tbuckley/cabot-search huggingface dataset:
Abstract 13992: Cardiovascular Disease Risk of Abnormal Glucose Tolerance Depends on Etiology: Insulin Resistance versus Beta-Cell Failure
Authors: Annemarie Wentzel, MC Sage Ishimwe, Nana H Osei-Tutu, Thomas Hormenu, Arielle C Patterson, Christopher W DuBose, Anne E Sumner
Journal: Circulation (2021)

Background: Cardiovascular disease (CVD) and abnormal glucose tolerance (Abnl-GT) are rapidly increasing in sub-Saharan Africa. Abnl-GT is a primary risk factor for CVD. Yet, different Abnl-GT etiologies, insulin resistance (IR) or β-cell failure, may have different CVD risk profiles. Therefore, in 493 African-born Blacks living in the United States [male: 64%, age: 38±10y (mean±SD)], we evaluated the CVD risk profile within each Abnl-GT etiology. Methods: OGTT were performed. Abnl-GT, a term combining diabetes and prediabetes, was defined as fasting plasma glucose (FPG)≥100 mg/dL and/or glucose at 2h≥140 mg/dL. IR was defined by the upper quartile of HOMA-IR (≥2.03). Abnl-GT-IR required both Abnl-GT and IR. Abnl-GT-β-cell failure was defined as Abnl-GT without IR. Fasting lipids, including high-density lipoprotein (HDL), low-density lipoprotein (LDL) particle sizes, were measured. Dyslipidemia was defined as total cholesterol, TC&gt;200mg/dL, LDL&gt;130mg/dL, HDL&lt;35mg/dL and triglycerides, TG&gt;150mg/dL or any combination thereof. CVD risk was determined by the Pooled-Cohort Equation (PCE) [age, TC, HDL, SBP, diabetes, smoking status], as developed in the ARIC cohort. Results: Abnl-GT occurred in 37% (183/493) of participants, with Abnl-GT due to IR in 28% (69/183) and β-cell-failure in 62% (114/183). Neither systolic nor diastolic BP differed between the Abnl-GT groups (both P &gt;0.05). HDL, HDL-size and LDL-size were lower and TG higher in the IR group compared to the β-cell-failure group (all P &lt;0.01). The prevalence of dyslipidemia was higher in the IR than the β-cell-failure group at 49% (34/69) vs 28% (32/114) ( P &lt;0.05). The IR had a higher PCE score versus the β-cell failure group [26.5±2.7 vs 18.8.0±1.9 ( P =0.001)]. Conclusions: Although IR was a less common cause of Abnl-GT than β-cell failure, the IR group had a more adverse lipid profile and therefore a higher CVD risk compared to the β-cell failure group. Thus, the etiology of Abnl-GT should be taken into account when developing treatment strategies for patients at higher CVD risk.
High Dose Fractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone (mHyperCVAD) Is an Active Regimen in Heavily Pretreated Relapsed/Refractory Multiple Myeloma, Enabling Access to Experimental Therapies
Authors: Nicole Watts, Smith Giri, Kelly N. Godby, Gayathri Ravi, Luciano J. Costa, Susan Bal
Journal: Blood (2021)
SETD5 modulates homeostasis of hematopoietic stem cells by mediating RNA Polymerase II pausing in cooperation with HCF-1
Authors: Mengke Li, Chen Qiu, Yujie Bian, Deyang Shi, Bichen Wang, Qiuyi Ma, Xiaomin Wang, Jun Shi, Lianfeng Zhang, Yuanwu Ma, Ping Zhu, Tao Cheng, Yajing Chu, Weiping Yuan
Journal: Leukemia (2021)

Abstract SETD5 mutations were identified as the genetic causes of neurodevelopmental disorders. While the whole-body knockout of Setd5 in mice leads to embryonic lethality, the role of SETD5 in adult stem cell remains unexplored. Here, a critical role of Setd5 in hematopoietic stem cells (HSCs) is identified. Specific deletion of Setd5 in hematopoietic system significantly increased the number of immunophenotypic HSCs by promoting HSC proliferation. Setd5 -deficient HSCs exhibited impaired long-term self-renewal capacity and multiple-lineage differentiation potentials under transplantation pressure. Transcriptome analysis of Setd5 -deficient HSCs revealed a disruption of quiescence state of long-term HSCs, a cause of the exhaustion of functional HSCs. Mechanistically, SETD5 was shown to regulate HSC quiescence by mediating the release of promoter-proximal paused RNA polymerase II (Pol II) on E2F targets in cooperation with HCF-1 and PAF1 complex. Taken together, these findings reveal an essential role of SETD5 in regulating Pol II pausing-mediated maintenance of adult stem cells.
Abstract 10144: Xcr1 <sup>+</sup> Dendritic Cell-Induced Cd4 <sup>+</sup> T Helper-1 Activation Leads to Exacerbation of Remodeling After Myocardial Infarction
Authors: Hiroyasu Inui, Makoto Nishida, Masumi Asaji, Ayami Saga, Kotaro Kanno, Chang Jiuyang, Yinghong Zhu, Takeshi Okada, Katsunao Tanaka, Tohru Ohama, Masahiro Koseki, Shizuya Yamashita, Yasushi Sakata
Journal: Circulation (2021)

Background and Aim: Immune response including T cell activation after myocardial infarction (MI) is important mechanism in cardiac remodeling. We established a new model of ischemic cardiomyopathy using SR-BI KO/ApoeR61 h/h (SRBI KO) mice in which MI is induced by high fat diet (HFD) for 7 days. We aimed to clarify the precise mechanism leading to post-MI cardiac remodeling: activation of inflammatory CD4 + T-cell subsets and conventional dendritic cells (cDCs), using our non-surgical MI, coronary ligation MI and conditional cCDs KO mice model. Methods and Results: Probucol, a potent antioxidant, was known to improve cardiac remodeling in rat MI model. Using SRBI +/- mice as a non-MI control group, we fed SRBI KO mice HFD to induce MI (non-treatment group) and added probucol (treatment group). With probucol treatment, survival rate and EF were improved, and fibrosis area was reduced. We analyze CD4 + cell subsets in the heart, blood and spleen. Th1 was predominantly increased and activated in border and infarcted area, and decreased with probucol treatment. RNA-seq revealed, specifically Th1 related chemokines, CXCR3 was down-regulated with probucol treatment. Flow data revealed, CXCR3 was highly expressed in Th1 (up to 50%) and decreased with probucol treatment. To elucidate the mechanism of the predominant activation of Th1 after MI, we analyze the dynamics of cDCs. XCR1 + cDCs was activated and decreased with probucol treatment. Furthermore, CXCR3 ligands, CXCL9 and CXCL10, were highly expressed in XCR1 + cDCs (up to 50%). In bone marrow, siglec-H – Ly6C – pre-DCs (XCR1 + cDCs lineage) were increased in non-treatment group and also in coronary ligation MI model, and decreased with probucol treatment. Finally, to confirm the induction of post-MI Th1 type inflammation by XCR1 cDCs, we conducted the conditional depletion of XCR1 + cDCs. In XCR1 KO mice, infiltration of CXCR3 + Th1 in the infarcted area and fibrosis area was decreased, and deterioration of EF, which was evaluated by cardiac MRI, was suppressed after MI. Conclusions: The predominant activation of Th1 after MI exacerbated cardiac remodeling. CXCR3 chemokine system were characteristic of Th1 and XCR1 + cDCs. The modulation of Th1- XCR1 + cDCs interaction could be a novel therapeutic target in post-MI remodeling.
Abstract 14102: National Trends and Disparities in Hospitalization for Hypertensive Emergencies Among Medicare Beneficiaries, 1999-2019
Authors: Yuan Lu, yun wang, Erica S Spatz, Oyere K Onuma, Khurram Nasir, Fatima Rodriguez, Karol E Watson, Harlan M Krumholz
Journal: Circulation (2021)

Introduction: In the last two decades, hypertension control in the U.S. population has worsened, and there are widening disparities. Less is known, however, about trends in hospitalizations related to hypertensive emergencies. Methods: We conducted serial cross-sectional analysis of Medicare fee-for-service beneficiaries aged 65 years or older between 1999 and 2019 using Medicare denominator and inpatient files. We evaluated trends in national hospitalization rates for hypertensive emergencies, overall and by demographic and geographic subgroups. Results: The sample consisted of 397,238 individual Medicare fee-for-service beneficiaries. From 1999 through 2019, the annual hospitalization rates for hypertensive emergencies increased significantly from 51.5 to 125.9 per 100,000 beneficiary-years; this increase was most pronounced among the following subgroups: adults ≥85 years (66.8 to 274.1), females (64.9 to 160.1), Blacks (144.4 to 369.5), and Medicare-Medicaid insured (dual eligible, 93.1 to 270.0). Across all subgroups, Black adults had the highest hospitalization rate in 2019, and there was a significant increase in the differences in hospitalizations between Blacks and Whites from 1999 to 2019. Marked geographic variation was also present, with the highest hospitalization rates in the South (so-called “Stroke Belt”). Among 3,143 counties and county-equivalents included in the study, less than 1% of counties either had no change (n=7) or decreased (n=20) hospitalization rates since 1999. Conclusions: Among Medicare fee-for-service beneficiaries aged 65 years or older, hospitalization rates for hypertensive emergencies increased substantially and significantly from 1999 to 2019. Black adults had the largest increase in hospitalization rates across age, sex, race, and dual-eligible strata. There was significant national variation, with the highest rates generally in the South.
Abstract 12669: Precision Phenotyping of Left Ventricular Hypertrophy With Echocardiographic Deep Learning
Authors: Grant Duffy, Paul Cheng, Bryan He, Neal Yuan, Joseph Ebinger, James Zou, Jignesh K Patel, Ronald M Witteles, Susan Cheng, David Ouyang
Journal: Circulation (2021)

Introduction: Left ventricular hypertrophy (LVH) results from chronic remodeling caused by broad range of systemic and cardiovascular disease including hypertension, aortic stenosis, hypertrophic cardiomyopathy, and cardiac amyloidosis. Early detection and characterization of LVH can significantly impact patient care but is limited by under-recognition of hypertrophy, measurement error and variability, and difficulty differentiating etiologies of LVH. Methods: To overcome this challenge, we present EchoNet-LVH, a deep learning workflow that quantifies ventricular hypertrophy precision equal to human experts, identifies patients with LVH, and predict etiology of hypertrophy. Trained on 28,201 echocardiogram videos, our model was implemented in Pytorch and evaluated on an independent dataset from an international healthcare system. Human expert annotations of anatomic structures in parasternal long axis echocardiogram videos were used as labels for supervised training. Results: EchoNet-LVH accurately measures ventricular dimensions with an R 2 of 0.97 compared to expert annotations. EchoNet-LVH accurately evaluated intraventricular wall thickness (mean absolute error 0.14cm), left ventricular diameter (MAE 0.24cm), posterior wall thickness (MAE 0.12cm) and classifies cardiac amyloidosis (area under the curve of 0.83 on held-out test data) from other etiologies of LVH. In an external dataset of 1,791 echocardiogram studies, EchoNet-LVH reliably quantified ventricular parameters with R 2 of 0.90 and MAE 0.22cm, 0.36cm, and 0.17cm respectively for IVS, LVID, and LVPW. Conclusions: Leveraging measurements across multiple heart beats, our model can rapidly identify subtle changes in LVH, is more reproducible than human evaluation, and lays the foundation for precision diagnosis of cardiovascular disease.
Abstract 11643: ACTN4 Regulates HLA-DPA1-Related Pulmonary Endothelial Pathophenotypes in Pulmonary Arterial Hypertension Through Allele-Specific Binding to Functional SNP rs9277336
Authors: Neha Hafeez, Wei Sun, Danli Jiang, Ting Wu, Anna Kirillova, Gang Li, Stephen Y Chan
Journal: Circulation (2021)

Introduction: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary arterial pressure and vascular resistance. This vascular injury promotes immune dysregulation, further worsening the vasculopathy. A genome-wide association study identified a single nucleotide polymorphism (SNP) associated with PAH risk (rs2856830) at Human Leukocyte Antigen DPA1 (HLA-DPA1) locus, a gene known to be involved in adaptive immunity. However, little is known about the mechanism underlying this clinical association. Hypothesis: Allele-specific binding of transcription factors to a disease-associated functional SNP (fSNP) controls HLA-DPA1 expression, driving pulmonary vascular cell dysfunction and PAH. Methods: Oligonucleotides containing alleles of rs2856830 and eight SNPs in linkage disequilibrium (LD) were subjected to electrophoretic mobility shift assays (EMSA) to identify fSNPs characterized by allele-imbalanced binding to human pulmonary arterial endothelial cells (PAEC) nuclear proteins. SNP genotyping was done using blood from PAH (n=134) and control patients (n=131) at UPMC. Transcriptomics, angiogenesis, and migration were assessed in siRNA mediated HLA-DPA1 and Alpha Actinin 4 (ACTN4) knockdown (KD) in PAECs. Results: Through EMSA, rs9277336 (LD r 2 =0.87) was identified as a fSNP in HLA-DPA1 locus. SNP pulldown and immunoblotting confirmed allele-specific binding of nuclear ACTN4 protein to rs9277336 risk allele A (3.26 ± 0.49, p=0.001). SNP genotyping revealed a 2.04 ± 0.67 fold enrichment of risk allele A in PAH patients (χ 2 test, p=0.025). ACTN4 KD in cultured human PAECs decreased HLA-DPA1 transcript (0.30 ± 0.10, p&lt;0.001) . Transcriptomics revealed overlap of several cell structure and immune system-related pathways by HLA-DPA1 and ACTN4 KD. HLA-DPA1 and ACTN4 KD affected PAH associated pathophenotypes, including angiogenesis and migration. Conclusions: Our functional analysis identified ACTN4 as a novel regulator to disease-associated gene HLA-DPA1, affecting the endothelial pathophenotypes in PAH. The allele-specific binding to fSNP rs9277336 provides a mechanistic explanation for the clinical association between HLA-DPA1 locus and PAH outcomes.
Abstract 14208: Annexin A5 Inhibits Endothelial Inflammation Induced by Lipopolysaccharide-Activated Platelets and Extracellular Vesicles
Authors: Brent J Tschirhart, Xiangru Lu, Qingping Feng
Journal: Circulation (2021)

Introduction: Sepsis is a leading cause of death worldwide with no targeted therapeutics available. Sepsis results from a dysregulated immune and inflammatory response. During sepsis or lipopolysaccharide (LPS) stimulation, platelets are activated, and release procoagulant/proinflammatory membrane-derived extracellular vehicles (EVs). Our previous studies show recombinant human annexin A5 (Anx5), a phosphatidylserine-binding protein, inhibits inflammation and improves survival in endotoxic mice, a model of sepsis. Hypothesis: Anx5 will block the pro-inflammatory response induced by LPS-activated platelets and EVs in vascular endothelial cells (ECs). Methods: ECs were cultured from adult C57BL/6 mice. Platelets and EVs were activated by LPS and added to ECs for four-hours with/without AnxA5. Inflammatory cytokines and adhesion molecule expression was quantified in ECs using RT-qPCR. Endothelial monolayer structural integrity was measured in septic conditions using trans-endothelial electrical resistance (TEER). Monocytes were added to LPS-treated ECs and adhesion was quantified via brightfield microscopy. Results: Supplementation of annexin A5 (1 μg/ml) on ECs treated with LPS-activated platelets and EVs reduced the expression of inflammatory cytokines and adhesion molecules on ECs when compared to ECs treated with LPS (1 μg/ml) activated platelets and EVs alone. In septic conditions, endothelial monolayers that were treated with annexin A5 had a higher TEER compared to the monolayers without annexin A5, indicating that annexin A5 preserved endothelial monolayer structural integrity in septic conditions. Annexin A5 treated ECs also had significantly less monocytes adhesion in septic conditions when compared to ECs treated without annexin A5. Conclusions: The proinflammatory response induced by activated platelets and EVs is inhibited by Anx5. The ability to maintain the structural integrity of endothelial monolayers and reduce monocyte adhesion during septic conditions, makes Anx5 a promising treatment option for sepsis.
Abstract 14370: Mortality Among Patients With Heart Failure After Initiation of Hemodialysis
Authors: Joshua R Hirsch, Mahmoud Al Rifai, Sankar Navaneethan, Anita M Deswal
Journal: Circulation (2021)

Introduction: Patients with kidney failure on hemodialysis (HD) have a high risk of cardiovascular (CV) events and a high burden of heart failure (HF) morbidity and mortality. Standard HF therapies have not been proven to have similar benefits in patients with kidney failure. While comorbid HF and kidney failure requiring HD portends poor prognosis, the survival for patients with pre-existing HF who start HD and its relationship to left ventricular ejection fraction (EF) has not been well-described. Methods: We included patients with a diagnosis of HF (ICD-9/10 codes confirmed by chart review) and chronic kidney disease (CKD) seen at a tertiary care VA medical center and subsequently initiated on HD between 1/2005 and 12/2017. Echocardiographic data, including baseline and follow-up EF and baseline clinical data at time of HD initiation, and date of death or last follow-up were collected using chart review. Time to event analysis for all-cause mortality from date of HD initiation was conducted. Results: The cohort included 356 patients (mean age 66.2 ± 9.0 years, 96.6% male, 55.6% CAD, 20% CABG). HF with preserved EF (HFpEF; EF≥50%) was the most common HF subgroup (62%), followed by HF with reduced EF (HFrEF; EF≤40%) and HF with mid-range EF (HFmrEF; EF 41-49%) (23% and 15%, respectively). Mean time from HF diagnosis to HD start was 1.75 ± 1.95 years. Compared to HFrEF, HFpEF patients had shorter time to HD start (1.60 vs. 2.12 years, p=0.046). The overall survival after initiation of HD for patients with pre-existing HF was 80.9% at 1-year, 64.2% at 2-year, and 37.0% at 5-year follow-up. Median survival was longest for HFpEF (4.1 years), followed by HFmrEF (3.2 years) and HFrEF (1.6 years) ( Figure ). Conclusions: Patients with pre-existing HF and CKD who transition to HD experience significant mortality, with HFrEF patients having substantially worse survival. Further study of HF optimization prior to and after HD initiation is needed, especially in the highest risk HFrEF patients.
Abstract 11104: Association of Cigarette Smoking and Coronary Artery and Extra-Coronary Calcification in Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Ning Ding, Frances Wang, Olufunmilayo H Obisesan, Lynne Wagenknecht, Aaron R Folsom, Candace M Howard-Claudio, Josef Coresh, Matthew J Budoff, Michael J Blaha, Kuni Matsushita
Journal: Circulation (2021)

Introduction: Smoking is a major risk factor for atherosclerosis, but its impact is heterogeneous across different vascular beds (e.g., stronger association with peripheral artery disease than coronary disease). However, whether the association of cigarette smoking with vascular calcification is (dis)similar across vascular beds is uncertain. Methods: In 1,961 ARIC participants without a history of coronary heart disease at visit 7 (2018-19), we quantified the associations of pack-years of smoking and years since cessation with coronary artery calcium (CAC) and extra-coronary calcification (ECC) using multivariable logistic regression models. High CAC and ECC (aortic valve, aortic valve ring, mitral valve, ascending aorta, and descending aorta calcification) were defined as Agatston score &gt;75th percentile and were analyzed separately as dependent variables. Results: Pack-years of smoking demonstrated an independent and robust dose-response relationship with CAC, ascending and descending aorta calcification, and aortic valve ring calcification (Table). The association was particularly evident for descending aorta calcification (e.g., adjusted odds ratio [aOR] 3.57 [95%CI 2.46-5.19] for ≥40 pack-years). The results were similar for the duration since smoking cessation, with the most prolonged risk seen for the descending aorta (i.e., even ≥30 years of smoking cessation had OR of 1.34 [1.03-1.47]). Aortic valve and mitral valve calcification demonstrated modest associations with smoking. Conclusions: Cigarette smoking showed a robust association with coronary and extra-coronary calcification, and its association was particularly strong with descending aorta calcification. Our findings further emphasize the harm of smoking on broad ranges of vascular beds and simultaneously highlight unique pathophysiologic mechanisms across different vascular beds and cardiac valves.
Abstract 13849: Association of Optimal Blood Pressure and Risk of Atrial Fibrillation in Aged Type 2 Diabetes Mellitus Patients: From the JPAD Cohort Study
Authors: Chisa Matsumoto, Hisao Ogawa, Yoshihiko Saito, Sadanori Okada, Hirofumi Soejima, Mio Sakuma, Izuru Masuda, Masafumi Nakayama, Naofumi Doi, Hideaki Jinnouchi, Masako Waki, Takeshi Morimoto
Journal: Circulation (2021)

Introduction: Even, both type 2 diabetes (T2DM) and hypertension are important risk factors for nonvalvular atrial fibrillation (NVAF), the efficacy of strict blood pressure control for prevention of NVAF have not been established. Hypothesis: We assessed the hypothesis that optimal blood pressure is associated with lower risk of NVAF among T2DM patients in long term cohort of aged Japanese T2DM patients, JPAD cohort study. Methods: The JPAD cohort study was a follow-up cohort study of the JPAD trial, which was a randomized, standard-care controlled trial examining whether low-dose aspirin prevented cardiovascular disease (CVD) events in 2535 Japanese patients with T2DM from 2002. After that trial ended in 2008, we followed up the patients until 2019. Optimal blood pressured was defined as systolic blood pressure &lt; 120 mm Hg at baseline regardless of use of antihypertensive drugs. The association of optimal blood pressure and risk of NVAF was evaluated by Cox proportional hazard model adjusted for conventional risk factors for CVD. We also performed subgroup analysis by use of antihypertensive drugs. Results: Mean age of participants was 65 ± 10 years. During the median follow up of 10.9 years, 132 patients developed NVAF. The adjusted hazard ratio (HR) and its 95% confidence interval (CI) of NVAF of T2DM patients with optimal blood pressure comparing to those with higher blood pressure was 0.89 (0.45-1.75). In subgroup analysis by use of antihypertensive drugs, the results were not altered. The risk of NVAF among patients with optimal blood pressure comparing to those with higher blood pressure among patients using antihypertensive drugs and those not using antihypertensive drugs were 1.08 (0.34-3.45) and 0.78 (0.34-1.79), respectively. Conclusions: Optimal blood pressure was not associated with lower risk of NVAF among aged T2DM patients. However, due to high risk profile of NVAF among aged T2DM patents, careful follow up may be still necessary for prevention of CVD.