Fibulin-1 as a marker of cardiovascular disease in HIV-infected black South Africans : a prospective study

Abstract

BACKGROUND: There is a high prevalence of the human immunodeficiency virus (HIV) infection in South Africa and this chronic infection promotes vascular inflammation, leading to vascular damage in infected individuals. The extracellular matrix is a highly adaptive and dynamic structure that is influenced by mechanical stress, inflammation and oxidative stress and it has been suggested that changes contribute to arterial stiffness. Fibulin-1 is a fibrinogen-binding plasma protein and is part of a small group of extracellular matrix proteins (including fibronectin, laminin and von Willebrand factor) that are present in the blood at relatively high levels. Changes in fibulin-1 levels have consequences to vascular structural integrity and maintaining the integrity of the extracellular matrix in the blood vessel wall seems critical in the prevention of cardiovascular disease. OBJECTIVE: The objective of this study was to determine the association of fibulin-1 with markers of vascular function in HIV-infected black South-Africans in the baseline study of 2005 and follow-up study in 2008. METHODOLOGY: This substudy is embedded in the larger international Prospective Urban and Rural Epidemiology (PURE) study. The PURE study is a prospective study that addresses questions regarding the cause and development of cardiovascular risk factors and disease within populations, particularly of low- and middle-income countries, including South Africa. The South African leg of the PURE study was performed in the North-West Province, where a total of 2 010 participants (1 004 urban and 1 006 rural) were randomly recruited from a rural and urban setting and screened during the baseline phase in 2005. For this substudy, the HIV-infected participants (N=300) of the study population were individually matched with HIV-uninfected participants (N=300) at the baseline phase (2005). The participants were matched according to age, gender, body mass index (BMI) and locality (urban and rural), and were followed up in 2008. Anthropometric and cardiovascular measurements were determined. The OMRON HEM-757 (Omron, Kyoto, Japan) apparatus was used to determine systolic and diastolic blood pressure. The pulse pressure (PP) was subsequently calculated by the difference in systolic blood pressure and diastolic blood pressure. The carotid-radial pulse wave velocity (cr-PWV) was determined with the Complier SP Acquisition system (Artech Medical, Pantin, France). The lipid profile and inflammatory markers were also determined. Independent t-tests were used to compare cardiovascular variables between the HIV-infected and HIV-uninfected participants in the baseline study. Dependent t-tests were used to compare the baseline and follow-up measurements of cardiovascular variables within HIV-infected and HIV-uninfected participants. The percentage change in all the groups was also determined over a period of three years. Pearson and partial correlations were performed to explore unadjusted and adjusted associations between change of fibulin-1 and cardiovascular variables in each group. P-values of s 0.05 were regarded as statistically significant. RESULTS: At baseline, as well as after three years, the fibulin-1 levels were significantly higher in HIV-infected, compared to HIV-uninfected, South Africans. Percentage change in fibulin-1 is associated with percentage change in triglycerides (TG) to high-density lipoprotein cholesterol ratio (TG/HDL-C) in HIV-infected participants, but not in HIV-uninfected participants. A significant positive correlation was seen between percentage change in fibulin-1 and soluble urokinase-type plasminogen activator receptor (suPAR) levels in the HIV-uninfected group, but no positive correlation was found in suPAR levels in the unadjusted correlations. In the baseline study (2005), as well as the follow-up (2008), the HIV-infected participants had lower HDL-C and higher soluble forms of intercellular adhesion molecule-1 (slCAM-1), vascular cell adhesion molecule-1 (sVCAM-1) and suPAR levels in comparison with their HIV-uninfected control group. The slCAM-1 and sVCAM-1 levels were only determined in 2005. At baseline, the cr-PWV was significantly higher in the HIV-infected group (11.26 m/s vs.10.68 m/s, p=0.03) in comparison with the HIV-uninfected group. However, in the follow-up study, no significant difference was found in the cr-PWV values between the HIV-infected and HIV-uninfected participants. There were no significant differences in percentage change in fibulin-1, TC/HDL-C ratio, TG/HDL-C ratio, cr-PWV and PP between the HIV-infected and HIV-uninfected participants over the period of three years. DISCUSSION: The high suPAR levels and low HDL-C levels suggest the possibility that the HIV-infected participants could be more prone to develop vascular damage, which could result in further extracellular matrix remodelling. The latter is seen as the link between infection, inflammation, thrombotic activity and vascular dysfunction. The increased cr-PWV in the HIV-infected group at baseline supports the above possibility. Although no significant associations were found between fibulin-1 and inflammatory markers (namely slCAM-1, sVCAM-1, interleukin-6 [IL-6), plasminogen activator inhibitor-1 [PAl-1) or PWV), the association of the percentage change in fibulin-1 with the change in TG/HDL-C ratio suggests that TG/HDL-C ratio may contribute to probable vascular changes in HIV-infected participants and that the HIV-infected participants may be more at risk to develop cardiovascular disease in comparison with the HIV-uninfected participants.