High dose folic acid is a potential treatment for pulmonary hypertension, including when associated with COVID-19 pneumonia.

BACKGROUND: Pulmonary hypertension is a significant complication for some patients with COVID-19 pneumonia, especially those requiring intensive care. Tachyphylaxis to the current therapy, inhaled nitric oxide (iNO), is also common. In vitro, folic acid directly increases nitric oxide (NO) production and extends its duration of action; effects which could be of benefit in reversing pulmonary hypertension and severe hypoxaemia. Our work has shown that, in the systemic circulation, folic acid in high dose rapidly improves nitric oxide mediated vasodilation, by activating endothelial nitric oxide synthase (eNOS). HYPOTHESIS: A similar effect of high dose folic acid on pulmonary endothelial function would be expected from the same mechanism and would lead to improvement in pulmonary perfusion. We therefore hypothesise that folic acid, 5 mg or greater, is a useful therapeutic option for pulmonary hypertension and/or refractory severe hypoxaemia, in patients with severe COVID-19 associated pneumonia in whom NO therapy is considered, with a very low risk of adverse effects.

Folate fortification and supplementation do not provide vascular health benefits in type 1 diabetes.

OBJECTIVE: To evaluate the lowest effective dose-response of folic acid on endothelial function in children with type 1 diabetes. STUDY DESIGN: A randomized, double-blind, crossover, placebo-controlled trial was conducted in 20 children with type 1 diabetes (age range 10-18 years) after mandatory folate fortification in Australia. Each child received orally 4 interventions (1 per month)-3 folic acid doses (0.5, 2, and 5 mg) and 1 placebo dose--in random order. The primary outcome was 2-hour postintervention change in endothelial function measured with flow-mediated dilatation (FMD). Thirty-five children with type 1 diabetes from our folic acid interventional trial before folate fortification were used for comparison. RESULTS: All children completed the study. There were no differences in baseline FMD or folate status between the visits. Folic acid supplementation increased serum folate (P = .0001) and red cell folate (P < .0001), but none of the doses improved FMD (P = .96). Baseline serum folate and red cell folate levels and FMD and glyceryl trinitrate-mediated dilatation were significantly higher in these children compared with children from our trial before mandatory folate fortification (P = .0001, .0001, .014, and .04, respectively). CONCLUSIONS: Folate status and vascular function have improved in children with type 1 diabetes since the introduction of mandatory folate fortification, but the beneficial endothelial effects of additional folic acid are no longer present.

Adiponectin relates to smooth muscle function and folate in obese children.

OBJECTIVE: Adiponectin, an adipocyte-specific protein, stimulates nitric oxide production and may mediate associations between visceral obesity and vascular dysfunction. Adiponectin is lower in obese children but its relationship with vascular function has not been clarified in childhood. We aimed to evaluate the association between adiponectin and vascular function in obese and healthy children. METHODS: Forty-nine obese and thirty-three non-obese children (aged 13.4+/-2.8 years, 37 males) participated in a cross-sectional study. We measured adiponectin, vascular endothelial and smooth muscle function (Flow mediated dilatation [FMD] and glyceryl trinitrate induced dilatation [GTN]), serum folate, red cell folate (RCF), homocysteine, lipids, glucose and insulin. Because adiponectin related to RCF we examined the effect of folate supplementation on adiponectin levels in obese children in a previously conducted randomized folate intervention trial. This included two assessments prior to intervention and two post intervention. RESULTS: Adiponectin, FMD and GTN were lower in obese compared with non-obese children (p = 0.002, p = 0.03 and p < 0.001, respectively). In obesity, adiponectin related to GTN (beta = 0.46, p < 0.001), RCF (beta = 0.4, p = 0.001) and LDL cholesterol (beta = 0.33, p = 0.004). Adiponectin associations were affected by gender and adiponectin related to female gender (B = 0.22, p = 0.03). During the intervention trial, folic acid did not improve adiponectin levels (p = 0.8) in spite of increasing serum folate and RCF (p < 0.001, p < 0.001, respectively) and decreasing homocysteine levels (p = 0.008). CONCLUSIONS: Obese children have lower adiponectin, which relates to decreased smooth muscle function and lower folate status. Despite adiponectin relating to folate status, folic acid supplementation does not improve adiponectin in obese children.

Folic acid improves endothelial function in children and adolescents with type 1 diabetes.

OBJECTIVE: To evaluate the effect of folate supplementation on endothelial function in children and adolescents with type 1 diabetes. STUDY DESIGN: Thirty-six subjects with type 1 diabetes age 13.6+/-2.6 years completed a randomized, double-blind, placebo-controlled crossover trial. Each subject received 8 weeks of oral folic acid (5 mg/d) and 8 weeks of placebo, with an 8-week washout period. Before and after each intervention, we assessed endothelial function by using brachial artery responses to flow (flow-mediated dilatation [FMD]) and glyceryl trinitrate, von Willebrand factor, glucose, hemoglobin A1c, total plasma homocyst(e)ine (tHcy), vitamin B(12), serum folate, and red cell folate (RCF). RESULTS: Folic acid increased FMD by 2.58 (3.1-5.7) % (95% confidence interval, 1.28-3.88), whereas placebo did not change FMD (-0.42%; 95% confidence interval, -1.67 to 0.83; P<.001). Folic acid increased serum folate by 14 nmol/L (6.2 ng/mL, P<.001) and RCF by 467.2 nmol/L (206 ng/mL, P<.001). Change in FMD was related to change in serum folate (r=0.46, P=.005) and RCF (r=0.39, P=.02). Glyceryl trinitrate responses, von Willebrand factor, tHcy, and hemoglobin A1c were not affected by the intervention. CONCLUSIONS: Short-term high-dose folic acid improves endothelial function in children and adolescents with type 1 diabetes and normal folate status independently of tHcy.