Elevated Microparticle Tissue Factor Activity Is Associated With Carotid Artery Plaque in HIV-Infected Women.

BACKGROUND: Expression of tissue factor (TF) on the surface of activated monocytes may trigger thrombosis, leading to clotting risk, inflammation, and atherosclerosis. TF-positive microparticles (MP-TF) represent a functionally active form of TF that may be promulgated by long-term HIV infection. We hypothesized that greater MP-TF activity is associated with carotid artery plaque in HIV+ women. SETTING: In a case-control study nested within the Women's Interagency HIV Study (WIHS), eligible HIV+ participants underwent B-mode carotid artery ultrasound at 2 study visits occurring 7 years apart. Cases were defined by the presence of at least 1 carotid artery plaque assessed at either visit. Cases were matched 1:2 to controls who were found not to have carotid artery plaques. METHODS: Conditional logistic regression estimated the association of MP-TF activity with the presence of carotid artery plaque, adjusting for demographic and behavioral characteristics, HIV-related factors, cardiometabolic risk factors, and serum inflammation biomarkers (high-sensitivity C-reactive protein, IL-6, sCD14, sCD163, Gal-3, and Gal-3BP). RESULTS: Elevated MP-TF activity (>0.537 pg/mL) was found to be significantly associated with greater odds of plaque (adjusted odds ratio 3.86, 95% confidence interval: 1.06 to 14.07, P = 0.04). The association was attenuated after further adjustment for IL-6 but was unaffected by adjustment for other biomarkers including those denoting monocyte activation. CONCLUSIONS: Our findings suggest a link among HIV infection, innate immune system perturbation, coagulation, and atherosclerosis.

Midlife blood pressure, plasma ß-amyloid, and the risk for Alzheimer disease: the Honolulu Asia Aging Study.

ß-Amyloid (Aß), a vasoactive protein, and elevated blood pressure (BP) levels are associated with Alzheimer disease (AD) and possibly vascular dementia. We investigated the joint association of midlife BP and Aß peptide levels with the risk for late-life AD and vascular dementia. Subjects were 667 Japanese-American men (including 73 with a brain autopsy), from the prospective Honolulu Heart Program/Honolulu Asia Aging Study (1965-2000). Midlife BP was measured starting in 1971 in participants with a mean age of 58 years; Aß was measured in specimens collected in 1980-1982, and assessment of dementia and autopsy collection started in 1991-1993. The outcome measures were prevalent (present in 1991-1993) and incident AD (n=53, including 38 with no contributing cardiovascular disease) and vascular dementia (n=24). Cerebral amyloid angiopathy, ß-amyloid neuritic plaques, and neurofibrillary tangles were evaluated in postmortem tissue. The risk for AD significantly increased with lower levels of plasma Aß (Aß1-40 hazard ratio: 2.1 [95% CI: 1.4 to 3.1]; Aß1-42 hazard ratio: 1.6 [95% CI: 1.1 to 2.3]). Evidence of interaction between diastolic BP and plasma Aß (1-40 P(interaction)<0.05; 1-42 P(interaction)<0.07) levels indicated that the Aß-related risk for AD was higher when BP was higher. Low plasma Aß was associated with the presence of cerebral amyloid angiopathy (P(trend)<0.05) but not the other neuropathologies. Aß plasma levels start decreasing ≥15 years before AD is diagnosed, and the association of Aß to AD is modulated by midlife diastolic BP. Elevated BP may compromise vascular integrity leading to cerebral amyloid angiopathy and impaired Aß clearance from the brain.

Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators.

To identify the genetic basis of circulating concentrations of monocyte chemoattractant protein-1 (MCP-1), we conducted genome-wide association analyses for MCP-1 in 3 independent cohorts (n = 9598). The strongest association was for serum MCP-1 with a nonsynonymous polymorphism, rs12075 (Asp42Gly) in DARC, the gene for Duffy antigen receptor for chemokines, a known vascular reservoir of proinflammatory cytokines (minor allele frequency, 45.6%; P < 1.0 * 10(-323)). This association was supported by family-based genetic linkage at a locus encompassing the DARC gene (genome-wide P = 8.0 * 10(-13)). Asp42Gly accounted for approximately 20% of the variability in serum MCP-1 concentrations and also was associated with serum concentrations of interleukin-8 and RANTES. While exploring a lack of association between this polymorphism and EDTA plasma MCP-1 concentrations (P = .82), we determined that both clotting and exogenous heparan sulfate (unfractionated heparin) released substantial amounts of MCP-1 from Darc. Quantitative immunoflow cytometry failed to identify meaningful Asp42Gly-associated differences in Darc expression, suggesting that a functional change is responsible for the differential cytokine binding. We conclude that Asp42Gly is a major regulator of erythrocyte Darc-mediated cytokine binding and thereby the circulating concentrations of several proinflammatory cytokines. We have also identified for the first time 2 mechanisms for the release of reservoir chemokines with possible clinical implications.