tbuckley/cabot-search huggingface dataset:
Abstract 10359: Prevalence of Traditional and Non-Traditional Cardiovascular Risk Factors in Adults with Congenital Heart Disease
Authors: Jacqueline Levene, Lidija McGrath, Craig Broberg, Katrina Ramsey, Abigail Khan
Journal: Circulation (2021)

Introduction: Previous studies examining the prevalence of cardiovascular risk factors in adults with congenital heart disease (CHD) were mainly based on single center data or non-United States (US) populations. Adults with CHD may be at increased risk of acquired cardiovascular disease (CVD) for a variety of reasons. Understanding the prevalence of non-traditional and traditional cardiovascular risk factors in this population is an important first step in developing strategies to mitigate long-term risk. Methods: The Oregon All Payer All Claims database for the years 2010-2017 was queried for adults 18 to 65 years of age with ICD codes consistent with CHD. CVD risk factors were identified using ICD-9 or ICD-10 codes. The prevalence of risk factors in any year were measured and averaged over the 7 year period. Results: 13,896 individuals with ICD codes consistent with CHD were identified ( Table 1 ). 53.2% had at least one risk factor for acquired CVD and 31.1% had ≥ 2 risk factors. The prevalence of ≥ 1 risk factor increased with age (18-24: 19% vs. 77% in those 55-65). The most common risk factor was hypertension (31.7%). Non-traditional risk factors were uncommon (hypertensive disorder of pregnancy: 1.5%, rheumatoid arthritis: 1.5%, lupus: 1.1%, HIV: 0.28%). Risk factors were more prevalent in men than women and in rural-dwelling individuals as compared to urban-dwelling individuals. Conclusions: To our knowledge, this is the first comprehensive, population-level attempt to measure both traditional and non-traditional cardiovascular risk factors in adults with CHD in the US. Our data shows that the prevalence of one or more traditional cardiovascular risk factors is high even in the young, and that men and rural-dwelling individuals are at increased risk. Given the potentially additive effect of acquired CVD on CHD with respect to adverse cardiovascular events, identifying and addressing risk factors should be an important priority for adult CHD providers and patients.
Abstract 9775: The Effect of Microvascular Injury on Temporal Evolution of Invasive Microvascular Function Indices After Reperfused ST-Segment Elevation Myocardial Infarction
Authors: Ahmet Demirkiran, Lourens F Robbers, Nina W van der Hoeven, Henk Everaars, Luuk H Hopman, Gladys N Janssens, Hans J Berkhof, Jorrit S Lemkes, Maarten A van Leeuwen, Alexander Nap, Ramon B van Loon, Albert C van Rossum, Niels v Royen, Robin Nijveldt
Journal: Circulation (2021)

Background: Despite successful primary percutaneous coronary intervention (PCI), the restoration of the microvascular flow fails in up to 50% of the reperfused ST-segment elevation myocardial infarction (STEMI) patients, worsening the prognosis. This study aims to identify how post-STEMI microvascular function indices evolve over 1-month and how these changes are affected by the presence of microvascular injury. Methods: The study was performed in 110 STEMI patients who underwent angiography for primary PCI and at 1-month follow-up. Invasive assessment of the coronary microcirculation in the culprit artery was performed during both procedures and included coronary flow reserve (CFR), index of microcirculatory resistance (IMR), and baseline microcirculatory resistance (BMR). Cardiovascular magnetic resonance imaging was performed 2 to 7 days after PCI to evaluate microvascular injury by microvascular obstruction (MVO) and intra-myocardial hemorrhage (IMH). Results: Over 1-month, mean CFR, IMR, and BMR all changed significantly (fig. 1). CFR increased in all patients both with and without MVO and IMH (all, p&lt;0.001). IMR significantly decreased in patients with MVO (p&lt;0.001) and IMH (p&lt;0.01), but less apparently in patients without MVO (p=0.04) and IMH (p=0.05). There was no significant difference for the absolute CFR change over 1-month between patients with/without MVO (p=0.34) and with/without IMH (p=0.41). The absolute IMR change over 1-month differed significantly between patients with/without MVO (p&lt;0.01) and with/without IMH (p=0.001). Conclusion(s): In STEMI patients, coronary microvascular function indices significantly improved one month after PCI. The occurrence of microvascular damage presented a close interaction with the recovery of IMR but not with the course of CFR.
Abstract 12965: Race-Specific Models to Predict In-Hospital Mortality in Patients With Heart Failure Using Machine Learning: The American Heart Association Get With the Guidelines Registry
Authors: Ambarish Pandey, Matthew Segar, Jennifer Hall, Ann M Navar, Tiffany Powell-wiley, Alanna A Morris, David P Kao, Gregg C Fonarow, Rosalba Hernandez, Nasrien E Ibrahim, Christine Rutan, Laura Stevens
Journal: Circulation (2021)

Background: Prior prognostic models for acute decompensated HF (ADHF) have incorporated race as a covariate may not have completely account for the social and biological factors that underlie the racial disparities in outcomes. We developed race-specific models to improve risk prediction and better identify race-specific predictors of mortality in patients with ADHF using machine learning (ML) methods. Methods: Race-specific ML-models for in-hospital mortality were developed and validated in ADHF patients enrolled in the GWTG-HF registry between 2007 to 2020 (14,586 Black and 50,351 Non-Black adults) using over 40 candidate variables. External validation was performed among participants from the ARIC study with ADHF (n=1,115 Black and 2,028 Non-Black adults). The discrimination and calibration was compared with a previously validated risk score and cohort-specific logistic regression (LR) models. The changes in model reclassification performance with addition of zip-code level data of socioeconomic (SES) parameters was also assessed. Results: In the GWTG-HF cohort, the ML models had superior performance in both Black and Non-Black participants compared with the traditional GWTG-HF risk score ( Table ). The superior performance of the ML-model was also observed in the external validation cohort as compared with the other LR models ( Table ). Addition of measures of SES did not meaningfully change the performance but improved the reclassification metrics of the ML-models with net up-classification of risk in Black [NRI = 0.21 (0.07, 0.35)] and down-classification in Non-Black patients [NRI = -0.08 (-0.12, -0.04)]. SES was responsible for 21.7% of the total attributable mortality risk in Black adults compared to 0.4% in Non-Black adults. Conclusion: Race-specific, ML-based mortality models demonstrated superior performance when compared to traditional HF mortality risk models. Socioeconomic distress is an important contributor to risk in Black adults.
Histopathologic Characterization of Vexas Syndrome
Authors: Mohammad I. Barouqa, Aishwarya Ravindran, Dong Chen, Jennifer L Oliveira, Horatiu Olteanu, Matthew T Howard, Gang Zheng, Mrinal M. Patnaik, Kebede H. Begna, Allison M. Bock, Ronald Go, Matthew Koster, Taxiarchis Kourelis, Abhishek A. Mangaonkar, Jay Ryu, Matthew Samec, Julio C. Sartori Valinotti, Kenneth Warrington, Kaaren K. Reichard
Journal: Blood (2021)
The effects of altered BMP4 signaling in first branchial-arch-derived murine embryonic orofacial tissues
Authors: Jue Xu, Meiling Chen, Yanan Yan, Qiaoxue Zhao, Meiying Shao, Zhen Huang
Journal: International Journal of Oral Science (2021)

Abstract The first branchial arch (BA1), which is derived from cranial neural crest (CNC) cells, gives rise to various orofacial tissues. Cre mice are widely used for the determination of CNC and exploration of gene functions in orofacial development. However, there is a lack of Cre mice specifically marked BA1’s cells. Pax2 -Cre allele was previously generated and has been widely used in the field of inner ear development. Here, by compounding Pax2 -Cre and R26R- mTmG mice, we found a specific expression pattern of Pax2 + cells that marked BA1’s mesenchymal cells and the BA1-derivatives. Compared to Pax2 -Cre; R26R -mTmG allele, GFP + cells were abundantly found both in BA1 and second branchial arch in Wnt1 -Cre; R26R -mTmG mice. As BMP4 signaling is required for orofacial development, we over-activated Bmp4 by using Pax2 -Cre; pMes -BMP4 strain. Interestingly, our results showed bilateral hyperplasia between the upper and lower teeth. We also compare the phenotypes of Wnt1 -Cre; pMes -BMP4 and Pax2 -Cre; pMes -BMP4 strains and found severe deformation of molar buds, palate, and maxilla-mandibular bony structures in Wnt1 -Cre; pMes -BMP4 mice; however, the morphology of these orofacial organs were comparable between controls and Pax2 -Cre; pMes -BMP4 mice except for bilateral hyperplastic tissues. We further explore the properties of the hyperplastic tissue and found it is not derived from Runx2 + cells but expresses Msx1, and probably caused by abnormal cell proliferation and altered expression pattern of p-Smad1/5/8. In sum, our findings suggest altering BMP4 signaling in BA1-specific cell lineage may lead to unique phenotypes in orofacial regions, further hinting that Pax2 -Cre mice could be a new model for genetic manipulation of BA1-derived organogenesis in the orofacial region.
Abstract 13622: Current of Injury is an Indicator of Lead Depth and Acute Perforation During Left Bundle Branch Pacing Lead Implantation
Authors: Xueying Chen, Shalaimaiti Shali, Yangang Su
Journal: Circulation (2021)

Background: Left bundle branch(LBB)pacing has emerged as a favorable option that utilizes cardiac conduction system. Monitoring lead depth in the septum is crucial to reach the LBB area and to avoid lead perforation but lacks informative approach. We aimed to assess the hypothesis that current of injury (COI) is a useful tool in guiding depth of lead and forecasting perforation. Methods: Consecutive patients who received LBB pacing with distinct LBB potential were enrolled from January 2018 to December 2020. Unipolar intracardiac electrogram was recorded from both tip and ring electrode at the time of lead fixation. The maximum amplitude of ST-segment elevation from baseline was defined as COI. Results: LBB pacing lead implantation was attempted for 1223 times in 512 patients (age 66.25 ± 15.20 years, 310 male). Discrete COI (ST-segment elevation more than 25% of intrinsic R wave amplitude) was present in 92.70% of the cases (1134/1223) on tip electrode while only in 68.1% of the cases (833/1223) on ring electrode. COI tip/COI ring was correlated with the lead depth determined by sheath angiography (Spearman’s Correlation Coefficient=-0.624, p =0.000). Acute lead perforation has occurred in 11 cases when COI was either absent or very low on tip electrode. Among them, only eight cases, noted as microperforation, displayed significant COI on ring electrode, and COI tip/COI ring was extremely low (0.063, 0.035-0.123). The COI tip/COI ring&lt;1 is associated to lead perforation (OR: 30.24, 6.47 -141.3, p=0.000). Sensitivity, specificity, and positive and negative predictive values of COI tip/ring&lt;1 as an early marker for lead perforation were 81.8%, 87.1%, 54.2% and 99.8%, respectively. Conclusions: In conclusion, COI tip/ring could help to understand the depth of lead inside ventricular septum. Lack of COI on tip electrode or a very low COI tip/COI ring may signal lead perforation.
Life Expectancy After Surgical Aortic Valve Replacement
Authors: Andreas Martinsson, Susanne J. Nielsen, Milan Milojevic, Björn Redfors, Elmir Omerovic, Theis Tønnessen, Tomas Gudbjartsson, Göran Dellgren, Anders Jeppsson
Journal: Journal of the American College of Cardiology (2021)

Surgical risk, age, perceived life expectancy, and valve durability influence the choice between surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation. The contemporaneous life expectancy after SAVR, in relation to surgical risk and age, is unknown. The purpose of this study was to determine median survival time in relation to surgical risk and chronological age in SAVR patients. Patients ≥60 years with aortic stenosis who underwent isolated SAVR with a bioprosthesis (n = 8,353) were risk-stratified before surgery into low, intermediate, or high surgical risk using the logistic EuroSCORE (2001-2011) or EuroSCORE II (2012-2017) and divided into age groups. Median survival time and cumulative 5-year mortality were estimated with Kaplan-Meier curves. Cox regression analysis was used to further determine the importance of age. There were 7,123 (85.1%) low-risk patients, 942 (11.3%) intermediate-risk patients, and 288 (3.5%) high-risk patients. Median survival time was 10.9 years (95% confidence interval: 10.6-11.2 years) in low-risk, 7.3 years (7.0-7.9 years) in intermediate-risk, and 5.8 years (5.4-6.5 years) in high-risk patients. The 5-year cumulative mortality was 16.5% (15.5%-17.4%), 30.7% (27.5%-33.7%), and 43.0% (36.8%-48.7%), respectively. In low-risk patients, median survival time ranged from 16.2 years in patients aged 60 to 64 years to 6.1 years in patients aged ≥85 years. Age was associated with 5-year mortality only in low-risk patients (interaction P < 0.001). Eighty-five percent of SAVR patients receiving bioprostheses have low surgical risk. Estimated survival is substantial following SAVR, especially in younger, low-risk patients, which should be considered in Heart Team discussions.
Abstract 10231: Parp1-Pkm2 Axis Mediates Right Ventricular Failure Associated with Pulmonary Arterial Hypertension
Authors: Tsukasa Shimauchi, Wenhui Wu, Yann Grobs, Junichi Omura, Eve Tremblay, Sandra Martineau, Tetsuro Yokokawa, Kana Shimauchi, Valerie Nadeau, Sandra Breuils Bonnet, Mark Orcholski, Roxane Paulin, Francois Potus, Olivier BOUCHERAT, Steeve Provencher, Sebastien Bonnet
Journal: Circulation (2021)

Introduction: Right ventricular (RV) function is the poor prognosis factor in pulmonary arterial hypertension (PAH) patients. Inflammation, oxidative DNA damage, and glycolysis are key triggering pathways that induce cardiomyocytes (CM) dysfunction. Oxidative DNA damage-dependent Poly (ADP ribose) Polymerase 1 (PARP1) activation was documented to promote glycolysis and inflammation through nuclear retention of Pyruvate Kinase Muscle isozyme 2 (PKM2). Despite PARP1/PKM2 axis is involved in many pathologies, their role in RV failure (RVF) remains unclear. We hypothesized that sustained PARP1 activation induces nuclear PKM2 localization, cardiac inflammation, and myocytes apoptosis resulting in transition from compensated (cRV) to decompensated RV (dRV). Methods and Results: We found that PARP1/PKM2 expression/activity (IF, WB) is upregulated in dRV patients (died of RVF, n=11) compared to cRV patients (CI&gt;2.2, n=12) and control donors (n=19). Similar findings were seen in two rat models of RVF (monocrotaline, PA banding). In vitro , we confirmed that oxidative DNA damage (ET-1+H 2 O 2 ) as well as inflammatory stress (ET-1+LPS) induced nuclear expression of PARP1/PKM2 (IF, WB) leading to inflammation (NF-κB nuclear translocation) and CM death (TUNEL). These effects were prevented by treatment with PARP1 inhibitor (ABT-888, Olaparib) or enforced cytosolic retention of PKM2 (TEPP-46, DASA-58). Cardiomyocytes isolated from neonatal Parp1 deficient mice were resistant to myocyte dysfunction (PKM2 nuclear upregulation, NF-κB nuclear translocation, TUNEL) induced by oxidative DNA damage (ET-1+H 2 O 2 ). In vivo , Olaparib (10mg/kg) as well as TEPP-46 (25mg/kg) prevented RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis) induced by PAB in rats (n=8~12 per group). Moreover, we confirmed that global Parp1 loss-of-function confers protection against PAB induced-RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis, n=10 per group). (All p&lt;0.05) Conclusions: We demonstrated for the first time that PARP1/PKM2 axis is a critical signal pathway RV decompensation. Targeting PARP1/PKM2 axis may represent a promising avenue for tackling maladaptive RV remodeling and pulmonary circulation, simultaneously.
INO-CD22: A Multi-Center, Real-Life Study on Inotuzumab-Ozogamicin Safety and Effectiveness in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia
Authors: Cristina Papayannidis, Patrizia Zappasodi, Nicola S Fracchiolla, Francesco Di Raimondo, Daniele Giovanni Mattei, Francesco Lanza, Endri Mauro, Maria Ilaria Del Principe, Erika Borlenghi, Monica Fumagalli, Elisabetta Todisco, Simona Sica, Nicola Di Renzo, Paolo De Fabritiis, Paolo Corradini, Daniele Vallisa, Fara Petruzziello, Mario Luppi, Fabrizio Pane, Felicetto Ferrara, Francesco Passamonti, Antonino Mulè, Chiara Zingaretti, Giovanni Marconi, Irene Valli, Elisabetta Petracci, Alberto Clemente, Giuseppe Nicola Saglio, Fabio Ciceri, Giovanni Martinelli
Journal: Blood (2021)
Roles of negative regulators in the hematopoietic differentiation of murine ES cells
Authors: Sung Lee, Andrew Sharabi, Si Chen
Journal: Cancer Research (2007)

1267  Negative regulators of proinflammatory signal transduction pathways play an important role in control of cell growth, differentiation, survival and apoptotic cell death. Our laboratory has demonstrated that suppressor of cytokine signaling (SOCS-1), a key regulator of cytokine-mediated JAK/STAT signaling, plays a critical role in regulation of the function of antigen-presenting cells such as dendritic cells (DCs). Twist-2, a basic Helix-loop-Helix (bHLH) protein, is a transcription repressor. Recently it was reported that Twist-2 represses of NF-kappaB-mediated transcription of cytokine genes in immune cells. However, it is unknown whether these negative regulators of proinflammatory signaling play roles in the regulation of self-renewal and differentiation of murine embryonic stem (ES) cells. To investigate the biological roles of SOCS1 and Twist-2, we have established LV-siSOCS1-ES, LV-siTwist2-ES, LV-siGFP-ES clones by transducing them with recombinant lentiviral vectors expressing SOCS1-siRNA (siSOCS1), siTwist2, or control siGFP, respectively. We found that SOCS1-silenced ES clones exhibited an enhanced ability to generate embryonic bodies (EBs) compared with control LV-siGFP-ES clones. In addition, Twis-2 or SOCS1 -silenced ES clones were more efficiently differentiated into hematopoietic progenitors and mature cells. These results suggest that SOCS1 and Twist-2 negatively regulate the self-renewal and differentiation of hematopoietic stem cells (HSC). Further study is under way to elucidate molecular mechanisms for their regulation of ES renewal and differentiation.
Abstract 10979: Liver-Humanized Mice Provide a New Platform to Study Human Cardiometabolic Diseases
Authors: Mirko E. Minniti, Lander Foquet, Matteo Pedrelli, Emilia Gierer, Devorah Goldman, Robert Copenhaver, Serge H. Luquet, Markus Grompe, Parini Paolo
Journal: Circulation (2021)

Introduction: Conventional mouse models do not fully recapitulate human cardiometabolic diseases (CMD), e.g. , atherosclerosis and nonalcoholic steatohepatitis (NASH), due to species differences in metabolism. Liver-humanized mice (LHM), i.e. , mice repopulated with human hepatocytes, have been shown to be an improved translatable model to study human hepatic and lipoprotein metabolism. Hypothesis: As dietary challenge is often used to induce CMD in animal models, we sought to characterize lipoprotein and lipid metabolism in LHM challenged by different diets. Methods: Immune-deficient FRGN mice receiving hepatocytes from different human donors (LHM) or NOD mouse (liver-murinized mice, LMM) were fed a high-fat/high-sucrose diet (HFHSD) for 8 weeks or a high-fat/high-fructose/high-cholesterol diet (NASH-diet) for 8, 12, 16 or 20 weeks. Plasma lipids and lipoproteins were quantified after size-exclusion chromatography separation or by routine clinical assays. Cholesterol in the descending aorta was analyzed by GC-MS. Histologic analysis of hearts or livers was done using hematoxylin/eosin or Oil Red O staining, and anti-mouse CD68-antibody was used to detect murine macrophages. Results: Compared with LMM, LHM fed either HFHSD or NASH-diet accumulated plasma cholesterol and triglycerides within LDL and triglyceride-rich particles (VLDL and remnants). However, only the NASH-diet induced a notable hyperlipidemia and a substantial increase in cholesteryl esters within the aorta. NASH-diet also determined a clear accumulation of neutral lipids and CD68-positive cells in the aortic valves of LHM. Similarly, hepatocyte ballooning, liver steatosis and fibrosis were also induced by the NASH-diet. All these pathologic changes occurred during diet challenge at different time points. Conclusions: LHM developed severe hyperlipidemia, atherosclerosis and NASH when fed a NASH-diet, but not on HFHSD. The high quantity of cholesterol in the NASH-diet likely compensates for the high utilization of cholesterol of LHM due to their known increase in bile acid synthesis, prompting dyslipidemia and CMD. LHM fed a NASH-diet is an improved model for human CMD and for the development of therapeutic strategies rapidly translatable to the human condition.
Abstract P370: The Role Of PJ-34 In The Protection Of Burn-induced Cardiomyopathy
Authors: Jake J Wen, Ravi Radhakrishnan, Keyan Mobli, Geetha L Radhakrishnan
Journal: Circulation Research (2021)

Burn injury results in adverse myocardial remodeling and heart failure through circulatingcatecholamines and androgen and cytokine cascades. The DNA binding protein PARP1(poly ADP ribose polymerase 1) catalyzes a post translational modification to generatePARylation proteins,which changes the normal function of the modified proteins. Bothof PARP-1 and SIRT1 (sirtuin1) are NAD + dependent. In this study, we propose that PJ34 (PARP-1 inhibitor) would protect the function of burn-remodeled cardiomyocytes.Commercial rats were obtained and were subject to 60% total surface body area (TSBA)scald burns by immersing the abdomen and back in boiling water. They were immediatelytreated with the PJ34 post injury. Separately, the cardiomyocytes (Ac16) were exposedto burn-serum replaced culture medium with or without treatment of lentivirus-PARP1 KOand/or SIRT-PGC-1α agonists in vitro . The in vivo experiments showed that burn-ratsexhibited cardiac hypertrophy, fibrosis and an increase in the inflammatory markers IL-1β, IFN-γ and TNFα. Burned rats had an increased oxidative stress, concomitant withelevated PARP-1 activity and reduced Sirtuin-1 (SIRT1) expression. PJ34 treatment ledto increased SIRT1 and Peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) levels and attenuated oxidative stress, inflammation, and fibrosis. In vitro tests demonstrated that the treatments of PJ34 and SIRT1-PGC-1α axis agonists incardiomyocytes exposed to burn-serum replaced culture medium led to a significantreduction in mit ROS and mitochondrial dysfunction. In Conclusion, PARP1 depletion byPJ34 in vivo and Letivirus-PARP1 KO Ac16 in vitro attenuated cardiomyopathic featuresin burn-rats through the activation of SIRT1 and its downstream antioxidant defensemechanisms. The results of this study suggest a pivotal role of PARP-1 inhibition intreating burn-induced cardiomyopathy. Keywords: Burn injury; PJ34; PARP1; Cardiomyocyte; Lentivirus.