tbuckley/cabot-search huggingface dataset:
Abstract 4144107: ApoB-100 peptide nanoparticles inhibit established atherosclerosis progression in female HLA-A*0201 transgenic mice
Authors: Jianchang Zhou, Xiaoning Zhao, Paul Dimayuga, Nicole Lio, Bojan Cercek, Noah Trac, Eun Ji Chung, Prediman Shah, Kuang-Yuh Chyu
Journal: Circulation (2024)

Background: Sex, cholesterol and immune responses play significant roles in atherosclerosis development. Cholesterol lowering and global anti-inflammatory therapy have therapeutic limitations. Immune modulation with ApoB-100 peptide-based nanoparticles, named P210-PAM, reduced atherosclerosis in ApoE –/– mice carrying human HLA-A*0201 allele ( A2Kb-Tg) when administered before significant atherosclerosis formed. In this study, we investigated the potential interaction among sex, cholesterol and immune responses in modulating atherosclerosis with P210-PAM therapy. Methods: A2Kb-Tg mice of both sexes fed high fat diet for 8 weeks were injected s.q. 3x with P210-PAM at 2–3-week intervals with or without change to normal chow at the second injection time point. PBS injections served as controls. Aortic atherosclerosis, splenic monocyte/macrophage and T cells were evaluated. Results: P210-PAM therapy without diet change had no effect on established atherosclerosis in both sexes (Table). P210-PAM therapy in female mice with diet change significantly inhibited growth of established atherosclerosis (Table) and reduced IL1R1 expression on splenic monocyte/macrophages (106.1±16.9, N=12, vs 137.5±23.6, N=13; P&lt;0.05) with increased splenic CD8 + T CM (25.6±7.8%, N=13, vs 19.5±4.9%, N=14; P&lt;0.05). P210-PAM therapy with diet change had no effect in male mice (Table). Conclusion: P210-PAM therapy with cholesterol lowering has a sex-specific effect on atherosclerosis highlighting the potential interaction among sex, cholesterol and immune responses in modulating atherosclerosis.
Abstract 4144115: Suppressed T cell Response to the ApoB-100 Antigen P210 In Stable ASCVD Patients Is Rescued By Nanoparticle-conjugated P210-PAM
Authors: Paul Dimayuga, Kuang-Yuh Chyu, Xiaoning Zhao, Jianchang Zhou, Janet Wei, Noah Trac, Bojan Cercek, Eun Ji Chung, Prediman Shah
Journal: Circulation (2024)

Background: The apoB-100 peptide P210 is an atherosclerosis-related antigen. P210 conjugated-nanoparticles (P210-PAM) are internalized by antigen-presenting cells to elicit T cell responses and reduce atherosclerosis in mice. However, if and how P210 modulates human T cell responses is not known. We investigated the intrinsic T cell response to P210 in both healthy and atherosclerotic cardiovascular disease (ASCVD) subjects. Methods: We evaluated the T cell response to unconjugated P210 or P210-PAM in PBMCs of healthy subjects (N=15) and stable ASCVD patients (N=27) using the Activation Induced Marker (AIM) assay, where a change of 1.5-fold relative to unstimulated cells is considered the activation threshold and a value of 1 considered no response. Under IRB approval, PBMCs from stable ASCVD patients were collected within 1 year of acute MI or stroke, or a diagnosis of peripheral artery disease (PAD). To investigate effects on innate cells, monocytes from healthy subjects were phenotyped by flow cytometry staining after stimulation with P210-PAM. Results: P210 significantly increased CD4+CD69+CD154+ T cells in healthy subjects compared to ASCVD patients (2.2±1.9 vs 0.8±0.6 fold-change; P=0.01) without affecting other T cell activation markers. In healthy subjects, CD4+CD69+CD154+ T cell response to P210-PAM stimulation was similar compared to P210 stimulation (1.5±0.7 vs 2.2±1.9 fold-change) but was significantly increased in ASCVD patients (1.8±1.8 vs 0.8±0.7 fold-change, respectively; P=0.02). CD4+CD134+CD137+ T cells were also significantly increased by P210-PAM compared to P210 in ASCVD patients (2.8±2.0 vs 1.9±1.8 fold-change; P&lt;0.01) but not in control subjects. Monocyte-enriched PBMCs of healthy subjects (N=13) stimulated with P210-PAM significantly increased CD64+CD80+ cells (32.3±11.9% vs 3.1±2.8%; P&lt;0.001), CD11b+CD209+ cells (3.7±2.2% vs 2.0±1.6%; P&lt;0.01), CD14+CD16+ cells (13.9± 9.5% vs 0.9±0.8%; P&lt;0.001) and CD14-CD16+ cells (37.3±18.7% vs 0.9±1.1%; P&lt;0.001), with significantly reduced CD14+CD16- cells (16.9±14.6% vs 60.0±21.0%; P&lt;0.001). Conclusions: CD4+ T cell response to P210 is impaired and can be rescued by P210-PAM in stable ASCVD patients. Such rescue may be mediated by P210-PAM provoking a shift in monocytes from classic inflammatory to non-classic anti-inflammatory phenotype. Our results support the dynamic existence of T cell response to P210 and the development of P210-PAM as potential immune-modulator therapy for human ASCVD.
Abstract 4144056: Quantitative Testing Reveals Severity of Autonomic Dysfunction after Acute COVID-19 Infection: A Comparison with Controls and Autonomic Failure
Authors: Ciana Keller, Lorraine Mascarenhas, Sue Duval, David Benditt
Journal: Circulation (2024)

Background: COVID-19 infections have been associated with cardiovascular autonomic dysfunction (AD). Clinical findings include fatigue, cognitive impairment, and postural intolerance. However, quantitative post-COVID AD assessments are lacking. Objective: Compare autonomic testing measures of post-COVID-19 subjects to controls and those with pure autonomic failure (PAF). Methods: Autonomic testing included 1) change in heart rate (HR) and blood pressure (BP) with active standing (AS) and tilt table testing (TT), 2) time to BP nadir and recovery during AS and TT, 3) Valsalva ratio (VR), and 4) respiratory sinus arrhythmia (RSA). Comparisons between two groups were made using t-tests, Kruskal-Wallis, or chi-square tests. Multivariable linear regression was used to adjust findings for age and sex. A p-value of &lt;0.05 was considered significant. Results: Control subjects (n=25, median 32 [21-39] years, 76% female) and post-COVID patients (n=91, median 36 [25-50] years, 84% female, mean 11.96 [±9.14] months from infection) were similar in age and sex, while the PAF group (n=38, median 64 [56-74] years, 53% female) was older and comprised of more males (Table 1). The VR and RSA of the post-COVID group was significantly lower than controls, but higher than the PAF group (Table 2). The change in BP with AS and TT for post-COVID subjects was significantly higher than controls and lower than the PAF group. The post-COVID group also had a significantly increased change in HR with TT compared to both the control and PAF groups. Across all four tests, the post-COVID group had a higher proportion of abnormal results compared to controls. After adjusting for age and sex, post-COVID subjects continued to have a greater change in HR and BP with AS and TT and a lower RSA compared to controls. However, with this adjustment several differences compared to the PAF group were attenuated (Table 3). Conclusion: Post-COVID subjects were observed to have multiple quantitative autonomic testing abnormalities. Once corrected for sex and age, AD severity in post-COVID-19 patients is comparable to that seen in neurodegenerative PAF.
Abstract 4144098: Mechanisms Of Reduced IgG Autoantibodies Specific to the ApoB-100 Peptide P210 Associated With Increased Risk For Myocardial Infarction
Authors: Paul Dimayuga, Kuang-Yuh Chyu, Christopher Farina, Xiaoning Zhao, Jianchang Zhou, Bojan Cercek, Daniel Berman, Prediman Shah
Journal: Circulation (2024)

Background: Reduced level of IgG autoantibodies specific for the apoB-100 peptide P210 is associated with increased risk for myocardial infarction (MI). However, the underlying mechanism for reduced P210 IgG levels in patients at risk of MI is unknown. Methods: We evaluated the baseline P210 IgG and immune complex (P210 IgG-IC) levels using ELISA of plasma samples of a sub-cohort of volunteers having coronary artery calcium scans (CACS) as part of the EISNER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) trial. The sub-cohort selected were those that did not have MI (No MI, N=90) and those that had a future MI (FMI, N=23) during follow-up (13.2±2.1 years). We also evaluated plasma samples collected from patients admitted to Cedars-Sinai for acute coronary syndrome (ACS, N=15). ELISA for P210 IgG and ICs were standardized against a pool of healthy control plasma and expressed as adjusted optical density (Adj OD). Flow cytometry evaluation of CXCR5+ T follicular helper (Tfh) cells that regulate IgG levels was performed in peripheral blood mononuclear cells (PBMCs) from ACS patients (N=8) in response to in vitro stimulation with P210. Specimen and data collection were IRB approved. Results: P210 IgG was significantly lower in FMI patients compared to No MI and ACS patients (FMI=0.6±0.6 vs No MI=1.5±1.6 and ACS=1.4±0.9 Adj OD; P&lt;0.001). Plasma LDL was significantly higher in FMI patients compared to No MI and ACS patients (FMI=160.7±25.2 vs No MI=126.0±40.6 and ACS=114.9±53.4 mg/dL; P&lt;0.0001). Since P210 is a peptide antigen of LDL apolipoprotein apoB-100 and considering that P210 IgG may form ICs with LDL, we evaluated plasma P210 IgG-ICs using a P210 capture monoclonal antibody. The No MI group for P210 IgG-IC ELISA only included subjects with the lowest risk of MI (CACS 0; N=23) to minimize variability within the group. FMI patients had significantly higher P210 IgG-ICs (FMI=3.3±2.4 vs No MI=2.0±2.0 and ACS=2.2±2.9 Adj OD; P&lt;0.01), suggesting P210 IgG may have been depleted in FMI plasma by forming ICs with LDL. CD4+CD154+CXCR5+ Tfh cell response to P210 in PBMCs from ACS patients was significantly reduced compared to cells with no peptide stimulation (P&lt;0.05). Conclusion: The results suggest that increased P210 IgG-IC formation may account for reduced P210 IgG in FMI patients. Reduced CD4+CD154+CXCR5+ Tfh cells in response to P210 stimulation may underly the lack of compensatory increase in P210 IgG in ACS patients.
Abstract 4144135: The Pulmonary Resistance-Compliance Relationship: Real or Mathematical Artefact?
Authors: Sara Hungerford, Navin Kapur, Stuart Rich, Daniel Burkhoff
Journal: Circulation (2024)

Background: It has previously been suggested that pulmonary vascular resistance (PVR), the steady component of VA, and arterial compliance (PAC) are physiologically and inexorably linked through an inverse hyperbolic relationship and that their product, the pulmonary vascular time constant (τ), is roughly equal across a range of disease states. A critical and often overlooked concern, however, emerges from the way PAC has come to be estimated in many realms of clinical reearch as the ratio of stroke volume (SV) to pulse pressure (PA PP, PAC clinical ). We sought to explore the foundation of the reported link between PVR and PAC because they both share the value of SV in their determination.In other words, plotting a parameter that is dependent on SV (i.e., PVR) versus another that is dependent on 1/SV (i.e., PAC clinical ) is inherently prone to yield a hyperbolic relationship. Methods: We performed both joint density analysis (JDA) as well as a simple set of simulations using hemodynamic data from a cohort of patients with PH from left-sided disease. PAC clinical was calvulated as SV/PA PP. PVR was calculated as: (PA M – PCWP)/CO , expressed in Wood Units. Log values were plotted to determine PVR-PAC clinical relationships. Results: JDA of predicted PVR against PAC clinical demonstrated a Spearman’s R of -0.88 (CI -0.92 to -0.82). With bootstrapping, this increased to -0.92 (CI -0.93 to -0.91) demonstrating very high mathematical correlation and precision (Figure 1a). Hemodynamic model simulation demonstrated a consistent inverse dependence characterized by a first-order hyperbolic decay function ( PAC = τ avg /PVR ; r 2 0.86; p&lt;0.001; Figures 1b-d). Compared with data from points associated with lower PCWP, the log 10 -transformed relationship was shift downward in a nearly parallel manner (Figures 1e-g). Conclusions: By performing JDA, as well as creating a random, albeit physiologically constrained hemodynamic simulation, we were able to recreate, with high-fidelity, the inverse hyperbolic relationship between PVR and PAC clinical reported in prior studies and the effect of PCWP on this relationship. Re-exploration of the PVR-PAC relationship, using more accurate methods of PAC determination, is now required to understand whether this relationship is truly physiological, or simply, mathematical artefact.
Abstract 4144041: AI-Based ECG Denoising Improves Smartwatch ECG Interpretation
Authors: Shun Liao, Paolo Di Achille, Tanay Vakharia, Tony Faranesh, Jacqueline Shreibati, Ming-Zher Poh
Journal: Circulation (2024)

Background/Aim: Smartwatch ECGs (SW-ECG) have emerged as a noninvasive solution to assess abnormal heart rhythms such as atrial fibrillation (AF). However, SW-ECGs recorded in free-living settings are often noisy and yield Inconclusive results from automated AF detection algorithms. We developed a deep learning model to denoise single-lead ECGs and reduce the number of inconclusive tracings that require manual overread. Methods: Using the MIMIC-III waveform database (N=2,988 patients, 10.1% AF), we created pairs of clean (high signal quality index based on dynamic beat template matching) 30-sec, single-lead ECGs and their noisy counterparts by injecting various combinations of noise including baseline wander, electrode motion and synthetic noise of different colors. The noisy ECGs served as the input to a 1D U-Net that was trained to reconstruct the corresponding clean ECG (AI-ECG-Denoise). We evaluated the performance of an offline automated ECG classifier before and after applying AI-ECG-Denoise on a held-out test set from MIMIC-III (N=34 patients, 52.9% AF) comprising 1,000 single-lead ECGs that we injected with noise at different signal-to-noise ratios (SNRs), and an external test set of 701 free-living SW-ECGs from 115 healthy consented study subjects using a prototype watch. Results: In the MIMIC-III test set, AI-ECG-Denoise significantly reduced the number of Inconclusive ECG results across noisy ECGs with SNRs ranging from -10 to 30 dB with no significant difference in sensitivity and specificity for AF down to an SNR of 3 dB. In the external wrist-worn test set, AI-ECG-Denoise significantly reduced the number of Inconclusive free-living SW-ECG Interpretations (p&lt;0.001) by 33.3% [95% CI: 25.1, 39.9], recategorizing the majority as Normal, with no significant difference in specificity per McNemar’s test (99.2% [98.4, 99.8] before and 98.8% [97.8, 99.6] after denoising). Conclusion: A deep learning model for ECG denoising decreased the number of Inconclusive results in the detection of AF from SW-ECGs. This could help reduce user anxiety and limit the overreading time spent by the physicians.
Abstract 4144096: Outcomes of Left Atrial Appendage Occlusion in Patients with Atrial Fibrillation and Gastrointestinal Bleeding: Insights from a Multicenter Registry
Authors: Muhammad Talha Ayub, Stefan Preisendorfer, Dan Wann, Ato Howard, Floyd Thoma, Jianhui Zhu, Aakash Sheth, George Jabbour, Madhurmeet Singh, chinmay patel, Hemal Gada, Aditya Bhonsale, Nathan Estes, Krishna Kancharla, Alaa Shalaby, Virginia Singla, Aditi Naniwadekar, Andrew Voigt, Samir Saba, Sandeep Jain
Journal: Circulation (2024)

Background: The patient population undergoing left atrial appendage occlusion (LAAO) in the US is older and at a higher bleeding and thromboembolic risk than that enrolled in the initial trials that led to FDA approval. Real world outcomes in this population have implications for the use of LAAO. Goals: We sought to compare clinical outcomes of LAAO in patients with atrial fibrillation (AF) with prior major gastrointestinal (GI) bleeding to continued oral anticoagulation (OAC). Methods: Using data from a large US hospital system, patients with AF who underwent LAAO from 01/2016 to 11/2022 with a history of at least one major (requiring admission or transfusion) GI bleed event (LAAO group) were identified and compared to a control group with prior GI bleed with continued OAC. Controls were selected in a 1:2 fashion using propensity score matching based on 17 variables. Hospital admissions for major bleeding, ischemic stroke or transient ischemic attack (TIA) as well as survival were tracked during follow-up. Results: Patients in the LAAO group (n=642, age 76.5±8.2 years, 47.8% female) had higher CHA 2 D 2 -VASc (4.3±1.7 vs. 4.1±1.6, p=0.003) and lower HAS-BLED (3±0.9 vs. 3.3±0.9, p&lt;0.001) scores than the control group (n=1273, age 76.3±10.1 years, 47.8% female) but were otherwise comparable. At baseline, a higher proportion of patients in the LAAO group was on a direct oral anticoagulant (59.7% vs. 44.9%, p&lt;0.001), while fewer patients were on warfarin (15.9% vs. 53.3%, p&lt;0.001). Over a median follow-up of 2.95 (1.53-4.89) years, patients in the LAAO group had lower rates of a major bleeding event (97.8 vs. 140 events per 1,000 person-years, p&lt;0.001) as compared to the control group. Similarly, fewer patients in the LAAO group were admitted for ischemic stroke or TIA (15.4 vs. 26.1 events per 1,000 person-years, p=0.016) when compared to the control group. Finally, survival rates in the LAAO group were improved as compared with the control group (89.4 vs. 119.9 events per 1,000 person-years, p&lt;0.001), Figure 1. Conclusions: In patients with prior major GI bleeding, LAAO is associated with superior clinical outcomes with lower bleeding and stroke rates when compared to OAC.
Abstract 4143504: Genetically Prolonged Beige Fat In Male Mice Confers Long-lasting Metabolic Health
Authors: YANYU QIAN, Ruifan Wu, Jooman Park, Yuwei Jiang
Journal: Circulation (2024)

Background: Beige adipocytes, express UCP1 and have thermogenic capability, making them a promising target for obesity treatments. However, beige adipocytes quickly transition into white adipocytes upon removal of stimuli. Our research identifies the cyclin-dependent kinase inhibitor 2A ( Cdkn2a ) as a crucial regulator of this transition. Ablation of Cdkn2a prolongs beige adipocyte lifespan, enhances energy expenditure, and improves glucose tolerance by inhibiting BECN1-mediated autophagy. These findings offer a potential therapeutic strategy to maintain beige adipocytes and combat obesity and related diseases. Methods: We used Ucp1-Cre ERT2 mice with a Rosa26R RFP indelible labeling reporter and Cdkn2a floxed mice. All mice were maintained on a mixed C57BL6/J-129SV background. To induce Cre recombination, mice received tamoxifen for 2 days. For in vitro induction, cells were treated with 2 µM 4-hydroxy-tamoxifen. In our in vitro study, we isolated stromal vascular fraction (SVF) cells from the inguinal white adipose tissue (IGW) or brown adipose tissue (BAT) of 6-week-old male mice for seeding. For the in vivo study, we used cold exposure, metabolic cages, and glucose tolerance tests. Results: Cdkn2a plays a pivotal role in the beige-to-white transition. Its absence prolongs the lifespan of beige adipocytes and in male mice, confers long-term metabolic protection against diet-induced obesity, along with enhanced energy expenditure and improved glucose tolerance. Mechanistically, Cdkn2a promotes the expression and activity of beclin 1 (BECN1) by directly binding to its mRNA and its negative regulator BCL2 like 1 (BCL2L1), activating autophagy and accelerating the beige-to-white transition. Reactivating autophagy by pharmacological or genetic methods abolishes beige adipocyte maintenance induced by Cdkn2a ablation. Furthermore, hyperactive BECN1 alone accelerates the beige-to-white transition in mice and human. Hence, blocking Cdkn2a -mediated BECN1 activity holds therapeutic potential in treating obesity and related metabolic diseases. Conclusion: Cdkn2a depletion extends beige adipocyte lifespan, providing long-term metabolic benefits against diet-induced obesity in male mice. Cdkn2a boosts BECN1 expression, triggering the beige-to-white transition by directly interacting with BECN1 mRNA and its negative regulator BCL2L1, activating autophagy. Targeting Cdkn2a -mediated BECN1 activity holds promise as a therapeutic approach for treating obesity.
Abstract 4143804: Factors Associated With Increased Inpatient Mortality Risk In End Stage Heart Failure Patients That May Help Providers To Identify triggers For Palliative Care Consultation
Authors: Juan Cedeno, Galen Ogg, Akhil Chandra, Matthew Atienza, Vidish Pandya, Paul Ippolito, Patricia Chavez, Serife Eti
Journal: Circulation (2024)

Introduction: Palliative care interventions for patients with heart failure have been shown to significantly improve quality of life, reduce symptom burden, and enhance functional status. Timing of referral becomes challenging as disease progresses and readmission rates increase. We studied factors associated with inpatient mortality in patients with end stage heart failure, ineligible for additional advanced therapies. Methods: Individuals with acute decompensated heart failure admitted between 2021-2023, who were ineligible for further advanced cardiac therapies and referred to palliative care, were included to this retrospective study. Data on demographic variables, clinical parameters (NYHA classification, Karnofsky Performance Scale (KPS) scores, comorbidities, type of heart disease, BNP, albumin, creatinine levels), and palliative care interventions (symptom burden assessments, family meetings, and advanced care planning (ACP) discussions) were collected. We conducted bivariate and multivariate analyses using Kruskal-Wallis and chi-square tests, and adjusted regression models to compare characteristics between individuals who died while admitted and survivors. Results: A total of 97 individuals were included in the study, with a mean age of 68 ± 17.7 years, 33.0%(n=32) of whom were female. Patients who died during admission had significantly higher rate of established ACP following palliative care consult (p&lt; 0.01) and had a shorter time from consultation to discharge and were more likely to be declared DNR/DNI during admission. Hospital length of stay was shorter for patients who died in the hospital Lower KPS scores, with KPS scores &lt;40 associated with increased hospital mortality (OR = 3.6 [CI 1.16–10.57], p &lt; 0.01). Albumin levels were lower in this group, and levels &lt;2.5 g/dL were associated with increased mortality (OR = 3.2 [CI 1.4–9.3], p &lt; 0.01). Conclusions: individuals with end-stage heart failure who have lower KPS scores, and reduced albumin levels may face a higher risk of in-hospital mortality and rapid disease progression. Identifying triggers such as severe symptom burden, complex decision-making needs, and functional decline can ensure timely and appropriate palliative care referrals.