Relationship between Inflammatory Markers, Endothelial Activation Markers, and Carotid Intima-Media Thickness in HIV-Infected Patients Receiving Antiretroviral Therapy

HIV-infected individuals appear to be at higher risk of cardiovascular disease (CVD) than the general population [1, 2]. The etiology of the increased risk remains unclear. Some data suggest that long-term protease inhibitors use contributes to risk [3–5], whereas others cite more traditional risk factors, such as smoking, dyslipidemia, and advanced age [6–8]. Measurement of carotid intima-media thickness (IMT) is a well-accepted, noninvasive method of monitoring subclinical atherosclerotic formation and progression, and increased IMT correlates with an increased risk of CVD events, such as myocardial infarction and stroke, in the general population [9–12]. Although no studies to date show prediction of CVD events on the basis of IMT values in the HIV-infected population, several studies demonstrate increased IMT in HIV-infected individuals, compared with healthy control persons [8, 13–15], and IMT progresses more rapidly over time in HIV-infected patients [8, 14, 16]. Likewise, data show that HIV infection status, when controlled for other factors, is associated with increased carotid IMT [15, 17]. There is mounting evidence to support the role of inflammation and endothelial activation and dysfunction in the development of plaque formation and progression of atherosclerosis in the general population [18–27]. For example, elevated levels of the proinflammatory cytokines interleukin (IL)-6 and C-reactive protein (CRP) are associated with subclinical atherosclerosis [18] and are independently predictive of future cardiovascular events [19, 20]. In addition, tumor necrosis factor (TNF)–α has been implicated in myocardial dysfunction after acute coronary syndromes, and levels of TNF-α have been shown to be higher in patients at baseline who experience recurrent myocardial infarctions or cardiac death [21, 22]. The effects of TNF-α are mediated by 2 receptors, TNFR-I and TNFR-II; these soluble receptors are stable in plasma, easily measured, and reflect activity of TNF-α. Myeloperoxidase, a peroxidase enzyme found in leukocytes and released when leukocytes are activated, has also been established as an independent predictor of early risk of myocardial infarction in patients presenting with chest pain [23], and myeloperoxidase levels are associated with the presence of coronary artery disease and endothelial dysfunction in the general population [24]. Likewise, levels of 2 circulating adhesion molecules, soluble vascular cell adhesion molecule–1 (sVCAM-1) and soluble intercellular adhesion molecule–1 (sICAM-1), as well as levels of von Willebrand factor antigen (vWF), arise from shedding or proteolytic cleavage from activated endothelial cells and are useful markers for increased activation of endothelial cells in atherosclerosis [25–27]. Few studies have examined the relationship between markers of inflammation and endothelial activation and measurements of carotid IMT. In the general population, the Offspring Cohort of the Framingham Heart Study found an association between inflammatory markers and IMT [28], whereas studies examining the role of chronic inflammation as a cause of the increased CVD risk in patients with type-2 diabetes have produced conflicting results [29–31]. Nevertheless, increased levels of inflammatory markers and evidence of endothelial dysfunction are evident in HIV-infected individuals [32–35] and may be correlated with increased risk of CVD. Even in patients who are receiving antiretroviral therapy (ART), inflammatory cytokine levels do not completely normalize to that of the general population [33], suggesting that there is ongoing inflammation despite an undetectable virus level. To date, no study has comprehensively examined the relationship among inflammatory markers, carotid IMT, and endothelial activation markers in HIV-infected individuals. We hypothesized that inflammatory markers are correlated with both carotid IMT and endothelial activation markers in HIV-infected subjects receiving ART and that both inflammatory and endothelial activation markers are associated with carotid IMT. In this study, we measured plasma levels of proinflammatory cytokines, TNF-α, sTNFR-I and -II, IL-6, high-sensitivity CRP (hsCRP), and myeloperoxidase, and of 3 endothelial activation markers, sICAM-1, sVCAM-1, and vWF, to explore their relationship to carotid IMT in HIV-infected individuals receiving ART with virologic control. As a secondary objective, we examined carotid IMT, inflammatory markers, and endothelial activation markers in ART-treated, HIV-infected subjects, compared with a small convenience sample of healthy control subjects.