SLE is associated with an increased risk of subclinical and clinical atherosclerosis (1
), although the biological mechanisms underlying this risk are not well understood. Data presented here describe pro-inflammatory HDL as a risk factor for subclinical atherosclerosis on carotid ultrasound, manifested as increases in both the frequency of plaque and high IMT. There was no association in our cohort between quantitative HDL levels and either plaque or IMT. Furthermore, quantitative HDL levels were not associated with HDL function in either this cohort (data not shown) or in our previously published cohort of patients (21
), highlighting that biological HDL function, not simply quantity, confer risk in SLE. In agreement with this concept, higher levels of “dysfunctional” HDL have been demonstrated in a cohort of patients with known cardiovascular disease, (9
) as well as in patients with both inactive and active Crohn's disease when compared to healthy controls (22
). In addition, dysfunctional HDL were associated with increased IMT in a small cohort of South Asian immigrants to the US, even after adjusting for quantitative HDL level, age, family history of cardiac disease, and hypertension (23
Normal functioning HDL-C has several anti-atherogenic properties. HDL transports excess cholesterol from cells in artery walls to the liver for disposal (10
), removes reactive oxygen species from OxLDL, prevents OxLDL-mediated recruitment of inflammatory mediators and monocytes into the vessel wall (25
), and inhibits endothelial cell expression of adhesion molecules (26
) and release of chemokines/cytokines (27
). Several components of HDL contribute to these protective effects, including apoA-1 and the enzyme paraoxonase (28
Conversely, piHDL cannot prevent oxidation of LDL-C and actually increase it, leading to impairment of reverse cholesterol transport, increased recruitment of monocytes, and probably an enhanced inflammatory response (11
). Multiple mechanisms confer pro-inflammatory characteristics on HDL molecules (29
). In acute inflammation, hepatic synthesis of the protective lipoproteins in HDL-C, including apoA-1 and antioxidant enzymes such as PON1, decrease (28
). Additionally, protective components in the HDL particles, such as apoA-1, are partly replaced with pro-oxidant acute phase reactants such as serum amyloid A and ceruloplasmin (29
). Furthermore, HDL-C and apoA-1 can be readily oxidized during periods of inflammation by myeloperoxidase, a product of white blood cell activation (30
); oxidation of HDL probably contributes to its dysfunction. Oxidized HDL has pro-inflammatory characteristics (29
), and upregulates the expression of pro-inflammatory genes such as cyclo-oxygenase-2 (31
) and plasminogen activator inhibitor-1 (32
) in endothelial cells.
Previous studies in SLE subjects have described alterations in some protective components of HDL, including decreased PON enzymatic activity (33
) and decreased apoA-1 levels (35
). Our data show that piHDL is a better predictor of subclinical atherosclerosis than either apoA-1 or PON1 activity. Decreased PON1 activity correlated with higher IMT, but not with plaque, in univariate but not multivariate analysis (data not shown). This is similar to data described in a group of subjects with metabolic syndrome who had more pro-inflammatory HDL than dyslipidemic controls, despite similar levels of HDL-C and PON activity (36
). Interestingly, there was no association in either this cohort or our previously published cohort (21
) between pro-inflammatory HDL function and traditional markers of disease activity and inflammation such as hs-CRP or SELENA-SLEDAI (data not shown).
Although high quantities of HDL cholesterol have been regarded as a negative risk factor for atherosclerosis, there is increasing evidence that HDL function
may be as important as quantity for atheroprotection (28
). This was highlighted recently by the failure of the experimental drug torcetrapib, a cholesterol ester transfer protein (CETP) inhibitor that increases quantitative levels of HDL-C, to protect from coronary artery disease (32
). It has been suggested that CETP inhibition results in dysfunctional pro-inflammatory HDL-C (37
). Evidence from other groups also suggests that abnormal HDL function can contribute to excess mortality. In hemodialysis patients, piHDL was associated with a 2.5-fold increased risk of mortality over a 30-month period (14
). It is not clear if the HDL function abnormalities described with hemodialysis are similar to those in patients with piHDL in SLE; however, the results presented here highlight the importance of HDL function in addition to quantity in the prevention of atherosclerosis in the general population. In patients with SLE, abnormal function of HDL seems more important that quantities of HDL in influencing excess risk for atherosclerosis.
Our study has some limitations. Our study population differs from previously published SLE cohorts (3
) in that the prevalence of plaque in our SLE study group was lower than in previously published cohorts. Possible explanations include exclusion from our study of individuals taking statins (which biased towards patients without known hyperlipidemia and/or clinical atherosclerosis (9
)) and inclusion of a higher proportion of Asians, who may have a lower prevalence of subclinical atherosclerosis than other racial groups (39
). It is also possible that the SLE population in Los Angeles differs significantly from patients in other geographic areas, not only in ethnicities but also in habits such as physical exercise (41
), years of protection from public smoking (42
), and in hours of exposure to sunlight with influences on Vitamin D levels (43
). The fact that cohorts from different centers thousands of miles apart differ in prevalence of plaque is not surprising given the differences in geography, climate, ethnic mix, behaviors, diet, exercise and the many other factors that influence health.
Another limitation of our study is that we did not measure all potential atherosclerosis biomarkers. Most notably, since the inception of our study, several groups have demonstrated an association between high homocysteine levels and subclinical atherosclerosis in SLE (6
). Future studies in our cohort will determine whether homocysteine and piHDL are independent predictors of atherosclerosis, or whether synergy exists between them.
For practical reasons, our study focused on the association between piHDL and subclinical atherosclerosis. There are currently no published studies that specifically demonstrate that lupus patients with carotid plaque or increased IMT have an elevated risk for cardiovascular events, and it is possible that these are not valid measures in women with lupus. Multiple large cohort studies, however, that have demonstrated the predictive power of these measures in the general population (46
). Further longitudinal studies are needed to establish the predictive power of carotid plaque and IMT in women with SLE, and also to determine whether the presence of piHDL can predict future cardiovascular events in these patients.
In summary, piHDL contribute to a 17-fold increased odds for presence of atherosclerosis in female SLE patients. With a negative predictive value of 96%, piHDL may be one effective biomarker to determine which SLE patients are at low risk for subclinical atherosclerosis. These data also suggest that further studies are needed to determine whether interventions that restore protective anti-inflammatory functions of HDL-C, including statins (9
), exercise and diet (47
), and/or treatment with apo-AI mimetic peptides (48
), will be useful to prevent atherosclerosis in patients with SLE.