimics the procoagulant environment in many cardiovascular surgical settings. Results: An EXACT inhibitor termed HD1-12dmA-DAB was synthesized by attaching the DNA aptamer HD1, that binds to thrombin exosite I, through a poly-adenosine linker to the thrombin active site inhibitor dabigatran (DAB). The EXACT inhibitor showed stronger thrombin inhibition (IC 50 = 0.2 nM) than DAB (IC 50 = 80 nM) or HD1 (IC 50 &gt; 1 µM) alone. HD1-12dmA-DAB (2 µM) also achieved equal or higher anticoagulant activity than UFH (5U/mL) in all clotting assays and showed anticoagulation efficacy rivaling UFH in the ex vivo ECMO circuit with minimal clot observed over 120 min. Notably, the EXACT inhibitor’s effect can be rapidly reversed by an antidote oligo. We also used the same strategy to develop a potent EXACT inhibitor against factor Xa. Conclusions: EXACT inhibitors demonstrate extraordinary anticoagulation activity as potential rapid onset anticoagulants to support cardiovascular procedures. Using this generalizable strategy, selective, potent, and rapidly reversible EXACT inhibitors can be created against many enzymes for numerous therapeutic applications.
Abstract 4140068: Apical resection preserves the proliferative capacity of cardiomyocytes located throughout the left ventricle of the heart
Authors: THANH NGUYEN, Yuji Nakada, Yuhua Wei, Jianyi Zhang
Journal: Circulation (2024)

Background: When newborn pigs underwent apical resection (AR) surgery on postnatal day (P) 1, the apex fully regenerated by P28, and when pigs underwent AR on P1 (AR P1 ) followed by myocardial infarction (MI) surgery on P28 (AR P1 MI P28 ), or MI on P28 without previous AR surgery (MI P28 -only), a large infarct persisted in hearts from the MI P28 -only group on P56, while AR P1 MI P28 hearts had little evidence of scarring at the same time point, and the improvement appeared to be driven primarily by cardiomyocyte (CM) proliferation. Thus, whereas mammalian CMs normally undergo cell-cycle arrest just a few days after birth, AR P1 prolonged the duration of CM cell cycle activity and the cells’ proliferative capacity through at least P28. Hypothesis: The two surgical procedures were performed ~5 mm (AR) and ~20 mm (MI) above the heart base; thus, we hypothesize that AR P1 preserved the cell-cycle machinery of CMs located throughout the left ventricle (LV), rather than only near the resection site. Approach: CM single-nucleus RNA sequencing (snRNAseq) data were collected from uninjured (CTL) pigs on P14 (CTL-P14) and from the apex zone (AZ) and remote zone (RZ) of the LV in AR P1 pig hearts on P2, P4, P8, and P15. These data were integrated with data collected from AR P1 hearts on P28, from the hearts of CTL pigs on P1, P2, and P28, and from the hearts of fetal pigs (Fetal) in our previous studies, and then the expanded snRNAseq dataset was evaluated with our cell-cycle-specific Autoencoder to identify clusters of cycling CMs, which were defined by the co-enrichment of each of five markers for cell-cycle activity or proliferation (AURKB, MKI67, INCENP, BIRC5, and CDCA8). CM proliferation was also evaluated in AR P1 hearts on P15 and CTL hearts on P14 via immunohistological analysis of phosphorylated histone 3 (PH3) and symmetric Aurora B (sAUB). Results: Cycling CMs were significantly more common in Fetal hearts and in both the AZ and the RZ of AR P1 hearts on P8 and P15 than in CTL hearts on P14. PH3- and sAUB-expressing CMs were also more common in the AZ and RZ of AR P1 hearts on P15 than in CTL hearts on P14. Conclusion: AR P1 preserved the cell-cycle activity and proliferative capacity of CMs throughout the LV.
Abstract 4139600: Characteristics and Pattern of Stress Cardiomyopathy in High Grade Subarachnoid Hemorrhage
Authors: Michael Chiu, Erica Mckenzie, Kimberly Wong, Justin Wong, Andreas Kramer
Journal: Circulation (2024)

Background: Cardiac injury after subarachnoid hemorrhage (SAH) is a well-recognized phenomenon with electrocardiogram (ECG) changes, arrhythmias and myocardial dysfunction. Neurocardiac injury has been commonly reported with increased severity of SAH, however much of the evidence has focused on high grade SAH requiring hemodynamic support or mechanical ventilation. In this study we focused on neurocardiac injury with high grade World Federation of Neurological Surgeons (WFNS) grade 3-5 SAH requiring intensive care management. Methods: Patients admitted to our intensive care unit from 2009-2019 with an WFNS 3-5 aneurysmal SAH with an echocardiogram within 7 days of admission were included in our study. Electrocardiogram, cardiac biomarkers and data regarding mortality and neurological complications were collected retrospectively. Results: A total of 242 patients were included in our study analysis with 11 (5%), 89 (37%), and 142 (59%) had WFNS grade 3, 4 or 5 SAH, respectively. Of the 95 patients that underwent echocardiography in the first week, 38 (40%) had a reduced ejection fraction, which was mild (LVEF 40-52%) in 13 (14%), moderate (LVEF 30-39%) in 14 (15%), and severe (LVEF &lt; 30%) in 11 (12%). Independent predictors of reduced ejection fraction included a lower presenting GCS score (OR 1.2 per one point reduction in (Glasgow Coma Score) GCS, 95% CI 1.0-1.5, p = 0.03), elevated troponin T concentration (OR 6.1, 95% CI 1.2-31.3, p = 0.03) and T wave inversion on ECG (OR 9.1, 95% CI 1.6-52.3, p = 0.01). In patients with reduced ejection fraction, classical apical wall motion abnormality was more prevalent in older populations (median age 64 years (apical) vs 50 years (basal wall motion abnormality) and 52 years (other) p = 0.03). In all wall motion abnormality groups, there was a female predominance. Classic Takotsubo wall motion was associated with an anterior SAH aneurysm location (p = 0.03) and highest proportion of moderate to severe LV dysfunction (p = 0.04). ICU mortality did not differ based on the pattern of wall motion abnormalities. Conclusion: Predictors of neurocardiac injury in high grade SAH include troponin elevation, T wave abnormalities and lower presenting GCS. Aneurysm location was associated with wall motion abnormalities and degree of LV dysfunction. Patients with WFNS 3-5 SAH are at increased risk of neurocardiac injury. ECG changes, cardiac biomarker elevation and aneurysm location can help identify patients who warrant echocardiography.
Abstract 4139204: Impact of Myocardial Injury Assessment in Emergency Department on Disposition Distribution and Time to Disposition
Authors: Alexander Landry, Kirolos Michael, Karita Lidani, Benjamin Palmer, Shubham Tomar, Meng Xu, Michael Libre, Mitchell Sexton, Jesse Wrenn, Andrew DeFilippis
Journal: Circulation (2024)

Background: Emergency department (ED) overcrowding is a significant healthcare challenge that continues to strain medical facilities internationally. The need to assess myocardial injury in the ED is thought to be common, accounting for greater than 13 million visits annually. Therefore, we sought to assess the frequency and impact of myocardial injury assessment on the intermediates to ED overcrowding – ED disposition distribution and time to disposition – at an urban ED. Methods: In this single-center, retrospective cohort study from February 1, 2023, to January 31, 2024, the disposition distribution and median time to disposition were recorded for ED patient encounters. The study population was divided into encounters resulting in ED assessment for myocardial injury with conventional troponin measurement (ED-Tn group) and all other encounters without ED assessment for myocardial injury (control group). Pearson test was used for analyzing disposition distribution and Wilcoxon test for comparing time to disposition between the two defined groups. Results: 66,984 patient encounters resulted in a disposition of discharge or admission during the study period. 15,918 (23.8%) were categorized into ED-Tn group, while 51,066 (76.2%) were categorized into control group. The ED-Tn group had a significantly lower discharge frequency of 51% compared to the control group with 59.1% (p&lt;0.001). The median time to disposition was significantly higher for the ED Tn group at 212 minutes (IQR = 124, 325) compared to the control group at 184 minutes (IQR = 95, 313; p&lt;0.001). When considering only those patients who were discharged from the ED, the difference in median time to disposition was even more pronounced for the ED-Tn group at 226 minutes (IQR = 139, 340) compared to the control group at 178 minutes (IQR = 86, 311; p&lt;0.001). Conclusions: In an urban ED, myocardial injury assessments comprised a quarter of all ED evaluations, linked to increased admission and extended time to disposition for these patients. Implementing high-sensitivity troponin could improve efficiency of ED assessment for myocardial injury and alleviate overcrowding, given the resource-intensive and time-intensive nature of these assessments.
Abstract 4139994: Deep-learning Assisted ECG-based Emergent Cathlab Activation: First Prospective Implementation of a Smartphone-based System
Authors: Robert Herman, Rinaldo Lauwers, David Pletnickx, Harvey Meyers, Stephen Smith, Timea Kisova, Anthony Demolder, Peter Herman, Radka Grendova, Monika Beles, Leor Perl, Olivier Nelis, Emanuele Barbato, Jozef Bartunek, Dan Schelfaut
Journal: Circulation (2024)

Introduction: Standard ST-segment elevation myocardial infarction (STEMI) pathways misidentify up to 50% of patients with an acutely occluded culprit coronary artery (OMI) with false positive emergent cathlab activations in up to 35% of cases. Recently, an artificial intelligence (AI) electrocardiogram (ECG) model outperformed standard of care in detecting OMI in international retrospective cohorts. Hypothesis: We sought to prospectively evaluate the rule-in performance of an AI ECG model in a large tertiary care STEMI network compared to ECG machine readings of STEMI and AI-assisted emergency physicians. Methods: An AI model trained to detect acute coronary occlusion regardless of ST elevation was implemented using smartphones in a tertiary care STEMI network consisting of 1 hub hospital, 1 spoke center, and 2 emergency medical service crews (EMS) (Fig 1A). Outcomes of all patients presenting with atraumatic chest pain during a 10-week period between January and March 2024 were adjudicated using ECG, laboratory, and angiographic chart review and classified based on the presence of OMI. Results: A total of 731 consecutive patients (68% male) with atraumatic chest pain were included; 142 patients were hospitalized of whom 23 (16%) met the primary outcome of OMI. The AI model showed a significantly higher sensitivity detecting OMI as compared to ECG machine (95.7% vs. 47.8%, p&lt;0.001, Fig 1B) at comparable specificity (95% vs. 96%, respectively) with overall superior predictive accuracy (Chi-squared=8.1; p=0.004). The AI model correctly identified 15 cases that the ECG machine misclassified (80% were false negatives by ECG machine). All AI false positives were patients post recent myocardial infarction or angioplasty. Sensitivity of AI-assisted emergency physicians interpreting OMI was 78.2% indicating potential instances of AI underutilization. Conclusions: This first prospective performance evaluation in a large all-comer atraumatic chest pain cohort indicates high accuracy of unbiased, AI-powered ECG detecting acute coronary occlusion. The findings suggest its potential to improve ACS patient outcomes through timely referral for invasive management in a real-world clinical setting.
Abstract 4140345: 3D Statistical Shape Analysis Predicts Type A Aortic Dissection Better Than Aortic Diameters
Authors: Prabhvir Marway, Carlos Alberto Campello Jorge, Catherine Wagner, Timothy Baker, Nicholas Burris
Journal: Circulation (2024)

Introduction/Background: The vast majority of type A aortic dissection (TAAD) patients do not meet diameter thresholds for ascending aortic repair before their dissection. Increased ascending aortic length has been suggested to improve risk predictions, but this metric simplifies the aortic shape to a single dimension and doesn’t capture 3D features like tortuosity/torsion. Research Questions/Hypothesis: Are there distinct shape features of the ascending aorta that differentiate patients with TAAD better than aortic diameter? Methods/Approach: We retrospectively identified patients with good quality, pre-dissection CT imaging of the chest at our center prior to surgical repair of acute TAAD, excluding those with pre-existing dissection or prior aortic intervention. This pre-TAAD group was compared to a reference cohort of ‘normal’ patients (no aortic disease), patients with borderline ascending aortic dilation (35-44 mm) and ascending aneurysm (≥45 mm; aTAA). A shape score, based on statical shape modeling (SSM) and cosine similarity was computed (tubular ascending and arch) to quantify the similarity between an individual aortic shape compared to the mean ‘normal’ shape (defined as -1) and mean pre-TAAD shape (defined as +1). Results/Data (descriptive and inferential statistics): We identified 30 spontaneous TAAD patients with CTs at a median of 1.5 (IQR: 0.7-3.8) years pre-dissection. We compared against pre-existing cohorts with normal aortas (n=165), borderline dilation (n=119) and aTAA aneurysm (n=42). Age, sex and hypertension did not significantly differ between TAAD and aTAA groups. Max diameter (47.7 ± 2.0 vs. 40.6 ± 6.0 mm, p&lt;0.01), centerline length (130 ± 11.5 vs. 120 ± 16.7 mm, p&lt;0.01) and tortuosity (1.33 ± 0.08 vs. 1.27 ± 0.07, p&lt;0.01) were higher in aTAA versus TAAD. Median SSM scores were higher in the (TAAD group 1.25, IQR: 0.76-1.46) compared to the aTAA group (-1.25, IQR: -1.60, -0.95; p&lt;0.01) and the borderline dilation group (-1.03, IQR: -1.25, -0.84; p&lt;0.01), Figure 1 . SSM scores for normal, borderline dilated and aTAA did not significantly differ. Conclusion: A novel SSM-based scoring method of assessing ascending aorta and arch geometry reveals clear shape differences among patients prior to TAAD.
Abstract 4139473: Deep Learning Model for Identification of Patients with Acute Heart failure using electrocardiogram in Emergency Room
Authors: Cha Jung-Joon, Jose Moon, Jong-ho Kim, Soon Jun Hong, Cheolwoong Yu, Yong Kim, Eung Ju Kim, Hyung Joon Joo
Journal: Circulation (2024)

Background: Acute heart failure (AHF) poses significant diagnostic challenges in emergency room (ER) settings due to its varied clinical presentations and the limitations of traditional diagnostic methods. This study aims to develop and evaluate a deep learning model that uses electrocardiogram (ECG) data to enhance the identification of AHF in ER patients. Methods: In this retrospective cohort study, we analyzed ECG data from 19,285 patients who visited the ERs of three hospitals between 2016 and 2020. Among the patients, 9,119 patients with available left ventricular ejection fraction and NT-proBNP levels, who were diagnosed with AHF were included. We extracted morphological and clinical parameters from the ECG data to train and validate four machine learning models: a baseline linear regression and more advanced models including XGBoost, Light GBM, and CatBoost. Results: The CatBoost algorithm outperformed other models, showing superior AUROC and AUPRC diagnostic accuracy across both internal (0.89±0.01 and 0.89±0.01) and external validation datasets (0.90 and 0.89). In addition, the model demonstrated high metrics in accuracy, precision, recall, and f1-score, indicating robust performance in the identification of AHF. Conclusion: The developed machine learning model significantly enhances the detection of AHF in ER patients using conventional 12-lead ECGs combined with clinical data. These findings suggest that ECGs, a commonplace tool in ERs, can effectively screen for AHF.
Abstract 4139023: Clinical Outcomes and Hemodynamic Findings Following Transcatheter Aortic Valve Replacement with a Balloon-Expandable Valve in Patients with Small and Non-Small Annulus
Authors: Besir Besir, Maryam Muhammad Ali Majeed-Saidan, Judah Rajendran, Tamari Lomaia, Shivabalan Kathavarayan Ramu, Odette Iskandar, James Yun, Serge Harb, Rhonda Miyasaka, Grant Reed, Rishi Puri, Amar Krishnaswamy, Samir Kapadia
Journal: Circulation (2024)

Background: Patients with a small aortic annulus are at risk for worse hemodynamic performance after transcatheter aortic valve replacement (TAVR). There is a debate on whether they have worse clinical outcomes compared to patients with a non-small annulus. Hypothesis: Patients with a small annulus have worse hemodynamic and clinical outcomes post-TAVR than those with a non-small annulus. Aims: To explore the hemodynamic and clinical outcomes following TAVR in patients with a small annulus compared to those with a non-small annulus. Methods: This is a retrospective cohort of patients &gt;18 years of age who underwent TAVR at Cleveland Clinic between 2016 and 2020. Patients were classified into 2 groups according to the annular size assessed by contrast-enhanced computed tomography or cardiac magnetic resonance: small (area ≤430 mm 2 ), and non-small annulus (&gt;430 mm 2 ). Patients who underwent TAVR with a self-expanding valve and those with annular sizing using transesophageal echocardiography were excluded. Clinical outcomes included overall mortality, and heart failure rehospitalization at 3 years using Cox regression, in addition to ischemic stroke, and permanent pacemaker (PPM) implantation. Echocardiographic outcomes included moderate to severe paravalvular leak (PVL), aortic valve (AV) mean gradient, and dimensionless valve index (DVI), with up to 3 years of follow-up. Results: A total of 2630 patients underwent TAVR between 2016 and 2020. The study included 2122 patients, of which, 782 (37%) had a small annulus. Patients with a small annulus had significantly higher AV mean gradients and lower DVI at all follow-up intervals. However, there was no difference in clinical outcomes between the 2 groups. The hazard ratio [HR] for mortality was 0.89 (p-value= 0.328), and for heart failure rehospitalization was 1.06 (p-value= 0.712) (reference is non-small annulus). The incidence of moderate to severe PVL was not significantly different between the 2 groups at any of the follow-up intervals (Figure 1). Conclusions: Patients with a small annulus had higher AV mean gradients post-TAVR than those with a non-small annulus. However, there was no significant difference in clinical outcomes or PVL between the 2 populations.
Abstract 4139609: Impact of Metformin on Cardiovascular Outcomes in Breast Cancer Patients Receiving Chest Radiation Therapy
Authors: Abiodun Idowu, Olayinka Adebolu, XElvisX XObomanuX, Tochi Okwuosa
Journal: Circulation (2024)

Introduction: Metformin has anti-inflammatory and anti-oxidant properties that have been associated with protective effects against radiation in animal studies. However, there is limited evidence demonstrating similar effects in humans. This study evaluated the impact of metformin on cardiovascular outcomes in breast cancer patients receiving chest radiotherapy. Methods: A retrospective propensity-matched analysis of women aged 18-65 with breast cancer who received chest radiotherapy between January 1, 2000, and December 31, 2018, using the TriNetX database. The patients were categorized into two groups - metformin users (used metformin within 3 months before or after exposure to chest radiation therapy) and metformin non-users. Adjusted odds ratio (aOR) for outcomes was calculated and the Kaplan-Meier survival curve using log-rank tests for a five-year follow-up was performed. All analyses were performed using R software. Result: 131 patients were propensity-matched to each group (Table 1). None of the patients was dialysis-dependent or had chronic liver disease and none was taking SGLT2i. The median number of days of follow-up was 1825 days. Major adverse cardiovascular events – MACE, a composite of all-cause mortality, Heart failure, Myocardial infarction, and cerebrovascular accident - were comparable between metformin users and non-users (19.8% vs 19.3%, aOR: 1.03, 95%CI: 0.54-1.97, p=0.923). Survival probability at 5 years was also comparable in both groups (78.5% vs 79.1%, Hazard ratio = 1.04, 95% CI (0.59 – 1.86), p=0.89) (fig. 1). Conclusion: Metformin use around the time of radiation therapy did not significantly lower or increase the future risk of MACE in breast cancer patients.
Abstract 4139472: Increased Arachidonic Acid Eicosanoids in African Americans with Heart Failure with Preserved Ejection Fraction
Authors: XBellaX XKhatib-ShahidiX, Vaishnavi Aradhyula, Anas Fares, Prabhatchandra Dube, Alborz Sherafati, Alex Kloster, Sadik Khuder, Steven Haller, David Kennedy, Rajesh Gupta, Samer Khouri
Journal: Circulation (2024)

Background: African Americans demonstrate increased prevalence, earlier onset, and worse prognosis of heart failure with preserved ejection fraction (HFpEF) compared to non-African Americans. Recent studies have implicated circulating, bioactive lipids such as eicosanoids in mediating systemic inflammation. Eicosanoids may play a role in HFpEF pathogenesis. In addition, prior studies have identified arachidonic acid (AA) gene variants in African Americans that predispose to elevated circulating AA eicosanoid levels. Objective: We sought to analyze the differences in eicosanoid levels between African American and non-African American patients with HFpEF. Methods: Venous and arterial blood samples were collected during right heart catheterization from 22 African American and 68 non-African American patients with HFpEF. AA lipids were analyzed using liquid chromatography-mass spectrometry. Statistical analysis was performed using Student’s unpaired T-test and Chi-squared analysis. Results: African American patients demonstrated higher venous anti-inflammatory prostaglandin E1 (PGE1) (p&lt;0.0001), prostaglandin E2 (PGE2) (p=0.0002), pro-inflammatory thromboxane B3 (TXB3) (p=0.0152), pro-inflammatory 20-hydroxyeicosatetraenoic acid (20-HETE) (p&lt;0.0001), anti-inflammatory 14,15-epoxyeicosatrienoic acid (14,15-DiHETrE) (p=0.0005), and pro-resolutory lipoxin A4 (LXA4) (p&lt;0.0001). Similarly, African American patients had elevated arterial 20-HETE (p=0.0029) and LXA4 (p=0.0421). Conclusion: This study demonstrates significant differences in levels of venous and arterial eicosanoids between African Americans and non-African Americans with HFpEF.