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.

Thrombus volume is associated with cardiovascular events and aneurysm growth in patients who have abdominal aortic aneurysms.

BACKGROUND: Patients with abdominal aortic aneurysms (AAA) are predisposed to cardiovascular events and often experience continual expansion of their aneurysm. Cardiovascular events and expansion rates are positively correlated with aneurysm size. AAA is usually associated with intraluminal thrombus, which has previously been implicated in AAA pathogenesis. This study prospectively assessed the association of infrarenal abdominal aortic thrombus volume with cardiovascular events and AAA growth. METHODS: Ninety-eight patients with AAAs underwent computed tomography angiography (CTA). The volume of infrarenal aorta thrombus was measured by a previously validated technique. Patients were monitored prospectively for a median of 3 years (interquartile range [IQR], 2.0-3.6 years), and cardiovascular events (nonfatal stroke, nonfatal myocardial infarction, coronary revascularization, amputation, and cardiovascular death) were recorded. Of the original patients, 39 underwent repeat CTA a median of 1.5 years (IQR, 1.1-3.3 years) after entry to the study. Kaplan-Meier and Cox proportional analysis were used to examine the association of aortic thrombus with cardiovascular events and average weighted AAA growth. RESULTS: There were 28 cardiovascular events during follow-up. The incidence of cardiovascular events was 23.4% and 49.2% for patients with small (smaller than the median) and large (median or larger) volumes of aortic thrombus, respectively, at 4 years (P = .040). AAA thrombus volume of median or larger was associated with increased cardiovascular events (relative risk [RR] 2.8, 95% confidence interval [CI], 1.01-5.24) independent of other risk factors, including initial AAA diameter, but was only of borderline significance when patients were censored at the time of AAA repair (RR, 2.35; 95% CI, 0.98-5.63). In the subset of patients with CTA follow-up, the median annual increase in AAA volume was 5.1 cm³ (IQR, 0.8-10.3 cm³). Annual AAA volume increase was positively correlated with initial AAA diameter (r = 0.44, P = .006) and thrombus volume (r = 0.50, P = .001). Median or larger aortic thrombus volume was associated with rapid AAA volume increase (≥ 5 cm/y), independent of initial aortic diameter (RR, 15.0; 95% CI, 1.9-115.7; P = .009). CONCLUSION: In this small cohort, infrarenal aortic thrombus volume was associated with the incidence of cardiovascular events and AAA progression. These results need to be confirmed and mechanisms underlying the associations clarified in large further studies.

Association between serum lipoproteins and abdominal aortic aneurysm.

The importance of dyslipidemia in the etiology of abdominal aortic aneurysm (AAA) is poorly defined, in part because previous association analyses have often not considered the use of current lipid-modifying medications. Medications targeted at altering the concentrations of circulating lipids have an established role in occlusive atherosclerosis but are of unknown value in the primary prevention of AAA. We examined the association between fasting serum levels of triglycerides low- and high-density lipoprotein and the presence of an AAA in a cohort of 3,327 men aged 65 to 83 years. The analyses were adjusted for established risk factors of AAA and the prescription of lipid-modifying agents using multiple logistic regression analysis. Of the 3,327 men, 1,043 (31%) were receiving lipid-modifying therapy at the fasting lipid measurement. The lipid-modifying therapy was statins in most cases (n = 1,023). The serum high-density lipoprotein concentrations were lower in patients with AAAs. The serum high-density lipoprotein concentration was independently associated with a reduced risk of having an AAA in men not receiving current lipid-modifying therapy (odds ratio 0.72, 95% confidence interval 0.56 to 0.93 per 0.4-mM increase) and in the total cohort (odds ratio 0.76, 95% confidence interval 0.63 to 0.91 per 0.4-mM increase, adjusted for lipid-modifying therapy). The concentrations of low-density lipoprotein and triglycerides were not associated with the presence of AAAs. In conclusion, high-density lipoprotein appeared to be the most important lipid in predicting the risk of AAA development, with potential value as a therapeutic target. Current cardiovascular strategies aimed at lowering low-density lipoprotein might not have any effect on the prevention of AAAs.

Association of osteoprotegerin with human abdominal aortic aneurysm progression.

BACKGROUND: Abdominal aortic aneurysm (AAA) is characterized by destruction of the arterial media associated with loss of vascular smooth muscle cells, infiltration of mononuclear cells, and high concentration of metalloproteinases (MMPs) and cytokines. Osteoprotegerin (OPG) has recently been identified in atherosclerosis. The presence and functional importance of OPG in human AAA was investigated. METHODS AND RESULTS: In 146 men with small AAA followed up by ultrasound for 3 years, serum OPG was weakly correlated with aneurysm growth rate. Western analysis showed 3-, 8-, and 12-fold-greater OPG concentrations in human AAA biopsies compared with biopsies of atherosclerotic narrowed aorta (1.4+/-0.1 versus 0.5+/-0.1 ng/mg tissue; P=0.002), postmortem nondiseased abdominal aorta (1.4+/-0.1 versus 0.2+/-0.1 ng/mg tissue; P<0.001), and nondiseased thoracic aorta (1.4+/-0.1 versus 0.1+/-0.06 ng/mg tissue; P<0.001). Healthy human aortic vascular smooth muscle cells incubated with recombinant human (rh)OPG (0 to 20 ng rhOPG/10(5) cells per 1 mL per 24 hours) developed an aneurysmal phenotype defined by impaired cell proliferation (P<0.001), increased apoptosis (P<0.01), and increased MMP-9 (92 kDa) expression (P<0.001). Incubation of monocytic THP-1 cells with 1 ng rhOPG/10(5) cells per 1 mL per 24 hours induced a 2-fold increase in MMP-9 expression (P<0.001), a 1.5-fold increase in MMP-2 activity (P=0.005), and a 2-fold stimulation of IL-6 production in these cells (P=0.02). Finally, secretion of OPG from human AAA explant was abrogated by treatment with the angiotensin II blocker irbesartan, with the reduction in secreted levels averaging 63.0+/-0.9 ng/mg tissue per 48-hour period. CONCLUSIONS: These findings support a role for OPG in the growth of human AAA and suggest a potential benefit for angiotensin II blockade in slowing aneurysm expansion.

Osteoprotegerin and osteopontin are expressed at high concentrations within symptomatic carotid atherosclerosis.

BACKGROUND AND PURPOSE: The aim of this study was to compare the concentration of osteoprotegerin (OPG), receptor activator of nuclear factor kappaB ligand (RANKL), and osteopontin (OPN) in stable (asymptomatic) and unstable (symptomatic) carotid atherosclerosis. In addition, we were interested in the effect of angiotensin II blockade on the secretion of these proteins by unstable atherosclerosis. METHODS: Endarterectomy samples removed from patients with recent (within 6 weeks) or no previous focal neurological symptoms were assessed by immunohistochemistry, Western analysis, and explant culture. Concentrations of OPG, RANKL, and OPN were measured by mean optical density (MOD), densitometry of protein bands, and enzyme-linked immunosorbent assay of supernatants from explant culture, and compared between symptomatic and asymptomatic patients. RESULTS: The concentration of OPG and OPN within the proximal internal carotid (PIC) part of the endarterectomy specimen removed from symptomatic patients was elevated 2- and 4-fold, respectively. Although the concentration of RANKL did not differ according to patients' symptoms, the quantity of OPG secreted by explants of the PIC was greater in explants from symptomatic patients and could be significantly reduced within 48 hours of incubation with the angiotensin II blocker irbesartan. CONCLUSIONS: 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.