tbuckley/cabot-search huggingface dataset:
Abstract 12042: Does Gender Impact the Outcomes of Durable Left Ventricular Assist Device Implantation in Patients With Advanced Heart Failure- Latest Outcomes From Nationwide Inpatient Sample (2015-2018)
Authors: Krishna Prasad Kurpad, Sumit Sohal, Harsh Mehta, Keith A Hawthorne, Matthew Montgomery, Saurabh Kapoor, Marc Cohen
Journal: Circulation (2021)

Introduction: Women make up approximately 50% of the patients living with heart failure but remain underrepresented in clinical trials and advanced heart failure therapies. This disparity exists among the durable left ventricular assist device (LVAD) recipients, with men receiving more LVADs than women but whether this gap is due to differences in outcomes or not, remain unresolved. Our aim was to study the in-hospital outcomes of LVAD recipients and compare them between the male and female groups. Methods: Using Nationwide Inpatient Sample (NIS) for years 2015-2018, all patients who underwent LVAD implantation during the hospitalization were identified. Cohort was divided into two groups, males and females. Baseline characteristics, comorbidities, in-hospital outcomes were compared between both the groups. Statistical significance was assigned at p&lt;0.05. Analysis was performed using STATA. Results: A total of 7,185 patients underwent LVAD implantation between 2015-2018 out of which only 1,515 (21.09%) patients were female. Baseline characteristics are compared in table 1. The in-hospital mortality was numerically higher in females as compared to males but was not statistically significant (8.91% vs 7.94%, p=0.57). Similarly, both groups had similar length of stay (38.26 ±2.16 days vs a 34.09±0.80 days, p=0.06) and cost of stay ($918,047.7±446,613.2 vs $947,554.7±29686.7, p=0.54). After multivariable analysis, female sex was not predictive of inpatient mortality (OR: 1.26, 95% CI (0.70-2.24), p=0.43). The bleeding, infectious and thromboembolic outcomes (Table 2) were similar between males and females. Conclusions: Females continue to be underrepresented among the patients receiving LVAD despite having similar outcomes and complication rate after implantation. This suggests underutilization of life saving therapy among the female patients and the need for efforts to close this gender gap.
Abstract 14367: Elevated Creatinine Levels Are Associated With Vascular Dysfunction in Liver Transplant Recipients
Authors: Domenico A Chavez, Moriah C Carper, Natalie J Bohmke, Linsey Martin, Chandra Bhati, Susan Wolver, Mohammad S Siddiqui, Danielle L Kirkman
Journal: Circulation (2021)

Introduction: Liver transplant (LT) recipients have an increased risk of developing cardiovascular disease (CVD) after transplant. The physiological mechanisms driving LT-related CVD are not fully understood. Renal impairment post-transplant may contribute to CVD risk in LT recipients. The aim of this study was to investigate the relationship between plasma creatinine levels and vascular function in LT patients. Methods: Conduit artery endothelial function was measured via flow-mediated dilation of the brachial artery (FMD BA ) with duplex ultrasound in 13 LT patients (7 Male, 6 Female; Median [IQR]: Age 59 [56 - 64] years). Parameters of carotid artery function (distension, distensibility, compliance and stiffness) were assessed using B mode ultrasound and central aortic pressure waves that were synthesized from radial artery waveforms acquired by applanation tonometry in 13 LT patients (6 Male, 7 Female; Age 57 [56 - 64] years). Blood samples were analyzed for plasma creatinine by nuclear magnetic resonance spectroscopy. Results: Conduit artery endothelial function via FMD BA (4.07 [3.52 - 6.40] %) was negatively associated with plasma creatinine levels (1.30 [1.08 - 1.56] mg/dL; r = -0.63, p = 0.03). Plasma creatinine levels were also inversely associated with carotid artery distension (0.53 [0.35 - 0.61] mm, r = -0.74, p = 0.006), distensibility (25.62 [20.65 - 33.03] 10 -3 ·kPa -1 , r = -0.59, p = 0.04), and compliance (1.19 [0.82 - 1.41] 10 -6 ·m 2 ·kPa -1 , r = -0.66, p = 0.02), and positively associated with carotid stiffness (6.07 [5.35 - 6.76] m·s -1 , r = 0.59, p = 0.04) as shown in Figure 1. Conclusions: Our results indicate that LT patients with higher levels of creatinine have impaired conduit artery endothelial function and compromised carotid artery function, making these individuals more susceptible to the development of atherosclerosis and stroke. The presence of renal dysfunction after LT may contribute to CVD risk and warrants investigation in future trials.
Abstract 12968: mitoTEMPO Improves Expression of Pulmonary Artery Soluble Guanylate Cyclase β1 and Lowers Exercise Associated Elevations in Pulmonary Artery Pressures in a Rat Model of Combined Pre- and Post-Capillary Pulmonary Hypertension
Authors: Georgios Triantafyllou, Taijyu Satoh, Charles F MCTIERNAN, Sruti Shiva, Adam C Straub, Mark T Gladwin
Journal: Circulation (2021)

Introduction: Exercise induced pulmonary hypertension (EIPH) portends worse prognosis compared to isolated resting PH. Exercise increases mitochondrial reactive oxygen species (mROS) production in peripheral blood mononuclear cells of patients with heart failure. Metabolic syndrome related mROS contribute to EIPH by decreasing the expression of the vasodilatory enzyme soluble guanylate cyclase (sGC) via downregulating an sGC transcription factor, namely nuclear factor Y alpha (NFYA; Satoh et al in press). Hypothesis: mROS scavenging with mitoTEMPO will restore sGC expression and ameliorate EIPH in a rat model of combined pre-and post-capillary pulmonary hypertension (CpcPH). Methods: Obese ZSF1 rats treated with sugen were used to model CpcPH. Half received mitoTEMPO (2mM) for 2 weeks. CpcPH rats treated with vehicle and lean ZSF1 rats served as controls (n=6/group). Hemodynamics were evaluated at rest and during treadmill exercise. Cardiac function was assessed using Doppler-echocardiography. We cultured pulmonary artery vascular smooth muscle cells (PAVSMCs) from lean rats in palmitate, glucose and insulin (PGI) containing media to simulate the metabolic syndrome milieu. Cells were treated with vehicle or mitoTEMPO. Expression of sGCβ1 and NFYA in pulmonary arteries of animals and in cultured cells was quantified by Western Blot. Data were analyzed with repeated measures two-way ANOVA. Results: MitoTEMPO significantly improved EIPH by reducing pulmonary vascular resistance (fig1A), significantly improved right ventricular function (fig1B) and significantly restored NFYA/sGCβ1 expression in pulmonary arteries (fig1C) and PAVSMCs of rats with CpcPH (fig1D). MitoTEMPO significantly blunted PGI-induced downregulation of NFYA and sGCβ1 in PAVSMCs from lean rats (fig1E). Conclusions: Mitochondria targeted antioxidants can improve EIPH in CpcPH by restoring NFYA/sGCβ1 expression, identifying a potential therapeutic target for CpcPH.
EXTH-76. DEVELOPING THE NOVEL COMBINATION THERAPY OPTIONS FOR CANCER THERAPY USING TUMOR TREATING FIELDS TOGETHER WITH THE CHEMO AGENTS TARGETING THE REPLICATION STRESS PATHWAY
Authors: Narasimha Kumar Karanam, Michael Story
Journal: Neuro-Oncology (2021)

Abstract Tumor Treating Fields (TTFields) as a component of cancer therapy has been shown to provide significant clinical benefit. The disruption of mitosis was identified as the first mechanism of action, however, a novel role for TTFields outside of mitosis where TTFields downregulates the Fanconi’s Anemia genes and proteins results in replication stress and reduced DNA repair capacity. Given these results we hypothesized that TTFields would increase the sensitivity of tumor cells to chemotherapy agents that increase replication stress. An analysis of agents that target replication stress in different ways was initiated. PARP1: Targeting PARP1 protects DNA breaks by recruiting DNA repair and checkpoint proteins to the sites of damage. Using the PARP1 inhibitor olaparib followed by radiation resulted in synergistic cell killing compared to radiation or olaparib alone or in combination. Etoposide: Etoposide forms a ternary complex with topoisomerase II and prevents re-ligation of DNA strands to elicit DNA strand breaks and replication stress. When combined with TTFields cell killing increased synergistically vs. etoposide alone. AZD6738: ATR is an essential kinase regulator of the replication checkpoint that plays a critical role in safeguarding genome integrity from replication stress. The advantage of combining TTFields with the ATR inhibitor-AZD6738 was tested for cell killing and the combination vs. AZD6738 was found to be synergistic. Irinotecan: Irinotecan traps topoisomerase I- DNA in a ternary cleavage complex and inhibits the initial cleavage reaction and re-ligation steps resulting in increased replication stress. Irinotecan and TTFields was tested and found to be highly effective at tumor cell killing. Collectively, our results suggest that it is likely of considerable clinical benefit to combine TTFields with chemotherapy agents that cause replication stress. This notion may explain the results of a number of clinical trials and suggests that there may be novel TTFields/replication stress-inducing chemotherapy agent combinations worth exploring.
US Supreme Court seems likely to accept Mississippi law that would limit abortion
Authors: Janice Hopkins Tanne
Journal: BMJ (2021)

Questions posed by conservative justices of the US Supreme Court during oral arguments on 1 December have indicated the right leaning court may uphold proposed new limits on abortion for American women.

The court’s final decision is expected in June next year.

US president Joe Biden opposes the Mississippi law, according to his press secretary, Jen Psaki, who said on 1 December, “The president believes that the Mississippi law blatantly violates women’s constitutional rights to safe and legal abortions. This case presents a grave threat to women’s fundamental rights, to all our rights—as protected under Roe v Wade for nearly half a century. Every woman, every American, deserves access to healthcare, including reproductive healthcare, and the president is deeply committed to the constitutional right.”1

The nine justices heard arguments on a Mississippi law that would ban abortions after 15 weeks of pregnancy with no exception for rape or incest. The Mississippi law would also overturn Roe v Wade, the 1973 Supreme Court decision that legalised abortion until “fetal viability,” considered to be 23-24 weeks.

Another Supreme Court decision, the 1992 Planned Parenthood v Casey ruling, allowed …
Abstract 13129: FXR1 Regulates Blood Pressure by Altering Vascular Contractility
Authors: Amanda St Paul, Kyle Preston, Cali Corbett, Tani Leigh, Sheri E Kelemen, Rachael Okune, Michael Autieri
Journal: Circulation (2021)

Introduction: Hypertension is a major risk factor for heart disease and stroke. Despite current medication, half a million deaths in the United States include hypertension as a primary contributing cause, presenting a need for additional targets. Vascular smooth muscle cells (VSMCs) play a central role in vascular contractility and the regulation of blood pressure (BP). Fragile X-related protein (FXR1) is a muscle-enhanced RNA binding protein. Knock down of FXR1 increases inflammatory mRNA stability, and overexpression of FXR1 decreases inflammatory mRNA stability in VSMC. FXR1 knock out mice have a muscle-specific phenotype. While little is known concerning FXR1 protein binding partners and its role in vascular disease, its muscle-enhanced expression suggests a specialized role in VSMC. The specific aim of this study is to test the hypothesis that FXR1 regulates vascular contractility by regulation of RNA stability and protein-protein interactions. Results: To characterize an in vivo role of FXR1 in vascular disease, we generated a novel, VSMC-specific FXR1 conditional knock out mouse (FXR1 VSMC/VSMC ). Preliminary data indicates that these mice are hypotensive as they show decreased systolic (P &lt; 0.001) and diastolic (P &lt; 0.01) BP, and increased resting heart rate (P &lt; 0.05) at baseline compared to controls. To identify mRNA binding targets, gene ontology of RNA immuno-precipitation sequencing analysis (RIPseq) in human VSMCs identified that FXR1 preferentially binds to mRNA that participate in VSMC contractility and regulation of BP. Although considered an RNA stability protein, mass-spectrometry identified that FXR1 interacts with proteins related to VSMC contractile processes such as cell migration, adhesion and stress fiber formation. At a functional level, siRNA knock down of FXR1 decreased VSMC migration and collagen gel contraction corroborating in vivo observations. Conclusion: These data show that deletion of FXR1 decrease BP and VSMC contractile processes. They are the first to suggest FXR1 regulates BP and vascular contractility potentially by two mechanisms: mRNA stability and functional activity by protein-protein interactions. The findings support FXR1 activity may represent a target for therapeutic invention to regulate BP.
Strategies and interventions for healthy adolescent growth, nutrition, and development
Authors: Dougal Hargreaves, Emily Mates, Purnima Menon, Harold Alderman, Delan Devakumar, Wafai Fawzi, Geva Greenfield, Weeam Hammoudeh, Shanshan He, Anwesha Lahiri, Zheng Liu, Phuong Hong Nguyen, Vani Sethi, Haijun Wang, Lynnette M Neufeld, George C Patton
Journal: The Lancet (2021)
Abstract 12392: Rethinking Re-Hospitalization in Heart Failure Care Transitions: Heterogeneity in Utilization Typologies
Authors: Sijia Wei, Eleanor S McConnell, Wei Pan, Kirsten N Corazzini, Bradi B Granger
Journal: Circulation (2021)

Introduction: Re-hospitalization for patients with heart failure (HF) is a persistent challenge. Person-oriented analysis may highlight heterogeneities and inform strategies to avert acute-care utilization. Purpose: To evaluate how outpatient utilization and sociodemographic, health behavior, and clinical factors are associated with high acute-care utilization using trajectory modeling. Methods: This retrospective cohort study used group-based trajectory modeling to identify latent groups of emergency department (ED), inpatient, and outpatient utilization one year before and after the initial HF hospitalization in adults (n= 1269) who had the index hospitalization between January 2016 and December 2018. Factors associated with high acute-care utilization were assessed by multinomial logistic regression. Results: People with medium or high outpatient utilization (44.9%) versus those with low outpatient utilization (37.7%) were associated with higher acute-care utilization after controlling for other significant factors such as insurance and comorbidities. Patients had six distinct typologies of acute-care utilization (Figure 1). Four typologies (14.3%) with higher acute-care utilization (ED or inpatient or both) accounted for 52% and 33.0% of the total ED and inpatient encounters. However, the association between outpatient and higher acute-care utilization was not significant among people with fluctuating outpatient utilization (17.4%). Conclusions: A person-oriented approach characterizing heterogeneity in acute-care utilization complements the hospital-focused 30-day readmission metric by revealing patients’ unique changes in utilization over time. High-frequency outpatient care may indicate fragmented care. Developing tailored interventions in the outpatient setting to address the small subgroup of patients with consistently high ED or inpatient utilization may improve re-hospitalization for patients with HF.
EXTH-23. PRECLINICAL EFFICACY OF A TARGETED, BRAIN PENETRANT INHIBITOR OF FATTY ACID DESATURATION IN GLIOBLASTOMA
Authors: Katharina Eyme, Alessandro Sammarco, Rudolph Neustadt, Hayk Mnatsakanyan, Daniel Tardiff, Chee Yeun Chung, Christian Badr
Journal: Neuro-Oncology (2021)

Abstract There is increasing evidence that targeting de novo fatty acid synthesis could be effective for the treatment of primary and metastatic brain tumors, but brain penetrant inhibitors of this pathway are still lacking. We have previously reported that Stearoyl CoA Desaturase (SCD), a desaturase enzyme which converts saturated fatty acids into their unsaturated counterparts is a therapeutic target in glioblastoma (GBM). We showed that SCD exerts a cytoprotective role by protecting GBM cells against lipotoxicity and is essential for maintaining self-renewal and tumor initiating properties in GBM stem cells (GSCs). Using a panel of patient derived GSCs, mouse orthotopic GSC models, isogenic astrocytes models of gliomagenesis as well as in silico analysis, we report that in addition to SCD1, a second SCD isoform is also essential for GSCs maintenance. Further we demonstrate that while EGFR/PI3K/AKT signaling promotes lipogenesis, the activation of RAS/MEK/ERK signaling creates a metabolic vulnerability and sensitizes to SCD inhibitors. We tested a first-in-class, clinically relevant SCD inhibitor and showed that this compound effectively inhibits fatty acid desaturation in GSCs in a mouse orthotopic GSC model. Importantly, using different GSCs mouse models, we demonstrate that this SCD inhibitor can effectively increase overall survival as a monotherapy. Further, SCD inhibition impairs DNA-damage repair via homologous recombination thereby sensitizing to the standard of care therapeutics for GBM, ionizing radiation and temozolomide (TMZ). Consequently, combining this inhibitor with TMZ in mouse orthotopic GSC models leads to a significantly increased overall survival. Altogether, our results provide a deeper understanding of de novo fatty acid dynamics in GBM and support the clinical testing of a new SCD inhibitor, with favorable pharmacokinetic and pharmacodynamic properties, in patients diagnosed with GBM.
Abstract P382: Transcriptomic Analysis Of Human Left Atrial Tissue Reveals Mitochondrial Gene Co-expression
Authors: Julie H Rennison, Sojin Y Wass, Cheryl R Lin, Han Sun, Jeffrey Hsu, Catherine Cantlay, Laurie Castel, Beth Lovano, Meghan McHale, A M Gillinov, Christine S Moravec, Jonathan D Smith, Mina K Chung, John Barnard, David R Van Wagoner
Journal: Circulation Research (2021)

Atrial fibrillation (AF) risk is heritable. High rate electrical activity in AF requires increased energy. Atrial mitochondrial structure and function are altered in AF patients in an effort to generate adequate ATP through oxidative phosphorylation. Genomic studies have identified putative AF risk genes, but the association of AF risk genes with expression of mitochondrial genes is unclear. We tested the hypothesis that putative AF risk genes are co-expressed with mitochondrial genes that play a role in atrial energy production. RNA-seq was performed on left atrial appendage (LAA) tissues obtained from 251 cardiac surgery patients. RNA coexpression profiles were evaluated for 222 putative AF risk genes. Genes encoding proteins that localize to the mitochondria were identified using MitoCarta 2.0. Changes in metabolic pathways were detected using Ingenuity Pathway Analysis (IPA). Our analysis identified 128 AF risk genes that coexpressed with at least one mitochondrial gene. The highest level of mitochondrial gene coexpression was evident with PCCB, in which 30% (253 of 848) of coexpressed genes were mitochondrial. CASQ2 (24%, 104 of 431) and ASAH1 (20%, 37 of 182) also showed high levels of mitochondrial gene coexpression. The IPA Oxidative Phosphorylation Pathway was significantly altered (p&lt;0.05) for 26 AF risk genes, with CASQ2 (9.42E-79), MYH6 (4.73E-78), YWHAE (4.96E-75), and TTN (4.30E-71) the most strongly associated (Table). Additionally, 12 AF risk genes coexpressed with genes encoded by mitochondrial DNA (mtDNA) (Table). ASAH1, CASQ2, MYH6, NACA, NUCKS1, PLN, TTN, and YWHAE coexpressed with all 13 mtDNA encoded components of the electron transport chain. Many AF risk genes show significant coexpression with mitochondrial genes. We propose that genetic risk scores based on these AF risk genes may identify a subset of AF patients that would benefit from AF therapies that enhance metabolic activity.
Abstract 10647: Accreditation Identifies Operator Variability and Gaps
Authors: Bonnie H Weiner, Joaquin E Cigarroa, Michael J Cowley, J J Marshall
Journal: Circulation (2021)

Background: Accreditation (A) is an ongoing process to assist facilities in achieving and maintaining quality in the catheterization laboratory. Independent review of randomly selected cases can provide insight into changes that occur over time. The current analysis assesses the differences between new operators (NO) and those previously reviewed (PO) over a series of reviews at 2 year intervals. Methods: Randomly selected cases from each site and at each timepoint are reviewed by blinded, independent interventional cardiologists and all data are recorded on a standard case report form. After the review was completed, each operator was identified as NO or PO. Statistical analysis was performed using JMP pro (version 15.2.1, SAS Institute Cary NC). Results: 17 facilities underwent initial and as many as 3 reaccreditation visits. A total of 2702 cases were reviewed and this analysis was limited to the 1550 PCI (608 Initial, 663 RA1, 224 RA2, 35 RA3). Selected variables are shown in Table 1. Although many findings are not different between NO and PO, those differences identified are primarily those related to documentation. Conclusions: We have previously identified changes over time from a facility standpoint where after initial improvement, there is a loss of improvement. Similar findings are identified when NO are compared to PO but documentation differences are identified. Locum Tenens physicians are increasing used for coverage. Adequate onboarding is critical to maintaining a quality culture and continued reinforcement will assist existing operators. Table
Abstract 14237: Myocardial Work Indices by Pressure-Strain Loop Analyses Predict Cardiovascular Outcome in the General Population
Authors: Flemming J Olsen, Kristoffer G Skaarup, Mats H Lassen, Niklas Johansen, Peter Schnohr, Gorm B Jensen, Jacob Marott, Peter Sogaard, John Aalen, Espen W Remme, Otto A Smiseth, Rasmus Mogelvang, Tor Biering-Sørensen
Journal: Circulation (2021)

Introduction: A novel tool to assess myocardial work by echocardiography has recently become available through pressure-strain loop (PSL) analyses. We sought to evaluate the prognostic value of non-invasive myocardial work indices in the general population. Methods: This was an echocardiographic substudy based on a prospective community-based cohort study (n=4,466). PSL analyses were performed to acquire myocardial work index (MWI), global constructive work (GCW), global wasted work (GWW), and myocardial work efficiency (MWE). The endpoint was a composite of heart failure or cardiovascular death (HF/CVD) at 5-years of follow-up. Multivariable logistic regression was applied to adjust for SCORE chart risk factors. Spline curves were constructed with Poisson regression. Results: A total of 3,896 participants were included in this analysis (mean age: 56 years, 43% men). Of these, 232 (6%) experienced the outcome within 5 years. Participants who experienced HF/CVD had reduced MWI (2202 vs. 2295mmHg%, p=0.001), reduced MWE (95.8 vs. 96.9%, p&lt;0.001), and higher GWW (95 vs. 73mmHg%, p&lt;0.001), whereas GCW was similar between outcome groups. In addition, decreasing MWI and MWE as well as increasing GWW was associated with a higher risk of HF/CVD in univariable analyses. After multivariable adjustments, however, all work parameters were associated with HF/CVD (MWI: OR=1.15 (1.10-1.19), per 100mmHg% decrease; GCW: OR=1.14 (1.10-1.19), per 100mmHg% decrease; GWW: OR=1.19 (1.05-1.34), per 50mmHg% increase; MWE: OR=1.14 (1.08-1.19), per 1% decrease). The risk of HF/CVD was curvilinear for MWI and GCW, whereas there was a linear association for GWW and MWE (figure). Conclusions: Myocardial work indices by PSL analysis are associated with 5-year risk of HF/CVD in a large-scale general population independently of clinical risk factors.