tbuckley/cabot-search huggingface dataset:
Abstract 456: YAP-TEAD1-OSM Amplification Loop Plays a Critical Role in Mediating Cardiomyocyte De-differentiation
Authors: Wataru Mizushima, Shouhei Ikeda, Peiyong Zhai, Junichi Sadoshima
Journal: Circulation Research (2018)

The Hippo pathway regulates organ size by inhibiting cell proliferation and promoting apoptosis through negative regulation of YAP, a transcription factor co-factor. Suppression of Hippo and activation of YAP promotes myocardial regeneration after myocardial infarction. However, our recent results suggest that Hippo downregulation and activation of YAP induce de-differentiation of cardiomyocytes (CMs) through activation of genes regulated by TEAD1, which in turn induces contractile dysfunction in the presence of pressure overload (PO). Since oncostatin M (OSM), a member of the interleukin-6 family of cytokines, is a mediator of CM de-differentiation, we evaluated whether OSM plays an important role in mediating CM de-differentiation in WW45 cKO mice, a mouse model of Hippo downregulation, during PO. RNA sequencing analyses showed that OSM receptors (OSMRs) are upregulated in WW45 cKO mice in response to PO. Immunoblot analyses showed that both OSM and OSMR are upregulated by PO and that their levels are further increased in WW45 cKO mice. Upregulation of OSM and OSMR was also observed in adult cardiomyocytes (ACM) isolated from WW45 cKO mice after PO. Downregulation of YAP and TEAD1 significantly decreased OSM reporter gene activity in vitro , suggesting that OSM and OSMR are downstream targets of the YAP-TEAD1 pathway in CMs. Treatment of mice with OSM increased the levels of MYH7 and ACTA2, as well as YAP and TEAD1, in ACM at baseline, indicating the existence of an amplification loop composed of YAP, TEAD1 and OSM to promote CM de-differentiation. Suppression of any component of the amplification loop inhibited CM de-differentiation and cardiac dysfunction in WW45 cKO mice in response to PO. These results indicate that the YAP-TEAD1-OSM loop plays a critical role in mediating CM de-differentiation.
RENIN ACTIVITY PREDICTS OUTCOME IN PATIENTS WITH HEART FAILURE AND PRESERVED EJECTION FRACTION
Authors: Christina Binder, Marko Poglitsch, Franz Duca, Caroline Zotter-Tufaro, Christian Nitsche, Stefan Aschauer, Andreas A. Kammerlander, Begüm Öztürk, Julia Mascherbauer, Diana Bonderman
Journal: Journal of the American College of Cardiology (2019)
ALBUMIN LEVEL AS A RISK MARKER AND PREDICTOR OF PERIPARTUM CARDIOMYOPATHY
Authors: Ahmed Amro, Giancarlo Acosta Baez, George Augustine Koromia, Niharika Bhardwaj, Rodrigo Aguilar, Mehiar El-Hamdani, Affan Irfan
Journal: Journal of the American College of Cardiology (2019)
Abstract 581: Determining the Nuclear Transcription Factor Network Controlling Expression of the Cardiac Inotropic Factor S100A1
Authors: Martin Busch, Lukas Adrian, Fabian Guenther, Christoph Dieterich, Hugo A Katus, Melanie Boerries, Patrick Most
Journal: Circulation Research (2018)

Down-regulation of cardiac inotropic EF-hand calcium sensor protein S100A1 expression is a hallmark of human heart failure and drives progression and mortality. An AAV-S100A1 gene replacement therapy, which has been shown in preclinical models to rescue chronic heart failure, is in preparation for first clinical trials. However, the nuclear mechanisms that convey S100A1 gene locus silencing in the failing heart have not been determined yet. Given the steady increase of S100A1 expression in the developing heart until young adulthood and its decrease in the aged and failing heart, we developed a novel approach to decipher the mechanisms of S100a1 transcriptional regulation. We performed serial RNAseq analyses in an in vitro cardiac differentiation model of H9c2 cells that displays robust concurrent S100A1 and e.g. sarcoplasmic reticulum calcium ATPase 2 (SERCA2a) mRNA and protein during differentiation. Potential transcription factors (TF) were derived by computational motif analysis from S100A1’s gene locus regulatory elements that delivered more than 200 candidates. Subsequent computational TF footprint binding motive analysis from all differentially expressed transcripts of the serial RNAseq data provided a smaller group of less than 30 putatively TF families in the cH9C2 model that is actively during the in vitro biological process. Additional comparative TF expression analyses with developing rat hearts then enabled subtraction of a final TF group of 10 members for RNA interference screens in the cH9C2 model using S100A1 RNA expression as a read-out. Using a siRNA-mediated TF knock-down screen, we identified a small group of TFs such as zink finger and coiled-coil TFs (e.g. KLFs) and signal transducer and activator of transcription (STATs) TFs with an hitherto unknown ability to independently regulate S100A1 expression. Of note, other inotropic factors such as SERCA2a were found to be positively co-regulated by some of the TFs, such as KLFs, that enhance S100A1 expression. Further analyses were performed to confirm these results. In summary, we present a feasible computational filter and experimental strategy to identify relevant TF networks which we have successfully applied to identify cardiac regulatory networks.
TAVR FOR ACQUIRED BICUSPID AORTIC VALVES: A COMPARISON OF ANNULAR VERSUS SUPRA- ANNULAR SIZING STRATEGIES
Authors: John Cyril Lisko, Norihiko Kamioka, Isida Byku, Lucia Alvarez, Patrick Gleason, Kendra Grubb, Peter Block, Adam B. Greenbaum, Vasilis Babaliaros
Journal: Journal of the American College of Cardiology (2019)
Abstract 210: Assessment of Cardiac Cell Culture Electrical Excitability Using Strength Duration Relationships
Authors: Michael N Sayegh, Natasha Fernandez, Hee Cheol Cho
Journal: Circulation Research (2018)

Understanding the factors that influence the electrical excitability is important for successful engineering and therapeutic translation of cardiac tissue. Electric field excitation is widely utilized in vitro and in vivo to assess the response of cardiomyocytes to electrical excitation. The excitability of cardiac tissue is influenced by a variety of factors, including anatomic location in the heart, disease status, and age. We dissect properties that alter the electrical excitability of ventricular myocardial tissue constructs in vitro in 2D and 3D models of neonatal rat ventricular myocytes, using a custom-made integrated live-cell imaging and pacing setup. We find that for both 2D and 3D constructs, the electrical signal strength correlates negatively with the threshold stimulation duration required for pacing and driving the engineered tissue, and the resulting strength-duration curve is well approximated by the Lapicque-Hill model of electrically excitable membranes. By comparing strength-duration relationships, we find that pacing 2D constructs at 2 Hz requires 1.7 to 1.9 times the stimulus strength compared to pacing at 1 Hz (n=3, p&lt;0.05). Similarly, we find that pacing 3D constructs at 3 Hz requires 1.2 to 1.5 times the stimulus duration compared to pacing at 1 Hz (n=3, p&lt;0.05). By comparing strength-duration relationships of 3D spheroids of diameters ranging from 100 to 210 um (n=7), we find that the signal strength required for capture at 10 ms duration correlates negatively with the spheroid diameter (r =-0.87, p=0.02). When cell culture anisotropy is induced by seeding the cells on abraded plastic substrate, we find that a 1.3 to 1.9 times higher threshold duration of stimulus is required to pace and drive cultures aligned perpendicular to the direction of the electric field compared to those aligned parallel to the direction of the electric field (n=3, p&lt;0.05). Finally, when fibroblasts are added in equal density to the NRVMs, we find a significant increase in threshold duration at lower stimulation strength (n≥2, p&lt;0.05). Therefore, we conclude that 2D and 3D primary NRVM cultures are better electrically entrained when driven at slower frequencies, are large in size and aligned with the electric field, and have low fibroblast content.
ADDITIONAL ROLE OF UNMODIFIABLE RISK FACTORS IN PULMONARY ARTERIAL HYPERTENSION RISK STRATIFICATION ACCORDING TO CURRENT ESC/ERS GUIDELINES
Authors: Fabio Dardi, Alessandra Manes, Massimiliano Palazzini, Enrico Gotti, Andrea Rinaldi, Enrico Monti, Elisa Zuffa, Daniele Guarino, Alessandro De Lorenzis, Filippo Pasca, Ilenia Magnani, Mariangela Rotunno, Nazzareno Galiè
Journal: Journal of the American College of Cardiology (2019)
PLASMA CELL-FREE DNA AS A NOVEL MARKER OF DISEASE SEVERITY IN PULMONARY ARTERIAL HYPERTENSION
Authors: Samuel B. Brusca, Jason M. Elinoff, Moon K. Jang, Cumhur Y. Demirkale, Hannah A. Valantine, Michael A. Solomon, Sean Agbor-Enoh
Journal: Journal of the American College of Cardiology (2019)
Importance of Treatment Status in Links Between Type 2 Diabetes and Alzheimer’s Disease
Authors: Elissa C. McIntosh, Daniel A. Nation
Journal: Diabetes Care (2019)

To investigate relationships among type 2 diabetes treatment, Alzheimer's disease(AD) biomarkers, and risk for dementia.Participants were from the Alzheimer's Disease Neuroimaging Initiative (N = 1,289) and were dementia-free at baseline and underwent health assessment, cognitive testing, and MRI. A subset (n = 900) obtained a lumbar puncture to determine cerebrospinal fluid (CSF) phosphorylated tau (p-tau), total tau (t-tau), and β-amyloid 1-42 (Aβ1-42). Participants were grouped by fasting blood glucose and medication history: euglycemia (EU), prediabetes (PD), untreated diabetes (UD), and treated diabetes (TD). Relationships were investigated between treatment status and CSF biomarkers and risk for dementia.The UD group displayed greater p-tau, t-tau, and p-tau/Aβ1-42 levels than the EU, PD, and TD groups (P values <0.05) and higher t-tau/Aβ1-42 than the EU and PD groups (P values <0.05). The UD group progressed to dementia at higher rates than the EU group (hazard ratio 1.602 [95% CI 1.057-2.429]; P = 0.026).Treatment status may alter the relationship between type 2 diabetes and both AD biomarker profile and risk for dementia. UD is associated with elevated tau pathology and risk for dementia, whereas TD is not. Although this study is observational and therefore causality cannot be inferred, findings support the potential importance of treatment status in AD risk associated with type 2 diabetes.
CORRELATION OF ECHOCARDIOGRAPHIC FINDINGS WITH SYMPTOMS IN HYPERTROPHIC CARDIOMYOPATHY PATIENTS
Authors: Nikolaos Papoutsidakis, Carolyn Ho, Neal Lakdawala, Justin Vincent-Tompkins, Sharlene Day, Euan A. Ashley, Michelle Michels, Steven Colan, Iacopo Olivotto, James Ware, Alexandre Pereira, Daniel Jacoby
Journal: Journal of the American College of Cardiology (2019)
EOSINOPHILIC MYOCARDITIS ASSOCIATED WITH HYPEREOSINOPHILIC SYNDROME
Authors: Junya Komatsu, Ayaka Machida, Hikaru Imafuku, Ryota Kida, Yoshihiro Ohkawa, Sho-Ichi Kubokawa, Hiroshi Sakaeda, Kazuya Kawai, Naohisa Hamashige, Yoshinori Doi
Journal: Journal of the American College of Cardiology (2019)
A Functional Landscape of Resistance to MEK1/2 and CDK4/6 Inhibition in NRAS-Mutant Melanoma
Authors: Tikvah K. Hayes, Flora Luo, Ofir Cohen, Amy B. Goodale, Yenarae Lee, Sasha Pantel, Mukta Bagul, Federica Piccioni, David E. Root, Levi A. Garraway, Matthew Meyerson, Cory M. Johannessen
Journal: Cancer Research (2019)

Combinatorial inhibition of MEK1/2 and CDK4/6 is currently undergoing clinical investigation in NRAS-mutant melanoma. To prospectively map the landscape of resistance to this investigational regimen, we utilized a series of gain- and loss-of-function forward genetic screens to identify modulators of resistance to clinical inhibitors of MEK1/2 and CDK4/6 alone and in combination. First, we identified NRAS-mutant melanoma cell lines that were dependent on NRAS for proliferation and sensitive to MEK1/2 and CDK4/6 combination treatment. We then used a genome-scale ORF overexpression screen and a CRISPR knockout screen to identify modulators of resistance to each inhibitor alone or in combination. These orthogonal screening approaches revealed concordant means of achieving resistance to this therapeutic modality, including tyrosine kinases, RAF, RAS, AKT, and PI3K signaling. Activated KRAS was sufficient to cause resistance to combined MEK/CDK inhibition and to replace genetic depletion of oncogenic NRAS. In summary, our comprehensive functional genetic screening approach revealed modulation of resistance to the inhibition of MEK1/2, CDK4/6, or their combination in NRAS-mutant melanoma. SIGNIFICANCE: These findings reveal that NRAS-mutant melanomas can acquire resistance to genetic ablation of
Abstract 454: Role of Foxf1 During Protein Quality Control in Cardiomyocytes
Authors: Bidur Bhandary, Qing Hang Meng, Na Xu, Hanna Osinska, Kritton Shay-Winkler, James Gulick, Jeffrey Robbins
Journal: Circulation Research (2018)

Introduction: Impairment of protein quality control leads to the accumulation of intracellular misfolded protein aggregates, contributing to cardiac disease and heart failure. Essential protein quality control pathways, including proteasomal degradation and autophagy, are involved in maintaining cellular homeostasis and cardiac function during proteotoxic insult. In a prior study, we undertook an unbiased, total genomewide screen for RNA transcripts and their protein products that affect aggregate accumulations in the cardiomyocytes. Forkhead box F1 (Foxf1) gene was one of the hits from our high throughput screening. In this study, we have performed further validation of Foxf1, a transcription factor and previously unknown player in proteotoxic processes. Aims and Methods: The objective of this study was to validate Foxf1 as a contributor to protein quality control and understand its role in contributing to protein aggregate formation during proteotoxic-induced cardiac disease. We knocked down Foxf1 expression using siRNA mediated transfection in neonatal rat ventricular cardiomyocytes that expressed the protein aggregate inducing mutation of the chaperone α B crystallin (CryABR120G). Proteasomal function and relative activity in cells was analyzed using a degron-destablized green fluorescent protein (GFPu) based reporter protein. Similarly, autophagy activity was determined by autophagic flux assay using bafilomycin treatment. Results: CryABR120G expression leads to aggregate formation and decreased proteasomal function in cardiomyocytes. Knockdown of Foxf1 gene expression in CryABR120G-transfected cardiomyocytes reduced the proteotoxic sequelae, decreasing aggregate concentration. Knockdown of Foxf1 significantly increased proteasomal function in the model without altering autophagy activity. Conclusion: Decreased Foxf1 expression reduced CryABR120G induced aggregate protein accumulation and decreased proteotoxic stress in cardiomyocytes, likely through the maintenance of clearance of the misfolded protein via the proteasomal pathway.
LEFT ATRIAL FIBROSIS, FUNCTIONAL CHANGE, AND A RISK OF THROMBUS IN PATIENTS WITH ATRIAL FIBRILLATION: LEFT ATRIAL FIBROSIS BEGETS ATRIAL FIBRILLATION OR VICE VERSA?
Authors: Hee-Dong Kim, Dong-Hyuk Cho, Mi-Na Kim, Sung Ho Hwang, Jaemin Shim, Jong-Il Choi, Young-Hoon Kim, Yu-Whan Oh, Wan Joo Shim, Seong-Mi Park
Journal: Journal of the American College of Cardiology (2019)
Abstract 228: RNA Aptamer 9.14T79VRT7 Modifies Canine Ex vivo Platelet Reactivity
Authors: Spencer E Talentino, Matthew E Joseph, Chase M Byington, Camille F Bratton, Caitlin M Hatten, Gabriel S Shimmin, Cole P Anderson, Jenna L Wilson, Allyson L Huttinger, Debra G Wheeler, Shahid M Nimjee
Journal: Circulation Research (2018)

Objective: To compare the prophylactic and thrombolytic effects of RNA aptamer (9.14T79VRT7) on ex vivo canine platelet function. Approach and Results: We previously demonstrated that inhibition of von Willebrand Factor (VWF) by a targeted RNA aptamer prevents thrombosis and thrombolyses stabilized clots in a FeCl 3 -induced murine vascular injury model suggesting a pivotal role for VWF in the pro-thrombotic and anti-thrombotic milieu. We hypothesize that 9.14T79VRT7, which demonstrated no hemorrhagic complications and greater re-perfusion compared to rTPA in murine and canine thrombotic models, may affect additional agonist pathways to mitigate platelet activation, aggregation, and adhesion. Platelet aggregation before and after 9.14T79VRT7 addition was analyzed utilizing WB aggregometry based on impedance in five adult beagles. Agonist concentrations were selected from previous publications which had optimized platelet reactivity in canine WB and included: collagen (3.2 ug/ul), ADP (20 uM), arachidonic acid (0.5 mM), and botrocetin (1 ug/ul). The 9.14T79VRT7 concentration used (25 nM) was selected as the most effective as assessed by Total Thrombus Analysis System (TTAS). Botrocetin elicited the greatest response before 9.14T79VRT7 addition, followed by Collagen, ADP, and Arachidonic acid. Impedance resulting from prophylactic addition of 9.14T79VRT7 before Collagen, ADP, and Botrocetin resulted in a 50.00%, 34.83%, and 38.26% change in amplitude, respectively and a 43.70%, 14.28%, and 35.14% change in slope, respectively (p&lt;.0001). There was no significant difference in response after Arachidonic acid. Impedance resulting from thrombolytic addition of 9.14T79VRT7 after agonist response to Collagen, ADP, and Botrocetin resulted in a 78.66%, 94.08%, and 84.58% change in amplitude, respectively and a 67.28%, 61.28%, and 63.73% change in slope, respectively (p&lt;.0001). Although amplitude and slope decreased with 9.14T79VRT7 addition after Arachidonic acid, the change was not significant. Both control groups (9.14T79VRT7 and platelet buffer diluent) resulted in no significant changes. Conclusion: 9.14T79VRT7 markedly changes platelet response both before and after agonist treatment in canine ex vivo impedance analysis.
A YOUNG PATIENT WITH RECURRENT ACUTE ST-ELEVATION MYOCARDIAL INFARCTION AND APICAL THROMBUS CAUSED BY ANTIPHOSPHOLIPID SYNDROME
Authors: Ariel F. Gonzalez, Marcel Mesa Pabon, Hilton Franqui-Rivera, Melissa Ruiz Rodriguez, Bayoan M. Ramos Parra, Juan Carrillo Navas
Journal: Journal of the American College of Cardiology (2019)
Abstract 236: Histone Variant H2A.Z Defines Cell Identity in Smooth Muscle Cells as Revealed by Single-Cell Transcriptomics
Authors: Li Wang, Fang Yao, Peng Yu
Journal: Circulation Research (2018)

Background: Histone variants endow chromatin with specific structures, and play essential roles in development and diseases. However, little is known about their roles in controlling cell identity in vascular diseases. Methods and Results: Given the cell heterogeneity in atherosclerotic lesions, we applied single-cell RNA-Seq to analyze human diseased arteries, and identified histone variant H2A.Z as a key histone signature to maintain vascular smooth muscle cell (VSMC) identity. We show that H2A.Z occupies genomic regions near VSMC marker genes and its occupancy is decreased in VSMC undergoing dedifferentiation. Mechanistically, H2A.Z occupancy preferentially promotes nucleosome turnover, facilitates the recruitment of Smad3 and Med1, thereby activating VSMC marker gene expression. In human diseased vascular tissue, H2A.Z expression is dramatically decreased. Notably, in vivo overexpression of H2A.Z rescued injury-induced loss of VSMC identity and neointima formation. Conclusions: Together, our data introduce dynamic occupancy of a histone variant as a novel regulatory basis contributing to cell fate decisions, and imply H2A.Z as a potential intervention node for vascular diseases.
Stand-Alone Artificial Intelligence for Breast Cancer Detection in Mammography: Comparison With 101 Radiologists
Authors: Alejandro Rodriguez-Ruiz, Kristina Lång, Albert Gubern-Merida, Mireille Broeders, Gisella Gennaro, Paola Clauser, Thomas H Helbich, Margarita Chevalier, Tao Tan, Thomas Mertelmeier, Matthew G Wallis, Ingvar Andersson, Sophia Zackrisson, Ritse M Mann, Ioannis Sechopoulos
Journal: JNCI Journal of the National Cancer Institute (2018)

Artificial intelligence (AI) systems performing at radiologist-like levels in the evaluation of digital mammography (DM) would improve breast cancer screening accuracy and efficiency. We aimed to compare the stand-alone performance of an AI system to that of radiologists in detecting breast cancer in DM.Nine multi-reader, multi-case study datasets previously used for different research purposes in seven countries were collected. Each dataset consisted of DM exams acquired with systems from four different vendors, multiple radiologists' assessments per exam, and ground truth verified by histopathological analysis or follow-up, yielding a total of 2652 exams (653 malignant) and interpretations by 101 radiologists (28 296 independent interpretations). An AI system analyzed these exams yielding a level of suspicion of cancer present between 1 and 10. The detection performance between the radiologists and the AI system was compared using a noninferiority null hypothesis at a margin of 0.05.The performance of the AI system was statistically noninferior to that of the average of the 101 radiologists. The AI system had a 0.840 (95% confidence interval [CI] = 0.820 to 0.860) area under the ROC curve and the average of the radiologists was 0.814 (95% CI = 0.787 to 0.841) (difference 95% CI = -0.003 to 0.055). The AI system had an AUC higher than 61.4% of the radiologists.The evaluated AI system achieved a cancer detection accuracy comparable to an average breast radiologist in this retrospective setting. Although promising, the performance and impact of such a system in a screening setting needs further investigation.
Slow Conduction in Cardiac Tissue, II
Authors: Jan P. Kucera, André G. Kléber, Stephan Rohr
Journal: Circulation Research (1998)

Abstract —In cardiac tissue, functional or structural current-to-load mismatches can induce local slow conduction or conduction block, which are important determinants of reentrant arrhythmias. This study tested whether spatially repetitive mismatches result in a steady-state slowing of conduction. Patterned growth of neonatal rat heart cells in culture was used to design unbranched cell strands or strands releasing branches from either a single point or multiple points at periodic intervals. Electrical activation was followed optically using voltage-sensitive dyes under control conditions and in elevated [K + ] o (5.8 and 14.8 mmol/L, respectively; in the latter case, propagation was carried by the L-type Ca 2+ current). Preparations with multiple branch points exhibited discontinuous and slow conduction that became slower with increasing branch length and/or decreasing inter-branch distance. Compared with unbranched strands, conduction was maximally slowed by 63% under control conditions (from 44.9±3.4 to 16.7±1.0 cm/s) and by 93% in elevated [K + ] o (from 15.7±2.3 to 1.1±0.2 cm/s). Local activation delays induced at a single branch point were significantly larger than the delays per branch point in multiple branching structures. Also, selective inactivation of inward currents in the branches induced conduction blocks. These 2 observations pointed to a dual role of the branches in propagation: whereas they acted as current sinks for the approaching activation thus slowing conduction (“pull” effect), they supplied, once excited, depolarizing current supporting downstream activation (“push” effect). This “pull and push” action resulted in a slowing of conduction in which the safety was largely preserved by the “push” effect. Thus, branching microarchitectures might contribute to slow conduction in tissue with discontinuous geometry, such as infarct scars and the atrioventricular node.
B-Type Natriuretic Peptide During Treatment With Sacubitril/Valsartan
Authors: Peder Langeland Myhre, Muthiah Vaduganathan, Brian Claggett, Milton Packer, Akshay S. Desai, Jean L. Rouleau, Michael R. Zile, Karl Swedberg, Martin Lefkowitz, Victor Shi, John J.V. McMurray, Scott D. Solomon
Journal: Journal of the American College of Cardiology (2019)