bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 415: Lipid Profiles in Minority and Non-Minority Veterans following Percutaneous Coronary Intervention
Authors: Siddiqui Saifullah , Blumenkrants Dmitry , Ladani Amit , Challa Karthic , Shroff Adhir
Published: March 2022

Background

Lipid lowering therapy is an established core measure of secondary prevention in coronary artery disease management. The National Cholesterol Education Program - Adult treatment panel III (NCEP ATPIII) guidelines recommend a goal low density lipoprotein (LDL) level less than 100 mg/dL for CAD management. Statins remain the preferred agent for LDL reduction. It is unclear whether race plays a role in lipid control.

Methods

We conducted a retrospective, observational study on all patients undergoing PCI at an urban veterans hospital from September 2004 to December 2011. Statin use and lipid profiles at six months post-PCI were compared to pre-PCI values between minorities and non-minorities.

Results

A total of 1052 patients (60% minorities of which 88% were African American) were analyzed. The mean LDL decreased at six-month follow up in both groups. The mean LDL decreased by 15.2 mg/dL in the minority group and by 15.1 mg/dL in the non-minority group (p<0.0001). The percentage of patients at LDL goals of <100 mg/dL pre-PCI and at six month follow-up increased from 56% to 74% in the minority group (p<0.0001), respectively, and from 64% to 78% in the non-minority group (p=0.0002), respectively. The percentage of patients on a statin pre-PCI and at six-month follow up increased from 69% to 90% in the minority group (p<0.0001), respectively, and 72% to 86% in the non-minority group (p<0.0001), respectively.

Conclusion

Both groups exhibited an improvement in LDL levels six months after PCI and while on statin therapy. The mean difference was equivalent for minorities and non-minorities. This improvement was also reflected in the increased proportion of patients meeting ATPIII guidelines in both groups. There was also an increase in the usage of statin therapy in both groups at six months; however, the minority subgroup displayed a greater increase in statin use when compared to the non-minority subgroup.
Abstract 416: Baseline Electrocardiographic Findings Are Associated With Insulin Sensitivity and Beta-Cell Function in Type 2 Diabetes
Authors: Bhatt Anish B , Mulvey Claire K , Qasim Atif N , Rickels Michael R , Nair Jayamohan , Reilly Muredach P
Published: March 2022

Introduction

Cardiovascular disease rates are higher in type II diabetes mellitus, but often it remains silent until too late. It is unknown if baseline EKG changes are associated with the degree of impaired insulin sensitivity or with other markers of diabetes control. We sought to investigate these relationships in the Penn Diabetes Heart Study (PDHS), a cross-sectional study of diabetic patients without overt coronary artery disease.

Methods

EKG intervals were measured in a subset of PDHS participants (n=732; mean age 59.4 ± 8.4 years, 66.5% males, 60.1% Caucasians). At the same visit, subjects underwent 75 g oral glucose tolerance testing after overnight fast with measurement of glucose and insulin at 0, 30, 60, and 120 minutes. The Matsuda Insulin Sensitivity Index (MISI) was calculated to estimate insulin sensitivity and the Insulinogenic Index (IGI) to estimate pancreatic beta-cell function. We used spearman correlations, chi-squared tests, and logistic regression to test associations of EKG changes with clinical factors, log-transformed MISI, and inverse normal-transformed IGI.

Results

In unadjusted analysis, there was a higher prevalence of left ventricular hypertrophy (LVH) (3.6% vs. 0.9%, p = 0.005) and ST changes (24.5% vs. 14.6%, p = 0.004) in African Americans compared to Caucasians. In fully adjusted models controlling for age, race, sex, history of hypertension and Framingham risk score, a higher MISI was associated with lower incidence of Q waves (OR 0.50, CI 0.33-0.76, p = 0.001). In addition, higher IGI scores were associated with a lower incidence of nonspecific ST changes (OR 0.82, CI 0.65-0.96, p= 0.035). There was also a trend for higher HbA1c values associated with LVH; however, this association was not statistically significant in fully adjusted models (OR 1.29, CI 0.90-1.86, p = 0.163).

Conclusion

Q wave abnormalities on routine EKGs were associated with reduced insulin sensitivity at baseline, while nonspecific ST changes were associated with lower pancreatic beta-cell function in patients with diabetes. Specific baseline EKG changes are indicators of the degree of metabolic disturbance in type 2 diabetes and may provide insight into the extent and risk of macrovascular and microvascular complications in diabetic patients.
Abstract 419: Two Models of Endothelial Dysfunction: the Importance of Intrinsic Cardioprotective Properties of the Coronary-endothelium
Authors: Leucker Thorsten M , Zhi-Dong Ge , Procknow Jesse , Liu Yanan , Kersten Judy R
Published: March 2022

The coronary endothelium plays a major role in protecting cardiomyocytes (CMs) from hypoxia/reoxygenation injury. We are describing two models of endothelial dysfunction compromising the intrinsic cardioprotective properties of endothelial cells (ECs). Tetrahydrobiopterin (BH4) is an essential cofactor for coupling of endothelial nitric oxide synthase (eNOS) to produce the cardioprotective mediator nitric oxide (NO). However, hyperglycemia (HG) leads to significant increases in oxidative stress, oxidizing BH4 to dihydrobiopterin and thereby causing endothelial dysfunction. Additionally, Langendorff-perfused mouse hearts were treated by triton X-100 to produce endothelial dysfunction and subsequently subjected to 30 min of ischemia followed by 2 h of reperfusion. The recovery of left ventricular systolic and diastolic function during reperfusion was impaired in triton X-100 treated hearts compared with vehicle-treated hearts. CMs were co-cultured with ECs and subsequently subjected to 2 h of hypoxia followed by 2 h of reoxygenation. Addition of ECs to CMs at a ratio of 1:3 significantly increased NO production and decreased lactate dehydrogenase activity compared with CMs alone. This EC-derived protection was abolished by HG. The addition of 100 μM sepiapterin (a BH4 precursor) or overexpression of GTP cyclohydrolase 1 (the rate-limiting enzyme for BH4 biosynthesis) in ECs by gene trasfer enhanced endothelial BH4 levels, the ratio of eNOS dimer/monomer, eNOS phosphorylation, and NO production and decreased lactate dehydrogenase activity in the presence of HG. These results demonstrate the important intrinsic cardioprotective properties of the coronary endothelium, more specifically increased BH4 content in ECs by either pharmacological or genetic approaches reduces myocardial damage during hypoxia/reoxygenation in the presence of HG. Maintaining sufficient endothelial BH4 is crucial for cardioprotection against hypoxia/reoxygenation injury.
Abstract 421: Anti-Atherosclerotic Effect of Ellagic Acid
Authors: Rani Uma P , Kesavana Rushendhiran , Ganugula Raghu , T Avaneesh , Reddy Bhanuprakash G , Dixit Madhulika
Published: March 2022

Introduction

Abnormal proliferation and migration of medial vascular smooth muscle cells (VSMC) of vessel wall result in atherosclerotic plaque growth. Targeting proliferation of VSMC could reduce atherosclerotic complications. Therefore, the objective was to study the anti-proliferative effect of Ellagic acid (EA) on primary rat aortic smooth muscle cells (RASMCs) against an atherogenic agonist PDGF
in vitro
and also anti atherosclerotic effect in streptozotocin (STZ) induced diabetic rats.

Methods

Proliferation of cells was measured via Alamar blue assay and through propidium iodide based cell cycle analysis in flow cytometer. Reactive oxygen species (ROS) were measured via 2’, 7’-dichlorofluorescin diacetate (DCF-2DA) and Amplex red methods. Expression of proliferation markers and activation of kinases were assessed by immunoblot analysis. Immunohistochemistry was done on aortic tissue sections obtained from
in vivo
experiments.

Results

Co-treatment of primary cultures of RASMCs with 25μmol/L of EA significantly reduced PDGF-BB (20ng/ml) induced proliferation by blocking S-phase entry. EA effectively blocked PDGF receptor-β (PDGFR-β) tyrosine phosphorylation, intracellular ROS and downstream activation of extra cellular signal-regulated kinase 1/2. It also blocked PDGF-BB induced expression of cyclin D1. Docking analysis with AutoDock4 revealed two binding pockets for EA in the PDGF-BB-PDGFR-β complex with predicted free energy of bindings similar to known inhibitor, AG1295. In diabetic rats, supplementation of diet with 2% EA significantly blocked diabetes-induced medial thickness, and lipid and collagen deposition in the arch of aorta as well as proliferation marker cyclin D1 expression.

Conclusion

Therefore, EA is effective as anti atherogenic nutrient therapy.
Abstract 427: Apoliporotein A-I Improves Glucose Tolerance and Enhances Insulin-Dependent and Insulin-Independent Glucose Uptake in the db/db Mouse Model of Type 2 Diabetes
Authors: Cochran Blake J , Tang Shudi , Rye Kerry-Anne
Published: March 2022

Introduction

Type 2 diabetes is characterised by decreased high-density lipoprotein (HDL) levels, as well as the level of apolipoprotein A-I (apoA-I), the main apolipoprotein of HDL. Pharmacological elevation of HDL levels is associated with improved glycemic control in patients with type 2 diabetes and HDL also improves glucose uptake into skeletal muscle in vitro. With the current interest in HDL raising therapeutics, understanding how apoA-I/HDL improve glucose tolerance in type 2 diabetes is important.

Objective

To determine the impact of increasing plasma apoA-I levels on glycemic control and glucose uptake in the db/db mouse model of type 2 diabetes.

Methods

Fasted 6-7 week old male db/db mice received a single intraperitoneal injection of human apoA-I (40 mg/kg) or PBS. Two hours after the infusion mice were randomly assigned into 3 groups (n=7-8/group) and subjected to a glucose tolerance test (1 g/kg D-glucose), an insulin tolerance test (3 U/kg human insulin) or used to determine glucose uptake into skeletal muscle. For the glucose and insulin tolerance tests blood glucose levels were measured with a glucometer. For the glucose uptake experiments, gastrocnemius muscles were incubated with 1 mM [3H]2-deoxy-glucose and 7 mM D-[14C]mannitol in the presence or absence of insulin, then homogenized. 3H and 14C content of the homogenates was determined by liquid scintillation counting.

Results

Plasma apoA-I levels reached 65.2±16.6 μg/mL by 2 h post-injection, and remained elevated for >10 h. Mice that received apoA-I had significantly improved glucose tolerance (AUC apoA-I=2574±70; PBS=2927±137, p<0.05) and insulin sensitivity (AUC apoA-I=388.8±23.8; PBS=194.1±19.6, p<0.001). In the absence of insulin, apoA-I increased glucose uptake by 1.8 and 1.7 fold in red and white gastrocnemius muscle, respectively. In the presence of insulin, apoA-I increased glucose uptake 2.5 and 1.8 fold, in red and white gastrocnemius muscle, respectively.

Conclusion

A single infusion of apoA-I significantly increases glucose tolerance, insulin sensitivity and skeletal muscle glucose uptake in db/db mice. Insulin and apoA-I work synergistically to improve skeletal muscle glucose uptake.
Abstract 432: Post-translational Regulation of Group X Secretory Phospholipase A2
Authors: Layne Joseph D , Shridas Preetha , Forrest Kathy , Webb Nancy R
Published: March 2022

Group X secretory phospholipase A2 (GX sPLA2) hydrolyzes phospholipids within membrane bilayers, liberating free fatty acids and lysophospholipids. We reported previously that C57BL/6 mice deficient in GX sPLA2 (GX KO) have increased plasma corticosterone levels under both basal and adrenocorticotropic hormone (ACTH) stimulated conditions (Shridas et al. 2010, J. Biol. Chem. 285:20031-9). Conversely, overexpression of GX sPLA2 but not a catalytically inactive mutant, suppresses steroid production in mouse Y1 adrenal cells. GX sPLA2 is produced as a proenzyme that contains an N-terminal 11 amino acid propeptide ending in a dibasic motif, suggesting cleavage by a furin-like proprotein convertase. While propeptide cleavage is clearly required for enzymatic activity, the protease(s) responsible for GX sPLA2 activation have not been identified. In this study we report that ACTH treatment increases the phospholipase activity secreted by Y1 adrenal cells stably expressing GX sPLA2 (Y1-GX cells). Western blot analysis showed an increase in the ratio of mature/total GX sPLA2 in the media of ACTH-treated Y1-GX cells. Use of broad specificity proprotein convertase inhibitors confirmed the involvement of furin-like proteases in the processing and subsequent activation of GX sPLA2. Results from qRT-PCR analysis indicated that furin and PACE4, but not other members of the convertase family, are upregulated by ACTH in Y1 cells. siRNA-mediated gene targeting indicated that both furin and PACE4 mediate GX sPLA2 activation under both basal and ACTH-induced conditions. These results clearly demonstrate a role for furin and PACE4 in the proteolytic activation of GX sPLA2 in Y1 adrenal cells.
Abstract 433: Lipophagy Aids in VLDL-Mediated Lysosomal Sterol Clearance from Macrophage Foam Cells
Authors: Netherland-Van Dyke Courtney , Romer Carrie E , Jerome W. Gray
Published: March 2022

Lipophagy, a selective form of autophagy, has the potential to aid in clearance of sterol from macrophage foam cells by moving cytoplasmic lipid to lysosomes for removal. However, in advanced atherosclerosis, macrophage foam cells retain most of their cholesterol in large, lipid-swollen lysosomes and this inhibits lysosome function, including digestion of autophagic-derived lipids. Triglyceride rich particles are also found in atherosclerotic lesions and we have shown that in sterol-engorged cells uptake of triglyceride-rich particles can restore lysosome function and dramatically reduce lysosome and cell sterol content. Given that triglyceride is able to restore lysosome function and lysosome-mediated removal of sterol, we investigated the role of lipophagy in this restoration. We loaded THP-1 macrophages with 50μg/mL aggregated LDL (aggLDL) for six days to produce sterol-mediated lysosomal dysfunction similar to that of advanced lesions. Then cells were chased with either media alone or media containing 30μg/mL VLDL for three days. The VLDL chase produced a 23% decrease in the autophagic marker LC3 compared to controls. Fluorescence microscopy confirmed a decrease in overall LC3 levels but also revealed a 26.3% increase in LC3 colocalization with the lipid droplet marker adipophilin following the VLDL chase. We also found a significant increase (24.6%) in association of adipophilin with the lysosomal marker LAMP-1. These results suggest that VLDL uptake by foam cells increases the lipophagic targeting of lipid-droplet components to lysosomes and increases clearance of this material (as identified by decreased LC3). Thus, VLDL-mediated restoration of lipophagic clearance of cellular sterol by lysosomal hydrolysis has the potential to be an important mechanism for reducing lipid burden in late-stage foam cells and possibly other neutral lipid-engorged tissues.
Abstract 436: Hypercholesterolemia Impairs Erythropoiesis in an Intrinsic Scavenger Receptor BI Deficiency-dependent Manner
Authors: Ai Junting , Zheng Zhong , Guo Ling , Song Zhiqing , Howatt Deborah , Daugherty Alan , Li Zhenyu , Li Xiang-An
Published: March 2022

Scavenger receptor BI (SR-BI) is an HDL receptor. SR-BI
-/-
mice display abnormal erythropoiesis as indicated by reticulocytosis, accumulation of erythroid cells in spleen and blockage of erythroblast development. Previous studies proposed that hypercholesterolemia induced by SR-BI deficiency led to the abnormal erythropoiesis in SR-BI
-/-
mice. However, the expression of SR-BI on erythroid cells leaves us to ask what the role of intrinsic SR-BI in erythropoiesis is. In this study, we utilized three independent animal models to assess the hypothesis that intrinsic SR-BI is required for erythropoiesis and its deficiency is permissive for hypercholesterolemia to impact erythropoiesis.

First, in an LDLR knockout model, we found that SR-BI
+/+
LDLR
-/-
mice had high cholesterol concentrations similar to SR-BI
-/-
LDLR
+/+
mice, but had normal erythropoiesis. In contrast, SR-BI
-/-
LDLR
-/-
mice had a 2.2-fold increase in reticulocyte percentage, 40% increase in spleen erythroid cells, and a significant increase in the early-to-late erythroblast ratio compared with SR-BI
-/-
LDLR
+/+
mice, suggesting that hypercholesterolemia can exacerbate the abnormal erythropoiesis only in the absence of SR-BI. Secondly, in a liver specific SR-BI deficiency model (SR-BI I179N mutant mice), we found that a 90% decrease in liver SR-BI expression in the mutant mice resulted in a 70% increase in plasma cholesterol concentrations, but did not induce reticulocytosis or spleen erythroid cell accumulation, implying the existence of other factor rather than SR-BI deficiency-induced hypercholesterolemia. Finally, in a bone marrow transplantation model, we found that compared with those received SR-BI
+/+
BMCs, SR-BI
+/+
mice receiving SR-BI
-/-
BMCs had a more than 2-fold increase in reticulocyte percentage, 32% increase in spleen erythroid cells, and a more than 5-fold increase in early-to-late erythroblast ratio. Conversely, SR-BI
+/+
BMCs injection decreased the percentage and number of erythroid cells in spleen and the early-to-late erythroblast ratio in SR-BI
-/-
mice.

In conclusion, our data demonstrated that intrinsic SR-BI is required for erythropoiesis and hypercholesterolemia impairs erythropoiesis in an intrinsic SR-BI deficiency-dependent manner.
Abstract 446: Therapeutic Silencing of MicroRna-33 In Mice Inhibits the Progression of Atherosclerosis in Ldlr-/- Mice
Authors: Rotllan Noemi , Ramírez Cristina M , Esau Christine C , Fernández-Hernando Carlos
Published: March 2022

Objective-

To study the efficacy of anti-miRNA-33 therapy on the progression of atherosclerosis.

Methods and Results-

LDLr
-/-

mice were injected subcutaneously with PBS, control or miR-33 antisense oligonucleotides (ASO) weekly and fed a Western diet for 12 weeks. As expected, hepatic levels of miR-33 were significantly decreased in anti-miR-33 treated mice. Accordingly, the expression of miR-33 target genes was increased in the liver and aorta. Interestingly, plasma HDL cholesterol (HDL-C) was significantly increased in anti-miR-33 treated mice but only when they were fed a chow diet. Analysis of atherosclerosis revealed a significant reduction of plaque size and macrophage content in mice receiving miR-33 ASO. In contrast, no differences in collagen content and necrotic areas were observed between the three groups.

Conclusions-

Long-term anti-miR-33 therapy significantly reduces the progression of atherosclerosis. The miR-33 ASO anti-atherogenic effect is independent of plasma HDL-C.
Abstract 448: The Association of 5A Peptide With Sphingomyelin Increases Its Ability to Efflux Cholesterol Both in vitro and in vivo
Authors: Sviridov Denis O , Schwendeman Anna A , Kim Gwangseong , Stonik John , Turner Scott , Remaley Alan T
Published: March 2022

Introduction

5A (DWLKAFYDKVAEKLKEAF-P-DWAKAAYDKAAEKAKEAA) is an apolipoprotein A-I mimetic peptide that is specific for promoting cholesterol efflux by the ABCA1 transporter and has been shown to reduce atherosclerosis and inflammation in animal models.

Hypothesis

In this study, we complexed the 5A peptide with sphingomyelin (SM) or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) to compare the cholesterol efflux capacity of the complex and its affect on atherosclerosis.

Results

The optimal peptide to lipid ratio was found to be 1 to 7 (mole/mole) for both lipids. The average particle size measured by light scattering technique was 15.9 ± 2.2 nm for 5A-SM complex and 14.4 ± 3.5 nm for 5A-POPC complex. 5A-SM exhibited higher physical binding of fluorescently labeled cholesterol relative to 5A-POPC with Bmax of 182.6 ± 14.4 versus 124.8 ± 8.2, respectively. In the cholesterol efflux assay (18h), both complexes showed near equal efflux capacity through ABCA-1 transporter (25.4 ± 1.2 efflux for 5A-SM and 23.0 ± 0.2 % efflux for 5A-POPC). Interestingly, 5A-SM showed significantly higher cholesterol efflux in ABCG-1 and SR-B1 transfected cell lines compere to 5A-POPC (42.7 ± 1.8% vs. 29.1 ± 0.6 and 29.0 ± 2.4% vs. 13.3 ± 0.2%, respectively). Lipid free 5A peptide showed lower cholesterol efflux through ABCA-1 transporter (15.8 ± 1.2%) and showed no efflux through ABCG-1 or SR-B1. The abilities of the peptide-lipid complexes to mobilize cholesterol in vivo were tested on wild type rats. Two hours after intravenous injection of 100 mg/kg 5A-SM plasma cholesterol increased about 3-fold above baseline with a peak at 6 hours and returned to the baseline by 24 hours. 5A-POPC increased plasma cholesterol 2-fold above and returned to baseline by 24 hours.

Conclusions

The 5A complexed with SM showed similar ability to efflux cholesterol by ABCA1 than the 5A-POPC complex but improved cholesterol efflux capacity by ABCG1 and SR-BI. A greater rise in HDL-C was observed in vivo after treatment of rats with 5A-SM versus 5A-POPC, suggesting that the 5A-SM complex may show superior ability in increasing Reverse Cholesterol Transport and in reducing atherosclerosis, which will be examined in future studies.
Abstract 454: Cationic Peptides Neutralize Ox-LDL and Acetyl LDL Negative Charge and Prevent Their Uptake by Macrophages
Authors: Aluganti Narasimhulu Chandrakala , Brown Matt , Selvarajan Krithika , Parthasarathy Sampath
Published: March 2022

Background

Apoprotein (Apo A1) and apoprotein E mimetic peptides are known to reduce atherosclerosis. Antioxidant, anti-inflammatory, and hypolipidemic properties have been suggested to contribute to the anti-atherosclerotic effects. In this study, we tested whether three distinct and unrelated cationic peptides would inhibit the oxidation of lipoproteins and whether they would counteract and neutralize the negatively charged modified lipoproteins and inhibit their uptake by macrophages.

Methods

5F-mimetic peptide of apoA1, LL27 derived from the anti-microbial peptide CAMP, and a human glycodelin derived peptide were commercially synthesized. The number of positively charged amino acid residues (K+R) and negatively charged residues (D+E) were 4/4, 7/4, 6/2 respectively. Their abilities to reduce lipid peroxides (LOOH), inhibit the oxidation low density lipoprotein (LDL) and high density lipoprotein (HDL), interact with modified lipoproteins, and to inhibit macrophage uptake of modified LDL were measured.

Results

Cationic peptides decomposed the peroxide content of 13-HPODE and inhibited the oxidation of LDL and HDL by copper in a lysine dependent manner. Incubation of Ox-LDL and Ac-LDL with the peptides resulted in charge neutralization as noted by agarose gel electrophoresis. Pre-incubation of the peptides with modified lipoproteins reduced the uptake of the latter by macrophages and foam cell formation as detected by Oil-Red O staining.

Conclusions

Based on these studies, we postulate that cationic peptides may have properties that may affect a) events that are unrelated to lipid lowering, b) may play additional role in immune competent cells, including macrophages, and c) may interact with other biologically important anionic molecules, including lipids and proteins. These results also suggest there may be other cationic proteins that may influence the atherogenic processes.
Abstract 455: Prooxidative Effects of Ambient Pollutant Chemicals are Inhibited by HDL
Authors: Yin Fen , Ramanathan Gajalakshmi , Zhang Min , Araujo Jesus A
Published: March 2022

Exposure to air pollution leads to adverse pulmonary and systemic vascular effects. High levels of plasma HDL cholesterol reduce cardiovascular risk. We explored whether HDL could protect against the prooxidative effects of an organic extract of diesel exhaust particles (DEP) in vascular cells. We used a cell-free fluorescent assay to evaluate DEP oxidation by air, estimated by the degree of Dichlorofluorescein (DCF) fluorescence and tested the ability of HDL to inhibit it. We also evaluated DEP prooxidative effects in bovine aortic endothelial cells and RAW264.7 macrophages by DCF fluorescence. DEP oxidation and prooxidative cellular effects occurred in concentration- and time-dependent manners. Normal HDL inhibited DEP oxidation and prooxidative cellular effects while dysfunctional HDL failed to inhibit DEP oxidation and instead, it promoted further oxidation. In conclusion, DEP prooxidative effects in endothelial cells and macrophages are inhibited by normal HDL. Therefore, HDL may protect against air pollution-mediated adverse vascular effects.
Abstract 459: Noninvasive Measures of Arterial Stiffness in a Young Normotensive/Prehypertensive Patient Population
Authors: Cheng Cynthia , Daskalakis Constantine
Published: March 2022

Introduction

Noninvasive measures of atherosclerosis have become established tools for cardiovascular risk prediction, largely studied in older individuals. Pulse pressure (PP) is a simple surrogate measure of arterial stiffness, while Ambulatory Arterial Stiffness Index (AASI) is a relatively new vascular compliance measure calculated as 1 minus the regression slope of DBP over SBP readings obtained from 24 hour ambulatory blood pressure monitoring (ABPM). We examined the hypothesis: PP and AASI correlate with blood pressure (BP), along with microvascular and endothelial function, in young adult normotensive and prehypertensive subjects.

Methods

24 hour BP, PP, and AASI were calculated from ABPM, and clinic BP obtained in 140 subjects (87 female, 53 male; 117 non-black, 23 black) with mean +/- sd age 26 +/- 6 years. Strain gauge plethysmography was used to assess endothelial function. Microvascular function was measured with direct capillaroscopy visualization of capillaries. Pearson correlation coefficients and multiple linear regression were used to analyze BP, microvascular, and endothelial function as predictors of PP and AASI, controlling for BMI, gender, age and race.

Results

PP and AASI are correlated (r=0.59; p<0.001). Both PP and AASI were significantly associated with ABPM and clinic SBP measures (SBP24: p=0.001/p=0.002; SBP daytime: p=0.001/p=0.009; SBP clinic: p=0.001/p=0.047; p values =PP/AASI). No association was seen for any measures with DBP. Both PP (p=0.08) and AASI (p=0.056) were marginally associated with endothelial function, while only AASI was significantly associated with microvascular function (p=0.027) along with BP dipping (drop of 10% or more during sleep: SBP and DBP p<0.001), another known predictor of cardiovascular risk.

Conclusions

In conclusion, both PP and AASI are associated with SBP in young normotensive and prehypertensive patients, indicating potential usefulness of these measures for early identification of arterial stiffness and associated cardiovascular risk, prior to development of established hypertension. Microvascular and endothelial dysfunction may contribute to the pathophysiology underlying higher PP/AASI values, with AASI more closely correlated with these processes.
Abstract 461: Inhibition of Four- and- a- Half LIM Domain Protein-2 Decreases Atherosclerosis in Apoe -/- Mice model: Role of Immune T- Cells
Authors: Ebrahimian Talin , Heidari Maryam , Lemarie Catherine A , Simon David , Rivas Daniel , Mann Koren , Wassmann Sven , Lehoux Stephanie
Published: March 2022

OBJECTIVE

Four-and-a-half LIM domain protein-2 (FHL2), a member of the FHL family of proteins, is expressed in endothelial and vascular smooth muscle cells. FHL2 negatively regulates endothelial cell survival and migration, but its role in atherogenesis is unknown.

METHODS AND RESULTS

To investigate the role of FHL2 in atherosclerosis, we crossed FHL2 knockout (FHL2-/-) with apolipoprotein (Apo) E-deficient (ApoE -/-) mice, and fed them a high fat diet for 7 weeks. Despite a total plasma cholesterol levels comparable to the ApoE-/- mice, FHL2-/-ApoE-/- mice showed a strong increase in plasma HDL-cholesterol as compared to ApoE -/- mice (P<0.01; n=6) and had significantly smaller atherosclerotic plaques in the aortic sinus (0.14±0.02 vs. 0.29±0.04 mm
2
) and aorta (6.9±0.9 vs 10.3±1%) (P<0.05; n=6), assessed by oil red O staining, compared with ApoE-/- mice. The relative monocyte/ macrophage content within atherosclerotic plaques, determined by MOMA-2 immunostaining, was equivalent in both animal groups. However, we observed an enhanced relative content of collagen (16±2 vs 8.6±3 %) and smooth muscle cells (4.5±0.8 vs 1.8±0.5%) within the plaques in the aortic sinus of FHL2-/-ApoE-/- mice compared with ApoE-/- mice, determined by Sirius red and alpha-actin staining respectively. These results suggest that absence of FHL2 promotes smaller and more stable plaques. The reduced plaque size in FHL2-/-ApoE-/- mice could be explained, at least in part, by the 40% reduction in ICAM-1 mRNA expression observed in aortas (p<0.05 vs ApoE-/-). Moreover, although the relative monocyte/ macrophage content in spleens was equivalent in both animal groups, FACS analysis of T cells in spleens showed a significant increase in CD4+CD25+Foxp3+ regulatory T cell numbers, in FHL2-/-ApoE-/- compared with ApoE-/- mice (19.5±1.6 vs. 16.2±2% of CD3+CD4+ cells, respectively) (P<0.005).

CONCLUSIONS

These results suggest that FHL2 may play an important role in atherosclerosis by promoting plaque formation, through upregulation of adhesion molecule expression and suppression of regulatory T cells.
Abstract 470: Aip1 Suppresses Atherosclerosis by Limiting Hyperlipidemia-Induced Inflammation and Vascular Endothelial Dysfunction
Authors: Min Wang , Huang Qunhua , Zhou Jenny Huanjiao , Qin Lingfeng
Published: March 2022

Objective-

Apoptosis signal-regulating kinase 1 (ASK1)-interacting protein-1 (AIP1) is a signaling adaptor molecule implicated in stress and apoptotic signaling induced by proinflammatory mediators. However, its function in atherosclerosis has not been established. In the present study, we use AIP1-null (AIP1-/-) mice to examine its effect on atherosclerotic lesions in an ApoE-null (ApoE-/-) mouse model of atherosclerosis.

Methods and Results-

ApoE-/- control mice developed atherosclerosis in the aortic roots and descending aortas upon Western-type diet for 10 weeks, while the atherosclerotic lesions are significantly augmented in ApoE-/-AIP1-/- double knockout (DKO) mice. DKO mice show increases in plasma inflammatory cytokines with no significant alterations in body weight, total cholesterol levels or lipoprotein profiles. Aortas in DKO mice show increased inflammation and endothelial cell (EC) dysfunction with NF-κB activity, correlating with increased accumulation of macrophages in the lesion area. Importantly, macrophages from DKO donors are not sufficient to augment inflammatory responses and atherogenesis when transferred to ApoE-KO recipients. Mechanistic studies suggest that AIP1 is highly expressed in aortic EC but not in macrophages, and AIP1 deletion in EC significantly enhance oxidized LDL-induced NF-κB signaling, gene expression of inflammatory molecules and monocyte adhesion, suggesting that vascular EC are responsible for the increased inflammatory responses observed in DKO mice.

Conclusion-

Our data demonstrate that loss of AIP1 in aortic EC primarily contributes to the exacerbated lesion expansion in the ApoE-/-AIP1-/- mice, revealing an important role of AIP1 in limiting inflammation, EC dysfunction and atherosclerosis.
Abstract 481: Athero-metabolic and Inflammatory Alterations Promote In-stent Restenosis in ApolipoproteinE Deficient Rats
Authors: Borinski Mauricio , Simsekyilmaz Sakine , Afify Mamdouh , Flege Christian , Krott Nicole , Marx Nikolaus , Vogt Felix
Published: March 2022

Purpose

Recently, Apoliprotein E deficient (ApoE-/-) rats have been generated by genetic manipulation, while the bench-to-bedside relevance of this novel model for coronary stenosis research has not been elucidated. Here, we seek to characterize vascular inflammation and in-stent cross-sectional stenosis (ICS) development in the abdominal aorta of ApoE-/- rats.

Methods

Trans-abdominal aorta bare-metal stent (Multi-LinkMini Vision, Abbott Vascular Inc., Santa Clara, CA; 2.5 x 8 mm; 12 atm) implantation was performed in ApoE-/- rats (Sigma Aldrich Genetic Engineering, Saint Louis, MO). At 7 and 28 days, quantification of ICS, neointimal (NI) area, injury score and inflammation score was conducted using image analysis software (DISKUS, Hilgers, Königswinter). Blood serum analysis for Interleukin (IL)-6, -8 and -10 and for cholesterol levels was performed.

Results

Serum cholesterol levels were elevated in ApoE-/- rats (8.63±1.73mmol/l vs. 1.98±0.55mmol/l; p<0.001) as compared to ApoE+/+ rats. IL-6 and (294.7±80.2pg/ml vs. 187.2±2.8pg/ml; p<0.05) and IL-8/CXCL8 (767.5±127.5pg/ml vs. 342.0±39.7pg/ml; p<0.05) were upregulated, while IL-10/cytokine-synthesis inhibitory factor was downregulated (16.8±1.4pg/ml vs. 90.7±6.5pg/ml; p<0.001) in ApoE-/- rats. After stent implantation, injury scores were similar in all groups. At 7 days, ICS (11.1±1.9% vs. 2.1±0.5%; p<0.01) and NI area (0.59±0.09mm2 vs. 0.075±0.02mm2; p<0.01) was increased as compared to controls; concomitantly, at 28 days, ICS (26.6±3.9% vs. 13.1±1.9%; p<0.001) and NI area (1.47±0.37mm2 vs. 0.54±0.10mm2; p<0.01) were elevated. Furthermore, infiltration by chronic inflammatory cells was increased in ApoE-/- rats at 28 days (456.2±181.4 vs. 108.0±25.9 per high power field; p<0.05).

Conclusions

In ApoE-/- rats, cholesterol levels as well as pro-inflammatory IL-6 and -8 are upregulated, while anti-inflammatory IL-10 is downregulated. Concomitantly, ApoE-/- rats develop increased ICS after abdominal stent implantation. This novel small animal model enables the characterization of distinctive molecular and mechanical ICS mechanisms in an atherogenic milieu that, notably, renders disposable any miniaturization of tested stents as opposed to mouse models.
Abstract 485: Percutaneous Catheter-directed Local Thrombolysis of Arterial, Venous and Shunt Thrombus Using Tissue Plasminogen Activator in Critically-ill Children - A Single Center Experience
Authors: Singh Dhiraj , Ross-Ascuitto Nancy , Siwik Ernest , Ascuitto Robert , Sernich Steffan
Published: March 2022

OBJECTIVE

To retrospectively determine the success and complication of local catheter directed thrombolysis using recombinant tissue plasminogen activator (rTPA) in critically ill children with acute arterial, venous or shunt thrombus.

BACKGROUND

Local catheter directed thrombolysis is a well-described treatment modality for thrombotic events in adults, with maximal thrombolytic effect and minimal systemic sequelae. However, this treatment option in life threatening thrombosis is not well defined in pediatrics.

METHOD

We report an observational study in a retrospective cohort (2008-2013) of 14 cases presenting with sudden life threatening thrombosis, necessitating immediate intervention. All patients had >95% vascular/shunt occlusion which was treated with percutaneous catheter-based procedure, and rTPA administration directly at site of thrombus. The efficacy, dosage, duration, additional endovascular intervention and complications of this approach are reported.

RESULTS

The median age was 1.7 months (range, 10 days - 29 years) and median weight was 4.4 kilograms (range, 2.2 - 101 kg). Nine (64%) patients presented with shunt (Sano or aorto-pulmonary) thrombosis, three (22%) with arterial thrombosis and two (14%) with venous thromboembolism. All patients received a local bolus of rTPA [median dose 0.24 mg/kg (range, 0.01 - 1.0 mg/kg)]. Eight (57%) received an additional infusion of rTPA [median dose 0.17 mg/kg/hr (range, 0.02 - 1.0 mg/kg/hr)] of varying duration [median 1.3 hours (range, 0.3 - 18 hours)]; one patient received a prior systemic bolus of rTPA. Anticoagulation was administered in 12 (86%) and supplementary endovascular intervention (balloon angioplasty and/or stenting) was done in 4 (28%) patients. Thrombolytic success (defined as >95% return of antegrade flow) was achieved in 13 (93%). No major bleeding or other serious complication directly related to this approach occurred.

CONCLUSION

Catheter-directed local thrombolysis with rTPA can be accomplished rapidly in critical thrombosis, as a pragmatic alternative to surgery. This approach can offer satisfactory short term palliation without significant complications and improve outcome in children with life threatening thrombosis.
Abstract 487: Aspirin Treatment Hampers the Use of Plasma MicroRNA-126 as Biomarker for the Progression of Vascular Disease
Authors: de Boer Hetty C , van Solingen Coen , Prins Jurrien , Duijs Jacques M , Huisman Menno V , Rabelink Ton J , van Zonneveld Anton Jan
Published: March 2022

Rationale

MicroRNA-126 (miR-126) facilitates angiogenesis and regulates endothelial cell function. Recent data suggest that miR-126 can serve as a biomarker for cardiovascular disease. Although endothelial cells are enriched for miR-126, platelets also comprise a major pool of miR-126. We investigated the contribution of platelets to the level of miR-126 circulating in the plasma from patients with type 2 diabetes and how this level is affected by aspirin.

Methods & Results

In vitro
platelet activation resulted in the transfer of miR-126 from the platelet- to the plasma-compartment, which was prevented by aspirin.
In vivo
platelet activation was studied in patients with type 2 diabetes, who exhibit disease-mediated platelet activation and are prone to develop cardiovascular disease. Platelet activation was monitored by measuring soluble P-selectin in plasma and correlated significantly with circulating levels of miR-126. Administration of aspirin to the patients in a randomized, placebo-controlled cross-over design, resulted in platelet inhibition and concomitantly reduced circulating levels of platelet-derived microRNAs including miR-126.

Conclusion

The profile of circulating miRs constitutes a fingerprint of activated platelets rather then activated endothelial cells. In particular miR-126 can be derived from activated platelets and the circulating levels of this miRNA can be markedly reduced when aspirin is used in patho-physiological conditions associated with platelet activation such as diabetes type 2. Therefore, the use of platelet inhibitors should be taken into account when using plasma-levels of miR-126 as a biomarker.
Abstract 492: Docosahexaenoic Acid-Enriched and Oleic Acid-Enriched Canola Oils Reduce Whole Blood Nuclear Factor Kappa-B Gene Expression in Men and Women with Abdominal Obesity
Authors: Labonté Marie-Ève , Couture Patrick , Jenkins David J , Connelly Philip , West Sheila , Kris-Etherton Penny , Jones Peter , Lamarche Benoît
Published: March 2022

Introduction

As part of the large Canola Oil Multicenter Intervention Trial (COMIT) study, we have recently shown that consumption of a canola oil enriched with docosahexaenoic acid (DHA) under strictly controlled feeding conditions exerts anti-inflammatory effects compared with a control diet rich in linoleic acid (LA) and a diet rich in flax oil and alpha-linolenic acid (ALA).

Objective

In this study, we have investigated the impact of different oils containing various amounts of ALA, LA, oleic acid (OA) and DHA on the expression of key pro- and anti-inflammatory genes in a subset of adults having participated in COMIT.

Methods

COMIT is a randomized, crossover controlled full feeding trial involving 118 men and women with abdominal obesity and at least one other component of the metabolic syndrome who consumed 5 experimental isoenergetic diets (15.5% protein; 35.7% fat; 50.6% carbohydrate) for 4 weeks each. Here we report the impact of 4 of those 5 diets, which provided 60 g/3000 kcal of different oils: 1- High LA corn/safflower oil (CONTROL, 10.6 g OA; 0.2 g ALA; 41.6 g LA), 2- High ALA flax/safflower oil (FLAX, 10.7 g OA; 19.2 g ALA; 22.5 g LA), 3- High oleic canola (HO-CAN, 42.8 g OA; 1.4 g ALA; 8.8 g LA), 4- High DHA canola (DHA-CAN, 37.9 g OA; 1.2 g ALA; 7.6 g LA; 3.5 g DHA). Inflammatory genes expression in whole blood cells was assessed by real-time polymerase chain reaction from samples collected at the end of each diet in a random subset of 10 individuals (6 men, 4 women).

Results

DHA-CAN lowered the mRNA expression of the nuclear transcription factor kappa-B (NF-[[Unable to Display Character: к]]B) compared with CONTROL (-15.2%,
P
=0.07) and FLAX (-22.4%,
P
=0.007). NF-[[Unable to Display Character: к]]B gene expression was also lower after HO-CAN compared with FLAX (-16.5%,
P
=0.02). There was no apparent between-diet difference in mRNA expression of other inflammatory genes (interleukin (IL)-18, IL-1β, tumor necrosis factor-α) and transcription factors (natriuretic peptide receptor C).

Conclusions

Data from this controlled feeding study suggest that anti-inflammatory effects of a DHA-enriched canola oil and oleic acid-enriched canola oil compared with polyunsaturated fatty acids from plant sources are mediated, at least partly, through an alteration in the NF-[[Unable to Display Character: к]]B pathway.
Abstract 493: The Regulation of Thrombospondin-1 Release through SIRPa-CD47 Mediated-Signaling in Platelets
Authors: Clark Katherine A , Johnston Ian , Raouva Lubica , Fishbein Ilia , Levy Robert , Stachelek Stanley
Published: March 2022

Introduction

Decreasing the inflammatory response to medical devices remains an unmet clinical need. Our group has recent evidence that CD47, a ubiquitous transmembrane protein that serves as a self-marker via interactions with its receptor, Signal Regulatory Protein alpha (SIRP-α), confers significant anti-inflammatory properties on synthetic surfaces. Also, our group was the first to find the presence of SIRP-α on platelets. Interestingly, platelets are the primary source of Thrombospondin-1 (TSP-1), a CD47 ligand involved in pro-inflammatory processes. These experiments test the hypothesis that SIRPα-CD47 mediated signaling in platelets, in part, regulates TSP-1 release.

Methods and Results

As our group previously published, clinical-grade PVC tubing was modified via a photo-activated polymer with recombinant human CD47. Citrated whole blood or platelet-rich plasma (PRP), (30 cc), was obtained from healthy volunteers and added to the unmodified and CD47-modified tubing. The blood or PRP was perfused, via a Chandler Loop apparatus, over the PVC surfaces for 3 hours. All samples were then processed for platelet poor plasma, and TSP-1 expression was analyzed via western blot and ELISA. Confirmed with western blot and densitometry, when whole blood was exposed to CD47-coated PVC, TSP-1 concentration (as compared to the percent of the time-zero control) was consistently reduced compared to that of unmodified PVC (CD47: 78.42% ± 5.62, PVC: 189.87% ± 28.95). In contrast, when PRP was exposed under analogous conditions, there was no significant difference in TSP-1 concentration (CD47: 2.55% ± 1.02, PVC: 2.72% ± 0.81). To ensure that changes in TSP-1 concentration were not the result of TSP-1 adsorption to the CD47-modified surface, proteins were eluted from the luminal tube surface, and western blot analysis confirmed a 30% decrease in relative intensity from the CD47-coated PVC compared to that of unmodified PVC.

Conclusion

CD47-modified PVC tubing significantly decreases TSP-1 levels in isolated plasma from whole blood, suggesting that CD47 decreases platelet activation. However, work so far with PRP suggests that platelet TSP-1 release is mediated indirectly through monocytes. Further work on this cascade includes SEM analysis of PVC tubing.
Abstract 504: Drug-Eluting Stent Placement for Treatment of Below-The-Knee Critical Limb Ischemia: A Report of Parameter for Wound Healing with Measurement of Transcutaneous Oxygen Tension
Authors: Junpaparp Parichart , Wongpraparut Nattawut , Chinsakchai Kamin , Ruangsetakit Chanean , Pongakasira Rungtiwa
Published: March 2022

Objectives

The aim of this study is to evaluate the efficacy of drug-eluting stents (DES) placed below-the-knee level in the parameters for wound healing.

Background

Critical limb ischemia (CLI) has a serious impact on quality of life with a major amputation rate of 30 percent within 12 months. Endovascular treatment has been used to perform revascularization of limbs over the past decade. However, the role of drug-eluting stent (DES) placement at below-the-knee level to improve wound healing is still inconclusive.

Methods

A single center retrospective study was conducted at Faculty of Medicine, Siriraj Hospital, Mahidol University. The outcomes of infrapopliteal DES placement among forty-six patients with critical limb ischemia (category 4-6 of Rutherford’s classification) from 2007 to 2011 were retrospectively reviewed. The primary endpoints were pre- and post-procedural Ankle-Brachial index (ABI) and transcutaneous oxygen tension (TcPO2). The secondary endpoints were limb salvage rate, time-to-major amputation and healing of ulcers. The differences between pre- and post-procedural parameters were analyzed with paired T-test.

Results

The mean follow-up time in the study was 490.21 days with limb salvage rate of 93.8 percent. Complete wound healing was observed in 81.3 percent of patients. Three of the patients underwent major amputations with the time-to-amputation ranging from 40 to 277 days post-procedure. The overall ABI was significantly improved from 0.64 ± 0.12 to 0.88 ± 0.28 (p-value <0.001). Among subjects with isolated below-the-knee DES placement, ABI was also significantly improved from 0.62 ± 0.12 to 0.82 ± 0.26 (p-value 0.004). Furthermore, TcPO2 was also increased from 25.82 ± 15.77 to 40.18 ± 13.21 mmHg (p-value 0.023).

Conclusions

DES placement at below-the-knee level is both a safe and effective limb saving therapy in CLI patients. It has been shown to significantly improve parameters for wound healing: ABI and transcutaneous oxygen tension (TcPO2).
Abstract 505: Diabetic Women are Poor Responders to Exercise Rehabilitation in the Treatment of Claudication
Authors: Gardner Andrew W , Parker Donald E , Montgomery Polly S , Blevins Steve M
Published: March 2022

Introduction.

It is not clear whether subgroups of patients with peripheral artery disease (PAD) and claudication respond more favorably to exercise rehabilitation than others. We determined whether sex and diabetes were factors associated with the response to exercise rehabilitation in patients with claudication.

Hypothesis.

Women will experience less improvement in the primary outcome measures of claudication onset time (COT) and peak walking time (PWT), that the presence of diabetes will blunt the improvement in the primary outcomes, and that the effect of diabetes will be greater in women than in men.

Methods.

Eighty patients were randomized to home-based and supervised exercise programs, and 60 completed with complete exercise intervention data. Exercise consisted of intermittent walking to near maximal claudication pain for 12 weeks. Primary outcome measures included COT and PWT. Patients were partitioned into diabetic and non-diabetic groups, and then further partitioned by sex to form four groups.

Results.

Overall, exercise adherence was high (84%), and there was no significant difference (p > 0.05) in the amount of exercise completed among the four groups. All groups had significant improvements (p < 0.05) in COT and PWT following exercise rehabilitation, except for diabetic women (p > 0.05). Only 37% of women with diabetes had an increase in COT compared to 100% of men (p < 0.01), and their risk ratio for non-response was 9.2 (p < 0.0001).

Conclusions.

Women with PAD and claudication, particularly those with diabetes, represent a vulnerable subgroup of patients who respond poorly to a program of exercise rehabilitation. Diabetic women with PAD and claudication may need greater exercise volume to achieve similar improvements in claudication measures compared to non-diabetic women and to diabetic and non-diabetic men.