FDG accumulates within metabolically active macrophages infiltrating affected vessels such that increased FDG uptake reflects heightened vascular inflammation5–8
. Indeed, through pathologic/histologic analyses of plaque specimens from participants with occlusive carotid disease who went on to carotid endarterectomy, we and others have previously shown that arterial FDG uptake correlates closely with plaque macrophage infiltration characterized by increased CD68 staining5–8
. Increased aortic FDG uptake is known to correlate with increased FDG uptake in the left main coronary artery16
Moreover, increased arterial PET-FDG uptake is associated with subsequent progression of atherosclerotic plaques17
and identifies patients at risk for subsequent atherothrombotic events12,18
. Hence, the signal that we see likely reflects atherosclerotic inflammation with macrophage infiltration into arterial atheroma. The results from the current study using the PET-FDG technique suggest that macrophage infiltration and resulting arterial inflammation, measured here in the aorta, are increased among HIV-infected patients.
Our observation that HIV-infection is associated with increased arterial inflammation, even among relatively young HIV-infected patients with low FRS and undetectable viremia, is concordant with the epidemiological observations that patients with HIV have a higher risk of stroke and MI than non-HIV patients1,19
and demonstrates that this risk may not be measured adequately by traditional risk assessment tools, such as the FRS. Indeed, recent studies among non HIV-infected patients demonstrate that consideration of TBR can improve net reclassification index compared to use of FRS and traditional risk factors20
. Moreover, these studies demonstrate that a TBR > 1.7 is associated with an approximate 40% reduction in CVD event free survival over 3 years12
, whereas a TBR > 2.25 (vs. < 1.84) is associated with a markedly increased risk of CVD events over 5 years20
. These data suggest a clinically relevant degree of added CVD risk due to increased arterial inflammation in the HIV population we studied. One potential mechanistic link to this observation is suggested by our demonstration that a marker of monocyte/macrophage activation, sCD163, was significantly associated with this inflammatory signal. CD163 is expressed specifically on the surface of monocytes and macrophages and has a known role as a scavenger receptor involved in the uptake of hemoglobin-haptoglobin complexes21
. Soluble CD163 (sCD163) is shed via proteolytic cleavage at the cell surface and can be found in the circulation. sCD163 has been previously shown as a circulating marker of atherosclerosis in non HIV-infected patients22,23
. Macrophages expressing CD163 have been found in human atherosclerotic plaques of non HIV-infected patients24
as well as within plaque lesions in SIV-infected monkey models25
. In chronically HIV-infected patients, we have previously demonstrated sCD163 to be independently associated with increased noncalcified plaque among young, asymptomatic men2
. Here we extend the observations further, by observing a significant correlation between sCD163 and the extent of arterial inflammation. In contrast, markers of generalized inflammation (hsCRP) and thrombosis (D-dimer) were not statistically significant in terms of their relationships to vascular inflammation in the current study. Hence, in HIV, macrophage activation markers correlate with non-calcified plaques and arterial wall inflammation, two separate predictors of subsequent atherothrombosis. These observations suggest that sCD163 may be able to uniquely provide an index of risk of atherosclerotic disease in HIV. For example, in this study we show that among HIV-infected patients, a sCD163 level of > 800 ng/ml, identifies a group with a markedly elevated TBR, >2.35. Further studies are needed to determine if the demonstration of an elevated sCD163 level in clinical practice will predict events and provide unique information to that of traditional risk indices.
One hundred percent of the HIV patients studied were receiving antiretroviral therapy, and had been receiving such therapy for a long duration of approximately 12 years. A significant majority had undetectable HIV viral load. Viral load was not related to TBR and the observation of markedly increased TBR in HIV was confirmed in the subset with undetectable viremia. Thus, the observation of increased vascular inflammation by PET occurred in well–treated patients in whom significant detectable viremia was neither present nor likely to be a contributing factor. In contrast, increasing degrees of monocyte activation even within this well controlled group were associated with increased arterial inflammation. The patients we studied are similar to the majority of patients undergoing treatment with ART today, with well-controlled virus and absent history of cardiovascular disease. Such patients, particularly with low FRS, are not considered to be at high risk for cardiovascular disease, yet we now show that such patients have increased arterial wall inflammation, equal to that of non-HIV patients with established CAD.
CAC was higher in non-HIV patients with established CAD than in the HIV group. This difference may be due to the increased rate of traditional CVD risks in the atherosclerotic controls compared to the HIV group, and persisted controlling for age. It is notable that the degree of inflammation is similar between the HIV group with very little CAC and low FRS and the established CAD group with significant CAC and traditional risks, suggesting that inflamed noncalcified plaque related more to nontraditional risk factors is likely to be present in the HIV group. Over time, the increased inflammation seen in the HIV group might itself induce an increase in CAC.
The design of this study limits definitive conclusions regarding causality of increased inflammation, but our data suggest monocyte/macrophage activation may be contributing. We cannot completely rule out an effect of ART directly on arterial inflammation, but evidence from SMART26
showing that ART decreases inflammation and endothelial activation, the lack of any ART class effect in our data and the low traditional risk factors in our group on ART (ruling out an indirect effect) make this unlikely. We included a relatively small proportion of women, and thus our findings may not be fully generalizable for women. Additionally, while the HIV population was prospectively identified, the control groups were subsequently selected from a database of imaged individuals. However, the analysis of aortic TBR was identical for all participants in the study, was performed only after matching and subject selection and was performed blinded to clinical history. The study was adequately powered to detect a clinically relevant 0.83 SD difference between the study groups.
Our study demonstrates that HIV is associated with a high degree of inflammation within the arterial wall, even in patients with low FRS and well-controlled viremia. These findings advance our understanding of the unique pathophysiology and predilection to early increased CVD among HIV-infected patients and suggest that monocyte/macrophage activation could play a critical role in the early expression of subclinical atherosclerosis in HIV-infected patients. These data have clinical relevance and suggest that HIV patients with chronic infection have significant vascular inflammation, and thus added CVD risk, beyond that estimated by traditional risk factors. This information should now be considered in determining optimal monitoring and CVD prevention strategies for this group. Future studies will be useful to further investigate unique immune-based mechanisms of arterial inflammation and potential agents to reduce the pro-atherogenic activation of monocytes/macrophages with hopes of reducing risk of atherothrombosis in HIV-infected patients.