HIV infected persons have a higher risk of developing cardiovascular disease compared with age-matched uninfected persons [1
]. The mechanism for this increase is unknown, but is almost certainly multi-factorial. Prior work from our group and others suggest that uncontrolled viral replication (and its effect on biomarkers of inflammation) appear to be causally associated with this increased risk [3
]. Among treated patients, certain drugs such as the protease inhibitor class and perhaps abacavir are also associated with increased risk of disease [1
]. The relative degree of immunodeficiency—as defined by nadir and recent CD4+ T cell counts—may also be associated with cardiovascular risk. Here, we performed a detailed assessment of arterial stiffness by pulse wave analysis and tonometry. Arterial stiffness has been associated with all-cause mortality, cardiovascular mortality [12
], coronary artery disease [26
], and stroke [27
] in HIV uninfected persons. As expected, age, blood pressure, and antihypertensive medication use were associated with increased arterial stiffness in our population. We also found that the peripheral CD4+ T cell count was a strong and consistent predictor of both PWV and arterial stiffness. This association appeared to be independent of other important clinical factors that are known to influence measures of arterial stiffness, such as age, BP, and diabetes mellitus. More importantly, the relationship between nadir CD4+ T-cell count and arterial stiffness was independent of other HIV-associated characteristics, including HIV duration, the use of protease inhibitors, and current CD4+ T-cell count.
Among long-term treated patients, there is a growing body of evidence that suggests the degree of prior or residual immunodeficiency while on therapy is associated with the short-term risk of cardiovascular disease. In our earlier studies, we found that a nadir CD4+ T-cell count ≤ 200 cells/μl was associated with carotid intima-medial thickness [24
] while other studies have failed to detect an effect [28
]. The discrepancies between study results may be due to differences in methods of assessment of carotid artery IMT [30
]. Some studies have also suggested that the on-therapy CD4+ T-cell count is independently associated with an increased risk of cardiovascular disease [31
]. These observations suggest that for unclear reasons, persistent immunodeficiency during HAART has negative cardiovascular consequences. Given the manner in which treatment has been historically administered, the vast majority of individuals in these cohorts had chronic infection at the time they started HAART, and most had a CD4 nadir below 350 cells/μl. These studies were hence unable to determine whether earlier initiation of HAART is associated with better cardiovascular outcomes than delayed initiation of HAART. Defining with more precision the role of prior or current immunodeficiency in driving heart disease could prove to be informative for the ongoing debate as to when to start combination antiretroviral therapy [34
]. Our data show that advanced immunodeficiency as represented by a nadir CD4+ T-cell count < 350 cells/μl is independently associated with increased arterial stiffness. While it is not possible to conclude from our cross-sectional study that earlier initiation of antiretroviral therapy may help reduce cardiovascular risk, our study results provide important initial evidence that might support the further pursuit of prospective studies addressing this question.
Prior studies of arterial stiffness in the HIV population have focused mainly on case-control study designs demonstrating increased (i.e. worse) arterial stiffness in HIV-infected subjects when compared with non-infected controls [13
]. HIV-specific disease characteristics that have been associated with arterial stiffness include HAART duration [29
], concomitant impaired glucose tolerance [36
], and HIV disease duration [37
]. However, prior studies were limited in the number of HIV-infected participants enrolled, which diminished the ability to explore the impact of HIV-specific disease characteristics on arterial stiffness in detail. Van Vonderen et al compared carotid intima-medial thickness (IMT), arterial stiffness and other markers of endothelial function in 37 HAART-naïve men after randomization to 2 different HAART regimens. Compared with baseline measurements, carotid IMT and femoral arterial stiffness worsened after 24 months of HAART, whereas serum markers of endothelial function improved [28
]. Of note, worsening arterial stiffness in this study was observed only in the femoral artery, and assessment of systemic arterial stiffness by AIx did not change over the treatment course. In a second study by the same group, 77 HIV-infected men (55 on HAART and 22 treatment-naïve individuals) were found to have similar PWV compared with non-infected controls, although the effect of nadir CD4+ T-cell count on PWV in HIV-infected individuals was not reported [38
The pathophysiologic mechanism by which immunodeficiency may mediate arterial stiffness and cardiovascular risk remains unclear. In the SMART study, elevations in IL-6 and D-dimer were strongly associated with all-cause mortality, suggesting that interruption of HAART may result in higher levels of HIV-associated inflammation [25
]. In our study, there was no correlation with hs-CRP and the degree of arterial stiffness, however this may have been due to insufficient power to detect differences between participants.
Chronic activation of the immune system in HIV infection may be due to microbial translocation in the gastrointestinal tract, leading to elevated levels of circulating microbial products such as lipopolysaccharide, which may activate immune and inflammatory pathways [39
]. It is known that residual microbial translocation during suppressive HAART is associated with the degree of immune reconstitution, as reflected by CD4+ T-cell count recovery [40
]. It has also been shown that initiation of HAART at CD4+ T-cell nadir ≤ 350 is associated with incomplete reconstitution of T-cell subsets and T-cell activation [41
]. It is thus possible that the relationship between nadir CD4+ T-cell counts and arterial stiffness may be mediated via microbial translocation, which in turn may activate inflammatory pathways, leading to premature atherosclerosis.
Our study has many limitations common to cross-sectional studies. Although our study demonstrates a strong association between nadir CD4+ T-cell count and measures of arterial stiffness, it was a cross-sectional observational study, and is therefore subject to potential selection biases and limitations in establishing cause-effect relationships. Our data argue for early use of antiretroviral therapy, however we were unable to analyze whether treatment initiation during the acute versus chronic phases of HIV infection (and potential associated differences in lifestyle or behavioral factors), affected cardiovascular risk, independent of nadir CD4+ T-cell count, due to limited number of individuals who started HAART during acute infection.
In addition, while a nadir CD4 T-cell count above 350 appeared to be associated with improved cardiovascular risk in our study, it is unclear from our data whether this relationship extends beyond a CD4+ T-cell count of 500 cells/μl, as few participants met these criteria. Thus, whether earlier initiation of HAART at a CD4+ T-cell count of 500 rather than 350 cells/μl may impact cardiovascular risk is unclear. It is also unclear from our study whether it is exposure to HIV replication or low CD4+ T-cell counts or both were driving vascular dysfunction. However, because nadir but not current CD4+ T-cell count in persons with undetectable viral load predicted arterial stiffness suggests that duration of untreated HIV or exposure to viremia may be more important than persistent depressed CD4+ T-cell counts. Finally, we failed to detect consistent associations between diabetes mellitus, smoking, and our two vascular outcome measures. This may be due to the limited number of individuals with clinical diabetes mellitus. Also, a recent systematic review examining cardiovascular risk factors associated with PWV reported that only 6 of 44 studies reported an association between smoking and PWV [42
], thus the lack of association between these parameters in our study is not surprising. Finally, given that arterial stiffness is a surrogate and not direct measure of atherosclerosis, the ultimate clinical significance of our findings is unclear. Prior studies have shown a 5 m/s increase in PWV to be associated with a 2-fold greater odds of all-cause mortality in hypertensive patients [12
], and each quartile increase in AIx was associated with a 2-fold greater odds of coronary artery disease [26
]. Whether or not our findings of increased AIx@75 or increased PWV in association with nadir CD4+ T-cell counts < 350 translate into clinically significant outcomes is unclear and will require further study.
Despite these limitations, the strengths of this study are that participants were recruited from two unique ongoing longitudinal cohorts which included individuals who were treated with HAART both early and late in the course of their HIV infection, and were thus were extremely well-characterized with respect to their clinical and HIV-related parameters. Our study is the largest study examining arterial stiffness to date, and may provide important initial evidence to prompt longitudinal studies addressing whether early initiation of HAART may have any impact on cardiovascular risk.
In conclusion, among treated HIV-infected individuals, increased arterial stiffness was independently associated with both traditional cardiovascular risk factors including age and diabetes, as well as a low nadir CD4 count. While inferences drawn from our findings must be interpreted with caution due to the cross-sectional nature of our study, our data may provide initial evidence that earlier initiation of antiretroviral therapy before low CD4 counts occur may be a means of reducing cardiovascular risk among individuals with HIV infection. Prospective studies are needed to evaluate potential beneficial effects of HAART initiation at higher CD4 T-cell counts on cardiovascular risk.