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Background-The natural histories of equally severe symptomatic and asymptomatic carotid stenoses are very different, which suggests dichotomy in plaque behavior. The vascular biology of the symptomatic carotid plaque is presented in this review. Summary of Review-Histology studies comparing asymptomatic and symptomatic plaques were identified from MEDLINE. Reports in which stenosis severity was not stated or not similar for symptomatic and asymptomatic patients were excluded. In vitro studies and reports from the coronary circulation were reviewed with regard to the vascular biology of the plaque. Histology studies comparing carotid plaques removed from symptomatic and asymptomatic patients reveal characteristic features of unstable plaques: surface ulceration and plaque rupture (48% of symptomatic compared with 31% of asymptomatic, PϽ0.001), thinning of the fibrous cap, and infiltration of the cap by greater numbers of macrophages and T cells. In vitro studies suggest that macrophages and T cells release cytokines and proteinase, which stimulate breakdown of cap collagen and smooth muscle cell apoptosis and thereby promote plaque rupture. Conclusions-Infiltration

The association of bone pathologies with atherosclerosis has stimulated the search for common mediators linking the skeletal and the vascular system. Since its initial discovery as a key regulator in bone metabolism, osteoprotegerin (OPG) has become the subject of intense interest for its role in vascular disease and calcification. Studies in vitro and in animal models suggest that OPG inhibits vascular calcification. Paradoxically however, clinical studies suggest that serum OPG levels increase in association with vascular calcification, coronary artery disease, stroke and future cardiovascular events. This has led to extensive debate on the potential of OPG as a biomarker of vascular disease. However the exact significance and mechanisms by which this bone-regulatory protein influences cardiovascular pathophysiology is still unclear. The need for a more complete picture is being addressed in increasing valuable research indicating OPG as not only a marker but also a mediator of vascular pathology modulating osteogenic, inflammatory and apoptotic responses. By integrating the results of recent experimental research, animal models and clinical studies, this review summarises the present understanding of the role of OPG in vascular disease and calcification.

Abstract-Abdominal aortic aneurysm (AAA) affects approximately 5% of elderly men and is responsible for a significant number of deaths in Western Countries. At present surgery by open or endovascular means is the only widely used therapy for this condition. In this review we examine the risk factors, serum, and genetic associations of AAA. Epidemiology studies suggest that smoking cessation and control of cholesterol and blood pressure should reduce the number of patients developing AAA. Natural history studies suggest that smoking cessation should reduce the rate of progression of AAA. Clear level 1 evidence for drug treatments of AAA are presently lacking; however, animal and human in vitro studies suggest that medication targeted at reducing inflammation and proteolysis are most likely to be beneficial, with limited data to support the use of statins, Angiotensin II inhibitors, and macrolides. Work has commenced in understanding which patients, identified by clinical, serum, and genotype, are more at risk of AAA progression and thus should be selected out for aggressive treatment.Well designed large multicenter randomized controlled trials are required to examine the medical treatment of AAA.

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Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.

OPG and OPN are upregulated in symptomatic human carotid atherosclerosis with possible implications for plaque stability. Angiotensin II blockade is able to downregulate OPG secretion in vitro.

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.