tbuckley/cabot-search huggingface dataset:
Abstract 14387: Dose-Related Reductions in Blood Pressure With a RNA Interference (RNAi) Therapeutic Targeting Angiotensinogen in Hypertensive Patients: Interim Results From a First-In-Human Phase 1 Study of ALN-AGT01
Authors: Stephen A Huang, Jorg Taubel, Giuseppe Fiore, Peter Dewland, George L Bakris, Akshay S Desai, Yansong Cheng, Sagar Agarwal, Jamie Harrop, Huy V Nguyen, Jiandong Lu, Don Foster, Akshay Vaishnaw, Jae B Kim
Journal: Circulation (2020)

Background: Angiotensinogen (AGT) is the sole precursor of all angiotensin peptides and plays a key role in hypertension pathogenesis. We evaluated the effect of ALN-AGT01, a subcutaneous investigational RNAi therapeutic targeting hepatic AGT synthesis, on blood pressure in hypertensive patients. Methods: As part of a phase 1 program designed to assess the safety and tolerability of ALN-AGT01, we conducted a multicenter study randomizing patients aged 18-65 years with mild to moderate hypertension (mean seated systolic blood pressure [SBP] of &gt;130 and ≤165 mmHg after washout of antihypertensive medication) 2:1 to ascending single doses of ALN-AGT01 or placebo. Change from baseline in BP at 8 weeks was measured by ambulatory BP monitoring (ABPM). We report interim results as of May 14, 2020. Results: Sixty patients (mean age 52 years, 45% female, mean baseline 24h SBP 139 +/- 7 mm Hg) were enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg. Dose-related reductions in serum AGT levels were observed (figure), with reductions &gt;90% in the 100 and 200 mg dose cohorts. AGT remained durably reduced through 12 weeks after single dose administration. Concomitant reductions in BP from baseline were observed with AGT knockdown, with an over 10 mm Hg reduction of mean 24-hour SBP observed at Week 8 after single doses of 100 mg or 200 mg. No symptomatic hypotension, treatment-related serious adverse events, or clinically significant elevations in blood creatinine or potassium were seen. Conclusions: Single dose administration of ALN-AGT01 to hypertensive patients resulted in dose-related reductions in serum AGT and BP over 8 weeks without hypotension or other related serious adverse events. Durable AGT knockdown to 12 weeks supports further evaluation of once quarterly or potentially less frequent dose administration.
Abstract 15968: Adults With Congenital Heart Disease Have an Altered Body Composition - Evidence of Gender Differences
Authors: Camilla Sandberg, Karna Johansson, Christina Christersson, Joanna Hlebowicz, Ulf Thilén, Bengt Johansson
Journal: Circulation (2018)

Introduction: Due to advances in medical care, adults with Congenital Heart Disease (CHD) is a growing population. Previous research has shown that adults with CHD have impaired muscle function and...
Abstract 16937: Gender Differences in Baseline Body Composition Profiles and Improvements With Visceral Fat-Focused Weight Loss Program
Authors: Gerald Dembrowski, Jessica Barnes
Journal: Circulation (2020)

Cardiovascular disease (CVD) in women remains a leading cause of death. A recent study in the Journal of the American Medical Association highlighted the significant risk that central (or visceral) obesity confers in normal-weight postmenopausal women versus normal-weight women without central obesity- a 31% increase in premature death, including death from CVD and obesity-related cancer. Strategies targeting central obesity (visceral adipose tissue or visceral fat, VF) are a promising means to reduce the risk of, and events associated with CVD. A comprehensive telehealth program (20Lighter, 20L) combining patented customizable VLCD meal plans, nutritional supplementation, and expert daily oversight significantly reduces VF. Here we present data assessing body composition (BC) improvements between female (n= 931) and male (n= 1269) participants. We found the baseline BC profiles differed, with 3 of the 4 measures varying significantly between female and male participants (shown as female versus male, mean ± SEM): BMI (33.7 ±0.722 vs 35.4 ±0.511, p=0.0548), Body Fat (45.7% ±0.754 vs 38.8% ±0.613, p&lt;0.0001), VF (15.2 ±0.664 vs 22.7 ±0.563, p&lt;0.0001), and Intracellular Fluid (38.6% ±0.539 vs 45.2% ±0.303, p&lt;0.0001) (Figure1A). Interestingly, while baseline measures differed, both women and men achieved the same magnitude of relative percentage improvements in BC measures: BMI (12.9% ±0.192 vs 13.3% ±0.228, p=0.1798), Body Fat (19.5% ±0.560 vs 19.7% ±0.634, p=0.8131), VF (24.7% ±0.643 vs 25.9% ±0.633, p=0.1837), and Intracellular Fluid (6.9% ±0.366 vs 7.9% ±0.486, p=0.0970) (Figure1B). Our data suggest that while women and men have different baseline BC profiles, they achieve equally statistically significant and clinically meaningful changes in outcomes in an expert-supervised, structured comprehensive program that are associated with risk reduction for CVD and CVD-associated events including premature death, heart attack, and stroke.
Abstract 16781: Ventriculo-Arterial Coupling is Associated With Death and Need for Ventricular Assist Device or Heart Transplant in Patients With Transthyretin Cardiac Amyloidosis
Authors: Ossama K Abou Hassan, Muzna Hussain, Balint Laczay, Michael Martyn, Mazen A Hanna, Paul C Cremer, Zoran B Popovic, Wael A Jaber, Patrick H Collier
Journal: Circulation (2020)

Background: Transthyretin (TTR) cardiac amyloidosis (CA) results from TTR protein deposition in the extracellular space of the heart altering cardiac chamber mechanics and efficiency. Ventriculo-arterial coupling (VAC) is calculated from 2D echo derived measurements and reflects cardiac function and efficiency. We aimed to identify whether VAC assessment at diagnosis improves current risk stratification models as a prognostic tool. Methods: The Amyloid Heart Disease registry at our institution was used to identify 365 TTR-CA patients. Primary outcome was mortality and advanced heart failure therapy (ventricular assist device (VAD) or heart transplant). Results: At a median follow up of 1.9 years, VAD, transplant or death occurred in 163 (44.7%) patients. On adjusted multivariable Cox survival analysis, the Gillmore Stage which incorporates eGFR and NTproBNP (HR=2.5, 95% CI 1.96-3.18), CAD (HR=1.50 95% CI 1.02-2.20), therapy with Tafamidis (HR=0.31, 95% CI 0.19-0.51), and VAC greater than median (&gt;1.01) (HR=2.28 95% CI 1.57-3.29, p&lt;0.001) were independently associated with outcome (all p&lt;0.05) (Figure). Conclusion: The easily measurable and widely available echo parameter VAC provides incremental independent value in patients with TTR-CA.
Folate Receptor Beta Designates Immunosuppressive Tumor-Associated Myeloid Cells That Can Be Reprogrammed with Folate-Targeted Drugs
Authors: Gregory M. Cresswell, Bingbing Wang, Erin M. Kischuk, Meaghan M. Broman, Rami A. Alfar, Renee E. Vickman, Dimiter S. Dimitrov, Sumith A. Kularatne, Chandru P. Sundaram, Sunil Singhal, Evgeniy B. Eruslanov, Scott A. Crist, Bennett D. Elzey, Timothy L. Ratliff, Philip S. Low
Journal: Cancer Research (2020)

Abstract Although immunotherapies of tumors have demonstrated promise for altering the progression of malignancies, immunotherapies have been limited by an immunosuppressive tumor microenvironment (TME) that prevents infiltrating immune cells from performing their anticancer functions. Prominent among immunosuppressive cells are myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) that inhibit T cells via release of immunosuppressive cytokines and engagement of checkpoint receptors. Here, we explore the properties of MDSCs and TAMs from freshly isolated mouse and human tumors and find that an immunosuppressive subset of these cells can be distinguished from the nonimmunosuppressive population by its upregulation of folate receptor beta (FRβ) within the TME and its restriction to the TME. This FRβ+ subpopulation could be selectively targeted with folate-linked drugs. Delivery of a folate-targeted TLR7 agonist to these cells (i) reduced their immunosuppressive function, (ii) increased CD8+ T-cell infiltration, (iii) enhanced M1/M2 macrophage ratios, (iv) inhibited tumor growth, (v) blocked tumor metastasis, and (vi) improved overall survival without demonstrable toxicity. These data reveal a broadly applicable strategy across tumor types for reprogramming MDSCs and TAMs into antitumorigenic immune cells using a drug that would otherwise be too toxic to administer systemically. The data also establish FRβ as the first marker that distinguishes immunosuppressive from nonimmunosuppressive subsets of MDSCs and TAMs. Because all solid tumors accumulate MDSCs and TAMs, a general strategy to both identify and reprogram these cells should be broadly applied in the characterization and treatment of multiple tumors. Significance: FRβ serves as both a means to identify and target MDSCs and TAMs within the tumor, allowing for delivery of immunomodulatory compounds to tumor myeloid cells in a variety of cancers.
Abstract 13923: Incidence and Outcomes of Infective Endocarditis After 180 Days in Transcatheter Aortic Valve Replacement and Mitraclip
Authors: Manpreet Kaur, Anas M Saad, Keerat Ahuja, Simrat Kaur, Toshiaki Isogai, Beni R Verma, Shashank Shekhar, Mohamed M Gad, Omar M Abdelfattah, Samir R Kapadia
Journal: Circulation (2020)

Background: Infective endocarditis (IE) after Transcatheter aortic valve replacement (TAVR) and Mitra Clip (MC) occurs less commonly but is associated with grave complications. We aim to report the incidence and outcomes of IE within 180 days of TAVR and MC. Methods: We used the Nationwide Readmissions Database (NRD) between 2014 and 2017 to select patients who underwent either TAVR or MC between January and June every year (to allow for at least 180 days of follow up in the NRD) using the appropriate International Classification of Diseases-9 th and 10 th revision (ICD) codes. We performed a chi-square test to compare baseline characteristics and rates of IE after TAVR and MC procedures. All statistical analyses were performed the using SPSS version 26. Results: We included 68,270 and 7,080 patients who underwent TAVR and MC respectively, of which 0.68% vs. 0.94% (P=.012), developed IE respectively within 180 days of procedure. During that index hospitalization, in-hospital mortality rates did not differ between the two groups (15.08% in TAVR vs. 17.91%, in MC P=.587). Other outcomes are presented in table 1. Conclusion: Our study suggests that the overall incidence of IE following TAVR and MC is relatively low but appropriate preventive measures should be taken after the procedures to reduce the morbidity and mortality. Further studies and analysis are required in modern MC and TAVR techniques to circumvent this critical complication.
Abstract 16753: Baseline Prediction of Atrial Fibrillation Recurrence After Catheter Ablation: Comparative Analysis of Prognostic Models Using Data Recorded by Implanted Cardiac Monitors
Authors: Lisa YW Tang, Kendall Ho, Nathaniel Hawkins, Roger Tam, Michael Lim, Jason Andrade
Journal: Circulation (2020)

Intro: Tools for baseline prediction of catheter ablation outcome are instrumental to treatment management that best balances positive outcomes against risk of treatment complications. To date, many such predictive models exist in the literature; yet, it is unclear which should be adopted as no study has compared all using a single dataset. Goals: examine 8 published models using a single dataset with expert-annotated data recorded by implanted monitors. Methods: We collected data from a cohort of ~350, acquired from a randomized clinical trial blinded to ablation outcome. Based on a 2020 review, we shortlisted 12 models for baseline prediction of recurrences recorded between days 91-365 post ablation per standard. Models that use postoperative data, thus unsuited for baseline prediction, were excluded. Four models were further dropped from this work as their required variables (e.g. normalized atrial area) are unavailable in our cohort. Results: There was no missing variable; 34% were female and 53% of patients experienced recurrence. Figure reports each model’s performance with metrics as sensitivity (SEN), specificity (SPEC), positive predictive value (PPV), negative predictive value (NPV), area under receiver operating characteristic curve (AUC), positive and negative clinical utility indices (SENxPPV; SPECxNPV, resp.). The digit after each model name indicates the cut-off used (some studies used different cut-offs). Models are presented in rank-order by utility indices. All evaluated scores achieved AUC&lt;65 and deemed to have poor utility. A model that examines age, stroke, hypertension, heart failure, chronic obstructive pulmonary disease, and obstructive sleep apnea, performed best in this cohort (SEN=54, SPEC=70,PPV=65,NPV=60,AUC=62). Conclusions: Our results reinforce statements of previous reviews that many published models are lacking and that there remains a need to develop and validate models for prediction of AFR post ablation.
Abstract 14230: Integration of Vascular Phenotyping With Metabolomic Profiling in Black Subjects With Heart Failure With Reduced Ejection Fraction
Authors: Alanna A Morris, Aditi Nayak, Chang Liu, Qingchun Jin, Yi-An Ko, Eisha Udeshi, karan uppal, Ken Liu, Javed Butler, Dean Jones, Arshed A Quyyumi
Journal: Circulation (2020)

Introduction: Impaired vascular function in blacks contributes to a higher risk of heart failure (HF) compared to other race/ethnicities. Hypothesis: Black patients with HF with reduced ejection fraction (HFrEF) will have worse digital microvascular function measured using peripheral arterial tonometry (PAT). High resolution metabolomics profiling will identify novel biomarkers of vascular function. Methods: PAT was used to estimate the reactive hyperemia index (RHI) in blacks and whites with HFrEF (N=154, age: 53.7 ± 13.0 yrs, 48.7% female, 61.0% black) and healthy controls (N=200, age: 43.2 ± 14.0 yrs, 47.0% female, 27.0% black). Linear regression was used to determine if race was associated with RHI after adjustment for traditional CV risk factors. High-resolution plasma metabolomics profiling and pathway analysis, followed by metabolite confirmation with mass spectrometry were used to derive a metabolomics score (MS) from metabolites that were significantly associated with RHI, different between blacks and whites, and attenuated the association of black race with RHI. Results: Black subjects were younger in both the HFrEF and control cohorts. Blacks with HFrEF were more likely to have nonischemic HF and hypertension, more likely to be on hydralazine-nitrates and diuretics. RHI was lower in blacks than whites both in subjects with HFrEF (1.8 ± 0.5 vs. 2.0 ± 0.5, P=0.02) and in healthy controls (2.1 ± 0.5 vs. 2.4 ± 0.5, P=0.003). Black race was independently associated with lower RHI (adjusted β=-0.221, P=0.03). MS comprising metabolites representative of cardiac cachexia (3-Methyl-Histidine, L-Histidine, Creatinine), vascular collagen turnover (4-hydroxyproline), purine metabolism and oxidative stress (uric acid) attenuated the association of black race with RHI by 49.8%. Conclusion: Integration of vascular phenotyping with metabolomic profiling reveals a novel MS that attenuates the association of black race with impaired microvascular function.
Abstract 15800: Inter-race and Ethnicity Comparisons in Pulmonary Hypertension From the Pulmonary Vascular Phenomics (PVDOMICS) Program
Authors: Franz Rischard, Milena Radeva, Erika B Rosenzweig, Robert Frantz, Paul Hassoun, Anna R Hemnes, Evelyn M Horn, Jane A Leopold, Wilson Tang, and the PVDOMICS Study Group
Journal: Circulation (2020)

Intro: Recent World Symposium of Pulmonary Hypertension (WSPH) Group 1 data indicate significant racial and ethnic disparities in disease severity and mortality. It is unclear if these differences extend to other forms of PH and if they are a reflection of comorbidities. The PVDOMICS program incorporates deep phenotyping across all WSPH groups allowing for a first-time side-by-side comparison. The aims of this study are to evaluate inter-racial/ethnic factors of disease severity and comorbidities among patients with PH. Methods/Results: Participants in PVDOMICS prospectively underwent comprehensive testing for echocardiography, PFT, chest imaging, 6-minute walk, cardiac MRI, and hemodynamics with provocation. WSPH group assignment was assessed according to guideline recommendations. Race and ethnicity were self-reported. Statistical testing and sample sizes are described in the Table . In 692 PH participants, Non-Hispanic whites (NHW) were older and more often male than non-Hispanic African American (AA) and Hispanic patients. WSPH Group 1 was less but Groups 4 and 5 more common in AA than NHW. There were no inter-race/ethnicity differences in the percent of PH patients on PH therapy (range 53-63%, p=0.23). Comorbidities such as diabetes and lung disease were more common in AA vs. NHW. Hispanics showed lower left atrial (LA) volume on echo, LA filling pressures with exercise, as well as increased cardiac index relative to NHW. Right ventricular function on cardiac MRI was similar between groups ( Table ). When WSPH Group 1 was analyzed separately, inter-racial/ethnic comparisons were generally similar. Conclusions: Significant inter-racial/ethnic differences are evident across all WSPH groups. Comorbidities appear to drive part of the differences among AA patients while Hispanic patients exhibit factors that may prove beneficial. How these differences contribute to varying disease risk and outcomes across race and ethnicity remain to be seen.
Abstract 13099: Evaluation of Right Ventricular Myocardial Mechanics by 2D-and 3D-STE in Patients With End-stage Heart Failure
Authors: Yuman Li, Fangyan Tian, Mingxing XIE
Journal: Circulation (2020)

Background: Speckle-tracking echocardiography (STE) has emerged as a more accurate tool for assessing the right ventricular (RV) function.We aimed to assess RV myocardial mechanics by 2D- and 3D-STE in patients with end-stage heart failure (HF). Methods: We enrolled 105 patients with end-stage HF and 50 normal subjects. The results of coronary artery angiography divided these patients into two subgroups : ischaemic cardiomyopathies (ICM, n=23) and non-ischaemic cardiomyopathies subgroups (NICM, n=82). RV end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF) were measured by 3D-STE. RV free wall longitudinal strain (RVLS-fre),and RV septal wall LS (RVLS-sep) were also determined by 3D-and 2D-STE. The conventional RV function parameters (fractional area change [FAC], tricuspid annular plane systolic excursion [TAPSE]) were obtained. We compared these parameters between patients and normal subjects. RVLS-fre and RVLS-sep obtained by 3D- and 2D-STE were compared between ICM and NICM. Results: Compared with controls, patients had higher RVEDV, RVESV(P&lt;0.001),and lower RVLS-fre, RVLS-spe, RVEF, RVSV, FAC, TAPSE(P&lt;0.001).In 105 patients, 3D-RVLS-fre was lower than 2D-RVLS-fre (-11.43±3.83% VS -12.30±3.95%;P=0.003); whereas 3D-RVLS-sep was not different from 2D-RVLS-sep. Patients with NICM had significant lower 3D-RVLS-fre(-10.68±3.55% VS -14.06±3.70%;P&lt;0.001)and 3D-RVLS-sep (-6.68±2.76% VS -8.26±2.64%;P=0.006)than patients with ICM. There was no difference in 2D-STE between the two subgroups. Conclusions: End-stage HF patients present significant difference in RVLS values between 3D- and 2D-STE. 3D-STE is superior to 2D-STE for RV systolic function assessment in end-stage HF patients with different pathologies.
Abstract 14966: Non-biased Fat Scoring System for Human Cardiac Variability and Body Mass Index Correlation Analyses
Authors: Kyra Peczkowski, Farbod Fazlollahi, Mohammed Mashali, Nancy Saad, Salome Kiduko, Amanda Huang, Austin Hare, Gina Torres Matias, Divyaam Satija, Nahush Mokadam, Bryan Whitson, Courtney Campbell, Paul M Janssen
Journal: Circulation (2020)

Introduction: It remains unclear if body mass index (BMI) is correlated to the amount of cardiac adipose tissue in humans. Echocardiography is typically utilized to measure epicardial fat in live patients, but has yielded inconclusive results, as it is difficult to measure cardiac adipose tissue levels from a single location on a 1-dimensional image, as fat is not always distributed equally across the heart. Methods: Through the Ohio State Cardiac Research Tissue program, we have collected over 200 human hearts of various conditions. Multi-angle photographs are available for every heart. We developed an adipose tissue scoring system, so correlations can be drawn between the adipose tissue score (ATS), and BMI in failing and non-failing human hearts. Hearts were scored based on the multi-angle photographs. Each heart was given an atrial (AATS) and a ventricular score (VATS) ranging from 0-7, based on fat distribution and epicardial fat thickness. Nine sets of scores by individuals blinded to any patient information were averaged for each heart and the average ATS was plotted for correlation analyses against BMI and etiology. Results: A strong correlation was not apparent by plotting BMI versus VATS for all failing and non-failing hearts (R 2 = 0.011915 failing, 0.017262 non-failing). It is of interest to note that the lower right quadrant of the correlation plot is empty, indication that in patients with high BMI, the ATS was also high. However, in individuals with low BMI, there was a wide distribution of ATS. VATS and AATS are closely correlated in both failing (R 2 = 0.67082) and non-failing (R 2 = 0.84446) hearts. Conclusions: Our analysis shows that in humans, a high BMI is typically correlated with a high ATS score, but a low BMI does not necessarily correlate with a low ATS. The non-failing hearts have a stronger correlation between VATS and AATS compared to the failing hearts, suggesting that failing hearts do not always have an equal distribution of adipose tissue between the atria and ventricle. Future studies will investigate the presence of correlation between ATS with other parameters, such as age, gender, and race.
Using antibiotics wisely for respiratory tract infection in the era of covid-19
Authors: Jerome A Leis, Karen B Born, Guylene Theriault, Olivia Ostrow, Allan Grill, K Brian Johnston
Journal: BMJ (2020)

Calcium waves represent a widespread form of intercellular communication. Although they have been thought for a long time to require gap junctions, we recently demonstrated that mouse cortical astrocytes use an extracellular messenger for calcium wave propagation. The present experiments identify ATP as a major extracellular messenger in this system. Medium collected from astrocyte cultures during (but not before) calcium wave stimulation contains ATP. The excitatory effects of medium samples and of ATP are blocked by purinergic receptor antagonists and by pretreatment with apyrase; these same purinergic receptor antagonists block propagation of electrically evoked calcium waves. ATP, applied at the concentration measured in medium samples, evokes responses that are qualitatively and quantitatively similar to those evoked by those medium samples. These data implicate ATP as an important transmitter between CNS astrocytes.