tbuckley/cabot-search huggingface dataset:
Abstract 11671: Inpatient Cardiac Rehabilitation After Hospitalization for Acute Decompensated Heart Failure is Associated With Reduced Cardiovascular Events
Authors: Nobuyuki Enzan, Shouji Matsushima, Tomomi Ide, Hidetaka Kaku, Takeshi Tohyama, Kouta Funakoshi, Taiki Higo, Hiroyuki Tsutsui
Journal: Circulation (2021)

Introduction: The effects of cardiac rehabilitation during acute decompensated heart failure (HF) hospitalization remain to be elucidated. This study sought to determine whether inpatient cardiac rehabilitation after HF hospitalization could improve outcomes in HF patients. Methods: We analyzed HF patients enrolled in the Japanese Registry Of Acute Decompensated Heart Failure (JROAD-HF), a national database of HF. Eligible patients were divided into two groups according to the inpatient cardiac rehabilitation. The primary outcome was the composite of cardiovascular death or re-hospitalization due to cardiovascular event after discharge. The secondary outcomes were cardiovascular death and re-hospitalization due to cardiovascular event. Results: Out of 10,473 eligible patients, 3,210 patients underwent cardiac rehabilitation. Propensity score matching yielded 2,635 pairs. The mean age was 77.2 years and 2,927 (55.5%) was male. Ischemic heart disease was accounted for 28.8% and the mean left ventricular ejection fraction was 45.2 ± 17.1. During a mean follow-up of 2.8 years, the cardiac rehabilitation group had a lower incidence rate of the composite of cardiovascular death or re-hospitalization due to cardiovascular event (284.0 vs. 311.7 events per 1000 patient-years; rate ratio [RR] 0.89; 95% confidence interval [CI] 0.83-0.96; P = 0.003), and re-hospitalization due to cardiovascular event (255.4 vs. 283.9 events per 1000 patient-years; RR 0.90; 95% CI 0.83-0.97; P = 0.007) than the no cardiac rehabilitation group. Cardiovascular death was not different between groups (71.0 vs. 75.5 events per 1000 patient-years; RR 0.94; 95% CI 0.83-1.06; P = 0.31). Cubic spline analysis showed that patients with lower Barthel index were benefited by cardiac rehabilitation. Conclusions: The implementation of cardiac rehabilitation during HF hospitalization was associated with better long-term outcomes in patients with HF.
Abstract 13028: Cannabis Use Disorder Adversely Affects Outcomes of Diabetics Hospitalized With Prior Myocardial Infarction and Revascularization: A National Propensity-Matched Analysis
Authors: Rupak Desai, Viralkumar Patel, Divyank Patel, Dipen Zalavadia, Akhil Jain, Gautam Kumar, Rajesh Sachdeva
Journal: Circulation (2021)

Background: Increasing unmonitored use of recreational cannabis in the United States is alarming especially among patients with known cardiovascular disease (CVD) risk. Considering mixed reports of cannabis use and its impact on diabetes mellitus and associated outcomes, we aimed to assess the impact of cannabis use disorder (CUD) on outcomes of diabetics hospitalized with prior myocardial infarction (MI) and revascularization [PCI and/or CABG]. Methods: We queried the National Inpatient Sample (2015Oct-2017Dec) to identify admissions among diabetics with prior revascularized MI and CUD. Propensity score-matched analysis (1:1) was performed adjusting for demographic and hospital characteristics to obtain CUD+ &amp; CUD- cohorts which were then compared for comorbidities and in-hospital outcomes. Primary outcomes were major adverse cardiac and cerebrovascular events (MACCE: all-cause mortality, acute MI, cardiac arrest and stroke) and subsequent revascularization and secondary outcomes were median hospital stay and charges. Results: Each diabetic cohort with prior MI and revascularization consisted of 190 patients with and without CUD (CUD+ vs. CUD-). Both matched cohorts were comparable in terms of demographics (Table 1) and had balanced distribution of most of the CVD risk factors except hypertension (92.1% vs. 97.4%; p=0.022) and renal failure (18.4% vs. 28.9%; p=0.016) which were lower in the CUD+ cohort. The rates of MACCE (28.9% vs. 10.5%) and revascularization (23.7% vs. 7.9%, p&lt;0.001) were significantly higher in the CUD+ cohort (p&lt;0.001). Furthermore, the CUD+ cohort was less often routinely discharged (63.2% vs. 76.3%) with higher length of stay (4 vs. 3 days) and hospital charges. Conclusion: This nationwide propensity-matched analysis revealed that the CUD increases the rates of MACCE, subsequent revascularization with higher healthcare resource utilization in diabetics hospitalized with a prior history of MI and revascularization.
Abstract 12352: Reducing Inflammation In Coronary Atherosclerosis: A Renewed Look At Colchicine
Authors: Mustafa Alam, Olga V Savinova, Sunny Jhamnani
Journal: Circulation (2021)

Introduction: Atherosclerosis is an inflammatory disease. Randomized controlled trials (RCT) have demonstrated that targeting inflammation is important for the secondary prevention of major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS) and chronic coronary artery disease (CAD). Out of these trials, low-dose colchicine has emerged as an inexpensive therapy for coronary atherosclerosis. This meta-analysis focuses to understand colchicine’s anti-inflammatory efficacy via reduction in high sensitivity C-Reactive Protein (hs-CRP) in patients with ACS and CAD Methods: A computerized search of MEDLINE was conducted to retrieve journal articles reporting the results in human studies performed from January 1, 2005 to January 1, 2021 using the keywords: “Colchicine” AND “Coronary” OR “CRP” OR “Coronary Artery Disease.” Studies were included if they measured hs-CRP changes from baseline and colchicine or placebo were given to patients with ACS or CAD. Studies were graded on quality via the Jadad scoring criteria. Results: A total of nine studies with a total population of 1502 patients and mean Jadad score of 4 were included in the meta-analysis. Five studies were RCT. The mean/median age ranged from 57 to 67 years while the duration of therapy ranged from one day to one year. Overall, colchicine treatment reduced hs-CRP levels compared with placebo (standardized mean difference [SMD]: -0.45; 95% CI: -0.68, -0.22; p=0.0001). Conclusions: Colchicine reduces hs-CRP in patients with ACS and CAD. This finding supports the role of colchicine in the reduction of inflammation associated with ACS or CAD. Further randomized control trials are needed to quantify long-term inflammatory control and subsequent MACE reduction.
Abstract 12597: Phenotypic Drug Screen Reveals That Lacidipine, a Calcium Channel Blocker, Enhances the Vascular Lumen Formation
Authors: Dorota Nawrot, Lutfiye Yildiz Ozer, Ayman Al Haj Zen
Journal: Circulation (2021)

Background: Vascular lumen formation is a critical process of angiogenesis towards establishing a functional circulatory system capable of delivering oxygen and nutrients to tissues. Targeting lumen formation is required for the development of efficient therapeutic angiogenesis. Objective: Perform a drug screen to identify compounds regulating the vascular lumen formation using a novel 2D angiogenesis assay that mimics the lumen formation of blood vessels and suitable for high throughput applications. Methods and Results: First, we optimized the phenotypic angiogenesis assay that captures the cellular process of lumen formation. Human Umbilical Vein Endothelial Cells (HUVEC) were seeded on Matrigel-coated wells. A mixture of matrix gel was added on top of adhered HUVEC. HUVECs form luminized vascular-like structures in 48 hours. To identify modulators of lumen formation, we conducted a high content screen of a library containing 150 FDA-approved cardiovascular drugs. The screening resulted in five calcium channel blockers being able to increase the lumen area compared to controls. Lacidipine was selected for further mechanistic studies. We found the cells in the luminal space stained positively for activated caspase-3 at 24 hours using immunofluorescence. Pharmacological inhibition of RAC1 or caspase activity abolished the Lacidipine-enhancing effect on lumen formation, suggesting the involvement of apoptosis and cell polarization. Next, we found that the addition of ML7, an MLCK inhibitor, enhances the lumen formation by inducing apoptosis. In contrast, the addition of the ROCK inhibitor GSK429286 or blebbistatin, an inhibitor of non-muscle myosin II ATPase, did not affect the lumen formation. Using a Ca2+ biosensor imaging, Lacipidine reduces the intracellular Ca2+ oscillations amplitude in the migrating cells at the early stage (6 hours), whereas Lacidipine blocked these Ca2+ oscillations completely at the late stages (24-48 hours). Conclusions: This study highlights a novel high throughput phenotypic assay to evaluate vascular lumen formation. Our findings suggest that calcium signaling plays a vital role during lumen morphogenesis, and calcium channel blockers could be used for more efficient angiogenesis-mediated therapies.
Abstract P503: Aldehyde Dehydrogenase 2 Activator 1 Potentiates The Effects Of Empagliflozin, A Sodium-glucose Cotransporter 2 Inhibitor, In Diabetes-mediated Heart Failure With Preserved Ejection Fraction
Authors: Guodong Pan, Bipradas Roy, Suresh Palaniyandi
Journal: Circulation Research (2021)

4-hydroxy-2-nonenal (4HNE), a cellular reactive aldehyde which is significantly increased in diabetic hearts due to decrease in the activity of its metabolizing enzyme, aldehyde dehydrogenase (ALDH)2, contributes to diabetes mellitus (DM)-mediated cardiotoxicity. Therefore, we hypothesize that lowering 4HNE ameliorates heart failure with preserved ejection fraction (HFpEF) in DM. To ameliorate DM mediated HFpEF, we will lower diabetes-mediated oxidative stress-induced 4HNE accumulation as well as augment 4HNE detoxification by activating ALDH2, via pharmacological agents. We induced type-2 DM by feeding high-fat diet (HFD) in ALDH2*2 mutant mice which have intrinsically low ALDH2 activity and thus having increased cardiac 4HNE levels. After 4 months of DM, the mice exhibited features of HFpEF and we treated the diabetic ALDH2*2 mice with vehicle (Veh), empagliflozin (EMP) (3mg/kg/d), a sodium-glucose cotransporter (SGLT) 2 inhibitor to reduce hyperglycemia and Alda-1 (10mg/kg/d), an ALDH2 activator to enhance ALDH2 activity as well as combination of EMP + Alda-1 (E + A), via subcutaneous osmatic pumps. After treating for 2 months, cardiac function was assessed by conscious echocardiography before and after exercise stress. EMP + Alda-1 improved running distance (RD, 231 ± 53 m), ejection fraction after running (EF, 69 ± 5 %), and decreased left atrial area (LA, 3.0 ± 0.2 mm 2 ), cardiomyocyte cross-section area (CA, 251 ± 32 μm 2 ) and myocardial fibrotic area (FA 1.0 ± 0.3 %) in ALDH2*2 mice with diabetic HFpEF compared to EMP (RD 142 ± 53 m; EF 62 ± 5 %; LA 3.5 ± 0.3 mm 2 ; CA 303 ± 55 μm 2 ; and FA 3.2 ± 1.8 %), Alda-1 (RD 183 ± 73 m; EF 68 ± 3 %; LA 3.2 ± 0.2 mm 2 ; CA 288 ± 34 μm 2 ; and FA 2.5 ± 1.2 %) and Veh (RD 52 ± 66 m; EF 55 ± 5.0 %; LA 4.7 ± 0.4 mm 2 ; CA 448 ± 65 μm 2 ; and FA 11 ± 3.5 %). This improvement was exerted by decreasing 4HNE levels as well as attenuating 4HNE-mediated decrease in cardiac liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. In conclusion, our data implicate that ALDH2 activation along with the treatment of hypoglycemic agents may be important strategy to alleviate diabetic HFpEF.
STEM-14. THE WRAD COMPLEX REPRESENTS A THERAPEUTIC TARGET FOR CANCER STEM CELLS IN GLIOBLASTOMA
Authors: Kelly Mitchell, Joseph Alvarado, Christopher Goins, Steven Martinez, Jonathan Macdonald, Daniel J Silver, Gustavo Roversi, Kristen Kay, Rachel Schafer, Anjali Kashyap, Adam Lauko, Erin E Mulkearns-Hubert, Sadie Johnson, Jeremy N Rich, Shaun Stauffer, Christopher Hubert, Justin Lathia
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) progression and resistance to conventional therapies is driven in part by cells within the tumor with stem cell properties including quiescence, self-renewal and drug efflux potential. It is thought that eliminating these cancer stem cells (CSCs) is a key component to successful clinical management of GBM. However, currently, few known molecular mechanisms driving CSCs can be exploited for therapeutic development. Core transcription factors such as SOX2, OLIG2, OCT4 and NANOG maintain the CSC state in GBM. Our laboratory recently uncovered a self-renewal signaling axis involving RBBP5 that is necessary and sufficient for CSC maintenance through driving expression of these core stem cell maintenance transcription factors. RBBP5 is a component of the WRAD complex, which promotes Lys4 methylation of histone H3 to positively regulate transcription. We hypothesized that targeting RBBP5 could be a means to disrupt epigenetic programs that maintain CSCs in stemness transcriptional states. We found that genetic and pharmacologic inhibition of the WRAD complex reduced CSC growth, self-renewal and tumor initiation potential. WRAD inhibitors partially dissembled the WRAD complex and reduced H3K4 trimethylation both globally and at the promoters of key stem cell maintenance transcription factors. Using a CSC reporter system, we demonstrated that WRAD complex inhibition decreased growth of SOX2/OCT4 expressing CSCs in a concentration-dependent manner as quantified by live imaging. Overall, our studies assess the function of the WRAD complex and the effect of WRAD complex inhibitors in preclinical models and specifically on the stem cell state for the first time in GBM. Studying the functions of the WRAD complex in CSCs may improve understanding of GBM pathogenesis and elucidate how CSCs survive despite aggressive chemotherapy and radiation. Our ongoing studies aim to develop brain penetrant inhibitors targeting the WRAD complex as an anti-CSC strategy that could potentially synergize with standard of care treatments.
Abstract 11433: Protein-Energy Malnutrition is Associated with Higher Mortality and Adverse Clinical Outcomes in Patients with Systolic Heart Failure with History of Atrial Fibrillation
Authors: Michael Fatuyi, Leanne Pereira, Awfa Zain elabidin, Vahid Namdarizandi, Bassman Tappuni, Emmanuel Akuna, Belal Kaseer, Rukayat Otulana, Vivek Sharma, Asimul H Ansari, Kamal Shemisa
Journal: Circulation (2021)

Introduction: Poor nutritional status worsens clinical outcomes in multiple disease states. Protein-Energy Malnutrition (PEM) worsens outcomes for patients with systolic heart failure (SysHF). Similarly, Atrial Fibrillation (AF) worsens outcomes of SysHF. The impact of PEM on patients with SysHF &amp; AF is not known. Therefore, our study sought to measure the effect of PEM on clinical outcomes in patients with SysHF &amp; AF. Methods: We queried the National Inpatient Sample (NIS) between 2016 &amp; 2017. NIS was searched for adult patients hospitalized with SysHF with a history of AF as a principal diagnosis with &amp; without PEM as a secondary diagnosis using ICD-10 codes. The primary outcome was inpatient mortality, while secondary outcomes were the length of stay (LOS), total hospital charge, cardiac arrest, cardiogenic shock, &amp; respiratory failure. A multivariable logistic &amp; linear regression analysis was applied to estimate the odds for the clinical outcome. A p-value &lt;0.05 was considered significant. Results: There were 270,580 SysHF with history of AF admissions, approximately 5.4% (14,611) had PEM. PEM vs No PEM cohorts include; (Mean Age of 77 vs 75 years], Males [57.8% vs 60.9%], Whites [76.5% vs 76.4%], Black [11.8% vs 13%]. PEM resulted in increased LOS (10 days vs 5.4 days, Adjusted LOS 3.6 days [3.1-4.3, P = &lt;0.0001], Increase in hospital charge (PEM $117,969 vs No PEM $50,050, Adjusted charge $59,322 [$46,633-$72,012, P = &lt;0.0001]. Conclusion: In conclusion, PEM raised the risk of adverse clinical outcomes &amp; increased hospital expense in patients hospitalized with SysHF &amp; AF. Assessing nutritional status will aid in risk assessment &amp; help guide cardiovascular treatment. Whether treating protein malnutrition will improve cardiovascular outcomes is unknown.
Abstract 11047: Racial Balance in Heart Failure Treatment, Use of Implantable Left Ventricular Assist Devices, and Cardiac Transplantation
Authors: Fadi I Musfee, randa hamden, Mrinalini Buddha, Hayden Naizer, Alexandra Q Zingg Guzman, Cecilia M Ganduglia Cazaban, George V Letsou
Journal: Circulation (2021)

Introduction: The incidence of left ventricular assist device (LVAD) implantation in heart failure (HF) patients across various racial groups has not been examined in large databases. We present an analysis of racial groups and LVAD implantation using a large US database. Methods: We analyzed data from a commercial and a national Medicare database using OPTUM® Clinformatic® Data Mart and a Medicare National Sample that comprised 57,585,519 US patients. We identified 346,345 adults with HF from 2014 to 2016. Comorbidities were identified including diabetes, coronary artery disease, hypertension, and cardiomyopathy. Data were collected for LVAD implantation, stroke, cerebral injury, mechanical ventilation, heart transplantation, renal insufficiency, and death through 2019 or until they were no longer enrolled. Race, sex, and age were discerned from enrollment information. Results: The incidence of HF was similar across all 5 racial groups (Table). Age at the time of HF diagnosis and LVAD implantation was lower in Blacks than in other races. LVADs were implanted at a higher rate in Blacks than in other groups. Age at LVAD implantation was lower in black men than in men of other races. Whites had a lower incidence of stroke, intracranial bleed, and cerebral injury after LVAD implantation than did Blacks, Hispanics, and Native Americans. The rate of eventual transplantation was similar among all groups. Because of the large database population analyzed, differences between groups were highly significant, with p&lt;0.0001. Conclusions: In the largest US database analysis to date, we found that US racial groups showed no significant differences in the incidence of HF, rate of LVAD implantation, survival after LVAD implantation, or progression to cardiac transplantation. However, Blacks were diagnosed with HF and underwent LVAD implantation at somewhat younger ages than other groups.
Abstract 10446: Sex-Specific Genetic Loci Shared Between Sex Hormone Biomarkers and Coronary Heart Disease Are Associated with Sex- and Tissue-Specific Gene Expression
Authors: Jie Hu, Jun Li, Xin Xu, Kathryn M Rexrode, Liming Liang
Journal: Circulation (2021)

Introduction: Sex differences in coronary heart disease (CHD) have been well-recognized, but the underlying mechanisms are poorly understood. To examine sex differences in the shared genetics between sex hormone biomarkers and CHD, we have previously performed a sex-stratified genome-wide association study for testosterone (T), sex-hormone binding globulin (SHBG), and CHD using data from the UK Biobank (187,888 men and 221,014 women). We then performed sex-stratified genome-wide cross-traits meta-analyses and identified 13 loci coregulating T or SHBG and CHD, with the coregulation effects specific to one sex ( P meta &lt;5х10 -8 in one sex and P meta ≥1х10 -5 in the other). Hypothesis: The identified sex-specific coregulatory loci are associated with gene expression in a sex-dependent manner, which could help elucidate sex-specific biological functions of shared genetics between sex hormones and CHD. Methods: Based on gene expression data in 49 different human tissues for &gt;900 post-mortem donors of both sexes (the Genotype-Tissue Expression project; V8 release), we estimated genetic effects on sex- and tissue-specific expression for the 13 identified sex-specific coregulatory loci. False discovery rate (FDR) was used to account for multiple testing. Results: We observed 149 significant locus-gene associations in men (FDR men &lt;0.05) and 72 in women (FDR women &lt;0.05) in various tissues. Moreover, 19 locus-gene pairs showed sex-differed associations in various tissues (FDR for sex-locus interactions &lt;0.05), 13 of which were in brain tissues (5 in cortex, 3 in cerebellum, 3 in hypothalamus, and 2 in basal ganglia); all of these loci were associated with expressions of genes whose transcription start sites are located at over 1 million bases away or on a different chromosome. We also observed 11 locus-gene pairs in male-specific tissues (9 in testis and 2 in prostate) and another 9 pairs in female-specific tissues (5 in vagina, 3 in ovary, and 1 in uterus). Conclusions: Sex-specific genetic loci shared between T or SHBG and CHD are associated with gene expressions in various tissues, predominantly in brain tissues, and such associations significantly differ by sex. Our findings may help advance the understanding of mechanisms underlying sex differences in CHD.
Abstract 11860: Long Term Outcomes and Risk Stratification in Patients With Heart Failure With Recovered Ejection Fraction
Authors: Andrew Perry, Parvathi Mudigonda, Gary Huang, Richard Cheng, Wayne C Levy, Song Li
Journal: Circulation (2021)

Introduction: Data are lacking on the natural history of heart failure with recovered ejection fraction (HFrecEF) with no available risk model for future heart failure events. This study aimed to understand the long-term outcomes of patients with HFrecEF, identify predictors of adverse events, and develop a risk stratification model. Methods: From an academic healthcare system we retrospectively identified patients who had an improvement in left ventricular ejection fraction (LVEF) from &lt;40% to ≥53%. Significant predictors of all-cause mortality, hospitalization and recurrent reduction in LVEF were identified via Cox regression analysis. A Cox proportional hazard risk model was developed for all-cause mortality. Results: 133 patients were included (median age 67, 39% female, 30% ischemic etiology). Kaplan-Meier survival was 70% at 5 years. Freedom from hospitalization was 58% at 1 year, and the risk of recurrent LVEF reduction to &lt;40% was 28% at 3 years. Diuretic dose and BNP at the time of LVEF recovery were the strongest predictors of mortality and hospitalization in multivariate adjusted analysis (BNP HR per 100pg/mL increase 1.13 [p&lt;0.01]; furosemide equivalent dose HR per 40mg increase 1.19 [p=0.02]). An all-cause mortality risk model incorporating NYHA functional class, BNP and diuretic dose at the time of recovery showed excellent risk discrimination (c-statistic 0.79) and calibration. Conclusions: Patients with HFrecEF have significant heterogeneity in clinical outcomes ranging from persistent recovery to requiring advanced heart failure therapies or death. A risk model utilizing NYHA functional class, BNP and diuretic dose can accurately stratify mortality risk.