tbuckley/cabot-search huggingface dataset:
Abstract 9745: Exosome Delivery for Therapeutic Cardiac Reprogramming
Authors: Hualing Sun, Conrad Hodgkinson, Richard E Pratt, Victor J Dzau
Journal: Circulation (2021)

We, and others, have demonstrated that directly reprogramming scar fibroblasts into new cardiomyocytes improves cardiac function in the infarcted heart. A major challenge is the specific delivery of reprogramming factors to cardiac fibroblasts in vivo. Currently, reprogramming factors are delivered into the heart by viruses which are often poor delivery vehicles; typically lacking cell specificity and suffering from packaging size constraints. We hypothesized that the efficacy of direct cardiac reprogramming would be improved by optimizing delivery. To that end, we focused on identifying a fibroblast-targeting exosome. Exosomes were isolated from a variety of different cells and assessed for their ability to deliver fluorescent RNA molecules into cardiac fibroblasts in vitro. We found that exosomes derived from C166 cells targeted fibroblasts; ~95% of cardiac fibroblasts were labelled with the fluorescent RNA (N=5, P&lt;0.001). C166 derived exosomes were similarly effective in vivo. C166 derived exosomes containing fluorescent RNA were injected into the infarcted heart. Subsequent analysis of heart tissue indicated that the fluorescent RNA was preferentially found within fibroblasts (85±6%, N=3, P&lt;0.01) and rarely present in cardiomyocytes (10±4%, N=3, P&lt;0.01) or endothelial cells (5±3%, N=3, P&lt;0.01). C166 derived exosomes were similarly effective at delivering reprogramming factors in vitro and in vivo. In vitro, reprogramming factors delivered by C166 derived exosomes induced cardiomyocyte-specific gene expression (Actn2, Myh6 and Tnni3; 5 to 20 fold; N=5; P&lt;0.05) and induced cardiomyocyte formation (6±3%, N=3, P&lt;0.05). In vivo, reprogramming factors delivered by C166 derived exosomes efficiently converted ~20% of cardiac fibroblasts into cardiomyocytes (N=3, P&lt;0.01). Importantly, reprogramming was associated with significant improvements in cardiac function in a myocardial infarction injury model (~20% increase in Ejection Fraction, N=5, P&lt;0.01). In summary, C166 derived exosomes are an effective tool for the delivery of reprogramming factors into the heart.
Abstract P377: Collagen Remodeling Of Spontaneously Hypertensive Rats Undergoing Quinapril Treatment Measured By Three Dimensional Shape Analysis
Authors: Alexander J Wilson, Abdallah I Hasaballa, Gregory B Sands, Martyn P Nash
Journal: Circulation Research (2021)

Introduction: Myocardial collagen structure is a complex three dimensional (3D) hierarchy, organizing cardiomyocytes and providing structural integrity. Changes in collagen organization have a crucial role in cardiac remodeling. However, quantitative methods for the analysis of collagen structures are still lacking. Herein, we apply our collagen shape analysis framework to compare within-sheetlet collagen (both endomysial collagen surrounding myocytes and perimysial cords) against sheetlet-surface collagen (perimysial meshwork collagen deposited between sheetlets) in spontaneously hypertensive rats undergoing quinapril treatment. Hypothesis: The different functional properties of endomysial and perimysial meshwork collagen are linked to their structure and will have markedly different features quantifiable by 3D shape analysis. Methods: Rat myocardium was stained for collagen (picrosirius red), and the left ventricular free wall imaged using extended volume confocal microscopy (0.4 μm 3 voxel size). The 3D image volumes were segmented into within-sheetlet and sheetlet-surface regions. Shape analysis was performed using eigenanalysis of the inertia matrix to derive 3D morphological (elongation and flatness) parameters, characterizing the collagen shape in the two regions. Results: Shape analysis revealed marked differences between within-sheetlet and sheetlet-surface collagen organization. Long-term quinapril treatment resulted in notable differences in within-sheetlet collagen shape in rats at 14 months of age (mo) compared with 24 mo. At 14 mo, the within-sheetlet collagen is a mix of sheet-, ribbon-, and rod-like structures (elongation: 0.43, flatness: 0.05), but by 24 mo this has remodeled to predominately thin rod-like structures (elongation: 0.03, flatness: 0.35). The sheetlet-surface collagen consisted of thick sheet-like structures in both 14 and 24 mo rats (elongation: 0.83 vs 0.79, flatness: 0.13 vs 0.09). Conclusion: Shape analysis in 3D showed marked differences between within-sheetlet and sheetlet-surface collagen structure, as well as differences between early treatment and late treatment of diseased hearts.
Additional burden of iron deficiency in heart failure patients beyond the cardio‐renal anaemia syndrome: findings from the <scp>BIOSTAT‐CHF</scp> study
Authors: Ridha I.S. Alnuwaysir, Niels Grote Beverborg, Martijn F. Hoes, George Markousis‐Mavrogenis, Karla A. Gomez, Haye H. van der Wal, John G.F. Cleland, Kenneth Dickstein, Chim C. Lang, Leong L. Ng, Piotr Ponikowski, Stefan D. Anker, Dirk J. van Veldhuisen, Adriaan A. Voors, Peter van der Meer
Journal: European Journal of Heart Failure (2021)
National responses to covid-19: drivers, complexities, and uncertainties in the first year of the pandemic
Authors: Anne-Sophie Jung, Victoria Haldane, Rachel Neill, Shishi Wu, Margaret Jamieson, Monica Verma, Melisa Tan, Chuan De Foo, Salma M Abdalla, Pami Shrestha, Alvin Qijia Chua, Nellie Bristol, Sudhvir Singh, Michael Bartos, Shunsuke Mabuchi, Mathias Bonk, Christine McNab, George K Werner, Raj Panjabi, Anders Nordström, Helena Legido-Quigley
Journal: BMJ (2021)

Anne-Sophie Jung and colleagues argue that research and policy making must embrace complexity to build sustainable and long term approaches to pandemic preparedness
Abstract 13762: In-Hospital Outcomes of Mechanical Circulatory Support in MitraClip Implantation
Authors: Qasim Jehangir, Yi Lee, Nikolaos Kakouros, Osama Abdel-Hafez, Deepthi tirunagari, Ruchit Shah, Dinesh Reddy Apala, Nihar Jena, Asrar Abdou, Mohammed Salih, Abdul R Halabi, Kirit Patel, Waqas Qureshi
Journal: Circulation (2021)

Introduction: MitraClip, an efficacious strategy for patients with heart failure and severe mitral regurgitation, can be complicated by acute circulatory collapse in rare instances. Data on the use of mechanical circulatory support (MCS) in these patients is scarce. Methods: Using the Nationwide Inpatient Sample Database from 2016 to 2018, we identified patients who underwent MitraClip insertion and required MCS using ICD-10 codes. The MCS devices included intra-aortic balloon pump (IABP) (group 1), Impella (group 2), and extracorporeal membrane oxygenation (ECMO) (group 3). Patients &lt;18 years and those requiring more than one device use were excluded. The primary outcome was in-hospital mortality and secondary outcomes were myocardial infarction (MI), cerebrovascular accident, sepsis, and major bleeding. Results: Our analysis included 17,070 MitraClip patients (based on weighted sample) with 360 requiring MCS devices (IABP N=270, Impella N=75, ECMO N=15). Patients who required Impella were older than those who required ECMO and IABP (mean age group 1 75.8 ± 11.3, group 2 78.3 ± 10.1, group 3 77.1 ± 8.9; p &lt; 0.0001). The utilization of MCS devices was different among races (Whites 80.8%, African Americans 7.6%, Hispanics 6.53%; p = 0.0078) but not among gender (males 52.3%; p = 0.8467). Incidence of in-hospital mortality was highest in Impella (group 1 31.5%, group 2 46.7%, none in group 3; p &lt; 0.001) (Figure). The multivariate logistic regression model adjusted for MCS devices, age, race, sex, hypertension, diabetes, cardiopulmonary disease, kidney disease (CKD), liver disease, peripheral arterial disease, and arrhythmias indicated that the use of IABP, Impella, CKD, and liver disease were independent predictors of in-hospital mortality. Conclusions: In MitraClip, the use of ECMO was associated with a higher incidence of major bleeding and sepsis when compared to Impella and IABP, however, Impella use was associated with higher in-hospital mortality and MI.
Aggressive containment, suppression, and mitigation of covid-19: lessons learnt from eight countries
Authors: Shishi Wu, Rachel Neill, Chuan De Foo, Alvin Qijia Chua, Anne-Sophie Jung, Victoria Haldane, Salma M Abdalla, Wei-jie Guan, Sudhvir Singh, Anders Nordström, Helena Legido-Quigley
Journal: BMJ (2021)

<b>Shishi Wu and colleagues</b> examine three distinct response strategies for covid-19 in eight countries and argue that aggressive containment is the optimal approach to limiting loss of lives and livelihoods and achievable in the absence of vaccines and effective therapies
Abstract 12895: Superior Effectiveness and Safety of Ticagrelor in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: A Nationwide Registry-Based Study
Authors: Sissel Johanne Godtfredsen, Manan Pareek, Peter Leutscher, Steen Hylgaard Jørgensen, Jawad Butt, Gunnar Gislason, Lars Kober, Emil Fosbøl, Deepak L Bhatt, Christian Torp-Pedersen, Kristian Kragholm
Journal: Circulation (2021)

Introduction: Dual antiplatelet therapy with aspirin and a P2Y 12 inhibitor is recommended following PCI for ACS. The optimal choice of P2Y 12 inhibitor remains debated. We compared effectiveness and safety of clopidogrel, ticagrelor, and prasugrel in a large, nationwide cohort of patients with ACS undergoing PCI. Methods: Registry-based study of first-time ACS patients who underwent PCI ≤7 days of admission and redeemed a prescription of a P2Y 12 inhibitor ≤30 days of the index event. The primary outcome was major adverse cardiovascular events (MACE): a composite of cardiovascular death, recurrent myocardial infarction, stroke, or repeat revascularization at 12 months. The safety outcome was bleeding requiring hospitalization at 12 months. Multivariable logistic regression with average treatment effect modeling was used to calculate standardized absolute and relative risks for outcomes across age, sex, comorbidity, bleeding, and concomitant anticoagulant therapy distributions. Results: We included 26,997 patients; 6,585 were discharged on clopidogrel, 18,425 on ticagrelor, and 1,987 on prasugrel. Corresponding median ages were 70, 64, and 59 years (p&lt;0.001). Patients in the clopidogrel group were more likely to have had a prior bleeding episode (p&lt;0.001). Adjusted relative risks of MACE were 0.80 for ticagrelor vs clopidogrel (p&lt;0.001), 0.85 for prasugrel vs clopidogrel (p&lt;0.001), and 1.05 for prasugrel vs ticagrelor (p=0.22). Adjusted relative risks of bleeding were 0.82 for ticagrelor vs clopidogrel (p=0.001), 1.07 for prasugrel vs clopidogrel (p=0.56), and 1.30 for prasugrel vs ticagrelor (p=0.03). While statistically significant, the absolute differences in risk of bleeding among groups were modest (Figure). Conclusion: Ticagrelor and prasugrel were associated with lower risk of MACE than clopidogrel but did not significantly differ from each other. Ticagrelor was associated with a lower risk of bleeding than both clopidogrel and prasugrel.
Abstract 14107: Racial and Income Inequities in Cardiovascular Disease in Cancer versus Non-Cancer Patients: Propensity Score and Machine Learning Augmented Nationally Representative Case-Control Study of Mortality and Cost Among 30 Million Hospitalizations
Authors: Dominique Monlezun, Nikhil Agrawal, Nicolas L Palaskas, Mehmet Cilingiroglu, Konstantinos Marmagkiolis, Abhijeet Dhoble, Salman A Arain, Cezar Iliescu
Journal: Circulation (2021)

Introduction: We conducted the first known nationally representative propensity score analysis of racial and income inequities in cardiovascular disease (CVD) for patients with and without active cancer. Methods: Propensity score adjusted and backward propagation neural network machine learning augmented multivariable regression was performed by race and income (and their interaction) for the above outcomes in this case-control study of the United States’ largest and first ICD10-coded all-payer hospitalized dataset, the 2016 National Inpatient Sample (NIS). Models were stratified by active cancer and CVD (defined by the 2021 WHO). Results: Of the 30,195,722 adult hospitalized patients, 25.64% had CVD, and 7.11% had active cancer. In fully adjusted regression among patients without cancer, Hispanic (OR 1.34, 95%CI 1.03-1.25; p=0.012) and Asian (OR 1.22; 95%CI 1.11-1.34; p&lt;0.001) had significantly increased mortality compared to Caucasian patients as did the lowest (OR 1.11; 95%CI 1.07-1.15; p&lt;0.001) and second lowest (OR 1.05; 95%CI 1.01-1.08; p=0.006) income quartiles compared to the highest. Among patients with cancer, similar significant racial inequities were noted but without income disparities. Mortality was not significantly increased by the interaction in either strata. Among patients without cancer, Hispanics ($14,196.68; 95%CI 12,887.86-15,505.51; p&lt;0.001) and Asians ($19,377.06; 95%CI 17,939.38-20,814.74; p&lt;0.001) had significantly increased costs compared to Caucasians; African American, Hispanic, and Asian patients in the lowest and second lowest income quartiles had significantly increased costs compared to Caucasians in the highest quartile. Patients with cancer had comparable cost inequities by race but not by income or the interaction. Conclusions: This nationally representative study suggests that significant income and racial inequities exist in inpatient mortality and cost among patients with CVD, though these disparities are less pronounced among cancer versus non-cancer patients.
Abstract 10041: Long Term Durability of Transcatheter Bioprosthetic Aortic Valves
Authors: Koki Shishido, Futoshi Yamanaka, Noriaki Moriyama, Shigeru Saito
Journal: Circulation (2021)

Introduction: Transcatheter aortic valve implantation (TAVI) is an alternative to surgical aortic valve replacement in patients with severe aortic stenosis. However, data on long-term durability of bioprosthetic valve dysfunction (BVD) remain not enough. Therefore, we investigated the durability of transcatheter heart valve (THV) using new standardized criteria in patients at 5-year after TAVI. Hypothesis and Methods: From January 2012 to September 2015, among 114 patients with severe aortic stenosis, 28 and 86 patients underwent TAVI with self-expandable Medtronic CoreValve and balloon-expandable Edwards SAPIEN-XT, respectively.BVD was defined as Valve Academic Research Consortium 3 (VARC-3) criteria. Moderate/ severe hemodynamic valve deterioration (HVD) was defined as increase in mean transvalvular gradient &amp;gt; 10 mmHg/ &amp;gt; 20 mmHg resulting in mean gradient &amp;gt; 20 mmHg/ &amp;gt; 30 mmHg with concomitant decrease in effective orifice area (EOA) &amp;lt; 0.3 cm 2 / &amp;lt; 0.6 cm 2 or new occurrence or increase of &amp;gt; 1 grade/ &amp;gt; 2 grade of intra-prosthetic aortic regurgitation (AR) resulting in moderate/ severe AR. Bioprosthetic valve failure (BVF) was defined as valve related death, aortic valve reintervention, any bioprosthetic valve dysfunction associated with clinically expressive criteria or severe hemodynamic HVD. Results: During 5-year follow-up period, all-cause mortality was 43.8% (50 patients). There was 1 patient with severe BVD due to severe aortic regurgitation after CoreValve implantation. Four patients (3.5%) showed moderate BVD, which resulted in increased mean THV gradient, and all of whom received SAPIEN-XT implantation. BVF occurred in 2 patients (1.8%) during 5 years after CoreValve and SAPIEN-XT implantation. Follow-up echocardiography at 5 year were conducted in 48 patients (42.1%). The mean pressure gradient was 7.7 ± 3.8 mmHg and 11.9 ± 4.9 mmHg in patients with CoreValve and SAPIEN-XT, respectively (p=0.012). Conclusions: This study was evaluated THV durability using the VARC-3 definition. The incidence of BVD were uncommon during long-term follow-up period. Furthermore, the 5-years’ THV performance of early generation balloon-expandable and self-expandable device were maintained after TAVI.
Abstract MP229: Signaling Mechanisms Leading To CD4+ T-lymphocyte Activation During Ischemic Heart Failure
Authors: Sahil Gupta, Shyam S Bansal
Journal: Circulation Research (2021)

CD4 + T-cells turn pathological during chronic heart failure (HF). Phenotypic changes that mediate this transition are unknown. Thus, at 8 weeks post-infarction we conducted limited cell RNA-sequencing on 150 CD4 + T-cells isolated from rodent failing hearts and using ingenuity pathway analysis (z score&gt;2) compared them either with CD4 + T-cells isolated from the mediastinal lymph nodes (mLNs) of the same mice or cardiac CD4 + T-cells from sham mice. T-cells isolated from the mLNs of HF mice showed enhanced TCR signaling (p&lt;2X10 -4 ) with 3-6 fold increase in several downstream mediators such as ITK, MAPK, LCK and Zap70. We also observed heightened leukocyte extravasation signaling (p&lt;2X10 -5 ) with significant increase in PKCθ, and Rho GTPase activating and Ras association domain proteins. These are consistent with enhanced antigen-presentation, and TCR activation during HF. Moreover, we observed significant upregulation of oxidative phosphorylation (p&lt;3X10 -15 ) in cardiac CD4 + T-cells as compared to mLN T-cells with 2-3 fold increase in the gene expression of ATP synthase subunits and cytochrome C indicative of their increased metabolic activity upon infiltration into the failing hearts. Compared to CD4 + T-cells from sham hearts, significant upregulation of inflammatory genes (p&lt;3X10 -5 ), chemotactic factors (p&lt;8X10 -4 ), and several pro-inflammatory cytokine-mediated pathways such as IL-6 (p&lt;2X10 -4 ), IL-1a (p&lt;2X10 -3 ) and TNFα (p&lt;2X10 -3 ) was observed in cardiac CD4 + T-cells from HF mice. Interestingly, we also observed a significant upregulation of homing (p&lt;3X10 -4 ) and connective tissue remodeling genes (p&lt;1.8X10 -3 ) with &gt;8-fold increase in genes like LCN2, SLPI, IGF1, FGFR1, LTF, and TIMP2 required for transmigration and homing of CD4 + T-cells into the ischemic hearts. Our studies show enhanced antigenic CD4 + T-cell activation in the mLNs supporting enhanced pro-inflammatory signaling, metabolic activation, and extravasation into the ischemic hearts.
Strengthening the basics: public health responses to prevent the next pandemic
Authors: Victoria Haldane, Anne-Sophie Jung, Chuan De Foo, Mathias Bonk, Margaret Jamieson, Shishi Wu, Monica Verma, Salma M Abdalla, Sudhvir Singh, Anders Nordström, Helena Legido-Quigley
Journal: BMJ (2021)

Victoria Haldane and colleagues argue that to make covid-19 the last pandemic, public health responses to outbreaks must be strengthened, starting with their most basic functions
PATH-40. SPORADIC NF2 WILD-TYPE MULTIPLE MENINGIOMAS HARBOR DISTINCT DRIVER MUTATIONS
Authors: Insa Prilop, Thomas Pinzer, Daniel Cahill, Priscilla Brastianos, Gabriele Schackert, Tareq Juratli
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE Multiple meningiomas (MM) are rare and present a unique management challenge. While the mutational landscape of single meningiomas has been extensively studied, understanding the molecular pathogenesis of sporadic MM remains incomplete. The objective of this study is to elucidate the genetic features of sporadic MM. METHODS We identified nine patients with MM (n=19) defined as ≥2 spatially separated synchronous or metachronous meningiomas. We profiled genetic changes in these tumors using next-generation sequencing (NGS) assay that covers a large number of targetable and frequently mutated genes in meningiomas including AKT1, KLF4, NF2, PIK3CA/PIK3R1, POLR2A, SMARCB1, SMO, SUFU, TRAF7, and the TERT promoter. RESULTS Most of MM were WHO grade 1 (n= 16, 84.2%). Within individual patients, no driver mutation was shared between separate tumors. All but two cases harbored different hot spot mutations in known meningioma-driver genes like TRAF7 (n= 5), PIK3CA (n= 4), AKT1 (n= 3), POLR2A (n=1) and SMO (n= 1). Moreover, individual tumors differed in histologic subtype in 8/9 patients. The low frequency of NF2 mutations in our series stands in contrast to previous studies that included hereditary cases arising in the setting of neurofibromatosis type 2 (NF2). CONCLUSIONS Our findings provide evidence for genomic inter-tumor heterogeneity and an independent molecular origin of sporadic NF2 wild-type MM. Furthermore, these findings suggest that genetic characterization of each lesion is warranted in sporadic MM.
Trends in Use and Expenditures for Brand-name Statins After Introduction of Generic Statins in the US, 2002-2018
Authors: Shuo-yu Lin, Kyle Baumann, Chenxuan Zhou, Weiyu Zhou, Alison Evans Cuellar, Hong Xue
Journal: JAMA Network Open (2021)

<h3>Importance</h3> The high and increasing expenditures for prescription medications in the US is a national problem. <h3>Objective</h3> To explore the association of generic statin competition on relevant use and cost savings and to provide use and expenditure trends for all available statins for private and public payers and for out-of-pocket spending. <h3>Design, Setting, and Participants</h3> This survey study evaluated data from the January 1, 2002, to December 31, 2018, Medical Expenditure Panel Survey by using a difference-in-differences analysis. Participants included noninstitutionalized individual statin users. Data were analyzed from November 1, 2020, to March 30, 2021. <h3>Exposures</h3> The market entry of 5 generic statin medications (atorvastatin, rosuvastatin, simvastatin, lovastatin, and pravastatin). <h3>Main Outcomes and Measures</h3> National- and individual-level reductions in the annual number of statin purchases and total expenditures across private insurance, public insurance (Medicaid and Medicare), and out-of-pocket spending (presented in 2018 US dollars). <h3>Results</h3> Between January 1, 2002, and December 31, 2018, an average of 21.35 million statins (95% CI, 16.7-25.5 million) were purchased annually, with an average total annual cost of $24.5 billion (95% CI, $18.2-$28.8 billion). The number of brand-name statin purchases decreased by 90.9% (95% CI, 56%-98%) nationally and 27.4% (95% CI, 13%-40%) individually after the end of market exclusivity. Among major payers, the end of market exclusivity was associated with individual cost savings of $370.00 (95% CI, $430.70-$309.20) for private insurers, $281.00 (95% CI, $346.80-$215.30) for Medicare, $72.34 (95% CI, $95.22-$49.46) for Medicaid, and $211.90 (95% CI, $231.20-$192.50) for out-of-pocket spending. Combining all payers, the decrease translates to $925.60 (95% CI, $1005.00-$846.40) of annual savings per individual and $11.9 billion (95% CI, $10.9-$13.0 billion) for the US. <h3>Conclusions and Relevance</h3> Results of this survey study suggest that full generic competition of statins was associated with significant cost savings across all major payers within the US health care system.