Paula Clancy

Association of statin prescription with small abdominal aortic aneurysm progression

BACKGROUND Statins have been suggested to reduce expansion of abdominal aortic aneurysms (AAAs) independent of lipid-lowering effects. METHODS We assessed the association of statin treatment and serum low-density lipoprotein (LDL) concentrations with small AAA expansion. Six hundred fifty-two patients undergoing surveillance of small AAAs were entered into the study from 5 vascular centers. In a subset, fasting lipids (n = 451) and other biomarkers (n = 216) were measured. The AAA diameter was followed by ultrasound surveillance for a median of 5 years. RESULTS Three hundred forty-nine (54%) of the patients were prescribed statins. Adjusting for other risk factors, statin prescription was not associated with AAA growth (odds ratio [OR] 1.23, 95% CI 0.86-1.76). Above-median AAA growth was positively associated with initial diameter (OR 1.78 per 4.35-mm-larger initial aortic diameter, 95% CI 1.49-2.14) and negatively associated with diabetes (OR 0.37, 95% CI 0.22-0.62). Above-median serum LDL concentration was not associated with AAA growth. Patients receiving statins had lower serum C-reactive protein concentrations but similar matrix metalloproteinase-9 and interleukin-6 concentrations to those not prescribed these medications. CONCLUSIONS We found no association between statin prescription or LDL concentration with AAA expansion. The results do not support the findings of smaller studies and suggest that statins may have no benefit in reducing AAA progression.

Obesity, Adipokines, and Abdominal Aortic Aneurysm Health in Men Study

Background— Obesity is associated with occlusive artery disease but is not considered a risk factor for abdominal aortic aneurysm (AAA). We investigated the association between anthropometric measures of obesity, serum adipokines, and AAA. Methods and Results— As part of a population study, we screened 12 203 men 65 to 83 years of age for AAA using ultrasound; 875 had an AAA (≥30 mm). Cardiovascular risk factors and waist and hip circumference were recorded. Serum adipokines were measured in 952 men, 318 of whom had an AAA. Waist circumference (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.06 to 1.22) and waist-to-hip ratio (OR, 1.22; 95% CI, 1.09 to 1.37) were independently associated with AAA after adjustment for other known risk factors. The association was stronger for AAA ≥40 mm (waist-to-hip ratio: OR, 1.53; 95% CI, 1.26 to 1.85). Serum resistin concentration was strongly independently associated with AAA (OR, 1.53; 95% CI, 1.32 to 1.76) and aortic diameter (&bgr;=0.19, P<0.0001). Serum adiponectin was associated with AAA ≥30 mm (OR, 1.26; 95% CI, 1.07 to 1.50) but not AAA ≥40 mm (OR, 1.03; 95% CI, 0.77 to 1.39). Serum leptin was not associated with AAA. Conclusions— Measures of obesity are independently associated with AAA. Serum resistin concentrations were more strongly associated with aortic diameter than adipokines that are more intimately associated with adiposity. Further studies are required to investigate the mechanisms linking resistin and AAA.

Reduced expansion rate of abdominal aortic aneurysms in patients with diabetes may be related to aberrant monocyte–matrix interactions

AIMS Diabetes increases the risk of atherothrombosis, but reduces the risk of abdominal aortic aneurysm (AAA). The reason for this difference is unknown. We examined the role of diabetes and glycation on AAA expansion and extracellular matrix-monocyte interactions. METHODS AND RESULTS We followed 198 patients (20 with diabetes) who had 30-45 mm AAAs with yearly aortic ultrasound for 3 years. Diabetes was independently associated with reduced AAA growth (beta = -0.17, P = 0.01; OR for expansion above median 0.18, 95% confidence interval 0.06-0.57). In vitro incubation of resting human monocytes with glycated bovine serum albumin or monomeric type I collagen increased matrix metalloproteinase (MMP) secretion. In contrast, exposure of activated monocytes to glycated type I collagen lattices induced a marked reduction in MMP and interleukin-6 secretion. This de-activating effect was also demonstrated in cross-linked non-glycated collagen lattices, healthy decellularized aortic media, and decellularized aortic media from diabetes patients with atherosclerosis. In contrast, decellularized aortic media from patients with atherosclerosis, but no diabetes, induced increased MMP secretion. CONCLUSION These findings confirm that the progression of AAA is slower in patients with diabetes and suggest a mechanism by which the aortic media may be protected from degradation in these individuals.

Association Between Osteopontin and Human Abdominal Aortic Aneurysm

Objectives—In vitro and animal studies have implicated osteopontin (OPN) in the pathogenesis of aortic aneurysm. The relationship between serum concentration of OPN and variants of the OPN gene with human abdominal aortic aneurysm (AAA) was investigated. Methods and Results—OPN genotypes were examined in 4227 subjects in which aortic diameter and clinical risk factors were measured. Serum OPN was measured by ELISA in two cohorts of 665 subjects. The concentration of serum OPN was independently associated with the presence of AAA. Odds ratios (and 95% confidence intervals) for upper compared with lower OPN tertiles in predicting presence of AAA were 2.23 (1.29 to 3.85, P=0.004) for the population cohort and 4.08 (1.67 to 10.00, P=0.002) for the referral cohort after adjusting for other risk factors. In 198 patients with complete follow-up of aortic diameter at 3 years, initial serum OPN predicted AAA growth after adjustment for other risk factors (standardized coefficient 0.24, P=0.001). The concentration of OPN in the aortic wall was greater in patients with small AAAs (30 to 50 mm) than those with aortic occlusive disease alone. There was no association between five single nucleotide polymorphisms or haplotypes of the OPN gene and aortic diameter or AAA expansion. Conclusions—Serum and tissue concentrations of OPN are associated with human AAA. We found no relationship between variation of the OPN gene and AAA. OPN may be a useful biomarker for AAA presence and growth.

On a mouse monoclonal antibody that neutralizes all four dengue virus serotypes.

The flavivirus envelope glycoprotein (E) is responsible for viral attachment and entry by membrane fusion. Its ectodomain is the primary target of the humoral immune response. In particular, the C-terminal Ig-like domain III of E, which is exposed at the surface of the viral particle, forms an attractive antigen for raising protective monoclonal antibodies (mAb). 9F12, a mouse mAb raised against a dengue virus (DENV) serotype 2 recombinant domain III, cross-reacts with corresponding domains from the other three DENV serotypes and also with West Nile virus. mAb 9F12 binds with nanomolar affinity to a conserved epitope that maps to the viral surface comprising residues 305, 307, 310 and 330 of the E protein. mAb 9F12 neutralizes all four DENV serotypes in plaque reduction assays. We expressed a single-chain Fv from 9F12 that retains the binding activity of the parent mAb. Adsorption and fusion inhibition assays indicate that mAb 9F12 prevents early steps of viral entry. Its virus inhibition activity and broad cross-reactivity makes mAb 9F12 a suitable candidate for optimization and humanization into a therapeutic antibody to treat severe infections by dengue.

Epitope analysis of the envelope and non-structural glycoproteins of Murray Valley encephalitis virus.

Previous studies have shown that antibodies produced against strategic flavivirus epitopes play an important role in recovery and immunity. Definition of the conformation and location of these epitopes and the degree of their conservation among flaviviruses is important to understanding the humoral response to flavivirus infection. In this study we have examined epitopes recognized by 14 monoclonal antibodies (MAbs) produced to the envelope (E) and non-structural (NS1) proteins of Murray Valley encephalitis virus (MVE). These antibodies were analysed for specificity, neutralization, haemagglutination inhibition (HI) and competitive binding. We have identified six distinct epitopes on the E protein which are located in four non-overlapping domains. MAbs to epitopes in one domain neutralized virus, were specific for MVE and Japanese encephalitis virus, and reacted with epitopes resistant to reduction. Two other E domains, one specific to MVE and the other shared by all flaviviruses, also contained neutralization sites and were stabilized by disulphide bonds. The fourth domain on E was conserved among the flaviviruses, sensitive to SDS denaturation and did not induce neutralizing antibody. Studies with MVE NS1 MAbs revealed that they were mostly type-specific, unreactive with conserved epitopes, and unreactive in HI and neutralization tests. The six epitopes identified on NS1 did not overlap and represent antigenic domains either resistant or sensitive to reduction. Immunoblotting of viral proteins in MVE-infected C6/36 cells revealed two distinct forms of NS1 and high Mr proteins of 97K and 108K that represented disulphide-linked heterodimers of E and NS1.

Evaluation of the diagnostic and prognostic value of plasma D-dimer for abdominal aortic aneurysm

AIMS A number of biomarkers have been associated with abdominal aortic aneurysm (AAA), but there has been no assessment of how such markers along with clinical risk factors can be used to stratify the risk of AAA presence and its progression. The aims of this study were to assess the diagnostic, prognostic, and risk stratification potential of plasma D-dimer for AAA presence and growth. METHODS AND RESULTS We included 1260 subjects (337 with AAA) recruited from a population screening study and 132 (41 with AAA) from a referral clinic. A total of 299 of the population group were followed by repeat ultrasound imaging for a median of 5.5 years to monitor AAA growth. The diagnostic and prognostic potential of plasma D-dimer was assessed by multivariate regression (adjusting for other AAA risk factors), receiver operator characteristic, and classification and regression tree (CART) analyses. In both groups, the dominant risk factor for AAA was D-dimer; thus in the population group, cut-off values of > 400 and > 900 ng/mL had adjusted odds ratios of 12.1 (95% CI 7.1-20.5) and 24.7 (95% CI 13.7-44.6), respectively. In both groups, CART analyses confirmed the dominating role of plasma D-dimer in defining extreme risk-groups with AAA prevalence as disparate as 3 and 82%. Average yearly AAA growth was positively and significantly associated with D-dimer which was able to predict growth as disparate as 0.4 and 2.5 mm/year. CONCLUSION This study suggests that plasma D-dimer can play a role in the diagnosis and prognosis of AAA.

Assessment of a Serum Assay for Quantification of Abdominal Aortic Calcification

Intimal vascular calcification is an important marker of atherosclerosis, and its severity is an independent risk factor for cardiovascular events. Measurement of coronary or aortic calcification requires CT-based imaging and elaborate data analysis to ensure accuracy. A blood assay which could quantify the severity of vascular calcification would be less expensive, avoid exposure to radiation, and be more accessible than present imaging based methods. Osteoprotegerin (OPG) and osteopontin (OPN) are present in human serum and have been implicated in vascular calcification. In this prospective study we assessed the value of a number of serum assays for OPG and OPN in determining abdominal aortic calcification. Firstly, we investigated the assay characteristics and reproducibility of 5 ELISAs using a subset of patients. Based on the findings of these assessments, we selected 3 assays for full evaluation in the entire cohort.

The role of tenascin C in cardiovascular disease

The extracellular matrix protein tenascin C (TnC) is expressed in a variety of embryonic tissues, but its expression in adult arteries is co-incident with sites of vascular disease. TnC expression has been linked to the development and complications of intimal hyperplasia, pulmonary artery hypertension, atherosclerosis, myocardial infarction, and heart failure. This review identifies the growing collection of evidence linking TnC with cardiovascular disease development. The transient upregulation of this extracellular matrix protein at sites of vascular disease could provide a means to target TnC in the development of diagnostics and new therapies. Studies in TnC-deficient mice have implicated this protein in the development of intimal hyperplasia. Further animal and human studies are required to thoroughly assess the role of TnC in some of the other pathologies it has been linked with, such as atherosclerosis and pulmonary hypertension. Large population studies are also warranted to clarify the diagnostic value of this extracellular matrix protein in cardiovascular disease, for example by targeting its expression using radiolabelled antibodies or measuring circulating concentrations of TnC.

The structures of the PII proteins from the cyanobacteria Synechococcus sp. PCC 7942 and Synechocystis sp. PCC 6803

The PII proteins from the cyanobacteria Synechococcus sp. PCC 7942 and Synechocystis sp. PCC 6803 have been crystallized and high-resolution structures have been obtained using X-ray crystallography. The core of these new structures is similar to that of the PII proteins from Escherichia coli, although the structures of the T- and C-loops differ. The T-loop of the Synechococcus protein is ordered, but appears to be stabilized by crystal contacts. The same loop in the Synechocystis protein is disordered. The C-terminus of the Synechocystis protein is stabilized by hydrogen bonding to the same region of a crystallographically related molecule. The same terminus in the Synechococcus protein is stabilized by coordination with a metal ion. These observations are consistent with the idea that both the T-loop and the C-terminus of PII proteins are flexible in solution and that this flexibility may be important for receptor recognition. Sequence comparisons are used to identify regions of the sequence unique to the cyanobacteria.