tbuckley/cabot-search huggingface dataset:
Abstract 13062: The Effect of Empagliflozin on Contractile Reserve in Heart Failure: Prespecified Sub-Study of a Randomized, Double-Blind, and Placebo-Controlled Trial
Authors: Jesper Jensen, Massar Omar, Ali Mulham, Peter H Frederiksen, Caroline Kistorp, Christian Tuxen, Camilla Andersen, Julie H Larsen, Mads K Ersbøll, Lars Kober, Finn Gustafsson, Julie L Forman, Jacob E Moller, Morten Schou
Journal: Circulation (2021)

Introduction: Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve cardiac structure but most studies suggest no change in left ventricular (LV) systolic function at rest. Whether SGLT2 inhibitors improve LV contractile reserve is unknown. We investigated the effect of empagliflozin on LV contractile reserve in patients with heart failure (HF) and reduced ejection fraction (HFrEF). Methods: Prespecified sub-study of the Empire HF trial, a double-blind, placebo-controlled, and randomized trial. Patients with LV ejection fraction (LVEF) ≤40% on guideline-directed HF therapy were randomized (1:1) to empagliflozin 10 mg or placebo for 12 weeks. The treatment effect on contractile reserve was assessed by low dose dobutamine stress echocardiography. Results: In total, 120 patients were included. The mean age was 68 (SD 10) years, 83% were male, and the mean LVEF was 38 (SD 10) %. Respectively 60 (100%) and 59 (98%) patients in the empagliflozin and placebo groups completed stress echocardiography. No statistically significant effect of empagliflozin was observed for the contractile reserve assessed by LV-GLS [adjusted mean absolute change, empagliflozin versus placebo, 0.7% (95% CI -0.5 to 2.0, P=0.25)] or LVEF [adjusted mean absolute change, empagliflozin versus placebo, 2.2% (95% CI -1.4 to 5.8, P=0.22)] from baseline to 12 weeks. LV-GLS contractile reserve was associated with accelerometer-measured daily activity level [coefficient, -24 accelerometer counts (95% CI -46 to -1.8, P=0.03)] as opposed to LVEF contractile reserve [coefficient, -2.9 accelerometer counts (95% CI -10 to 4.5, P=0.43)]. Conclusions: Empagliflozin for 12 weeks added to guideline-directed HF therapy did not improve LV contractile reserve in patients with HFrEF. Registration: NCT03198585. https://www.clinicaltrials.gov/ct2/show/NCT03198585?term=Empire+HF&amp;draw=2&amp;rank=1
Abstract 14437: Mental Health and Substance Abuse Patterns Within the Adult Congenital Heart Disease Population
Authors: Louis Peterson, Michelle Mizrahi, Andrew Well, Alexandra Lamari-fisher, Gregory Johnson, Hanoch Patt, Carlos M Mery, Charles D Fraser, Ziv Beckerman
Journal: Circulation (2021)

Background: With the advancement in medical and surgical care, most children born with congenital heart disease survive into adulthood. The adult congenital heart disease (ACHD) population has increased incidence of mental health disorder (MHD) over the general population (20.6%), which has been shown to negatively impact health outcomes. This study evaluates the prevalence and associations of MHD and substance abuse (SA) in a large, clinic-based ACHD population. Methods: Retrospective chart review of ACHD patients from a large congenital cardiology practice. All patients ≥18 years of age at most recent visit were included. SA and MHD were classified if documented in the most recent clinic note or if treated with psychiatric medications. Congenital heart disease (CHD) lesions were classified by the American College of Cardiology/American Heart Association lesion severity score (LSS). Descriptive and univariate analyses were used. Results: The study population included 817 patients, 395 (48.3%) females, mean age of 28.0±9.9 years. Of the 817 patients, 27 (3.3%) had documented SA and 173 (21.2%) had MHD. Of those, 62 (35.8%) had only psychiatric medications listed and 56 (32.4%) had only MHD listed. MHD increased with increasing LSS: 14% in LSS1, 34% in LSS3 (p&lt;0.001). SA had a similar increase from 1.3% to 5.7% (p=0.058). The anatomic lesions with the highest prevalence of MHD and SA were: single-ventricle population (39.7%), transposition of the great arteries (31.4%), and tetralogy of Fallot (26.7%) (p&lt;0.001). Conclusions: MHD and SA are prevalent in the ACHD population, particularly among the more complex lesions. Given the prevalence and impact on clinical outcomes, more consistent documentation is needed for both MHD and SA. As ACHD patients are recommended to have regular follow-up, this presents an important opportunity for screening, identifying, and providing resources for MHD and SA in this population.
Abstract 12604: Prescribing Patterns of Cardioprotective Antihyperglycemics Among Medicare Beneficiaries Across United States Counties by their Socioeconomic Disadvantageousness
Authors: Jonathan Hanna, Arash Aghajaninargesi, Veer Sangha, Zhenqiu Lin, Harlan M Krumholz, Rohan Khera
Journal: Circulation (2021)

Background: Cardioprotective agents, SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1RA), improve the outcomes of patients with diabetes, but their cost may lead to inequitable use. We evaluated whether the use of these agents is lower in US counties with larger populations of socioeconomically disadvantaged groups. Methods: For 2018, we merged national prescription data for Medicare Part D prescribers with county-level demographic measures from the AHRQ. We compared the number of beneficiaries receiving cardioprotective antihyperglycemics to those on metformin across US counties (Figure A/B). By county we determined demographics (median age, sex and race), median income, urbanization, and markers of health status, including prevalence of diabetes, obesity, and smoking. In multivariable linear regression with SGLT2i/metformin and GLP1RA/metformin prescriptions as outcomes, we evaluated county factors associated with use of cardioprotective agents. Results: There were 2,983 counties with ≥10 prescribers of metformin. Counties had a median of 155 SGLT2i, 108 GLP1RA, and 2307 metformin-receiving beneficiaries per 100,000 population. There was a large variation in county-level SGLT2i and GLP1RA prescribing relative to number of metformin users (Fig A/B). In analyses that accounted for the sociodemographic characteristics of counties and the prevalence of cardiovascular risk factors, higher % black population, higher median age, higher median income, and urbanization were associated with lower use at the county level of people on SGLT2i and GLP1RA in contrast to metformin (p&lt;0.05) (Fig C/D). Conclusion: There was marked variation by county in the use of new, cardioprotective agents. Urban counties and those with large black populations had fewer beneficiaries receiving cardioprotective antihyperglycemic agents.
Abstract 9925: Impaired Cardiac Output and Peripheral Reserve Predict Morbidity and Mortality in Heart Failure and Preserved Ejection Fraction
Authors: Kazunori Omote, Frederik Verbrugge, Yogesh Reddy, Hidemi Sorimachi, Massar Omar, Masaru Obokata, Barry A Borlaug
Journal: Circulation (2021)

Introduction: Reduced peak oxygen consumption (VO 2 ) is common and associated with adverse outcomes in patients with heart failure (HF) and preserved ejection fraction (HFpEF). According to the Fick principle, VO 2 is equal to the product of cardiac output (CO) and arterial-venous O 2 difference (AVO 2 diff). Patients with HFpEF display abnormalities each component, but no study has yet evaluated their prognostic impacts. Methods: Patients with HFpEF (n=501) and controls without HF (n=207) underwent invasive hemodynamic exercise testing with expired gas analysis and clinical follow up for the composite event of HF hospitalization or death. Results: Compared to controls, patients with HFpEF displayed slightly lower CO at rest with higher pulmonary capillary wedge pressure (PCWP). On exercise, subjects with HFpEF displayed blunted increases in CO and greater increase in PCWP (Figure A). As compared with controls, the slope of the increase in CO relative to VO 2 was lower in HFpEF (6.4 ± 3.3 vs 5.4 ± 3.2 L/L; P =0.0004), while augmentation in AVO 2 diff relative to VO 2 was greater in HFpEF (7.7 ± 5.4 vs 10.0 ± 5.6 min/dL; P &lt;0.0001). Over a median 2.8 (1.1-4.6) years of follow up, 101 patients experienced the composite event. Patients with CO reserve below the median and increases in AVO 2 diff below median displayed higher risk of the composite endpoint (Figure B-C). After adjustments for age, sex, BMI, atrial fibrillation, LV mass, and EF, CO reserve remained strongly associated with the primary outcome (HR [95%CI] = 0.51 [0.38-0.68]; P &lt;0.0001, per 1 SD increase) and the change of AVO 2 diff remained significant, but was less predictive (HR [95%CI] = 0.74 [0.60-0.92]; P =0.007, per 1 SD increase) in patients with HFpEF. Conclusions: Impaired ability to augment CO and peripheral O 2 delivery are associated with increasing risk of adverse events in HFpEF. Further study is required to identify therapeutic interventions targeting these hemodynamic perturbations to improve outcomes in HFpEF.
Abstract 10189: A Novel Hypothermia-Triggered and Controlled-Release Hydrogen Sulfide Delivery System Exerts Myocardial Protection from Ischemia-Reperfusion Injury
Authors: Tao Yan, Wenyi Xia, Lianlei Wen, Shijie Zhu, Miao Zhu, Meidong Lang, Chunsheng Wang, Changfa Guo
Journal: Circulation (2021)

Introduction: Hydrogen sulfide is a cardio-protective gas molecule, which prevents cardiocytes from ischemia-reperfusion injury, and then further improves the transplanted heart performance. However, the instability of hydrogen sulfide restricts its application in cryogenic heart reserving solution. The present study aimed to construct a novel hypothermia-triggered mesoporous silica nanoparticles (HT-MSN) for controlled hydrogen sulfide release. Methods: A polymer as hypothermia trigger was synthesized through free radical copolymerization of N-n-propylacrylamide and N-tert-butylacrylamide with azodiisobutyronitrile as the initiator. The selected diallyl trisulfide, as the hydrogen sulfide donor, was encased in mesoporous silica nanoparticles (MSN) to obtain controlled-release and drug-loaded particles. In order to controllably release hydrogen sulfide from drug-loaded particles in hypothermia, the polymers were coated on the surface of drug-loaded MSN. Characteristics of obtained HT-MSN were evaluated. Cytotoxicity and effects on myocardial protection were further assessed. Results: Combination of nuclear magnetic resonance spectroscopy and gel permeation chromatography determined the synthesized success of the hypothermia-triggered polymer. Further, through adjusting composition of those co-monomers, the polymer showed a lower critical solution temperature of around 7 o C estimated by ultraviolet, indicting the potential for application at lower temperatures. Transmission electron microscope identified characteristics of obtained HT-MSN with uniform size and regular mesoporous. Furthermore, the novel HT-MSN system exhibited low cytotoxicity and acceptable myocardial protection, including anti-apoptosis and antioxidant activities. Conclusion: This study provided a novel hypothermia-triggered platform for controlled hydrogen sulfide release to protect cardiocytes against ischemia-reperfusion injury.
Abstract 14132: The Crystal Structures Of Human Cytochrome P450 2C9 Provide Insights Into The Effect Of Genetic Variation And The Binding Of Losartan
Authors: Manish Shah
Journal: Circulation (2021)

The human cytochrome P450 2C9 (CYP2C9) enzyme metabolizes many of the currently available medications that include anti-coagulant warfarin, anti-hypertensive losartan, anti-diabetics tolbutamide and glimepiride. Genetic variations in CYP2C9 that include the common alleles *2 and *3 have resulted in reduced enzyme activity leading to altered metabolism of various drug substrates compared with the wild-type (WT). The CYP2C9*2 genetic variant represent an amino acid change from arginine to cysteine at position 144. The crystal structure of CYP2C9 WT and the *2 variant complexed with losartan were recently published. However, the structure of these enzymes in the absence of any ligand or losartan is not available. Thus, the aim was to determine the ligand free structure of these enzymes and assess the hypothesis that the drug binding orchestrates the conformational change and leads to reorientation of amino acid sidechains to interact with losartan in the active site. The data for the CYP2C9 WT and the CYP2C9*2 crystals in the absence of any ligands was collected remotely at the Stanford Synchrotron Radiation Light Source and the structures were solved using x-ray crystallography. The ligand-free structure of the *2 variant revealed markedly different conformation compared to the recently published structure in complex with losartan. The changes in the F, F’, G and G’ helices indicate an open conformation in the absence of losartan compared to the losartan complex. Whereas the ligand-free structure of the WT illustrated similarity in the overall conformation to the previously published structures with losartan bound. Comparison of the ligand free structure of the CYP2C9 WT or the *2 variant with the losartan bound structure identified the amino acid sidechains important for interaction with the drug in the active site. Furthermore, the structure of the *2 variant in the absence or presence of losartan provided a useful framework to investigate the effect of amino acid substitution that leads to altered binding of the drug. In conclusion, the structural characterization of the CYP2C9 WT and the *2 variant yield insights into the conformational changes that occur upon binding of losartan and help understand the effect of genetic polymorphisms on drug metabolism.
Abstract 11017: Prognostic Impact of Simple Nutrition Index on the Long-Term Mortality in Acute Decompensated Heart Failure Patients with and Without Reduced Left Ventricular Ejection Fraction
Authors: Takeshi Fujita, Takahisa Yamada, Tetsuya Watanabe, Masahiro Seo, Takashi Morita, Masato Kawasaki, Atsushi Kikuchi, Tsutomu Kawai, Jun Nakamura, Kiyomi Kayama, Daisuke Sakamoto, KUMPEI UEDA, Yuto Tamura, Takehiro Kogame, Keisuke Nishigaki, Yuki Kokubu, Yuto Fukuda, Masatake Fukunami
Journal: Circulation (2021)

Background: The novel nutrition index; triglyceride (TG) х total cholesterol (TC) х body weight (BW) index (TCBI) has been reported to be an easy and useful predictor for patients with coronary artery disease. However, there is no information available on the prognostic role of TCBI in the patients admitted for acute decompensated heart failure (ADHF), relating to left ventricular ejection fraction (LVEF). Methods and Results: We studied 605 patients admitted for ADHF in our prospective cohort study (HFrEF[LVEF&lt;45%] n=259 and HFpEF[LVEF≥45%]:n=311). Echocardiography and venous blood sampling including TG, TC were performed just before discharge. TCBI was calculated by the formula; TG х TC х BW / 1000 at discharge. The endpoint of this study is all-cause death. During a follow up period of 2.8±1.4years, 171 patients died (79 patients in HFrEF and 92 patients in HFpEF). TCBI was significantly associated with all-cause death in patients with HFrEF (p=0.004) and HFpEF (p=0.0001) at univariate Cox analysis. All cause-death was significantly frequently observed in patients with than those without lower TCBI (&lt;861.7=medcan value) in HFrEF (23% vs 38%, p=0.003) and HFpEF (20% vs 39%, p=0.00006). After adjustment for major confounders, TCBI remained a significant independent predictor for the total mortality in patients with HFpEF (adjusted hazard ratio: 1.88 [95%CI 1.18-3.00], p=0.008), while TCBI showed no independent association with the total mortality in HFrEF patients (adjusted hazard ratio: 1.15 [95%CI 0.71-1.85], p=0.58). Conclusion: TCBI at the discharge, a simple and novel nutrition index, provides a prognostic value for the prediction of total mortality in ADHF patients with HFrEF and HFpEF, although the prognostic significance of TCBI in patients with HFpEF was weakened by adjustment for relevant covariates.
Abstract 12025: Phosphodiesterase 3A Mutations Limit Hypertension-Induced Cardiac Damage
Authors: Maria Ercu, Enno Klussmann
Journal: Circulation (2021)

Hypertension affects more than 1 billion people worldwide and can cause cardiac hypertrophy and ultimately heart failure, a condition with an unmet medical need. We have shown that missense mutations in a 15 bp regulatory domain of the phosphodiesterase 3A ( PDE3A ) gene cause hypertension with brachydactyly type E (HTNB). 1, 2 We recently discovered two HTNB families with new mutations in the region encoding the catalytic domain of PDE3A. CRISPR-Cas9 was used to generate rat models of HTNB by introducing mutations in the regulatory or catalytic domain of the PDE3A gene. Surprisingly, despite the hypertension the hearts of the HTNB rats, even in response to catecholamine challenge, were similar to those of the wild type controls, as indicated by echocardiography. mRNA and protein expression analyses did hardly detect significant differences between the left ventricles of the mutant and wild type animals. However, the mutations consistently caused aberrations of PDE3A phosphorylation, enhanced interaction with the adaptor protein, 14-3-3θ, and aberrant cellular localisation. Fluorescence resonance energy transfer (FRET) experiments showed that all PDE3A mutants were hyperactive. Calcium imaging of cardiac myocytes isolated from the rat models revealed differences in calcium cycling between the mutants and wild type animals. Taken together, the data indicate that mutant PDE3A causes aberrant signalling, and suggest that an enhanced local activity of PDE3A is cardioprotective and may provide a basis for new approaches towards heart failure treatment. 1.Maass PG et al. PDE3A mutations cause autosomal dominant hypertension with brachydactyly. Nat Genet . 2015;47:647-53.2.Ercu M, Marko L et al. Phosphodiesterase 3A and Arterial Hypertension. Circulation . 2020;142:133-149. HTNB Consortium: Ryan Walker-Gray, Anastasiia Sholokh, Claudia Loica, Tamara Pallien, Michael B. Mücke, Kerstin Zühlke, Andrea Geelhaar, Michael Russwurm, Lajos Markó, Theda U.P. Bartolomaeus, Hanna Napieczynska, Stefanie Schelenz, Martin Taube, Arnd Heuser, Tatiana Borodina, Daniele Yumi Sunaga-Franze, Jenny Eichhorst, Martin Lehmann, Fatimunnisa Qadri, Elena Popova, Reika Langanki, Sofia K. Forslund, Dominik N. Müller, Norbert Hübner, Sylvia Båhring, Michael Bader
Abstract P461: Phospho-regulated Spatial Regulation Of α-tat1 Mediates Dynamic Microtubule Acetylation
Authors: Abhijit Deb Roy, Evan G Gross, Gayatri S Pillai, Shailaja Seetharaman, Sandrine Etienne-Manneville, Takanari Inoue
Journal: Circulation Research (2021)

Microtubules (MTs) provide mechanical strength to cardiomyocytes and dysregulation of MT network is implicated in cardiac diseases. MT acetylation mediates mechanotransduction, provides structural flexibility to cardiomyocytes and protects against proteinopathy-induced cardiac failure. MT acetylation is exclusively catalyzed by α-TAT1, whose only known substrate is α-tubulin in polymerized MTs. However, little is known about how α-TAT1 itself is regulated. Here we report that intracellular spatial localization of α-TAT1 mediates MT acetylation. Specifically, we identified a conserved signal motif in the intrinsically disordered C-terminus of α-TAT1, consisting of three competing regulatory elements - nuclear export, nuclear import and cytosolic retention. Inhibition of Exportin 1-mediated nuclear export induced nuclear accumulation of α-TAT1 and loss of MT acetylation. We found that α-TAT1 nuclear localization is inhibited by CDKs, CK2 and PKA kinases, pharmacological inhibition of which increased nuclear localization of α-TAT1 and inhibited MT acetylation. We identified a critical phosphoThreonine (T 322 ) that binds to 14-3-3 proteins (β, γ, ε and ζ isoforms) downstream of kinases and mediates cytosolic retention of α-TAT1. Inhibition of 14-3-3 proteins also increased nuclear accumulation of α-TAT1. Fibroblastic cells expressing a phosphodeficient α-TAT1 (T322A) show defects in DNA damage response and increased cell proliferation, which may be pertinent to cardiac hypertrophy. Based on these observations, we developed an optogenetic tool, named optoATAT1, which rapidly and reversibly shuttled from the nucleus to the cytosol on blue light stimulation. HeLa cells expressing optoATAT1 exposed to light showed increased MT acetylation unlike those kept in dark, validating the tool. In summary, we have identified a novel role for the C-terminal region of α-TAT1 in regulating its function through dynamic intracellular localization downstream of kinases and 14-3-3 proteins. We have identified multiple pharmacological agents to modulate MT acetylation through spatial regulation of α-TAT1. We have also developed an optogenetic tool to control MT acetylation that will help in elucidating the role of MT acetylation in disease states.
The Impact of Tyrosine Kinase Inhibitors on Fatherhood in Patients with Chronic Myeloid Leukemia, a Single Institution Experience
Authors: Mohammad Abu-Tineh, Elrazi Awadelkarim A Ali, Awni Alshurafa, Khalid Alhaj, Yousef Hailan, Waail Rozi Kashgary, Abdulqadir Jeprel Nashwan, Mohamed A Yassin
Journal: Blood (2021)
DDRE-36. INVESTIGATING MEDULLOBLASTOMA HETEROGENEITY AND PREDICTING COMPOUND RESPONSE
Authors: Luz Ruiz, Nagi Ayad
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma is the most common malignant brain tumor found in children. It is a cerebellar tumor that affects motor and cognitive processes such as coordination and movement. The standard of care is surgical removal, radiation, and chemotherapy. These treatments can be very damaging to the developing child, in that they can impair vision and walking, among other body functions. Due to this, new treatments are necessary. Treatment plans for children with medulloblastoma need to be tailored to the specific subtype that they have. Genetic studies have revealed that there are four subtypes of pediatric medulloblastoma: Group 3, Group 4, SHH, and WNT. Beyond these bulk-resolution subtypes, we hypothesize intratumor heterogeneity as a barrier to new effective treatments. I have mined single-cell RNA sequencing data to investigate cellular heterogeneity and predict compound response. I analyzed Medulloblastoma patient tumor data along with data obtained from a 10X Genomics Chromium single-cell RNA sequencing experiment performed in the laboratory from a Tg (Neurod-Smoothened*A1) mouse. We hypothesize that distinct cell populations within medulloblastoma should show different predicted compounds that would target them. We have ranked compound predictions to investigate whether compounds may selectively target any of these populations using transcriptional response signatures derived from the LINCS L1000 perturbagen-response dataset. We also hypothesize that Medulloblastoma tumors have distinct subtypes of cells that are preferentially sensitive to BET bromodomain, casein kinase, and ATM/ATR inhibitors. Our analysis identified ten transcriptionally distinct cell types across these medulloblastoma tumors as well as compounds predicted to target them in each transcriptional subtype. Furthermore, we identified bromodomain and casein kinase inhibitors as a potential combination therapy due to their predicted synergy at targeting all cell populations within medulloblastoma. Our studies show the importance of considering cellular heterogeneity when identifying new treatments for medulloblastoma and other brain cancers.