tbuckley/cabot-search huggingface dataset:
Abstract 17370: Activation of Endothelial GCN2 Kinase Contributes to Pulmonary Vascular Remodeling and Pulmonary Arterial Hypertension
Authors: Maggie M Zhu, Jingbo Dai, Yi Peng, Youyang Zhao
Journal: Circulation (2023)

Rationale: Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and pulmonary vascular remodeling that result in right heart failure. Published studies show that recessive mutations in the EIF2AK4 gene (encoding GCN2, General control nonderepressibe 2 kinase) resulting in reduction of GCN2 are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients and EIF2AK4 mutation was also found in PAH patients although very rare. Objective: To determine the role of endothelial GCN2 kinase in the pathogenesis of PAH. Results: Employing Eif2ak4 -/- mice, we found that loss of GCN2 induced neither spontaneous PVOD nor pulmonary hypertension (PH). In response to chronic hypoxia, loss of GCN2 inhibited hypoxia-induced PH and pulmonary vascular remodeling. RNA-sequencing analysis of mouse lung samples indicated Endothelin-1 as the downstream target of GCN2 in regulating pulmonary vascular remodeling and PH. In cultured human lung microvascular endothelial cells, GCN2 was phosphorylated and activated in response to hypoxia, which mediated hypoxia-induced Endothelin-1 expression through the GCN2/ATF4/HIF-2a/Endothelin-1 pathway. Endothelial cell-targeted nanoparticle delivery of plasmid DNA expressing Endothelin-1 selectively in endothelial cells in Eif2ak4 -/- mice markedly reversed the phenotype in response to hypoxia. Furthermore, nanoparticle delivery of the CRIPSR/Cas9 system-mediated knockout of Eif2ak4 in adult C57BL/6 mice also attenuated hypoxia-induced PH. Additionally, monocrotaline-induced vascular remodeling and PH in rats were inhibited by GCN2 inhibitor A-92 treatment. In lung samples of idiopathic PAH patients, we observed endothelial GCN2 hyperphosphorylation of pulmonary vascular lesions, without marked differences in GCN2 mRNA and protein levels compared to normal donor lungs. Conclusion: These studies demonstrate that endothelial GCN2 activation mediates pulmonary vascular remodeling and PAH development through the GCN2/ATF4/HIF-2a/Endothelin-1 pathway. Targeting GCN2 signaling is a promising therapeutic strategy for treatment of PAH in patients without GCN2 loss of function mutations.
Abstract 17386: Pulmonary Vein Stenosis After Pediatric Heart Transplant
Authors: Arene Butto, Conor Ohalloran, James Kuo, Anna Joong, Alan W Nugent, William T Mahle, Paul Tannous
Journal: Circulation (2023)

Introduction: Pulmonary vein stenosis (PVS) is a rare condition in which neointimal proliferation of the pulmonary veins leads to venous and arterial hypertension. Little is known about the development of PVS after heart transplant (HTx) in children, which is a rare but known complication of HTx. Research Question: To describe the clinical characteristics, progression of disease, and outcomes of children who develop PVS after HTx. Methods: We performed a retrospective review of patients ≤18 years old who underwent HTx at two pediatric centers, Children’s Healthcare of Atlanta and Lurie Children’s Hospital, between April 2012-April 2022. Patients with a diagnosis of PVS were identified through queries of PVS databases at each center. Details related to the underlying cardiac diagnosis, location and extent of PVS, and post-HTx outcomes were recorded. Results: During the study period, 374 patients underwent HTx across both centers. Seventeen PVS patients (9 male) were identified, 15 of whom had de novo PVS. Fifteen had underlying congenital heart disease (CHD) and 2 had cardiomyopathy. Among CHD patients, 2 had a history of anomalous pulmonary venous return and 14 had prior cardiac surgery. Two patients had undergone catheter based PVS intervention prior to Tx. PVS was diagnosed at a median of 2 months (range 2 weeks-14 years) after HTx. At initial diagnosis, 12 patients had one-vessel PVS, most commonly the left upper pulmonary vein (n=8). At final follow-up, 2 patients had 2-vessel PVS and 7 had 3-4 vessels involved. Surgical intervention was required in 8 unique patients, most commonly for the left veins. Stent or balloon angioplasty were used in all left-sided veins, most commonly in the left lower pulmonary vein (n=8). Two patients were medically treated for pulmonary hypertension following PVS diagnosis. There were 3 deaths in the cohort, 2 of which were thought to be caused by right heart failure secondary to PVS. Conclusions: This is the first study to describe the characteristics of post-HTx PVS in children. PVS occurs in 4.5% of HTx and history of CHD is a strong risk factor. Multiple vessels can be involved and may require catheter-based or surgical intervention. Clinicians must be vigilant in monitoring for the development of PVS in this population.
Abstract 18638: Myocardial Infarction Induces Dysfunction of Endothelial Colony Forming Cells With Independence of Common Cardiovascular Comorbidities
Authors: Francisco Rafael Jimenez Trinidad, Marta Arrieta Ruiz, Nuria Solanes, Blanca Llonch Bertran, Angela Vea, Merce Roque, Xavier Freixas, Luis G. Ortega-Paz, Juan Jose Rodriguez Arias, Salvatore Brugaletta, Manel Sabate, Ana Paula V Dantas, Olga Tura, Montserrat Rigol
Journal: Circulation (2023)

Introduction: Endothelial Colony Forming Cells (ECFCs) present a dysfunctional and senescent phenotype in ischemic heart disease. However, the effect of myocardial infarction (MI), independently of common cardiovascular comorbidities (CCVC), on ECFCs functionality has not been evaluated up to date. Hypothesis: MI induces dysfunction of ECFCs with independence of CCVC Methods: To determine the potential effect of MI on ECFCs, human ECFCs (hECFCs) were isolated from peripheral blood from healthy volunteers (n=6), patients immediately after MI (n=6) (AMI-hECFCs) and patients 6 months after MI (n=6) (CMI-hECFCs). To determine the effect of MI on ECFCs impairment, isolated from the effect of common cardiovascular comorbidities that are found in patients, 6 healthy pigs were subjected to 90 minutes of myocardial ischemia by coronary balloon occlusion followed by reperfusion. Porcine ECFCs (pECFCs) (n=6) were isolated from blood samples before the MI and 1 month after the procedure (CMI-pECFCs) (n=6). For all groups, the following parameters were determined: days until colonies appearance, morphometry, percentage of senescent cells, and migratory, proliferatory and angiogenic capacities. Results: Both CMI-hECFCs and CMI-pECFCs showed a delayed time until colonies appearance (p-ANOVA=0,0117 and p-ANOVA=0,0159 respectively) but no differences were found in AMI-hECFCs. AMI- and CMI-hECFCs showed changes in their area and shape, but only shape changes were observed in CMI-pECFCs. In terms of senescence, both AMI- and CMI-hECFCs, but not CMI-pECFCs, presented an increment of senescence (p-ANOVA= 0,0011). In terms of functionality, AMI- and CMI-hECFCs and CMI-pECFCs showed a significant reduction of angiogenesis and proliferation, and only CMI-hECFCs showed an impaired migratory capacity. Conclusions: MI Induces dysfunction of ECFCs with independence of CCVC
Abstract 198: Protective Effects of Exosomes Derived From Remote Ischemic Adaptation on Neurological Function After Cardiac Arrest in Rats
Authors: Heng Zhai, Chenglei Su, Tie Xu, Xianliang Yan
Journal: Circulation (2023)

Objective: To assess the therapeutic effects and underlying mechanisms of exogenous exosomes derived from RIC in improving post-resuscitation neurologic dysfunction in a rat model of CA. Methods: Exogenous exosomes were isolated from the plasma of healthy adult male Sprague-Dawley rats that underwent RIC.36 adult male SD rats were randomly assigned to three groups: 1) Sham, 2) Control, or 3) Exosome. The control and exosome groups underwent 7 minutes of asphyxia-induced cardiac arrest. Five minutes after the ROSC, either exosome (1х10 10 Particles) or placebo (normal saline) were administered via intravenous infusion. Neurological outcomes were assessed using the neuropsychological deficit score (NDS), open field test, Y maze, and Morris Water Maze. Levels of plasma hyaluronic acid (HA) and syndecan-1 (Sdc-1) were measured to evaluate the degree of endothelium glycocalyx degradation. Results: Compared with Sham group, the Control group showed significant neurological dysfunction after ROSC. Compared to the control group, the exosome group exhibited significantly better performance in the open field, Y maze experiments and Morris water maze ( p &lt; 0.05). Compared with the Sham group, the plasma levels of HA and Sdc-1 in the Control group were significantly increased 24 hours after ROSC (P&lt;0.05), while the plasma levels of HA and Sdc-1 in the Exosome group were significantly lower than those in the Control group(P&lt;0.05). Conclusions: Exosomes derived from RIC have been shown to be effective in improving neurological dysfunction following cardiac arrest. The reduction of endothelium glycocalyx degradation may be involved in the underlying mechanism.
Abstract 16952: Comparative Outcomes of Below-the-Knee Stent Deployment Interventions: A Report From the XLPAD Registry
Authors: Blake M Bruneman, David Fernandez Vazquez, Sarah Weideman, Aravinda Nanjundappa, Christopher Metzger, sameh sayfo, Zachary Rosol, Shirling Tsai, Mehdi H Shishehbor, Subhash Banerjee
Journal: Circulation (2023)

Background: Stent use in the below-the-knee (BTK) peripheral arteries remains controversial, with scarce data on real world outcomes. Methods: We examined 1572 patients from the XLPAD Registry (NCT01904851) from 2006-2021 that underwent BTK endovascular intervention and stratified them based on stent vs non-stent interventions. The primary outcome was the incidence of major adverse limb events (MALE), which includes death, clinically driven revascularization, amputation, non-fatal myocardial infarction, and stroke. Results: 517 (33%) patients received a stent and 1055 did not. Mean age 68 years, predominantly male (72%). White race was more frequent in stent group (64% vs. 55%, p&lt;0.0001), whereas Hispanic were more prevalent in the non-stent group (19% vs. 9%, p&lt;0.0001). Higher proportion of stented patients were smokers (53% vs. 26%, p&lt;0.0001), fewer were diabetic (63% vs. 72%, p=0.0003) and had chronic kidney disease (17% vs. 28%, p&lt;0.0001). Multivessel treatment was more common in stented patients (1.8 vs 2.8 lesions per case, p&lt;0.0001) and involved SFA (70% vs. 32%, p&lt;0.0001) and popliteal arteries (36% vs. 24%, p&lt;0.0001). Stented patients had more diffuse disease (60% vs. 48%, p&lt;0.0001), in-stent restenosis (10% vs. 4%, p&lt;0.0001) and CTOs (67% vs 46%, p&lt;0.0001). Fluoroscopy time was longer (33 min vs. 30 min, p=0.005) with higher procedural (95% vs. 91%, p=0.008) and technical success rates (98% vs. 94%, p=0.0009). MALE (22 vs. 22%, p=NS) events at 12- months follow-up were similar in both groups. Only surgical revascularization after 12-months was more frequent in stent group (3% vs. 1%, p=0.02). Conclusion: A third of patients undergoing BTK artery intervention received stents in the XLPAD registry with higher rates of procedural and technical success and similar 12-month MALE events.
Abstract 18959: Glycosphingolipid-Mediated Cardiomyocyte and Immune Cell Dysfunction in Hypoplastic Left Heart Syndrome
Authors: Mary E Turner, Ashley E Pietra, Erin E Sanchez, Anastacia M Garcia
Journal: Circulation (2023)

Introduction: Hypoplastic Left Heart Syndrome (HLHS) is the leading indication for heart transplant and the most common cause of cardiovascular death in infants. However, the mechanisms associated with heart failure progression in HLHS are poorly understood. Glycosphingolipids (GSLs) have been implicated in a variety of biological and disease processes, however, the role of GSLs in the context of HLHS pathophysiology have not been explored. Here we test the hypothesis that aberrant GSLs drive maladaptive cardiac and immune cell responses and predispose HLHS patients to pathologic remodeling and eventual cardiac dysfunction. Methods: GSL content was measured by mass-spectrometry. To test the direct effect of the specific GSL species, lactosylceramide (LacCer), cardiac and peripheral immune cells (PBMCs) were treated with liposomes containing 3uM LacCer (C18:0 and C24:0). Mitochondrial respiration was assessed using the Seahorse Bioanalyzer (Agilent). Expression of metabolic proteins were assessed by western blot. Statistical analysis between 2 groups was performed using an unpaired T-test. Results: LacCer is significantly increased in heart tissue and in isolated PBMCs from patients with HLHS (A), and isolated mitochondria are highly enriched with LacCer. Moreover, exogenous LacCer is sufficient to impair cardiomyocyte mitochondrial fatty acid beta-oxidation (B), induce ROS generation, and decrease the expression of metabolic proteins Additionally, exogenous LacCer is sufficient to promote inflammation and decrease mitochondrial bioenergetics in PBMCs (C). Conclusions: These data highlight a novel role for LacCer in modulating cardiomyocyte and immune cell phenotypes and suggest aberrant GSLs contribute to the HLHS pathophysiology. Elucidation of the molecular mechanisms involved in impaired immune cell and cardiomyocyte responses in HLHS is crucial and these data suggest a unique avenue for therapeutic intervention in this population.
Abstract 16881: Endothelial KLF11 is a Novel Endogenous Protectant Against Diabetic Atherosclerosis
Authors: Guizhen Zhao, Yang Zhao, tianqing zhu, Eugene Chen, Jifeng ZHANG
Journal: Circulation (2023)

Background: Atherosclerosis is the leading cause of cardiovascular diseases, which is also the primary cause of mortality among diabetic patients. Endothelial cell (EC) dysfunction is a critical early step in the development of atherosclerosis and aggravated in the presence of concurrent diabetes. Krüppel like factor 11 (KLF11), a transcription factor involved in diabetes, inhibits EC inflammation via regulation of NF-κB signaling. However, the potential function of KLF11 in pathogenesis of diabetic atherosclerosis remains undefined. Methods and results: Diet-induced type 2 diabetic atherosclerosis model is established in LDLR -/- mice by feeding a diabetogenic high-fat diet with cholesterol (DDC). KLF11 expression was increased in ECs from ascending aorta of LDLR -/- mice fed DDC diet. Moreover, EC specific KLF11 gain- (transgenic) and loss-of-function (knockout) mice in a LDLR -/- background were fed a DDC for 16 weeks. Endothelial KLF11 deficiency (Klf11 ECKO -LDLR -/- ) markedly increased atherogenesis, while EC-selective KLF11 overexpression significantly inhibited DDC-induced atherogenesis. Single cell RNA sequencing profiling the ECs isolated from DDC-fed Klf11 ECKO -LDLR -/- mice and littermate controls showed that KLF11 depletion increased endothelial-to-mesenchymal transition (EndMT) during atherogenesis. In vitro studies showed that KLF11 not only inhibited EC inflammation and oxidative stress, but also diminished EndMT in response to high glucose. Conversely, knockdown of KLF11 augmented the EC dysfunction and EndMT. Conclusions: Our study indicates that endothelial KLF11 protects against diabetic atherosclerosis through inhibition of EC inflammation, oxidative stress and EndMT.
Abstract 18637: Lower α-Klotho is Associated With Vulnerable Coronary Artery Plaque Characteristics
Authors: Nadia Akhiyat, Ilke Ozcan, Lilach O Lerman, Amir Lerman
Journal: Circulation (2023)

Introduction: α-Klotho (klotho) is a geroprotective protein inversely associated with coronary artery disease CAD and vascular aging. This study used intravascular ultrasound (IVUS) to study coronary artery plaque characteristics of patients with low circulating klotho. Hypothesis: Lower klotho is associated with vulnerable coronary artery plaque characteristics. Methods: Patients undergoing coronary angiogram for chest pain who had no CAD (&lt;40% stenosis) underwent IVUS assessment. Images were obtained from the mid-LAD to the coronary ostium. Stored arterial plasma was used for α-klotho analysis by enzyme-linked immunosorbent assay. Results: A total of 58 consecutive patients were retrospectively studied. The median circulating klotho level of the cohort was 0.27 ng/mL [0.15; 1.24]. Patients with klotho less than the median were compared to those with levels greater than or equal to the median and were similar in age (53 ±11 vs. 56 ±10, p = 0.235) and sex distribution (86% vs. 76% female, p = 0.324). Patients with less klotho had higher coronary plaque burden (21.42% [17.185, 31.955] vs. 18.32 [10.5, 24.515], p=0.041) and larger plaque area (2.71 [2.03, 4.605] vs . 2.27 [1.41, 3.31] mm 3 /mm, p=0.058) compared to those with higher klotho. Lower klotho was associated with vulnerable plaque characteristics, including greater percentages of dense calcium (1.33% [0.265, 5.38] vs. 0.43% [0.015, 1.73], p=0.037) and necrotic core (5.43% [2.245, 10.5] vs. 2.22% [0.86, 4.50], p=0.011). Conclusions: Lower circulating klotho was associated with higher coronary plaque burden and vulnerable plaque characteristics. Klotho may be an early biomarker for risk in coronary artery disease.
Abstract 18731: Connexin 43 Hemichannels Contribution to Ischemia-Reperfusion-Induced Hyperpermeability
Authors: Pia Burboa, Walter Duran, Mauricio A Lillo Gallardo
Journal: Circulation (2023)

Introduction: Ischemia-reperfusion (I-R) injury is a significant complication in vascular surgery or organ transplantation. I-R injury involves intracellular Ca2+ overload, nitric oxide (NO), oxidative stress. I-R injury increases endothelial vascular hyperpermeability leading to tissue edema and damage mediated by endothelial Ca2+ increase. The role of Ca2+ permeable channels in I-R is not defined. Connexin (Cx) proteins form hemichannels, allowing the exchange of molecules between intracellular and extracellular spaces. The Cx43 isoform is highly expressed in endothelial cells (EC). Endothelial Ca2+ increase promotes NO-dependent Cx43 S-nitrosylation. However, whether Cx43 hemichannels are involved in I-R-induced hyperpermeability is unknown. Hypothesis: VEGF-induced hyperpermeability causes increased NO-mediated Cx43 S-nitrosylation and opening of endothelial Cx43 hemichannels, leading to Ca2+ entry and exacerbating reperfusion damage. Methods: We used VEGF as I-R related pro-inflammatory agonist. Using primary cultures of mesenteric endothelial cells, we tested Cx43 hemichannel activity by ethidium uptake and Ca2+ influx with Fluo-4 indicator. We evaluated hyperpermeability in vitro and in vivo Results: Results indicate that VEGF stimulation increased hemichannel activity in EC, associated with a rapid rise of Ca2+ influx. Both hemichannel activation and Ca2+ increase were abolished by treatment with specific Cx43 blocker (Gap19) or blocking NO production with NG-monomethyl-L-arginine (LNMMA). Cx43 inhibition blunted VEGF-induced hyperpermeability both in vitro in primary EC culture and in vivo mouse mesenteric vascular bed. To further understand the participation of NO-mediated S-nitrosylation in the VEGF-induced hyperpermeability, we replaced cysteine 271 by serine to create a Cx43C271S mouse that fails to cause S-nitrosylation of Cx43. We demonstrated that this knockin mouse exhibits a decrease in VEGF-stimulated hyperpermeability in vivo. Conclusions: These results indicate that Cx43 hemichannels activation is critical to VEGF (I-R inflammatory environment)-induced hyperpermeability and the S-nitrosylated Cx43 is a key regulator in I-R damage. AHA support: # 932684 and #23DIVSUP1054931
Abstract 18677: Residual Cardiovascular Risk Reduction Through a Digital App
Authors: Letizia R Romano, Antonio Curcio, Federica Bruno, Anna Bartone, Miriam Festa, Letizia Velato, Biagio Malizia, Giuseppe Scalzi, Florinda M Augusto, Ciro Indolfi
Journal: Circulation (2023)

Introduction: atherosclerotic cardiovascular disease (ASCVD) is the first cause of disability and death globally and represents the main etiological agent of myocardial infarction and ischemic stroke. The causal association between LDL cholesterol (LDL chol) and ASCVD is one of the most consolidated topics of modern medicine: it has gone from the demonstration that high levels of LDL Chol are a necessary condition for atherogenesis to the awareness that "the lower the better" and "the earlier the better" to underline the need for secondary and primary prevention to reduce atherosclerotic burden. Hypothesis: we hypothesized that motivational alerts sent through telemedicine to patients could affect escalation therapy in ASCVD patients. Aim: we evaluated the impact of a digital-APP in dyslipidemia management, and other CV risk factors, but focusing mainly on LDL chol. Methods: fifty dyslipidemic patients (APP_pts; 40 males; mean age 62±9 years; age range 40÷81 yrs) were followed through telemedicine-based APP from March 2022 to May 2023, in comparison with additional 50 dyslipidemic patients (ST_pts; 43 males; mean age 63±9 years; age range 40÷81 yrs) who underwent standard outpatient visits. Patients’ access to digital APP was remotely monitored and reports were used for therapy adjustments. Statistical analysis was performed with GraphPad Prism 7; comparisons were carried out by two-way ANOVA and by chi-square test. Results: baseline LDL chol values were 93,3±36,4 mg/dL, and 90,8±43,8 mg/dL, in APP_pts and in, ST_pts, respectively; six months after enrollment, both cohorts experienced significant reductions (APP_pts, 72,1±35,2 mg/dL, p=0,024; ST_pts, 76,7±38,6 mg/dL, p=0,008) vs baseline. We further subdivided both groups into ischemic and non-ischemic subjects (APP_pts: 26 vs 24; ST_pts : 33 vs 17). Remarkably, telemedicine control showed a 32% reduction in LDL chol for ischemic pts, while ischemic ST_pts gained only 11%. Overall, dyslipidemic control in non-ischemic pts appeared less beneficial (17 vs 15%). Finally, telemedicine-based APP resulted more effective than standard monitoring (p=0,04). Conclusion: aggressive lipid lowering therapies should be implemented with remote patients monitoring, mostly in the post-ischemic setting.