bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 442: Correlates of the Triglyceride/HDL Cholesterol Ratio: The Very Large Database of Lipids (VLDL-4)
Authors: Jones Steven R , Martin Seth S , Joshi Parag H , Elshazly Mohamed , Kulkarni Krishnaji R , Toth Peter P 
Published: July 2021

Background
The Triglyceride/HDL Cholesterol Ratio (TG/HDL-C) is predictive of atherosclerosis and vascular disease risk. It is frequently elevated in the metabolic syndrome and diabetes and tracks with measures of insulin resistance.

Methods
We investigated the correlates of TG/HDL-C in 3,609 serial subjects of the 1,340,614 U.S. adults from the VLDL dataset who had apoB, hsCRP, serum insulin levels, hemoglobin A1C (A1C) measurements in addition to ultracentrifugation lipid measurement by VAP method (Atherotech, Birmingham, AL). A continuous LDL density parameter (LLDR) was calculated as the natural log of the ratio of dense to buoyant LDL-C subfractions. Remnant lipoprotein cholesterol (RLP-C) was defined as dense remnant VLDL3-C + IDL-C. TG/HDL-C was modeled using multiple linear regression.

Results
The strongest correlates of TG/HDL-C in model 1 were serum insulin, RLP-C, LLDR and Lp(a)-C with overall model r=0.801, adjusted r2=0.641, p<0.001. Model 2 substituted dense VLDL3-C and IDL-C individually as independent variables in lieu of their sum, RLP-C; overall model r=0.855, adjusted r2=0.730, p<0.001. IDL-C was inversely correlated while VLDL3-C was more strongly and positively associated with TG/HDL-C. A1C was not significantly correlated in the multivariate models (Table).

Summary
TG/HDL-C ratio represents a composite of metabolic and lipid atherosclerosis risk markers including insulin levels, LDL density, RLP-C, lp(a)-C, homocysteine, gender and apoB.
Abstract 443: ABCA1 Up-Regulation but Not CETP Inhibition is Predicted to Increase the Reverse Cholesterol Transport (RCT) Input Rate: a Simulation Study of HDL-C Raising Targets Using a Novel in-silico Model of Lipoprotein Metabolism and Kinetics
Authors: Lu James , Nanjee M. Nazeem , Brinton Eliot A , Hübner Katrin , Mazer Norman A 
Published: July 2021

Introduction

HDL is believed to mediate RCT and hence lower CV risk. The recent failures of HDL-C raising drugs to improve CV outcomes raise questions on the link between HDL-C and RCT. We investigate the association between the two using an
in-silico
model.

Methods
The model describes the cyclic process of αHDL maturation from lipid-poor ApoA-I (pre-β1) and the regeneration of pre-β1 from αHDL particles via remodeling processes (e.g., particle fusion, SRB1 and CETP mediated lipid transfers). RCT is a complex process initiated by cholesterol efflux into plasma. In our model we assume that the ABCA1-dependent loading of cholesterol onto pre-β1 is the main contributor to cholesterol efflux and quantify this as the RCT input rate. The model is calibrated to literature data on normal and CETP deficient subjects and validated with data on ABCA1 deficiency. Using a virtual population of n=359 subjects with low HDL-C, we simulate two target modulations, 80% CETP inhibition and 100% ABCA1 up-regulation, chosen to raise HDL-C by comparable amounts.

Results
Table 1 shows that both target modulations increase HDL-C by approximately 50%. For ABCA1 up-regulation, this reflects an increased RCT input rate; while for CETP inhibition, the increase in HDL-C results from a decreased clearance rate. The model also predicts a larger increase in ApoA-I and a greater decrease in the pre-β1 level and fraction with ABCA1 up-regulation compared to CETP inhibition.

Conclusions

The level of HDL-CE reflects the ratio of the RCT input rate to the clearance rate. Our
in-silico
model provides a tool for evaluating HDL-C raising targets in terms of their differential effects on the underlying metabolic processes.
Abstract 445: Niacin Beneficially Alters the Secretion of Intestinal-derived TRL and HDL in a Rat Model of Insulin Resistance
Authors: Mangat Rabban , Borthwick Faye , Ullrich Tina , Jacome Miriam , Vine Donna F , Proctor Spencer D 
Published: July 2021

Introduction
The intestine secretes discrete fractions of triglyceride (TG) rich apoB-chylomicrons (CM) and HDL particles into mesenteric lymph. Insulin resistance (IR) is associated with overproduction of intestinal CM however, the effect of IR on intestinal HDL secretion remains unknown. Niacin has been shown to reduce plasma TG while increasing HDL-C, however it is unknown if niacin modulates intestinal lymphatic CM and HDL secretion.

Objective

To determine the effect of niacin on the secretion and composition of intestinal lymphatic CM and HDL in a model of IR (JCR:LA-
cp
rat).

Methods

IR rats were fed control chow or chow supplemented with niacin (0.5% or 1% w/w) for 6 weeks. The mesenteric lymph duct was cannulated and lymph sampled following an intra-gastric intralipid (
fed
) infusion for 6hrs. The lymphatic CM (<1.006g/ml) and HDL (1.063-1.21g/ml) fractions were separated by density ultracentrifugation.

Results
IR rats over-secreted (2-fold) lymph apoB-CMs, while simultaneously reducing lymphatic apoA1-HDL (-47%) secretion compared to non-IR rats. In addition, CM and HDL particles from IR rats were found to be enriched in TG (64 and 86% respectively). Interestingly, niacin stimulated the secretion of lymph HDL (>60%), as well as attenuated lymph CM (-53%) secretion compared to control. Niacin treatment was also found to normalize the TG content of both lymph-CM and lymph-HDL particles.

Conclusion
IR appears to stimulate the intestine to over-secrete apoB-CM as well as reduce apoAI-HDL secretion into lymph, potentially contributing to particle dysfunction. Niacin may contribute to improving CVD risk by reducing the over-secretion of intestinal pro-atherogenic apoB-particles, whilst restoring the number and TG enrichment of intestinal anti-atherogenic apoAI-particles.
Abstract 497: Clinical Significance of Heparin Induced Thrombocytopenic Thrombotic Syndrome with Initiation of Anti-heparin Antibodies Negative: A Case Report and Literature Review
Authors: Shi, MD Qi , Paulino Robert , Kiel Michael , Wu Huimin , Samavedam Sandhya , Kakde Amit , Bo Jiang , Malik Qasim , Crevecoeur Louis , Ravi Vimal 
Published: July 2021

Introduction
Heparin induced thrombocytopenia thrombosis Syndrome has a high mortality and morbidity in cardiac surgical patients in spite of early diagnosis and management. We present a case with multiple acute deep venous thrombosis (DVT) after using unfractionated heparin (UFH) during coronary artery bypass graft (CABG) with initiation of HIT antibodies negative.

Case presentation
A 70-year-old male complained of left leg pain 2 days after CABG for an acute ST-elevation myocardial infarction. Patient was treated with UFH intravenous during CABG. Platelet count was 78 x 109/L that was 130 x 109/L before the procedure. Anti-heparin antibodies IgM/IgG were negative. Venous Doppler ultrasound showed an acute deep venous thrombosis (DVT) in the left peroneal vein. However, after the patient was treated with Coumadin anticoagulation for 7 days with INR in therapeutic range (2-3), the patient presented for right low extremity pain. Platelet count was 40 x 109/L. Anti-heparin antibodies IgM and IgG were repeatedly positive. Venous Doppler ultrasound showed multiple bilateral lower extremities acute DVTs. Patient had thrombectomy and continued with coumadin anticoagulation at INR in therapeutic range for 3 months.

Discussion
HITTS is an immune-mediated drug reaction that occurs more frequently in patients undergoing cardiovascular surgery. Thrombosis caused by the HIT/T syndrome is most commonly venous thromboembolism. Thrombosis is arterial in about 20% of cases, including acute limb ischemia, myocardial infarction, or stroke. Previous clinical data has shown that about 40% of high titer-negative HIT antibodies were associated with a positive result in repeated testing several days later, which is the same as our presentation. The mortality and morbidity rates of HITTS are approximately 30% and 60%, respectively, and an additional ~10% of patients require amputations or suffer other major morbidity. However, with early recognition and intervention, mortality can be reduced from >30 to <10%. Obviously, repeated testing to identify patients who have HIT despite a negative initial HIT test in several days is greatly recommended. Diagnosis is essentially clinical and negative results from laboratory assays do not exclude the diagnosis.
Abstract 507: Genetic Correlates of Cognitive Change in Patients Undergoing Carotid Interventions
Authors: Hitchner Elizabeth , Liao Phoebe , White Sharla , Rosen Allyson , Lane Barton , Zhou Wei 
Published: July 2021

OBJECTIVES
Carotid interventions have been shown to decrease stroke risk and improve cerebral perfusion. However, nearly 40% of patients who undergo carotid revascularization procedures experience cognitive deterioration. We have demonstrated that subclinical microembolization is associated with memory decline, but whether genetic factors plays a role in post-procedural cognitive change is unclear. We herein seek to assess genetic determinants as potential risk factors for these procedures.

METHODS
Over one year period, patients undergoing carotid interventions at a single academic institution were recruited to participate. Patients underwent neuropsychological testing two weeks prior to and at one month following their procedure and MRI prior to and within 48 hours following their procedure. Saliva samples were collected for genetic testing and demographics were recorded. Logistic regressions were used to search for associations.

RESULTS
34 patients were included (18 CAS, 16 CEA); all were male with a mean age of 68. The majority of patients exhibit hypertension (94%) and have a history of smoking (76%). Other co-morbidities included diabetes (47%), obesity (35%), and CAD (44%). Consistent with previous findings, CAS was associated with higher incidence of microemboli (p=.0005) and with susceptibility to memory decline (p=.0085). Negative univariate associations were found for 5-HTT (serotonin transporter) short alleles with memory decline (p=.016) and brain-derived neurotrophic factor (BDNF) polymorphism with incidence of microemboli (p=.018). After adjusting for apolipoprotein E (ApoE) risk alleles, incidence of microemboli trended with memory decline (p=.099).

CONCLUSIONS
Despite a small number of patients, our study showed that genetic polymorphisms such as 5-HTT, BDNF, and ApoE may provide additional insight on post-operative changes in cognition. Further investigation of these polymorphisms is warranted to understand and potentially prevent cognitive deterioration following carotid revascularization procedures.
Abstract 52: Statin Therapy Accelerates Venous Thrombus Resolution: Assessment In Stasis And Chemical Injury Induced Thrombosis
Authors: Kessinger Chase W , Kim Jin Won , Thompson Brian , Sillesen Martin , Hara Tetsuya , McCarthy Jason R , Lin Charles P , Henke Peter K , Jaffer Farouc A 
Published: July 2021

Introduction
In deep vein thrombosis (DVT), both the induced inflammation response and fibrinolytic capacity are critical in resolving experimental DVT. Unresolved, obstructing thrombi can lead to the burdensome and costly sequelae of the post-thrombotic syndrome. Recently, statins have shown to reduce the incidence of DVT (JUPITER trial). In this study, we investigated the in vivo effects of statin therapy on resolution of already formed DVT using serial intravital microscopy (IVM) imaging and thrombus mass measurements.

Methods
DVT was induced in C57Bl/6J male mice (N=190) by topical ferric chloride of the femoral vein (chemical injury) or ligation of the IVC (stasis). One day after DVT induction, mice started treatment of atorvastatin (1.14mg/kg), mevastatin (10 mg/kg) or PBS by once daily oral gavage. Serial IVM was preformed at days 2, 4 and 6 utilizing FITC-dextran (ex/em 490/520nm), CLIO-AF555 (ex/em 555/565nm), and MMPSense680 (ex/em 680/700nm) imaging agents for thrombus architecture, macrophage content and MMP activity measurements. Thrombus masses were collected at days 4, 7, 10 in stasis DVT mice and combination statin/enoxaparin (10mg/kg/d, s.c.) were also compared to statin therapy. Platelet activation and coagulation were analyzed using aggregometry and thromboelastography on whole-blood.

Results
We found that statin therapy reduced DVT burden and inflammation in both chemical- and stasis-induced established DVT up to 10 days compared to control (p<0.05). Serial IVM imaging of statin animals showed an increase in DVT resolution from day 2 to 4 (Δlength -21± 6.0 vs. control -7.1± 5.6%, p<0.01), and decreased inflammation compared to controls (p<0.001). Inflammation was also found to predict the extent of DVT resolution(r=0.84). Statin therapy also reduced thrombus plasminogen activator inhibitor-1, tissue factor, and Mac-3 levels, as well as reducing platelet activation and clot strength(p<0.05).

Conclusion
Statin therapy accelerates DVT resolution despite reducing thrombus related inflammation. The net reduction of thrombus burden tracked with statin-mediated favorable effects on fibrinolysis, coagulation, and platelet function. These results support statins as a translatable therapy to improve the resolution of DVT.
Abstract 536: Metformin Accumulation and Accentuated Ampk Phosphorylation Contribute to Sustained Inhibition of Agonist-Induced Contractility in Endothelium-Denuded Rat Aorta
Authors: Pyla Rajkumar , Osman Islam , Hansen Paul , Fagan Susan C , Segar Lakshman 
Published: July 2021

Objective
Metformin, a widely used antidiabetic drug, has been shown to exert protective effects in the vasculature by improving endothelium-dependent vasodilation. However, the beneficial effect of metformin toward smooth muscle contraction and the molecular events involved in this process remain unclear. Using endothelium-denuded aorta, the present study has therefore examined the extent of metformin accumulation and the likely changes in AMP-activated protein kinase phosphorylation during smooth muscle contraction induced by G-protein coupled receptor agonists, including phenylephrine (PE) and serotonin (5-HT).

Methods
Endothelium-denuded rat aortic ring preparations were mounted in organ baths for isometric tension measurements. The contractile responses to cumulative concentrations of PE or 5-HT were determined before and after pretreatments with metformin or AICAR (a direct AMPK activator). The changes in AMPK phosphorylation were determined by immunoblot analysis. Metformin accumulation was determined by LC-MS/MS.

Results
Concentration dependency studies revealed that pretreatment with 3 mM metformin resulted in significant inhibition of PE- or 5-HT-induced contractility (p < 0.05). In parallel, pretreatment with 1 mM AICAR led to a similar inhibition of agonist-induced contractility (p < 0.05). Notably, the inhibitory effects of metformin on smooth muscle contractility persisted even after the washout of this drug. In contrast, washout of AICAR restored the contractile responses to PE or 5-HT. Pretreatment of aortic rings with 40 μM compound C, an AMPK inhibitor, resulted in significant reversal of metformin and AICAR-mediated decrease in agonist-induced contractility (p < 0.05). An association between metformin/AICAR treatment and AMPK phosphorylation was confirmed by immunoblot analysis. Importantly, metformin treatment resulted in its significant accumulation in the aortic tissue as revealed by LC-MS/MS analysis.

Conclusion

In conclusion, metformin accumulation contributes to sustained inhibition of arterial smooth muscle contractility
via
activation of AMPK. The present findings suggest that metformin has the potential to ameliorate chronic hypertension in patients with type 2 diabetes.
Abstract 567: Causal Assessment of Uric Acid and Risk of Myocardial Infarction, a Mendelian Randomization Study
Authors: Keenan Tanya , Ho Weang K , Voight Benjamin F , Rasheed Asif , Mucksavage Megan L , Reilly Muredach , Danesh John , Rader Daniel J , Saleheen Danish 
Published: July 2021

Introduction
Prospective studies suggest that high serum uric acid (UA) levels are associated with increased risk of myocardial infarction (MI), but causality of this association remains uncertain. Mendelian randomization studies assess causality by using genetic variants as unbiased proxies for circulating biomarkers. We tested the hypothesis that genetically raised UA levels are causally related to elevated MI risk.

Methods
All reported UA associated genetic variants were assessed for pleiotropy in public genome-wide association databases and in the Pakistan Risk of Myocardial Infarction Study (PROMIS), in which we measured >25 atherosclerosis-related biomarkers in >10,000 people. Genetic variants lacking pleiotropic associations (p<0.01) were evaluated for association with MI in 7031 cases and 6360 controls in PROMIS.

Results
Among the individuals studied (mean age 54 ± 10 years; 81% male), 1316 had UA measurements with mean UA 5.71 ± 1.54 mg/dl. Of the 36 genetic variants associated with UA at genome-wide significance (p <5x10-8), 5 were independent and not associated with any factors investigated. For each variant, genetically raised UA was not associated with MI risk in a concordant direction (Table). A score-based instrumental variable analysis found no causal relationship between UA levels and MI (OR 0.91, 95% CI 0.74 - 1.12, p = 0.39). This analysis will be repeated with CARDIoGRAM data in time for presentation.

Conclusions
(1) Genetically raised UA levels were not associated with elevated MI risk, and (2) the collection of UA genetic instruments did not reject the null hypothesis of no causal relationship. We suggest that UA levels are not causally related to MI risk.
Abstract 72: Vascular and Cardiac Effects of Inducible Nitric Oxide Synthase in Hyperhomocysteinemic Mice
Authors: Dayal Sanjana 
Published: July 2021

Background
Diet-induced hyperhomocysteinemia (HHcy) produces endothelial and cardiac dysfunction and promotes thrombosis through a mechanism proposed to involve oxidative stress. Inducible nitric oxide synthase (iNOS) is upregulated in HHcy and can generate oxidants such as superoxide. We tested the hypothesis that iNOS mediates the adverse oxidative vascular, thrombotic, and cardiac effects of HHcy.

Methods

Mice deficient in iNOS (
Nos2-/
-) and their wild-type (WT) littermates were fed either a control (C) diet or a high methionine/low folate (HM/LF) diet for 3-6 months. Vasomotor function was assessed in cerebral arterioles in response to the endothelium-dependent dilator acetylcholine or the endothelium-independent dilator nitroprusside. Thrombotic occlusion of the carotid artery was measured in response to photochemical injury (rose bengal). Regional myocardial injury was measured after 30 minutes of ischemia and 2 hours of reperfusion of the left coronary artery.

Results

Nos2
-/- and WT mice fed the HM/LF diet developed similar levels of HHcy, with a 2-fold increase in plasma total homocysteine (P<0.001 vs. C diet). As expected, WT mice with HHcy exhibited endothelial dysfunction, with impaired dilatation to acetylcholine but not nitroprusside, and enhanced susceptibility to thrombosis, with shortened times to occlusion of the carotid artery (P<0.05 vs. C diet). Interestingly, deficiency of iNOS resulted in decreased, rather than increased dilatation responses to acetylcholine (P<0.05 vs. WT mice).
Nos2
-/- mice also exhibited shortened times to thrombotic occlusion in mice fed the C diet (P<0.05 vs. WT mice) and failed to protect from endothelial dysfunction or accelerated thrombosis in mice fed the HM/LF diet. Deficiency of iNOS did not alter myocardial infarct size in mice fed the C diet but significantly increased infarct size and cardiac superoxide production in mice fed the HM/LF diet (P<0.05 vs. WT mice).

Conclusions
These findings suggest that endogenous iNOS protects from, rather than exacerbates, endothelial dysfunction, thrombosis, and myocardial ischemia-reperfusion injury. In the setting of HHcy, iNOS appears to function to blunt cardiac oxidative stress rather than as a source of superoxide.
Abstract 79: Examining the Role of Endoplasmic Reticulum Stress Induced Glycogen Synthase Kinase-3a/ß in Accelerated Atherosclerosis
Authors: McAlpine Cameron , Werstuck Geoff 
Published: July 2021

Introduction
Cardiovascular disease accounts for a third of all deaths in the western world, however our understanding of the molecular mechanisms of atherosclerosis development is incomplete. Our previous findings have suggested that endoplasmic reticulum (ER) stress plays a causative role in atherogenesis. The objective of this study is to investigate how ER stress promotes atherosclerosis with a specific focus on ER stress-induced Glycogen Synthase Kinase (GSK)-3α and β.

Methods and Results
Established mouse models of accelerated atherosclerosis including hyperglycemia, hyperhomocysteinemia and relative dyslipidemia in female ApoE-/- mice were examined. A subset of mice from each group was supplemented with valproate (625 mg/kg), a compound with GSK3α/β inhibitory properties. Hyperglycemia, hyperhomocysteinemia and high fat diet elevated ER stress levels in multiple tissues, enhanced GSK3β activity, increased atherosclerotic plaque size, and induced hepatic steatosis. Valproate-supplementation significantly attenuated GSK3 activation, aortic plaque development and hepatic steatosis without altering ER stress levels. ER stress and valproate appears to modulate GSK3 activity by altering its phosphorylation status.
To examine the mechanism linking ER stress to the activation of pro-atherogenic pathways, cultured THP1-derived macrophages were treated with the ER stress inducing agents, glucosamine (5mM), thapsigargin (1.5μM) or palmitate (800μM). GSK3α/β activity was inhibited with the specific inhibitor CT99021 (4μM). In macrophages, ER stress upregulated the mRNA expression of genes controlling lipid biosynthesis while GSK3α/β inhibition attenuated lipid synthesis. The expression of downstream targets of the PERK ER stress signaling pathway, CHOP and ATF4, were downregulated by GSK3α/β inhibition. Further, PERK-/- mouse embryonic fibroblasts (MEFs) had significantly attenuated lipid accumulation while expression of constitutively active GSK3β-S9A restored the ability of PERK deficient cells to accumulate lipids.

Conclusions
These findings support the a common pathway that links cardiovascular risk factors to the activationof pro-atherogenic pathways by a mechanism involving ER stress-induced GSK3α/β.