tbuckley/cabot-search huggingface dataset:
Abstract 13111: Circulating Extracellular Microvesicles: Mediators of Altitude-Related Vascular Inflammation
Authors: Madden Brewster, Anthony R Bain, Vinicius P Pacheco Garcia, Noah M DeSouza, Michael Tymko, Philip N Ainslie, Christopher Desouza
Journal: Circulation (2021)

Ascent to high altitude can adversely affect cardio- and cerebrovascular health, particularly in those with pre-existing disease. Pathologic vascular responses to acute and subacute high altitude exposure include, endothelial dysfunction, cerebral and pulmonary edema as well as pulmonary hypertension. Changes in vascular endothelial cell function, most notably the induction of a proinflammatory endothelial phenotype, is thought to be an underlying factor. Endothelial inflammation can induce cerebral edema in stroke and promote pulmonary edema. The mechanisms underlying high-altitude related vascular inflammation remain unclear. The vascular endothelium is significantly influenced by circulating cell-derived microvesicles (MVs). MVs are small (100-1000 nm) membrane vesicles that are released by various cell types (e.g. endothelial, platelets, leukocytes) in response to a myriad of physiologic and pathologic stimuli including hypoxia. Circulating MVs have emerged as biomarkers and mediators of endothelial inflammation. We tested the hypothesis that ascent to high altitude induces a proinflammatory circulating MV phenotype. Ten healthy adults (8 M/2 F; age: 28 + 2 yr ) residing at sea level (Kelowna, BC, Canada) were studied prior to and 4-6 days after ascending to high altitude (Cerro de Pasco, Peru; 4300 m). Circulating MVs were isolated, enumerated and collected from plasma by flow cytometry. Human umbilical vein endothelial cells were cultured and treated with MVs collected from each subject at sea level and altitude. Circulating MVs were significantly higher at altitude vs sea level (26637 + 3315 vs19388 + 1699 MV/μL). Altitude-related MVs induced higher (~25%; P&lt;0.05) release of interleukin (IL)-6 (63.9±3.9 vs 53.3±3.6 pg/mL) and IL-8 (140.2±3.6 vs 120.7±3.8 pg/mL) compared with MVs harvested at sea level. Although intracellular expression of total NF-κB p65 (83.4 + 6.7 vs 90.2 + 6.9 AU) was not significantly affected, high altitude-MVs resulted in ~55% higher (P&lt;0.05) cell expression of p-NF-κB p65 (active NF-κB: 129.6 + 19.8 vs 90.7 + 10.5 AU) than sea level-MVs. Circulating extracellular MVs increase at high altitude and induce endothelial inflammation, potentially contributing to altitude-related vascular pathologies.
Abstract 12646: Cryoablation vs. Radiofrequency Ablation in Persistent AFib: An Updated Meta-Analysis
Authors: Senthil S Balasubramanian, sisir siddamsetti, SANDEEP GAUTAM
Journal: Circulation (2021)

Introduction: Catheter ablation is recommended for drug-refractory atrial fibrillation (AF). Cryoablation (CBA) has shown to be equivalent to radiofrequency ablation (RFA) in paroxysmal AF. However, there is a paucity of evidence regarding the efficacy and safety of CBA compared to RFA in persistent AF. An updated meta-analysis was conducted comparing CBA to RFA in persistent AF. Methods: A systematic literature review was performed in Embase, PubMed and SCOPUS for all the related articles until May 2021 yielding 112 publications. Eight studies fulfilled inclusion criteria including 1 randomized clinical trial and 7 observational studies. The Mantel- Haenszel random-effects model was used to calculate odds ratio (OR) and 95% confidence intervals (CI). Outcomes analyzed were rate of freedom from atrial arrhythmias, conversion to sinus rhythm during ablation, need for repeat ablation, total complications, vascular injury, phrenic nerve palsy, and cardiac tamponade. Results: CBA was performed in 500 patients and RFA was performed in 533 patients. There was no difference in the rate of freedom from atrial arrhythmias (OR = 1.12, 95% CI [0.87-1.46], P=0.38), need for repeat ablation (OR = 0.73, 95% CI [0.44-1.23], P=0.24), total complications (OR = 1.00, 95% CI [0.56-1.76], P=0.99), vascular injury (OR = 1.06, 95% CI [0.45-2.50], P=0.89), phrenic nerve palsy (OR = 3.09, 95% CI [0.86-11.11], P=0.08) and cardiac tamponade (OR = 0.43, 95% CI [0.11-1.77], P=0.24). The rate of conversion to sinus rhythm during ablation was higher in the CBA arm (OR = 2.33, 95% CI [1.41-3.87], P=0.001). Conclusions: Cryoablation is a safe and effective alternative to RFA in patients with persistent AF.
Abstract 11998: The microRNA-378 and Estrogen-Related Receptor Gamma Axis Regulates Metabolic Inflammation and Lipoprotein Metabolism: A Potential Therapeutic Target for Atherosclerosis
Authors: Qiaozhu Su, Szczepan Kaluzny
Journal: Circulation (2021)

MicroRNAs (miRNAs) are non-coding small RNAs that interact with their targeted mRNAs, resulting in decay or translational repression of the targeted mRNAs. The estrogen-related receptor (ERR)γ is an orphan nuclear hormone receptor. MiRNAs and ERRγ play pivotal roles in the pathophysiological conditions of metabolic diseases. The objective of this study is to determine the impact of miR-378a and its targeted gene ERRγ in metabolic inflammation and HDL metabolism, and explore the therapeutic potential of antigomic miRNA in atherosclerosis. Bioinformatics analysis of hepatic miRNA sequencing profile from mice fed a lipogenic diet (high-fructose) revealed that miR-378a was upregulated and served as a hub in a regulatory network that collaboratively targets multiple metabolic signal molecules in energy metabolism, mitochondrial fatty acid β-oxidation (FAO), and lipoprotein metabolism. Specifically, the upregulated miR-378a induced by fructose suppressed expression of ERRγ and genes involved in FAO (e.g., PPARα, CPT1α and ACOX1). In contrast, genetic depletion of miR-378a (miR-378aKO) significantly enhanced ERRγ expression, ameliorated mitochondrial oxidative stress and metabolic inflammation. Furthermore, miR-378aKO markedly stimulated expression of genes involved in HDL metabolism, including LXRα, ABCA1 and aopA4, leading to the increase of HDL-cholesterol and decrease of LDL-cholesterol in blood circulation. An in vivo VLDL secretion assay further revealed that miR-378aKO inhibited biogenesis and secretion of VLDL from the KO mouse liver, suggesting an improvement of atherogenic status in the absence of miR-378a. More importantly, treated the fructose-fed mice with nanoparticles carrying antagomir against miR-378a successfully reduced hepatic miR-378a expression, which was associated with significant restoration of ERRγ signaling and the associated mitochondrial FAO and HDL metabolism, indicated by the increased gene expression of PPARα, CPT1α and ACOX-1 as well as LXRα and apoA4, in the treated mice. Conclusion: These data indicate that manipulating miR-378a level can restore ERRγ signaling, improve FAO and lipoprotein metabolism. This novel finding may lend support to the therapeutic strategy of atherosclerosis.
Importance of the second SARS-CoV-2 vaccination dose for achieving serological response in patients with rheumatoid arthritis and seronegative spondyloarthritis
Authors: Elisabeth Simader, Selma Tobudic, Peter Mandl, Helmuth Haslacher, Thomas Perkmann, Thomas Nothnagl, Judith Sautner, Helga Radner, Florian Winkler, Heinz Burgmann, Daniel Mrak, Daniel Aletaha, Stefan Winkler, Stephan Blüml
Journal: Annals of the Rheumatic Diseases (2021)

To assess the kinetics of humoral response after the first and second dose of messenger RNA (mRNA) vaccines in patients with inflammatory joint diseases compared with healthy controls (HC). To analyse factors influencing the quantity of the immune response.We enrolled patients with rheumatoid arthritis (RA) and seronegative spondyloarthritis (SpA), excluding those receiving B-cell depleting therapies and assessed the humoral response to mRNA vaccines after the first and the second dose of the vaccine in terms of seroconversion rate and titre. We compared the results to a HC group and analysed the influence of therapies as well as other characteristics on the humoral response.Samples from 53 patients with RA, 46 patients with SpA and 169 healthy participants were analysed. Seroconversion rates after the first immunisation were only 54% in patients with inflammatory arthritis compared with 98% in the HC group. However, seroconversion rates were 100% in all groups after second immunisation. Patients developed reduced antibody titres after the first vaccination compared with HC, but there was no difference after the second dose. While disease modifying anti-rheumatic drug (DMARD) monotherapy did not affect antibody levels, seroconversion rates as well as titre levels were reduced in patients receiving a combination of DMARDs compared with HC.Patients with inflammatory joint diseases under DMARD therapy show impaired humoral responses to the first vaccine dose but excellent final responses to vaccination with mRNA vaccines. Therefore, the full course of two immunisations is necessary for efficient vaccination responses in patients with inflammatory arthritis under DMARD therapy.
Abstract 11692: High-Sensitivity Cardiac Troponin and the Efficacy of Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: An Analysis of the DAPA-HF Trial
Authors: David D Berg, Marc S Sabatine, Naveed Sattar, Petr Jarolim, Paul WELSH, Pardeep S Jhund, Inder Anand, Rudolf A De Boer, Mikhail Kosiborod, Eileen O'Meara, Ann Hammarstedt, Anna Maria Langkilde, Daniel Lindholm, Mikaela Sjöstrand, John J McMurray, David Morrow
Journal: Circulation (2021)

Introduction: Circulating high-sensitivity cardiac troponin T (hsTnT) reflects myocardial injury, and higher levels are associated with an increased risk of worsening heart failure (HF) and death in patients with HF with reduced ejection fraction (HFrEF). Dapagliflozin reduces the rate of worsening HF or cardiovascular death in patients with HFrEF. The effect of dapagliflozin on the risk of worsening HF or CV death in relation to baseline concentration of hsTnT in patients with HFrEF is unknown. Methods: DAPA-HF was a randomized, double-blind, placebo-controlled trial of dapagliflozin (10 mg once daily) in patients with New York Heart Association class II, III, or IV HF and a left ventricular ejection fraction ≤40%. We measured hsTnT (Roche Diagnostics) at baseline in 3,138 patients randomized in DAPA-HF and at one year among 2,500 survivors. The primary outcome was adjudicated worsening HF or cardiovascular death. Secondary outcomes included each component individually, hospitalization for HF, and death from any cause. The median follow-up was 18.2 months. Results: By the time of this presentation, data will be available for presentation of the distribution of baseline hsTnT concentration and the clinical characteristics associated with strata of hsTnT concentration. The association between baseline hsTnT and 2-year outcomes will be presented and adjusted for potential confounders, including age, sex, eGFR, history of diabetes mellitus, and principal cause of HF (ischemic or non-ischemic). The effect of dapagliflozin on the change in hsTnT concentration from baseline to one year will be presented. The effect of dapagliflozin on the primary and secondary outcomes (both absolute and relative risk reductions) stratified by baseline hsTnT concentration will be analyzed. Conclusions: Biomarkers of myocardial injury identify patients with HFrEF at heightened risk of adverse outcomes. This analysis from a large, international, randomized, placebo-controlled trial will provide a robust assessment of the effect of dapagliflozin on hsTnT and the ability of dapagliflozin to improve outcomes in relation to baseline hsTnT concentration.
Abstract 12357: Discordant Mechanisms in Hypertrophy and Heart Failure
Authors: Aleksandra Binek, Justyna P Fert-bober, Simion Kreimer, Alejandro Rivas, Amy Bradshaw, Michael R Zile, Jennifer E Van Eyk
Journal: Circulation (2021)

Introduction: Patients with heart failure and a preserved ejection fraction (HFpEF) present heart function abnormalities that remain poorly understood. Defining proteomic signature of HF that is independent of left ventricular hypertrophy (LVH) should allow for stratification of its subtypes and potential mechanism that contributes to the disease. Hypothesis: We hypothesized that HFpEF proteomic signature would be comprised of the hypertrophy and contractile protein phenotype. Methods: Intraoperative left ventricular (LV) myocardial biopsies were obtained from patients (n=21) recruited to undergo coronary artery bypass grafting (CABG). Patients were categorized to: control non-hypertensive (n=9), LVH (n=5), and HFpEF (n=7). Myocardial tissue was subfractionated: cytoplasmic- (neutral pH), myofilament- (acidic pH), and membrane-enriched extract (SDS-soluble). Samples were assessed for protein quantity and Lys/Arg modifications using liquid chromatography mass spectrometry (LC-MS). Results: In HFpEF, 13% of the cardiac LV proteome changed compared to control heart, with a substantial proportion (77%) decreasing in quantity across all three cardiac fractions, while with LVH, 61% of the proteomic LV changes were increased. Although glycolysis and gluconeogenesis increased in both cardiopathies with respect to control, in HFpEF more subtly than in LVH. Modified proteome of the HFpEF was dominated by decreases in protein succinylation (e.g. ATP5L, THIM, IDHP, APOB, GSH1, KNTC1) and to a lesser degree in methylation (ROA3, HSP7C) or acetylation compared to control group. This general trend of down-regulation of succinylation can be attributed to depletion in the levels of succinyl-CoA, the cofactor of enzymatic Lys succinylation. Importantly, there was a striking discordant activation/inhibition of cell death and proliferation pathways between the HFpEF and LVH. Two major upstream regulator clusters linked the proteome changes in cell growth and proliferation to RICTOR and Myc that showed completely opposite trends in LVH and HFpEF groups. Conclusions: HFpEF has a unique proteome signature compared to LV hypertrophy profile which does not arise from sub-proteome involved in contraction but rather is involved in overall cell death.
Abstract 13171: The Role of Novel Brugada Syndrome Gene MAPRE2 in Maintaining Normal Cardiac Electrophysiology
Authors: David Y Chiang, Arie Verkerk, Babet van der Vaart, Nakul Narendran, Rachelle Victorio, Ashmita Kc, Jianing Wang, James Sampognaro, Eva P Buys, Tuomas O Kiviniemi, Anna Akhmanova, Connie R Bezzina, Calum Macrae
Journal: Circulation (2021)

Introduction: Brugada syndrome (BrS) is a significant cause of sudden cardiac death yet only ~20% of patients are found with a loss-of-function variant in SCN5A encoding the cardiac Na+ channel, le...
Abstract 11007: Prolonged QTc in Black and Latinx Cisgender and Transgender Women Who Are Living with Human Immunodeficiency Virus
Authors: Boniface Malangu, Sarah Bentil-Owusu, Arun Mattappallil, Joachim Sackey, Diana Finkel
Journal: Circulation (2021)

Background: QT prolongation can predispose to torsade de pointes, which occurs at higher rates in people living with HIV (PLWH). Increased prevalence of prolonged corrected QT interval (QTc) has been reported in PLWH, suggesting that it may play a role in the increased risk for sudden cardiac death in this patient population. However, gaps in research due to limited participation of gender, racial and ethnic minorities continue to limit the interpretation of these findings. Our study assessed the hypothesis that Black and Latinx cis and transgender women living with HIV (WLWH) would have greater odds of having prolonged QTc. Methods: A cross-sectional study was conducted by retrospectively reviewing electronic medical records to investigate the duration of the QTc interval between 2 groups, 137 WLWH versus 135 women who are not living with HIV. Associations between long QTc interval and ethnicity, smoking, alcohol use, BMI, medications (methadone, antibiotics, antiretroviral therapy, and psychiatric drugs), CD4 count, hepatitis C, and heart failure were also assessed. QTc &gt;460 milliseconds was considered prolonged. Results: In the univariate logistic regression, living with HIV had significantly higher odds of having prolonged QTc than the control group (odds ratio [OR] 1.842, 95% confidence interval [CI] 1.062-3.195, p=0.0298). After adjusting for the covariates selected a priori, living with HIV was associated with even higher odds of having prolonged QTc (OR 2.128, 95% CI 1.115-4.061, p=0.023). Having heart failure was also independently associated with higher odds of having prolonged QTc (OR 3.883, 95% CI 1.672-9.018, p=0.0016) even after adjusting for other covariates (OR 2.973, 95% CI 1.605-9.836, p=0.0029). Ethnicity, smoking, alcohol use, BMI, medications, CD4 count, and hepatitis C were not significantly associated with higher odds of having prolonged QTc. Conclusions: This study showed that in cis and transgender women of color, living with HIV and heart failure were both associated with higher odds of having prolonged QTc. In this patient population, implementing routine EKG screening should be considered by clinicians as a strategy, among others, to prevent cardiac rhythm disturbances and cardiovascular morbidity and mortality.
Abstract 13942: Racial Differences in 24-hour Urinary Sodium, Potassium, and Albumin: A Surrogate of Poor Cardiovascular Health Among American Adults
Authors: Vibhu Parcha, Nirav Patel, Brittain F Heindl, Rajat Kalra, Ishant Yadav, Orlando M Gutierrez, Garima Arora, Pankaj Arora
Journal: Circulation (2021)

Introduction: Higher urinary excretion of sodium and albumin, and lower urinary excretion of potassium, is associated with adverse cardiovascular (CV) events. The differences in 24h urinary sodium, potassium, and albumin between non-Hispanic Black (NHB) and NH White (NHW) individuals and their association with AHA Life Simple 7 metrics of ideal CV health (CVH) is unknown. Methods: We evaluated the 2014 National Health and Nutrition Survey restricted data to determine the 1) 24h urinary measures (sodium, potassium, and albumin) excretion in NHB and NHW participants, 2) association of urinary measures with ideal CVH and 3) their relative contribution to ideal CVH differences between racial groups. Multivariable-adjusted logistic regression analysis was performed to assess the association of 24h urinary measures with ideal CVH. Mediation analysis was used to determine the effect of 24h urinary measures on observed racial differences in ideal CVH. Results: Among 429 participants (mean age: 42.6 years, 61% NHB), the 24h urinary sodium, potassium, and albumin excretion were 256.7 (95% CI: 221.4-292.0) mg/dL, 134.8 (113.5-156.1) mg/dL, and 20.9 (3.5-38.3) mg/dL, respectively, in NHB individuals. In NHW individuals, the 24-hour urinary sodium, potassium, and albumin excretion were 209.4 (189.4-229.4) mg/dL, 135.0 (124.3-145.7) mg/dL, 22.9 (2.48-48.3) mg/dL, respectively. NHB individuals had lower odds of having ideal CVH (0.35 [0.21-0.60]). Higher 24h urinary sodium excretion was the only urinary measure associated with lower odds of ideal CVH (0.99 [0.99-1.00]; p=0.027). There was no interaction by race for the association of 24-hour urinary measures with ideal CVH. 24h urinary sodium mediated 25.5% (14.8-74.0%) of the association between race and ideal CVH. Conclusions: We present the race-stratified normative data for 24h urinary measures among American adults without CV disease and highlight the association of 24h urinary sodium with ideal CVH.
The Factor II (FII) Expression Quantitative Trait Locus (eQTL) Prothrombin G20210A Is Pleiotropically Associated with Plasma Fibrinogen Levels and Has a Profound Effect on Obesity in Mexican Americans of South Texas
Authors: Hoang Anh Thi Nguyen, Vincent P. Diego, Shuchita Jhaveri, Marcio A. Almeida, Satish Kumar, Juan M Peralta, Joanne E. Curran, Bernadette W. Luu, Donna M. Lehman, Ralph A DeFronzo, Miguel A. Escobar, Sarah Williams-Blangero, Ravi Duggirala, Jerry S. Powell, Laura Almasy, John Blangero, Tom E. Howard
Journal: Blood (2021)
Epitope spreading driven by the joint action of CART cells and pharmacological STING stimulation counteracts tumor escape via antigen-loss variants
Authors: Enrique Conde, Enric Vercher, Marta Soria-Castellano, Jesús Suarez-Olmos, Uxua Mancheño, Edurne Elizalde, M Luis Rodriguez, Javier Glez-Vaz, Noelia Casares, Estefanía Rodríguez-García, Mirja Hommel, Gloria González-Aseguinolaza, Iratxe Uranga-Murillo, Julian Pardo, Gorka Alkorta, Ignacio Melero, Juan Lasarte, Sandra Hervas-Stubbs
Journal: Journal for ImmunoTherapy of Cancer (2021)

Target antigen (Ag) loss has emerged as a major cause of relapse after chimeric antigen receptor T (CART)-cell therapy. We reasoned that the combination of CART cells, with the consequent tumor debulking and release of Ags, together with an immunomodulatory agent, such as the stimulator of interferon gene ligand (STING-L) 2'3'-cyclic GMP-AMP (2'3'-cGAMP), may facilitate the activation of an endogenous response to secondary tumor Ags able to counteract this tumor escape mechanism.Mice bearing B16-derived tumors expressing prostate-specific membrane Ag or gp75 were treated systemically with cognate CART cells followed by intratumoral injections of 2'3'-cGAMP. We studied the target Ag inmunoediting by CART cells and the effect of the CART/STING-L combination on the control of STING-L-treated and STING-L-non-treated tumors and on the endogenous antitumor T-cell response. The role of Batf3-dependent dendritic cells (DCs), stimulator of interferon gene (STING) signaling and perforin (Perf)-mediated killing in the efficacy of the combination were analyzed.Using an immune-competent solid tumor model, we showed that CART cells led to the emergence of tumor cells that lose the target Ag, recreating the cancer immunoediting effect of CART-cell therapy. In this setting, the CART/STING-L combination, but not the monotherapy with CART cells or STING-L, restrained tumor progression and enhanced overall survival, showing abscopal effects on distal STING-L-non-treated tumors. Interestingly, a secondary immune response against non-chimeric antigen receptor-targeted Ags (epitope spreading), as determined by major histocompatibility complex-I-tetramer staining, was fostered and its intensity correlated with the efficacy of the combination. This was consistent with the oligoclonal expansion of host T cells, as revealed by in-depth T-cell receptor repertoire analysis. Moreover, only in the combination group did the activation of endogenous T cells translate into a systemic antitumor response. Importantly, the epitope spreading and the antitumor effects of the combination were fully dependent on host STING signaling and Batf3-dependent DCs, and were partially dependent on Perf release by CART cells. Interestingly, the efficacy of the CART/STING-L treatment also depended on STING signaling in CART cells.Our data show that 2'3'-cGAMP is a suitable adjuvant to combine with CART-cell therapy, allowing the induction of an endogenous T-cell response that prevents the outgrowth of Ag-loss tumor variants.
Assessment of TRM-201 (Rofecoxib) Efficacy and Safety for Chronic Pain in Hemophilic Arthropathy: The Rofecoxib Efficacy and Safety Evaluation Trial in Hemophilic Arthropathy (RESET-HA), a Randomized, Double-Blind Placebo-Controlled Phase III Clinical Trial
Authors: Judith A. Boice, Tyler W. Buckner, Stacy E. Croteau, Nathaniel Katz, Robert F. Sidonio, Kim Mauer, James Bolognese, Mary Garfield, Mark Corrigon, Christopher E Walsh
Journal: Blood (2021)