bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 346: Platelet Reactivity to Aspirin and Clopidogrel in Patients with Acute ST Elevation Myocardial Infarction and its Correlation with High Sensitivity C- Reactive Protein
Authors: Rajdev Archana , Penciu Oana , Bradley Jacqueline , Mihu Cristina , Siqueros Alan , Petrini Joan , Wasserman Hal , Warshofsky Mark 
Published: July 2021

INTRODUCTION
Implantation of bare metal or drug eluting stents supported by dual antiplatelet therapy (DAPT) is standard treatment for the management of patients with ST elevation myocardial infarction (STEMI). Individual response to aspirin and clopidogrel is heterogeneous, and decreased response is associated with thrombotic events following stenting. We postulated that systemic inflammation at the time of STEMI would diminish responsiveness to DAPT. The aim of this study is to evaluate the correlation between elevated high-sensitivity C-reactive protein (hs-CRP) as a marker of inflammation and decreased platelet sensitivity to DAPT in STEMI.

METHODS
We recruited patients with STEMI undergoing percutaneous coronary intervention (PCI) who received oral clopidogrel 600 mg loading dose followed by 75 mg daily maintenance dose and aspirin 325 mg daily. Platelet reactivity and hs-CRP were measured within 72 hours of PCI and at 6 weeks. For patients receiving eptifibatide, blood samples were taken 48 hours after discontinuation. Platelet reactivity was assessed using the VerifyNow platelet function analyzer. A cut-off value of 208 platelet reaction units (PRU) was used to define high on-clopidogrel platelet reactivity (HCPR) and a value of 454 aspirin reaction units (ARU) was used to define high on-aspirin platelet reactivity (HAPR).

RESULTS
In 20 patients aged 31 to 85, in hospital and 6 weeks after STEMI, hs-CRP was 6.7 (SD 4.0) and 2.6 (SD 3.2) respectively, p< 0.01. Changes in ARU from 408.3 (SD 54.3) to 425.2 (SD 68.2) and PRU from 157.8 (SD 74.7) to 164.2 (SD 75) were not statistically significant. 2 patients had HAPR in hospital; 1 became sensitive at follow up. 2 patients developed HAPR and HCPR. We saw a trend towards higher PRU in diabetic patients and those prescribed statins.

CONCLUSIONS
Although we found a significant difference in hs-CRP levels between the first and second time point, no significant difference was found in on-aspirin and on-clopidogrel platelet reactivity between the time points.Thus, in this small series, the acute inflammatory state associated with STEMI did not appear to influence the on-DAPT reactivity at the dosages used. Trends among those with diabetics and prescribed statins will be discussed
Abstract 393: Anti-inflammatory Properties of Aqueous Extracts of Sesame Oil
Authors: Selvarajan Krithika , Aluganti Narasimhulu Chandrakala , Bapputty Reena , Parthasarathy Sampath 
Published: July 2021

Background
Dietary intervention to prevent atherosclerosis and inflammation has been a major focus in recent years. Sesame oil (SO), widely used in many Asian countries, has been reported to help reduce high blood pressure. It has also been shown to reduce plasma cholesterol, low density lipoprotein (LDL) cholesterol and triglyceride levels. We previously reported that SO was effective in inhibiting atherosclerosis in LDL-receptor negative mice. In this study we tested whether the aqueous, non-lipid components of SO might have anti-inflammatory effects.

Methods
Sesame oil was extracted using ethanol:water mixture, lyophilized and reconstituted in water. To study anti-inflammatory effect, RAW 264.7 cells (macrophage cell line) were treated with the aqueous extract in the presence or absence of lipopolysaccharide (LPS) for 24 hours. RNA was extracted using Trizol. mRNA expression of inflammatory cytokines such as IL-1α, IL-6 and TNF-α were analyzed by real time PCR. Protein expression was determined by western blot analysis. To identify the mechanism of action, we performed luciferase assay using HepG2-LXR reporter cell lines.

Results
LPS induced the expression of IL-1α, IL-6 and TNF-α mRNA levels in RAW cells. The extract alone did not significantly affect the expressions of inflammatory cytokine genes. However, when treated together with LPS, sesame oil aqueous extract inhibited the mRNA levels of these cytokines significantly. Treatment with LPS together with SO extract also decreased the protein expression of these cytokines. The SO extract induced LXR expression as identified by the luciferase assay system in HepG2-LXR reporter cells.

Conclusion
These findings suggest that the aqueous portion of SO might be effective in preventing inflammation. Furthermore, the activation of LXR might suggest additional effects on lipid metabolism. Identifying the specific components present in the aqueous extract will be instrumental in developing treatment modalities for atherosclerosis and other inflammatory conditions.
Abstract 413: Myeloperoxidase-mediated Methionine Oxidation Renders Apolipoprotein A-I Amyloidogenic
Authors: Jayaraman Shobini , Gantz Donald L , Chan Gary K , Witkowski Andrzej , Cavigiolio Giorgio 
Published: July 2021

Background
Elevated plasma levels of apolipoprotein A-I (apoA-I) correlate with cardiovascular health, while dysfunctional apoA-I promotes atherosclerosis. The high concentration of myeloperoxidase (MPO) produced by activated macrophages in the atherosclerotic lesions generates an oxidative environment that impacts apoA-I and reduces its antiatherogenic functions.
Recent clinical studies revealed that amyloid deposition in the atherosclerotic plaques increases with aging. Interestingly, apoA-I was identified as a central component of these atherosclerosis-related amyloids.

Hypothesis
In this study, we tested the hypothesis that MPO-mediated oxidation of apoA-I can produce protein variants that are structurally destabilized and amyloidogenic.

Methods

Plasma apoA-I purified from normal individuals was exposed to chemical (hydrogen peroxide) and enzymatic (MPO-H
2
O
2
-chloride system) oxidation. Oxidized apoA-I was incubated at 37 °C and pH 6.0 to induce fibril formation.

Results

While no fibril formation was detected in intact apoA-I, both chemically and enzymatically oxidized apoA-I produced fibrillar amyloids after 12 h incubation at 37 °C. A large molar excess (~1000:1) of H
2
O
2
was needed to generate apoA-I fibrils, whereas exposure of apoA-I to a 1:1 oxidant:apoA-I molar ratio in the presence of MPO was sufficient to confer amyloidogenic properties to the protein. Analysis by gel electrophoresis, CD spectroscopy and mass spectrometry of soluble oxidized protein and of isolated fibrils indicate that no significant protein degradation occurred upon oxidation (both chemical and enzymatic) or fibril formation. The amyloid fibrils were composed of full-length apoA-I with all three native methionines converted to methionine sulfoxide.

Conclusions

In contrast to hereditary amyloidosis wherein specific mutations of apoA-I cause protein destabilization and amyloid deposition, oxidative conditions similar to those promoted by local inflammation in atherosclerosis are sufficient to transform full-length wild-type apoA-I into an amyloidogenic protein. Thus MPO-mediated oxidation may be implicated in the mechanism that leads to amyloid fibril deposition in the atherosclerotic plaques
in vivo
.
Abstract 456: Comparative Effects of Angiotensinogen versus Renin Inhibition on Established Atherosclerosis and Obesity in Hypercholesterolemic Mice
Authors: Balakrishnan Anju , Howatt Deborah A , Lu Hong , Graham Mark J , Mullick Adam E , Crooke Rosanne M , Feldman David , Cassis Lisa A , Daugherty Alan 
Published: July 2021

Background and Objective
The renin angiotensin system plays a critical role in atherosclerosis. Inhibition of angiotensinogen (AGT) or renin prevents atherosclerosis. AGT inhibition also ablates diet induced obesity. The purpose of this study was to compare the effects of AGT and renin inhibition on established atherosclerosis and obesity.

Methods and Results
To determine the role of AGT, male LDL receptor -/- mice were fed a saturated fat-enriched diet for 12 weeks to establish atherosclerosis (N=80). Body weight increased about 1 g/week in the 12-week duration. Twenty mice were then terminated to assess baseline atherosclerosis, and the remaining mice were randomly grouped to administer either control- or AGT-antisense oligonucleotides (ASO) (50 mg/kg/week ip; N=20/group) for 12 weeks. To determine the role of renin inhibition, male LDL receptor -/- mice were fed the same fat-enriched diet for 16 weeks (N=55). Mean body weight gain was about 1 g/week. Twenty-one mice were terminated to assess baseline atherosclerosis, and the remaining mice were randomly grouped to infuse either PBS (N=24) or aliskiren (12.5 mg/kg/d; N=10) for 12 weeks. Inhibition of AGT or renin significantly decreased systolic blood pressure. Atherosclerotic lesions were quantified in the aortic arch. Inhibition of either AGT or renin attenuated the rogression of atherosclerosis as compared to their relative controls (P=0.047 and P≤0.001, respectively), whereas neither mode of inhibition regressed atherosclerosis compared to their respective baseline. Renin inhibition did not influence the fat diet-induced body weight gain. Surprisingly, inhibition of AGT not only abolished body weight gain, but also led to pronounced loss of body weight (baseline versus 12-week injection of AGT-ASO: 36.0±0.8 versus 32.2±0.9 g; P<0.001). Echo MRI analyses demonstrated that the lower body weight in mice administered AGT-ASO was attributed to less fat mass, while lean mass was comparable between control-ASO and AGT-ASO groups.

Conclusions
Inhibition of either AGT or renin attenuated the continued development of atherosclerosis. Inhibition of AGT also profoundly reduced body weight. This highlights a disparity between the two modes of RAS inhibition.
Abstract 498: Age-adjusted Cut-off Levels Improve Test Performance in the Diagnosis Strategy of Venous Thromboembolism in Elderly Patients With a Non-high Pre-test Probability
Authors: Toulon Pierre , Claessens Yann-Erick 
Published: July 2021

Background
D-dimer levels below a well defined cut-off level enable to safely rule out VTE in patients with non-high PTP. Ageing is associated with higher levels of D-dimer. To address the issue of their usefulness in elderly patients, we firstly managed data from 644 out-patients with non-high PTP included in a multicenter management study of a D-dimer assay (C.Legnani et al. 2010). We then validated our results in a cohort of 1,042 consecutive patients investigated using another assay.

Results
In the first part, D-dimer level, evaluated using the HemosIL D-dimer HS500 assay (Instrumentation Laboratory), was above the cut-off level (500 ng/ml) in all 88 patients with VTE and in 299 of those without (53.8%). Test negative predictive value (NPV) and sensitivity were 100%. Overall test specificity was 46.2%, but decreased in an age-dependent manner over 70 y. ROC-analysis of test results obtained in patients classified according to age allowed us to propose an age- adjustment of the cut-off level calculated by increasing its level by 100 ng/ml per 10 y-increments in patients aged over 59 y e.g. 600 ng/ml between 60 et 69 y, 700 ng/ml between 70 et 79 y. Using those age-adjusted cut-off levels yielded to significantly improve test specificity (56.1%), particularly in old patients. If an 84 y old patient (D-dimer=625 ng/ml) was missed, NPV remained high (99.6%). That strategy was then validated by evaluating data from 1,042 consecutive out-patients, investigated using the Vidas D-dimer assay (BioMérieux). When applied, that age- adjusted cut-off levels leaded to improve test specificity 62.2% vs. 55.1% using the fixed cut-off level. 3 additional patients, with D-dimer >500 ng/ml but below age- adjusted cut-off level, were missed but overall NPV remained high 99.0% vs. 99.4%.

Conclusions
Age-adjusted cut-off levels for D-dimer, calculated by increasing the traditional cut- off level (500 ng/ml) by 100 ng/ml per 10 y-increments in patients aged over 59 y, significantly increased the test specificity. Correlatively, NPV and sensitivity were slightly decreased, as some patients, with D-dimer above 500 ng/ml but below the age-adjusted cut-off level, could be misdiagnosed. However such a strategy was safe, as NPV remained above 99% in our studied populations.
Abstract 520: Elastic Fiber Fragmentation and Aberrant Angiogenesis Precede Inflammation in Early-Onset Aortic Valve Disease
Authors: Opoka Amy M , Juraszek Amy L , Osinska Hanna , Smith J Michael , Merrill Walter H , Eghtesady Pirooz , Mecham Robert P , Bove Kevin E , Hinton Robert B 
Published: July 2021

Introduction
Elastic fiber fragmentation (EFF) is a hallmark of aortic valve disease (AVD), and both inflammation and neovascularization have been identified as late findings, presumably due to atherosclerosis through a wound healing like response. However, EFF independently stimulates angiogenesis, suggesting an alternative mechanism for neovascularization in AVD.

Hypothesis
We hypothesized that aberrant angiogenesis would be an early AVD finding, preceding inflammation, due to EFF.

Methods
To examine disease progression, valve tissue was examined using histochemistry and immunohistochemistry from early (<40yo) and late (≥40yo) onset AVD specimens, as well as age-matched autopsy control aortic valves. Angiogenesis (VEGF-A, CD-31, SMA and chondromodulin), EFF (elastin, fibrillin-1, emilin-1, fibulin-5), progenitor valve interstitial cell phenotype (CD-34, CD-45) and inflammation (CD-68, LRP-5) were assessed.

Results
Bicuspid aortic valve was more common in early-onset AVD (n=21), and cardiovascular comorbidities were more common in late-onset AVD (n=11). Early-onset AVD specimens demonstrated angiogenesis without inflammation or atherosclerosis. A distinct pattern of EFF and elastic fiber components surrounded early-onset AVD neovessels, which were not present in control valves, including increased emilin and decreased fibulin-5, and the elastase/anti-elastase ratio and localization were altered in both early and late-onset AVD, suggesting a dynamic disease progression. Interestingly, progenitor VICs were present in control valves at both stages and were unchanged in age-matched AVD specimens.

Conclusions
Aberrant angiogenesis is an early mechanism in AVD pathogenesis preceding inflammation, implicating EFF as an inciting factor. Elucidation of the underlying mechanisms may inform the development of new pharmacologic therapeutics and durable bioprostheses.
Abstract 6: Co-targeting of Thrombomodulin and the Endothelial Protein C Receptor Protects the Pulmonary Vasculature in a Mouse Model of Acute Endothelial Injury
Authors: Greineder Colin F , Zaytsev Sergei , Muzykantov Vladimir R 
Published: July 2021

Background
Recombinant activated protein C is protective in animal models of sepsis, stroke, and focal thrombosis, but has a poor side effect profile. Thrombomodulin (TM) and the Endothelial Protein C Receptor (EPCR) are endothelial membrane proteins, which partner to bind thrombin and activate protein C at sites of inflammation, ischemia, and thrombosis. Both proteins can be lost from the endothelial surface in a variety of disease states. We have shown previously that targeted delivery of TM to the Platelet Endothelial Cell Adhesion Molecule (PECAM-1) on the endothelial surface is protective in mouse models of lung inflammation and ischemia. Unlike endogenous TM, however, recombinant TM targeted to PECAM-1 does not effectively partner with endogenous EPCR.

Objective
We hypothesized that co-delivery of TM and EPCR would enhance in vitro activity and therapeutic efficacy in vivo.

Methods
TM and EPCR were fused to single chain fragments of two anti-PECAM antibodies, which are known to demonstrate collaborative binding enhancement. TM and EPCR fusion proteins were tested on PECAM-expressing cells and mouse endothelial cells. Fusion proteins were injected intravenously in C57BL/6 mice prior to intratracheal injection of endotoxin. Expression of VCAM-1 was measured using qPCR and MIP-2 was quantified in bronchoalveolar lavage (BAL) fluid. Endothelial barrier dysfunction was quantified by measuring transendothelial leak of 125I-labeled albumin.

Results
TM and EPCR fusion proteins target PECAM-1 on endothelial cells and demonstrate collaborative binding. Independent of binding effects, the EPCR fusion protein results in a 50% increase in the activation of protein C by cell-bound TM, an effect blocked by anti-EPCR antibody. Consistent with in vitro results, the combination of TM and EPCR fusion proteins enhances protection in endotoxin-induced lung injury, reducing VCAM expression, BAL MIP-2, and transendothelial leak of albumin (p < 0.001), as compared to TM fusion protein alone.

Conclusion
Co-targeting of TM and EPCR to PECAM-1 enhances activation of protein C and represents a novel and promising therapeutic strategy for the treatment of diseases involving acute endothelial injury.
Abstract 84: Serum Amyloid A Does Not Modulate the Inverse Association of HDL with Coronary Artery Calcification in Type 2 Diabetes
Authors: Mulvey Claire K , Churchill Timothy W , Terembula Karen , Ferguson Jane F , Mehta Nehal N , Qasim Atif N , Reilly Muredach P 
Published: July 2021

Introduction
Although high-density lipoprotein (HDL) is inversely correlated with cardiovascular risk, HDL loses its protective role in pathologic inflammatory states like type 2 diabetes (T2DM). HDL dysfunction contributes to accelerated atherosclerosis in T2DM, but the mechanism is incompletely defined. The acute phase reactant serum amyloid A (SAA) displaces apolipoprotein A-I and may impair HDL-mediated reverse cholesterol efflux. We hypothesized that SAA alters the inverse association between HDL and coronary artery calcium (CAC) in the Penn Diabetes Heart Study, a cross-sectional study of T2DM patients free of overt cardiovascular or renal disease.

Methods

We measured SAA in serum samples by immunonephelometry (N=975; mean age 58 ± 9 years; 63% male, 57% Caucasian; mean BMI 33 ± 6 kg/m
2
). HDL was measured enzymatically in lipoprotein fractions after ultracentrifugation. Agatston CAC scores were quantified from electron beam tomography at the same visit. Spearman correlation and logistic regression were used to test associations of SAA with clinical factors and metabolic syndrome. We used Tobit regression to analyze associations between CAC and HDL, both overall and stratified by 3 categories of SAA: undetectable, lower half detectable, and upper half detectable.

Results
Spearman correlations revealed moderate association of SAA with C-reactive protein (r=0.52) and weak associations of SAA with BMI (r=0.25) and HDL (r=0.17; all p<0.001). In logistic regression, the group with highest SAA levels had increased odds of metabolic syndrome compared to those with undetectable levels (OR 1.56, 95% CI 1.03 to 2.38, p=0.036). In adjusted Tobit regression, HDL was inversely associated with CAC (Tobit coefficient for 1-SD increase in HDL: -0.30; 95% CI -0.54 to -0.06; p=0.013). Across the categories of SAA, however, there was no difference in the association of HDL with CAC (Tobit coefficient for 1-SD increase in HDL: -0.17 [95% CI -0.49 to 0.16] for undetectable vs. -0.31 [95% CI -0.79 to 0.17] for lower half detectable vs. -0.49 [95% CI -1.01 to 0.03] for upper half detectable).

Conclusions
Despite the association of SAA with metabolic syndrome, these data suggest that elevated SAA may not change the inverse relationship of HDL with CAC in T2DM.
Abstract 124: Association of AdipoR2 mRNA Expression on Peripheral Monocytes With Carotid Plaque Instability
Authors: Gasbarrino Karina , Zheng Huaien , Mantzoros Christos , Lai Chi , Veinot John , Daskalopoulou Stella S 
Published: July 2021

Adiponectin, an adipose tissue secreted protein, possesses anti-atherosclerotic properties. Its effects are partly mediated through its action on monocytes, via receptors, AdipoR1 and AdipoR2. Circulating monocytes play a crucial role both in plaque initiation and in the progression of atherosclerosis. The aim of this ongoing study is to investigate for the first time whether there is differential expression of AdipoR1/AdipoR2 on human peripheral monocytes in patients with unstable vs. stable carotid atherosclerotic plaques.
Patients (n=20) with carotid stenosis of ≥50% scheduled for a carotid endarterectomy (CEA) were recruited from the Royal Victoria Hospital, Montreal, Canada. Blood samples were collected the morning of the CEA. A radioimmunoassay was used for plasma total adiponectin measurement. Circulating monocytes were isolated from mononuclear cells using a Magnetic Cell-Sorting technique with CD14+ Human Microbeads. Expression of AdipoR1/AdipoR2 mRNA on peripheral monocytes was determined using quantitative RT-PCR. Carotid plaque specimens were processed for histological analyses. Plaque instability was categorized according to the gold standard American Heart Association classification.
All specimens were graded as either a Type V (n=11) or a Type VI plaque (n=9). Type VI represents a more unstable lesion than Type V. AdipoR2 gene expression on monocytes was inversely associated with greater plaque instability; compared to patients with a Type V plaque, those with a Type VI plaque had 1.88-fold decreased AdipoR2 mRNA levels (p=0.046). AdipoR2 gene expression was found to be a trending predictor of a Type VI plaque (OR=2.93; 95% CI=0.87-9.81; p=0.082). AdipoR1 gene expression on monocytes did not differ between the two groups, while plasma adiponectin levels were lower in Type VI plaques (Type VI: 2.73 [2.19-3.96] μg/ml vs. Type V: 6.97 [4.69-10.07] μg/ml; p= 0.067). Plasma adiponectin levels did not correlate with the expression levels of AdipoR1/AdipoR2 on monocytes.
These results indicate that carotid plaque instability is associated with decreased AdipoR2 expression on peripheral monocytes. Our ongoing study may determine the underlying mechanisms linking adiponectin and its receptors with plaque instability.