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Arterial Inflammation in Patients With HIV
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JAMA. July 25 2012
Sharath Subramanian, MD; Ahmed Tawakol, MD; Tricia H. Burdo, PhD; Suhny Abbara, MD; Jeffrey Wei, BA; Jayanthi Vijayakumar, MD; Erin Corsini, BS; Amr Abdelbaky, MD; Markella V. Zanni, MD; Udo Hoffmann, MD, MPH; Kenneth C. Williams, PhD; Janet Lo, MD, MMSc; Steven K. Grinspoon, MD
Context Cardiovascular disease is increased in patients with human immunodeficiency virus (HIV), but the specific mechanisms are unknown.
Objective To assess arterial wall inflammation in HIV, using 18fluorine-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET), in relationship to traditional and nontraditional risk markers, including soluble CD163 (sCD163), a marker of monocyte and macrophage activation.
Design, Setting, and Participants A cross-sectional study of 81 participants investigated between November 2009 and July 2011 at the Massachusetts General Hospital. Twenty-seven participants with HIV without known cardiac disease underwent cardiac 18F-FDG-PET for assessment of arterial wall inflammation and coronary computed tomography scanning for coronary artery calcium. The HIV group was compared with 2 separate non-HIV control groups. One control group (n = 27) was matched to the HIV group for age, sex, and Framingham risk score (FRS) and had no known atherosclerotic disease (non-HIV FRS-matched controls). The second control group (n = 27) was matched on sex and selected based on the presence of known atherosclerotic disease (non-HIV atherosclerotic controls).
Main Outcome Measure Arterial inflammation was prospectively determined as the ratio of FDG uptake in the arterial wall of the ascending aorta to venous background as the target-to-background ratio (TBR).
Results Participants with HIV demonstrated well-controlled HIV disease (mean [SD] CD4 cell count, 641 [288] cells/μL; median [interquartile range] HIV-RNA level, <48 [<48 to <48] copies/mL). All were receiving antiretroviral therapy (mean [SD] duration, 12.3 [4.3] years). The mean FRS was low in both HIV and non-HIV FRS-matched control participants (6.4; 95% CI, 4.8-8.0 vs 6.6; 95% CI, 4.9-8.2; P = .87). Arterial inflammation in the aorta (aortic TBR) was higher in the HIV group vs the non-HIV FRS-matched control group (2.23; 95% CI, 2.07-2.40 vs 1.89; 95% CI, 1.80-1.97; P < .001), but was similar compared with the non-HIV atherosclerotic control group (2.23; 95% CI, 2.07-2.40 vs 2.13; 95% CI, 2.03-2.23; P = .29). Aortic TBR remained significantly higher in the HIV group vs the non-HIV FRS-matched control group after adjusting for traditional cardiovascular risk factors (P = .002) and in stratified analyses among participants with undetectable viral load, zero calcium, FRS of less than 10, a low-density lipoprotein cholesterol level of less than 100 mg/dL (<2.59 mmol/L), no statin use, and no smoking (all P ≤ .01). Aortic TBR was associated with sCD163 level (P = .04) but not with C-reactive protein (P = .65) or D-dimer (P = .08) among patients with HIV.
Conclusion Participants infected with HIV vs noninfected control participants with similar cardiac risk factors had signs of increased arterial inflammation, which was associated with a circulating marker of monocyte and macrophage activation.
Coronary artery disease (CAD) is significantly increased in patients infected with human immunodeficiency virus (HIV), but the specific mechanisms remain unknown.1 Immunological modulations may play an important role in the pathogenesis of atherosclerosis in patients with HIV. Patients with HIV demonstrate a high prevalence of noncalcified coronary atherosclerotic lesions that are increased in association with markers of macrophage activation.2 This is significant because infiltration of activated monocytes and macrophages into the endothelium contributes to the development of vulnerable atherosclerotic plaque susceptible to rupture.3 - 4
Positron emission tomography (PET) with 18fluorine-2-deoxy-D-glucose (18F-FDG-PET) is widely used for measurement of inflammation in the arterial wall. Accumulation of FDG in human atherosclerotic arteries correlates with the amount of immunohistochemical staining and gene expression for macrophage-specific markers, including CD68,5 - 8 and is based on the fact that activated macrophages have an unusually high metabolic rate.9 - 11
Accordingly, we used 18F-FDG-PET imaging to test the hypothesis that arterial wall inflammation is increased in patients with HIV compared with patients not infected with HIV with similar cardiac risk factors, in association with increased monocyte and macrophage activation.
Comment
FDG accumulates within metabolically active macrophages infiltrating affected vessels such that increased FDG uptake reflects heightened vascular inflammation.5 - 8 Indeed, through pathologic and histologic analyses of plaque specimens from participants with occlusive carotid disease who went on to receive carotid endarterectomy, studies have previously shown that arterial FDG uptake correlates closely with plaque macrophage infiltration characterized by increased CD68 staining.5 - 8 Increased aortic FDG uptake is known to correlate with increased FDG uptake in the left main coronary artery.17 Moreover, increased arterial FDG-PET uptake is associated with subsequent progression of atherosclerotic plaques18 and identifies patients at risk for subsequent atherothrombotic events.12 ,19 Hence, the signal that is observed likely reflects atherosclerotic inflammation with macrophage infiltration into arterial atheroma. The results from our study using the 18F-FDG-PET technique suggest that macrophage infiltration and resulting arterial inflammation, measured here in the aorta, are increased among patients infected with HIV.
Our observation that HIV infection is associated with increased arterial inflammation, even among relatively young patients with HIV with low FRS and undetectable viremia, is concordant with the epidemiological observations that patients with HIV have a higher risk of stroke and myocardial infarction than patients without HIV1 ,20 and demonstrates that this risk may not be measured adequately by traditional risk assessment tools, such as the FRS. Indeed, recent studies among patients without HIV demonstrate that consideration of TBR can improve net reclassification index compared with use of FRS and traditional risk factors.21 Moreover, these studies demonstrate that a TBR of more than 1.7 is associated with an approximate 40% reduction in CVD event-free survival over 3 years,12 whereas a TBR of more than 2.25 (vs <1.84) is associated with a markedly increased risk of CVD events over 5 years.21 These data suggest a clinically relevant degree of added CVD risk due to increased arterial inflammation in the HIV population studied herein.
One potential mechanistic link to this observation is suggested by our demonstration that a marker of monocyte and 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 complexes.22 Soluble CD163 is shed via proteolytic cleavage at the cell surface and can be found in the circulation. Soluble CD163 has been previously shown as a circulating marker of atherosclerosis in patients without HIV.23 - 24 Macrophages expressing CD163 have been found in human atherosclerotic plaques of patients without HIV25 as well as within plaque lesions in simian immunodeficiency virus-infected monkey models.26 In patients chronically infected with HIV, we have previously demonstrated sCD163 to be independently associated with increased noncalcified plaque among young, asymptomatic men.2 We extend the observations further by observing a significant correlation between sCD163 and the extent of arterial inflammation. In contrast, markers of generalized inflammation (high-sensitivity C-reactive protein) and thrombosis (D-dimer) were not statistically significant in terms of their relationships to vascular inflammation in our study. Hence, in HIV, macrophage activation markers correlate with noncalcified plaques and arterial wall inflammation, 2 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 our study, we show that among patients infected with HIV, a sCD163 level of more than 800 ng/mL is associated with a markedly increased TBR of more than 2.3. Further studies are needed to determine if the demonstration of an increased sCD163 level in clinical practice will predict events and provide unique information to that of traditional risk indices.
One hundred percent of the patients with HIV studied were receiving ART 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 CVD. Such patients, particularly with low FRS, are not considered to be at high risk for CVD, yet such patients have increased arterial wall inflammation, equal to that of patients without HIV with established CAD.
Coronary artery calcium was higher in patients not infected with HIV 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 with the HIV group. 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 observed in the HIV group might itself induce an increase in CAC.
Our study design limits definitive conclusions regarding causality of increased inflammation, but our data suggest monocyte and macrophage activation may be contributing. We cannot completely rule out an effect of ART directly on arterial inflammation, but evidence from INSIGHT SMART27 and STACCATO28 study groups 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; thus our findings may not be fully generalizable to women. Additionally, although 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 participant 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 patients infected with HIV and suggest that monocyte and macrophage activation could play a critical role in the early expression of subclinical atherosclerosis in patients with HIV. These data have clinical relevance and suggest that patients with HIV 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 proatherogenic activation of monocytes and macrophages with hopes of reducing risk of atherothrombosis in patients infected with HIV.
Results
Participant Characteristics
The clinical characteristics of the HIV, non-HIV FRS-matched control, and non-HIV atherosclerotic control participants are shown in Table 1. Age was similar in the HIV and FRS-matched control groups and increased in the non-HIV atherosclerotic control group. All of the participants with HIV and all of the FRS-matched control participants demonstrated either low or intermediate FRS. Based on the matching, mean FRS was not significantly different between the HIV group and the FRS-matched control group (6.4; 95% CI, 4.8-8.0; vs 6.6; 95% CI, 4.9-8.2; P = .87). As expected, cardiovascular risk parameters were markedly increased and statin use was more prevalent in the non-HIV atherosclerotic control group. The majority of participants with HIV demonstrated well-controlled HIV disease (mean [SD] CD4 cell count, 641 [288] cells/μL) and virologic suppression (median [interquartile range {IQR}] HIV-viral RNA level, <48 [<48 to <48] copies/mL) (Table 2). The minimum duration of HIV infection was 5 years and mean (SD) duration of infection was 15.5 (5.7) years. The mean (SD) duration of treatment with ART was 12.3 (4.3) years (Table 2).
Arterial Inflammation in HIV and Non-HIV Control Groups
Arterial inflammation (TBR) in the aorta was higher in the HIV vs non-HIV FRS-matched controls (2.23; 95% CI, 2.07-2.40; vs 1.89; 95% CI, 1.80-1.97; P < .001) (Table 1 and Figure 2). In comparison, the arterial inflammation in the aorta was not significantly different between the HIV and the non-HIV atherosclerotic control group (2.23; 95% CI, 2.07-2.40; vs 2.13; 95% CI, 2.03-2.23; P = .29). The analysis was also repeated, limiting the comparison to those patients with HIV with undetectable viremia. The TBR of the aorta remained increased among the 21 patients with HIV with undetectable viremia (81%) compared with the 27 non-HIV FRS-matched control participants (2.24; 95% CI, 2.03-2.45; vs 1.89; 95% CI, 1.80-1.97; P < .001) (Table 3 and eTable 1) and similar to that in the non-HIV atherosclerotic control group (2.24; 95% CI, 2.03-2.45; vs 2.13; 95% CI, 2.03-2.23; P = .31). The TBR of the aorta did not differ by use of ART class (protease inhibitor vs no protease inhibitor: 2.21; 95% CI, 2.03-2.39; vs 2.25; 95% CI, 1.98-2.52; P = .81; and nonnucleoside reverse transcriptase inhibitor vs no nonnucleoside reverse transcriptase inhibitor: 2.25; 95% CI, 1.94-2.56; vs 2.22; 95% CI, 2.07-2.37; P = .84). The TBR remained similar (P = .82) between the HIV group and the group with established CAD, controlling for age and statin use.
Stratified Analyses by Traditional Risk Factors
Calcium score was significantly higher in the non-HIV atherosclerotic control group compared with either the HIV or non-HIV FRS-matched control groups (Table 1); however, the TBR of the aorta was not related to calcium score in univariate regression analysis among all participants (P = .60). Arterial inflammation in the aorta remained higher in the HIV group vs the non-HIV FRS-matched control group in stratified analyses limited to those participants with no coronary calcium (P = .009) (Table 3 and eTable ), and separately among those participants with coronary calcium score of more than 0 (P = .02). Smoking rates were not significantly different between the HIV group and the non-HIV FRS-matched control group (P = .12). Moreover, aortic TBR was increased in the HIV group compared with the non-HIV FRS-matched control group in an analysis limited to nonsmokers (2.23; 95% CI, 2.04-2.43; vs 1.90; 95% CI, 1.81-1.99; P = .001) (Table 3; for additional smoking analysis, see eMethods and eTable 3). Similarly, arterial inflammation in the aorta remained higher in the HIV group vs the non-HIV FRS-matched control group in stratified analyses limited to participants with low FRS (score, 0-10), low LDL-C level (<100 mg/dL), and those patients not receiving statins (all P ≤ .01) (Table 3, eTable 4, eTable 5, and eTable 6).
Multivariate Regression Analysis of Cardiovascular Risk Factors
Adjusting simultaneously for traditional cardiovascular risk factors in a multivariate regression model, including FRS, statin use, calcium score, smoking, and LDL-C, aortic TBR remained higher in the HIV group compared with the non-HIV FRS-matched control group (P = .002). In contrast, traditional risk factors were not significant in the model (eTable 7).
Aortic TBR and Circulating Immune and Inflammatory Markers in Patients With HIV
The sCD163 level was higher in the HIV group in our study (median [IQR], 855 [451-1543] ng/mL; mean [SD], 1200 [988] ng/mL) than observed in a group of previously published comparable non-HIV control participants (median [IQR], 765 [572-1054] ng/mL; mean [SD], 883 [561] ng/mL).2 The aortic arterial inflammation (TBR) significantly correlated with sCD163 levels (P = .04) (Table 4). In contrast with sCD163, high-sensitivity C-reactive protein and D-dimer were not significantly associated with aortic arterial inflammation (TBR) (Table 4). Limiting the analysis to the 21 patients with HIV with undetectable viral load (81%), sCD163 remained similarly and significantly associated with aortic TBR (P = .03) (Figure 3).
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