tbuckley/cabot-search huggingface dataset:
Abstract 17339: Deficiency of Sirtuin 3 in Endothelium Reduces Endothelial-Dependent Relaxation and Impairs Myogenic Response in Coronary and Middle Cerebral Arteries of Mice
Authors: Jin Zhang, Jian-Xiong Chen, Heng Zeng
Journal: Circulation (2023)

Previously, we demonstrated that specific knockout of Sirtuin 3 (Sirt3) in endothelial cells (ECs) impairs coronary flow reserve and diastolic function in mice. So far, the role of endothelial Sirt3 in the coronary arteries remains unexplored. Male and female Sirt3 EC-knockout (Sirt3 EC KO) mice and Sirt3-Lox-P mice at 14-15-month old age were used to assess the roles of endothelial Sirt3 on the microvascular functions. Mouse coronary arteries (CA) and middle cerebral arteries (MCA) were isolated and mounted in a myograph system. Myogenic response was evaluated by increasing perfusion pressure. Ach (Acetylcholine, 1nM-100μM)-induced EC-dependent vasodilation and NO donor SNP (sodium nitroprusside,1nM-10μM)-induced EC-independent vasodilation were examined. Myogenic response was significantly impaired in both CA and MCA of male and female Sirt3 ECKO mice, as evidenced by a lack of constriction while raising perfusion pressure from 10 mmHg to 150 mmHg. Both wall thickness and cross-sectional area were increased in CA and MCA of male and female Sirt3 EC KO mice. The wall to lumen ratio was increased in MCA, but did not change in CA of Sirt3 EC KO mice, compared to SIRT3-Lox-p mice. The wall tension and myogenic tone were significantly decreased in CA and MCA of both male and female Sirt3 EC KO mice. The vessel stiffness was not significantly different between SIRT3EC KO mice and SIRT3-Lox-p mice. In CA, the Ach-induced EC-dependent vasodilation was reduced in both male and female Sirt3 ECKO mice. Intriguingly, the SNP-induced EC-independent vasodilation was significantly reduced in female Sirt3 ECKO mice, but did not observed in male Sirt3 ECKO mice. In MCA, the Ach-induced EC-dependent vasodilation was only impaired in male Sirt3 ECKO mice, but was not observed in female Sirt3 ECKO mice. Whereas, the SNP-induced EC-independent vasodilation was impaired in both male and female Sirt3 EC KO mice as compared to their control SIRT3-Lox-p mice. These data revealed a sex and organ specific role of Sirt3 in EC, i.e. there is more EC-independent dysfunction in female CA, but greater impairment of EC-dependent relaxation in male MCA. Our study demonstrates the critical role of endothelial Sirt3 in maintaining microvascular function in coronary and cerebral arteries.
Abstract 19047: Comparison of Drug-Eluting Stent With Bare-Metal Stent Implantation in Femoropopliteal Artery Disease: A Systematic Review and Meta-Analysis
Authors: Zainali Chunawala, Aman Goyal, Vikash Jaiswal, Issam Moussa, Atif Hassan, Kirtipal Bhatia, Arman Qamar
Journal: Circulation (2023)

Introduction: Trials comparing drug eluting stent (DES) versus bare metal stents (BMS) in patients undergoing endovascular therapy for femoropopliteal artery disease (FPAD) have shown variable results. Data indicating clear patency benefit of DES has not been definitively demonstrated. Methods: Medline, Embase, &amp; Cochrane Central databases were searched to identify previous studies comparing efficacy of drug eluting stent versus bare metal stents in treatment of FPAD. The primary outcome of interest was risk of restenosis. Secondary outcomes included all-cause mortality, stent fracture, target vessel revascularization and primary patency. Odds ratios (OR) were pooled using a random-effect model while heterogeneity among studies was assessed using the Higgins I 2 value. Results: A total of 7 studies (5 RCTs and 2 retrospective cohorts) with 1786 patients were included in our analyses. The risk of target vessel revascularization was significantly reduced with the use of DES (OR: 0.69, 95% CI: 0.49-0.98, I 2 = 0) as compared with BMS. However, there was no significant difference observed in risk of restenosis (OR: 0.83, 95% CI 0.59-1.16), primary patency (OR: 1.09, 95% CI 0.91-1.29), stent fracture (OR: 0.84, 95% CI 0.27-2.67) and all-cause mortality (OR: 1.65, 95% CI 0.71-3.85). Conclusion: The risk of target vessel revascularization was significantly reduced with the use of DES implantation in patients with FPAD. However, DES does not seem to provide much benefit in terms of clinical outcomes. Further larger RCTs are needed to provide more evidence in the comparison between DES and BMS for FPAD.
Abstract 19043: Global Surgical Outcomes for Congenital Heart Disease: A Look at Databases
Authors: Adriana M Modrego, Babar Hasan, Patricia Garcia-Canadilla, Mishaal Ather, Corey Snyder, Kathy J Jenkins, Kimberlee Gauvreau, Ram Kumar Subramanyan, Zdzislaw Tobota, Nestor Sandoval, Bistra Zheleva, Georgios Sarris, Joan Sanchez-De-Toledo, John E Mayer, Kenneth Shaffer, Devyani Chowdhury
Journal: Circulation (2023)

Introduction: Congenital heart diseases (CHDs) are the most common congenital anomalies, and almost one-third of patients require an intervention in the neonatal period or first year of life. Unlike low- and middle-income countries (LMICs), the survival of patients with CHD in high income countries is over 90%. The aim of this study was to compare the different congenital heart surgery (CHS) outcomes databases and analyze geographical variations. Methods: We analyzed the STS-CHSD (North America), the ECHSA, the ECHSA (Only Europe), and the IQIC for CHD (LMICs) databases between 2016 and 2019. All databases include aggregated data consisting of the 10-benchmark CHS and CHS grouped by mortality risk categories. For each database and condition, we extracted the number of participants, number of operations, postoperative length of stay (LOS), and mortality, comparing regional findings. Results: Compared to ECHSA, STS-CHSD database had more operations (32066 vs 14327) despite lower participant numbers. 50% of surgeries in LMIC were VSD closure, while the STS database reported the largest number of complex interventions. Mortality was lowest in North America for all the operations. LMICs had the shortest LOS, while North America had the longest LOS for almost all the benchmark operations. (Figure) However, the relevance of LOS is limited due to lack of data on demographic findings like age at surgery and gestation. Conclusions: The analysis of these three databases, accounting for limitations of aggregate data, highlight the differences in the CHS outcomes among world regions, reflecting the geographical difference of the population. Furthermore, it emphasizes the critical need to develop collaborative databases to improve global outcomes.
Abstract 17363: Loss of Skeletal Muscle <i>Bmal1</i> Impairs Limb Perfusion and Muscle Regeneration in a Mouse Model of Peripheral Arterial Disease
Authors: Pei Zhu, Calvin Chao, Adam W Steffeck, Caitlyn Dang, Bin Jiang, Clara Peek
Journal: Circulation (2023)

Introduction: Peripheral arterial disease (PAD) is a growing pathologic condition worldwide and leads to severe myopathy. Traditional risk factors for PAD, including diabetes, smoking, and advanced age, are associated with disrupted circadian clock function. However, the contribution of circadian disruption to PAD remains poorly understood. Hypothesis: This study aims to investigate the role of skeletal muscle clock in the severity of PAD. Methods: We performed femoral artery ligation (FAL) surgery in male adult-life inducible skeletal muscle-specific Bmal1 knockout ( Bmal1 musc ) (n = 6) and control mice (n = 5). We measured limb perfusion with laser doppler imaging weekly and assessed post-surgical angiogenesis with CD31/αSMA co-immunostaining and muscle recovery with hematoxylin and eosin (H&amp;E) staining and Laminin immunohistochemistry at 30 days post-surgery. We also performed RNA-sequencing, qPCR, and Western blotting assays to characterize the differentially expressed genes in both ligated and non-ligated hindlimb muscles. Results: Adult-life deletion of skeletal muscle Bmal1 reduced reperfusion recovery, with an average rate of only 50% by 22 days post-surgery in Bmal1 musc mice compared to approximately 80% in control mice. HIF1α target genes including the pro-angiogenic factor Vegfα were significantly downregulated in Bmal1 musc mice. Conversely, genes enriched in the anti-angiogenic TGF-β signaling pathways were up-regulated in Bmal1 musc mice. Myostatin, a myokine that inhibits muscle growth, was downregulated in Bmal1 musc muscles. H&amp;E staining and Laminin immunohistochemistry revealed significantly less but enlarged newly formed myofibers in the tibialis anterior muscle in Bmal1 musc mice. Conclusions: Skeletal muscle BMAL1 plays a critical role in determining the severity of ischemic muscle injury in a mouse model of PAD. Circadian dysfunction impairs hindlimb ischemia reperfusion, decreases the number of newly formed myofibers, and promotes the formation of enlarged regenerating myofibers, which is however previously reported to be associated with compromised muscle force production. Restore muscle circadian function could be a promising strategy to ameliorate myopathic severity in PAD patients.
Abstract 17366: Effects of Acute Maternal Supplemental Oxygen on the Fetal Circulation in Transposition of the Great Arteries
Authors: Liqun Sun, Fu-Tsuen Lee, Adrienn Szabo, Mika Saito, Nathaniel Barber, Joshua van Ameron, Sharon Portnoy, Davide Marini, Brahmdeep Saini, Diana Balmer-Minnes, Vitor Guerra, Varsha Thakur, Christopher Macgowan, Steven Miller, Edgar T Jaeggi, Mike Seed
Journal: Circulation (2023)

Introduction: The presence of a restrictive atrial septum in the setting of transposition of the great arteries (TGA) is associated with a high risk of hypoxic ischemic injury upon transition to postnatal circulation. Fetal cardiovascular magnetic resonance (CMR) measures of vessel flow and oxygen saturation provide a unique opportunity to study fetal TGA hemodynamics at baseline and during acute maternal hyperoxygenation. Methods: Thirty-one pregnant mothers with fetuses diagnosed with TGA and an intact ventricular septum (n=23) or small ventricular septal defect (n=8) were recruited and underwent fetal CMR in room air and during administration of 10L/min of oxygen by face mask for up to 45 minutes. Blood flow and oxygen saturations were measured in the major fetal vessels using cine phase contrast MRI and MR relaxometry at baseline and during hyperoxygenation. Results: Two patients exhibited severe restriction at the atrial septum, one undergoing fetal atrial septostomy at 37 weeks and one requiring cannulation onto ECMO shortly after birth. Both revealed reversal of the usual relationship of oxygen saturation between the aorta and the main pulmonary artery at baseline and during hyperoxygenation, i.e. in TGA with restrictive atrial septum the saturations are higher in the aorta than pulmonary. Acute maternal supplemental oxygen was associated with increased pulmonary blood flow (p=0.008) and reduced foramen ovale (p=0.01) and ductus arteriosus shunting (p=0.01). There were no significant changes in umbilical vein, descending aorta and superior vena cava flow. Fetal oxygen saturations increased throughout fetal circulation (p&lt;0.0001) with an associated increase in fetal oxygen delivery (p=0.007), but no increase in fetal cerebral oxygen delivery (p=0.58). Conclusions: This study characterized the effects of acute maternal supplemental oxygen on the fetal circulation in patients with TGA and confirmed the redistribution of flow toward the fetal pulmonary circulation. We observed higher oxygen saturations in the aorta than main pulmonary artery in fetuses with TGA with an intact or highly restrictive atrial septal communication. This finding could be helpful in selecting patients for prenatal or emergency neonatal balloon atrial septostomy.
Abstract 17329: Histone Modifications Regulate Hypertrophy Pathways in Obstructive Hypertrophic Cardiomyopathy
Authors: Ramin Garmany, Surendra Dasari, Johan M Bos, David J Tester, Cristobal Dos Remedios, Joseph J Maleszewski, Keith Robertson, Joseph A Dearani, Steve R Ommen, John Giudicessi, Michael J Ackerman
Journal: Circulation (2023)

Introduction: Recently, we demonstrated transcriptional down-regulation of hypertrophy pathways in myectomy tissue derived from patients with obstructive hypertrophic cardiomyopathy (HCM) despite translational activation of associated hypertrophy pathways. Previous studies of other forms of cardiac hypertrophy demonstrate hypertrophy pathways are activated via histone acetylation and histone deacetylase (HDAC) inhibitors prevented development of hypertrophy. Whether histone modifications regulate hypertrophy pathways in HCM remains unexplored. Methods: Chromatin immunoprecipitation sequencing (ChIP-seq) was performed on myectomy tissues from 40 patients with HCM and 23 controls to characterize differential histone marks for H3K4me3 (active promoter), H3K9ac (active promoter), H3K9me3 (heterochromatin), H3K27ac (active enhancer), H3K27me3 (repression) across the genome. The differential histone marks were integrated with RNA-sequencing (RNA-seq) data derived from the same patients. Results: Overall, we identified 2,912 (7%) differential H3K4me3 peaks impacting 5 pathways, 23,339 (21%) differential H3K9ac peaks impacting 87 pathways, 33 (0.05%) differential H3K9me3 peaks, and 58,837 (42%) differential H3K27ac peaks impacting 50 pathways. There was increased H3K27ac (q-value = 0.002) and H3K9ac (q-value = 0.009) at RAS-MAPK loci. Univariate analysis of concordance between H3K9ac with RNA-seq data showed activation of cardiac hypertrophy signaling (z-score=4.5; -log [BH p-value] = 3.1), while H3K27me showed down-regulation of cardiac hypertrophy signaling (z-score=-2.4; -log [BH p-value] = 2.4). Multivariate integration of the ChIP-seq data with RNA-seq data identified 3,189 transcripts concordant with all five histone marks impacting 254 pathways, 18 (7%) of which are involved in cardiac hypertrophy. Conclusions: Myectomy tissue from patients with obstructive HCM shows enrichment of histone modifications at cardiac hypertrophy loci with activation via H3K27 and H3K9 acetylation and repression via H3K27 methylation. Further studies are needed to understand the balance and temporal relationship between these competing regulators in HCM pathobiology and the potential for epigenetic therapies.
Abstract 17384: Unraveling the Impact of VAMP-8 Deficiency on Atherogenesis: A Fresh Perspective on Platelet Involvement
Authors: Shayan Mohammadmoradi, Rania Al Hawas, Ming Zhang, Smita Joshi, Sidney W Whiteheart
Journal: Circulation (2023)

Introduction and Objective: Recognized for their intricate role in atherogenesis, platelets interact with oxidized low-density lipoprotein (oxLDL), immune cells, and endothelial cells and release granule proteins and microparticles, contributing to the onset and advancement of atherosclerosis. Despite the challenges of antiplatelet treatment in primary prevention, exploring alternative platelet targets could provide key insights into their role in atherogenesis. This study pivots on the soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) proteins, notably vesicle associated membrane protein 8 (VAMP-8) - the primary vesicle membrane (v-SNARE) and vital facilitator of platelet secretion. Approach and Results: The profound impairment in α-granule, dense granule, and lysosome release due to VAMP-8 deficiency directed our investigation towards its potential role in atherogenesis. Using RNA-seq data from washed platelets of VAMP-8-/- mice versus wildtypes, we first analyzed the molecular signature of VAMP-8 deficiency. Gene ontology analysis revealed that the major differences in enriched genes between the two groups involved triglyceride biosynthetic process and platelet calcium homeostasis. We initiated atherosclerosis studies using ApoE -/- mice crossed with VAMP-8 -/- mice (n=11) alongside littermate controls (n=9), all fed a high cholesterol diet for 15 weeks. Remarkably, the deletion of VAMP-8 led to a substantial reduction in atherosclerotic lesion development when compared to the control group. Notably, this phenotype manifested irrespective of total cholesterol levels, as plasma cholesterol remained consistent across all groups. Conclusion: Our findings reveal that VAMP8 deficiency markedly mitigates atherogenesis, thereby proposing a novel perspective to explore the influence of platelet cargo secretion on the inception of atherosclerosis. We are currently conducting additional studies to uncover the underlying mechanisms responsible for these observations
Abstract 16879: Endothelial Prolyl Hydroxylase 3 Regulates Post-Ischemic Kidney Injury Through HIF Dependent Mechanisms
Authors: Ratnakar Tiwari, Rajni Sharma, Gabriella S Borkowski, Susan E Quaggin, Pinelopi P Kapitsinou
Journal: Circulation (2023)

Introduction: Acute kidney injury (AKI) is highly prevalent clinical condition after cardiac surgeries and is associated with high morbidity and mortality in hospitalized patients. Ischemia reperfusion injury (IRI) is one of the major causes of AKI. Previously, we have reported a critical role for the endothelial oxygen sensor prolyl hydroxylase (PHD2) in ischemic AKI. Recently, we found that prolyl hydroxylase 3 (PHD3) shows robust increase in kidney endothelium after renal IRI. However, its role in ischemic AKI is unknown. Hypothesis: We hypothesized that endothelial PHD3 regulates post-ischemic kidney injury. Methods: To delete endothelial PHD3, VECadherin (Cdh5)-CreER transgenic mice were crossed to mice carrying conditional PHD3 allele, generating PHD3 iEC mice. To test the HIF-dependent role of PHD3, we generated Cdh5CreER; Phd3 flox/flox Arnt flox/flox mice ( PHD3ARNT iEC ). Inactivating ARNT (aryl hydrocarbon receptor nuclear translocator), also known as Hif-1β, blocks HIF signaling. Unilateral IRI was induced by renal artery clamping, and tamoxifen treatment was started at day 1 post IRI, followed by analysis at day 14. Results: Compared to Cre - controls, inactivation of Phd3 in endothelial cells (ECs) following IRI exacerbated kidney damage and inflammation, as indicated by increased expression of kidney injury molecule 1 ( Kim1 ) and profibrotic genes lysyl oxidase-like 2 ( Loxl2 ), transforming growth factor-beta 1 ( Tgfb1 ) , smooth muscle actin ( Acta2 ) and collagen deposition assessed by Picro Sirius red staining (n=6-7; p&lt; 0.05). Post-ischemic inactivation of ARNT along with PHD3 ameliorated the effects of only PHD3 inactivation and normalized levels of Kim1 , Loxl2 , Tgfb1 and collagen deposition ( n=7; p&lt; 0.05) . In vitro suppression of PHD3 in human primary EC using PHD3-siRNA showed significant upregulation of inflammatory molecules such as ICAM1 (Intercellular Adhesion Molecule 1), VCAM1 (Vascular Cell Adhesion Molecule 1), C-X-C motif chemokine ligand 9 and 10 ( CXCL9 and CXCL10 ), which were again blunted by ARNT- siRNA treatment (n= 3; p&lt; 0.05). Conclusions: In summary, our data support a critical role for endothelial PHD3 in regulating post-ischemic kidney inflammation and fibrosis through HIF-dependent mechanisms.
Abstract 186: Regional Cerebral Oxygen Saturation to Predict Neurologic Outcome During Out-of-Hospital-Cardiac -Arrest: An Ancillary Analysis of a Prospective Interventional Study
Authors: Guillaume Debaty, Nicolas Segond, Christophe Crespi, Caroline sanchez, Johanna Boeuf, Helene Duhem, José Labarere, Keith G Lurie
Journal: Circulation (2023)

Background: Very few prognosis markers are available to help emergency medical services decide whether to continue or terminate cardiopulmonary resuscitation (CPR). ETCO 2 has been described to predict return of spontaneous circulation (ROSC) but its ability to predict neurologic outcome is poor. Cerebral tissue oxygen saturation (RSO 2 ) during CPR, as measured by near-infrared spectroscopy (NIRS) represents hemoglobin oxygenation within the cerebral tissue. The measure is feasible during CPR. It has been associated with the probability of ROSC. The aim of this study was to assess the predictive value of RSO2 regarding 30 days favorable neurologic outcome after out-of-hospital cardiac arrest (OHCA). Method: Data were collected during a prospective single center before-after interventional study comparing conventional CPR (C-CPR) with Automated head and thorax elevation CPR (AHUP). C-CPR was performed manually and AHUP-CPR was delivered using a LUCAS Active Decompression (Stryker Medical, USA), an EleGARD Patient Positioning System (AdvancedCPR Solutions, USA), and an impedance threshold device (ResQPOD-16, Zoll, USA). The study was carried out in four fire stations and one physician staffed advanced life support emergency medical services in France. ETCO2 (using an EMMA, Massimo or Lifepack 15, Stryker, USA) and RSO2 (H500, Nonin, USA) were collected as soon as possible during CPR. Favorable neurologic outcome was defined as MRS score of 0 to 3 at 30 days. Results are presented as mean ± standard deviation. Results: ETCO 2 was collected in 118 patients (11 with good neurologic outcome) and RSO 2 in 69 patients (6 with good neurologic outcome). Maximum ETCO 2 during CPR was 43±19mmHg in favorable neurologic outcome patients vs. 35±16mmHg (p=0.13). ETCO 2 alone had an AUC of 0,63 (IC95% 0.46-0.79). Maximum RSO2 during CPR was 68±13% for favorable neurologic outcome patients vs. 49±13% (p&lt;0.001). For survival with favorable neurologic outcome, rSO 2 alone had an AUC of 0.85 (IC95% 0.71-0.99). With a maximum RSO 2 value below 51% there was no patient with favorable neurologic outcome. Conclusion: In this prospective interventional study, unlike EtCO 2 , RSO 2 values were significantly associated with favorable neurological survival at 30 days.
Abstract 18944: Affordability of Insulin for Non-Elderly Adults in the United States Following $35 Monthly Out-of-Pocket Cap
Authors: Kayvon Ghoreshi, Nidhish Lokesh, Lajja Ben Patel, Andrew Sumarsono
Journal: Circulation (2023)

Introduction: In March 2023, insulin manufacturers in the United States announced price reductions, with Eli Lilly adding a $35 OOP cap on their unbranded insulin products. Aims: To investigate estimated OOP savings of a $35 insulin cap for non-Medicare patients. Methods: We used the 2019 Medical Expenditure Panel Survey (MEPS). Non-Medicare adults aged 18-64 who filled at least one insulin prescription were included. We identified insulin prescriptions with OOP spending above $35 and estimated savings using a $35 OOP cap. For each respondent, we calculated annual insulin OOP spending, average OOP spending per prescription, and total estimated OOP savings with a $35 OOP cap. Analyses were done in SAS. Results: Over 4.1 million non-elderly civilians filled 32.7 million insulin prescriptions in 2019, totaling $1.7 billion in OOP costs, or $418 per person (Table 1). There were 1.6 million people (39.5%) eligible for reduced OOP spending under a $35 OOP cap. Those eligible were more often male and medium- or high-income. Only 16% of publicly insured patients were eligible for savings with a $35 OOP cap, compared to 53% among privately insured and 52% among uninsured groups. Of those eligible for savings, we estimated a $35 OOP cap would have reduced average annual OOP insulin spending from $984 to $231, saving an estimated $1.2 billion. Uninsured patients would see a 93% reduction in OOP spending. Hispanic patients would see an 87% reduction in OOP spending, compared to 73% among non-Hispanic patients. Near poor and low-income patients would see greater OOP reductions than patients in other income groups. Conclusions: Populations most likely to benefit under a $35 OOP insulin cap are those with the highest cost-sharing requirements, such as the uninsured and those just above the threshold for income-based social services. Future work should assess how insulin OOP caps affect patient adherence and outcomes.