tbuckley/cabot-search huggingface dataset:
Abstract 10770: Trans-Ancestry Multivariate Genome-Wide Analysis Highlights the Role of Common Genetic Variation in Cardiac Structure, Function, and Heart Failure-Related Traits
Authors: Michael Levin, Noah Tsao, Tiffany Bellomo, William P Bone, Renae Judy, Megan Burke, Michael Morley, Yifan Yang, Sharlene Day, Zoltan Arany, Patrick T Ellinor, Thomas P Cappola, Kenneth B Margulies, Benjamin F Voight, Scott Damrauer
Journal: Circulation (2021)

Introduction: The contribution of common genetic variation to heart failure (HF) risk has not been fully elucidated. Here, we applied multi-ancestry and multivariate methods to summary genetic data from &gt;1 million individuals to improve power to identify common genetic variants, genes, cells, tissues, and circulating proteins/metabolites associated with HF and related cardiac imaging traits. Methods: Trans-ancestry meta-analysis of HF (56,722 cases and 1,133,054 controls) was performed using METAL. Multivariate analysis including GWAS of HF and imaging traits (MRI and echocardiogram) was performed using N-GWAMA. Downstream transcriptome-wide association studies (TWAS; S-PrediXcan), tissue/cell enrichment (LDSC-SEG using RNAseq and snRNAseq of human left ventricle samples from the MAGnet consortium), and Mendelian randomization (MR) analyses were performed. Results: The multi-ancestry HF GWAS identified 15 loci associated with all-cause HF (p &lt; 5 x 10 -8 ). Multivariate analysis identified 48 (16 novel) loci (p &lt; 5 x 10 -8 ), with enrichment for loci near Mendelian cardiomyopathy genes (p &lt; 1 x 10 -4 ). Genetic associations were enriched (FDR &lt; 0.05) for cardiac and musculoskeletal gene expression and chromatin marks. Gene expression (p = 0.007) and splicing events (p = 0.01) were enriched for established cardiomyopathy genes. Branch chain amino acid dehydrogenase ( BCKDHA ) expression was prioritized in TWAS, and MR identified causal associations between circulating branch chain amino acids and cardiac imaging traits: LVEDV MRI (leucine β = -0.137, 95% CI -0.25 to -0.022, p = 0.02; isoleucine β = -0.276, 95% CI -0.38 to -0.17, p = 3 x 10 -7 ) and LVSEV MRI (leucine β = -.131, 95% CI -0.24 to -0.026, p = 0.01; isoleucine β = -0.217, 95% CI -0.33 to -0.11, p = 1 x 10 -4 ). Unbiased proteome-wide MR of 725 circulating proteins identified 18 significant (FDR &lt; 0.05) causal protein-trait associations, including between lipoprotein(a) and HF (OR 1.09 per 1-SD increase in lipoprotein(a), 95% CI 1.06 to 1.11, p = 1.6 x 10 -11 ). Conclusion: These analyses implicate novel common genetic variation in the pathogenesis of HF, highlight Mendelian cardiomyopathy genes in common HF, and identify circulating metabolites and proteins that may represent new treatment targets.
Abstract 9980: Cardio-Omentopexy Requires a Cardioprotective Innate Immune Response to Promote Myocardial Angiogenesis
Authors: Zhi-Dong Ge, Riley Boyd, Connor Lantz, Edward B Thorp, Joseph M Forbess
Journal: Circulation (2021)

Introduction: The greater omentum is replete with angiogenic factors and macrophages. Cardio-omentopexy (COP), wherein the pedicled greater omentum is applied onto ischemic or pressure-overloaded hearts, has been shown to be protective in both humans and animals. However, the protective mechanisms of COP remain unclear. Hypothesis: We hypothesized that COP protects the heart against pressure overload-induced cardiac hypertrophy and dysfunction via a macrophage-dependent mechanism of myocardial angiogenesis. Methods: C57BL/6 mice underwent transverse aortic constriction (TAC) for 6 weeks followed by COP for 8 weeks. Cardiac geometry and function were evaluated using echocardiography (n=12-13 mice/group). Histochemical analyses quantified cardiomyocyte size, fibrosis, microvessel density, and macrophages. Flow cytometry was performed to analyze neutrophil/monocyte/macrophage populations. Gene expression array was also performed. A group of mice receiving both TAC and COP were intraperitoneally injected with clodronate-liposomes (5 mg/kg every three days for 8 weeks) starting on day 3 after COP. Results: TAC produced concentric left ventricular hypertrophy, reduced mitral E/A ratio, increased cardiomyocyte size, and myocardial fibrosis in the mice undergoing sham COP surgery (TAC + /COP - ). These maladaptive effects of TAC were abrogated by COP (TAC + /COP + ). Myocardial microvessel density was elevated in TAC + /COP + mice. Gene array analysis showed activation of angiogenesis gene networks by COP. Flow cytometry revealed that COP resulted in the accumulation of cardiac MHCII lo Lyve1+TimD4+ resident macrophages at the omental-cardiac interface. Moreover, the depletion of macrophages with clodronate-liposomes (Clo + /TAC + /COP + ) resulted in the failure of COP to prevent left ventricular hypertrophy, enhance mitral E/A ratio, decrease cardiomyocyte size and myocardial fibrosis, and promote angiogenesis. Conclusions: COP protects the pressure-overloaded left ventricle from hypertrophy and dysfunction, with associated angiogenesis. Cardiac resident macrophages accumulate near COP, and macrophage depletion eliminates the benefits of COP. These studies support a novel macrophage-dependent effector function of COP.
Abstract 13264: Gender-Based Risk Prediction for 1-year Readmission Among Younger Women Hospitalized for Acute Myocardial Infarction
Authors: Andrew J Arakaki, Valeria Raparelli, Terrence Murphy, Sui Tsang, Gail DONOFRIO, Malissa Wood, Catherine F Xie, Louise Pilote, Rachel P Dreyer
Journal: Circulation (2021)

Background: Younger women (≤55 years) are at higher risk for readmission within one-year of hospitalization following acute myocardial infarction (AMI) compared to similarly aged men, yet there are no gender-specific risk prediction models for this population. Prior research suggests that gender-related factors more comprehensively explain sex-based differences in readmission risk. The objective was to develop and validate a risk prediction model of 1-year post-AMI readmission in young women considering demographic, clinical, and gender-related factors. Methods: We used data from women enrolled in the VIRGO study (n =2,007), a prospective observational study of young patients aged ≤55 years hospitalized with AMI in the US. Data were obtained from patient interviews, medical record abstraction, and adjudicated hospitalization records. Bayesian Model Averaging was used for model selection in a derivation cohort of 1338 women and subsequently validated in the remaining 669 women. Results: Within 1-year post-AMI, 684 (34.1%) women were readmitted at least once with a majority of readmissions due to cardiac causes (57.5%). The final model contained 9 predictors: experiencing any in-hospital complications, physical health at baseline (SF-12), disease-specific quality of life (Seattle Angina Questionnaire), diabetes, history of congestive heart failure, low income (≤30,000 USD), depression, length of hospital stay, and employment status (Figure) . Of the 9 predictors, 5 were gender-related. The model was well calibrated (calibration plots) and exhibited modest discrimination (C statistic=0.66 in development and validation cohorts). Conclusions: Younger women with diabetes, depression, history of congestive heart failure, and longer hospital stays were more likely to be readmitted. While clinical factors were the strongest predictors of readmission within 1-year among younger women with AMI, gender-related variables were important complements.
Abstract 11707: Incidence and Clinical Features of Transthyretin Amyloidosis Diagnosed by Histologic Analysis of Tenosynovial Tissue From Patients Undergoing Carpal Tunnel Surgery
Authors: Saheli Nandi, Michael R Dibenedetto, Maximillian Soong, Alice A Hunter, Philip Formica, Sarju Ganatra, David M Venesy, Sachin P Shah, Richard D Patten
Journal: Circulation (2021)

Introduction: Transthyretin (TTR) cardiac amyloidosis (CA) is an increasingly recognized cause of heart failure (HF) with preserved ejection fraction (HFpEF) that is associated with a poor prognosis. Retrospective series have demonstrated that amyloidogenic TTR (ATTR) deposition in tenosynovial sheaths such as that causing carpal tunnel syndrome precedes the onset of HF due to ATTR CA by several years. Methods: We conducted an analysis of 136 patients (pts) who presented for carpel tunnel surgery from whom tenosynovial material was analyzed with Congo Red staining to determine the frequency of samples positive for ATTR deposition and to explore whether this approach might lead to earlier diagnosis and treatment of ATTR CA. Results: Among these 136 pts, 31 were confirmed to have positive Congo Red staining tenosynovial tissue, all of which demonstrated the ATTR subtype determined by liquid chromatography/mass-spectroscopic analysis. ATTR positive pts were significantly older than negative pts (74 + 8 yrs vs. 59 + 13 yrs, p&lt;0.01). 58 % of ATTR positive pts were male and 42% female. At the time of this submission, only 1 of these 31 subjects demonstrated a TTR mutation (valine-isoleucine 122). 19 pts have undergone cardiac screening of which 2 males demonstrated ATTR CA by bone scintigraphic imaging. Conclusions: 23% of pts undergoing carpal tunnel release exhibit ATTR amyloid deposition by histologic analysis, all of whom tested positive for the ATTR subtype with 2 asymptomatic male pts exhibiting cardiac involvement. Among our positive ATTR pts, 42% are female exceeding the 10-20% percent female prevalence among patients with HF due to ATTR CA reported previously. This preliminary observation supports a protective role of female gender in limiting progression to HF due to ATTR amyloidosis. The evaluation of this population is ongoing and will be reported at the annual meeting. Broadly, however, our data support that identifying ATTR amyloid protein within tenosynovial tissue obtained during routine surgery is warranted as this approach, when combined with appropriate cardiac screening, facilitates early diagnosis and treatment of ATTR CA before the onset of overt clinical heart failure.
Abstract 11355: Contemporary Patterns of Lipoprotein(a) Testing and Associated Clinical Care and Outcomes
Authors: Michelle D Kelsey, Hillary Mulder, Karen Chiswell, Zachary M Lampron, Ester K. K Nilles, Jacquelyn P Kulinski, Parag H Joshi, William S Jones, Alanna M Chamberlain, Thorsten M Leucker, Wenke Hwang, Michael W Milks, Anuradha Paranjape, Kathleen M McTigue, Jihad Obeid, Macrae F Linton, Shia Kent, Emily C OBrien, Neha J Pagidipati
Journal: Circulation (2021)

Introduction: Elevated lipoprotein(a) [Lp(a)] is associated with atherosclerotic cardiovascular disease (ASCVD), yet little is known about Lp(a) testing patterns in real-world practice. We hypothesized that Lp(a) testing occurs in a different population than calculated low density lipoprotein (LDL-C) testing alone, and that elevated Lp(a) is associated with greater lipid-lowering therapy (LLT) initiation and cardiovascular (CV) events. Methods: We used data from 11 health systems participating in the National Patient-Centered Clinical Research Network. We created two cohorts based on lab tests from Jan 1, 2015 to Dec 31, 2019: 1) the Lp(a) cohort, of adults with an Lp(a) test and 2) the LDL-C cohort, of 4:1 date- and site-matched adults with an LDL-C test, but no Lp(a) test. We used logistic regression to assess the relationship between Lp(a) levels (&lt; 50, 50-100, and &gt; 100mg/dL) and initiation of LLT within 3 months; and cox proportional hazards to evaluate Lp(a) levels and time to all-cause hospitalization and the composite of MI, revascularization and ischemic stroke hospitalization. Results: Overall, 20,551 patients (0.06% per year) had Lp(a) tests, with median Lp(a) value 17.5mg/dL (Q1, Q3: 7.0, 56.0). Compared with the LDL-C cohort (N=82,204), the Lp(a) cohort more frequently had ASCVD (24.3% vs. 8.5%) or multiple prior CV events (8.6% vs. 2.6%). Elevated Lp(a) was associated with greater odds of LLT initiation (Figure 1). Elevated Lp(a) was not significantly associated with all-cause hospitalization; however, Lp(a) &gt; 100mg/dL was correlated with composite CV hospitalization compared with Lp(a) &lt; 50mg/dL [adj HR (95% CI): 1.24 (1.06-1.44), p=0.006]. Conclusions: Lp(a) testing occurs more often in adults with ASCVD and multiple CV events, but testing is infrequent. Elevated Lp(a) was associated with LLT initiation, including niacin, despite lack of evidence of CV benefit. There was an association between elevated Lp(a) and CV hospitalization outcomes.
Disease Kinetics Measured By Circulating Tumor DNA Correlates with Treatment Response after Tafasitamab in Combination with R-CHOP with or without Lenalidomide in First Line Treatment of DLBCL
Authors: Mouhamad Khouja, Anke Schilhabel, Michaela Kotrova, Monika Brüggemann, Christian Kuffer, Derek Blair, Nikos Darzentas, Christiane Pott
Journal: Blood (2021)
Asparaginase Induced Liver Enzyme Elevation Is More Prevalent in Hispanics Children with ALL and in Patients with <i>SOD2</i> rs4880 CC Genotype
Authors: Sharon Wu, Mengxi Wang, Amani Ali Alqahatni, Mimi Lou, Wendy Stock, Deepa Bhojwani, Houda Alachkar
Journal: Blood (2021)
Abstract 10200: Enhanced Human VIC Calcification and Altered RNA Expression in Dynamic Culture with Induction Media in Microphysiological Systems
Authors: Claudia Dittfeld, Maximilian Winkelkotte, Florian Schmieder, Stephan Behrens, Anett Jannasch, Klaus Matschke, Sems-Malte Tugtekin, Frank Sonntag
Journal: Circulation (2021)

Introduction: Aortic valve (AV) calcification is the main characteristic in AV stenosis affected by fibrosis, endothelial cell layer damage and altered shear stress. Osteogenic differentiation of valvular interstitial cells (VIC) is research focus. VIC culturing in micro-physiological systems (MPS) that allows the adjustment of flow rate/shear force and oxygen concentration are new approaches to evaluate AV disease processes. Culture media inducing VIC calcification were applied in dynamic MPS VIC culture to investigate the impact on calcification and gene expression. Methods: A MPS able to modulate fluidic conditions (pulsatile flow of 2.7 μl/s resulting in average shear forces of 0.04 dyn/cm 2 ) was applied for human VICs. ADGMedium (50 μM ascorbic acid phosphate, 100 nM dexamethasone,10 mM β-glycerophosphate) was compared with PMedium (2 mmol/L NaH 2 PO 4 , 0.3 mM ascorbic acid) and standard DMEM (72 h). VIC viability was proven using a lactate dehydrogenase assay. Calcium accumulation was quantified in dynamic vs. static culture and mRNA expression of ACTA2, FN1, COL1A1, COL3A1, RUNX2 and SOX9 was quantified via qRT-PCR. Results: Viability of MPS VIC cultures was confirmed. ADGM induced calcium accumulation was significantly enhanced to 5.1 ± 1.4 Ca 2+ mol/kg protein in dynamic but not static culture compared to static DMEM control (0.1 ± 0.2 Ca 2+ mol/kg protein; n=4). PM resulted in a significantly higher calcium level compared to static DMEM control in static and dynamic chip culture (7.8 ± 5.2 and 9.2 ± 1.6 Ca 2+ mol/kg protein). Myofibroblastic ACTA2, Fibronectin and osteogenic factor RUNX2 were significantly induced but SOX9 (prevents AV calcification) was downregulated in ADGM but not in PM and independent from culture dynamics. Collagen COL1A1 mRNA level was significantly enhanced two-fold in ADGM and PM but exclusively in dynamic culture. An induction of COL3A1 was detected in ADGM dynamic but not static culture vs. DMEM counterparts. Conclusion: Dynamic culture significantly enhances calcium content in ADGM induced VIC cultures accompanied with enhanced collagen expression. MPS culture allows the investigation of VIC pathogenesis at defined shear forces and seeking the combined adjustment of oxygen supply. SMT and FSo contributed equally
Abstract 12315: Circulating Gut Microbial Peptides Aggravate Cardiac Inflammation and Promote DNA Hypomethylation at the TLR-2 Promoter Region in Type 2 Diabetic Mice
Authors: Ram Prasad, Vikash Kansal, Prabhat Ranjan, Suresh K Verma, Maria Grant
Journal: Circulation (2021)

Introduction: Epigenetic modifications, especially DNA methylation, influence key biological processes, including inflammation, and are considered as a “switch” between gene silencing and gene activation. Promoter DNA hypomethylation activates TLR-2, a modulator of inflammation, and may impact cardiac function in T2D. Hypothesis: The gut microbial peptide peptidoglycan (PGN) enters the circulation via a leaky gut and activates TLR-2 in cardiac tissue by DNA hypomethylation contributing to cardiac dysfunction in T2D. Methods: T2D ( db/db ) and wild-type mice were euthanized after four months of diabetes. Assessment of gut permeability, gut and systemic inflammation, and hypomethylation (5hmC) of cardiac tissue was performed using IHC, qPCR, ELISA, and western blot analysis. In-vitro studies were conducted in PGN-treated cardiomyocytes with and without 2-hydroxyglutarate (2HG). Results: db/db mice showed cardiac dysfunction as measured by reduced percent of LVEF (46.2±2.7 vs. 65.8±1.8; p&lt;0.001), LVFS(22.7±1.6 vs. 35.4±1.3; p&lt;0.001), and increased LV mass (192.4±17.0 vs. 105.8±12.4; p&lt;0.006) compared with WT controls. db/db mice also exhibited higher gut permeability as observed by reduction of tight junction proteins (ZO-1, p120-catenin, and β-catenin) and increased levels of plasma FABP-2. The levels of PGN were higher in plasma (84.19 ± 13.56 vs. 27.21 ± 8.4; p&lt;0.003) and cardiac tissue (1361 ± 236.1 vs. 113 ± 25.58; p&lt;0.001) of db/db mice. The expression of TLR-2 (2.26 folds; p&lt;0.003), pro-inflammatory cytokines IL-1β (p&lt;0.008), and TNF-α (p&lt;0.0004) were significantly up-regulated compared to WT mice. Expression of 5hmC was significantly higher (18.48±1.32 vs. 5.91±0.28; p&lt;0.001) in the hearts of diabetic mice. Increased expression of 5hmC, ten-eleven translocation 1-3 (TET-1, 2, 3), IL-1β, IL-6, and TNF-α were also observed in PGN treated cardiomyocytes. 2HG treatment blocked PGN- mediated DNA hypomethylation and inflammation in cardiomyocytes. Conclusions: Circulating gut peptides have deleterious effects on cardiac health in diabetic mice by promoting DNA hypomethylation of TLR2 and increased inflammation. Strategies aiming to restore gut barrier integrity may beneficially impact diabetic cardiovascular complications.
Genomic medicine in the Middle East
Authors: Ahmad N. Abou Tayoun, Khalid A. Fakhro, Alawi Alsheikh-Ali, Fowzan S. Alkuraya
Journal: Genome Medicine (2021)

We discuss the current state of genomic medicine in Arab countries of the Middle East, a region with outsized contribution to Mendelian genetics due to inbreeding yet has poor representation in global variome datasets. We focus on genomic testing, clinical genetics, and genetic counseling services along with associated training and research programs. Finally, we highlight opportunities for improvement in genomic medicine services in this region.
Abstract 13586: Association Between Subclinical Atherosclerosis and Midlife Cognitive Function: <i>The Bogalusa Heart Study</i>
Authors: Ileana De Anda-duran, Camilo Fernandez, David J Libon, Owen T Carmichael, Shakira F Suglia, Vijaya B Kolachalama, Rhoda Au, Lydia A Bazzano
Journal: Circulation (2021)

Introduction: Alzheimer’s disease and related dementias (ADRD) are increasing in prevalence. While overt atherosclerosis is recognizable from childhood and has been linked to cognitive impairment and dementia in late life, information is scant on the association between subclinical atherosclerosis and cognitive impairment in midlife. We examined this observation in a cohort of middle-aged noninstitutionalized participants living in a semirural community. Hypothesis: Increased cIMT is associated with worse cognitive performance in midlife. Methods: The analysis included 1,217 participants (age 48 ± 5.28 years; 66% white, 58% women) of the Bogalusa Heart Study. Multivariable-adjusted regression models were used to determine the association between composite cIMT, dichotomized at the 50thpercentile, and a standardized global cognitive z-score (GCS), as well as individual cognitive domains z-scores. Results: The composite cIMT (&gt;0.87mm) was inversely associated with GCS (B= -0.39, SE= 0.18, p = 0.03), independent of cardiovascular risk factors (CVRF’s) and education. (Table1) The cIMT-composite was independently associated with poorer episodic memory (B= -0.23, SE=0.10, p = 0.015). The effect remained significant in Black and White participants after adjustment for CVRF’s (Blacks:B= -0.45, SE: 0.17, p = 0.008; Whites: B= -0.29, SE= 0.13, p = 0.028), but not for education. Conclusions: Subclinical atherosclerosis, as assessed via cIMT, is associated with worse cognitive function in midlife, independent of major CVRFs. The association is buffered by education, and this effect may be stronger among black participants than white. These findings reinforce the importance of establishing preventive measures in midlife and suggest subclinical atherosclerosis as a potential target to prevent cognitive decline.
Abstract 10462: Increased Bone Morphogenetic Protein 10 Activity is Associated with Increased Right Atrial Wall Stress and Disease Severity in Pulmonary Hypertension
Authors: Aida Llucià-Valldeperas, Jessie Van Wezenbeek, Joanne A Groeneveldt, Gonzalo Sanchez-Duffhues, Rowan Smal, Xiaoke Pan, anton vonk noordegraaf, Harm J Bogaard, Marie Jose Goumans, Frances S De Man
Journal: Circulation (2021)

Background: Pulmonary Hypertension (PH) is characterized by increased right atrial (RA) stretch and pressure. The major predisposing risk factor for PH involves mutations in bone morphogenetic protein (BMP) receptor 2 (BMPR2), for which BMP9 and BMP10 are ligands. In adults, BMP10 is produced by RA cardiomyocytes, however, the mechanism to BMP10 release is unknown. We hypothesize that RA wall stress may be a trigger for BMP10 secretion. Methods: We determined BMP10 and BMP9 levels in plasma samples from PH-patients (22 idiopathic pulmonary arterial hypertension (iPAH), 14 hereditary PAH (hPAH) and 11 chronic thromboembolic PH (CTEPH)) and 16 controls by ELISA. To study BMP10 and BMP9 activity, we exposed endothelial cells to 10% serum and analyzed BMP-activity as read out of the BRE-luciferase reporter assay. Serum was incubated with trap antibodies: anti-BMP9 to inhibit BMP9 ligand, and ALK1-Fc to inhibit both BMP9 and BMP10 ligands. BMP9 and BMP10 activity were deducted from the difference vs baseline and BMP9-activity, respectively. Results: Circulating BMP10 levels were higher in PH-patients: 16.5 [9.5-69.7] pg/mL in iPAH, 17.1 [1.4-113.4] pg/mL in hPAH and 37.8 [10.7-87.1] pg/mL in CTEPH, vs 6.1 [0-8.7] pg/mL in controls (A). No differences were observed in BMP9 levels (B). BMP10 and BMP9 activity appeared lower in iPAH, only a trend was seen in BMP9-activity in iPAH vs hPAH (C,D). Next, we divided the PH cohort on median BMP10-activity. Higher active BMP10 in PH was associated with an increase in RA volume and pressure, and reduced RA compliance (E). Further, higher BMP10-activity in PH-patients was associated with worse disease status, shown by worse right ventricular function, lower stroke volume and increased NTproBNP (F). Conclusions: BMP10 circulating levels were increased in PH, whereas no difference in circulating BMP10-activity was observed. High BMP10-activity was associated with increased RA wall stress and disease severity in PH-patients.