tbuckley/cabot-search huggingface dataset:
Abstract 12478: Investigating the Shared Genetic Architecture Between Coronary Artery Disease and Major Depressive Disorder
Authors: Kritika Singh, Tyne M Miller-Fleming, Emily C Hodges, Lea K Davis
Journal: Circulation (2021)

Coronary Artery Disease is a highly polygenic disorder and has increased comorbidity with Major Depressive Disorder (MDD). Our previous work demonstrated that the PRS for MDD was significantly associated with manifestations of CAD including ischemic heart disease (OR = 1.09, p=8.28x10-6) and coronary atherosclerosis (OR = 1.10, p=1.08x10-5) in a large hospital population. Furthermore, the association remained robust after adjusting for known CAD risk factors, suggesting that some proportion of genes that increase susceptibility to MDD act pleiotropically to increase CAD risk. Therefore, the aim of our study was to identify genes that increase risk for both CAD and MDD. We first performed an imputed TWAS using existing GWAS data on CAD from the CARDIoGRAMplusC4D consortium and UKBB and MDD from Psychiatric Genomics Consortium. TWAS uses the summary statistics from a GWAS and expression prediction models to infer the association between the genetically predicted expression of each gene and a phenotype of interest. We identified genes for which predicted expression was associated with increased risk of both MDD and CAD. We then further tested the relationship between those genes and quantitative biomarkers recorded in the Vanderbilt electronic health record (EHR). For this, we used Vanderbilt’s collection of de-identified biosamples (BioVU) which currently includes ~100k genotyped patient DNA samples linked with their EHRs. We used PredixVU, a gene-based association method to determine whether genes identified in the TWAS were associated with clinical biomarkers. We identified significant overlap in the genes associated with both MDD and CAD at an FDR of 0.01 (hypergeometric enrichment factor of 3.2; p = 0.002) and 0.05 (hypergeometric enrichment factor of 2.4; p = 8.35e-9). TMEM106B was significantly associated with both MDD and CAD after Bonferroni correction was applied. TMEM106B is involved in lysosomal activity and has been independently associated with both, CAD and MDD. The predicted expression of TMEM106B in the putamen is associated with decreased levels of hydroxyproline (OR = 0.830, P-Value = 7.5 e-5). For our future work, we aim to investigate the shared pathways of these genes across Asian, European and African ancestry using BioVU.
Abstract 9820: WATCH-DM Risk Score is Associated with Functional Capacity and Prognosis in Diabetic Patients with Heart Failure with Preserved Ejection Fraction
Authors: Katsuomi Iwakura, Toshinari Onishi, Masato Okada, Nobuaki Tanaka, Yasushi Koyama, ATSUNORI OKAMURA, Kenshi Fujii, Masahiro Seo, Masamichi Yano, Takaharu Hayashi, Akito Nakagawa, Yusuke Nakagawa, Shunsuke Tamaki, Takahisa Yamada, Yoshio Yasumura, Shungo Hikoso, Yohei Sotomi, Yasushi Sakata
Journal: Circulation (2021)

Introduction: The coexistence of type 2 diabetes mellitus (T2DM) and heart failure (HF) is frequent and associated with a higher mortality. WATCH-DM risk score is recently developed to predict the risk of HF among patients with T2DM using a machine learning approach (Segar et al, Diabetes Care 2019). Hypothesis: We hypothesized that WATCH-DM risk score would be associated with functional capacity and clinical outcomes in diabetic patients with HF with preserved ejection fraction (HFpEF). Methods: The PURSUIT-HFpEF (Prospective, Multicenter, Observational Study of Patients with Heart Failure with Preserved Ejection Fraction) study is a multicenter registration of patients hospitalized for acute decompensated HFpEF. Among 1095 patients registered between 2016 and 2020, 418 patients (38.2%) had T2DM (male gender 49.5%, age 80±9 years, HbA1c 6.8±1.0%). WATCH-DM risk score was calculated in each patient, using BMI, age, systolic/diastolic blood pressure, serum creatinine, HDL-C, fasting plasma glucose, QRS duration, history of myocardial infarction or coronary bypass graft, and patients were divided as the low to average (≤10 points), high (11-13 points) and very high (≥14 points) risk groups. We measured 6 minute walk distance (6MWD) and NT-proBNP before discharge. We followed the study patients for median of 386 days (IQR 221 to 729 days) to observe the major adverse cardiovascular events (MACE; composite of death, heart failure hospitalization and stroke). Results: The WATCH-DM score in the study patients were 12.8±3.1 points, and 108 patients (25.8 %) had low-average, 147 patients (35.2%) high, and 163 patients (39.0%) very high HF risk. There was significant difference in 6MWD (p=0.004) among the groups, and the low-average risk group had significantly longer 6MWD than the high risk group (p=0.049). NT-proBNP was lower in the low-average risk group than in other 2 groups. Cox proportional hazard model selected the WATCH-DM score as an independent predictor for MACE (p=0.006). Kaplan-Meier curve demonstrated that patients with the low-average risk had significantly lower incidence of MACE than the others (p=0.049). Conclusions: The WATCH-DM risk score predicted functional capacity and prognosis in diabetic patients with HFpEF.
Clinical Outcomes of Elderly Patients with Advanced-Stage Classic Hodgkin Lymphoma Who Received an ABVD Regimen: A Multi-Center Retrospective Study in Japan (HORIZON study)
Authors: Shinichi Makita, Shigeru Kusumoto, Akiko Miyagi Maeshima, Hiroya Hashimoto, Hideki Tsujimura, Toshiki Uchida, Hiroaki Inoue, Eiichi Ohtsuka, Mitsutoshi Kurosawa, Nobuyuki Takayama, Eiju Negoro, Yasuhiro Suzuki, Junya Kuroda, Kayoko Murayama, Naoki Takahashi, Kazuyuki Shimada, Masataka Okamoto, Masanori Makita, Hiromi Iwasaki, Masahiro Yoshida, Naoko Asano, Jun-ichi Tamaru, Dai Maruyama, Motoko Yamaguchi, Hirokazu Nagai
Journal: Blood (2021)
Abstract P365: Neutrophils Contribute To Doxorubicin-induced Cardiotoxicity
Authors: Anchit Bhagat, Eugenie Kleinerman
Journal: Circulation Research (2021)

Doxorubicin is one for the most effective chemotherapy agents for the treatment of childhoodcancer. Unfortunately Dox treatment causes damage to the heart and childhood cancer survivorsare at higher risk of developing cardiovascular disease at an earlier age than community controls.Understanding the mechanisms by which Dox induces cardiotoxicity is crucial to identifyingpreventive interventions. Innate immune cells, in particular neutrophils, have been shown to playa role in other forms of cardiac disease such as atherosclerosis and myocardial infarction.However, the role of these immune cells in Dox-induced cardiotoxicity is poorly understood.We hypothesized that neutrophils contribute to the cardiac damage caused by Dox treatment andinvestigated this hypothesis using our juvenile mouse cardiotoxicity model. Mice were treated withDoxorubicin for 2 weeks. Echocardiograms were performed before and 24 hours after therapy.Hearts were then harvested, and the heart tissue evaluated for neutrophil infiltration using flowcytometry. There was a decrease in heart function as quantified by echocardiography (ejection fraction [EF] and fractional shortening [FS]) 24 hours after therapy which persisted for 12 weeks. There was also an elevation in neutrophils in heart tissue of Dox-treated mice as compared to controls. To determine whether neutrophils contributed to the functional decline seen in the Dox-treated mice, neutrophils were depleted using an anti-Ly6G antibody prior to Dox treatment. Neutrophil depletion was confirmed by flow cytometry in the blood and hearts of Dox-treated mice. Neutrophil depletion prevented the Dox-induced decrease in EF and FS seen at 24 hours and 12weeks after therapy. Additionally, we also analyzed heart sections for fibrosis and found that neutrophil depletion protected against excessive collagen deposition 12 weeks after therapy. Together these findings suggest that neutrophils contribute Dox-induced cardiotoxicity and that targeting neutrophils may be a potential strategy to prevent Dox-induced cardiotoxicity.
Abstract 9315: Mortality Risk Associated With Cessation of Mineralocorticoid Receptor Antagonists in Heart Failure Patients and Hyperkalemia; A Real-World Study From a Nationwide Administrative Database
Authors: Shun Kohsaka, Takashi Kikuchi, Rashad Mogalli, Tomoko Ishizu, Suguru Okami, Toshitaka Yajima
Journal: Circulation (2021)

Introduction: Mineralocorticoid receptor antagonists (MRAs) are guideline-directed therapy for improving clinical outcomes in heart failure (HF) patients. While maximum tolerated dose is recommended, MRA increases serum potassium (sK), leading to dose reduction or cessation. However, optimal threshold of sK level for MRA cessation or continuation in HF patients remains unclear. In this study, we assessed impact of MRA cessation on risk-benefit balance of hyperkalemic (HK) HF patients. Methods: A retrospective observational study was conducted using a Japanese hospital claim database (April 2008-September 2018). HK was defined as at least two sK ≥5.1 mmol/L within a 12-months interval. MRA cessation was defined as discontinuing MRA ≥ 30 days within 1 year from first HK episode. We examined relative mortality risk between hyperkalemic HF patients with or without MRA cessation by employing propensity score (PS) matching method. To evaluate risk-benefit balance between the two groups, cubic spline regression curve was generated by calculating mean hazard ratios (HR) in each sK strata. Results: Out of 15,442 hyperkalemic HF patients, we found 2,220 patients with MRA prescriptions (mean age, 77.77±10.95 years; follow-up period, 2.4±1.9 years). Cumulative incidence of MRA cessation and dose reduction was 52.7% and 6.5% at 1 year, respectively. In the PS matching analysis including HK patients, mortality rate was significantly higher in MRA cessation group compared to no cessation group (HR 1.21, 95% CI: 1.01-1.44, p=0.038). In cubic-spline analysis, increased relative mortality risk with MRA cessation compared to no cessation was observed in sK level below 5.7 mmol/L (Figure). Conclusions: We found a high MRA cessation rate amongst HF patients with HK, despite increased mortality risk in those with ceased MRA at sK level below 5.7 mmol/L in our real-world cohort. Careful consideration of risk-benefit balance is needed for MRA cessation in hyperkalemic HF patients.
Abstract 11539: Causes of Thirty Day Readmissions Following Left Atrial Appendage Closure
Authors: Murtaza A Sundhu, Usama Nasir, Tayyab Ali Waheed, Keerat Rai Ahuja, SALIK NAZIR, Dhaval Kolte, P. Kasi Ramanathan
Journal: Circulation (2021)

Introduction: Left Atrial Appendage Occlusion (LAAO) devices provide non pharmacological methods of preventing stroke in patients with atrial fibrillation who cannot tolerate anticoagulation. Data on 30-day readmission measures following LAAO is limited. Methods: Nationwide Readmissions Database from 2016 to 2018 was utilized to identify patients undergoing LAAO. Incidence, prevalence, and causes of readmission were identified. Predictors of 30-day readmission were also identified using complex sample multivariable regression model. Results: Among 29,367 patients receiving LAAO, the average rate of readmission was 9.2%. Readmitted patients were more likely to be females with heart failure, peripheral vascular disease, chronic lung disease, chronic liver disease, and chronic kidney failure especially end stage renal disease (ESRD).The most common overall cause of 30-day readmission was gastrointestinal bleeding (18.5%), followed by heart failure (13.1%), and infection (7.3%) (Figure 1). The odds of readmission were highest in the end stage renal disease patients (OR - 2.75; 95% CI, 2.13 - 3.55; p&amp;lt;0.001) followed by presence of pericardial effusion requiring intervention (OR - 2.13; 95% CI, 1.26 - 3.61; p=0.005) and Stroke/TIA (OR - 1.82; 95% CI, 1.10 - 3.01, p=0.02). Conclusions: The highest odds of readmission were associated with ESRD, periprocedural pericardial effusions requiring intervention, and in hospital stroke/TIA. Gastrointestinal bleeding remained the most common overall cause of readmission, followed by heart failure, and infections. To improve 30-day post-procedural outcomes, further studies are warranted to better identify reversible factors.
Abstract 11475: A Genetically Modified pH Resistant NCX1 Mouse Prevents Calcium Overload During Acidosis and is Cardioprotective
Authors: Rui Zhang, Xiaokang Wu, Catherine Xie, Devina Gonzalez, Sabine Lotteau, Joice Thomas Gavali, Liang Li, Scott John, Kenneth D Philipson, Michela Ottolia, Joshua I Goldhaber
Journal: Circulation (2021)

Acidosis inhibits the cardiac sodium(Na)/calcium(Ca) exchanger (NCX1), allegedly contributing to elevated cytoplasmic Na and Ca concentrations during ischemia. Upon reperfusion and restoration of normal pH, a reactivated NCX1 abruptly shifts into reverse (Ca influx) mode because of the abnormally high cellular Na concentration, thus producing massive Ca overload and cell damage. To test the dependence of ischemia/reperfusion (I/R) injury on NCX1’s pH sensitivity, we used CRISPR/Cas9 technology to create mice with a pH-resistant NCX1 by substituting Alanine for Histidine at position 165 (H165A). These mice live into adulthood with slightly reduced LV function (EF% H165A: 50 ± 5; Wildtype (WT): 67 ± 2; p&lt;0.025, N=4-6). In enzymatically isolated adult ventricular myocytes, we used the patch clamp technique and voltage ramps from +80 to -120 mV to confirm that NCX1 current in H165A mice is resistant to pH reduction (from 7.4 to ~pH 6.4 by substituting 80 mM Na-Acetate for equimolar NaCl) when compared to WT animals (% reduction at +80mV: WT 77.7± 2.8, P&lt;0.027 in 3 cells from 2 mice; H165A 0.21 ± 11.35, P=0.31 in 7 cells from 3 mice). We then performed I/R studies in explanted hearts perfused in Langendorff fashion with oxygenated Tyrode’s containing (in mM): 136 NaCl, 1.8 CaCl 2 , 5.4 KCl, 0.33 NaH 2 PO 4 , 1.0 MgCl 2 , 10 HEPES, and 10 glucose, pH 7.4, 37 o C. 20 minutes of stop-flow ischemia were followed by reperfusion for 120 minutes. Necrosis area (pixels 2 ) in WT was 26 ± 3 (N=11), compared to only 9 ± 1 (N=7) in H165A mice (P&lt;0.0004). To compare effects of lower pH on isolated cardiomyocyte Ca, we used a photometric epifluorescence detection system to measure cytosolic Ca in enzymatically isolated ventricular myocytes loaded with the Ca indicator fura-2 AM (2 μM). When pH was lowered to ~6.4, Ca transients (ΔF340/F380) increased in WT from 0.6 to 0.9 (P &lt; 0.0004, N=19 cells from 3 mice) but notably did not change in H165A (0.5 ± 0.03 @ pH 7.4, 0.5 ± 0.04 @ pH 6.4, P=0.307, N=21 cells from 3 mice). pH changes were verified in separate cells using the pH indicator SNARF-AM (10 μM). We conclude that eliminating pH sensitivity in NCX1 has major effects on intracellular Ca regulation, is cardioprotective, and a potential strategy for therapies in patients with prolonged ischemia prior to reperfusion.
CSIG-30. TARGETING TELOMERASE VIA MEK INHIBITION IN AGGRESSIVE TERT PROMOTER MUTATED BRAIN TUMORS
Authors: Daniela Lötsch-Gojo, Lisa Gabler, Carola Jaunecker, Kerstin Fürnweger, Katharina Bruckner, Lisa Mayr, Sibylle Madlener, Dominik Kirchhofer, Sabine Spiegl-Kreinecker, Karl Roessler, Walter Berger, Johannes Gojo
Journal: Neuro-Oncology (2021)

Abstract Activating point mutations within the TERT promoter (C228T or C250T) account for the most frequent alteration in aggressive brain tumors. Presence of these alterations results in the generation of binding sites for E-twenty-six (ETS) transcription factors accompanied by enhanced TERT expression. Accordingly, TERT promoter mutations foster cellular immortalization and subsequently tumor aggressiveness. Due to the limitation of treatment options in aggressive brain tumors, including glioblastoma and medulloblastoma, new therapeutic targets need to be discovered. As we previously described a strong interaction of oncogenic MEK/ETS signaling and TERT promoter mutations, we hypothesize that inhibition of these factors halters cell immortalization in TERT-driven brain tumors. Our study included three TERT promoter wild-type (TERTwt), six mutated (TERTmut) glioblastoma and three TERTmut medulloblastoma cell models and tested the effect of MEK inhibitors (U0126 and trametinib) and the ETS inhibitor YK-4-279 on cell viability and clone formation. Cellular senescence upon treatment was evaluated by beta-galactosidase assays. Impact on TERT mRNA expression and TERT promoter activity were analyzed by quantitative real-time PCR and luciferase reporter assays, respectively. Furthermore, the effects on MAPK- and PI3K pathway activation were evaluated by Western blot. Amongst the investigated inhibitors, tumor cells harboring C228T mutation were distinctly more sensitive against trametinib as compared to TERTwt and C250T TERTmut cells. Similar effects were observed on clonogenicity upon long-term exposure to this inhibitor. Regarding MAPK signaling activation, trametinib treatment completely blocked ERK phosphorylation in every cell model, while activation of ETS1 was more effectively reduced in C228T TERTmutcells. Accordingly, exposure to trametinib reduced TERT expression and promoter activity accompanied by induction of cellular senescence in cells with C228T mutation. Impact of trametinib is currently investigated in preclinical experiments using TERTmut brain tumor models. Summarizing, MEK inhibition represents a novel strategy to overcome cell immortalization especially in C228T TERTmut brain tumors.
Abstract 17024: Treatment of Drug-coated Balloon Combined With Rotational Atherectomy is Effective for the Dcb Failure In-stent Restenosis Lesions
Authors: Hiroyuki Nagai, Atsunori Okamura, Katsuomi Iwakura, Kenshi Fujii
Journal: Circulation (2017)

Background: Drug-coated balloon (DCB) angioplasty could be a standard treatment for in-stent restenosis (ISR) lesions. Previously studies have reported that repeat DCB angioplasty for DCB failure h...
Abstract 13530: Epi+Gen CHD: A More Sensitive and Cost-Effective Tool to Assess Risk and Monitor Treatment Response for Coronary Heart Disease
Authors: Meesha Dogan, Willem Philibert, Younsoo Jung, Tim Dogan, David Frisvold, Allan Andersen, Eric Hoffman, Robert Philibert
Journal: Circulation (2021)

Coronary heart disease (CHD) is preventable, but current lipid-based risk assessment tools such as The Framingham Risk Score (FRS) and ASCVD Pooled Cohort Equation (PCE) have limitations. Using DNA-based genetic and epigenetic biomarkers, we have developed a more sensitive and cost-effective incident CHD risk assessment tool, Epi+Gen CHD, that can provide actionable insights and monitor treatment response. This test can be administered remotely via telemedicine using at-home sampling, or in a clinical setting. Epi+Gen CHD was developed and validated using machine learning techniques and datasets from the Framingham Heart Study (FHS) and Intermountain Healthcare (IM). It incorporates five SNPs and three methylation markers for predicting 3-year incident CHD. It was more sensitive than FRS and PCE and had high generalizability across cohorts with sensitivity/specificity of 79/75% in the FHS test set and 75/72% in the IM set. In contrast, the sensitivity/specificity was 15/93% in FHS and 31/89% in IM for FRS, and sensitivity/specificity was 41/74% in FHS and 69/55% in IM for the PCE. To assess cost effectiveness, we conducted cost-utility analyses of Epi+Gen CHD. As compared to the PCE, we found that the use of Epi+Gen CHD was associated with both better survival and highly competitive negative incremental cost-effective ratios (cost savings) ranging from -$42,000 to -$-8,000 per quality-adjusted life year with and without accounting for a secondary test. Finally, to understand if the epigenetic biomarkers in Epi+Gen CHD could be leveraged to monitor treatment response, we performed a proof-of-concept study that assessed the three Epi+Gen CHD methylation sites in 39 subjects before and after 3 months of biochemically verified smoking cessation, then analyzed the relationship between change in methylation at each of the sites to the change in smoking intensity (cg05575921 methylation). We showed that in those who quit smoking, methylation change at one Epi+Gen CHD site (cg00300879) was significantly associated with change in smoking intensity (p &lt; 0.04). We conclude that Epi+Gen CHD can identify patients at risk for CHD, save more lives, reduce more healthcare spending and guide prevention interventions better than current methods.
Abstract 10766: Sovateltide Induces Neuroprotection in a Neonatal Rat Model of Hypoxic Ischemic Encephalopathy
Authors: Seema Briyal, Michelle Davis Ramos, Sarah Hurrell, Preetha Prazad, Anil Gulati
Journal: Circulation (2021)

Introduction: Hypoxic-ischemic encephalopathy(HIE) is a major cause of morbidity, mortality, and severe neurodevelopmental disability in term neonates. The development of a treatment strategy that could provide neuroprotection is still required. We have shown that agonism of endothelin B(ETB) receptors mediated through sovateltide provides neuroprotection and enhances neurovascular remodeling in several neuropathological conditions. Hypothesis: We hypothesize that administering sovateltide alone or as an adjuvant therapy with hypothermia could provide neuroprotection by reducing oxidative stress and promoting cell survival post-HIE brain injury. Methods: Sprague-Dawley male and female rat pups were grouped separately and were divided into 5 different subgroups (1) Control; (2) HIE+Vehicle; (3) HIE+Hypothermia; (4) HIE+sovateltide; and (5) HIE+sovateltide+hypothermia. HIE was induced by ligating the right carotid artery on a postnatal day (PND) 7, followed by hypoxia for 120 min and hypothermia (32-34°C) for 5 h. On PND 7, sovateltide (5 μg/kg, ICV) was injected after hypoxic-ischemic injury. Pups were euthanized on PND 10. Brains were isolated, and ETB receptors, VEGF, NGF, cell death and oxidative stress makers - malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were assessed. Results: Animals receiving sovateltide showed a significant (p&lt;0.0001) upregulation of ETB receptor (135%), VEGF (110%), and NGF (183%) expression in the brain compared to vehicle. Vehicle-treated animals had high oxidative stress levels, as indicated by increased lipid peroxidation, MDA, and decreased antioxidants, SOD, and GSH compared to control. These effects were reversed (p&lt;0.001) in sovateltide alone or in combination with the hypothermia, indicating reduced oxidative stress in these animals. Additionally, sovateltide alone or in combination with hypothermia reduced (p&lt;0.001) cell death compared to vehicle or hypothermia alone. Similar findings were obtained in both male and female rats. Conclusion: Sovateltide alone or as an adjunct to hypothermia exerts neuroprotective effects in HIE-induced brain injury in rat pups, suggesting sovateltide could be a potential therapeutic agent for neonatal HIE.