tbuckley/cabot-search huggingface dataset:
Abstract 217: <i> TBX5 <sup>Clover2</sup> /NKX2-5 <sup>TagRFP</sup> </i> hiPSCs for Simultaneously Isolating Lineage-Specific Cardiovascular Cells
Authors: Joe Z Zhang, Vittavat Termglinchan, Ilanit Itzhaki, Vicky Wang, Ningyi Shao, Alex Chang, Ning Ma, Chun Liu, Tomoya Kitani, Nazish Sayed, Haodi Wu, Chi Lam, Helen Blau, Joseph Wu
Journal: Circulation Research (2018)

In vertebrate, the heart is the first organ to develop, comprises multiple highly specialized cell types arising from different lineages. Early animal studies have identified two cardiac lineages: the first and second heart fields which contribute to the four-chamber heart formation. These cardiac progenitor cells develop into different parts of the heart and any perturbation of them frequently leads to congenital heart disease. However, given the difficulty in studying human embryology, current understanding of the hierarchy of cardiac lineages is primarily based on mouse models. The recent breakthrough in generation of human induced pluripotent stem cells (hiPSCs) from somatic cells and de novo differentiation into cardiomyocytes offers an unprecedented opportunity to investigate the genetic control of the cellular process of the heart development and investigate cardiac lineages under human genetic background. Despite the prominent advantages of hiPSCs in cardiac research, heterogeneity of hiPSC-derived cardiomyocytes (hiPSC-CMs) significantly impede their applications in regenerative medicine, disease modeling, and personalized drug testing. Using CRISPR/Cas9 genome-editing technology, I have generated a dual-color iPSC reporter line by targeting fluorescent protein sequences to two transcription factors (TBX5 and NKX2.5) which play a critical role in cardiac differentiation. Using this novel reporter line, I was able to simultaneously isolate four distinct subpopulations which exhibited different gene expression patterns. Continuous culture after isolation, it was found that TBX5 + NKX2.5 + subpopulation primarily differentiated into ventricular myocytes (90% purity), whereas TBX5 - NKX2.5 + subpopulation differentiated into atrial myocytes (80% purity). Moreover the TBX5 + NKX2.5 - subpopulation exhibited the epicardial lineage characteristics and contributed to nodal myocytes (80% purity). However, TBX5 - NKX2.5 - subpopulation developed into endothelial cells. In conclusion, using this reporter line, different lineage subpopulations can be identified and isolated from a heterogeneous pool of cardiac cells. These purified myocyte subtypes hold the potential for precise disease modeling and drug testing.
Abstract 495: The Loss Of Pka Activity And Activation In Cardiomyocytes Does Not Induce Cardiac Abnormalities
Authors: Xiaoying Zhang, Ying Zhang, Ying Li, Xiaojie Ai, Xiaoxiao Zhang, Chen Zhang, Mingxin Tang, Hua Xiang, Steven Houser, Xiongwen Chen
Journal: Circulation Research (2018)

Protein Kinase A (PKA) is the major mediator of β-adrenergic (βAR) regulation of cardiac contractility but other mediators (e.g., EPAC) have also been suggested. Reduced PKA basal activity and activation are linked to cardiac diseases. However, the roles of PKA in cardiac physiology and pathology have not been clearly defined because it has been difficult to knockout all expressed PKA catalytic subunit genes in cardiomyocytes. We ablated PKA activity and activation in cardiomyocytes by expressing a PKA inhibitor peptide (PKAi-GFP) in cardiomyocytes in transgenic (TG) mice. We made novel discoveries that: (1) Basal PKA-mediated phosphorylation was reduced for proteins in myofilaments and longitudinal SR but not for proteins in subsarcolemmal and dyadic spaces in PKAi TG hearts, suggesting basal PKA activity is different in individual cellular compartments; (2) PKAi increased the expression of CaMKII, the L-type Ca 2+ channel β subunits and current, but decreased CaMKII phosphorylation; (3) These changes resulted in significantly enhanced myofilament Ca 2+ sensitivity with prolonged contraction and relaxation, decreased myocyte Ca 2+ transient decay rate but enhanced myocyte contractility. (4) PKA inhibition fully abolishes the increases of heart rate, and cardiac and myocyte contractility by a β-adrenergic agonist (isoproterenol, ISO), showing a surprising dominant role of PKA in heart rate regulation and a minimal role of PKA-independent βAR signaling in regulating cardiac function; (5) The increased phosphorylation of proteins mediated by PKA and CaMKII after ISO was prevented by PKAi because increased PKA and CaMKII activation by ISO was eliminated by PKAi in vivo and in vitro . (6) PKAi TG mice maintained partial exercise capability by enhancing basal cardiac function, vascular constriction and ventricular filling (i.e., preload) during βAR stimulation. These features resemble some of the characteristics of diseased hearts. However, PKAi TG mice did not show any cardiac functional or structural abnormalities during the 1-year study period. In conclusion, PKA is the essential mediator of acute βAR regulation of cardiac function and exercise capacity, but the loss of PKA basal activity and activation by βAR agonists do not cause cardiac disease.
Abstract 526: Free Fatty Acid Receptor 4 is Required for an Adaptive Response to Pathologic Pressure Overload-induced Heart Failure in Mice
Authors: Sonal S Joshi, Chastity L Healy, Brandon M Wagner, Timothy D O’Connell
Journal: Circulation Research (2018)

Background: Our previous results indicate that eicosapentaenoic acid (EPA) prevents interstitial fibrosis and pathologic remodeling in the transverse aortic constriction (TAC) model of pressure overload induced heart failure in mice. However, EPA supplementation did not lead to incorporation into cardiac myocytes or fibroblasts in vivo , a traditional mechanism of action. Interestingly, we found that free fatty acid receptor 4 (Ffar4), a G-protein coupled receptor for long-chain fatty acids, was expressed in cardiac myocytes and fibroblasts. In primary cultures of cardiac fibroblasts, Ffar4 was sufficient and required to prevent TGFβ1-induced fibrosis, suggesting Ffar4 might mediate EPA cardioprotection. Methods: To understand the function of Ffar4 in the heart in vivo , we examined the response to TAC in male and female Ffar4 knockout mice (Ffar4KO) under basal conditions without EPA supplementation. Results: In male Ffar4KO mice, TAC induced a worsened dilated cardiomyopathy relative to wild-type (WT) mice. Specifically, in male Ffar4KO mice, TAC produced more hypertrophy (Heart weight: WT: 175±8 mg, n=14; Ffar4KO: 223±14 mg, n=10; P &lt;0.05), and generated more severe systolic and diastolic dysfunction (Ejection Fraction: WT: 42±3%, n=14; Ffar4KO: 28±4%, n=10; P &lt;0.05) (E/A ratio: WT: 2.0±0.2, n=12; Ffar4KO: 3.7±0.5, n=9; P &lt;0.05). However, TAC induced similar levels of interstitial fibrosis in male Ffar4 KO and WT mice (WT: 9.6±1.8%, n=14; Ffar4KO: 7.4±1.1%, n=10; ns ). While TAC worsened outcomes in male Ffar4KO mice, TAC in Ffar4 KO female mice produced no significant differences in the degree of hypertrophy or contractile dysfunction relative to WT mice. Discussion: Our results indicate that Ffar4 is required for an adaptive response to pathologic pressure overload in male mice. The lack of an exaggerated fibrotic response was surprising given our previous results indicating that in cardiac fibroblasts, Ffar4 prevents TGFβ1-induced fibrosis. This might indicate that Ffar4 signaling is minimal in fibroblasts under conditions of low omega-3 fatty acid levels. This result also suggests that the worsened contractile dysfunction in Ffar4KO mice is unrelated to fibrosis, but involves a direct effect in cardiac myocytes.
CIRCULATING LEVELS OF INTERFERON-γ AND TUMOR NECROSIS FACTOR-α ARE ASSOCIATED WITH LIPID-RICH CORONARY PLAQUE IN PSORIASIS
Authors: Noor Khalil, Martin Playford, Amit Dey, Youssef Elnabawi, Jonathan Chung, Harry Choi, Milena Aksentijevich, Jenis Argueta-Amaya, Eric Munger, Justin Rodante, Parag Shukla, Andrew Keel, Heather Teague, Yvonne Baumer, Veit Sandfort, Marcus Chen, David A. Bluemke, Joel Gelfand, Nehal Mehta
Journal: Journal of the American College of Cardiology (2019)
Misleading use of FGM statistics compounds concerns about their reliability
Authors: Alison Macfarlane
Journal: BMJ (2019)

Karlsen and colleagues raise concerns about the quality of statistics on female genital mutilation (FGM).1 Their limitations are compounded by the misleading ways in which the statistics are used to support or refute public claims of high rates of prevalence of FGM among girls born in the United Kingdom.

Even the otherwise excellent editorial wrongly states, “Girls are considered at risk if born to a mother who has FGM. Estimates based on migration data suggest there are up to 60 000 such girls in the UK.”2 Our report, based on birth registration statistics, estimated that 60 273 girls were born in England and Wales to migrant mothers with FGM from 1996 to 2010, and a further 17 344 were born in 2011-13.3 We specifically warned that these children could not be assumed to be “at …
AN EXTREMELY RARE CASE OF ADULT-ONSET KAWASAKI DISEASE, WITH CORONARY COMPUTED TOMOGRAPHY, INTRAVASCULAR ULTRASOUND, AND OPTICAL FREQUENCY DOMAIN IMAGING
Authors: Toshiki Kuno, Akimichi Shibata, Shohei Imaeda, Masaki Kodaira, Yohei Numasawa
Journal: Journal of the American College of Cardiology (2019)
Consensus-based recommendations for the management of juvenile localised scleroderma
Authors: Francesco Zulian, Roberta Culpo, Francesca Sperotto, Jordi Anton, Tadej Avcin, Eileen M Baildam, Christina Boros, Jeffrey Chaitow, Tamàs Constantin, Ozgur Kasapcopur, Sheila Knupp Feitosa de Oliveira, Clarissa A Pilkington, Ricardo Russo, Natasa Toplak, Annet van Royen, Claudia Saad Magalhães, Sebastiaan J Vastert, Nico M Wulffraat, Ivan Foeldvari
Journal: Annals of the Rheumatic Diseases (2019)

In 2012, a European initiative called Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile localised scleroderma (JLS) is a rare disease within the group of paediatric rheumatic diseases (PRD) and can lead to significant morbidity. Evidence-based guidelines are sparse and management is mostly based on physicians' experience. This study aims to provide recommendations for assessment and treatment of JLS. Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was formed, mainly from Europe, and consisted of 15 experienced paediatric rheumatologists and two young fellows. Recommendations derived from a validated systematic literature review were evaluated by an online survey and subsequently discussed at two consensus meetings using a nominal group technique. Recommendations were accepted if ≥80% agreement was reached. In total, 1 overarching principle, 10 recommendations on assessment and 6 recommendations on therapy were accepted with ≥80% agreement among experts. Topics covered include assessment of skin and extracutaneous involvement and suggested treatment pathways. The SHARE initiative aims to identify best practices for treatment of patients suffering from PRDs. Within this remit, recommendations for the assessment and treatment of JLS have been formulated by an evidence-informed consensus process to produce a standard of care for patients with JLS throughout Europe.
TIME-DEPENDENT PROGNOSTIC EFFECT OF HIGH SENSITIVITY C-REACTIVE PROTEIN WITH STATIN THERAPY IN ACUTE MYOCARDIAL INFARCTION
Authors: Dong Oh Kang, Yoonjee Park, Ji Hoon Seo, Myung Ho Jeong, Won Young Jang, Woohyeun Kim, Eun Jin Park, Byoung Geol Choi, Jin Oh Na, Cheol Ung Choi, Eung Ju Kim, Seung-Woon Rha, Chang Gyu Park, Hong Seog Seo
Journal: Journal of the American College of Cardiology (2019)
SC tape‐stripping in children with AD with light and dark skin types
Authors: L. Hulshof, D.P. Hack, Q.C.J. Hasnoe, B. Dontje, I. Jakasa, C. Riethmüller, W.H.I. McLean, W.M.C. Aalderen, B. van't Land, S. Kezic, A.B. Sprikkelman, M.A. Middelkamp‐Hup
Journal: British Journal of Dermatology (2019)

Atopic dermatitis (AD, atopic eczema) is a very common skin condition affecting 10‐20% of children. It affects children of all skin colours and seems to occur more often in Asian children and children with dark skin types. However, most research is performed on children with light skin types. This study, performed in Amsterdam, the Netherlands, aimed to investigate differences between AD in children with dark and light skin types. To study this, the investigators took tape strips from 53 AD children aged 0‐12 years and 50 healthy children as control (comparison). Tape stripping is a painless procedure which is ideal to perform in children, in which a small round sticker is attached to the skin. When removing this special sticker, a thin layer of skin cells remains attached to the sticker, allowing the investigators to study several aspects of skin inflammation and skin barrier. The authors found that AD skin from children with light and dark skin have similar levels and types of skin inflammation. However, they found differences in skin barrier markers between these two groups. In light skinned children, markers of good skin barrier were lower in AD skin when compared to healthy children's skin, while in dark AD skin these skin barrier markers were not significantly different from healthy dark skin. This study showed that dark‐skinned and light‐skinned AD children are similar when it concerns skin inflammation, but in light skinned AD children the skin barrier dysfunction may play an additional role in the development of AD. This suggests that AD in light and dark skin has different mechanisms of development.
THE ECONOMIC IMPACT OF MITRAL REGURGITATION ON MEDICALLY MANAGED INCIDENT HEART FAILURE PATIENTS
Authors: David Patrick Cork, Hirsch Mehta, Colin Barker, Patrick Verta, Candace Gunnarsson, Michael P. Ryan, Erin R. Baker, Sarah Mollenkopf, Joanna Van Houten, Peter McCullough
Journal: Journal of the American College of Cardiology (2019)
SUCCESSFUL STRATEGY USING MECHANICAL CIRCULATORY DEVICE FOR MANAGEMENT OF LEFT MAIN OCCLUSION ACUTE MYOCARDIAL INFARCTION COMPLICATED WITH CARDIOGENIC SHOCK
Authors: Ankur Jain, Erik Schneibel, Richard Kerensky, Ellen Keeley, Juan Aranda, R. David Anderson, Michael Massoomi
Journal: Journal of the American College of Cardiology (2019)
TRENDS, OUTCOMES, AND READMISSIONS AMONG LEFT VENTRICULAR ASSIST DEVICE RECIPIENTS WITH ACUTE KIDNEY INJURY REQUIRING HEMODIALYSIS: AN INSIGHT FROM THE NATIONAL READMISSIONS DATABASE 2012-2014
Authors: Alexandros Briasoulis, Oluwole Adegbala, Dinesh Voruganti, Chakradhari Inampudi, Paulino Alvarez
Journal: Journal of the American College of Cardiology (2019)
Monoamine Oxidase B Total Distribution Volume in the Prefrontal Cortex of Major Depressive Disorder
Authors: Sho Moriguchi, Alan A. Wilson, Laura Miler, Pablo M. Rusjan, Neil Vasdev, Stephen J. Kish, Grazyna Rajkowska, Junming Wang, Michael Bagby, Romina Mizrahi, Ben Varughese, Sylvain Houle, Jeffrey H. Meyer
Journal: JAMA Psychiatry (2019)

Monoamine oxidase B (MAO-B) is an important, high-density enzyme in the brain that generates oxidative stress by hydrogen peroxide production, alters mitochondrial function, and metabolizes nonserotonergic monoamines. Recent advances in positron emission tomography radioligand development for MAO-B in humans enable highly quantitative measurement of MAO-B distribution volume (MAO-B VT), an index of MAO-B density. To date, this is the first investigation of MAO-B in the brain of major depressive disorder that evaluates regions beyond the raphe and amygdala.To investigate whether MAO-B VT is elevated in the prefrontal cortex in major depressive episodes (MDEs) of major depressive disorder.This case-control study was performed at a tertiary care psychiatric hospital from April 1, 2014, to August 30, 2018. Twenty patients with MDEs without current psychiatric comorbidities and 20 age-matched controls underwent carbon 11-labeled [11C]SL25.1188 positron emission tomography scanning to measure MAO-B VT. All participants were drug and medication free, nonsmoking, and otherwise healthy.The MAO-B VT in the prefrontal cortex (PFC). The second main outcome was to evaluate the association between MAO-B VT in the PFC and duration of major depressive disorder illness.Twenty patients with MDEs (mean [SD] age, 34.2 [13.2] years; 11 women) and 20 healthy controls (mean [SD] age, 33.7 [13.1] years; 10 women) were recruited. Patients with MDEs had significantly greater MAO-B VT in the PFC (mean, 26%; analysis of variance, F1,38 = 19.6, P < .001). In individuals with MDEs, duration of illness covaried positively with MAO-B VT in the PFC (analysis of covariance, F1,18 = 15.2, P = .001), as well as most other cortex regions and the thalamus.Fifty percent (10 of 20) of patients with MDEs had MAO-B VT values in the PFC exceeding those of healthy controls. Greater MAO-B VT is an index of MAO-B overexpression, which may contribute to pathologies of mitochondrial dysfunction, elevated synthesis of neurotoxic products, and increased metabolism of nonserotonergic monoamines. Hence, this study identifies a common pathological marker associated with downstream consequences poorly targeted by the common selective serotonin reuptake inhibitor treatments. It is also recommended that the highly selective MAO-B inhibitor medications that are compatible for use with other antidepressants and have low risk for hypertensive crisis should be developed or repurposed as adjunctive treatment for MDEs.
Tumor Landscapes: β-Catenin Drives Immune Desertification
Authors: Denarda Dangaj, David Barras, George Coukos
Journal: Clinical Cancer Research (2019)

Immune checkpoint blockade therapy requires a preestablished activated immune landscape. Understanding tumor-intrinsic mechanisms that lead to T-cell desertification is key to resensitizing them to such therapies. The WNT/β-catenin tumor-intrinsic signaling is emerging as an immune exclusion pathway that holds high promise to counteract resistance to immunotherapy.See related article by Luke et al., p. 3074.
Abstract 337: Long Term Safety and Efficacy of a Cardiac Graft in a Swine Model of Heart Failure
Authors: Jordan Lancaster, Jen Koevary, Sherry Daugherty, Steven Goldman
Journal: Circulation Research (2018)

Introduction: We have shown efficacy with cardiac grafts in the rat coronary ligation model of chronic heart failure (CHF) and feasibility of implantation and assessment in a swine model. Now we propose testing its long term safety and efficacy in a swine model of CHF. Our aims are: 1) Evaluate long term (6 months) left ventricular functional improvements after implantation of the graft in a swine coronary artery occlusion model of CHF, 2) Evaluate quality of life and functional capacity improvements of swine treated with the graft, and 3) Evaluate long term safety of the graft. Hypothesis: An engineered tissue comprised of differentiated cardiac myocytes and fibroblasts will effectively integrate into the host tissue, and restore cardiac function in swine with CHF. Methods: Male Yucatan mini swine 30-40kg were infarcted using percutaneous methods. Balloon occlusions (90 minute) are performed via catheter, distal to the first diagonal branch of the left anterior descending (LAD) coronary artery and animals. Four weeks after myocardial infarction (MI) cardiac grafts engineered with bio absorbable knitted mesh are implanted on the infarcted epicardium. Cardiac magnetic resonance imaging (MRI) is performed prior to MI, 1 month after MI, 1 month after patch placement, again at 3 month and 6 months. All swine are implanted with continuous event recorders to acquire surface electrocardiogram during the entire study. In addition, quality of life/functional capacity are assessed using FitBark collar activity monitors and treadmill exertion testing. Infarct size is determined using MRI images and 2,3,5-triphenyltetrazolium chloride staining at study end. Results: Medium to large transmural infarcts are generated with 90min balloon occlusion of the LAD which demonstrate compensatory remodeling of the LV as assessed via cardiac MRI. Upscale cardiac matrix grafts to 6cm diameter are easily handled by the surgeon and can be surgically implanted on the epicardium using sub-xiphoid median sternotomy. No adverse arrhythmic activity has been observed. Conclusion: Our cardiac graft is well suited for upscale to clinical size, can be easily handled and implanted in a swine model of CHF.
IMPACT OF RESIDUAL INFLAMMATORY RISK IN PATIENTS WITH LOW LDL-CHOLESTEROL UNDERGOING PERCUTANEOUS CORONARY INTERVENTION: INSIGHT FROM A LARGE SINGLE-CENTER REGISTRY
Authors: Paul Guedeney, Bimmer Claessen, Deborah Kalkman, Melissa Aquino, Sabato Sorrentino, Moritz Blum, Gennaro Giustino, Serdar Farhan, Birgit Vogel, Samantha Sartori, Gilles Montalescot, Joseph Sweeny, Jason Kovacic, Nitin Barman, George Dangas, Annapoorna Kini, Usman Baber, Samin Sharma, Roxana Mehran
Journal: Journal of the American College of Cardiology (2019)
PRIOR EXPOSURE TO A CONVENTIONAL RENIN-ANGIOTENSIN SYSTEM ANTAGONIST AND ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITION IN ACUTE DECOMPENSATED HEART FAILURE: A PRESPECIFIED SUBGROUP ANALYSIS OF THE PIONEER-HF TRIAL
Authors: Andrew P. Ambrosy, Adam DeVore, David Morrow, Eugene Braunwald, Carolyn Duffy, Kevin McCague, Ricardo Rocha, Eric Velazquez
Journal: Journal of the American College of Cardiology (2019)
Abstract 398: GLP-1 Receptor Agonist Administered After the Infarct Suppresses miR-33 Expression in Lean Mice Subjected to Permanent Coronary Artery Occlusion
Authors: Juliana de F. Germano, Chengqun Huang, Yang Song, Jon Sin, Robert M Mentzer, Roberta A. Gottlieb, Allen M Andres
Journal: Circulation Research (2018)

MicroRNAs (miRs) regulate post-transcriptional gene expression and protein translation. There is now increasing evidence that miRs regulate mitochondrial turnover. miR-33 regulates cholesterol metabolism and mitochondrial function in cardiac fibroblasts and macrophages and has been implicated in promoting fibrosis. Excessive fibrosis contributes to the development of adverse LV remodeling. Given our recent findings that a glucagon-like peptide-1 receptor agonist (GLP1Ra) [Sigma] induces mitophagy and mitigates post-MI LV remodeling, the purpose of this study was to determine its effects on miR-33 expression after MI. We analyzed miR-33 expression in the viable regions of hearts in lean mice after permanent coronary arterial ligation (PCAL) and subsequent treatment with GLP1Ra administered 2h and 48h after the infarction (total of 2 doses). PCAL was associated with a marked increase in miR-33 that peaked at day 3 (data not shown). In the presence of GLP1Ra, miR-33 expression was suppressed 3 days post-PCAL ( A ). Polysome profiling revealed that miR-33 was decreased in the translating fractions of GLP1Ra-treated mice and increased in the non-translating fraction (80S free ribosomes) compared to vehicle ( B and C ). Decreased association of miR-33 with polysomes in GLP1Ra-treated mice would allow for increased target translation. Given that suppression of miR-33 is implicated in promoting fibrosis, a suppression of this miR by acute GLP1Ra treatment could explain the beneficial effects of this drug in limiting adverse cardiac remodeling.
IN HOSPITAL AND LONG TERM OUTCOMES IN PATIENT WITH CHRONIC KIDNEY DISEASE UNDERGOING PERCUTANEOUS CORONARY INTERVENTION FOR CORONARY CHRONIC TOTAL OCCLUSION: A META-ANALYSIS
Authors: Udit Joshi, Harsh Rawal, Hiren Patel, Sagar Ranka, Hitesh Chawla, Vamsi Kodumuri
Journal: Journal of the American College of Cardiology (2019)
PODOCAN IS INVERSELY RELATED TO WINGLESS SIGNALING PATHWAY MOLECULES DICKKOPF-RELATED PROTEIN 1 IN RELATION TO AORTIC DIAMETERS IN PATIENTS WITH BICUSPID AORTIC VALVE
Authors: Saeeda Fatima, Kanjit Leungsuwan, Jennifer Victory, Julie Tirrell, Melissa Scribani, Paul Jenkins, Deborah Hyanik, Paul Klotman, Randolph Hutter, Daniel Katz
Journal: Journal of the American College of Cardiology (2019)