Attenuated nitric oxide bioavailability in systemic sclerosis: Evidence from the novel assessment of passive leg movement.

NEW FINDINGS: What is the central question of this study? Do systemic sclerosis patients exhibit impaired nitric oxide-mediated vascular function of the lower limb and are these decrements correlated with plasma biomarkers for inflammation and oxidative stress? What is the main finding and its importance? Findings indicate impaired nitric oxide-mediated vascular function, linked to the incidence of digital ulcers and a milieu of inflammation and oxidative stress. However, the absence of significant correlations between individual biomarkers and blood flow responses suggests that the vasculopathy observed in systemic sclerosis may not be solely the result of derangements in the redox balance or inflammatory signalling.

ABSTRACT: Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, which may be the consequence of inflammation and oxidative stress that ultimately leads to a reduced nitric oxide (NO) bioavailability. Passive leg movement (PLM) is a novel methodology for assessing lower limb vascular function that is predominantly NO dependent. We combined this vascular assessment with a comprehensive panel of plasma biomarkers to assess the axis of inflammation, oxidative stress and NO in SSc patients (n = 12; 62 ± 11 years of age) compared with healthy control subjects (n = 17; 60 ± 16 years of age). The PLM-induced changes in leg blood flow (LBF; 191 ± 104 versus 327 ± 217 ml min-1 ) and LBF area under the curve (39 ± 104 versus 125 ± 131 ml) were reduced in SSc compared with control subjects. Stratification of patients according to history of digital ulcer (DU) formation revealed a further reduction in LBF area under the curve in DU (-13 ± 83 ml) versus non-DU (91 ± 102 ml) patients. Biomarkers of inflammation (C-reactive protein) and oxidative stress (malondialdehyde and protein carbonyl) were all elevated in SSc (C-reactive protein, 3299 ± 2372 versus 984 ± 565 ng ml-1 ; malondialdehyde, 3.2 ± 1.1 versus 1.1 ± 0.7 μm; and protein carbonyl, 0.15 ± 0.05 versus 0.12 ± 0.03 nmol mg-1 ), and C-reactive protein was further elevated in patients with a history of DU (4551 ± 2752 versus 2047 ± 1019 ng ml-1 ) compared with non-DU, although these were not individually correlated with changes in LBF. These findings of impaired NO-mediated vascular function, linked to DU and a milieu of inflammation and oxidative stress, suggest that redox balance plays an important, but not necessarily deterministic, role in the vascular pathophysiology of SSc.