Cumulative Rheumatic Inflammation Modulates the Bone-Vascular Axis and Risk of Coronary Calcification

Background Rheumatic diseases are related to both abnormal bone turnover and atherogenesis, but a mechanistic link was missing. Methods and Results We investigated the effect of cumulative rheumatic inflammation ( CRI ) on risk of coronary calcification in a retrospective cohort of 145 rheumatoid arthritis patients. A time-adjusted aggregate CRI score was derived by conglomerating all quarterly biomarker encounters of serum C-reactive protein over 60 months immediately preceding computed tomography coronary angiography. Flow cytometry was performed to measure the osteocalcin-positive ( OCN ⁺) CD 34⁺ KDR ⁺ and OCN ⁺ CD 34⁺ circulating endothelial progenitor cells ( EPCs ). Conventional early circulating EPCs CD 34⁺ CD 133⁺ KDR ⁺ was determined. Coronary calcification was defined as any Agatston score >0. 50% of patients (n=72/145) had coronary calcification. CRI score was associated with presence of coronary calcification ( P=0.004) (multivariable-adjusted: highest versus lowest quartile: odds ratio=5.6 [95% CI 1.1-28.9], P=0.041). Receiver operating characteristics curve revealed divergent behavior of OCN -expressing circulating EPCs ( OCN ⁺ CD 34⁺ EPCs : area under the curve=0.60, P=0.034; OCN ⁺ CD 34⁺ KDR ⁺ EPCs : area under the curve=0.59, P=0.053, positive predictors) versus conventional early EPCs ( CD 34⁺ CD 133⁺ KDR ⁺: area under the curve=0.60, P=0.034, negative predictor) for coronary calcification, which persisted after multivariable adjustments ( OCN ⁺ CD 34⁺ KDR ⁺ [>75th percentile]: odds ratio=7.2 [95% CI 1.8-27.9], P=0.005; OCN ⁺ CD 34⁺ EPCs [>75th percentile]: odds ratio=6.0 [95% CI 1.5-23.3], P=0.010; CD 34⁺ CD 133⁺ KDR ⁺ [>75th percentile: odds ratio=0.3 [95% CI 0.1-1.0], P=0.053). Intriguingly, the CRI score was associated with increased OCN ⁺ CD 34⁺ EPCs (highest versus lowest quartile: B=+25.6 [95% CI 0.8-50.5] [×10³/mL peripheral blood], P=0.043), but reduced CD 34⁺ CD 133⁺ KDR ⁺ EPCs (highest versus lowest quartile: B=-16.2 [95% CI -31.5 to -0.9], P=0.038). Conclusions Preceding 60 months of CRI is associated with increased risk of coronary calcification and altered OCN expression in circulating EPCs .