Patients with systemic lupus erythematosus (SLE) have a 4–10-fold greater risk of atherosclerotic cardiovascular disease (ASCVD) compared with the general population (1). Although traditional Framingham risk factors may be inadequate for assessing ASCVD risk in patients with SLE (2), the high incidence of cardiovascular morbidity and mortality in these patients underscores the need for objective and accurate means by which to identify those with subclinical disease and to apply targeted interventions.
Electron beam computed tomography (EBCT) is used to detect coronary artery calcification (CAC) within atheromatous plaques. CAC scoring by EBCT correlates with the total histopathologic and arteriographic burden and can be used to predict future cardiovascular events (3). CAC scoring by EBCT has been used in many large population-based studies to evaluate the prognostic utility of this approach in the primary prevention setting (4, 5).
The pathogenesis of ASCVD in SLE is likely multifactorial, involving traditional risk factors, early menopause, treatment side effects, and immunologic/inflammatory components. Although elevated homocysteine levels have been associated with stroke and thrombosis in patients with SLE, reports linking hyperhomocysteinemia with ASCVD are lacking (6). In the general population, however, hyperhomocysteinemia is independently associated with an increased risk of ASCVD (7), and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with hyperhomocysteinemia in healthy individuals with low-folate status (8).
The aim of this study was to determine the incidence and extent of CAC, an early manifestation of ASCVD, in patients with SLE compared with controls, and to identify variables that are associated with CAC in this population. We postulated that patients with SLE are more likely than controls to have CAC, and that EBCT could identify subclinical ASCVD in women with SLE.
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- PATIENTS AND METHODS
We have shown that female patients with SLE have a statistically significantly higher incidence of CAC, as quantified by EBCT, compared with age- and race-matched female controls. Although many traditional risk factors were significantly associated with CAC, in a multivariate analysis only age, hyperhomocysteinemia, and disease duration were associated with an elevated rCAC score in patients.
Hyperhomocysteinemia has been observed in other SLE cohorts and has been identified as a risk factor for atherothrombotic events in SLE (17, 18). This study is the first to identify hyperhomocysteinemia as a statistically significant risk marker for CAC, as assessed by EBCT, although a nonsignificant trend in another SLE cohort was previously reported (19). Additionally, a nonsignificant trend was observed using carotid ultrasonography (20).
These results are consistent with a growing body of literature in which the relationship between hyperhomocysteinemia and atherothrombotic disease has been reported in the general population. An interaction between hyperhomocysteinemia and inflammation may predispose members of vulnerable populations to premature ASCVD. Because folic acid can lower homocysteine concentrations, SLE patients with hyperhomocysteinemia may be able to lower their risk of ASCVD and consequent excess morbidity and mortality by using vitamin supplements that contain folic acid.
In healthy persons and in patients with ASCVD but without overt inflammatory disease, hyperhomocysteinemia is underpinned, at least partly, by the MTHFR C677T genotype (21). Surprisingly, we observed no association between the MTHFR genotype and the homocysteine concentration in either patients with SLE or controls. Published reports that have linked the MTHFR 677TT genotype and hyperhomocysteinemia have often been biased toward older male subjects. The lack of association between the MTHFR genotype and hyperhomocysteinemia in the controls reported here may reflect their relatively young age, female sex, African American race, or other demographic feature. The lack of association between the MTHFR genotype and hyperhomocysteinemia or CAC in patients with SLE suggests that other mechanisms, not directly involving differential MTHFR activity, generate an SLE-related phenotype characterized by high homocysteine levels and premature ASCVD. Nonetheless, in our study, hyperhomocysteinemia was clearly associated with higher rCAC scores in patients with SLE and may be one of the few laboratory markers that correlate with ASCVD in such patients.
In contrast to homocysteine, the levels of hsCRP and sCD154, each of which has received attention as a predictive marker in patients who have an enhanced risk of cardiovascular events (22, 23), were not associated with CAC in our SLE patients. This is not entirely surprising, because most patients with SLE have some systemic inflammation; i.e., a serologic marker of inflammation that varies over time may not identify unique subsets of patients with SLE who are at risk for ASCVD.
More than half of our SLE population was African American. Before undertaking this study, it was unclear how race might affect the analysis of ASCVD detected by EBCT in a racially diverse population, because the software of the EBCT scanners compares each rCAC score with an age- and sex-matched, but not-race matched, control group of subjects who are predominantly white (16). The Coronary Artery Risk Development in Young Adults study (4) previously demonstrated that race does not significantly affect the prevalence of CAC in either men or women, even after adjustment for traditional risk factors. However, in another study (24), CAC was almost twice as prevalent in whites as in African Americans. In the current study, the incidence and extent of CAC were similar for African American and white participants in both the SLE and control groups, validating the use of EBCT as an effective screening tool in patients of both races.
In summary, we have shown that EBCT can be used to detect CAC, an objective indicator of the early stages of ASCVD, in a racially diverse population of patients with SLE. The only SLE-related variable significantly associated with CAC was disease duration. Although the incidence and extent of CAC are known to increase with age, this alone did not explain the CAC variances in our model. However, a simple laboratory measure, an elevated homocysteine level, was also associated with CAC in both patients with SLE and controls. Therefore, our findings suggest that hyperhomocysteinemia is a potentially useful marker for CAC and subclinical ASCVD. If our results are confirmed by other investigators, patients with SLE who have raised homocysteine levels might benefit from EBCT screening. Clinical management of those with CAC could then incorporate strategies, perhaps including aggressive folic acid supplementation, designed to limit cardiovascular comorbidity.