tbuckley/cabot-search huggingface dataset:
Abstract 16740: Foxo1-Activated Cd36 Transcription Switches Arteriolar Differentiation of Endothelial Cells
Authors: Nicholas Barnekow, Rong Yuan, Patrick Moran, Bin Ren
Journal: Circulation (2018)

Transcription factor FoxO1 is the most physiologically critical regulator of endothelial stability, essential for vascular homeostasis via its modulation of downstream genes important for angiogenesis and vascular maturation. FoxO1 has been shown to promote expression of vascular endothelial growth factor. Unfortunately, the mechanisms by which FoxO1 specify the different cellular responses and gene targets in endothelial cells (ECs) have not been fully elucidated. The CD36 gene contains FoxO1 binding sites that control its transcription. CD36 is an angiogenic regulator and fatty acid receptor. The LPA/PKD-1 signaling inhibits CD36 transcriptional expression by regulating FoxO1 activities and chromatin remodeling, and mediates transcriptional reprogramming of microvascular ECs (MVECs) for proarteriogenic responses. We thus hypothesize that FoxO1 initiates an arteriolar switch that regulates the development of the microvasculature via regulation of CD36 transcription. To test this hypothesis, we transduced FoxO1 into late passages of primary human MVECs by lentiviral infection and observed that forced expression of FoxO1 significantly increased CD36 mRNA levels by qPCR. FoxO1-induced CD36 expression was attenuated by co-transduction of FCoR, a specific FoxO1 co-repressor. LPA exposure also inhibited FoxO1-induced mRNA expression of CD36. Intriguingly, FoxO1 transduction stimulated the expression of ephrin B2 and Hey2 in primary HUVECs. Our studies thus suggest that FoxO1 does indeed initiate an MVEC arteriolar switch likely via promoting increases in CD36-mediated fatty acid metabolism and VEGF signaling, thus enhancing functional angiogenesis. We have created EC-specific cd36 null TRAP mice, in which not only is the EC’s CD36 gene deleted, but the EC’s ribosomes are also genetically tagged with GFP, which facilitates isolation of ribosomal mRNA directly in vivo. Further studies are being undertaken to understand the means by which FoxO1 functions at the transcriptional level as a switch to trigger arteriolar differentiation of MVECs.
Abstract 13862: Appropriate Therapy in the Subcutaneous and Transvenous ICD: A Secondary Analysis of the PRAETORIAN Trial
Authors: Reinoud Knops, Willeke van der Stuijt, Peter Paul Delnoy, Lucas V Boersma, Juergen Kuschyk, Mikhael F El-Chami, Hendrik Bonnemeier, Elijah R Behr, Tom F Brouwer, Stefan Kaab, Suneet Mittal, Anne-Floor B Quast, Lonneke Smeding, Anouk De Weger, Nick Bijsterveld, Sergio Richter, Marc Brouwer, Joris R de Groot, Kirsten Kooiman, Pier Lambiase, Petr Neuzil, Kevin Vernooy, Marco Alings, Tim Betts, Frank Bracke, Martin C Burke, Jonas S de Jong, David Wright, Ward P Jansen, Zachary I Whinnet, Peter Nordbeck, Michael Knaut, Berit Thornvig Philbert, Jurren M Van Opstal, Alexandru Chicos, Cornelis Allaart, A.E. Borger van der Burg, Jude f Clancy, Jose Dizon, Marc Miller, Dmitry Nemirovsky, Ralf Surber, Gaurav A Upadhyay, Raul Weiss, Jan G Tijssen, Louise R Olde Nordkamp, Arthur A Wilde
Journal: Circulation (2021)

Introduction: The randomized PRAETORIAN trial demonstrated non-inferiority of the subcutaneous implantable cardioverter-defibrillator (S-ICD) compared to the transvenous ICD (TV-ICD) with regard to inappropriate shocks and complications. Due to its extrathoracic position, the S-ICD lacks the possibility to provide antitachycardia pacing (ATP) which might result in more appropriate shock therapy. In this pre-specified secondary analysis, we aim to compare first occurrence of appropriate therapy in the S-ICD and TV-ICD. Methods: The PRAETORIAN trial is an international, multicenter, randomized trial (NCT01296022) in which 849 patients with a class I or IIa indication for ICD therapy and without the need for pacing were randomized in a 1:1 ratio to receive either an S-ICD (n = 426) or a TV-ICD (n = 423). Analyses were performed in the modified intention-to-treat population, which included patients according to the group to which they had been randomly assigned regardless of the device they received, but excluded patients who did not receive any ICD. Results: At a median follow-up of 49.1 months, 164 patients received appropriate therapy, of whom 86 in the S-ICD group and 78 in the TV-ICD group (48-month Kaplan-Meier estimated cumulative incidence 19.4% and 17.5%, respectively; hazard ratio 1.12; 95%CI, 0.83 to 1.53; p=0.45). In 83 patients (97%) in the S-ICD group the first arrhythmia was treated with a shock and in 3 patients (3%) with ATP. In 25 patients (32%) in the TV-ICD group the first arrhythmia was treated with a shock, in 31 patients (40%) solely with ATP and in 22 patients (28%) with ATP followed by a shock. Conclusions: In this secondary analysis of the PRAETORIAN trial, we found no statistical difference in first occurrence of appropriate therapy in the S-ICD group and TV-ICD group. Due to ATP, patients were less often treated with shocks in the TV-ICD group. A further analysis of all appropriate therapy in the PRAETORIAN trial could reveal the true benefit of ATP.
Abstract 16853: Peer Relationships of Children With Critical Congenital Heart Defects
Authors: Kathryn Vannatta, Emeric Quade, Jennifer Kelleher, May Ling Mah, Jamie L Jackson
Journal: Circulation (2018)

Introduction: Neurodevelopmental and executive functioning deficits place survivors of critical congenital heart defects (CHD) at risk for poor adaptive outcomes. Peer relationships play a critical role in development, but have received little scientific attention in CHD. Brief, general ratings of ‘social problems’ by children and parents inconsistently identify difficulties, but lack the rigor and specificity of school-based sociometric methods that identify impairment in other children with acquired brain injury. Our objective was to compare the peer interactions and social adjustment of CHD survivors to healthy control classmates (CC) using school-based methods. Hypothesis: CHD survivors would be higher in victimization, isolation, and disruptive behavior, lower in peer acceptance and mutual friendships than CC. Method: Data were collected in the classrooms of 34 children (9-12 yoa, 68% male) with critical CHD (dTGA, TOF, HLH/SVA, coarctation of aorta). One CC, matched for gender and age, was identified per class. Classmates with parental consent (N=723, 89% available) rated each other using the Extended Class Play (ECP; nominations of social and nonsocial attributes), Peer Acceptance Ratings (1-5, “like a lot” to “don’t like a lot”), and named Three Best Friends. Self-ratings were made on the PROMIS Peer Relationships scale. Teachers completed the Teacher Report Form (TRF). Independent two-tail t-tests compared the CHD and CC groups. Results: CHD survivors were higher in Victimization ( d = 0.76, p = 003) and Isolation ( d = 0.46, p = .063) but not Aggressive-disruptive behavior ( d = 0.09, p = .674) on the ECP. CHD survivors had fewer mutual friends ( d = -0.62, p = .015) but not lower Peer Acceptance ( d = 0.24, p = 325). The ECP found that CHD survivors were seen as doing worse academically ( d = -0.61, p = .014) and athletically ( d = -0.99, p = .000) than CC, but not seen as more “ill” (tired, sick, or absent) ( d = -0.30, p = .215). Differences on the PROMIS were not found. TRF for the CHD group suggested Social Problems ( M T = 55.6) and Academic deficits ( M T = 45.4) but not Internalizing ( M T = 51.4) or Externalizing ( M T = 51.2) behavior. Conclusion: Peer relations of children with critical CHD are a concern, may signal further developmental risk, and warrant more study.
Abstract 16707: Human Embryonic Stem Cell-Derived Cardiomyocytes Are Safe and Improve Infarct Size and Cardiac Function in a Porcine Model of Myocardial Infarction
Authors: Monisha N Banerjee, Luiza Bagno, Victoria Florea, Angela C Rieger, Raul Mitrani, Jose Rodriguez, Marcos Rosado, Jennifer Sanchez, Sohil S Desai, Alexandra L Alvarez, Ren Chase, Aisha Khan, Wayne Balkan, Evgenios Neofytou, Joseph C Wu, Joshua M Hare
Journal: Circulation (2018)

Introduction: Stem cell therapy is an emerging means of stimulating cardiac repair after myocardial infarction (MI). Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) are a novel therapeutic option, with the potential for cell derived remuscularization. This study assessed the safety and efficacy of these cells, is the first to test these cells in a porcine model of MI, and used electrophysiologic (EPS) testing to evaluate potential arrhythmogenicity. Methods: Yucatan swine underwent a left anterior descending coronary artery ischemia/reperfusion protocol to form an MI. Four weeks later, either placebo (n=3) or 3 x 10 8 hESC-CMs were delivered via transendocardial stem cell injection (TESI) (n=4). All animals received immunosuppression for 2 weeks following TESI. Three uninfarcted animals received cells. Cardiac function and LV chamber volumes were measured using pressure volume catheterization and cardiac MRI at 4, 8 and 12 weeks post-TESI. Inducibility of ventricular tachycardia (VT) was tested at 4 and 12 weeks post-TESI by programmed ventricular stimulation via a catheter in the RV apex. Histology of heart tissue and organs was evaluated. Results: Twelve weeks post-TESI, scar size (scar mass as a % of total LV mass) was reduced in the cell treated group by -2.33±0.03% (p=0.034), a 12.69±1.87% reduction from pre-TESI. Scar size remained constant in the placebo group. The rise in end diastolic volume at 12 weeks in the placebo group (15.6±7.35 mL; p=0.032) was attenuated in the cell treated group (10.39±6.36mL; p=0.17). By 12 weeks post-TESI, Ees (slope of ESPVR) increased by 0.51±0.15 mmHg/mL (p=0.045) and in the cell treated group but was unchanged in placebo (-0.09±0.85 mmHg/mL; p= 0.92). Following TESI, only 1 animal from each group had inducible VT. No animals had spontaneous VT as measured by an implantable loop recorder. Cardiac function and structure of uninfarcted animals did not change over the study, and none of these animals had inducible VT. Histology did not reveal ectopic tissue formation or signs of rejection. Conclusion: TESI of hESC in a porcine MI model is safe, does not increase the risk of either spontaneous or inducible arrhythmias compared to placebo, reduces scar size and remodeling and improves cardiac contractility as measured by Ees. Translation to clinical studies is warranted.
Abstract 16859: Prevalence of Mechanical Complications and Associated Mortality in Patients With ST-Segment Elevation Myocardial Infarction (STEMI) Treated With Thrombolysis (TT) Compared to Primary-PCI (P-PCI): A Nationwide Study Using National Inpatient Sample (NIS)
Authors: Rishi Shrivastav, Prateeth Pati, Stuthi Perimbeti, Jacqueline Tamis-holland
Journal: Circulation (2018)

Introduction: Papillary muscle rupture (PMR), ventricular septal rupture (VSR) and cardiac free wall rupture (FWR), are dreaded complications of STEMI and are associated with increased morbidity and mortality. In multiple previous small to intermediate sized studies, TT as compared to P-PCI was associated with an increase in these mechanical complications. However, large scale observational studies are lacking. Methods: Adult admissions with a primary diagnosis of STEMI between 1999 and 2014 were extracted from the NIS using the ICD-9 code 410.x, except 410.7x (NSTEMI). ICD-9-CM procedure codes 36.01 to 36.07, 36.09, 00.66 and 99.10 were used to stratify the extracted data into patients who underwent P-PCI (Time-to procedure function was used to filter PCI performed within first 24 hours of presentation) and those treated with TT. The incidence of PMR (ICD-9 Code 429.6) and VSR (ICD-9 Code 429.71), VSR (ICD-9 Code 429.71) and FWR (ICD-9 Code 429.79) within 30 days of hospitalization were compared between these two groups. We performed multivariate analysis using Cox Proportional Hazard Regression to control for confounders and determine the hazard of all three complications in patients who had undergone P-PCI vs TT, and the relative mortality of these complications by reperfusion strategy. Results: Of the weighted 2,534,019 admissions for STEMIs, 1,335,711 (52.71%) underwent P-PCI whereas 125,009 (4.93%) were treated with TT. Among these, 748 (0.02%) developed PMR, 3122 (0.12%) developed VSR, and 4850 (0.19%) developed FWR. The adjusted hazard for a complication according to reperfusion modality, and the mortality by treatment are depicted below in Table 1. Conclusions: As compared with P-PCI, patient who were treated with TT had a higher risk of mechanical complications, including PMR, VSR and FWR, and a higher mortality associated with each of these complications.
Abstract 16777: Augmentation of Spinal Cord Pre-Collateralization to Prevent Paraplegia After Aortic Surgery
Authors: Mohamed Eldeiry, Patrick Kohtz, Allison Halpern, Joseph C Cleveland, David Fullerton, T. B Reece, Muhammad Aftab
Journal: Circulation (2018)

Introduction: Spinal cord ischemia from complex aortic surgery can lead to paraplegia. Spinal cord is supplied by a rich collateral network of segmental arteries. Emerging data demonstrate that patients with staged aortic repairs suffer fewer spinal cord injuries than those with a single operation. Hypothesis: Paraplegia can be induced in a swine model by ligation of segmental spinal arteries. Induction of spinal cord pre-collateralization by staging the spinal segmental arterial coverage can minimize the risk of paraplegia. Methods: Twenty-four female Yorkshire pigs (50-70kg) underwent abdominal exposure of the aorta. Lumbar aortic group underwent ligation of the lumbar segmental arteries (5-7) and median sacral trunk. Thoracic aortic coverage consisted of stent graft placement from the left subclavian to celiac artery. Full coverage un-staged group underwent a simultaneous lumbar and thoracic coverage. Similar procedure was performed one week apart in staged full coverage group. Fluorescent microspheres were injected to evaluate regional spinal cord flow distribution. Protein expression in the spinal cord was analyzed using Western Blot. Results: Reproducible paresis was demonstrated in full coverage animals. This was associated with decreased viable spinal cord neurons. In the staged full coverage, complete motor recovery occurred within 24h of the second stage. Neurologic recovery was associated with higher levels of Neuropilin-1. Regional blood flow was quantified by microsphere density in various segments of spinal cord using laser confocal microscopy. Conclusions: A reproducible model of spinal cord injury can be carried out in swine by disrupting spinal cord segmental blood flow. This injury can be ameliorated by partial or staged coverage of the segmental arteries. Induction of regional spinal cord pre-collateralization can be demonstrated using fluorescent microspheres. This may be dependent on Neuropilin-1 expression in the tissue.
Abstract 16889: A Novel Single-Chain Enzyme Complex With Triple-Catalytic Activities Controlling the Metabolism of Arachidonic Acid Toward the Anti-Bleeding Thromboxane A <sub>2</sub> Biosynthesis
Authors: Yan Li, Qunying Li, Qinglan Ling, Chang Chen, Ke-He Ruan
Journal: Circulation (2018)

Background: One of the most common bleeding emergencies in interventional cardiology and surgical procedures is caused by the use of nonsteroidal anti-inflammatory drugs (NSAIDs), which strongly inhibit enzymatic biosynthesis of thromboxane A 2 (TXA 2 ). Objectives: We want to investigate an effective approach to overcome such NSAIDs-mediated severe bleeding emergencies. Methods: In this study, according to structure-based enzymatic design, we have created a novel single-chain hybrid enzyme complex (SCHEC), COX-1-10-aa-TXAS, by linking the C-terminus of cyclooxygenase-1 (COX-1) to the N-terminus of the TXA 2 synthase (TXAS) through a 10-residue amino acid linker. Results and conclusions: The recombinant COX-1-10aa-TXAS could not only maintain full activities of the parent enzymes, but also more effectively pass COX-1-derived intermediate prostaglandin (PG) H 2 to the active site of TXAS. This results in rapidly redirecting the cellular metabolism of arachidonic acid (AA) toward TXA 2 ; meanwhile, reducing PGH 2 being passed to other prostanoid synthases, such as prostaglandin-I and prostaglandin-E synthases (PGIS, PGES), which compete with TXAS to isomerize PGH 2 into bleeding mediators, prostacyclin (PGI 2 ) and prostaglandin E 2 (PGE 2 ). With these multiple effects, the novel COX-1-10aa-TXAS demonstrated a strong anti-bleeding ability to treat normal bleeding, aspirin-resulted TXA 2 -deficient bleeding, as well as PGI 2 -mediated bleeding in vitro and in vivo . Therefore, this novel SCHEC has a great potential to be developed into a biological anti-bleeding reagent to deal with acute and severe bleeding situations.
Abstract 16649: Recovery of Myocardial Perfusion After Percutaneous Coronary Intervention of Chronic Total Occlusions is Comparable to Non-Occlusive Lesions
Authors: Stefan P Schumacher, Roel S Driessen, Wijnand J Stuijfzand, Pieter G Raijmakers, Ibrahim Danad, Jo Dens, James C Spratt, Colm G Hanratty, Simon J Walsh, Ronald Boellaard, Albert C van Rossum, Maksymilian P Opolski, Alexander Nap, Paul Knaapen
Journal: Circulation (2018)

Background: The benefits of chronic coronary total occlusion (CTO) percutaneous coronary intervention (PCI) are being questioned. The aim of this study was to assess the effects of CTO PCI on absolute myocardial perfusion, as compared to PCI of hemodynamically significant non-occlusive lesions. Methods: Consecutive patients with a preserved left ventricular ejection fraction (≥50%) and a CTO or non-CTO lesion, in whom [ 15 O]H 2 O positron emission tomography was performed prior and after successful PCI, were included. Change in quantitative (hyperemic) myocardial blood flow (MBF), coronary flow reserve (CFR) and perfusion defect size (in myocardial segments) were compared between CTOs and non-occlusive lesions. Results: Ninety-two patients with a CTO and 31 patients with a non-occlusive lesion were included. CTOs induced larger perfusion defect sizes (4.51±1.69 vs. 3.23±2.38 segments, p&lt;0.01) with lower hyperemic MBF (1.30±0.37 vs. 1.58±0.62 mL·min -1 ·g -1 , p&lt;0.01) and similarly impaired CFR (1.66±0.75 vs. 1.89±0.77, p=0.17) compared with non-occlusive lesions. After PCI both hyperemic MBF and CFR increased similarly between groups (p=0.57 and p=0.35) to normal ranges with higher hyperemic MBF values in non-CTO compared to CTO (2.89±0.94 vs. 2.48±0.73 mL·min -1 ·g -1 , p=0.03). Perfusion defect sizes decreased similarly after CTO PCI and non-CTO PCI (p=0.14), leading to small residual defect sizes in both groups (1.15±1.44 vs. 0.61±1.45 segments, p=0.054). Conclusions: Percutaneous revascularization of CTOs improves absolute myocardial perfusion similarly to PCI of hemodynamically significant non-occlusive lesions, leading to satisfying results. Myocardial perfusion findings are less favorable in patients with a CTO before and after PCI, suggesting a more advanced stage of coronary artery disease.
Abstract 13768: Gender Differences in ICD-Related Complications in the PRAETORIAN Trial
Authors: Reinoud Knops, Louise R Olde Nordkamp, Peter Paul H Delnoy, Lucas V Boersma, Juergen Kuschyk, Mikhael F El-Chami, Suneet Mittal, Lonneke Smeding, Willeke Van Der Stuijt, Anouk De Weger, Marc Brouwer, Kevin Vernooy, Tim Betts, David Wright, Arthur A Wilde
Journal: Circulation (2021)

Introduction: The PRAETORIAN trial has investigated the difference in complications between the subcutaneous implantable cardioverter-defibrillator (S-ICD) and the transvenous ICD (TV-ICD). Retrospective studies suggest that women experience more ICD-related complications, specifically related to the lead, than men. We aimed to evaluate this gender difference as a subanalysis of the PRAETORIAN trial. Methods: The PRAETORIAN trial (NCT01296022) is an international multicenter randomized trial. Patients with a class I or IIa ICD indication with no need for pacing therapy were randomized 1:1 to receive either an S-ICD or a TV-ICD and followed for a median of 49.1 months. ICD-related complications included all complications related to the lead or generator that led to medical or surgical intervention. Lead-related complications were defined as complications directly caused by insertion or chronic placement of the ICD lead, or leading to extraction, repositioning or replacement of the ICD lead. Results: A total of 849 patients were included, of whom 167 (19.7%) were female. ICD-related complications occurred in 6/89 women in the S-ICD group and 11/78 women in the TV-ICD group (HR 0.46, 95%CI 0.17-1.25). In men, 25/337 in the S-ICD group and 33/345 in the TV-ICD group had an ICD-related complication (HR 0.77, 95%CI 0.46-1.29). Kaplan Meier curves of both genders are shown in the figure. In Cox regression analysis, women had a higher risk of lead-related complications (HR 2.1, 95%CI 1.04-4.16, p = 0.04). Conclusions: Our prospective data show a more prominent trend in women to experience more ICD-related complications with the TV-ICD. This difference may be due to a significantly higher risk of lead-related complications in women. However, numbers are low and more research is needed to gain more insight into the gender-specific risks and benefits of ICD therapy.
Abstract 13967: Macrophages Store Low Density Lipoprotein-Delivered Microbial Small RNAs in Lipid Droplets
Authors: Mark Castleberry, Chase A Raby, Ryan M Allen, Macrae F Linton, Kasey C Vickers
Journal: Circulation (2021)

Low-density lipoproteins (LDL) are causal factors in atherosclerosis. Inflammation is a driving force for both atherogenesis and advanced lesion progression. LDL stimulates inflammation in the lesion; however, the mechanism by which LDL activates macrophages and promotes atherosclerosis inflammation remains to be fully defined. Recently, we reported that LDL is enriched with microbial small RNAs (msRNA) derived from bacteria in the microbiome and environment. Most importantly, we showed that LDL-delivered msRNA activated toll-like receptor 8 (TLR8) in recipient macrophages and inhibition of this pathway reduced atherosclerosis. Nevertheless, the processes by which macrophages store and catabolize exogenous LDL-delivered msRNA are unknown. We hypothesize that LDL-delivered msRNA is stored in lipid droplets of macrophages . LDL was found to transport approximately 37μg of total RNA per mg of protein, and macrophages were found to take up LDL-msRNAs through an LDL receptor-independent process (pinocytosis). Confocal microscopy and RNA quantification of purified organelles indicate that macrophage lipid droplets (LD) contain RNA and that LDL treatment increases LD-associated RNA. Macrophages transfected with msRNA fluorescence-labeled (msRNA-Cy5) contain signal in both the organic and aqueous phases after Bligh-Dyer lipid extraction, indicating a potential acyl esterification of the msRNA. To evaluate LDL-msRNA delivery to macrophages in vitro , cells were treated with reconstituted LDL (rLDL) loaded with msRNA-Cy5. Utilizing confocal microscopy, rLDL was found to deliver msRNA-Cy5 to macrophages. Ongoing research aims to determine the subcellular processing of LDL-delivered msRNA in macrophages; however, results from microscopy studies support that the endo-lysosome and LD compartments are involved. Moreover, rLDL provides a powerful tool for the study of LDL-msRNA delivery to macrophages by reducing the heterogeneity of lipid cargo that may confound analyses, while enabling the enrichment of specified RNA cargo for cellular delivery. These results support that i) LDL can transfer pro-inflammatory msRNA to macrophages, ii) LDL treatment increases LD-associated RNA, and iii) RNA can be isolated by organic lipid extraction.