Background/Purpose: Rheumatoid arthritis (RA) patients have an elevated risk of cardiovascular (CV) disease unexplained by traditional CV risk factors. Markers of systemic inflammation, including those elevated in RA, are associated with increased plaque vulnerability. Neovascularization of the vasa vasorum (VV) is a key early feature of vulnerable plaque that is also associated with inflammation in the general population. RA-related factors may promote vulnerable plaques with increased VV neovascularization, leading to elevated CV risk. Microbubble contrast-enhanced ultrasound (CU) is a novel technique validated for quantifying VV neovascularization, which is not measured by traditional imaging techniques. Increased carotid adventitial vasa vasorum density (aVVD) indicates increased plaque vulnerability. We use CU to measure and compare aVVD in RA subjects and non-RA control subjects. We further examine correlations of aVVD with biomarkers of inflammation and atherosclerosis.

Methods: We performed a cross-sectional study of RA (n=87) and non-RA control subjects (n=101). All RA patients met 2010 ACR classification criteria. Subjects were assessed for traditional cardiovascular risk factors. Nitrite, CD40L, E-selectin, MMP-9, ICAM-1, VCAM-1, CRP, and ESR were measured in serum. CU was performed along the common carotid arteries bilaterally. CU images were analyzed using Myocardial Contrast Echocardiography 2.9 software. aVVD was quantified as the ratio of mean common carotid artery adventitial to lumen videointensity using maximum of both sides. Demographic data, CV risk factors, and biomarker levels were compared between RA and control subjects using Wilcoxon rank-sum or chi-square tests. Association of aVVD with biomarkers and CV risk factors, stratified by case status, was examined using Pearson and Spearman correlation, respectively, and linear regression models adjusted for number of CV risk factors and age.

Results: RA subjects were older (59.6 ± 12.0 versus 56.1 ± 14.8 years; p = 0.01) and had higher number of CV risk factors (40.2% versus 20.6% had ³3 risk factors; p = 0.003) compared to controls. aVVD was higher in RA subjects (0.64 ± 0.14 versus 0.61 ± 0.15; p = 0.02). In RA subjects, MPO was lower (422.8 ± 516.4 versus 604.4 ± 455.1 ng/mL; p = 0.0002) and ESR was higher (21 ± 16 versus 16 ± 13 mm/hr; p = 0.01). The other biomarkers did not differ significantly between groups. aVVD was correlated with MPO (r = -0.33, p = 0.001) and CRP (r = 0.25, p = 0.02) in control subjects, associations which remained significant after adjusting for number of CV risk factors and age. No significant correlations were found between aVVD and biomarkers in RA patients. Number of CV risk factors was not significantly correlated with aVVD in RA and controls.

Conclusion: Using the novel CU technique, we found that aVVD is significantly higher in RA compared to control subjects, suggesting CU may quantify increased plaque vulnerability in RA patients with subclinical atherosclerosis. The differences in correlation of aVVD with biomarkers of atherosclerosis and traditional CV risk factors between RA and control subjects suggests RA-related differences in atherosclerotic progression.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/identifying-vulnerable-plaque-in-rheumatoid-arthritis-using-novel-microbubble-contrast-enhanced-carotid-ultrasonography-and-serum-biomarkers-of-inflammation-and-atherosclerosis/