Increased augmentation index in rheumatoid arthritis and its relationship to coronary artery atherosclerosis

OBJECTIVE: Arterial stiffness, assessed by the augmentation index and pulse wave velocity, is an independent risk factor for cardiovascular disease. Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis and increased cardiovascular mortality. We examined the hypothesis that augmentation index and pulse wave velocity are increased in RA, and are related to coronary artery atherosclerosis. METHODS: We measured augmentation index and brachial pulse wave velocity in 117 patients with RA [57 with early (< 6 yrs) and 60 with late disease (> 10 yrs)] and 65 healthy controls. Coronary artery calcification was measured by electron beam computed tomography. Augmentation index and pulse wave velocity were compared in patients with early RA, late RA, and controls, and the association with coronary atherosclerosis was examined. RESULTS: Patients with late RA had a higher augmentation index (median 33.8%, interquartile range 27.5% 37.0%) than those with early disease (median 27.5%, IQR 21.0% 34.0%) (p = 0.008) and controls (median 27.0%, IQR 20.4% 33.0%) (p < 0.001). After adjusting for height and cardiovascular risk factors, the association between late disease and augmentation index remained significant (p = 0.02). Augmentation index was associated with coronary calcification score (rs = 0.19, p = 0.046), and the association was marginal after adjustment for cardiovascular risk factors, disease status, and disease activity (p = 0.09). There was no significant difference in brachial pulse wave velocity among patients with late (9.2 +/- 1.7 m/s) and early RA (9.1 +/- 1.6 m/s) and controls (8.9 +/- 1.5 m/s) (p = 0.78). CONCLUSION: Patients with RA have increased augmentation index independent of cardiovascular risk factors. Augmentation index was associated with coronary artery calcification in patients with RA; this was attenuated after adjusting for cardiovascular risk factors.     

Free fatty acids are associated with insulin resistance but not coronary artery atherosclerosis in rheumatoid arthritis

Background

Free fatty acids (FFAs) affect insulin signaling and are implicated in the pathogenesis of insulin resistance and atherosclerosis. Inflammatory cytokines such as interleukin-6 (IL-6) increase lipolysis and thus levels of FFAs. We hypothesized that increased IL-6 concentrations are associated with increased FFAs resulting in insulin resistance and atherosclerosis in rheumatoid arthritis (RA).

Methods

Clinical variables, serum FFAs and inflammatory cytokines, homeostasis model assessment for insulin resistance (HOMA-IR), and coronary artery calcium were measured in 166 patients with RA and 92 controls. We compared serum FFAs in RA and controls using Wilcoxon rank sum tests and further tested for multivariable association by adjusting for age, race, sex and BMI. Among patients with RA, we assessed the relationship between serum FFAs and inflammatory cytokines, HOMA-IR, and coronary artery calcium scores using Spearman correlation and multivariable regression analyses.

Results

Serum FFAs did not differ significantly in patients with RA and controls (0.56 mmol/L [0.38–0.75] and 0.56 mmol/L [0.45–0.70] respectively, p = 0.75). Presence of metabolic syndrome was associated with significantly increased serum FFAs in both RA and controls (p = 0.035 and p = 0.025). In multivariable regression analysis that adjusted for age, race, sex and BMI, serum FFAs were associated with HOMA-IR (p = 0.011), CRP (p = 0.01), triglycerides (p = 0.005) and Framingham risk score (p = 0.048) in RA, but not with IL-6 (p = 0.48) or coronary artery calcium score (p = 0.62).

Conclusions

Serum FFAs do not differ significantly in patients with RA and controls. FFAs may contribute to insulin resistance, but are not associated with IL-6 and coronary atherosclerosis in RA.     

Interaction between oxidative stress and high‐density lipoprotein cholesterol is associated with severity of coronary artery calcification in rheumatoid arthritis

Objective

To test the hypothesis that oxidative stress is increased in patients with rheumatoid arthritis (RA) due to increased inflammation and contributes to the pathogenesis of atherosclerosis.

Methods

The independent association between urinary F₂‐isoprostane excretion, a measure of oxidative stress, and RA was tested using multiple linear regression models in 169 patients with RA and 92 control subjects, frequency matched for age, race, and sex. The relationship between F₂‐isoprostane excretion and coronary calcium, a marker of atherosclerosis, was examined in multivariable proportional odds logistic regression models that also assessed the interactions between oxidative stress and low‐density lipoprotein and high‐density lipoprotein (HDL) cholesterol.

Results

F₂‐isoprostane excretion was significantly higher in patients with RA (median 2.75 [interquartile range (IQR) 1.60–4.06] ng/mg creatinine) than in control subjects (median 1.86 [IQR 1.25–2.62] ng/mg creatinine; adjusted P = 0.006). In patients with RA, F₂‐isoprostanes were positively correlated with body mass index (P < 0.001), but not with disease activity or mediators of inflammation such as the Disease Activity Score in 28 joints or serum tumor necrosis factor α, interleukin‐6, and C‐reactive protein concentrations in adjusted multivariable models (P > 0.05 for all). In patients with RA, F₂‐isoprostanes significantly modified the effect of HDL cholesterol on coronary calcification (P = 0.02 for interaction) after adjustment for age, sex, and race. As F₂‐isoprostane levels increased, HDL lost its protective effect against coronary calcification.

Conclusion

Oxidative stress measured as F₂‐isoprostane excretion was higher in patients with RA than in control subjects. Among patients with RA, higher F₂‐isoprostane excretion and HDL cholesterol concentrations interacted significantly and were positively associated with the severity of coronary calcification.     

Inflammatory mechanisms affecting the lipid profile in patients with systemic lupus erythematosus

OBJECTIVE: Increased low density lipoprotein (LDL) cholesterol and triglycerides, and decreased high density lipoprotein (HDL) cholesterol concentrations are associated with adverse cardiovascular risk in the general population. Patients with systemic lupus erythematosus (SLE) have an altered lipid profile characterized by increased triglycerides and decreased HDL cholesterol concentrations. We examined the relationships between lipid concentrations, cytokines, and inflammatory markers in patients with SLE. METHODS: Fasting lipid concentrations, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were measured in 110 patients with SLE. Disease activity was quantified by the SLE Disease Activity Index (SLEDAI), and disease damage by the Systemic Lupus International Collaborating Clinics (SLICC) score. Concentrations of circulating tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and insulin were measured and insulin sensitivity calculated. RESULTS: Lower concentrations of HDL cholesterol were independently associated with higher ESR (p < 0.001), IL-6 (p = 0.02), SLEDAI (p = 0.04), and TNF-alpha (p = 0.04) after adjustment for age, sex, race, body mass index, insulin sensitivity, and current use of corticosteroids or hydroxychloroquine. Triglyceride concentrations were associated with higher CRP concentrations (p = 0.02) and SLICC score (p = 0.04). CONCLUSION: Deleterious changes in lipid profile are independently associated with higher concentrations of markers and mediators of inflammation and disease activity and damage in patients with SLE.     

Plasma leptin concentrations in lean and obese human subjects and Prader-Willi syndrome: comparison of RIA and ELISA methods.

Immunoassays for circulating leptin are important research tools for examining the role and regulation of leptin expression in human obesity. However, uncertainty exists regarding the comparability between studies of reported plasma or serum leptin concentrations. The purpose of the present study was to directly compare plasma leptin concentrations by using two of the most widely reported immunoassay methods-namely, a commercially available radioimmunoassay (RIA) and a proprietary enzyme-linked immunosorbent assay (ELISA). Plasma leptin concentrations were measured in healthy lean and obese volunteers and in patients with Prader-Willi syndrome (PWS). Over a wide range of plasma concentrations (2 to 70 ng/mL), leptin measurements obtained with the RIA and ELISA methods were highly correlated (r = 0.957, P<.0001) and were essentially indistinguishable. Leptin levels measured by RIA and ELISA were highly correlated with body mass index (BMI) overall (r = 0.784, P<.0001 and r = 0.732, P<.0001, respectively) and in the lean and obese subgroups. When compared with the results in the lean individuals (mean +/- SEM, 11.6+/-3.2 ng/mL), plasma leptin was significantly higher in both the obese (35.5+/-4.0 ng/mL, P<.0001) and the PWS subjects (30.7+/-6.9 ng/mL, P<.05). However, after we controlled for differences in BMI, the leptin levels were similar in all three groups. In conclusion, we found that the RIA and ELISA used in the present study yield plasma leptin concentrations that are essentially indistinguishable. Our findings should facilitate comparisons of leptin levels measured by these two widely used immunoassays in previous and future studies that examine the role of leptin in body weight regulation.