tbuckley/cabot-search huggingface dataset:
Abstract 11903: Assessment of Left Ventricular Relaxation Time by Pulse Wave Analysis: Association With Arterial Compliance
Authors: Vladimir N Melnikov
Journal: Circulation (2021)

Introduction: The long left ventricular relaxation (LVR) has been shown as a marker of diastolic dysfunction. This parameter is usually measured by such complex methods as echocardiography and radionuclide technique. This study tests a possibility to evaluate LVR time by applanation tonometry and explores its association with arterial distensibility basing on the assumption of a parallelism in contractile mechanics between striated cardiac muscle and arterial smooth muscle. Methods: Overall, 352 normotensive subjects (age 18-76 yrs.) were enrolled in this study. The LVRT was assessed by pulse wave analysis (SphygmoCor) and measured as difference between the end of systole (ejection duration point, ED, corresponding to the closure of aortic valve) and the time of peak pressure (T1, figure) generated by systolic antegrade wave in aortic root (LVRT,%=(ED-T1)/Tf*100). Intima-media thickness of brachiocephalic arteries and heart dimensional indices were measured by ultrasonography. Results: A difference was established in LVRT between age-matched female (47.9 yr., 24.8±2.8 %, M±SD, n=158) and male groups (47.1 yr., 21.7±2.9 %, n=192, p&lt;0.001, T-test). In men, LVRT was associated with age (r=0.33), end systolic volume (partial r=0.39; age and HR= const.), augmentation index (AIx@75, r=0.33), aorta-to-radial pulse pressure amplification (r=-0.24), and time to reflection wave (r=-0.25, two-sided p&lt;=0.001 for all cases). The association of LVRT with AIx remains significant after adjusting for age, Tf, and SBP in multiple regression analysis (GLM module, SPSS). In women, less pronounced associations were found. No relations were seen of LVRT with intima-media thickness of brachiocephalic arteries and carotid-radial pulse wave velocity in both sex groups. Conclusions: In healthy subjects, the long LVR assessed by PWA was associated with stiff conduit arteries of upper limbs. Figure . Pulse pressure profile in the aortic root as a result of pulse wave analysis
Abstract MP204: Pyruvate Dehydrogenase Kinase Isozyme Specific Regulation Of Protein Acetylation In Cardiac Tissue
Authors: Chae-Myeong Ha, Adam R Wende
Journal: Circulation Research (2021)

Heart disease is the number one cause of death in developed countries. Metabolic diseases influence the severity of heart disease linked to risk factors which are thought to alter epigenetic mechanisms. Pyruvate dehydrogenase (PDH) kinases (PDK), which phosphorylate and reduce the activity of PDH the nexus of glucose oxidation and fatty acid oxidation are sensitive to metabolic status. Four isozymes of PDK (PDK1-4) exist with PDK2 and PDK4 as the major regulators in cardiac tissue. Owing to the role of PDH in regulating pyruvate to acetyl-CoA, we hypothesized that PDK inhibition may regulate protein acetylation through increasing acetyl-CoA because of PDH activation leading to post-translational modifications both directly to proteins in metabolic pathways as well as to histones associated with the genes encoding them. To test this, we utilized PDK2 germline knockout mice (P2KO), PDK4 germline knockout mice (P4KO), and PDK2 and PDK4 double knockout (DKO) mice for molecular analysis. Our results identify a novel increase in whole-cell protein acetylation in P2KO left ventricle tissue (LV). However, protein acetylation in P4KO LV was not changed compared to WT mice. The most robust protein acetylation was observed in the DKO LV. Furthermore, when we explored sub-cellular distribution of protein acetylation, the greatest increases were found on cytoplasmic proteins, with moderate changes in mitochondrial proteins. We also found PDK2 ablation induces histone H3 acetylation, which may also lead to changes in gene expression. Moreover, this protein acetylation in P2KO and DKO was not seen in other tissues examined (e.g., liver, skeletal muscle). The hyperacetylation is robust in male LV compared to female LV. In conclusion, our study supports a novel protein acetylation mechanism that is both tissue and PDK isozyme specific highlighting the role of PDK2, which is relatively understudied compared to PDK4 in heart disease. Further study will evaluate if the hyperacetylation has a beneficial effect in various heart disease settings as well as identify the impact on changes in gene expression. This study supports PDK isozyme-specific inhibition strategies will be required to develop therapeutic targets of cardiovascular disease with metabolic inflexibility.
Abstract 14336: Association of Mid-Life Cardiovascular Disease and Late-Life Alzheimer's Disease Pathology: Insights From Heart Score Study
Authors: Anum Saeed, Yue-Fang Chang,, Oscar L Lopez, Steven Reis, Ann D Cohen
Journal: Circulation (2021)

Introduction: Data show an association of CVD risk factors in mid-life with older age dementia. Atherosclerosis (ATH) and arteriosclerosis (ART) are both implicated in incident dementia however their relationship with incident Alzheimer’s disease (AD) remains elusive. We investigated the association of mid-life cardiovascular risk factors and mid-life subclinical CVD (ATH and ART) with late-life AD pathology. Methods: Non-demented participants over the age of 65 from the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study underwent brain PET acquisition (2018-2020) for AD specific amyloid deposition [by Pittsburgh Compound B (PiB)]. Pearson’s correlation and OR (95% CI) using Cox regression for association of cortical PiB retention with mid-life (2003-2005) markers of ATH (coronary artery calcium [CAC] score and carotid intima thickness [CIMT]) and ART (vascular stiffness) were calculated. Results: Among 121 participants in late-life (mean age ~79y), age was significantly correlated to lower cognition ( r =0.19, p=0.03) but gender, race and diabetes were not. Late-life AD pathology was not significantly associated with mid-life CAC (&gt;150) [OR=0.12 (0.01, 2.36); p=0.16] or CIMT [OR=1.80 (0.84, 3.86); p=0.40]. Presence of increased vascular stiffness in mid-life showed a significant association with late-life PiB retention (Table ). Conclusions: In a small number of biracial middle-aged adults, subclinical markers of atherosclerosis did not independently predict increased biomarkers of AD pathology. However, vascular stiffness in mid-life was significantly associated with late-life brain biomarkers of Alzheimer’s disease pathology. Further research can elucidate the role of mid-life athero- and arteriosclerosis in Alzheimer's disease dementia.
NIMG-60. PREDICTING OVERALL SURVIVAL IN GLIOBLASTOMA USING HISTOPATHOLOGY VIA AN END-TO-END DEEP LEARNING PIPELINE: A LARGE MULTI-COHORT STUDY
Authors: Ruchika Verma, Mark Cohen, Paula Toro, Mojgan Mokhtari, Pallavi Tiwari
Journal: Neuro-Oncology (2021)

Abstract PURPOSE Glioblastoma is an aggressive and universally fatal tumor. Morphological information as captured from cellular regions on surgically resected histopathology slides has the ability to reveal the inherent heterogeneity in Glioblastoma and thus has prognostic implications. In this work, we hypothesized that capturing morphological attributes from high cellularity regions on Hematoxylin and Eosin (H&amp;E)-stained digitized tissue slides using an end-to-end deep-learning pipeline will enable risk-stratification of GBM tumors based on overall survival. METHODS A large multi-cohort study consisting of N=514 H&amp;E-stained digitized tissue slides along with overall-survival data (OS) was obtained from the Ivy Glioblastoma atlas project (Ivy-GAP (N=41)), TCGA (N=379), and CPTAC (N=94). Our deep-learning pipeline consisted of two stages. First stage involved segmenting cellular tumor (CT) from necrotic-regions and background using Resnet-18 model, while the second stage involved predicting OS, using only the segmented CT regions identified in the first stage. For the segmentation stage, we leveraged the Ivy-GAP cohort, where CT annotations confirmed by expert neuropathologists were available, to serve as the training set. Using this training model, the CT regions on the remaining cohort (TCGA, CPTAC) (i.e. test set) were identified. For the survival-prediction stage, the last layer of ResNet18 model was replaced with a cox layer (ResNet-Cox), and further fine-tuned using OS and censor information. Independent validation of ResNet-Cox was performed on two hold-out sites from TCGA and one from CPTAC. RESULTS Our segmentation model achieved an accuracy of 0.89 in reliably identifying CT regions on the validation data. The segmented CT regions on the test cohort were further confirmed by two experts. Our ResNet-Cox model achieved a concordance-index of 0.73 on MD Anderson Cancer Center (N=60), 0.71 on Henry Ford Hospital (N=96), and 0.68 on CPTAC data (N=41). CONCLUSION Deep-learning features captured from cellular tumor of H&amp;E-stained histopathology images may predict survival in Glioblastoma.
Abstract 13260: Relationship Between Localization of Myocardial Asynergy and Presence of Pathological Q Wave in Synthetic Posterior Lead Electrocardiogram
Authors: Takashi Kikuchi, Takahide Kodama, Mitsuhiko Ota, Yukako Koike
Journal: Circulation (2021)

Background: Synthesized posterior lead derived from 12-lead ECG can represent ST elevation in posterior acute myocardial infarction with high accuracy. However, the validity of pathological Q wave (Q) in synthesized lead ECG remained unclear. Objective: To investigate the relationship between localization of ventricular wall motion abnormality (Asynergy) and presence of Q in synthetic V7-V9 lead (synV7-V9). Subjects: Consecutive 1319 walk-in patients (68±13y, Male 67.5%, LVEF 64.0±10.4%) who underwent ECG and transthoracic echocardiography (TTE) were extracted from our database. Method: (1) Posterior lead: synV7-V9 was obtained from synECi18 system (Nihon Kohden) and V2-V5, II•aVF, and I•aVL•V6 leads were obtained from 12-lead ECG. (2) Asynergy was detected as increased wall motion score on 16-segments from TTE and classified into coronary perfusion regions. We analyzed the relationship between Q in synV7-V9 and patient characteristics, ECG parameters, or TTE parameters. Results: Wall motion abnormality was observed in 217 cases (16.5%). Q in synV7-V9 was detected in 79 cases (6.0%), and 38 cases out of them showed asynergy in any coronary perfusion site (Figure. A). In order to clarify relationship between Q in synV7-V9 and asynergy, wall motion score of 16-segments were compared in Presence of Q in synV7-V9 limited group and Non Q in all lead group (Figure. B). As a result, in the former, the scores in basal to mid on inferior to infero-lateral wall were found to be significantly higher. Logistic regression analysis for presence of Q in synV7-V9 limited showed asynergy in RCA to LCx region (OR 4.5, 95%CI 1.6-13.0), in RCA region (OR 4.0, 95%CI 1.4-11.0), in LCx region (OR 5.8, 95%CI 1.2-27.7), male (OR 2.6, 95%CI 1.2-6.0), right bundle brunch block (OR 3.2, 95%CI 1.4-7.3) remained as significant factors. Conclusion: Present study suggests Q in posterior lead using synthesized ECG can help diagnose myocardial scarring in RCA to LCx region including posterior wall.
Abstract 12361: Yelp Data on Fast Food and Exercise Facilities Predict Cardiovascular Events
Authors: Javier Cabrera, Jin Wang, Stavros Zinonos, William J Kostis, Krishnamurthy Subramanian, John B Kostis
Journal: Circulation (2021)

Introduction: Yelp includes information on nearly all businesses and socioeconomic data in any region of the United States. This database maybe used to obtain socio-economic data that may affect the incidence of cardiovascular disease. This project focuses on access to poor quality food such as fast food and lack of exercise that may have a negative impact in cardiovascular disease. A dataset including the number of fast-food restaurants, non-fast-food restaurants, grocery stores, gyms, other fitness facilities, nursing homes, and pharmacies were aggregated by zip code. In addition, demographic variables such as gender, age, and comorbidities were included. Cardiovascular outcomes were obtained from the Myocardial Infarction Data Acquisition System (MIDAS) database of all hospitalizations in New Jersey. Ten percent of the zip codes that did not have sufficient data were excluded. Hypothesis: Yelp variables will predict the occurrence of stroke, myocardial infarction and heart failure requiring hospitalization. Methods: The yelp data were used to predict three outcomes as identified by the MIDAS database: stroke, myocardial infarction and heart failure requiring hospitalization. Linear models followed by stepwise selection of the predictors were used to define the final models used in these analyses. Results: The results of the regressions in the table show that the number of fast-food restaurants and nursing homes were associated with increased frequency of all 3 outcomes controlling for population size. Access to grocery stores, gyms, and other fitness facilities are associated with lower rate of stroke, myocardial infarction and heart failure requiring hospitalization. Conclusions: Socioeconomic variables obtained from the yelp database predicted the occurrence of stroke, myocardial infarction and heart failure requiring hospitalization with high degree of accuracy.
Abstract 10067: A Nitric Oxide Donor Binds to SARS-CoV-2 Papain-Like Protease with Therapeutic Implications
Authors: John F Schmedtje, Zahra Assar, Fred Ciske
Journal: Circulation (2021)

Novel compounds developed as nitric oxide (NO) donors for cardiovascular diseases were created by linking an urea-like NO donor to the 5-carbon of the generic agent isosorbide-2-nitrate. NO also appears to have antiviral effects on SARS-CoV-2. A study of drug-protein interactions was undertaken in silico using Maestro, Schrödinger Suite software to determine if the novel compounds could be antivirals. SARS-CoV-2 papain-like protease (PL pro ) was a primary target as it mediates viral replication and inhibition of host interferon-based responses. Compared with known antiviral drugs, including the known PL pro inhibitor GRL-0617, CR-0305 had a better Glide Score (a predictor of ligand affinity) against PL pro . Molecular Mechanics / Generalized Born Surface Area (MM/GBSA) calculations and Molecular Dynamics simulations predicted CR-0305 binding to the PL pro catalytic pocket where it makes the most of key residues in the catalytic site. Subsequently, CR-0305, or (3S,3aS,6R,6aR)-6-((3-(2-hydroxyacetamido)propyl)amino) hexahydrofuro[3,2-b]furan-3-yl nitrate, was synthesized by ligating a (TBDPS) Tert-Butyldiphenylsilyl-protected side chain to the 5-carbon of 1,4:3,6-Dianhydro-L-Iditol Triflate Mononitrate followed by a de-protection reaction that removed TBDPS. Toxicity of CR-0305 was examined using MitoCheck Complex I-V activity assays in an Agilent Seahorse XFe96 analyzer in isolated mitochondria with mitochondrial stress tests in HMEC-1 human dermal endothelial cells and measurement of the effect of drug on ATP synthesis in HMEC-1 cells. No significant toxicity was identified at 10-100 μM concentrations. GRL-0617, CR-0202 and CR-0305 were tested in Vero E6 and A549-ACE2 cells exposed to SARS-CoV-2 using a drug dose response regimen from 20 μM down to 40 nM in 2-fold serial dilution. There was no evidence of cytotoxicity. GRL-0617 gave an approx. 50% reduction in SARS-CoV-2 infection compared to vehicle at the highest dose tested (20 μM), as measured by virus N protein staining with a specific antibody. CR-0305 gave a consistent but weak effect on total N protein expression in A549-ACE2 cells. In conclusion, CR-0305 binds in silico to SARS-CoV-2 PL pro and appears to inhibit viral replication in vitro , justifying further development.
Abstract 11392: Sex Differences in Fat Deposition: The Relationship with Exercise Capacity and Symptom Severity in a Case-Control Model in Heart Failure with Preserved Ejection Fraction
Authors: Katlyn Koepp, Yogesh Reddy, Masaru Obokata, Hidemi Sorimachi, Frederik Verbrugge, Kazunori Omote, Alexander C Egbe, Eric Bruhn, Barry A Borlaug, Thomas P Olson
Journal: Circulation (2021)

Introduction: Obesity is prevalent in HFpEF, a syndrome that disproportionality affects women, and is associated with poor exercise tolerance (VO 2 ), reduced quality of life, and greater symptoms. Visceral adipose tissue (VAT), more than general obesity, is related to metabolic and cardiovascular dysfunction common to HFpEF. While fat deposition varies between sexes, these differences and the relation to exercise tolerance remain unclear in HFpEF. Hypothesis: Compared to sex-matched controls, HFpEF patients will demonstrate reduced lean mass, excess VAT, subcutaneous, visceral, and intramuscular fat, and will be associated with reduced VO 2 . Methods: HFpEF females (F) and males (M) (n=78; 37 F/41 M; age 70±9) and non-HFpEF controls (n=50; 30 F/20 M; age 65±5) prospectively underwent body composition measurement via dual-energy x-ray absorptiometry and magnetic resonance imaging (MRI) and cardiopulmonary exercise testing for measurement of peak oxygen consumption (peak VO 2 ). Muscle quality calculated as peak Watts (W) achieved divided by MRI thigh lean mass. Results: HFpEF had greater VAT, subcutaneous (SAT) and intramuscular (IMAT), and poorer muscle quality than controls (all p&lt;0.01). Exercise performance was lower in HFpEF (peak VO 2 : 14±4 vs. 22±6; peak W: 69±29 vs. 116±34; both p&lt;0.01). HFpEF demonstrated increased odds for VAT (OR: 2.02, 95% CI: 1.22-3.37), SAT (OR: 2.05, 95% CI: 1.20-3.49), and IMAT (OR: 2.04, 95% CI: 1.35-3.39) (all p&lt;0.01). Sex-stratification revealed increased odds of excess VAT in HFpEF females (OR: 2.76, 95% CI: 1.16-7.72, p=0.03), SAT in HFpEF males (OR: 3.64, 95% CI: 1.10-12.07, p=0.03), and IMAT in HFpEF females (OR: 2.38, 95%CI: 1.10-5.29, p=0.03) with a trend in males (OR: 1.67, 95%CI: 0.97-2.86, p=0.06). Impaired VO 2 was associated with all AT depots as a combined cohort and among controls (all p&lt;0.01) and linked to poor muscle quality individually for men and women in HFpEF and controls (all p&lt;0.01). Conclusion: HFpEF patients have significantly altered body composition profiles and reduced exercise tolerance compared to controls. Sex differences in regional fat deposition impact peak VO 2 and may serve a distinct role in the pathophysiology of HFpEF.
Abstract 13014: Sex-Differences in Nonagenarians With ST Elevation Myocardial Infarction
Authors: Rebekah Lantz, Janki Shukla, David Larson, Mehmet Yildiz, Christian Schmidt, Georgia Mattingly, Scott W Sharkey, Teresa Coulson, Jenny Chambers, Timothy D Henry, Odayme Quesada
Journal: Circulation (2021)

Introduction: Longevity of the population continues to increase but frequently elderly patients are excluded from clinical trials. Women with STEMI have been reported to have higher mortality, delay to treatment, and suboptimal prescription of goal directed medical therapy compared to men. We recently demonstrated higher utilization of PCI with improved outcomes in elderly patients treated in regional STEMI systems with standardized protocols. We evaluated sex-differences in nonagenarians with STEMI. Methods: The Midwest STEMI Consortium (MSC) consists of four regional STEMI centers includes 15,039 consecutive STEMI activations between March 2003 and December 2020. Sex differences were assessed in the subgroup of patients ≥ 90 years old (n=303, 2%), including baseline demographic, intervention, mortality outcomes, and pre/post hospitalization residence status. Results: Of 303 nonagenarians, women (N=194, 64%) were less likely to have a smoking history, family history of coronary artery disease (CAD), and personal history of CAD (including MI, PCI or CABG). Surprisingly, there were no sex differences in time to treatment, use of PCI (84 vs 78%), adjunctive medical therapy or clinical outcomes including in-hospital and 1-year mortality (Table). Conclusions: In 4 established regional STEMI systems, in elderly patients ≥ 90 years old women were more common (64%) and although the risk profiles were different, there were no sex differences in reperfusion strategy, time to treatment, or adjunctive therapy. Importantly, there were no differences in clinical outcomes including mortality. The high rate of PCI, excellent treatment times and clinical outcomes compared to historical data likely reflect the benefit of regional STEMI programs using standardized protocols.
Abstract 12446: Lipocalin10 Deficiency Exacerbates Myocardial Ischemia/Reperfusion Injury via Impairing Macrophage Efferocytosis
Authors: Yutian Li, Xiaohong Wang, Wei Huang, Qianqian Li, Yi-gang Wang, Jing Chen, Guo-chang Fan
Journal: Circulation (2021)

Introduction: Efficient clearance of dead cells by macrophages (termed as efferocytosis) is critical for timely repairing the injured heart after ischemia/reperfusion (I/R), as defective removal of dying cells could cause secondary necrosis and infarct expansion. Recent studies have shown that lipocalin 10 (Lcn10) is significantly downregulated in cardiac tissue from patients with heart failure. However, the role of Lcn10 is virtually unknown during cardiac I/R, and its function in macrophage efferocytosis has never been explored. Hypothesis: Our initial data showed that Lcn10 expression was upregulated in bone marrow-derived macrophages (BMDMs) during efferocytosis. Thus, we hypothesize that knockout (KO) of Lcn10 would diminish macrophage efferocytosis, leading to exacerbated cardiac I/R injury. Methods/Results: Since Lcn10 is a secreted protein, we generated a global Lcn10-KO mouse model. After co-culturing BMDMs with GFP-labeled dead myocytes for 2h, we observed a 25% reduction on efferocytosis by KO-BMDMs, compared to wild-type (WT) controls. Using Lcn10-KO mCherry mouse model (cardiac-specific overexpression of mCherry in Lcn10-KO mice), we detected that KO cardiac macrophages ingested fewer dead myocytes at 3 days post-I/R, compared to WT-mCherry controls. Accordingly, cardiac contractile function, measured by echocardiography at the same time, was significantly declined in KO-mice, together with increased accumulation of apoptotic cells and higher serum levels of troponin I, a marker of cardiac damage, compared with WTs (n=7-10, p &lt;0.05). In addition, pre-treatment of KO-BMDMs with recombinant Lcn10 protein could rescue the impaired efferocytosis. Mechanistically, RNA-seq analysis showed that many downregulated genes (i.e., ItgaV, Itga6, Cx3cr1, and Msr) in KO-macrophages are associated with efferocytosis. Interestingly, we identified that Lcn10 contains a potential phosphatidylserine (PS)-binding motif (RxKRK), located at a helix-turn-helix structure, which is the primary “find-me” signal for efferocytosis. Conclusions: Our data indicate that Lcn10 is pivotal for macrophage efferocytosis to remove cardiac dead cells during I/R. Thus, Lcn10 could be used as a new mediator for the treatment of cardiac I/R injury.