tbuckley/cabot-search huggingface dataset:
Abstract 10747: Genetic Enhancement of Epicardial Paracrine Signalling for Cardiac Regeneration
Authors: Liliana Brito, Ioanna Mylonaki, Christopher L Grigsby, Hyejeong Seong, Stuart G Higgins, Nicola Smart, Michela Noseda, Nadia Rosenthal, Sian Harding, Molly Stevens
Journal: Circulation (2021)

After myocardial infarction (MI), paracrine signalling has been shown to contribute to heart regeneration. The epicardium, as an important signalling centre, is crucial for heart development and it is re-activated after MI, indicating its involvement in the response to injury. This project aims to accomplish in situ transfection of the epicardium to stimulate the overexpression of growth factors that will enhance regenerative signalling pathways after MI, with cardiomyocyte proliferation as the primary target. Selective epicardial transfection can potentially be achieved via a surface-mediated delivery. Therefore, we developed a novel transfection approach consisting of the deposition of bioreducible cationic polymeric polyplexes onto flat and nanostructured silicon surfaces by freeze-drying. Recombinant growth factors (rGF) were used in single and combinatorial proliferation assays to select for genes to be delivered to the epicardium. The proliferative effects were assessed on cardiomyocytes, cardiac mesenchymal stromal cells, endothelial cells and cardiac fibroblasts via high-content image analysis. Neuregulin-1 led consistently to higher S-phase proliferation marker in IMR90- and H7-derived cardiomyocytes and higher cardiomyocyte cell numbers (fold increase 1.28 ± 0.12), quantified by flow cytometry. Hepatocyte Growth Factor induced proliferation of cardiac mesenchymal stromal cells (fold increase 2.75 ± 0.31) and angiogenesis (fold increase 1.47 ± 0.34). Follistatin-like 1, from animal and bacterial sources, was also tested but no proliferative effect was detected. The relevant rGF for each cell type maintained its positive effect in combination with other rGFs. Furthermore, preliminary results from in vitro transfection of epicardial cells with these GF genes indicate the proliferative advantage of enriched epicardial paracrine signalling over the incubation of cardiac cells with the rGF . This study remains to be a first-in-field potential material-based gene delivery strategy specific to the epicardium that explores a combinatorial treatment via the delivery of more than one gene for induction of cardiomyocyte proliferation and other regenerative mechanisms for MI treatment.
Abstract 10620: Real-World Use of Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Heart Failure and Hypertension Initiating Sodium Zirconium Cyclosilicate: The Optimize Study
Authors: Abiy Agiro, Alpesh Amin, Fan Mu, Joshua A Young, Erin E Cook, Esteban Lemus Wirtz, Yasmin Ghanshyam Brahmbhatt, Keith A Betts, Charles Pollack
Journal: Circulation (2021)

Introduction: Renin-angiotensin-aldosterone system inhibitors (RAASis) in patients (pts) with heart failure (HF) and hypertension (HTN) are associated with a reduced risk of death or disease progression, but increased risk of hyperkalemia (HK) with RAASis may lead to discontinuation and reduced benefit. This real-world study evaluated RAASi use patterns in pts who initiated sodium zirconium cyclosilicate (SZC) for HK. Methods: Adult (≥18 years) outpatients who initiated SZC (index date) while on RAASis were retrospectively identified from a large US claims database (Jan 2018 to Jun 2020). Analyses were conducted among all pts with HK and separately in those with HF or HTN. Outcomes included the proportion of pts with a new RAASi script (different or refill RAASi within 90 days of ending their index RAASi) and median time from index to RAASi discontinuation. A multivariable logistic regression assessed predictors of a new RAASi script among all pts. Results: Of 589 pts who initiated SZC during RAASi therapy (mean age 61.0 years, male 65%), 487 (83%) received a new RAASi script post index. In the HF (n=149) and HTN (n=538) cohorts, 120 (81%) and 446 (83%) received a new RAASi script. At index, the most common RAASi prescribed were ACE inhibitors (51%) and ARBs (42%). Among pts with a new RAASi script, median time from index to RAASi discontinuation was not reached ( Figure ), whereas in pts with no new RAASi script, median time from index to RAASi discontinuation was 29 days. Significant predictors of a new RAASi script (vs no new RAASi script) after SZC initiation were fewer prior hospitalizations (adjusted OR 0.77; 95% CI 0.60-0.98; P &lt;0.05) and fewer ED visits (0.78; 0.63-0.97; P &lt;0.05). Conclusions: Consistent with clinical trial findings, &gt;80% of pts on RAASi therapy who initiated SZC for HK had a new RAASi script; similar results were observed in pts with HF or HTN. Pts with inpatient and ED visits may require additional follow-up care to encourage continuation of RAASi therapy.
Abstract 10244: The Long-Term Residual Chest Compression Performance Following a Novel Chest Compression Training: A Cohort Study
Authors: Christian Vincelette, Philippe Voizard, François Martin Carrier, Sokoloff Catalina
Journal: Circulation (2021)

Introduction: The Timely Chest Compression Training (T-CCT), a 20-minutes in-situ intervention, was created locally to ensure frequent training in chest compressions for personal support workers (PSW). While it was effective in improving chest compression performance immediately after training, skills retention remained unknown. Method: A retrospective cohort study was conducted in a tertiary university-affiliated hospital in Quebec, Canada. Chest compression performance scores were measured with manikins and a subtractive scoring model (Laerdal QCPR®). PSW were invited to participate in a T-CCT. At baseline before receiving any new training, we measured the proportion of PSW that had an “excellent” score, defined as a score greater or equal to 90 out of 100. We compared the baseline performance of PSW who received the T-CCT 10 months prior with those who did not receive it. Results: In total, 404 PSW were included. Of these, 229 (55%) had received the T-CCT before and 175 (43%) had not. Close to half of PSW who had received the T-CCT met the excellent performance threshold (46 % [106/229]), as opposed to 30 % (53/175) in those who had not received the intervention 10 months prior. In a univariable log-binomial model, being previously exposed to the T-CCT increased by 1.53 times (RR 1.53, 95%CI [1.17-1.99]) the risk of having an excellent chest compression score. When adjusted for covariables (i.e., age, experience, sex, and belonging to a critical care unit), the effect of the intervention remained (RR 1.57, 95%CI [1.19-2.07]). Conclusions: Although the T-CCT is a novel chest compression training intervention, our results suggest that acquired performance is sustained over time. Further research is needed to identify the optimal interval between these training.
Abstract 13044: Hemodynamic Changes In Neonates Born To Mothers With Graves’ Disease
Authors: Takamichi Ishikawa, Hiroki Uchiyama
Journal: Circulation (2021)

Purpose: Cardiac insufficiency is a major morbidity in neonatal hyperthyroidism. It is therefore important to assess the hemodynamics in neonates born to mothers with Graves’ disease (GD). This study prospectively evaluated the hemodynamic changes in neonates born to mothers with GD. Methods: The subjects of this study were neonates born to mothers with GD who became pregnant between April 2006 and May 2018 and visited Hamamatsu University Hospital. This study included two groups: neonates born to mothers consistently negative for thyroid-stimulating hormone (TSH) receptor antibody (TRAb) in the third trimester of pregnancy, and neonates born to mothers with at least one positive TRAb assay in the third trimester of pregnancy. The serum levels of TSH, free triiodothyronine (FT3), free thyroxine (FT4), and N-terminal-pro-B-type natriuretic peptide (NT-proBNP), the cardiac output, and cardiac index (CI) evaluated by echocardiography were compared between the two groups at several postnatal points (day of delivery and 5, 10, and 30 days of life). Results: Overall, 80 newborns were enrolled. Thirty-six neonates were born to mothers with GD who were positive for TRAb, and 44 were born to mother negative for TRAb. During the study period, four newborns (11.1%) in the TRAb-positive group required treatment with ATD for overt neonatal hyperthyroidism. Eight newborns (22.2%) in the TRAb-positive group were diagnosed with subclinical hyperthyroidism based on findings of laboratory tests in the absence of any clinical symptoms. One neonate in the TRAb-positive group had subclinical hypothyroidism at birth, but there were no symptoms, so no treatment was required. The TRAb-positive newborns had higher FT4 levels and CI on Day 5 (both p &lt; 0.05) and higher FT3 (p &lt; 0.05) and FT4 levels (p &lt; 0.01) and CI (p &lt; 0.01) but lower TSH levels (p &lt; 0.05) on Day 10 than the TRAb-negative newborns. The TRAb-positive newborns had significantly higher NT-proBNP levels on Days 5 (median 752 vs. 563 pg/mL, p = 0.034) and 10 (median 789 vs. 552 pg/mL, p = 0.002) than the TRAb-negative newborns. Conclusions: Hemodynamic changes in neonates born to TRAb-positive mothers with GD resulted in a higher CI and NT-proBNP levels than in those with TRAb-negative mothers from postnatal days 5 to 10.
Abstract 11780: Longitudinal Echocardiographic Parameters Before and After Pacemaker Placement in Congenital Complete Heart Block
Authors: Scott J Weinreb, Steve Ampah, Oluwatimilehin Okunowo, Heather M Griffis, Victoria L Vetter
Journal: Circulation (2021)

Introduction: Congenital complete heart block (CCHB) is rare, 1:15,000 - 1:20,000 live births, with left ventricular (LV) dysfunction developing in 7-14% of subjects. We investigate longitudinal trajectories of echo parameters in CCHB and the effect of pacemaker implantation on those parameters. Methods: This is a retrospective cohort study of identifiable CCHB subjects at the Children’s Hospital of Philadelphia from 1970-2018, excluding those with structural, genetic, or acquired cardiac conditions. Subjects with echo data available before and after pacemaker implantation are included. LV end diastolic diameter (LVEDD) z-score and LV ejection fraction (EF) are modeled with least-squares regression models, with slopes compared before and after pacemaker placement. Results: Of 114 subjects with CCHB, 52 (40% male, 73% white) have echo data available before and after pacemaker placement. Median age of diagnosis is 0.6 years, age at pacemaker placement 3.4 years, and duration of pacing 10.8 years. Figure 1 displays modeled trajectories of LVEDD z-score and EF over 20 years. Mean LVEDD z-score at pacemaker placement is less than 2 and decreases significantly over time, especially 10 years post placement. Participants have mean LV ejection fraction of 54% at pacemaker placement, rising significantly prior to placement and in the first 10 years post-placement, after which significant decreases are observed. Older age at pacemaker placement is associated with a higher EF at placement but an earlier and steeper decline in EF beginning at 8 years post-placement. LVEDD and EF trajectories do not vary significantly by sex, race, maternal antibody status, age at diagnosis, or initial pacemaker mode. Conclusions: In a cohort of 52 subjects with CCHB, LVEDD z-score steadily decreases over time whereas EF rises for 10 years post-pacemaker placement and subsequently decreases. Pacemaker placement has no apparent immediate effect on trajectories of these echo parameters.
Outcomes of Patients with Extranodal Natural Killer/T-Cell Lymphoma: Single Institution Series
Authors: Ranjit Nair, Lei Feng, Jillian R. Gunther, Jie Xu, Luis Malpica-Castillo, Auris Huen, Carlos Torres Cabala, Meghan Heberton, Penny Fang, Sairah Ahmed, Roberto N. Miranda, Luis Fayad, Raphael Steiner, Hun Ju Lee, Dai Chihara, Preetesh Jain, Samer A. Srour, Yago Nieto, Loretta Nastoupil, Chelsea C. Pinnix, Sattva S. Neelapu, Christopher R. Flowers, L. Jeffrey Medeiros, Chitra Hosing, Michael Wang, Bouthaina S. Dabaja, Francisco Vega, Swaminathan Padmanabhan Iyer
Journal: Blood (2021)
Initial Safety Results from a Phase II Study of Acalabrutinib Plus RICE Followed By Autologous Hematopoietic Cell Transplantation and/or Acalabrutinib Maintenance Therapy for Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Authors: Neil Bailey, Tenzin Tsomo, Tori Braun, Jennie Szeto, William I. Bensinger, Daniel Egan, Raya Mawad, Livia Hegerova, Gayle Funk, Joanna Fesler, Sonia Glennie, Judson Hall, Vanessa Dunleavy, Heidi Hohmann, Jordan Briggs, Joshua Mark, Megumi Bailey, John M. Pagel, Krish Patel
Journal: Blood (2021)
INNV-05. MULTIDISCIPLINARY SPINE ONCOLOGY CARE ACROSS THE DISEASE CONTINUUM - UPDATES FOR THE BEDSIDE AND THE BOARDS
Authors: Erin Dunbar
Journal: Neuro-Oncology (2021)

Abstract In response to the increased prevalence and complexity of metastatic and primary spine oncology, there has been a resultant increase in stakeholders, treatments and outcomes. A subset of the global multidisciplinary authors will present a timely and concise review of the contents of NOP’s Volume-7, supplement-1, “Multidisciplinary Spine Oncology Care Across the Disease Continuum”. The first portion will review: Epidemiology, Tumor Types, Presentation, Initial Tumor-directed Management, Initial Symptom-directed Management, Subsequent Tumor-directed Management, Subsequent Symptom-directed Management, and Multidisciplinary Program Development and Resources for Stakeholders. The second portion will challenge the current state of care and engage the attendees toward developing initiatives needed for a future state of care. Attendees will receive an update for both the bedside and the boards.
Abstract 13328: Effect of Atrial Fibrillation on Patient-Reported Outcomes in Heart Failure and Preserved Ejection Fraction: Secondary Analysis of Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) Trial
Authors: Khaled Elkholey, Seabrook Whyte, Zain Ul Abideen Asad, Udho THADANI, Stavros Stavrakis
Journal: Circulation (2021)

Introduction: Atrial fibrillation (AF) and heart failure (HF) both significantly impact morbidity and mortality, and also account for impaired quality of life. Patient-reported outcomes represent the most direct measurement of quality of life, without influence of interpretation by the clinician. We sought to evaluate the effect of AF on patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in patients with HF with preserved ejection fraction (HFpEF) enrolled in TOPCAT trial. Methods: This was an exploratory post-hoc analysis of the TOPCAT trial. Patients with reported KCCQ at randomization were included in this analysis. KCCQ was collected at randomization, 4, 12, 24, 36, 48, and 72 months. Mixed model repeated measure ANOVA was used to explore the effect of AF status at the time of randomization on longitudinal changes in the KCCQ- overall symptom score (OSS) over the duration of follow-up. Covariates adjusted for included age, gender, race, diabetes mellitus, history of HF hospitalization and use of ACEIs or ARBs. Results: A total of 3403 patients (mean age 68.5±9.5 years, females 51.5%) with available KCCQ-OSS at baseline were included. AF was prevalent in 1202 (35.3%) patients at baseline (mean age 71.0±9.3, 46.3% women, 91.7% white). AF patients had higher prevalence of stroke, diabetes mellitus, hypertension and lower prevalence of HF hospitalization. Over the duration of follow-up, there was a significant time by AF status interaction (p&lt;0.001), suggesting that KCC-OSS changed differently overtime based on the AF status. Conclusions: Among patients with HFpEF from TOPCAT cohort, prevalent AF at baseline was associated with lower quality of life and lower KCCQ-OSS over 5 years of follow-up, suggested by the significant interaction between AF status and time of follow-up.
Abstract P307: An Exquisite Cardiac Performance And Protection Package Emerges In Mouse With Cardiac-specific Overexpression Of Adenylyl Cyclase Type 8
Authors: Jia-Hua Qu, Kirill Tarasov, Khalid Chakir, Edward G Lakatta
Journal: Circulation Research (2021)

Young adult (three-month old) mice with cardiac-specific overexpression of AC type 8 (TGAC8) have a markedly elevated heart rate and markedly enhanced ejection fraction around the clock, mimicking cardiac responses of sympathetic autonomic input during acute exercise on a chronic base, but the TGAC8 mice do not exhibit heart failure or increased mortality up to about a year. Using this incessant young TGAC8 mouse as an ideal model to elucidate a high grade cardiac “Performance and Protection Package” (PPP) in response to chronic cardiac stress, we hypothesized that the TGAC8 heart adjusts to the chronical stress by reprogramming itself at multiple omics scales to code the exquisite cardiac PPP. To this end, we compared three-month old TGAC8 mice and their wildtype (WT) littermates using multiple omics analyses, from transcriptome to proteome, to phosphoproteome. Compared to WT, the phosphorylation level of most proteins was increased in the TGAC8 mice, including transcription factors (TF), kinases and phosphatases that are important in regulating transcription and phosphorylation. Among the 191 TFs identified in phosphoproteome, 91 were increased significantly, in line with the general upregulation in transcriptome. Many important stress response signaling pathways were enriched from phosphoproteome. Wherein, three protein quality control pathways, PI3K/AKT signaling, ERK/MAPK signaling and ubiquitination, were consistently enriched across the three omics scales. Most components in PI3K/AKT signaling pathway were upregulated, especially at protein and phosphorylation levels. Consistently, PI3K/AKT substrate phosphopeptides were increased, and downstream effects and functions of PI3K/AKT signaling were activated, including energy metabolism, protein synthesis, cell growth, cardiovascular functions, and NF-kB mediated functions. In summary, profiling the transcriptome, proteome and phosphoproteome of the TGAC8 heart unraveled the mechanism that controls its PPP. The cardiac overexpression of AC8 activates the AC8-cAMP-PKA axis to increase phosphorylation; widespread phosphorylation of the TFs promotes the transcription of numerous additional molecules that also regulate phosphorylation to reprogram the heart. Thereby, the TGAC8 mouse upregulates many stress response signaling pathways to activate the exquisite cardiac PPP.
Abstract 10486: Single-Beat Estimation Right Ventricular End Diastolic Pressure Relationship
Authors: Hannah Oakland, Lissa Sugeng, Phillip Joseph, Ray Amendola, Ian Crandall, Amjad Raza, Daniel Izzi, Felicia Zalik, Ahmed Elassal, Paul M Heerdt, Inderjit Singh
Journal: Circulation (2021)

Introduction: An abnormal right ventricular (RV) end-diastolic pressure-volume relationship (EDPVR) is an early marker of poor prognosis in pulmonary arterial hypertension (PAH). Prior studies assessing RV diastolic impairment utilized pressure (P) measured at right heart catheterization (RHC) and non-simultaneous volume (V) measured by cardiac magnetic resonance imaging (cMRI), which serves as the current reference standard for V. Our aims were: (a) to validate a single-beat (SB) method to assess RV EDPVR in an animal model against multi-beat (MB) measurements during preload variation, and (b) to use V obtained via transthoracic 3D echocardiography (3DE) during simultaneous RHC. Methods: In six anesthetized swine under an Institutional Animal Care &amp; Use Committee-approved protocol, a SB method was used to derive EDPVR as V 15 , the previously described predicted ventricular V at a theoretical EDP of 15 mmHg. A multi-beat (MB) reference EDPVR was defined using conductance/micromanometer catheter-measured RVP and V during preload variation. The V 15 value derived from the SB method was compared by Bland-Altman analysis to that defined by the reference EDPVR. Clinically, the SB method was applied to 13 patients with PAH and 10 age- and gender-matched controls who underwent RHC with simultaneous transthoracic 3DE. V 15 values between groups were compared by t-test. Results: In the animal model there was strong correlation between MB and SB estimates of V 15 (r=0.95; p&lt;0.0001) with acceptable accuracy and precision (bias -4.2±6.1 mL, overall error 8.4%). Consistent with previous reports using cMRI, PAH patients exhibited greater V 15 (166±43 mL vs. 131±30 mL; p=0.04) (Figure 1) . Conclusion: This study demonstrates validity of a SB assessment of RV EDPVR using data obtained from transthoracic 3DE performed during RHC, obviating the need for non-simultaneous cMRI. Further studies are needed to examine SB assessment of RV EDPVR across the spectrum of PH phenotypes.
Abstract P334: Biophysical Properties Of A Novel Mitochondrial Large Ubiquitous Non-selective Amiloride Sensitive (luna) Current
Authors: Enrique Balderas-Angeles, Thirupura Shankar, Anthony Balynas, Xue Yin, Dipayan Chaudhuri
Journal: Circulation Research (2021)

Inner mitochondrial membrane (IMM) ion channels and transporters account for communication of the matrix with the intermembrane space (IMS) and the cytosol. Transport of solutes and ions is keep under strict regulation mainly because small changes in solute concentrations could generate changes in mitochondrial volume or membrane potential (ΔΨ m ), interrupting ATP synthesis and leading to mitochondrial damage. The list of recently discovered mitochondrial ion channels has been growing in the past decades. In this work, using the patch-clamp technique we observed the activity of a novel mitochondrial current, named here LUNA current, in mitoplasts (IMM striped of outer membrane) from mouse liver, spleen, brain and heart, as well as established cell lines. LUNA is a novel non-selective cation current (K + &gt;Na + &gt;NMDG + &gt;H + ) active at depolarized membrane potentials. The basal activity of whole-mitoplast LUNA currents from wild type mice hearts changed from 445±106 pA/pF to 1232±287 pA/pF upon chelation of external divalent cations (Ca 2+ and Mg 2+ ). Moreover, the activity of LUNA is independent of the mitochondrial Ca 2+ uniporter and of the non-selective reactive oxygen species modulator channel (ROMO1). In the heart, the activity of LUNA was enhanced in both the Tfam -KO mice, which have impaired electron transport chain (ETC) activity and are a model for mitochondrial cardiomyopathies, and mice with cardiac pressure overload due to transverse aortic constriction (TAC) compared to sham-operated hearts (729±197; n=7 vs 283±137 pA/pF). LUNA current is reversibly inhibited by amiloride with no sensitivity to the vast majority of common K + , Na + and Ca 2+ channels and ETC inhibitors. The molecular identity of mitochondrial LUNA current remains to be determined.