Systemic lupus erythematosus (SLE) affects primarily women and causes chronic vascular inflammation. Women with SLE, particularly those under age 45 years, experience higher than expected rates of clinical cardiovascular disease, i.e., hypertension (1–3), myocardial infarction (1, 4), and stroke (4). In addition to traditional cardiovascular risk factors, other factors specifically associated with SLE appear to be equally, if not more, important (5, 6). It is likely that these factors are related to the underlying immune-mediated, inflammatory processes inherent in SLE.
Although the pathogenesis of vascular disease in SLE is unknown, it is thought to be multifactorial and of atherosclerotic origin. Atherosclerosis involves both atherosis (fatty degeneration) and sclerosis (vessel stiffening). Both of these processes can be evaluated with noninvasive ultrasound imaging techniques. Atherosis in the carotid arteries is evaluated using B-mode ultrasound, which measures the degree of focal plaque and intima-media wall thickness (IMT) (7). Vascular stiffness is evaluated using pulse-wave velocity (PWV), which measures the rate at which arterial pulse waves move along the vessel (8). Plaque and IMT are measures of the structural properties of the arterial wall, whereas vascular stiffness is a measure of the functional properties. Longitudinal studies have shown that all 3 of these subclinical measures of cardiovascular disease are significant predictors of future cardiovascular events and mortality (9–12).
In a previous study, we used B-mode ultrasound to evaluate carotid plaque and IMT among 175 unselected women with SLE (13). We found that 40% of those women had evidence of focal carotid plaque and that their IMT was 0.71 ± 0.14 mm (mean ± SD). Because that study included women who had experienced a prior clinical coronary event, it did not evaluate subclinical cardiovascular disease exclusively and represented a different end of the spectrum of severity.
When we used PWV to evaluate aortic stiffness in women with SLE, we found that traditional cardiovascular risk factors predominated among the postmenopausal women, but a mix of traditional and SLE-specific factors predominated among the younger, premenopausal women (5). The SLE-related factors included leukopenia, serum C3 levels, double-stranded DNA (dsDNA) antibodies, and nonuse of hydroxychloroquine. These results suggest that the associations between SLE-related factors and aortic stiffness might contribute to the premature cardiovascular disease observed among younger women with SLE. Early in the disease process, SLE may cause stiffening of the vascular wall that then sets the stage, as these women age, for an acceleration of the atherogenic process by the traditional risk factors.
Epidemiologic studies to identify the risk factors associated with subclinical vascular disease in different vascular beds and in different stages of the process will provide important foundational information for investigating the mechanisms by which these factors may function in the development of overt cardiovascular events. In particular, identifying factors specific to SLE may help to focus mechanistic studies on the premature development of cardiovascular disease in these young women.
The present study was designed to extend and improve on our previous studies by examining and comparing risk factors for various stages of subclinical vascular disease in different vascular beds (carotid and aorta) in 214 women with SLE who were free from clinical cardiovascular disease and who have been well characterized with respect to both SLE and cardiovascular risk factors.
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- PATIENTS AND METHODS
This is the first study to examine the prevalence and risk factors associated with both anatomic and functional facets of subclinical cardiovascular disease in women with SLE. Because SLE is a systemic disease, subclinical cardiovascular disease may be manifested in different forms and in different vascular beds. By distinguishing atherosis (plaque and IMT) from sclerosis (aortic stiffening), we attempted to identify risk factors specific to these processes. We found that the risk factors associated with subclinical carotid plaque and IMT were, primarily, the traditional cardiovascular risk factors as well as CRP, a marker of inflammation that is now recognized as an important risk factor for cardiovascular disease in the general population. In contrast, subclinical aortic stiffness was associated with not only the traditional factors but also factors more specific to SLE, such as a low white cell count and elevated levels of C3. These findings are among the results obtained when we examined aortic stiffness in an unselected cohort of women with SLE (5).
A low white cell count is a manifestation of active SLE and may reflect higher disease activity. However, lower C3 levels resulting from complement activation are traditionally associated with higher SLE disease activity. There are several possible explanations for our previous and current observations showing that an elevated C3 level is related to aortic stiffness. First, it may reflect an acute-phase response in which complement acts as an acute-phase reactant and is elevated during inflammation (27). This is unlikely, however, because the other acute-phase reactants we tested, fibrinogen and CRP, were not associated with aortic stiffness in these same patients. Second, vascular pathogenesis may stimulate complement synthesis without complement activation. Third, complement activation may actually contribute to vascular stiffness, but activation is masked by compensatory synthesis of these parent complement proteins. In ongoing studies in our laboratory, we are testing these possibilities.
The systemic nature of SLE may contribute to atherosclerosis by more than one mechanism and may operate at more than one point in the evolution of atherosclerosis. Early in the atherogenic process, mechanisms of SLE related to immune dysregulation and complement metabolism may reduce arterial elasticity, creating an atherogenic milieu. It is thought that reduced elasticity of the arterial walls (sclerosis) may be one of the earliest changes in the development of major vascular disease. Changes to the geometric configuration of vessels may lead to smooth muscle cell hypertrophy and increased collagen. The intimal layer of these stiffened vessels then becomes vulnerable to atherosis and to increased lipoprotein, albumin, and leukocyte permeability (28, 29). Thus, an early effect of SLE on vascular stiffening may set the stage for an acceleration of the atherosclerotic process through traditional risk factors. Although our data suggest that SLE may operate in this way, mechanistic studies will be required to establish causality. We considered the possibility that vascular stiffness is reversible in SLE and related to disease activity. However, our observations of the strong and linear association between age and vascular stiffness (Figure 1) would suggest that there is at least a component of vascular stiffness in women with SLE that is irreversible and progresses with age.
Our findings also suggest that mechanisms of SLE related to inflammation may affect vessel wall thickening and the development of plaque. It is now generally believed that inflammation plays an integral role in atherogenesis (30, 31), and prolonged exposure to even low levels of acute-phase reactants may cause vascular injury (32) leading to cardiovascular disease. We found that low albumin levels were associated with both focal carotid plaque and high IMT. Albumin is a negative acute-phase reactant, and low serum albumin levels may signal generalized inflammation. Furthermore, an inverse relationship between serum albumin and coronary disease has been identified (33). We also evaluated the potential association between low serum albumin and renal disease, a common SLE condition. The hypoalbuminemia found in the participants of this study was not associated with overt renal disease.
We also observed an association, albeit not statistically significant (at P < 0.05) after adjusting for other important factors, between current antidepressant use and the presence of carotid plaque. This is consistent with the findings of a recent study of women at mid-life, which demonstrated that after controlling for biologic and behavioral risk factors for carotid atherosclerosis, a lifetime history of recurrent major depression more than doubled the risk of plaque relative to no history of major depression (34). This relationship between depression and cardiovascular disease may be relevant to lupus patients because they frequently experience depression. Psychosocial factors have been linked to cardiovascular disease, and although antidepressant use is not a psychosocial factor, it may be a marker of depression or anxiety. Chronic psychosocial stress can lead to hypercortisolemia and enhanced platelet function, which are considered proatherogenic (35).
The importance of traditional risk factors should not be overlooked. Our findings that traditional risk factors were associated with all 3 measures of subclinical cardiovascular disease are consistent with our previous findings in women with SLE and the findings of other studies in nonlupus populations (36–41). These factors include older age, high blood pressure, high cholesterol, smoking, and elevated glucose and insulin levels. Many of these factors are modifiable and they should be aggressively treated.
We recognize that our study was limited in that our population consisted predominantly of well-educated white women, which is a reflection of the population in Pittsburgh and the surrounding metropolitan area. Because SLE is prevalent among African American women and other minorities, our results may not be generalizable to all populations. We also recognize that these results should be interpreted with caution due to our relatively small study sample. This is reflected by wide confidence intervals reported for certain significant risk factors.
In this study of women with SLE without evidence of clinical cardiovascular disease, we found that the risk factors associated with carotid plaque and IMT are those typically associated with cardiovascular disease in the general population. However, SLE-specific variables emerge as important factors in aortic stiffness. Thus, the high prevalence of cardiovascular disease among lupus patients may result from both early adverse effects on vascular stiffening as well as later promotion of wall thickening and plaque through inflammatory-mediated processes. This theory may be supported by our finding of a trend toward an association between longer SLE disease duration and the presence of carotid plaque (P = 0.09) and high IMT (P = 0.07), but no association with aortic stiffness (P = 0.18) (data not shown).
Although cross-sectional observational studies such as the present one cannot determine causality or temporal relationships, they provide valuable information for focusing future studies. Areas for further investigation include determining the process by which lupus-specific factors and inflammatory factors have their effect, and examining the role of immune dysregulation and complement metabolism in arterial stiffness. Such research might lead to potential interventions that may slow or even reverse the progression of atherosclerosis in these women.