tbuckley/cabot-search huggingface dataset:
Abstract 13236: Differing Relations Of Arterial Stiffness And Carotid Intima-Media Thickness In Adolescence With Metabolic Risks In Young Adulthood: The ALSPAC Study
Authors: Andrew O Agbaje, Alan R Barker, Tomi-Pekka Tuomainen
Journal: Circulation (2021)

Introduction: Carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and carotid intima-media thickness (cIMT) are strong predictors of cardiovascular and all-cause mortality in adults. However, due to the unavailability of hard outcomes among adolescents and young adults, it remains unclear how cfPWV and cIMT predict metabolic outcomes in these age groups. Hypothesis: We tested whether cfPWV and cIMT during adolescence similarly or differently predict higher insulin, glucose, plasma lipid, and increased inflammation in young adulthood. Methods: Altogether 3862 British (56% females) participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, England, UK were studied. cfPWV was measured by Vicorder device, cIMT by CardioHealth ultrasound scan, systolic blood pressure (BP) and heart rate by Omron BP/pulse monitor, total fat mass and lean mass by dual-energy Xray absorptiometry, moderate to vigorous physical activity by accelerometer, and smoking status by questionnaire. Insulin, plasma glucose, lipid profiles, and high sensitivity C-reactive protein were measured during a fasting state. Insulin resistance (HOMA-IR) was estimated from (insulin x glucose)/22.5. We conducted linear regression analyses and adjusted for cardiometabolic and lifestyle factors at 17.7 years. Results: Participants' mean (SD) age in years at different time points were [17.72 (0.33) and 24.54 (0.73)]. cfPWV at age 17.7 years was inversely associated with high-density lipoprotein cholesterol [β = -0.32 (CI: -0.60 to -0.04); p=0.028] and directly associated with insulin [0.28 (0.05 to 0.50); p=0.019] and HOMA-IR [0.28 (0.04 to 0.53); p=0.026] at 24.5 years. cIMT at age 17.7 years was inversely associated with insulin [-0.33 (-0.59 to -0.07); p=0.024] and HOMA-IR [-0.32 (-0.59 to -0.04); p=0.026] at 24.5 years. cfPWV and cIMT at 17.7 years were unrelated to other metabolic and inflammatory markers at 24.5 years. Conclusions: Arterial stiffness during adolescence may be a novel risk factor for predicting reduced high-density lipoprotein cholesterol and increased insulin resistance in young adults. However, carotid wall thickening in adolescence predicted higher insulin sensitivity 7 years later.
Abstract 9186: Maslinic Acid Alleviates Atherosclerosis by Suppressing Mitochondrial ROS-Dependent NLRP3 Inflammasome Activation in Vascular Endothelial Cells via SIRT1/Nrf2 Pathway
Authors: Li Zhuqing, Lu Chengzhi
Journal: Circulation (2021)

Introduction: Maslinic acid (MA), a pentacyclic triterpenoid primarily found in food plants, has exhibited multiple inhibitory effects on proatherogenic factors, such as obesity, dyslipidemia, and inflammation. However, its effect on atherosclerosis remains unknown. In this study, we determined if MA can inhibit atherosclerosis progression and explored the underlying molecular mechanisms. Methods: To assess the anti-atherogenic effect of MA in vivo, ApoE deficient mice were treated with MA contained in high-fat diet for 16 weeks. After treatment, mouse aorta and serum samples were collected to determine atherosclerotic lesions, lipid profile, mitochondrial morphology and expression of related molecules. Additionally, human aortic endothelial cells (HAECs) were treated with ox-LDL to induce the endothelial injury model. Prior to the procedure, vehicle or MA were treated in the absence or presence of a SIRT1 inhibitor nicotinamide (NAM) and an Nrf2 inhibitor ML385. Concurrently, we investigated the effects and mechanisms of MA on mitochondrial dysfunction, oxidative stress injury and apoptosis in HAECs. Results: In vivo, MA conferred an anti-atherosclerotic effect as shown by reduced en face and aortic root sinus lesions size. From the electron microscopic analysis, MA ameliorated the mitochondrial damage in aortic endothelium. MA could promote the protein expression of SIRT1 and Nrf2, and enhance the expression of mitochondrial antioxidant enzymes. In addition, MA suppressed NLRP3 inflammasome activation to reduce apoptosis in vascular endothelium. In vitro, MA could inhibit ox-LDL-induced mitochondrial ROS generation by activating SIRT1/Nrf2 pathway, thereby inhibiting NLRP3 inflammasome activation and apoptosis in HAECs. NAM and ML385 eliminated the MA-mediated endothelial protective effect by restraining the expression of SIRT1 and Nrf2, respectively. Conclusions: In conclusion, our findings suggested that MA ameliorated endothelial apoptosis by suppressing mitochondrial ROS-dependent NLRP3 inflammasome activation via SIRT1/Nrf2 pathway and showed efficacy in exerting an anti-atherogenic effect.
Abstract 11264: Medicaid Expansion and Association with Cardiovascular Care: A Systematic Review
Authors: Ginger Jiang, Jason Wasfy
Journal: Circulation (2021)

Background: One of the goals of the Affordable Care Act was to improve health outcomes through expanding insurance, including through Medicaid expansion. It remains unclear whether Medicaid expansion was associated with improvement in cardiovascular (CV) outcomes. Objectives: To systematically review the available literature on the association of Medicaid expansion with cardiovascular outcomes. Methods: In adherence with guidelines established by Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), we performed systematic searches in PubMed, the Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases for studies that evaluated the relationship between Medicaid expansion and CV outcomes. Results: A total of 24 studies met inclusion and exclusion criteria. Of these, 22 studies utilized a quasi-experimental study design. The median number of post-expansion years evaluated was 2 (range, 0.5-4) and the median number of expansion states included was 23 (range, 1-33). Commonly assessed outcomes included access to cardiovascular care (25.5%), morbidity/mortality (19.1%), disparities in care (12.8%), and preventive care (42.6%). Medicaid expansion was generally associated with improved access to CV care, reduction in overall CV mortality, and some increase in screening and treatment of CV comorbidities, but was not commonly associated with improvement in disparities in care. Conclusions: Current literature demonstrates in general that Medicaid expansion was associated with improved access to care, some improvement in clinical outcomes outside of acute care settings, and some improvements in prevention and screening. In general, Medicaid expansion has not been associated with reductions in disparities. Conclusions are limited because quasi-experimental comparisons of expansion and non-expansion states cannot account for unmeasured state-level confounders.
Abstract 9914: Three Months vs 12-Months Dual Antiplatelet Therapy Duration in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention
Authors: Vijairam Selvaraj, Abdelmoniem Moustafa, Chirag Bavishi
Journal: Circulation (2021)

Introduction: Recent American Heart Association/American College of Cardiology guidelines on duration of dual antiplatelet therapy (DAPT) recommend DAPT for 12 months in patients presenting with an acute coronary syndrome (ACS) who underwent percutaneous intervention (PCI) (grade IIb recommendation). With the advent of newer generation stents, multiple randomized controlled trials (RCTs) have studied the role of short term -3 months DAPT compared to the guideline-indicated12 months DAPT. We aim to assess the evidence using a meta-analytic approach. Methods: PubMed, Embase and Cochrane Central databases were searched from inception until May 31, 2021. RCTs comparing short term (3 months) vs extended (12 months) DAPT in patients with ACS undergoing PCI were included. Outcomes assessed were MACE, cardiovascular mortality, all-cause mortality, myocardial infarction, stent thrombosis and bleeding events. A random-effects model was used to calculate pooled relative risk (RR) and 95% confidence intervals (CI). Results: We included 5 trials comprising 16,781 patients with an acute coronary syndrome that underwent percutaneous intervention. There was no significant difference in MACE (RR 0.92; 95% CI, 0.76-1.11), cardiovascular mortality (RR 1.26; 95% CI, 0.38-4.17), or all-cause mortality (RR 0.92; 95% CI, 0.48-1.77) between the 2 groups. In addition, there was no difference in rates of myocardial infarction (RR 0.98; 95% CI, 0.74-1.30), or stent thrombosis (RR 1.30; 95% CI, 0.55-3.05) between short-term and extended DAPT. However, compared with extended DAPT, 3-month DAPT showed significantly reduced risk of major bleeding (RR 0.53; 95% CI, 0.43-0.64). Conclusions: In patients with acute coronary syndrome undergoing PCI, short term DAPT may be reasonable for some patients, while extended DAPT may be appropriate for select others. An individualized approach on optimal DAPT duration should be used considering the risks of ischemic events and bleeding.
BIOM-36. SERIAL ASSESSMENT OF MEASURABLE RESIDUAL DISEASE IN MEDULLOBLASTOMA LIQUID BIOPSIES
Authors: Anthony Pak-Yin Liu, Kyle Smith, Rahul Kumar, Leena Paul, Tong Lin, Kendra Maass, Kristian Pajtler, Laure Bihannic, Brent Orr, David Ellison, Richard Gilbertson, Arzu Onar-Thomas, Amar Gajjar, Giles Robinson, Paul Northcott
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma is the most common malignant brain tumor in children. Despite the use of contemporary multi-modal therapy, up to one-third of patients will succumb to disease progression. Conventional response monitoring is based on magnetic resonance imaging and cerebrospinal fluid (CSF) cytology and a marker for measurable residual disease (MRD) is lacking. In this study, we show the clinical utility of profiling CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD based on a sizable cohort of children with medulloblastoma enrolled on a prospective, multi-center, risk-adapted trial (SJMB03; NCT00085202). A total of 476 CSF samples were serially collected from 123 patients by lumbar puncture at post-operative baseline, during therapy, and at regular surveillance after completion of therapy. Using low-coverage whole-genome sequencing (lcWGS), tumor-associated copy-number alterations in CSF-derived cfDNA were investigated as an MRD surrogate for correlation with clinical features and outcomes. MRD was detected in post-operative baseline CSF samples for 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients declined with therapy, yet those with persistent MRD detected at the end of therapy (20 of 68 CSFs at this timepoint) had significantly higher risk of disease progression (hazard ratio 8.94, 95%CI 4.10-19.49; log-rank p&amp;lt; 0.0001). Importantly, MRD-positivity from routine surveillance samples often preceded radiographic progression by more than 3 months. Comparative analyses of copy-number variations obtained from serial CSF samples enabled identification of relapse-specific alterations and early detection of relapse-dominant clones. Overall, our findings advocate for the routine incorporation of CSF-derived liquid biopsies in future medulloblastoma trials.
A longitudinal analysis of the impact of the COVID-19 pandemic on the mental health of middle-aged and older adults from the Canadian Longitudinal Study on Aging
Authors: Parminder Raina, Christina Wolfson, Lauren Griffith, Susan Kirkland, Jacqueline McMillan, Nicole Basta, Divya Joshi, Urun Erbas Oz, Nazmul Sohel, Geva Maimon, Mary Thompson, Andrew Costa, Laura Anderson, Cynthia Balion, Asada Yukiko, Benoȋt Cossette, Melanie Levasseur, Scott Hofer, Theone Paterson, David Hogan, Teresa Liu-Ambrose, Verena Menec, Philip St. John, Gerald Mugford, Zhiwei Gao, Vanessa Taler, Patrick Davidson, Andrew Wister, Theodore Cosco
Journal: Nature Aging (2021)
51321例の日本人高コレステロール血症患者を対象とした最小副作用での6年間の低容量シンバスタチン療法における血清コレステロールの持続的低下 大規模全国コホート試験J-LIT試験の意義
Authors: Matsuzawa Y, Kita T, Mabuchi H, Matsuzaki M, Nakaya N, Oikawa S, Saito Y, Sasaki J, Itakura H
Journal: Circulation (2003)
Abstract 13280: apoB-Containing Lipoproteins and Risk of Myocardial Infarction: Distinguishing Between Particle Concentration, Content, and Type
Authors: Nicholas A Marston, Robert Giugliano, Giorgio Melloni, Jeong-Gun Park, Brian A Ference, Evan A Stein, Christian T Ruff, Marc S Sabatine
Journal: Circulation (2021)

Background: Lipid management typically focuses on levels of LDL cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). Basic investigation and genetic studies, however, suggest that the atherogenic particle subpopulations (LDL &amp; VLDL) are similarly important and that the number of particles is more important than their lipid content. Methods: We performed a prospective cohort analysis in two populations: 1) 389,529 primary prevention patients w/o lipid-lowering therapy from UK Biobank, and 2) 45,708 statin-treated patients w/ established atherosclerosis from the FOURIER and IMPROVE-IT trials. Incident MI was assessed over a median follow up of 11.1 yrs in UKBB and 3.6 yrs in the trials. Adjusted HRs were calculated to determine whether lipid content (non-HDL-C &amp; TG) or particle type (using LDL-C concentration as a surrogate for LDL, and TG concentration as a surrogate for TG-rich lipoproteins) offer predictive value beyond atherogenic particle concentration (apoB). Results: In the primary prevention cohort, apoB, non-HDL-C, and TG each individually predicted incident MI. However, when assessed together, only apoB remained a significant predictor (adj HR per 1-SD = 1.28 [95%CI: 1.16,1.42], p&lt;0.0001) ( Fig, A/B ). Similarly, only apoB remained a predictor of MI in the secondary prevention cohort ( Fig, C/D ). Adjusting for apoB, there was no relationship between the ratio of TG to LDL-C (a surrogate for the ratio of TG-rich lipoproteins to LDL) and the risk of MI (p=0.32, Fig, E ), implying that for a given concentration of apoB-containing lipoproteins, the relative proportion of particle subpopulations is not an independent predictor of risk. Conclusion: Risk for MI is best captured by the number of apoB-containing lipoproteins, independent from lipid content (cholesterol or TG) or type of lipoprotein (LDL or TG-rich). Therefore, therapeutic strategies should take into account lowering the overall concentration of all apoB-containing lipoproteins.
Abstract 9949: Characterising the Impact of Type Two Diabetes on the Phenotypic Expression of Hypertrophic Cardiomyopathy
Authors: Nicholas Jex, Amrit Chowdhary, Sharmaine Thirunavukarasu, Anshuman Sengupta, Henry Procter, Ana Maria Poenar, John GREENWOOD, Sven Plein, Stephen Page, Eylem Levelt
Journal: Circulation (2021)

Background: Hypertrophic cardiomyopathy (HCM) and type 2 diabetes mellitus (DM) are increasingly frequent comorbidities. DM is associated with worsened survival outcomes in HCM patients. HCM and DM, though differing in their etiologies, share features of alterations in myocardial energetics and perfusion. The mechanisms for this adverse prognostic association are incompletely understood but are likely to include the collective impact of DM and HCM on myocardial metabolism and perfusion. Objectives: We aimed to determine if cardiac energetics, measured as the phosphocreatine (PCr)/ATP ratio, and rest and adenosine stress myocardial blood flows (MBF) showed greater reductions in patients with concomitant HCM and DM (HCMDM) compared to isolated HCM or isolated DM using 31 Phosphorus magnetic resonance spectroscopy ( 31 P-MRS) and cardiovascular magnetic resonance (CMR). Methods: A total of 75 age and sex matched participants were recruited (20 HCMDM, 20 HCM, 20 DM and 15 controls). HCM groups were matched for HCM phenotype (8 with apical and 12 with asymmetric septal hypertrophy in both groups). DM groups were matched for diabetes treatment and HBA1c. Patients with a history of ischemic heart disease were excluded. Results: Table-1 shows clinical and CMR/ 31 P-MRS data.Left ventricular ejection fraction and mass index were similar in both HCM groups. Global longitudinal strain and left atrial function were significantly reduced in HCMDM compared to HCM. PCr/ATP was similarly reduced in HCMDM and DM groups compared to HCM and controls. Stress MBF was significantly reduced only in HCMDM group. Conclusions: The presence of diabetes as a comorbidity confers a more malignant phenotypic expression in HCM patients with greater reductions in myocardial energetics, contractile function, and perfusion. These phenotypic differences may account for the worsened clinical outcomes in HCM patients with concomitant DM. Table 1: Clinical Characteristics and CMR findings
Abstract MP234: Novel <i>Mybpc3</i> Variant Disrupts Myosin S2 Binding And Induces Heart Failure
Authors: Taejeong Song, Rohit Singh, Darshini Desai, Sheryl E Koch, Jack Rubinstein, Sakthivel Sadayappan
Journal: Circulation Research (2021)

Rationale: Cardiac m yosin binding protein-C regulates a ctomyosin interaction in striated muscle, but mutations in the MYBPC3 gene can lead to hypertrophic cardiomyopathy (HCM) as seen in some South Asians living in the USA carrying a novel variant wherein an aspartic acid is mutated to a valine at position 389 (D389V). Individuals and iPSC-derived cardiomyocytes carrying D389V display hypercontractility, indicating early onset of HCM. However, the mechanisms underlying the pathophysiology of this mutant in the context of HCM are unknown. Objective: To define the pathophysiological consequences D389V on myosin and cardiac function in vivo . Methods and Results: Compared with wild-type controls, our D389V knock-in homozygous mouse model showed decreased cardiac function by percentage of ejection fraction (-23%, P&lt;0.01), but increased systolic left ventricular volume (+39%, P&lt;0.01) at 3 and 6 months of age. Heart weight to tibia length ratio was significantly increased (+ 15%, P=0.05), demonstrating distinct pathogenicity. Using recombinant proteins carrying D389V substitution at the N-terminal MYBPC3 domains (rC0C2 D389V ), cosedimentation and solid-phase binding assays showed significantly reduced binding rate of rC0C2 D389V to the myosin S2 region (-55% and -23%, P&lt;0.05, respectively), but in vitro actin motility over myosin increased 24% (P&lt;0.05) compared to rC0C2 WT control, indicating a causal relationship between variant and decreased MYBPC3 binding to myosin. Human iPSC-derived D389V het cardiomyocytes display an increase in lipid peroxide and reactive oxygen species by +3- and +7-fold P&lt;0.01, respectively, compared to noncarrier controls. Conclusion: D389V decreases interaction between MYBPC3 and myosin S2, causing reduced cardiac function and providing mechanistic evidence that it contributes to the etiology of HCM.
STEM-24. INTERFERON SIGNALING REGULATES THE PROLIFERATION AND MESENCHYMAL PHENOTYPE OF GLIOBLASTOMA STEM CELLS
Authors: Sabbir Khan, Rajasekaran Mahalingam, Shayak Sen, Kaitlin Gandy, Kristin Alfaro-Munoz, Nazanin Majd, Veerakumar Balasubramaniyan, John DeGroot
Journal: Neuro-Oncology (2021)

Abstract Interferon (IFN) signaling contributes to stemness, cell proliferation, cell death, and cytokine signaling in cancer and immune cells; however, the role of IFN signaling in glioblastoma (GBM) and GBM stem-like cells (GSCs) is unclear. This study aimed to investigate the cancer cell-intrinsic IFN signaling in tumorigenesis and malignant phenotype of GBM. We characterized cell-intrinsic IFN signaling in The Cancer Genome Atlas, patient-derived cohorts of GSCs, and published single-cell RNA sequencing datasets by in-silico analyses. The in-silico findings were further validated by evaluating the cytokine secretion and using pharmacological activators and blockers of IFN/transducer and activator of transcription 1 (STAT1) signaling. We found that GSCs and GBM tumors exhibited differential cell-intrinsic IFN signaling, and high IFN/STAT1 signaling is associated with mesenchymal phenotype and poor survival outcomes. Ruxolitinib, a pharmacological inhibitor of IFN/STAT1, abolished the IFN/STAT1 signaling in GSCs with intrinsically high IFN signaling. IFN-γ treatment for 1 week promotes the mesenchymal phenotype in GSCs with low IFN signature. In addition, chronic inhibition of IFN/STAT1 signaling with ruxolitinib decreased cell proliferation and mesenchymal signatures (CD44, YKL40, and TIMP1) in GSCs with intrinsically active IFN/STAT1 signaling. Publicly available human glioma single-cell RNA-seq (scRNA-seq) datasets analyses showed that both tumor and nontumor cells expressed IFN signaling genes, and the mesenchymal signature was highly expressed in the same cluster where IFN signaling genes were upregulated. We demonstrated that cell-intrinsic IFN signaling in GSCs and GBM tumors is associated with mesenchymal signatures and cell proliferation. Our study provides evidence for the possibility of targeting IFN signaling in a specific group of GBM patients.
Abstract P408: Mesenchymal Stem Cell-derived Angptl4 Improves Endothelial Permeability And Resolution Of Inflammation In Atherosclerosis
Authors: Dong-im Cho, Yong Sook Kim, Youngkeun Ahn
Journal: Circulation Research (2021)

Objective: Given the fundamental contribution of inflammation to atherosclerosis, we studied the effect of ANGPTL4 in regulating vascular lesions during atherosclerosis. Methods and Results: We analyzed plasma levels of ANGPTL4 and found that acute myocardial infarction (AMI) patients with higher levels of ANGPTL4 had fewer vascular events than did patients with lower ANGPTL4 levels ( p &lt;0.05). Moreover, in AMI patients with heart failure (HF) at admission, the recurrence of HF was lower in patients with a higher level of ANGPTL4. We then investigated the therapeutic application of ANGPTL4 in an atherosclerosis model. Apoe-/- mice fed a high-fat diet were injected with PBS or ANGPTL4 protein (2 μg per mouse, i.p. ) three times per week for 7 weeks. En face staining and mRNA analysis showed that plaque size, necrotic core area, lipid accumulation, and inflammatory molecules were greatly reduced in the ANGPTL4 group. Aortic permeability, measured by leakage of Evans blue dye, was significantly decreased in the ANGPTL4 group. The induction of pro-inflammatory mediators was significantly inhibited in endothelial cells, vascular smooth muscle cells, and macrophages by ANGPTL4 treatment. Endothelial Krüppel-like factor 2 (KLF2) and VE-cadherin were restored to contribute to maintenance of vascular integrity by ANGPTL4 treatment. Elevated levels of circulating leptin, interleukin-6, and interleukin-1β were profoundly reduced. Most importantly, the fibrous cap was significant thicker in the ANGPTL4 group than in the PBS group. Conclusions: ANGPTL4 treatment attenuated atherogenesis, which suggests that targeting vascular stability and inflammation may serve as a novel therapeutic strategy to prevent and treat atherosclerosis. More importantly, ANGPTL4 treatment inhibits necrotic core formation in lesions, leading to the formation of more stable plaques as evidenced by increased fibrous cap thickness.