tbuckley/cabot-search huggingface dataset:
Abstract 13878: Activated Fibroblasts and IL-1β Mediate Fibrotic Cardiac Remodeling Observed in Premature Ventricular Contraction-Induced Cardiomyopathy
Authors: Juana Maria de Lourdes Medina Contreras, Jaime Balderas Villalobos, Montserrat Samso, Rafael J Ramirez, Alex Y. Tan, Karoly Kaszala, Jose F Huizar, Jose M Eltit
Journal: Circulation (2021)

Introduction: The relevance of fibrosis in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remains unclear. Recent studies suggest that fibrosis promotes adverse extracellular matrix (ECM) remodeling that has been implicated in arrhythmogenesis. However, fibrotic areas and fibroblast activation have not been characterized in PVC-CM. The objective of this study was to assess cardiac remodeling by collagen fiber deposition, fibroblast activation (using αSMA as a marker), and the pro-fibrotic cytokine IL-1β level in LV myocardium. Hypothesis: Activation of fibroblasts promotes adverse cardiac remodeling in PVC-CM. Methods: Modified pacemakers were implanted in canines, half of them developing PVC-CM after 12 weeks of bigeminal PVCs (50% burden at 200-220 ms coupling interval), while the remaining were not exposed to PVCs (sham). Paraffin-embedded or simple formalin-fixed cardiac samples were sectioned and stained with Sirius Red/Fast Green (SR/FG) or immunofluorescence (IF) to assess collagen fiber deposits and αSMA content, respectively. Expression of IL-1β and αSMA were assessed by Western blot. Results: The percentage of fibrosis was three times greater in PVC-CM tissues compared to sham (10.2 ± 0.98 vs 3.3 ± 0.53, p = 0.014), consistent with an increase in αSMA (1 ± 0.08 vs 1.93 ±0.33, p &lt; 0.05) and IL-1β expression (1 ± 0.09 vs 1.69 ± 0.11, p &lt; 0.01). The figure shows differences in collagen fibers with SR/FG and αSMA with IF in (A) sham and (B) PVC-CM. Increased αSMA and IL-1β support the hypothesis that fibroblast activation is a key component in the PVC-CM phenotype. Conclusion: These findings strongly suggest that fibroblast activation during PVCs promote ECM expansion causing persistent structural remodeling which may disrupt electrical signal propagation and potentially contribute to arrhythmogenesis and worsening ventricular function associated with PVC-CM.
Abstract 12755: Effects of Intravenously Delivered Extracellular Vesicles on Cardiac Function in Chemotherapy-Induced Cardiomyopathy
Authors: Manon Desgres, Gwennhael Autret, Lorena Petrusca, Bruna Lima Correa, Céline Marigny, Line Le Gac, Chloé Guillas, Bertrand Tavitian, Pierre Croisille, Jean-Sébastien Silvestre, Philippe Menasche
Journal: Circulation (2021)

Introduction: Extracellular Vesicles (EV) are increasingly recognized as key mediators of the effects of cellular therapy but repeated dosing is likely required for optimizing their therapeutic benefits. This, in turn, requires a noninvasive delivery route. Hypothesis: Repeated intravenous (IV) EV infusions might improve cardiac function in chemotherapy-induced cardiomyopathy. Methods: All EV were collected from human iPSC-derived cardiovascular progenitor cells. In vitro experiments : iPSC-derived cardiomyocytes were stressed 3 times by doxorubicin (Dox, 0.2 μM), once every 48 hours (D0, D2, D4), and then exposed to EV once (D6) or twice (D6 and D8). Outcomes were assessed on D8 and D10 on mitochondrial function and intracellular ATP levels assessed by the Seahorse XF Cell Mito Stress Test and ATPlite Luminescence Assay System, respectively. In vivo experiments : Male BALB/c mice were subjected to 3 weekly injections of Dox (total cumulated dose: 12 mg/kg) followed by 3 IV infusions of EV (10 9 per dose, n=11) or an equivalent volume of saline (n=14) over 1-2 weeks. The main outcome measure was Global Longitudinal Strain (GLS), a robust and early marker of LV dysfunction, blindly assessed by MRI at baseline and 8-11 weeks following the onset of Dox treatment. Explanted hearts were then processed for histology and transcriptomics. Results: Compared with Dox-stressed controls, EV increased ATP levels by 30%±8% (n=7, each in triplicate, p=0.047; m±SEM) and enhanced both mitochondrial respiration and anaerobic glycolysis. In vivo , GLS at baseline averaged -14.98±0.24. It was well preserved after EV treatment with a decrease at end-study of only 2.96%±7.18% from baseline while it fell by 11.90%±3.51% in PBS-injected controls. Similar patterns of changes were seen for longitudinal endocardial strain which declined by 0.22%±7.29% and 8.39%±3.42% from baseline in EV- and PBS-injected hearts, respectively, while the corresponding declines for epicardial strains were 3.92%±7.20% and 13.44%±3.28%. Basal global circumferential strain was also better preserved in EV-treated hearts. Conclusions: Repeated IV infusions of EV decrease chemo-triggered cardiomyocyte toxicities and help preserving cardiac function in chemotherapy-induced cardiomyopathy.
Abstract 9831: Baseline Demographic and Health Characteristics of Scallop Consumers in the United States
Authors: Muzamil Khawaja, Chayakrit Krittanawong, Bharat Narasimhan, Zhen Wang
Journal: Circulation (2021)

Background: In animal studies, scallop consumption has been shown to reduce atherosclerotic aortic burden, body weight, visceral adipose tissue, serum lipid, and leptin levels. Data in human models, however, is scarce. We aim to assess baseline demographic and cardiovascular health characteristics of scallop consumers and compare them to non-scallop consumers in the United States. Methods: The National Health and Nutrition Examination Survey (NHANES) data between 1999 and 2016 were analyzed. This descriptive analysis compares baseline characteristics and cardiovascular health risk between scallop-consumers and non-consumers using demographics, comorbidities, laboratory values, dietary and lifestyle factors. Results: Of the total 4,177 individuals in this cross-sectional analysis, 11.6% of individuals report consuming scallops. The data show older individuals tended to consume scallops (p &lt;0.001). Caucasian ethnicity was associated with scallop consumption (p&lt; 0.0001), while Mexican Americans had a significantly negative association with scallop consumption (p&lt; 0.0001). Scallop consumption was more common among married and divorced individuals (p&lt;0.0001)). Regarding medical comorbidities, more scallop consumers had baseline underlying coronary artery disease, hypertension, diabetes mellitus, and hyperlipidemia as compared to those who did not consume (p= 0.0026, p&lt; 0.0001, p=0.0023, p&lt;0.0001). There was notably no significant association with baseline congestive heart failure, asthma or stroke history, and scallop consumption. Conclusion: Scallop consumption is likely associated with the prevalence of coronary artery disease, hypertension, diabetes mellitus, and hyperlipidemia. Prospective studies and clinical trials are needed to determine further the relationship between scallop consumption and cardiovascular health risk.
Abstract 12618: Feasibility of Non-Contrast Optical Coherence Tomography Imaging in Coronary Arteries
Authors: Dong Kang, Hyeong Soo Nam, Sunwon Kim, Hongki Yoo, Jin Won Kim
Journal: Circulation (2021)

Background/Objectives: Contemporary high-resolution intracoronary optical coherence tomography (OCT) requires injection of flushing media for image acquisition to avoid signal attenuation by red blood cells. There is a growing need for an alternative flushing media other than iodine contrast to reduce the risk of renal dysfunction. To address this issue, we investigated the safety and feasibility of pentastarch solution as a flushing media for OCT image acquisition and compared with the contrast media flushed images. Methods/Results: We prospectively enrolled 12 patients with 15 coronary lesions (12 stented lesions and 3 non-culprit lesions). Paired OCT images were obtained by manual injection of iodine contrast (average 12 mL), followed by pentastarch (average 18-20 mL). A total of 30 runs were analyzed and each OCT pullback was assessed on a frame-by-frame basis by automated customized pixel-wise comparison algorithm. The number of clear image segments (CIS) and pre-specified quantitative measurements were compared between the paired OCT images. Image quality as assessed by proportion of CIS showed no significant difference between the contrast media and pentastarch (98.5% vs. 97.5%; p=0.850). Quantitative measurements including minimal lumen area, mean lumen area, and pixel-wise blood flushing capability correlated well between the paired image segments (p&lt;0.001) (Figure). There were no clinically relevant complications associated with OCT imaging with pentastarch administration such as anaphylactic reaction, life-threatening arrhythmia, heart failure, or acute renal deterioration. Conclusions: Intracoronary OCT using pentastarch is safe and technically feasible without affecting the optical signal intensity and overall image quality. Non-contrast imaging with pentastarch significantly reduces the obligatory iodine contrast load, therefore, could be considered as a promising strategy in high-risk patients for renal impairment.
EXTH-80. PBI-200: IN VIVO EFFICACY OF A NOVEL, HIGHLY CNS-PENETRANT NEXT GENERATION TRK INHIBITOR
Authors: Kollol Pal, Anthony Regina, Aram Elagoz, Vincent Albert, Johnathan Boudreault, Marc Ouellet, Louise Pilote, Nicolas Bruneau-Latour, Hong Wang, Limei Tao, Edith Bellavance, Peter White, Stephane Ciblat, Jordan Leef, Robert Bishop
Journal: Neuro-Oncology (2021)

Abstract TRK kinases (TRK) are clinically validated targets for cancers harboring NTRK gene fusions. However, approved TRK inhibitors (TRKi) give rise to mutations reducing long-term clinical efficacy, and display limited CNS penetration that may impact their ability to address primary brain tumors (PBT), including high-grade gliomas. Second generation compounds in development address some resistance mutations, but are not sufficiently CNS penetrant. PBI-200 is a novel, orally active TRK inhibitor designed to overcome resistance, with high CNS penetration. In vitro assays demonstrate picomolar- to nanomolar potency against both wild-type TRK and the major acquired resistance mutations. A BaF3 xenograft model encoding the LMNA-NTRK1 gene fusion and G595R solvent front mutation showed superior efficacy with PBI-200 relative to first-generation compounds larotrectinib and entrectinib, and equivalent efficacy to the second-generation compound selitrectinib, in terms of tumor growth inhibition. Importantly, drug concentrations in the brains of PBI-200 treated mice showed an approximately 4-fold brain/plasma ratio (BPR). In contrast, BPR of other TRKi were &amp;lt; 0.17, indicating that only PBI-200 achieved sustained drug levels in brain. PBI-200 demonstrated statistically superior CNS efficacy and survival in a KM12-Luc intracranial murine model, as compared to other TRKi (chi-squared 45.6, p &amp;lt; 0.0001). By day 41, 50% of mice in the PBI-200 group remained alive, whereas mice in the other treatment groups had died on or before day 32. Of note, no gross or histopathological CNS adverse effects were observed in a 14d CNS Field Observation Battery study. Finally, PBI-200 was the most selective TRKi in a 125 kinase panel (ThermoFisher) with only 1 off-target kinase inhibited &amp;gt; 60% at 1 micromolar. Together, these data suggest that PBI-200 has potential as a best-in-class, highly CNS-penetrant next generation TRKi. A Phase 1/2 clinical trial evaluating PBI-200 in NTRK fusion-positive patients, including patients with PBT, is ongoing (NCT04901806).
Abstract 13252: Is There a Gender-Specific Association Between High Coronary Artery Calcium Score and High Polygenic CAD Risk Score?
Authors: Muhammad Hamza Saad Shaukat, Beatrice Rynders, Mark Petrasko, Catherine Hajek, Phillip Petrasko, Melissa Pham, patryk stys, Alexander Sjovold, Veronica Stys, Komaldeep Singh, Kevin Coy, Michael Lubke, Murat Sincan, Adam Stys, Marian S Petrasko, Tom Stys
Journal: Circulation (2021)

Introduction: Genetic predisposition for CAD is well established. Polygenic risk scores are emerging as tools which attempt to quantify the genomic component of an individual’s risk for CAD. However, their clinical utility for individual risk stratification is unclear. Hypothesis: 180 SNPs previously identified in Caucasian Genome Wide-Association Studies for CAD were used to construct a weighted restricted polygenic risk score (PRS; normalized range 11.18 -17.58). This study hypothesizes a gender-specific association between high PRS (&gt;=85th percentile) and high coronary artery calcium score (CAC) score, defined as &gt;400. Methods: Between January 2018 &amp; March 2020, 21,784 patients underwent CAC screening and/or PRS testing. Caucasian patients with both PRS and CAC scores were identified. Fisher’s exact test was utilized to test the association between high PRS and high CAC in men and women. Results: Both PRS and CAC were available for 3,197 Caucasian patients, out of which 2,106 (65.8%) were women (figure 1: gender adjusted PRS distribution). Odds ratio of high PRS and high CAC was 1.64 (95% CI: 0.86-2.97; p &gt;0.05) in women and 1.59 (95% CI: 0.98 - 2.53; p&gt;0.05) in men. Conclusions: There is no statistically significant, gender-specific association between high PRS and high CAC in our Caucasian cohort. However, there is a trend suggestive of a positive correlation in women. This clinical data is the first of its kind in a real world setting on the use of PRS for CAD risk assessment. Larger, ethnically diverse studies are needed.
Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Not Previously Treated with a BTK Inhibitor: Primary Analysis from a Phase 2 Study (CITADEL-205)
Authors: Amitkumar Mehta, Marek Trněný, Jan Walewski, Vincent Ribrag, Caroline Dartigeas, Jacob Haaber Christensen, Fabrizio Pane, Guillermo Rodriguez, Michal Taszner, Parameswaran Venugopal, Vittorio Ruggero Zilioli, Fred Zheng, Douglas J DeMarini, Wei Jiang, Pier Luigi Luigi Zinzani
Journal: Blood (2021)
Abstract 14093: Open Thoracic Surgical Implantation of Cardiac Pacemakers in Rodents
Authors: Rose T Yin, Sheena W Chen, Kyongjune B Lee, Yeon Sik Choi, Jahyun Koo, Quansan Yang, Helen S Knight, Philipp Gutruf, John A Rogers, Gregory D TRACHIOTIS, Igor R Efimov
Journal: Circulation (2021)

Introduction: Cardiovascular science has greatly benefited from bioelectronics and genetic engineering. However, combinations of these approaches have been hampered by challenges in genetic engineering of large animals and implantation of cardiac devices in rodents. New surgical approaches to reliably interface bioelectronics to the heart with minimal disruption to the native physiology are necessary for validation of novel bioelectronics therapies and bioelectronics-enabled in vivo studies of physiology. Objective: To develop an effective and reproducible surgical approach to implant epicardial devices in rodents. Methods: All rat surgeries (n = 138) were performed according to protocols approved by The George Washington University Institutional Animal Care and Use Committee. Inhaled isoflurane vapors provided general anesthesia. After orotracheal intubation, an intercostal incision was made and retracted in order to view the target cardiac implantation area (a). The electrode pad of a novel leadless battery-free pacemaker (b) was sutured or attached by bioadhesive to the epicardium with the device body placed subcutaneously. The ribs, muscle, and skin were subsequently closed. Post-operative care included injectable analgesics. Daily pacing trials confirmed device functionality. Results: Rats survive and quickly recover from the operation without complications. Electrocardiograms reveal that implanted miniature battery-free cardiac pacemakers pace the heart for up to 32 days after surgery (c). Echocardiography and assessment of biomarkers demonstrate no disruption to mechanical function (d) and no evidence of myocardial ischemia (e) or heart failure (f), respectively. Conclusions: This surgical technique reliably implants epicardial devices in rodents. It has broad applications to verify the long-term functionality and biocompatibility of innovative bioelectronics and to conduct in vivo studies of cardiovascular physiology.
Pembrolizumab Boosts Breast and Cervical Cancer Survival
Authors: Anita Slomski
Journal: JAMA (2021)

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Abstract 13666: Effectiveness and Durability of Remote Algorithmic Cholesterol Management
Authors: Alexander J Blood, Angela Miller, Christine Vogeli, Kira Chaney, William Gordon, Thomas Gaziano, Christopher P Cannon, Jorge Plutzky, Benjamin M Scirica
Journal: Circulation (2021)

Introduction: In collaboration with an insurer, a remote cholesterol management pilot in patients with elevated LDL cholesterol (LDL-C) with, or at increased risk of, ASCVD achieved an average 45% LDL-C reduction in program completers. A key question for this novel strategy is the durability of this benefit, reported here at 1 year vs LDL control in a matched cohort. Methods: 469 Blue Cross Blue Shield (BCBS) patients completed the Brigham-Lipid Optimization (B-LO) program between 2/2016-12/2017. Retrospectively, we identified a control cohort of non-BCBS commercial patients (n=3955) matched for demographic and clinical characteristics. A difference-in-differences analytic approach compared LDL-C changes as adjusted for sex, age, race, prior statin intolerance, diabetes, ASCVD, and prior LDL&gt;190. Results: B-LO patients who completed the program achieved 45.3% greater reduction in LDL-C from baseline to program exit than observed among matched-control patients receiving standard of care. This greater LDL-C reduction occurred despite higher baseline LDL-C among B-LO participants vs controls, even after extensive matching. 99% of program participants reached LDL goal, vs 16% of control patients (p&lt;0.01.). (Figure) At 1-year post intervention, adjusted estimates of being at LDL goal were 83% of intervention patients vs. 52% of control patients. Conclusions: A remote cholesterol algorithmic management program that reduced LDL-C effectively also achieved more durable LDL control 12 months post-intervention, and to a greater extent than in matched controls. The efficacy of remote LDL management may also offer longer term effectiveness than usual care, arguing for further study into scalability and economic feasibility of remote population-level health interventions.
Abstract 13467: Using Data Analytics Toward Precision Warfarin Dosing in Children With Heart Disease
Authors: Claudia Algaze, Annie Vesey, Kwai Mak, Claudia Algaze, Ronnie T Collins
Journal: Circulation (2021)

Introduction: Warfarin is the most common anticoagulant used in children with heart disease. Multiple factors make initial warfarin dose selection and management subjective and variable in children. This variability increases hospital length of stay and impacts efficacy and safety. We sought to develop a data-driven tool to optimize time to warfarin goal dose in children with heart disease. Methods: We collected all demographic and clinical data for all patients &lt;18 years who received warfarin at our institution. We developed a warfarin sensitivity metric (Δ International Normalized Ratio (INR)/mg warfarin) to assess individual medication processing and characterize influential factors. Each inpatient interaction with warfarin was analyzed to assess the impact of concomitant medications, hepatic impairment, and procedure type on dosing, sensitivity, and resultant INR. A linear regression model was formulated to predict ending warfarin dose based on these influential factors. Results: A total of 714 patients were identified; 334 patients met inclusion criteria, and 447 unique encounters with warfarin were analyzed. Warfarin sensitivity was 94.3% higher in patients receiving major anticoagulation enhancing drugs and 13.6% higher in patients with minor liver injury. Patients undergoing a Fontan procedure had increased warfarin sensitivity compared to other procedures; 60% and 66% increase from ventricular assist device and valve replacement, respectively. A linear regression model was used to predict a patient’s warfarin ed dose based on age, baseline INR, other medications, liver injury, and Fontan procedure status. The Fontan binary indicator and age were the most impactful in predicting end dose with an adjusted R 2 of 0.1792. Conclusions: We have identified multiple factors that could affect individualized warfarin. Further analysis will refine our warfarin sensitivity metric and finalize and validate our tool to allow accurate and efficient warfarin dose prediction.
Sickle Cell Disease (SCD) As a Risk for COVI19 Compared to Those without SCD Among Patients Admitted in a Large Urban Center, As Estimated By PCR Sars-v-2 Positive Vs Negative Testing
Authors: Tom Adamkiewicz, Mohamed Mubasher, Folashade Omole, Melvin R. Echols, Jason Payne, Tennille Leak-Johnson, Jan Morgan-Billingslea, Kathy Pines, Deborah A. Sundal, Shira Krebs, Eric Chang, Jennifer A Afranie-Sakyi, Eric Flenaugh, Judith Volcy, Marlene Garcia, Teclemichael Tewolde, Adel Driss, Olusola Gbinigie, Chad Evans, Marques Harvey, Ernest Alema-Mensah, Dennis Bryan, Charlye D. Majett, Herman Alfred Taylor
Journal: Blood (2021)