Sex Differences in Urinary Biomarkers of Vascular and Endothelial Function in HIV-Infected Persons Receiving Antiretroviral Therapy

Abstract

Background Cardiovascular disease (CVD) risk can be underestimated in HIV-infected patients receiving antiretroviral therapy (ART). Novel CVD risk markers in this population are needed. We hypothesized that eicosanoid metabolite production is increased with metabolic complications of ART. Our objective was to determine relationships between urine eicosanoids and traditional CVD risk factors in a cohort of HIV-infected persons receiving ART. Methods Cross-sectional analysis of 107 individuals from a prospective cohort study with urine eicosanoids (isoprostane [15-F2t-IsoP], prostaglandin-E metabolite [PGE-M], thromboxane metabolite [11dTxB2], prostacyclin metabolite [PGI-M]) determined by gas or liquid chromatography-mass spectrometry. Results 15-F2t-IsoP was higher (p=0.003), 11dTxB2 tended to be higher (p=0.07), and PGE-M was lower (p=0.003) in females than in males. The overall median Framingham score was 4 (IQR 1 – 7). In multivariable analyses adjusting for age, CD4+ T-cells, smoking status, nonsteroidal anti-inflammatory use, aspirin use, and body mass index (BMI), associations included: higher 15-F2t-IsoP with female sex (p=0.004) and current smoking (p=0.04), lower PGE-M with female sex (p=0.005) and higher BMI (p=0.03), higher 11dTxB2 with increasing age (p=0.02) and current smoking (p=0.04), lower 11dTxB2 with higher BMI (p=0.02), and higher PGI-M with current smoking (p=0.04). Conclusions In this pilot study of predominantly virologically suppressed HIV-infected individuals on ART, there were sex-specific differences in urinary eicosanoids, with females having more risk-associated parameters despite low Framingham score. Eicosanoids might be useful CVD biomarkers in ART-treated, HIV-infected patients. Future studies should examine eicosanoids while assessing effects of specific ART regimens and targeted interventions on CVD outcomes.

HIV Infection, Vascular Disease, and Stroke

“…32 Virologically suppressed HIV-infected women had urinary levels of eicosanoids consistent with a higher cardiovascular risk profile compared with virologically suppressed HIV-infected men. 33 HIV-infected women may also be at higher risk of stroke. In the Partners HIV cohort, the association between HIV and ischemic stroke was driven largely by women, with an adjusted IRR of 1.76 (95% CI 1.24-2.52) for women compared with 1.05 (95% CI 0.84-1.32) for men.…”

Urine Eicosanoids in the Metabolic Abnormalities, Telmisartan, and HIV Infection (MATH) Trial

“…[41] This profile is similar to smokers and persons with higher BMI, despite having a low Framingham risk score. Several studies in HIV-uninfected persons demonstrated similar trends,[42–44] but contrasting results exist.…”

Higher Serum Iron Is Associated With Increased Oxidant Stress in HIV-Infected Men

“…Heavy smokers in our study also had significantly higher F 2 -IsoP, consistent with data in HIV-negative populations 36 and other studies in HIV-infected populations. 11 However, women were less likely than men to be on ART, less likely to report heavy smoking, and adjusted models included both of these covariates. Thus, the relationship between sex and F 2 -IsoP was independent of ART and smoking status.…”

“…11 Both studies found that female sex was independently associated with higher F 2 -IsoP levels, an association also seen in HIV-uninfected populations. 12,13 Determining factors that explain higher F 2 -IsoP levels in HIV-infected women compared to men could lead to a better understanding of unique risks for HIV-infected women and provide guidance in management of these patients.…”