Background:  Cardiovascular disease (CVD) is an important cause of morbidity and mortality in HIV⁺ patients. Care would be facilitated by identification of a biomarker to detect the presence of inflammatory disease activity or reflect the response to therapy. The receptor for advanced glycation end-products (RAGE) plays a role in T cell priming, macrophage migration, and cytokine production, and the pathogenesis of atherosclerosis. Two soluble forms of RAGE, total sRAGE and a splice variant called endogenous secretory RAGE (esRAGE), have been detected in human plasma. To investigate whether RAGE may play a role in CVD, plasma was assayed for levels of sRAGE.

Methods:  Levels of sRAGE and esRAGE were assayed at 3 time-points (0, 72, and 96 of 144 weeks) from stored samples from a prospective study of carotid intima-media thickness (CIMT) in matched triads (ACTG 5078) at low risk for CVD:  HIV⁺ on PI therapy for ≥2 years (n = 25); HIV⁺ without prior PI use (n = 21); HIV^– (n = 34). The associations of sRAGE and esRAGE with HIV status and change in CIMT (based on specimen dates and a 48-week year) were assessed using repeated measures and conditional logistic regression analyses.

Results:  Samples from 80 subjects (91% male, 75% white, median age 41, median body mass index 24.7 kg/m²) were included. No statistically significant differences were noted in the week 0, week 72, week 96 of 144, or yearly rate of change of sRAGE or esRAGE between any pairs of groups. The yearly rate of change of CIMT decreased by 0.58 mm/y (95%CI 0.02 to 1.14); p = 0.04) for every 100 pg/mL increase in week 0 sRAGE, and increased by 0.24 mm/y (CI 0.001 to 0.48); p = 0.049) for every 10 pg/mL/yr increase in yearly rate of change in sRAGE. The odds of CIMT progression increased by 8% (CI 0.2% to 16%); p = 0.04) for every 10 pg/mL/y increase in the yearly rate of change in sRAGE. However, when HIV^– subjects were not considered in this analysis, there were no significant associations between levels of sRAGE and CIMT in the HIV⁺ subjects.

Conclusions:  In this low risk for CVD cohort, sRAGE and esRAGE did not significantly differ based on HIV (or PI use) status. Higher levels of sRAGE at week 0 appeared cardioprotective, while increasing sRAGE over time seemed detrimental. Further investigation to elucidate whether RAGE contributes to accelerated atherosclerosis in HIV⁺ subjects at high risk for CVD or in HIV⁺ women is warranted.