Vitamin C therapy ameliorates vascular endothelial dysfunction in treated patients with homocystinuria

Objectives: We sought to investigate the effects of short- and long-term vitamin C therapy on endothelial dysfunction in patients with homocystinuria.Background: Untreated homocystinuria due to cystathionine -synthase deficiency is associated with premature atherothrombotic disease; 25% of untreated patients suffer a vascular event by the age of 16 years and 50% by 29 years. Treatment directed at reducing homocysteine accumulation significantly reduces this risk. However, despite optimal treatment and compliance, hyperhomocysteinaemia usually persists and individuals exhibit endothelial dysfunction indicative of an adverse cardiovascular prognosis. Additional intervention is therefore required to further reduce cardiovascular risk.Methods: We investigated the endothelial effects of acute (2 g single dose) and chronic (1 g/day for 6 months) administration of oral vitamin C in 5 patients with homocystinuria (mean age 26 years, 1 male) and 5 age- and sex-matched controls. Brachial artery endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent responses to nitroglycerin (NTG) were measured using high-resolution ultrasonic vessel wall-tracking.Results:Baseline: Plasma total homocysteine was 100.8 ± 61.6 and 9.2 ± 1.9 mol/L in the patient and control groups, respectively (p < 0.001). FMD responses were impaired in the patient group (20 ± 40 m) compared with the controls (116 ± 30 m) (p < 0.001). Vitamin C administration: FMD responses in the patient group improved both acutely, 160 ± 65 m at 4 h (p < 0.001), and chronically, 170 ± 70 m at 2 weeks (p < 0.001) and 170 ± 40 m at 6 months (p < 0.001). FMD responses in the control group were unaltered (p = 0.526). Within both groups, neither the vascular response to NTG nor plasma homocysteine was altered (p > 0.4).Conclusions: Vitamin C ameliorates endothelial dysfunction in patients with homocystinuria, independent of changes in homocysteine concentration and should therefore be considered as an additional adjunct to therapy to reduce the potential long-term risk of atherothrombotic disease.