tbuckley/cabot-search huggingface dataset:
Transcriptome analysis of IPF fibroblastic foci identifies key pathways involved in fibrogenesis
Authors: Delphine Guillotin, Adam R Taylor, Manuela Platé, Paul F Mercer, Lindsay M Edwards, Ross Haggart, Gino Miele, Robin J McAnulty, Toby M Maher, Robert E Hynds, Mariam Jamal-Hanjani, Richard P Marshall, Andrew J Fisher, Andy D Blanchard, Rachel C Chambers
Journal: Thorax (2020)

Introduction Fibroblastic foci represent the cardinal pathogenic lesion in idiopathic pulmonary fibrosis (IPF) and comprise activated fibroblasts and myofibroblasts, the key effector cells responsible for dysregulated extracellular matrix deposition in multiple fibrotic conditions. The aim of this study was to define the major transcriptional programmes involved in fibrogenesis in IPF by profiling unmanipulated myofibroblasts within fibrotic foci in situ by laser capture microdissection. Methods The challenges associated with deriving gene calls from low amounts of RNA and the absence of a meaningful comparator cell type were overcome by adopting novel data mining strategies and by using weighted gene co-expression network analysis (WGCNA), as well as an eigengene -based approach to identify transcriptional signatures, which correlate with fibrillar collagen gene expression. Results WGCNA identified prominent clusters of genes associated with cell cycle, inflammation/differentiation, translation and cytoskeleton/cell adhesion. Collagen eigengene analysis revealed that transforming growth factor β1 (TGF-β1), RhoA kinase and the TSC2/RHEB axis formed major signalling clusters associated with collagen gene expression. Functional studies using CRISPR-Cas9 gene-edited cells demonstrated a key role for the TSC2/RHEB axis in regulating TGF-β1-induced mechanistic target of rapamycin complex 1 activation and collagen I deposition in mesenchymal cells reflecting IPF and other disease settings, including cancer-associated fibroblasts. Conclusion These data provide strong support for the human tissue-based and bioinformatics approaches adopted to identify critical transcriptional nodes associated with the key pathogenic cell responsible for fibrogenesis in situ and further identify the TSC2/RHEB axis as a potential novel target for interfering with excessive matrix deposition in IPF and other fibrotic conditions.
Abstract IA-06: Heterotypic 3D bioprinted tissues to study pancreatic cancer
Authors: Ellen M Langer, Brittany L Allen-Petersen, Isabel A English, Jason M Link, Rosalie C Sears
Journal: Cancer Research (2020)

Abstract Crosstalk between tumor cells and the tumor microenvironment contributes critically to tumor initiation, tumor progression, and therapeutic response. The tumor microenvironment (TME) is composed of multiple cell types (e.g. fibroblast, vascular, and immune cells) that are temporally and spatially dynamic. Stromal cells in the TME respond not only to the growing tumor cells, but are also affected by concurrent changes in the accessibility and composition of the extracellular matrix (ECM), signaling molecules, nutrients and oxygen. Together, the interactions of tumor cells and stromal cells regulates the tumor phenotype and, ultimately, affects patient outcomes. As more is understood about the dynamic relationship of multiple cell types in the tumor microenvironment, it has become clear that better models of human cancer are needed. In order to understand the impact of heterotypic crosstalk on tumor behaviors such as initiation, progression, and response to therapies, we recently developed heterotypic, scaffold-free tissue models of advanced cancer using an extrusion-based bioprinter system. Multiple cell types including cancer cells, fibroblasts, endothelial cells, mesenchymal stem cells, and immune cells can be incorporated into bioprinted tissues with defined spatial architecture, and the system is compatible with patient-derived cells. Within these structures, cells exhibit a tissue-like cellular density, deposit ECM, and self-organize to form complex structures, as illustrated by formation of nascent endothelial networks. Cell intrinsic, extrinsic, and spatial phenotypes, including cell survival, cell proliferation, differentiation state, ECM deposition, and cellular migration, can be assessed within these tissues following exposure to extrinsic signals or therapies. Our current work is focused in three main areas. First, we aim to understand the signaling between tumor and stromal cell types in early cancer development that contributes to malignant progression. Second, we are working to understand the influence of fibroblast heterogeneity on tumor cell phenotypes, using genetic or non-genetic perturbagens to alter fibroblast activation. Finally, we are building tissues comprising patient-derived cells to understand how the microenvironment influences therapeutic response. Together, our work demonstrates that bioprinted tumor tissues recapitulate many aspects of in vivo neoplastic tissues, and provides a manipulable model system to interrogate molecular mechanisms of tumor development, progression, and treatment response. Citation Format: Ellen M Langer, Brittany L Allen-Petersen, Isabel A English, Jason M Link, Rosalie C Sears. Heterotypic 3D bioprinted tissues to study pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-06.
Abstract 12789: Clinical Factors Associated With Mortality Among Patients Hospitalized for Heart Failure in Egypt
Authors: Ahmed Hassanin, Mahmoud M Hassanein, Madiha F Abdel-maksoud
Journal: Circulation (2020)

Introduction: Heart failure (HF) is a growing public health burden in many low and middle-income countries (LMIC). However, most HF registries were conducted in high income countries, which often have different ethnic and cultural backgrounds from that of LMIC. Hypothesis: Independent clinical variables associated with mortality in patients hospitalized for HF in Egypt are different from those established in the United States (US). Methods: Between 2011 and 2014, 1,660 patients hospitalized for HF were enrolled from 20 centers across Egypt as part of the European Society of Cardiology HF long-term Registry. Deceased patients were compared to survivors, to identify demographic, clinical and biochemical variables associated with in-hospital and one-year mortality. Variables associated with mortality on univariate analysis, and independent variables identified in the Acute Decompensated Heart Failure National Registry (ADHERE) and in the Seattle Heart Failure Model, both based in the US, were entered into the multivariate logistic regression model. Results: In-hospital mortality was 5%. Only two independent clinical factors associated with in-hospital mortality were identified: elevated serum creatinine (sCr), OR=1.47 [95% CI: 1.23, 1.74] for every point increases above one mg/dl; and low admission systolic blood pressure (SBP), OR=1.54; [95% CI: 1.43, 1.65] for every 10 points decrease in SBP below 140 mmHg. At one-year follow up, mortality was 27%. Independent predictors of one-year mortality were: age, OR=1.47; [95% CI: 1.23,1.75] for every 10-year increase above 40; low discharge SBP, OR=1.30 [95% CI: 1.08, 1.52] for every 10 points decrease below 140 mmHg; low ejection fraction, OR=1.51 [95% CI: 0.59,0.73] for every 5 points decrease from 65%; chronic liver disease, OR=3.0 [95% CI: 1.51,5.88]; history of stroke, OR=3.2 [95% CI: 1.52,6.65]. These variables overlapped with those identified in US registries. Conclusions: Independent clinical variables associated with mortality after HF hospitalization in Egypt are similar to those reported in HF registries in the US.
Abstract 14086: Early Results of a Novel EPTFE-based Pulmonary Valved Conduit in a Pediatric Patient Population
Authors: Mark E Galantowicz, Chris Baird, Carl Backer, Pedro J Del Nido
Journal: Circulation (2020)

Introduction: This prospective, multicenter, single-arm, early feasibility study evaluates the safety and performance of an investigational ePTFE-based valve for replacement of the pulmonary valve and reconstruction of the Right Ventricular Outflow Tract. A novel polymeric pulmonary valved conduit, resistant to calcification and structural valve deterioration, may provide a more durable therapy option for the pediatric population by preventing loss of right ventricular function and increased freedom from valve-related reintervention and mortality. Methods: The primary endpoints at 6 months adjudicated by an independent Clinical Events Committee are valve-related mortality and device-related reintervention. The investigational device is a valved conduit comprised of ePTFE with stretch technology and a flexible tri-leaflet polymeric valve made of an advanced proprietary composite material, which can be tailored to length requirements of the anatomy. All enrolled patients met study inclusion/exclusion criteria and had a signed informed consent form. All patients had pre- and postoperative evaluation via transthoracic echocardiography (TTE). Aspirin was administered for a minimum of three months post procedure and, per institutional protocols, four patients were on temporary Coumadin. Results: Of the 17 patients enrolled from three sites, 52.9% were male. Ages ranged from 6 to 17 years (mean 11.5 ± 3.7). BSA ranged from 0.82 to 1.57 m 2 . At six months follow up, 100% of subjects successfully met the primary endpoint of freedom from valve-related mortality and device-related reintervention. No patient exhibited an RVOT gradient &gt; 20 mmHg. No patients had pulmonary regurgitation above baseline (≤ mild) observed through six months. Throughout postoperative serial TTE evaluation at discharge, 1, 3, and 6 months, no evidence of worsening valvular insufficiency was observed. No patient developed endocarditis and TTE detected no clinically significant thrombus formation. Conclusions: These preliminary data of a novel Pulmonary Valve Conduit suggest improved pulmonic and right ventricular function based on TTE measurements, no unexpected findings, no valve-related adverse events and encouraging hemodynamic performance through 6 months.
Abstract 16766: Intraprocedural Ablation and Fluid Status Management in Heart Failure Patients Undergoing Catheter Ablation for Atrial Fibrillation
Authors: Sahitya Allam, Evan Harmon, Sula Mazimba, James M Mangrum, Ilana Kutinsky, David Haines, Nishaki K Mehta
Journal: Circulation (2020)

Background: Recent randomized clinical trial data has supported catheter ablation (CA) of atrial fibrillation (AF) in patients with heart failure (HF). Ablation and fluid management strategies could impact periprocedural outcomes especially in HF patients. Methods: We conducted a single-center retrospective analysis of 200 consecutive patients with and without HF undergoing CA at a tertiary care academic center from July 2017 through June 2018. HF was defined as any EF &lt; 40%, prior inpatient admission for HF exacerbation, or ambulatory management of HF confirmed by independent chart review. Diuretic regimens were reported as furosemide equivalent. Results: Among 200 patients, 65 (32.5%) had HF and 135 (67.5%) did not. HF patients had longer mean procedure times (299.8 ± 96 min vs 268.4 ± 96 min, p = 0.03) and were more likely to require mitral isthmus (p &lt; 0.001), posterior wall isolation (p = 0.002), and cavotriscupid isthmus (p = 0.004) ablations. There were no differences between the HF vs. non-HF groups’ intraprocedural volume intake, intraprocedural volume output, net fluid status, or intraprocedural diuretic dose (Table 1). HF patients received higher doses of IV (41.5 ± 43.0 mg vs 23.6 ± 11.8 mg, p = 0.007) and PO (43.2 ± 16.7 mg vs 26.7 ± 10.0 mg, p &lt; 0.001) postprocedural diuretic. There were no differences in the rates of major in-hospital complications (Table 1). In a multivariable regression analysis adjusted for procedural covariates, there were higher proportions of posterior wall isolation (p = 0.01) as well as postprocedural PO (p = 0.01) and IV diuretic (p = 0.002) administration in the HF cohort. Conclusion: Intraprocedural volume and diuretic management was similar between HF and non-HF patients undergoing CA of AF, though HF patients tended to receive more aggressive diuresis post procedurally with no difference in complications. Table 1. Intra- and post-procedural management and outcomes in HF vs non-HF patients undergoing CA for AF
Abstract 17191: Left Atrial Volume Index and E/E’ Predict Predominance of Post-Capillary Pulmonary Hypertension With Exercise Hemodynamics
Authors: Naga Dharmavaram, Aurangzeb Baber, Sofia C Masri, Ravi Dhingra, James Runo, Naomi C Chesler, Farhan Raza
Journal: Circulation (2020)

Introduction: Post-capillary pulmonary hypertension (PH) is diagnosed with rest hemodynamics and requires management of left heart disease. However, in subclinical PH and mixed PH (mixed pre- and post-capillary), it is imperative to identify a predominant post-capillary phenotype with exercise (aka. Pulmonary venous hypertension). Hypothesis: In suspected subclinical and mixed PH, greater left atrial volume index (LAVI; &gt;35) and E/E’ (&gt;8) on echocardiogram can reliably predict a predominant post-capillary PH with exercise, assessed with invasive cardiopulmonary exercise testing (iCPET). Methods: We reviewed clinical, echocardiographic and iCPET data for 37 patients undergoing exercise right heart catheterization and then analyzed the data with receiver operator curve (ROC) and area under the curve (AUC) analysis to estimate the different echo parameters to identify post-capillary PH. Results: Within the cohort, mean age (± SD) was 63.6±11.3 years, and 19 subjects were female (51%). On ROC analysis, LAVI and E/E’ had high predictive ability to identify a pulmonary venous hypertension response with exercise (AUC=0.860, p=0.003 for LAVI, and AUC=0.788, p=0.014) with optimal cut-offs identified as: LAVI &gt;35 and E/E’ &gt;8. These variables also notably had a significant association with PCWP/CO&gt;2. To understand the hemodynamics associated with these differentiable echo features, we divided the overall cohort (n=37) into 2 groups: group 1 ( Abnormal-LA group ) =LAVI&gt;35 and/or E/E’ &gt;8, group 2 ( Normal-LA group )=LAVI≤ 34 and E/E’≤8. The LAVI in group 1 vs group 2 was: 44.3±15.2 vs 23.1±4.4 (p&lt;0.001) and E/E’ was: 15.8±9.9 vs 7.7±1.95 (p&lt;0.01). Results are summarized in Table 1. Conclusions: Among individuals with suspected PH, LAVI&gt;35 and E/E’ &gt;8 are reliable non-invasive markers to identify post-capillary PH. In a patient with a new diagnosis of PH based on screening echocardiogram, LAVI≤ 34 and E/E’≤8 may identify a patient who is likely to benefit from PH drugs.
Abstract 14114: Sodium-glucose Cotransporter-2 Inhibitors Benefit Cardiac Diastolic Function
Authors: Anantha Madgula, Kai Chen
Journal: Circulation (2020)

Introduction: Sodium-glucose Cotransporter-2 (SGLT-2) inhibitors are drugs with profound interest because of their beneficial effect on multiple organ systems, including the cardiovascular and renal systems. Their interplay with these systems could prove beneficial in managing complex conditions like heart failure with preserved ejection fraction. We sought to compare cardiac diastolic function in patients on SGLT-2 inhibitors with those on metformin. Methods: Data were collected retrospectively after approval from our institutional review board. The study group included patients on SGLT-2 inhibitors (n=75), and the control group had patients on metformin (n=82), primarily for diabetes mellitus. Patients with ejection fraction less than 50% were excluded from the study. Data collected included age, systolic blood pressure (SBP), left ventricular (LV) ejection fraction, LV and left atrial dimensions, and diastolic parameters. Mean values, along with standard deviation, were calculated. Multivariate regression analysis for diastolic function was performed while adjusting for confounders, including age, body mass index, and SBP. Results: Study group showed better diastolic function as evidenced by significantly higher e’ medial (6.8 v/s 6.16 cm/s; p = 0.03) and e’ lateral (9.8 v/s 7.9 cm/s; p=0.008) when compared to the control group. E/e’, a marker of pulmonary capillary wedge pressure, was lower in the study group (12.87 v/s 14.36; p=0.08); however, it did not reach statistical significance. LA volume index was significantly lower in the study group, suggestive of favorable hemodynamic status (26.5 v/s 29.6 mL/m 2 ; p=0.03). SBP was significantly lower in the study group (127 v/s 135 mm Hg; p=0.01). Multivariate regression model demonstrated SBP as a significant confounder that contributed to e’ (average) difference between the two groups. Conclusions: SGLT-2 inhibitors favored better diastolic measurements when compared with metformin alone. The mechanism may be attributed to its BP-lowering effect. A larger prospective study is required to determine the role of SGLT-2 inhibitors.
Abstract 13950: Predicted Heart Mass and BMI: Evaluating Undersized Heart Transplantation in Obese vs. Non-Obese Patients
Authors: Samuel T Kim, Mark R Helmers, Peter Altshuler, Amit Iyengar, Jason Han, Benjamin Smood, Edo Birati, Pavan Atluri
Journal: Circulation (2020)

Introduction: Although guidelines for heart transplant currently recommend against donors weighing ≥ 30% less than the recipient, recent studies have shown that the detriment of under-sizing may not be as severe in obese recipients. Furthermore, predicted heart mass (PHM) has been shown to be more reliable for size matching compared to metrics such as weight and body surface area. In this study, we use PHM to characterize the effects of undersized heart transplantation (UHT) in obese vs. non-obese recipients. Methods: Retrospective analysis of the UNOS database was performed for heart transplants from Jan. 1995 to Sep. 2020. Recipients were stratified by obese (BMI ≥ 30) and non-obese (30 &gt; BMI ≥ 18.5). Undersized donors were defined as PHM ≥ 20% less than recipient PHM. Obese and non-obese populations separately underwent propensity score matching, and Kaplan-Meier estimates were used to graph survival. Multivariable Cox proportional-hazards analyses were used to adjust for confounders and estimate the hazard ratio for death attributable to under-sizing. Results: Overall, 50,722 heart transplants were included in the analysis. Propensity-score matching resulted in 2,214, and 1,011 well-matched pairs, respectively, for non-obese and obese populations. UHT in non-obese recipients resulted in similar 30-day mortality (5.7% vs. 6.3%, p = 0.38), but worse 15-year survival (38% vs. 35%, P = 0.04). In contrast, obese recipients with UHT saw similar 30-day mortality (6.4% vs. 5.5%, p = 0.45) and slightly increased 15-year survival (31% vs. 35%, P = 0.04). Multivariate Cox analysis showed that UHT resulted in an adjusted hazard ratio of 1.08 (95% CI 1.01 - 1.16) in non-obese recipients, and 0.87 (95% CI 0.78 - 0.98) in obese recipients. Conclusions: Non-obese patients with UHT saw worse long-term survival, while obese patients with UHT saw slightly increased survival. These findings may warrant reevaluation of the current size criteria for obese patients awaiting a heart.
Abstract 16488: Rural-urban Disparities in Hospital Care and Mortality Among Older Adults With Acute Myocardial Infarction, Heart Failure, and Ischemic Stroke in the United States
Authors: Emefah C Loccoh, Karen E Joynt Maddox, Yun Wang, Dhruv Kazi, Robert W Yeh, Rishi Wadhera
Journal: Circulation (2020)

Introduction: Over the last decade, disparities in cardiovascular mortality have widened between rural and urban areas of the US. Our objective was to determine whether there were differences in treatment patterns and outcomes for acute cardiovascular conditions at rural and urban hospitals. Methods: We used 100% Medicare Claims to identify beneficiaries age 65 years hospitalized 1/1/2016-12/31/2017 for acute myocardial infarction (AMI), heart failure (HF), and ischemic stroke. We fit a mixed effects model with a logit link function and hospital random intercepts to evaluate condition-specific procedure rates (PCI/CABG, cerebral arteriography, systemic thrombolysis) and 30-day and 1-year mortality rates for beneficiaries admitted to rural vs. urban hospitals, adjusted for age, sex, dual enrollment, and clinical comorbidities. Results: Our study included 398,673 beneficiaries hospitalized for AMI (mean age 77.3 years), 690,218 for heart failure (80.3 years), and 378,170 for stroke (79.4 years). The proportion of AMI, HF, and stroke hospitalizations that occurred at rural hospitals was 10.7%, 14.2%, and 10.6%. Procedures were performed less frequently for beneficiaries admitted to rural compared with urban hospitals (PCI/CABG within 30 days of AMI: adjusted odds ratio [aOR] 0.50, 95% CI 0.47-0.54; cerebral arteriography [aOR 0.15, 0.11-0.22]; and systemic thrombolysis [aOR 0.47, 0.43-0.52] for stroke). Thirty-day mortality was higher at rural vs. urban hospitals for AMI (aOR 1.26, 1.21-1.31), HF (aOR 1.14, 1.11-1.17) and stroke (aOR 1.11, 1.07-1.16), as was 1-year mortality (AMI: aOR 1.31, 1.26-1.35; HF: aOR 1.10, 1.08-1.12; Stroke: aOR 1.14, 1.10-1.17). Conclusion: Older adults admitted to rural hospitals for acute cardiovascular conditions receive lower intensity care and experience higher mortality rates than those admitted to urban hospitals. Policy initiatives that improve cardiovascular care at rural hospitals are urgently needed.
Abstract 15491: Effects of Intensive Smoking Cessation Counseling After Acute Coronary Syndrome on 5-year Incidence of Major Adverse Cardiovascular Events and Smoking Abstinence
Authors: Lauriane Gilgien Denereaz, Reto Auer, Baris Gencer, David Carballo, Lorenz Raeber, Roland Klingenberg, Christian M Matter, Isabella Sudano, Thomas F Luescher, Stephan Windecker, Olivier Muller, Stephane Fournier, Nicolas Rodondi, Francois Mach, David Nanchen
Journal: Circulation (2020)

Introduction: Smoking cessation is recommanded after an acute coronary syndrome (ACS). Long-term cardiovascular benefits of smoking cessation counseling during a hospitalization and shortly after discharge for an ACS remains unknown. We aimed to study the 5-year incidence of major adverse cardiovascular events (MACE, defined as cardiovascular death, myocardial infarction, stroke, unplanned coronary revascularization or hospitalization due to angina) and smoking abstinence after ACS, comparing usual care to an intensive smoking cessation counseling intervention in hospital and after discharge. Methods: We studied 951 smokers from the SPUM-ACS cohort hospitalized for ACS between 2009 and 2014 in a multicenter prospective study with information available at the 5-year follow-up visit on incident MACE. At baseline in 4 study centers, a non-randomized part of smokers with ACS received proactive in-hospital smoking cessation counseling along with several telephone counseling over a 2 months period after discharge. We compared this intensive counseling group to the usual care group, regarding the incidence of MACE at 5 years. We used a multivariate adjusted Cox-proportional hazards model to estimate hazard ratios (HR) and 95% confidence intervals (CI). The secondary outcome was smoking cessation rate 5 years post-ACS. Results: Out of 951 smokers with ACS, 228 (35%) received the intensive in-hospital smoking intervention, of which 186 (82%) accepted to receive counseling after discharge. After multivariable adjustment for age, sex, education and study site, the 5-year risk of a recurrent MACE was comparable between the intensive counseling group and the usual care group, with a multivariable HR of 1.02 (95% CI 0.71-1.46, p=0.92). Among 669 patients alive 5 years post-ACS with known smoking status, 95 (56%) had stopped smoking in the intensive counseling group and 234 (47%) in the usual care group, with a multivariate odds ratio of 0.69 (95% CI 0.47-1.03; p=0.07). Conclusions: In this observational study, an intensive smoking cessation intervention during hospitalization for ACS with post-discharge telephone counseling did not reduce 5-year recurrence of MACE. However, this early intervention may confer a benefit for long-term smoking abstinence.