tbuckley/cabot-search huggingface dataset:
Abstract 9755: Impact of Outflow Obstruction and Septal Myectomy on Long Term Risk of New Onset Atrial Fibrillation in Hypertrophic Cardiomyopathy
Authors: Craig Cooper, Richard Carrick, Melissa Tsoi, Martin S Maron, Barry Maron, Ethan J Rowin
Journal: Circulation (2021)

Background: Atrial fibrillation (AF) is the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM), with patients having a 4 to 6 fold greater likelihood of developing AF as compared to the general population, and is an important cause of morbidity, impaired quality of life and embolic stroke in HCM. The impact of outflow obstruction and the influence of surgical septal myectomy on the development of new-onset AF has not been well described. Aim: To characterize the risk of new-onset AF in nonobstructive and obstructive HCM and compare to AF risk in patients after myectomy. Methods: 1767 consecutive HCM patients without prior AF history, seen at the Tufts HCM Institute between 2004 and 2019, including 712 with obstruction (outflow gradients ≥ 30mmHg at rest or following provocation) who did not undergo invasive septal reduction therapy (SRT), 552 with nonobstructive HCM (outflow gradients &lt; 30mmHg), and 503 who underwent surgical myectomy were followed for an average of 4.3 ±4.2 years for new-onset symptomatic AF. Isolated post-operative episodes of AF, i.e., occurring within the first 3 months after myectomy, were excluded from analysis. Results: Patients with obstructive HCM who did not undergo SRT had a 1.5-fold increased risk for new-onset AF as compared to nonobstructive HCM (rate onset of 2.8%/year vs.1.7%/year, p=0.04), with freedom from AF at 10-years of 72% in obstructive patients. Patients undergoing myectomy were older (52 ± 15 vs. 50 ± 15 years; p&lt;0.01), had larger LA dimension (42 ± 7 vs 40 ± 6mm; p&lt;0.01), and higher HCM-AF risk scores (22 ± 3.5 vs. 19 ± 3.8; p&lt;0.01) as compared to nonobstructive HCM. However, despite a higher predicted risk for new-onset AF at time of myectomy (2.7%/year vs. 1.5%/year), after myectomy the risk of new onset AF was no different from patients with nonobstructive HCM (hazard ratio 0.9; rate of onset of 1.8%/year vs. 1.7%/year; p=.73), with freedom from AF at 10-years of 83% post-myectomy. Conclusions: Patients with obstructive HCM have a higher risk of AF as compared to nonobstructive HCM. After myectomy risk of new-onset AF is substantially reduced, such that risk is no different from patients with nonobstructive HCM. These data demonstrate efficacy of myectomy in decreasing long term risk of AF in obstructive HCM.
Abstract 9677: Therapeutic Improvements in Pulmonary Arterial Hypertension Are Related to Cardiopulmonary Function but Not Skeletal Muscle Oxygen Extraction
Authors: Steven Stroud, Michael Insel, Tushar Acharya, Franz Rischard
Journal: Circulation (2021)

Introduction: World Symposium Group 1 pulmonary arterial hypertension (PAH) patients have impaired function from both central oxygen delivery and skeletal muscle oxygen extraction. The effect of PH-directed therapy on skeletal muscle oxygen extraction is unknown. The aim of this study is to determine if therapy associated changes in muscle extraction parallel changes in cardiopulmonary function. Methods: Retrospective analysis was performed on twenty-nine PAH patients (24 female, mean age 54±11.4 years) receiving prostacyclin therapy (18 on monotherapy). Subjects underwent invasive cardiopulmonary exercise testing (iCPET) for treatment response evaluation followed by repeat surveillance iCPET with mean follow-up of 10.4±5.2 months. Skeletal muscle oxygen extraction was quantified by arterio-venous difference indexed to hemoglobin (Ca-vO 2 /Hgb) and systemic oxygen extraction ratio (SER) (Ca-vO 2 /CaO 2 ). Central oxygen delivery (DO 2 ) was calculated as peak cardiac output X CaO2 at peak exercise. Functional capacity was semi-quantified by six-minute walk test (6MWT) distances between assessments (n=20). Subjects were stratified into two groups: those with improvement (n=10) vs unimproved (n=19) in currently accepted ERS/COMPERA score ( Figure ). Results: Improvements in ERS/COMPERA score were related to DO 2 (318.3±273.1 vs -38.3±684.9 mL/min, P=.016 ) and PVR (-4.8±3.0 vs -0.6±3.2 WU, P=.002 ) (Figure A &amp; B). However, there was not a detectible difference between assessments in Ca-vO 2 /hgb (-0.01±0.14 vs 0.00±0.27 mL/g, P=.573 ), SER (-0.01±0.10 vs 0.00±0.20, P=.573 ), or 6MWT (7 improved, 13 unimproved) (77±115 vs 25±104 meters, P=.877 ) ( Figure C &amp; D ). Conclusions: Although PH-directed therapy improves both PVR and oxygen delivery, its effects on skeletal muscle extraction are questionable. Clinicians should consider that oxygen extraction may influence functional capacity when evaluating therapeutic improvement.
MAMMALIAN ZINC TRANSPORTERS
Authors: Juan P. Liuzzi, Robert J. Cousins
Journal: Annual Review of Nutrition (2004)

New insights into mammalian zinc metabolism have been acquired through the identification and characterization of zinc transporters. These proteins all have transmembrane domains, and are encoded by two solute-linked carrier (SLC) gene families: ZnT (SLC30) and Zip (SLC39). There are at least 9 ZnT and 15 Zip transporters in human cells. They appear to have opposite roles in cellular zinc homeostasis. ZnT transporters reduce intracellular zinc availability by promoting zinc efflux from cells or into intracellular vesicles, while Zip transporters increase intracellular zinc availability by promoting extracellular zinc uptake and, perhaps, vesicular zinc release into the cytoplasm. Both the ZnT and Zip transporter families exhibit unique tissue-specific expression, differential responsiveness to dietary zinc deficiency and excess, and differential responsiveness to physiologic stimuli via hormones and cytokines.
Abstract 13995: Proarrhythmic Electromechanical Heterogeneities in Patients With KCNJ2 Mutations
Authors: Peter M Deissler, Job Stoks, Bianca van Rees, Raphaela Lewetag, Pieter Koopman, Suzanne Gommers, Robert J Holtackers, Godelieve R Claes, Matthijs J Cluitmans, Robert Geukens, Frank R Heinzel, Katja E Odening, Paul G Volders, Rachel Ter Bekke
Journal: Circulation (2021)

Introduction: Loss-of-function mutations of the KCNJ2 gene encoding the inward-rectifier potassium channel, IK1, are associated with QT prolongation, prominent U waves, abnormal impulse formation a...
Who Will Own the Responsibility to Prescribe Statins? Tragedy of the Commons
Authors: E. Hope Weissler, W. Schuyler Jones
Journal: JAMA Network Open (2021)

Nikhil Singh, MD; Li Ding, MD, MPH; Justin Devera, MD; Gregory A. Magee, MD, MSc; Parveen K. Garg, MD, MPH
CTNI-08. DB102-01 ENGAGE STUDY: A BIOMARKER-GUIDED, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTI-CENTER PHASE 3 CLINICAL TRIAL OF DB102 IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)
Authors: Daniela Bota, Nicholas Butowski, David Piccioni, Macarena De la Fuente, Ying Mao, Wen-Bin Li, John Trusheim, Karen Fink, Jian Campian, Mina Lobbous, Jana Portnow, Jay-Jiguang Zhu, Michael Pearlman, Jeremy Rudnick, Glen Lesser, Jan Drappatz, Brian Vaillant, Show-Li Sun, Wen Luo
Journal: Neuro-Oncology (2021)

Abstract Precision medicine is vital for treating many cancers. Lack of valid biomarkers might contribute to the failure of drug therapy for GBM. The Denovo Genomic Marker 1 (DGM1), a novel pharmacogenomic biomarker, has been discovered by a genome-wide screen of patients treated with DB102 (enzastaurin) in a trial for lymphoma. Similarly, retrospective analyses showed that DB102 significantly improved outcomes in the biomarker positive GBM patients treated with DB102, regardless of MGMT promoter methylation status. The ENGAGE Study (DB102-01, NCT03776071) is a global Phase 3 clinical trial to confirm clinical benefits in patients with newly diagnosed GBM who are DGM1 biomarker positive. This is a prospective, randomized, double-blind, placebo-controlled, multi-center study. A total of 318 patients with newly diagnosed GBM will be enrolled. After screening, patients will be randomized to receive radiation therapy (RT) and temozolomide (TMZ) plus either DB102 or a matched placebo for 6 weeks in the Concurrent Phase, followed by DB102 or placebo for approximately 5 weeks in the Single-Agent Phase and then TMZ plus DB102 or placebo in the Adjuvant Phase (up to 12 cycles). Thereafter DB102 or placebo may be continued as a single agent for up to 2 years. The primary endpoint is overall survival (OS). The secondary endpoints include progression free survival (PFS), objective response rate (ORR) and drug safety. By April 2021, the safety-run-in part was completed. The study is now open for enrollment in the US and soon in Canada and China.
Abstract 10110: Sex and Ethnic/Racial Disparities in Ischemic Heart Disease Related Mortality Rates Among Older Adults
Authors: Abdul Minhas, Huzefa Bhopalwala, SALIK NAZIR, Muhammmad Khan, Sachin S Goel, Marat Fudim, Khurram Nasir
Journal: Circulation (2021)

Introduction: Ischemic heart disease (IHD) accounts for significant morbidity and mortality in the elderly population. The aim of this study was to examine the trends in IHD related deaths in elderly population in the United States from 1999 to 2019. Methods: We used CDC Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) to access National Vital Statistics System data from 1999 to 2019. IHD related deaths, age &gt;/=75 years were identified from multiple causes of death and were represented as age-adjusted mortality rates (AAMR) per 10,000 population. Joinpoint regression was used to examine changes in trend and annual percentage change (APC) overall and stratified by sex and racial/ethnic groups. Results: AAMR related to IHD decreased from 271.9 in 1999 to 137.3 in 2019 (average APC-3.4[95% CI, -3.7 to -3.0]). AAMR was higher in men (241.3) than women (156.9). Among the racial/ethnic groups, AAMR was highest in non-Hispanic whites (NHWs) (195.1) followed by non-Hispanic blacks (NHBs) (185.6), non-Hispanics American Indian or Alaska Natives (NH-AIAN) (152.7), Hispanics (147.4), and lastly non-Hispanics Asian or Pacific Islanders (NH-APIs) (110.5). AAMR was highest in NHW males (250.6). APC in AAMR decreased across all the subgroups. After initial decline, the decrease in APC in AAMR decelerated in both women (-2.7) and men (-2.0) since 2014, NHBs (-2.4) since 2014, Hispanics (-2.9) since 2012 and NH-API (-2.2) since 2015. After initial decline, AAMR remained stable in NHWs (APC -1.5) since 2016. After initially remaining stable, AAMR decreased in NH-AIAN (APC -3.3) since 2004. Conclusion: IHD related mortality in elderly has been decreasing at a variable pace across various sex and racial/ethnic groups. The causes of these disparities need to be examined and targeted interventions are required to address these disparities.
Abstract 12379: Distal Waveform Patterns in the Fontan Circulation Are Related to Pulmonary, Liver and Cardiac Function
Authors: Margaret R Ferrari, Michal Schafer, Kendall S Hunter, Michael V Di Maria
Journal: Circulation (2021)

Introduction: The lack of a sub-pulmonary ventricle in patients with a Fontan circulation leads to irreversible circulatory decline. Our group has determined that single-site waveform analysis correlates to clinical features of Fontan patients. The goal of this study was to determine if multi-site waveform analysis contributes to detecting early cardiovascular decline. Methods: Patients with a Fontan circulation that underwent cardiac MRI were included in this retrospective study. Hemodynamic flow curves were measured in the ascending aorta (AAo N=94), superior vena cava (SVC N=82), inferior vena cava (IVC N=91) and left pulmonary artery (LPA N=85). Flow curves were interpolated to equal temporal phases and were used to create three data matrices of proximal and distal waveforms. Principal component analysis (PCA), a data transformation method used to obtain a wieldy number of ranked components (the PCs) representing the variance of the input data, was performed on each matrix. PCs were correlated to clinical measures of current patient status. Results: PCs that accounted for more than 20% of the variance in a data matrix are reported (Pearson’s r, p ) in Table 1. Conclusions: These results indicate that increased liver enzyme levels, with a possible link to Fontan associated liver disease, are related to increased diastolic SVC flow and increased volume in the SVC and IVC throughout the cardiac cycle. An increased diastolic SVC flow profile relates to worsening pulmonary function and oxygen consumption during exercise. A decreased ventricular-vascular coupling ratio is related to increased IVC volume and low oxygen saturations may be indicative of increased LPA volume. Little variations were apparent in the AAo waveforms, suggesting cardiovascular decline may appear distally prior to proximal presentation. We have, for the first time, evaluated multi-site flow patterns and correlated them to functional status in one of the largest Fontan patient cohorts to date.
Abstract 11537: Progress Towards a Proteomic Surrogate Endpoint for Cardiovascular Outcomes
Authors: Stephen A Williams, Rachel Ostroff, Michael Hinterberg, Josef Coresh, Christie M Ballantyne, Kunihiro Matsushita, Christian Mueller, Joan E Walter, Christian Jonasson, Rury H Holman, Svati H Shah, Naveed Sattar, Roy Taylor, Michael Lean, Shintaro Kato, Hiroaki Shimokawa, Yasuhito Sakata, Kotaro Nochioka, Chirag Parikh, Steven Coca, Torbjoern Omland, Jessica Chadwick, David Astling, Yolanda Hagar, Natasha Kurieski, Jeremy Primus, Missy Simpson, Nelson P Trujillo, Peter Ganz
Journal: Circulation (2021)

Introduction: The critical path for novel treatment and prevention strategies, both pharmacological and non-pharmacological, requires clinical outcomes trials, which are slow, expensive and retard patient access to successful therapies. For marketed drugs, unreliable residual risk stratification hinders precision-directed therapy and facilitates payor reticence. Hypothesis: Large-scale proteomics and machine learning can identify a reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for multiple biologic mechanisms, with a resulting multimarker model that is more robust than individual biomarkers. Avoidance of immutable prognostic factors (e.g. age, sex, medical diagnoses) will enhance sensitivity to change in risk. Methods: We quantified ~5000 proteins in &gt;31,000 archived samples from &gt;21,000 higher risk individuals in nine clinical datasets, generating ~150M plasma protein measurements. We derived and validated a 27-protein model encompassing 10 biologic processes to predict the four-year likelihood of myocardial infarction, stroke, hospitalization for heart failure or death. We assessed the association of model-predicted change with observed outcomes in a variety of conditions in four clinical intervention trials. Results: See table for details. In validation, observed event rates were 7.8 fold higher in quintile 5 than quintile 1 for proteins vs. 2.9 for an optimized clinical factor model; the Net Reclassification Index was +0.43. AUCs were 0.73 for proteins vs. 0.63 for clinical, and c-statistics 0.71 vs. 0.62. The protein model also responded concordantly with outcomes in four intervention studies. Conclusions: A 27-protein model is more prognostic than clinical factors in higher risk populations and has directionally concordant responsiveness to all mechanistic challenges to date. These features are consistent with surrogacy, and may prove useful in clinical trials and precision medicine.
Abstract 13391: Increased LV Afterload Improves Rv Function in a Longitudinal Study of RV-Pressure Overloaded Mice
Authors: Melanie J Dufva, Kenzo Ichimura, Dunbar D Ivy, Edda F Spiekerkoetter, Vitaly O Kheyfets
Journal: Circulation (2021)

Introduction: The left ventricle (LV) is known to transfer kinetic mechanical energy to the right ventricle (RV) during systole. Normally, the RV relies on this mechanical assistance for up to 70% of its pressure generation. However, this biventricular relationship and its effect on RV function has not been explored in the progression in the pressure overloaded RV. In this study, we developed a longitudinal mouse model of pulmonary arterial (PA)-banding concomitant with transverse aortic constriction (TAC) to initiate an adaptive LV remodeling response. We hypothesized that adaptive LV remodeling would improve RV systolic function in an RV pressure overloaded setting. Methods: Surgical PAB was performed on mice to induce RV pressure overload and myocardial remodeling. Mild surgical TAC was performed on these mice 2-weeks (w) post-PAB. Steady-state free precession (SSFP) cardiac magnetic resonance (CMR) imaging (SSFP-CMR) was performed at 1w post-PAB, 1 w post-TAC (PAB-TAC) and 4 w and 7 w post-surgery (n=7). As controls we used Sham (n=5), TAC-only (n=4, TAC) as well as PAB-only (n=4, PAB) mice at 1, 4, and 7 w after surgery. These images were analyzed using feature-tracking (FT) software to compute measurements of ventricular volumes. Results: RV ejection fraction (RVEF) was reduced in PAB mice compared to Sham at 1w (p=0.02, 0.38±0.06 versus 0.52±0.08, respectively). After TAC, PAB-TAC mice showed an increase in RVEF compared to PAB-only mice at 4 w (p=0.03, 0.49±0.04 versus 0.39±0.08, respectively), and at 7 w (p=0.001, 0.50±0.06 versus 0.37±0.1, respectively). Similarly, tricuspid annular plane systolic excursion (TAPSE) showed a decrease in PAB mice compared to sham (p=0.002, 0.85±0.15mm versus 1.73±0.33mm, respectively) and an increase after TAC at 2 w (p=0.001, 1.55±0.29mm versus 0.85±0.15mm, respectively), 4 w (p=0.002, 1.75±0.32mm versus 0.93±0.21mm, respectively), and at 7 w post-surgery (p=0.001, 1.70±0.33mm versus 0.91±0.14mm, respectively). Conclusions: Even though LV-to-RV mechanical energy transfer is well established in normotensive animals, our data supports a mechanistic link between RV systolic function and LV pressure in remodeled and pressure-overloaded RVs.
Abstract 13867: Performance of the Pooled Cohort Equation and Cohort Specific Approaches to Estimate Atherosclerotic Cardiovascular Disease Risk of Type 2 Diabetic Patients in the Penn Medicine Biobank
Authors: Noah Tsao, Gabrielle Shakt, Renae Judy, Scott Damrauer
Journal: Circulation (2021)

Introduction: T2D is a widely-recognized risk factor for CVD, and leads to worse CVD outcomes. However, there remains considerable heterogeneity among individuals with T2D with respect to who will develop CVD. To develop more effective strategies for risk prediction of T2D-associated heart and vascular disease, we leveraged the ASCVD Pooled Cohort Risk Equation (PCE), a cohort optimized approach and polygenic risk scores (PRS) based on various CVD traits to generate 10-year CVD risk. Hypothesis: We hypothesize that a cohort optimized approach as well as the addition of PRS to traditional risk factors will allow for improved identification of individuals with T2D who are at risk for CVD. Methods: Among our cohort of 1845 T2D patients of African and European ancestries. PRS were derived using ischemic stroke (IS) from the MEGASTROKE consortium and coronary artery disease (CAD) from CardioGRAMplusC4D and calculated in the PMBB dataset using LDPred. A cox proportional hazards model was used for time-to-event analyses within our cohort and we compared model discrimination using AUC. Results: The PCE demonstrated an inadequate discrimination for the study population with an AUC of 0.494 (SD = 0.002), 0.41 (SD = 0.002), 0.609 (SD = 0.004) and 0.514 (SD = 0.004) for female and male Africans and Europeans respectively. A cohort optimized approach demonstrated an AUC of 0.598 (SD = 0.002), 0.440 (SD = 0.002), 0.564 (SD = 0.004) and 0.388 (SD = 0.002) for female and male Africans and Europeans respectively. The addition of CAD and IS PRS to the PCE demonstrated an AUC of 0.519 (SD = 0.002), 0.414 (SD = 0.002), 0.610 (SD = 0.007) and 0.505 (SD = 0.004) for female and male Africans and Europeans respectively. The addition of CAD and IS PRS to the cohort optimized approach demonstrated an AUC of 0.610 (SD = 0.001), 0.478 (SD = 0.001), 0.539 (SD = 0.007) and 0.403 (SD = 0.003) for female and male Africans and Europeans respectively. Conclusions: This study found that the PCE had an inadequate model discrimination across all race/gender categories, however, was improved by using a cohort specific approach and the incorporation of CAD and IS PRS. These findings support further study into the implementation of cohort specific and PRS based approaches in CVD risk prediction of T2D patients.
TAMI-16. THREE-DIMENSIONAL ORGANOID CULTURE UNVEILS RESISTANCE TO CLINICAL THERAPIES IN ADULT AND PEDIATRIC GLIOBLASTOMA
Authors: Swetha Sundar, Sajina Shakya, Lisa Wallace, Austin Barnett, Andrew Sloan, Violette Recinos, Christopher Hubert
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Glioblastoma (GBM) is the most common primary brain tumor with a dismal prognosis. The inherent cellular diversity and interactions within tumor microenvironments represent a significant challenge to effective treatment. Traditional culture methods may mask the complexity of such interactions while three-dimensional (3D) organoid culture systems derived from patient cancer stem cells (CSCs) can preserve cellular complexity and microenvironments. Our objective was to determine whether organoid cultures show increased patterns of resistance to potential clinical therapies compared to traditional sphere cultures. METHODS Adult and pediatric surgical specimens were collected and established as 3D organoids. We created organoid microarrays and visualized bulk and spatially defined differences in cell proliferation using immunohistochemistry (IHC) staining, as well as cell cycle analysis by flow cytometry with 3D regional labeling. We tested the response of CSCs grown in each culture method to temozolomide, ibrutinib, lomustine, ruxolitinib, and radiotherapy using proliferative and viability assays. RESULTS Compared to sphere cultures from the same patient, organoids showed diverse proliferative cell populations and broad resistance to all therapies tested, albeit with both intraspecimen and interspecimen variability in the extent of resistance. Organoid specimens demonstrated a blunt response to current GBM standard of care therapy (combination temozolomide and radiotherapy) and maintained both cellular proliferation in their outer rim and overall structure and viability compared to the matched sphere specimens. CONCLUSIONS Our results suggest that growth of tumor specimens as organoid cultures may better reflect the cellular diversity and clinical reality of GBM therapeutic response. Patient-derived GBM organoids offer a valuable complement to traditional culture methods and may have powerful predictive capability of personalized drug sensitivities and therapeutic resistance.