tbuckley/cabot-search huggingface dataset:
Abstract 19008: ATP-Dependent Citrate Lyase Drives Cardiac Left Ventricular Dysfunction by Metabolic Remodeling
Authors: Shijie Liu, Kyoungmin Kim, Yaqi Gao, Seth Gammon, Lin Tan, Heinrich Taegtmeyer, Philip Lorenzi, David Piwnica-Worms, James F Martin, Anja Karlstaedt
Journal: Circulation (2023)

Introduction: Cardiovascular diseases and cancer are the leading causes of death worldwide. Recurrent mutations of metabolic enzymes in cancer cells benefit tumor growth, creating a systemic metabolic phenotype and increasing the risk for adverse cardiac events. Computational analysis revealed an oncometabolic phenotype in the heart, characterized by a switch from oxidative towards reductive carboxylation of α-ketoglutarate and citrate. Our studies identified the ATP citrate lyase (ACL) as a critical regulatory enzyme driving metabolic adaptation during cancer by increasing acetyl-CoA synthesis and histone 3 acetylation in the heart. Hypothesis: We hypothesized that ACL is crucial for cardiac adaptation during oncometabolic stress. Methods: To answer these questions, we developed a cardiac-specific mouse model lacking ATP citrate lyase using clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas)9 genomic editing. Cas9-Myh6-dtTomato mice (n=14-17 male and female mice/group) were subcutaneously injected 6 days after birth with single gRNA targeting the Acly locus. Cardiac function was monitored using echocardiographic examinations weekly between 12 and 20 weeks. We used in vivo [ 18 F]-FDG-positron emission tomography (PET) and stable isotope tracer labeling to identify and quantify metabolic alterations in vivo in response to the loss of ACL. Results: Knockdown of ACL causes left ventricular systolic dysfunction as evidenced by significantly reduced ejection fraction and an increased left ventricular diameter. In vivo [ 18 F]-FDG-PET revealed that loss of ACL increased plasma glucose uptake which is consistent with maladaptive metabolic remodeling and impaired oxidative metabolism during heart failure. RNA-sequencing followed by pathway enrichment analysis revealed differential expression of genes involved in mitochondrial function and lipid metabolic processes. Mass spectrometry-based metabolic flux analysis showed an increased malate m+2 to citrate m+2 ratio, consistent with reduced citrate efflux from the mitochondria towards the cytosol. Conclusions: ACL activity regulates reductive citrate flux and drives metabolic adaptation associated with cardiac dysfunction
Abstract 18923: Associations of Park Access With Physical Activity Levels During 1 Month Period After Acute Coronary Syndrome
Authors: Adriana Wu Clark, Margaret Murdock, Ammie Jurado, Gabriel J Sanchez, Keith Diaz, Andrea Duran
Journal: Circulation (2023)

Introduction: Physical activity (PA) is an important predictor of recovery after an acute coronary syndrome (ACS) event, and research has demonstrated the importance of neighborhood walkability on PA. Walkability is shaped by land use, density, and the development of parks and pedestrian spaces, which may be particularly important in urban areas. However, it is unclear whether discrete components of walkability, such as park access, independently impact PA levels in ACS survivors. The purpose of this study was to investigate how residential park proximity and percentage of park land use impact PA levels during the month following a suspected ACS event. Methods: This sample included patients (n=374, 49% female, 63 ± 11.9 y) who presented to the emergency department for suspected ACS. PA data (sedentary behavior [SB], light intensity [LPA], moderate-vigorous intensity [MVPA]) were collected using a wrist worn GENEActiv accelerometer for 30 days post-discharge. Park access was assessed using Geographic Information System and operationalized to include count of parks and percentage of land use covered by parks within a 1km radius area around each geocoded home address. Multiple linear regressions were conducted to determine the relationship between park access factors (count and land use), PA levels, and SB. Results: Models adjusted for demographics, comorbidities, and disease severity indicators (Grace risk score, length of hospitalization) found a statistically significant positive association between park land use and MVPA (B [95% CI]= 44.25 [4.55-83.94], p-value=0.029). Additionally, there was a statistically significant positive association between park count and SB (B [95% CI]= 1.97 [0.42-3.53], p-value=0.013). Conclusions: We found that residential park land use was positively associated with MVPA in the first month following suspected ACS. Additionally, there was a positive association between park count and SB. These findings suggest that greater park access in neighborhoods may play a significant role in activity levels during ACS recovery. Future research is needed to understand which aspects of urban park design/environment should be modified to enhance physical activity and reduce sedentary behavior in ACS survivors.
Abstract 18771: Gender, Geographic and Subspeciality Differences in Mentorship in Cardiology: Results of the Global Mentorship Survey
Authors: Aaysha Cader, Martha Gulati, Sonya Burgess, Estefania Oliveros, Kristy Robledo, Mirvat Alasnag, Ki Park, Silvia Castelletti, sarita Y rao, Marie-Claude Morice, Rebecca Ortega, Roxana Mehran, Shrilla Banerjee
Journal: Circulation (2023)

Introduction: Mentorship is valued among cardiologists for career advancement globally. Hypothesis: We investigated differences in mentorship characteristics, trends and needs based on gender, continent of practice and cardiology subspeciality. Methods: An anonymous online survey was distributed globally to cardiologists, current and prospective cardiology trainees, collecting demographic data, mentoring experiences and best mentorship practice. Categorical variables were compared by Pearson's Chi-squared test. Results: A total 1210 responses, 51% women, 49% men, 0.3% non-binary, with most (33%) from Europe. 57% received mentorship, with no gender differences. Australians (82%) and North Americans (68%) were most likely to receive mentorship, South Americans (43%) and Africans (42%) least likely. Access to mentorship was the most common challenge (70%). Most valued mentor characteristics were trustworthiness, supportiveness and constructive feedback. Mentor ethnicity was deemed irrelevant by majority. More women than men considered their mentors’ gender relevant and placed more importance on work-life balance (p=0.03) and mentoring in pregnancy (p&lt;0.001). Among mentee objectives, professional networking &amp; resource-sharing were most important goals for both genders. Skill development via mentorship was important for both genders but more proceduralists valued this compared to non-proceduralists (53% vs 47% p=0.03). Lack of dedicated time, lack of training/understanding of mentorship and poor communication were key barriers to effective mentorship in both genders. More women than men considered gender differences as a barrier to good mentorship (10% vs 4.4%, p&lt;0.001), Australians and Europeans perceived lack of time, North Americans perceived lack of goal-setting and failure to sponsor as barriers. There was global interest in a mentorship training programme, more among women than men (95% vs 89%, p&lt;0.001). Conclusions: Mentorship is a valued for career and professional development, despite global variations in access to mentors. Most female cardiologists felt mentorship was beneficial to advise work life balance and during pregnancy. Mentoring training needs to be made available globally within cardiology.
Abstract 17139: Angiopoietin 2 Independently Predicts Heart Failure Hospitalization and is Beneficially Modified by GLP1RA: Results From the EXSCEL Trial
Authors: Josephine Harrington, Maggie Nguyen, Anthony Peters, Michael Felker, Ravi Karra, Naveed Sattar, Harald Sourij, Adrian F Hernandez, Jennifer Green, Robert J Mentz, Rury Holman, Svati H Shah
Journal: Circulation (2023)

Background: Higher plasma concentrations of angiopoietin 2 (ANGPT2) are associated with higher risk for hospitalization for heart failure (HF) and death in univariate analyses. However, the independent association of this ANGPT2 after adjustment for clinical factors or clinically available biomarkers is not known. Methods: High throughput proteomic profiling was performed using the SomaLogic SomaScan platform in 5473 patients with type 2 diabetes enrolled in the EXSCEL clinical trial of the GLP1RA exenatide vs. placebo who had available biospecimens at baseline. The association between ANGPT2 with time-to-HF hospitalization, MACE, and death was assessed using univariable and multivariable Cox modeling, with adjustment for age, sex, HbA1c, NT-proBNP, hs-TnT, left ventricular ejection fraction, HF etiology and study treatment. These analyses were also performed in the subset of participants living with obesity (BMI &gt;30 kg/m 2 ), and those with CKD (CrCl &lt;60ml/min). Results: In 5473 EXSCEL trial participants included in this biomarker sub-study, 215 (3.9%) experienced a hospitalization for heart failure, 813 (14.9%) a MACE event and 528 (9.7%) died during a median follow-up of 3.2 years. Relative ANGPT2 concentration was significantly associated with HF hospitalization (aHR 1.70 [95% CI 1.39 to 2.08]), MACE (1.20 [1.07 to 1.35]), and death (aHR 1.21 [1.05 to 1.39]) in univariable and multivariable analyses, including after adjustment for NT-proBNP and TnT (Figure). Exenatide use resulted in significant changes from baseline in ANGPT2 concentrations (p interaction&lt;0.001) (Figure). Conclusion: ANGPT2 is predictive of hospitalization for HF, MACE, and death independent of clinical factors including traditional biomarkers of NT-proBNP and TnT. ANGPT2 was beneficially modified by exenatide, a GLP1RA, suggesting a potential role for this biomarker in optimizing HF therapy.
Abstract 13624: Worrisome Atrial Fibrillation-Related Mortality Trends in Older Adults From 1999-2019
Authors: Shreyas Singireddy, Sammudeen Ibrahim, Saint-Martin Allihien, Mandeep Brar, Haripriya Andanamala, Raghav Chawla, Asha Ummidi, Onoriode Kesiena
Journal: Circulation (2023)

Introduction: The U.S. population is aging with concurrent increases in atrial fibrillation (AF) burden. However, AF-related mortality trends among adult’s ≥75 years have not been investigated. The purpose of this study was to assess the trends and regional differences in AF-related mortality among older adults in the United States. Methods: Death certificates from the CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research) database were examined from 1999 to 2019 for AF-related mortality in adult’s ≥75 years of age. Age-adjusted mortality rates (AAMRs) per 100,000 persons was calculated and stratified by year, sex, race/ethnicity, and geographic region. Results: Between 1999 and 2019, 323,349 AF-related primary deaths occurred among adult’s ≥75 years. The AAMR more than doubled from 44.8 (95% CI, 43.8 to 45.8) in 1999 to 91.7 in 2019 (95% CI: 87.2 to 89.6)). Women had consistently higher AAMR than men from 1999 (AAMR women: 45.8 vs men: 42.3) to 2019 (AAMR women: 93.2 vs men: 88.4). White adults had the highest overall AAMR (77.5), followed by NH American Indian/Alaska Native (41.6), NH Black (41.3) and NH Asian or Pacific Islander adults (36.6). AAMR also varied substantially by region (overall AAMR: Midwest 77.6; West: 75.0; Northeast: 71.6; and South: 69.7). States in the top 90th percentile of AF-related AAMR were Oregon, Idaho and Utah, which had approximately double the AAMRs compared with states that fell into the lower 10th percentile such as South Dakota and Florida. Conclusions: AF-related mortality in U.S. adult’s ≥75 years has continuously increased since 1999. The highest AAMRs were observed among White adults and women, and among patients living in the Midwest and western regions of the United States. Targeted strategies are needed to prevent and treat AF among older adults to curb increasing levels of AF-related mortality.
Abstract 18810: Mitochondria-Rich Extracellular Vesicles From Stem Cell-Derived Cardiomyocytes Restore Bioenergetic Metabolism of Ischemic Myocardium in a Porcine Chronic Heart Failure Model
Authors: Gentaro Ikeda, Tsuyoshi Ueyama, Eileen Tzng, Hiroyuki Takashima, jennifer lyins, Nathan Bayardo, Connor G OBrien, Phillip C Yang
Journal: Circulation (2023)

Introduction: The disruption of mitochondrial energy metabolism underlies the pathophysiology of ischemic heart failure. We previously demonstrated that intramyocardial injection of mitochondria-rich extracellular vesicles (M-EVs) derived from iPSC-derived cardiomyocytes (iCMs) transfers mitochondria and non-mitochondrial biologics into recipient cardiomyocytes. This process stimulates mitochondrial biogenesis and enhances functional capacities in murine and porcine acute myocardial infarction (MI) models. However, the therapeutic potential and underlying mechanism in chronic heart failure models remain to be assessed. Method: M-EVs were isolated from the conditioned medium of human iCMs using differential centrifugation. A total of 11 Yorkshire pigs underwent myocardial ischemia for one hour via balloon occlusion of the left anterior descending artery (Week-0). At week-4, 1.0 x 10 11 M-EVs or PBS control were administered transendocardially to the peri-infarct region (PIR) using a percutaneous catheter delivery system (Biocardia, Inc, CA). Cardiac functions and scar size were analyzed by cardiac MRI with gadolinium contrast at week-4 (pre-injection) and -8 (post-injection). Myocardial tissue samples were collected from the PIR and remote non-ischemic areas at week-8. Proteomic analysis and single-nucleus RNA sequencing were performed to investigate comprehensive protein and gene expression profiles of the myocardium. Results: Left ventricular (LV) ejection fractions were significantly decreased at Week-4 (32.7±5.4%). M-EV treatment significantly improved absolute LVEF from week-4 to -8 in the treatment vs. non-treatment groups, +3.15% vs. -4.99%, respectively, (p&lt;0.0001). No significant difference was observed in the scar size. Multiomic analysis of proteomes and single-nucleus transcriptomes suggested restoration of dysregulated cardiometabolic protein profile and mitochondrial energy metabolism in the myocardium. Conclusion: M-EV-mediated transfer of mitochondria and enriched proteins augmented LV dysfunction in the pig chronic MI model. M-EV therapy may represent a novel biologic approach that directly targets cardiac metabolism by restoring mitochondrial function and cellular bioenergetics.
Abstract 18931: A PCSK9 and APOB Double Heterozygote Presenting Phenotypically Similar to Homozygous Familial Hypercholesterolemia
Authors: Tiffany M Haynes, Laura Kukuc, Matthew Proute, Robert Fishberg
Journal: Circulation (2023)

Introduction: Familial hypercholesterolemia (FH) is an inherited disorder associated with mutations in APOB, PCSK9 and LDLR genes. Heterozygous FH (HeFH) generally has one gene mutation. Homozygous FH (HoFH) has two mutations in the same gene and is characterized by vastly elevated plasma LDL-C, accelerated ASCVD and resistance to standard lipid-lowering therapy. Combinations of mutations can present with a phenotype similar to HoFH. We present a double heterozygous patient with unreported mutations in PCSK9 and APOB genes, exhibiting clinical features of HoFH. Hypothesis: Patients with multiple gene mutations for FH can present clinically similar to HoFH and would benefit from novel lipid lowering therapies Methods: 73-year-old female with a history of diabetes and hyperlipidemia presented in 2018 with dyspnea on exertion. Cholesterol (TC) and triglycerides (TG) were 430 and 715 mg/dl respectively, on rosuvastatin 40 mg and omega 3 fatty acids. Physical exam showed arcus senilis. A nuclear stress test showed ST depressions in inferolateral leads but normal scintigraphy. Genetic testing revealed APOB and PCSK9 mutations. She was then treated with rosuvastatin, icosapentyl ethyl, ezetimibe and fenofibrate. TC, LDL, TG and ApoB levels were 463, 236, 747 and &gt;240 mg/dl respectively. Evolocumab was added, with reduction of TC, TG and ApoB levels to 326, 432 and 182mg/dl, despite maximal available therapy. Results: Genetic testing revealed APOB variant NP_000375.2:p.Gln3378His and PCSK9 variant NP_777596.2:pAla544Thr, which were unreported mutations with unknown clinical significance. Genetically, this patient is a double heterozygote but expresses a phenotype similar to HoFH due to a poor response to maximum therapy. Conclusions: Although usually genetically defined, the phenotype of HoFH can present with different genetic variations. Chaudhry et al established genetic diagnosis of HoFH in 0.9% of patients initially diagnosed as HeFH, of which 3 were true homozygotes and 3 were compound heterozygotes. These findings support the idea that various heterozygous combinations of mutations in the genes for LDLR, APOB and PCSK9, may present clinically similar to HoFH. Patients with these mutations could benefit from novel agents such as evinacumab.
Abstract 17212: Arterial Cannula Size and 30-Day Mortality in Adults With Cardiogenic Shock Supported With Venoarterial Extracorporeal Membrane Oxygenation and Concomitant Left Ventricular Mechanical Unloading: An ELSO Registry Analysis
Authors: Alvaro A Delgado, Laura Aguilar Franco, Daniela Hincapie Tabares, Roy Sriwattanakomen, Lisa Fleming, Pablo Quintero Pinzon, Jennifer E Ho, Marwa Sabe, Kevin Kennedy, A. Reshad Garan, E. Wilson Grandin
Journal: Circulation (2023)

Introduction: VA-ECMO with left ventricular mechanical unloading (LVMU), including intra-aortic balloon pump (IABP) or percutaneous left ventricular assist device (pVAD), is commonly used to support patients with cardiogenic shock (CS). The impact of arterial return cannula size on short-term mortality in the presence of LVMU is unknown. Hypothesis: The 30-day inpatient survival in patients with VA-ECMO and LVMU will be the same with a small vs large arterial cannula. Methods: We queried the ELSO Registry from 2017-2022 for adults with CS receiving VA-ECMO and concomitant LVMU, with either IABP or pVAD placed within -24h to +2h of ECMO initiation. We restricted to patients with body surface area (BSA) 1.8-2.2 m2 and excluded those with central cannulation, multiple ECMO runs, and ECPR. The primary outcome of 30-day inpatient mortality was compared using time-to-event analysis. Secondary outcomes included 24h lactate clearance and rates of acute renal and hepatic injury. Results: Among 2055 patients supported with VA-ECMO and LVMU (54.3% IABP; 45.7% pVAD), 292 (14.2%) patients received a small cannula and 1763 (86.8%) patients a large arterial cannula. Patients with a small cannula were less likely to be male, had smaller BSA, less often had a distal perfusion cannula, and had a lower incidence of pre-ECMO concomitant organ failures (Figure, A). There was no difference in 30-day inpatient mortality between the cannula size groups (Figure, B), which persisted in multivariable modeling with adjusted hazard ratio 0.94 (95% CI: 0.72-1.23), p=0.65. Patients with a small arterial cannula had no significant difference in 24h lactate clearance (Figure, C) or in the rates of acute renal injury (37.3% vs 39.8%, p = 0.42) or hyperbilirubinemia (5.5% vs 6.5%, p=0.52). Conclusions: In adults with CS receiving VA-ECMO with LVMU, the use of a smaller arterial return cannula was associated with no difference in 30-day inpatient mortality or metrics of end-organ perfusion.
Abstract 210: The Relationship Between Serum Free Fatty Acid Levels After the Return of Spontaneous Circulation and Neurological Outcomes in Out-of-Hospital Cardiac Arrest Patients
Authors: Seok Jin Ryu, Dong H Lee
Journal: Circulation (2023)

Background: Free fatty acids (FFA) are a known risk factor in the development of sudden cardiac death. However, the relationship between FFA and the outcome of out-of-hospital cardiac arrest (OHCA) patients remains unclear. We aimed to examine the association between FFA and neurological outcomes in OHCA patients. Methods: This prospective observational study included adult (≥ 18 years) OHCA patients between February 2016 and December 2022. We measured serial FFA levels within 1 h after ROSC and at 6 h, 12 h, 24 h, 48 h, and 72 h after the return of spontaneous circulation (ROSC). The primary outcome was neurological outcome at 6 months. A poor neurological outcome was defined by cerebral performance categories 3, 4, and 5. Results: A total of 147 patients were included. Of them, 104 (70.7%) had poor neurological outcomes, whereby the median FFA levels within 1 h after ROSC (0.72 vs. 1.01 mol/L), at 6 h (1.19 vs. 1.90 mol/L), 12 h (1.20 vs. 1.66 mol/L), and 24 h (1.20 vs. 1.95 mol/L) after ROSC were significantly lower than in good outcome group. The FFA levels at 6 h (odds ratio [OR], 0.583; 95% confidence interval [CI], 0.370-0.919; P = 0.020), and 12 h (OR, 0.509; 95% CI, 0.303-0.854; P = 0.011) after ROSC were independently associated with poor neurological outcomes. Conclusions: The lower FFA levels at 6 h and 12 h after ROSC were associated with poor neurological outcomes in patients with OHCA. FFA may reflect oxidative metabolism as well as oxidative stress.
Abstract 18612: Stem Cell-Derived Extracellular Matrix as a Treatment for Cardiac Remodeling in Post-MI Hearts: A Pilot Study
Authors: Mark Broadwin, Cynthia Xu, Dwight Harris, Katerina St Angelo, Frank W Sellke, Jeffrey Morgan, Ruhul Abid
Journal: Circulation (2023)

Introduction: Post-myocardial infarction (post-MI) cardiac remodeling and decline in cardiac function remains a vexing problem. Tissue engineered extracellular matrix (ECM) has been used in the past but was restricted by the manufactured structure and mechanical limitations. Here, we use a novel ECM substrate generated by self-assembled cells seeded into spherical molds, that are devoid of the hierarchical structure of ECM fabrication, as a treatment for post-MI cardiac remodeling. Hypothesis: Intramyocardial (IM) injection of ECM particles will result in improved cardiac function and reduced infarct size in post-MI hearts. Methods: Human bone marrow mesenchymal stem cells were cultured and ECM particles were isolated, seeded into micro molds, purified, and characterized. ECM particles were suspended at a concentration of 63,400 particles per mL to create an injectable solution. WT mice underwent left anterior descending (LAD) artery ligation followed by IM injection of 10uL of saline control (n=3) or ECM solution (n=7) to the infarcted area (Figure 1A). Mice then underwent post-operative day 3 (POD 3) and POD 7 echocardiogram to determine changes in cardiac function. Results: There was a trend in improving ejection fraction (EF) in ECM injection group compared to control injection in post-MI at POD 3 while no difference was seen at POD 7 (Figure 1B). No difference in fractional shortening (FS) was observed at POD 3 or POD7 (Figure 1C). Echos at POD 14, POD 21, and POD 28 and additional animals will be added to increase study power. Conclusion: IM injection of ECM trends towards mitigating decline in EF at POD3 and does not affect FS in post-MI hearts. These results are likely underpowered (n=3 versus n=7) and may be a portent of significant myocardial protection post-MI. Our ongoing studies (n=10 per group) investigating the mechanisms by which ECM injections assuage ischemic insult to the myocardium may represent a future strategy for clinical therapy.