tbuckley/cabot-search huggingface dataset:
Abstract 13103: Increased Mitochondrial Oxidative Stress and Decreased Mitochondrial Respiration in an <i>in vitro</i> Model of Ischemia Reperfusion Injury
Authors: Ahmed Ismaeel, Evlampia Papoutsi, Dimitrios Miserlis, William Bohannon, Robert Smith, Gleb Haynatzki, Panagiotis Koutakis
Journal: Circulation (2021)

Introduction: Peripheral artery disease (PAD) patients experience ischemia during activity and reperfusion of ischemic skeletal muscle during rest. Cycles of ischemia and reperfusion (I/R) result in a compromised metabolic myopathy that adds to the pathophysiology of PAD. We have recently developed an I/R in vitro model that can mimic the skeletal muscle damage seen in the PAD gastrocnemius. We hypothesized that cycles of I/R will increase mitochondrial oxidative stress and mitochondrial respiration in skeletal muscle myotubes. Methods: Primary human skeletal muscle cells derived from PAD patients and non-PAD-control gastrocnemius biopsy samples were differentiated in myotubes and exposed to constant normoxia, cycles of normoxia-hypoxia, or cycles of normoxia-hypoxia-hyperoxia, to mimic I/R, with the OxyCyler C42. A substrate inhibitor protocol was used to measure mitochondrial hydrogen peroxide and respiration using an Oroboros fluorespirometer. Mitochondrial gene and protein expressions and transmitted electron microscopy were used to identify changes in mitochondrial function and morphology. Results: The oxygen consumption rate was significantly reduced in the PAD myotubes compared to control myotubes followed by significant increase of H 2 O 2 production. The mRNA and protein expression of several mitochondrial energy metabolism components were significantly reduced in the PAD myotubes. Cycling of normoxia-hypoxia and normoxia-hypoxia-hyperoxia significantly altered the mitochondrial function and morphology in both control and PAD myotubes. Conclusions: Our in vitro model of I/R injury can alter oxidative stress, mitochondrial function and morphology in control and PAD myotubes. Therefore, the pathophysiology of PAD can be modeled in vitro , which allows for a method to test novel therapeutics to treat PAD.
Abstract 13092: Macrophage Specific IGF1 Overexpression on ApoE Deficient Mice Decreases Atherosclerosis, Reduces CXCL12 Chemokine Expression, and Increases Cholesterol Efflux
Authors: Patricia Snarski, Sergiy Sukhanov, Tadashi Yoshida, Svitlana Danchuk, Shaw-Yung Shai, Chandrasekar Bysani, Patrice Delafontaine
Journal: Circulation (2021)

Increased bioavailability of Insulin Like Growth Factor I (IGF1) has been shown to reduce cardiovascular events. Systemic IGF1 administration in ApoE deficient (Apoe -/- ) mice fed a high fat diet reduced atherosclerosis and reduced plaque macrophages. Results of our previous in vitro experiments suggest that macrophages play a predominant role in mediating IGF1 effects in atherosclerotic plaque. We hypothesized that increasing IGF1 levels strictly in macrophages will prevent atherosclerosis. After breeding a novel macrophage-specific IGF1 overexpressing transgenic mouse to an Apoe -/- background (MF-IGF1 mice), we assessed atherosclerotic plaque burden, stability, and monocyte recruitment. Macrophage IGF1 overexpression downregulated plaque burden by 30% (P&lt;0.01), reduced plaque macrophages by 47% (P&lt;0.001) and promoted a stable plaque phenotype. Monocyte recruitment was reduced by 70% (P&lt;0.05) in MF-IGF1 mice and was associated with a decrease in circulating levels of CXC Chemokine Ligand 12 (CXCL12) (27% reduction, P&lt;0.05). CXCL12 protein levels were reduced in plaque and peritoneal macrophages in MF-IGF1 mice. IGF1 completely blocked oxidized low-density lipoprotein (oxLDL)-dependent increase of CXCL12 mRNA transcription (98% reduction, P&lt;0.01) and IGF1 treatment reduced CXCL12 protein (56% decrease, P&lt;0.001) in vitro. ATP-binding cassette transporter A1 (ABCA1) is the key cholesterol transporter mediating macrophage cholesterol efflux and CXCL12 reduces its expression. We found that peritoneal macrophages isolated from MF-IGF1 mice have a 2 fold increase in ABCA1 protein levels. We loaded peritoneal macrophages with oxLDL to measure changes in cholesterol efflux and found that MF-IGF1 mice have a 42% increase in efflux (P&lt;0.01). We also found a 27% increase in cholesterol efflux in IGF1 (100 ng/mL) treated THP-1 cells (P&lt;0.01) with Apolipoprotein AI as a cholesterol acceptor. Overall, our results indicate that macrophage IGF1 reduces atherosclerosis and decreases CXCL12, a chemokine newly implicated in atheroprogression. IGF1 potentially exerts its atheroprotective effect via this reduction in CXCL12 by reducing monocyte recruitment and by increasing ABCA1, thereby increasing cholesterol efflux capacity.
Abstract 12527: Acceleration Time and Doppler Velocity Index Are Flow Dependent in Patients With Severe Bioprosthetic Aortic Valve Dysfunction
Authors: Aslannif Roslan, Jwan Naser, Cristina Pislaru, Vuyisile T Nkomo, Miller Fletcher, Jeremy J Thaden, Sorin Pislaru
Journal: Circulation (2021)

Introduction: Acceleration time (AT) and Doppler Velocity Index (DVI) are critical parameters in assessment of bioprosthetic aortic valve dysfunction (BAVD). AT&gt;100ms and DVI &lt; 0.25 are highly suggestive of prosthetic obstruction and are incorporated in all triage algorithms. Little is known about their relationship with flow. Hypothesis: AT and DVI may be affected by transprosthetic flow in patients with significant bioprosthetic aortic valve dysfunction (BAVD). Methods: Single center, retrospective analysis of patients with severe BAVD (confirmed at surgical re-replacement, transcatheter valve-in-valve implantation, or successfully treated bioprosthetic valve thrombosis). Standard prosthetic parameters (AT, DVI, effective orifice area (EOA), mean gradient, presence and degree of regurgitation), flow (stroke volume index, Svi; transprosthetic flow rate, FR) were measured on the transthoracic echocardiogram at the time of diagnosis with severe BAVD. Results: A total of 266 patients with severe BAVD underwent treatment between 2008-2020. BAVD mechanism was obstruction (N=192, 72%), regurgitation (n=48, 18%) mixed stenosis and regurgitation (n=15, 6%) and patient-prosthetic mismatch (n=12, 5%). DVI was moderately correlated with FR (r=0.50, p&lt;0.001); AT had a weak but significant inverse correlation with FR (r=0.24, p&lt;0.001). SVi had a weaker influence on DVI (r=0.35, p&lt;0.001) and no correlation with AT. Conclusions: AT and DVI are influenced by transprosthetic flow rate. This flow-dependency should be considered when assessing the mechanism of BAVD.
Abstract 12759: Iron Deficiency in Heart Failure is Associated With Upregulation of Pathways Also Related to Cancer Development
Authors: Niels Grote Beverborg, Haye van der Wal, Chim C Lang, Kenneth Dickstein, Gerasimos Filippatos, John Cleland, Stefan D Anker, Marco Metra, Dirk van Veldhuisen, Adriaan A Voors, Rudolf A De Boer, peter van der meer
Journal: Circulation (2021)

Introduction: Iron deficiency is common in patients with heart failure (HF) and associated with a poorer prognosis. Mechanisms underlying these associations in HF are currently mostly unknown. Hypothesis: We aimed to identify pathophysiological pathways which are altered in HF patients with iron deficiency versus those without. Methods: We studied 1,933 subjects with worsening HF from the BIOSTAT-CHF cohort. Patients were classified by iron deficiency (transferrin saturation&lt;20%). Biological processes were identified using the differential expression of 368 plasma proteins and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database using STRING v11.0. Analyses were adjusted for 13 potential confounders including hemoglobin concentration. Sensitivity analyses were performed on matched populations. Results: Patients were mainly men (74%) with a mean age of 69 (±12) years and a left ventricular ejection fraction of 31% (±11). Iron deficiency was identified in 1,219 (63%) patients. Plasma concentrations of 27 proteins were higher and three proteins lower in patients with iron deficiency compared to those without (false discovery rate&lt;0.05). The most strongly up-regulated proteins included the transferrin receptor, IL-6, fibroblast growth factor-23, (N-terminal pro-)B-type Natriuretic Peptide and mucin-16 (cancer antigen-125). KEGG analyses identified cytokine-cytokine receptor interaction and cancer-related pathways as enriched, including PI3K-Akt, MAPK, Rap1 and Ras signaling, and “gastric cancer” and “pathways in cancer”. Downregulated proteins were chemokine ligand-17, paraoxonase-3 and platelet derived growth factor subunit B, which resembled no networks. Conclusion: Our post-hoc analyses of the proteome shows that in patients with HF, those with iron deficiency have higher plasma concentrations of proteins involved in cancer related pathways.
Abstract 13063: Utilization and Diagnostic Yield of Cardiovascular Imaging in Hospitalized COVID-19 Patients
Authors: Yosef Manla, Amani Khalouf, Maria-Fernanda Bonilla, Mohammed Khalil, wael almahmeed, Feras Bader, Firas Al Badarin
Journal: Circulation (2021)

Background and Aims: Whereas several cardiovascular imaging (CVI) modalities can uncover cardiac involvement with COVID-19, judicious use of CVI in this population is crucial to avoid unnecessary exposure to hospital staff. Describing utilization patterns and diagnostic yield of CVI in COVID-19 patients will support rational utilization of CVI in this setting. Methods: Data on consecutive hospitalized COVID-19 patients at a single center (Feb-July 2020) were retrospectively collected. Baseline characteristics and outcomes were compared between those who did and did not receive CVI during index admission (defined as either transthoracic echocardiography, cardiac CT angiography, cardiac MR, or invasive coronary angiography). Predictors of detecting any abnormality with CVI were determined using multivariable logistic regression. Results: A total of 694 patients were hospitalized, of whom 242 (34.9%) received at least one CVI study. Echocardiography was the most commonly used modality (78.9%), followed by CT angiography (38%). Patients who underwent CVI were older with a greater burden of comorbidities and worse hospital outcomes ( Table ). An abnormality was detected in only 27.3% of patients who underwent CVI, while the studies were normal in the rest. ICU admission, history of coronary artery disease, elevated high-sensitivity troponin, and hypotension during hospitalization were independent predictors of detecting an abnormality with CVI. Patients with ≥ 3 risk factors were more likely to have abnormalities with CVI compared with those with no risk factors (50% vs. 9.3%, Figure) Conclusion: Imaging was frequently used in this cohort of COVID-19 patients. However, only 1 in 4 patients was found to have significant cardiac abnormalities. If validated in future studies, the current findings support selective utilization of CVI based on presence of clinical factors associated with higher CVI yield.
Abstract 13109: Epigenetic Regulation and Function of Pleiotropic GWAS Locus <i>LRP1</i> in Human Induced Pluripotent Stem Cells Derived Contractile Smooth Muscle Cells
Authors: LU LIU, Fatima ZAHRA HAIMOUD, Joséphine HENRY, Takiy BERRANDOU, Adrien GEORGES, Nabila BOUATIA-NAJI
Journal: Circulation (2021)

Introduction: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of myocardial infarction in young and middle-aged women. A common genetic variant, rs11172113, located in LRP1 (low density lipoprotein receptor-related protein 1) first intron, was associated with several vascular diseases, including SCAD, and regulation of LRP1 expression in arterial tissues. However, the biological mechanisms through which rs11172113 influence LRP1 function in the context of non-atherosclerotic arterial lesions are not known. Hypothesis: We hypothesized that rs11172113 genotype affects LRP1 expression through specific mechanisms in contractile smooth muscle cells (SMCs), leading to alterations of their physiological function. Methods: We differentiated 4 human induced pluripotent stem cells (iPSCs) lines (2 males, 2 females) towards either contractile or synthetic SMCs using a recently optimized 24-day protocol. We performed RNA-Seq and ATAC-Seq at 6 time points during differentiation. We silenced LRP1 using siRNAs in differentiated SMCs and used CRISPR-Cas9 to induce deletions of the enhancer region containing rs11172113 or frame-shift indels in exons 2 or 5 of LRP1 in iPSCs. Results: iPSCs derived SMCs presented the expected morphology and expression of SMC markers. Transcriptomic analyses showed that contractile SMCs harbored SMC properties during late differentiation and resembled SMCs of artery tissue, whereas genes involved in cell stress were upregulated in synthetic SMCs at the end of differentiation. In particular, LRP1 expression and DNA accessibility at rs11172113 were higher in contractile SMCs. The deletion of rs11172113 enhancer region led to a decrease in the expression of LRP1 in both contractile and synthetic SMCs. LRP1 inactivation decreased the proliferation and increased the migration capacity of contractile SMCs. Detailed characterization of the influence of LRP1 on extracellular matrix maintenance and cellular contraction is ongoing. Conclusions: We confirmed rs11172113 to regulate LRP1 expression in iPSCs derived contractile SMCs. Our results support LRP1 influence on SMCs phenotype as a causal factor in the genetic susceptibility to SCAD and related vascular diseases.
Abstract 12648: Improvements In Post-operative Cardiac Surgery Arrhythmia Identification Using The Atriamp Signals
Authors: Diane Brown, Awni Al-subu, Xiao Zhang, Nick VonBergen
Journal: Circulation (2021)

Background: Following cardiac surgery, as many as 60% of patients will experience an arrhythmia. These arrhythmias are associated with increased morbidity and occasional mortality. Therefore, rapid and accurate identification is paramount to the improvement of patient outcome. Unfortunately, until now monitoring was limited by lack of timeliness or clarity. Here we evaluate the confidence and accuracy of rhythm diagnosis using the AtriAmp, a UW device that allows continuous arrhythmia monitoring. Methods: An ongoing IRB approved prospective observational study of children less than or equal to 18 years of age admitted to the PICU with atrial pacing wires following congenital heart surgery. The AtriAmp was connected to atrial pacing wires and the atrial ECG (AEG) was displayed along with a surface ECG on GE monitors. Nine different types of arrhythmias were collected over the course of the first five months of the study. A 20-question online survey was given to critical care and cardiology providers. Ten questions displayed signals from only the surface leads, the other ten showed the same arrhythmias with AtriAmp signal also displayed. Answers were evaluated for confidence and accuracy. Results: 40 providers were given the survey with 72% completing at the time of this abstract submission. Paired t-tests and mixed effects modeling were used to assess the data. The overall accuracy of diagnosis increased when using the Atriamp signals along with the surface ECG, but it was not statistically significant (p=0.07). Improvements in accuracy were most notable with atrial ectopic tachycardia (AET), Ventricular tachycardia (VT) and junctional ectopic tachycardia (JET). Provider confidence in diagnosis increased significantly when using the Atriamp signals (48%) compared to using only the surface ECG (62%) to diagnose arrhythmias (p&lt;0.001). Conclusion: Use of the AtriAmp increased provider confidence in the diagnosis of post-operative arrhythmias when compared to the same arrhythmias seen on surface electrograms. Future research among a larger sample of providers is needed to further evaluate the use of AtriAmp in arrythmia diagnosis.
Abstract 12472: Development of an <i>in vitro</i> System to Study Mechanisms of Ultrasound-Targeted Microbubble Cavitation-Mediated Blood Brain Barrier Opening
Authors: Grace E Conway, Anurag Paranjape, Xucai Chen, Flordeliza S Villanueva
Journal: Circulation (2021)

Introduction: Ultrasound-targeted microbubble cavitation ( UTMC ) is being explored as a method to transiently open the blood brain barrier ( BBB ). While UTMC-mediated BBB opening is a promising avenue for increasing drug delivery to the central nervous system, its underlying mechanisms are incompletely understood. We sought to develop an in vitro system simulating cerebral endothelial barrier function, to facilitate studies aimed at exploring mechanisms of UTMC-mediated BBB opening. Methods: We developed a transwell model with murine brain microvasculature endothelial cells (bEnd.3) and rat C6 glioma cells on opposite sides of a support membrance. Three concentrations of lipid microbubbles ( MB ) were added before applying pulsed ultrasound (1 MHz, 10 μs pulse duration, 10 ms pulse interval) at 3 peak negative pressures ( PNP ) for 20 s. Endothelial barrier function was assessed using transendothelial electrical resistance ( TEER ) and permeability using 10 kDa Texas Red dextran. Cells were stained with Hoechst (nucleus), CellMask Deep Red (cell coverage), calcein-AM (viability), and propidium iodide ( PI ; sonoporation) Differences between experimental conditions were compared using unpaired 2-tailed t-test. Significance was defined as p &lt;0.05. Results: At a given MB:cell ratio, higher PNPs increased the percent of viably sonoporated cells ( Fig 1A ), but caused increasing cell loss from the transwell (decrease in % area coverage) at PNP greater than 250kPa and MB:cell ratio higher than 3:1 ( Fig 1B ). Therefore, 250kPa ultrasound and 3:1 MB ratio were used in the permeability studies: BBB permeability increased by 15 min after UTMC as measured by TEER ( Fig 1C ) and dextran flux ( Fig 1D ), but recovered 1 hour later. Conclusions: We developed a co-culture transwell model of the BBB to simulate UTMC-induced reversible endothelial barrier hyperpermeability. This model will uniquely allow systematic investigation of mechanisms of UTMC-mediated BBB opening.
Abstract 12776: Neighborhood Walkability is Not Associated With Attaining Recommended Physical Activity in a Behavioral Weight Loss Trial Testing Remotely Delivered Feedback Messages
Authors: Jacob K Kariuki, Zhadyra Bizhanova, Susan M Sereika, Margaret B Conroy, Bambang Parmanto, Britney Beatrice, India Loar, Jessica Cheng, I Wayan Pulantara, Yuhan Wang, Maribel Cedillo, Anmol Singh, Lora E Burke
Journal: Circulation (2021)

Background: Adding feedback messages (FB) to self-monitoring (SM) can help reinforce behavior change. However, socio-environmental barriers such as limited access to parks and sidewalks (i.e., low walkability) may limit one’s ability to respond to FB focused on physical activity (PA). Hypothesis: Residents of high walkability neighborhoods receiving FB will have higher PA levels than those not receiving FB. Methods: Secondary analysis of a 12-month behavioral weight loss intervention (SMARTER trial) in which participants were randomized to either SM+FB (n=251) or SM alone (n=251) groups. The SM+FB group received a smartphone pop-up message every other day that was tailored to their PA patterns. Neighborhood walkability was assessed via Walk Score (0-100), PA via Fitbit Charge 2 tracker, and weight via Tanita scale. Key study variables included the walkability of neighborhoods (Walk Score: low [&lt;50] vs. high [≥50]), and recommended PA (moderate-to-vigorous PA (MVPA) ≥150 min/week or step count ≥7500/day). Generalized linear mixed model results are reported as adjusted odds ratios (AOR) with 95% confidence intervals (CI). Results: The sample with complete PA data (n=297) was white (87.9%), female (78.1%), well educated (82% with ≥4 years of college), and on average 48.9±13.7 years of age. Compared to high walkability neighborhoods, low walkability neighborhoods had a higher proportion of the sample who were non-white (18.1% vs 8.3%, p=.011), &lt;45 years of age (45.7% vs 31.5%, p=.013), and with household income &lt;$60,000 (p&lt;.0001) at baseline. After adjusting for these baseline differences and exercise self-efficacy, on average neighborhood walkability did not moderate the effect of FB on the attainment of the recommended MVPA (AOR=1.48, 95% CI: 0.72 - 3.06) or step count (AOR=1.05, 95% CI: 0.48 - 2.29) goal at 12 months. Furthermore, there were no significant treatment or time main effects or interactions observed (p≥0.05), suggesting that there was no significant change in PA over 12 months for both treatment groups. Conclusion: Our findings suggest that FB and neighborhood walkability did not have significant impact on attaining PA goals in the SMARTER weight loss trial. More studies are needed to replicate our work in a more diverse sample.
Abstract 12658: Does Cell-Free DNA Rise With a Higher MFI Titer of DSA?
Authors: Olayiwola Babalola, Jignesh Patel, Michelle M Kittleson, Nikhil Patel, Tahli Singer-Englar, Seong Kyu Kim, Lawrence Czer, Jon A Kobashigawa
Journal: Circulation (2021)

Introduction: The use of donor-derived cell-free DNA (dd-cfDNA) has been demonstrated to detect heart transplant rejection as the donor has different DNA from the recipient. dd-cfDNA has also been correlated to the detection of donor-specific antibodies (DSA). It is believed that these DSA do cause injury to the donor heart, thus exposing the donor DNA to the recipient’s bloodstream. It is not known whether the degree or binding capacity of the dd-cfDNA correlates to the binding intensity of the DSA, characterized by mean fluorescence intensity (MFI). Methods: Between 2017 and 2020, we assessed 32 heart transplant patients who were sensitized and had a dd-cfDNA level drawn. Positive dd-cfDNA was defined as ≥0.25% and was then correlated to MFI binding of the DSA categorized as weak binding (MFI 2500-5000), moderate binding (MFI 5000-10000), and strong binding (MFI &gt;10000). 62 dd-cfDNA and associated HLA blood draws were used for this study. The Luminex Single Antigen Neat test was used to determine MFI binding of DSAs. Results: Positive dd-cfDNA did not correlate to the presence of DSA. However, there was a trend for positive dd-cfDNA correlating to DSA with higher MFI levels (see table). Conclusion: dd-cfDNA might signal the presence of DSA with higher MFI levels. This might suggest that these higher levels of DSA might be involved in injury to the donor heart. Larger number of patients will be needed to confirm this finding.
A First-in-Human Phase 1 Study of a Tumor-Directed RNA-Interference Drug against HIF2α in Patients with Advanced Clear Cell Renal Cell Carcinoma
Authors: James Brugarolas, Gregory Obara, Kathryn E. Beckermann, Brian Rini, Elaine T. Lam, James Hamilton, Thomas Schluep, Min Yi, So Wong, Zhongping Lily Mao, Erick Gamelin, Nizar M. Tannir
Journal: Clinical Cancer Research (2024)

ARO-HIF2 is an siRNA drug designed to selectively target hypoxia-inducible factor-2α (HIF2α) interrupting downstream pro-oncogenic signaling in clear cell renal cell carcinoma (ccRCC). The aims of this Phase 1 study (AROHIF21001) were to evaluate safety, tolerability, pharmacokinetics, and establish a recommended Phase 2 dose.