bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4163: Higher Dose Exposure of Lovastatin is Not Associated with Adverse Hepatic Outcomes in Patients with Existing Liver Disease
Authors: Avins Andrew L , Manos M Michelle , Ackerson Lynn , Levin TR , Zhao Wei , Murphy Rosemary , Watson Douglas J , Hwang Peggy M , Replogle Amy R , Levine Jeffrey G 
Published: April 2024

OBJECTIVE: We have previously shown that the rate of subjects developing adverse liver outcomes was substantially lower during lovastatin-exposed periods compared to non-exposed periods in patients with pre-existing liver disease. The objective of this analysis was to estimate the dose-response relationship between differing levels of lovastatin exposure and adverse hepatic outcomes.
METHODS: This was a retrospective cohort study. Eligible subjects were adult members of Northern California Kaiser Permanente with at least 2-fold ALT or AST elevations 6–18 months apart, evidence of chronic hepatitis B or C infection, or a diagnosis of a chronic liver disease. Outcomes included the composite of events as well as individual components:

liver injury, defined as moderate (3X ULN<ALT<10X ULN) or severe (ALT<10X ULN);

development of clinical cirrhosis;

liver failure.

The dose-response relationships were analyzed by estimating the risk of each outcome in subgroups defined by quartiles of total cumulative lovastatin exposure. Each of these risks was compared to that in the lovastatin-unexposed reference group and a test for trend applied, using orthogonal polynomial contrasts on the coefficients of categorical levels of the exposure variable.

RESULTS: 93,106 eligible patients were identified, of whom 15% had been exposed to lovastatin. A strong and monotonic dose-response relationship was found for the composite outcome and moderate liver-injury endpoints. For the composite endpoint, hazard ratios declined from 0.81 in the quartile with least lovastatin exposure to 0.44 in the highest exposed group (
p<
.00001). Similarly, for the moderate liver-injury endpoint, hazard ratios declined from 0.97 to 0.27 with increasing lovastatin exposure (
p<
.00001).

CONCLUSIONS: Among patients with liver disease, lovastatin exposure was associated with a dose-dependent reduction in the risk of several liver-disease outcomes. These results do not support labeling recommendations for avoiding the use of lovastatin at higher doses in patients with liver disease nor the need to closely monitor LFTs during lovastatin treatment.
Abstract 4171: Olive Oil Phenolic Antioxidants Reduce Metalloproteinase (MMP)-9 Expression and Release in Human Monocytoid Cells: Possible Contribution to Plaque Stability
Authors: Carluccio Maria Annunziata , Massaro Marika , Scoditti Egeria , Storelli Carlo , Distante Alessandro , Visioli Francesco , De Caterina Raffaele 
Published: April 2024

Background: Mediterranean diets, of which olive oil is an important component, are associated with low prevalence of cardiovascular diseases, but active dietary components and their mechanisms of action are incompletely understood. The local production of active matrix metalloproteinases (MMPs) by macrophages likely contributes to plaque matrix degradation and plaque instability leading to acute coronary events.
Aim: To examine the effect of the olive oil phenolic antioxidants, hydroxytyrosol (HT)and oleuropein (OE), on MMP-9 expression and activity in monocytoid cells and to explore mechanisms of action.
Methods: U937 human monocytoid cells were pre-treated with HT or OE (0–100 μmol/L) for 30 min before stimulation with 50 nmol/L phorbol myristate acetate (PMA) in a serum-free medium for 24 h. Cell supernatants were then tested for the release of MMP-9 and tissue inhibitor of metallopro-teinases (TIMP)-1 antigens (ELISA) and for gelatinase activity by zymography. MMP-9 mRNA expression was investigated by RT-PCR and the activation of transcription factors Nuclear Factor(NF)-κB and Activator Protein(AP)-1 by EMSA.
Results: MMP-9 antigen and activity in U937 cells increased by about 50 fold after stimulation with PMA for 24 h (from 0.5 ± 0.3 to 24 ± 1.5, p<0.01). HT and OE (1–100 μmol/L) reduced PMA-induced MMP-9 activity, at zymography analysis, in a concentration dependent manner with inhibitory concentration producing 50% of the effect (IC50) at 10 μmol/L (p<0.01) and 25 μmol/L (p<0.01) respectively. In addition HT and OE reduced MMP-9 protein release and MMP-9 mRNA levels by about 65% and 45% respectively at 25 mmol/L (p<0.01), without significantly TIMP-1 release. HT and OE at micromolar concentrations also significantly (p<0.05) inhibited PMA-induced activation of NF-κB and AP-1, suggesting a plausible mechanism for the downregulation of MMP-9 expression.
Conclusions: The olive oil phenolic antioxidants inhibit MMP-9 expression and release in monocytoid cells, associated with reduced activation of NF-κB and AP-1. This may contribute to plaque stabilization explaining at least in part the cardiovascular protection by specific components of Mediterranean diets.
Abstract 4186: The Association of Central Obesity With Sex Hormones Differs Between Men and Women in the MultiEthnic Study of Atherosclerosis (MESA)
Authors: Vaidya Dhananjay , Ouyang Pamela , Dobs Adrian S , Golden Sherita H , Szklo Moyses , Liu Kiang , Gapstur Susan M 
Published: April 2024

Sex hormones affect adipose tissue metabolism and adipose tissue also metabolizes sex hormones for local effects. Central obesity is associated with a pro-atherogenic metabolic state. We analyzed cross sectional associations of endogenous sex hormones (SH: bioavailable Testosterone, BioT; estradiol, E2; dehydroepiandrostenedione, DHEA; SH binding globulin, SHBG) with waist circumference (WC) or waist to hip ratio (WHR) in men and women.
Methods: Analysis included 3163 men and 2051 postmenopausal women who were not on hormone therapy, (45– 84 years, 36% white, 13% Chinese, 28% African-American, 23% Hispanic) at MESA baseline examination. Analyses of interaction by sex were performed on the whole as well as race-stratified dataset. Estimations of association measures were done on sex-stratified race-pooled models. Unadjusted associations were assessed by Spearman rank correlations. WC (or WHR) was regressed on log-transformed SH adjusted for age, race, systolic BP, smoking and fasting glucose.

Results: The WC was 99.2±12.2cm in men and 98.6±15.6cm in women (p= 0.100). WHR was higher in men (96±7%) than women (92±8%, p<0.001). We found an unadjusted negative association of WC with BioT in men, but in women the association was positive (Table

, Spearman rho). DHEA was negatively associated with WC in men. In both men and women, E2 was positively associated and SHBG was negatively associated with WC. In adjusted models (Table

, coefficients), the findings for BioT, E2 and SHBG remained, while DHEA was associated with lower WC in both men and women. Sex differences were similar in race-stratified models. The interactions by sex were qualitatively similar for WHR in pooled and race stratified models.

Conclusions: In men and women, E2 is associated with greater central obesity, while DHEA and SHBG are associated with lower central obesity. This suggests that the hypoandrogenic state may be metabolically favorable in women, but unfavorable in men.

Waist Circumference and Sex Hormones in MESA
Abstract 4853: Spironolactone Therapy is Associated With Rapid Improvements in Blood Pressure Control and Cardiac Remodeling in Patients With Resistant Hypertension
Authors: Ahmed Mustafa I , Gaddam Krishna K , Gladden James D , Desai Ravi V , Lloyd Steven G , Gupta Himanshu , Denney Thomas S , Oparil Suzanne , Dell’Italia Louis J , Calhoun David A 
Published: April 2024

Background: The addition of spironolactone to a multidrug regimen is emerging as an effective antihypertensive strategy in patients with resistant hypertension independent of underlying aldosterone status. The effect of spironolactone on cardiac remodeling in these patients is not clear however.
Aims: In the current prospective study we used 3D-magnetic resonance imaging (MRI) to accurately evaluate the effects of spironolactone therapy on cardiac remodeling in patients with resistant hypertension.
Methods and Results: Twenty-two resistant hypertension patients were evaluated by MRI, prior to, and then 3 and 6 months following addition of spironolactone to a multidrug regime (all were taking at least 3 antihypertensives including a diuretic). Patients had a mean age of 54±2 years, 27% were female, 27% were African American and mean left ventricular (LV) ejection fraction was 70±1%. At three-months following spironolactone therapy, systolic and diastolic blood pressures were significantly improved (141±3 vs. 122±2, p<0.001 and 85±3 vs. 77±2, p=0.002, respectively). Furthermore significant reductions were noted in LV mass index (86±3 vs. 72±3, p<0.001), LA volume index (46±3 vs. 39±2, p=0.003) and BNP levels (44±9 vs. 17±5, p=0.009). Reductions in blood pressures, LV mass index and LA volumes remained significant independent of underlying aldosterone status. At six-months, there were no significant further reductions in any of these parameters.
Conclusions: In addition to a marked antihypertensive effect, addition of spironolactone to a multidrug regimen is associated with rapid regression of LV hypertrophy and reductions in LA volumes and BNP, all of which are important prognostic indicators. These findings demonstrate the broad cardiovascular benefits associated with spironolactone therapy in patients with resistant hypertension.
Abstract 4920: Endothelial-Targeted BMPR2 Loss-of-Function Mutations Cause Increased Apoptosis and Pulmonary Arterial Hypertension
Authors: Yelle Dominique , Deng Yupu , West James , Stewart Duncan J 
Published: April 2024

Introduction: Pulmonary arterial hypertension (PAH) is a rare and fatal disease caused by excessive remodelling of small pulmonary arterioles. Heterozygous loss-of-function mutations in the bone morphogenetic protein receptor 2 (BMPR2) have recently been implicated in patients with familial and idiopathic PAH. However, how mutations in this ubiquitously expressed receptor result in a specific abnormality of the lung microcirculation is unknown. We hypothesized that mutations in BMPR2 lead to PAH by increasing the susceptibility of ECs to apoptosis, particularly within fragile pulmonary arterioles. Aims: To examine the effect of endothelial targeted overexpression of a BMPR2 deletional mutation on EC apoptosis, pulmonary hemodynamics and arteriolar remodelling.
Methods: We developed an endothelial-specific binary transgenic (BT) mouse model in which the driver mice express the tetracycline transactivator under the control of the endothelial-restricted V-cadherin promoter and the responder mice harbour a BMPR2 transgene containing an arginine-to-stop mutation in the receptor’s C-terminal domain driven by a tetracycline responsive promoter. Pulmonary artery pressure was evaluated by measuring right ventricular systolic pressure (RVSP). Fluorescent microangiography (FMA) was performed to visualize the 3D architecture of the pulmonary microcirculation.

Results: RVSP was significantly increased in BT mice compared to non binary controls (p < 0.05; n = 9), associated with increased muscularization of small pulmonary arterioles detected by
α
-smooth muscle actin immunostaining. In addition, FMA revealed decreased perfusion and distal pre-capillary discontinuity in BT mice. TUNEL staining also demonstrated a significant increase in the number of apoptotic cells in BT mice compared to non binary controls (5.8 ± 1.1, 1.0 ± 0.7 positive cells/HPF, respectively; p < 0.05; n = 4).

Conclusions: These data suggest that BMPR2 mutations increase the susceptibility to apoptosis, possibly leading to EC loss and pre-capillary arteriolar discontinuity. This new model will help elucidate the pathophysiological events leading to the development of PAH and provide a unique tool to evaluate novel potential treatments for this disease.
Abstract 4944: Bayesian Analysis of TRITON-TIMI 38: Reassessing Prasugrel versus Clopidogrel in the Treatment of Patients With Acute Coronary Syndrome
Authors: Lang Christopher , Arora Rohit 
Published: April 2024

Background: The application of Bayesian analytic techniques can provide clinically relevant information regarding efficacy of an intervention. Given the recent controversy surrounding prasgurel, as reported in the TRITON-TIMI 38 study, we sought to re-examine both the frequentist and Bayesian statistical methods which evaluated this study.
Methods: Magnitude of therapeutic benefit and a sensitivity analysis were performed, using posterior probabilities (Pr), in relation to probability of benefit versus harm, as well as probabilities of greater than 20% benefit (Pr>20%). The analysis was conducted with experiential probabilities obtained from the TRITON-TIMI 38 data, and a null prior probability with a log mean OR of 0, and a standard deviation of 2.
Results: Based on the study results, the Pr for the primary endpoint of death from cardiovascular causes, nonfatal MI, or nonfatal stroke is 99.9%. Calculated probability of at least a 20% benefit is 66.5%. This value is reasonably high enough to infer a clinically important benefit. All cause mortality was also found to have a clinically relevant benefit at Pr>20% of 99.1%. Analysis does indicate a clinically significant probability of harm pertaining to Non-CABG major and major plus minor bleeding, with a probability of at least 20% harm of 73.6 and 82.4% respectively.
Conclusions: On re-evaluation, the Bayesian analysis suggests the clinical relevance of prasugrel as a beneficial treatment in patients with ACS, which serves to support the implications of the conventional statistics reported in TRITON-TIMI 38. Of note, the clinically relevant benefit is juxtaposed against the harm related to bleeding complications.
Abstract 4959: Imaging of Atherosclerotic Lesions in Apoe−/− Mice by Targeting of CD40
Authors: Grafe Michael , Dietrich Thore , Stibenz Dietger , Klohs Jan , Lutgens Esther , Schulz Petra , Groetzinger Carsten , Bourayou Riad , Fleck Eckart , Graf Kristof 
Published: April 2024

We investigated whether in-vivo imaging of the CD40 receptor can be used for identification of inflammatory atherosclerotic lesions.
Methods: Monoclonal antibodies against CD40 (CD40ab), IgGA2 (Coab) and Fab2 fragments (CD40Fab) were coupled to the near-infrared fluorescence (NIRF) dyes Cy5′5 or Cy7. Apolipoprotein E deficient mice (apoE−/−) and apoE−/−CD40−/− deficient mice (apoE−/−CD40−/−) were fed with high cholesterol diet for 8 –12 month. Antibody conjugates were injected into the tail vein and mice were investigated 6 to 48 hours after injection by conventional NIRF imaging, fluorescence microscopy of the aortic arch and in-vivo 3D fluorescence molecular tomography (FMT). Sudan staining and histological analysis were performed after imaging procedures.
Results: Application of Cy5′5-labeled CD40ab resulted in accumulation of fluorescence signal intensity mainly in Sudan-positive areas of the thoracic aorta, which was also seen with the Coab at high concentrations. Fluorescence increased slightly after 24 hours compared to 6 hours after injection. In vivo imaging was not feasible using conjugated antibodies due to circulating intravasal fluorescence (>48h). Significant background fluorescence was detected after application of CD40ab and Coab in all mice, probably due to FC receptor-dependent binding. Application of Cy7-CD40Fab induced strong in-vivo fluorescence detected by FMT in projection to the aortic arch and carotid arteries of apoE−/− (n=4), but not in apoE−/−CD40−/− mice (n=4). No signal was observed in mice injected with unlabelled Cy7. Ex-vivo imaging of the thoracic aorta confirmed a Cy7 signal in atherosclerotic lesions of apoE−/−, but not in apoE−/−CD40−/− after application of CD40Fab. Data were also confirmed by microscopic fluorescence imaging of the aortic wall and atherosclerotic lesions.
Conclusion: In vivo detection of CD40 in atherosclerotic plaques was feasible using antibody fragments but not with full anti-CD40 antibodies. The approach is applicable for detection of vascular inflammation, since CD40 is strongly associated with inflammatory lesion formation.
Abstract 5075: Beneficial Effects of Combination of ACE Inhibitor and Rho-kinase Inhibitor on Tubulointerstitial Fibrosis Induced by Unilateral Ureteral Obstruction
Authors: Nishikimi Toshio , Takeda Yosuke , Ishimura Kimihiko , Tadokoro Kazuyoshi , Iemura-Inaba Chikako , Akimoto Kazumi , Ishimitsu Toshihiko , Matsuoka Hiroaki 
Published: April 2024

Objects: We recently reported that long-term Rho-kinase inhibition attenuates glomerulosclerosis in severe hypertension, salt-induced hypertension, and malignant hypertension rat model. In addition, ACE inhibitor is well known to prevent renal fibrosis. This study was design to compare the effects of ACE inhibitor (imidapril), Rho-kinase inhibitor (fasudil), and their combination on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). We also attempted to elucidate the mechanism involved.
Methods: Imidapril (50mg/L), fasudil (1g/L), or their combination was given in drinking water to mouse (C57BL/6, each group: n =8), and their effects were compared on renal interstitial fibrosis induced by UUO. We measured histological findings, immunohistological findings, oxidative stress, and various mRNA expressions in the kidney by UUO.

Results: Eleven days after UUO, wild type kidney was characterized increased fibrotic area (Masson’s trichrome stain positive area), dihydroethidium (DHE) positive area,
α
-SMA positive area, F4/80 positive area, and increased various mRNA expressions. Fasudil and imidapril similarly improved fibrotic area (−23%, −15%), DHE positive area (−13%, −11%),
α
-SMA positive area (−22%, −15%), F4/80 positive area (−42%, −34%), and various mRNA expressions (TGF-
β
: −20%, −18%; CollagenI: −37%, −19%; CollagenIII: −36%, −26%; MCP-1: −22%, −34%, TNF-
α
: −7%, −13%), most of which were significant (P< 0.05). Combination of imidapril and fasudil further improved fibrotic area (−52%), DHE positive area (−26%),
α
-SMA positive area (−33%), F4/80 positive area (−62%), and various mRNA expressions (TGF-
β
:−48%; CollagenI:−65%; CollagenIII:−59%; MCP-1:−54%, TNF-
α
: −33%) (all P <0.05 vs monotherapy).

Conclusion: Compared with either agent alone, the combination of an ACE inhibitor and a Rho-kinase inhibitor is more effective in the prevention of renal interstitial fibrosis due to inhibition of TGF-
β
/collagen, migration of monocyte/macrophage, differentiation of fibroblast, inflammation, and oxidative stress pathway. Combination of an ACE inhibitor and a Rho-kinase inhibitor may be a possible new therapeutic strategy for chronic kidney disease.
Abstract 5134: Distribution of Dipyridamole in Blood Components Among Post-Stroke Patients Treated With Extended Release Formulation
Authors: Serebruany Victor L , Sabaeva Elena , Booze Christopher , Atar Oliver , Hanley Dan 
Published: April 2024

Background and Purpose - Extended release dipyridamole (ERD) is widely used in patients after ischemic stroke; however, the ability of this antithrombotic agent to be stored in different blood cells has never been explored in post-stroke patients. We hypothesized that since ERD is known to be highly lipophylic, the drug may be present not only in plasma, but also accumulated in platelets, leukocytes, and erythrocytes.
Methods - Fifteen patients after documented ischemic stroke were treated with Aggrenox (ERD and low dose aspirin combination) BID for 30 days, and 12 of them completed the study. ERD concentrations in blood cells and platelet poor plasma were measured by spectrofluorimetry at Baseline, Day 14, and Day 30 after the initiation of therapy.
Results - The background level of spectrofluorometry readings differs slightly among the blood components (132–211 ng/mL) due to the differences in the preparation of samples and cell isolation techniques. As expected, 2 weeks of ERD therapy produced steady state plasma concentration of dipyridamole already at Day 14 (1680±542ng/mL), followed by a slight not significant decrease at one month (1619±408). Two weeks of therapy was sufficient to achieve a consistent dipyridamole accumulation in erythrocytes (361±43), but not in platelets (244±78), or leukocytes (275±49). In fact, while blood cells continued dipyridamole intake beyond 14 days period, and this increase (398±66) was significant (p=0.02) at thirty days.
Conclusion - Treatment with ERD in post-stroke patients resulted not only in the achieving of therapeutic plasma dipyridamole concentrations, but also deposition of the drug in erythrocytes and leukocytes, but not in platelets. If confirmed, these data will affect our better understanding of dipyridamole pleiotropy, and may expand future clinical indications of ERD formulation.
Abstract 5313: Reduction of S100A12 in Marfan Syndrome Aortic Smooth Muscle Cells Attenuates Inflammatory and Apoptotic Pathways
Authors: Bowman Marion Hofmann , Gawdzik Joseph , Nicolarsen Jeremy , Raman Jai , Dellefave Lisa , McNally Elizabeth 
Published: April 2024

Marfan syndrome (MFS) is associated with thoracic aortic aneurysms. S100A12 has been associated with initiation of inflammatory pathways via activation of the receptor for advance glycation endproducts (RAGE) and is up regulated in smooth muscle cells of ruptured human coronary artery plaques. We tested the hypothesis that S100A12 is expressed in SMC in human aortic aneurysms of MFS, and that downregulation of S100A12 may suppress inflammatory and apoptosis pathways.
Methods: Aortic tissue from a patient undergoing surgery for MFS aneurysm and control aortic tissue were compared and several cell lines of primary SMC’s were established. SMC that carry a mutation in the FBN-1 gene (Arg529Term) and control SMC were each transfected with siRNA-S100A12-GFP and siRNA-control-GFP. GFP positve SMC were isolated by FACS, followed by qRT-RCR using arrays for inflammation and apoptosis pathways (RT2 profiler PCR Array, SA Biosciences).
Results:

Immunohistochemistry of aortic tissue from MFS revealed expression of S100A12 in SMC, but not in SMC of control aortic tissue. S100A12 was expressed strongest in SMC near the focal areas of medial degeneration.

Cultured SMC that carry the FBN-1 mutation strongly expressed S100A12 protein. S1090A12 expression was completely abolished by transfection with siRNA-S100A12-GFP construct but not with siRNA control-GFP construct.

S100A12 reduction in FBN-1 mutant SMC suppressed at least two fold the mRNA of 80% of genes on the inflammation array and of 91% of the genes on the apoptosis array.

The death receptor Fas, caspase 10 and effector caspases 3 and their substrate DFFA were probed using semi-quantitative immunoblotting. FBN-1 mutant SMC showed approximately 2-fold increase for Fas, and two fold increase in Casp3 and DFFA compared to control SMC. Treatment with Fas CH11 activating monoclonal antibody induced Casp3 approximately 12 fold in FBN-1 mutant SMC compared to a two fold induction in control SMC (p< 0.001). Reduction of S100A12 in FBN-1 mutant SMC reversed this pattern with s significant reduction in Fas, caspase 10 & 3, and DFFB. Summary: S100A12 is upregulated in SMC in thoracic aneurysms and reduction of S100A12 reduces Fas-mediated apoptosis in aortic SMC in MFS.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).