Title: The influence of hypoxia and role of phospholipase C-γ (PLC γ) in proliferation of vascular smooth muscle cells (VSMC): potential mechanisms of neointimal hyperplasia formation in infra-inguinal bypass
Abstract: Objective: To determine whether folate supplementation improved arterial function in patients with peripheral arterial disease (PAD) in a randomised, double-blind, placebo-controlled trial.Method: Individuals with PAD were randomly assigned to receive 400 µg folic acid (n = 45), 400 µg methyl-tetrahydrofolate (5-MTHF) (n = 48) or placebo (n = 40) for 4 months.The primary endpoints were change in total plasma homocysteine (tHcy), ankle brachial pressure index (ABPI) and pulse wave velocity (PWV).The secondary outcomes were any change in plasma C-reactive protein (CRP), von Willebrand factor (vWF) or interleukin 6 (IL6) levels.Results: Plasma tHcy was significantly reduced in both the folic acid and 5-MTHF groups compared with controls (median difference: -2•12 µmol/l [95% CI -3•70, -0•75, p = 0•0024] and -2•07 µmol/l [95% CI 3•48, -0•54, p = 0•0072], respectively).ABPI improved significantly in the folic acid and 5-MTHF groups compared with the placebo group (median difference: 0•07 [95% CI 0•04, 0•10, p < 0•0003] and 0•04 [95% CI 0•00, 0•09, p = 0•0279], respectively).Brachial-knee PWV (bk-PWV) reduced significantly in the group receiving 5-MTHF and there was a reducing trend in the group taking 5-MTHF compared with the controls (median difference: -1•10m/s [95% CI -2•20, -0•20, p = 0•0105] and -0•90m/s [95% CI -2•10, 0•00, p = 0•05], respectively).Plasma levels of CRP, IL6 and vWF were not affected (p > 0•5).None of the variables changed significantly in the placebo group.Conclusion: Folate administration effectively reduced homocysteine and improved ABPI and bk-PWV.This effect was independent of plasma inflammatory markers.