key: cord-0719823-6rhgg4h2
authors: Wiltshire, Esko; Sophie Peña, Alexia; MacKenzie, Karen; Shaw, Geoffrey; Couper, Jennifer
title: High dose folic acid is a potential treatment for Pulmonary Hypertension, including when associated with COVID-19 pneumonia
date: 2020-07-26
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2020.110142
sha: 42bcc0a562e2a053514080ab92ec2eda499f1173
doc_id: 719823
cord_uid: 6rhgg4h2

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.

Abstract 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.

Pulmonary Hypertension may be primary or secondary to a variety of underlying pulmonary, pneumonia. The underlying mechanism for pulmonary hypertension is impaired pulmonary vascular function, particularly impaired function of the enzyme endothelial nitric oxide synthase (eNOS) and therefore lower local production of NO. Of note, significantly lower serum folate has also recently been reported in patients with severe COVID-19 infection. 4 Endothelial function and eNOS itself are both directly affected by folate supplementation.

Folate affects eNOS function, both directly and by enhancing availability of its cofactor, tetra-hydro biopterin (BH 4 ). 5 It may also enhance NO bioavailability via scavenging superoxide. 6 Endothelial function in the coronary circulation improves within hours of oral folate administration 7 and within minutes of intravenous 5-methyl-tetrahydrofolate, its active form. 8 In the systemic circulation, we have shown that a high dose of oral folic acid (5 mg) rapidly reverses endothelial dysfunction in children with type 1 diabetes, 9 assessed using flow-mediated dilatation, a nitric oxide mediated process. 10 This effect occurred within two hours following administration and was sustained acutely for 4 hours and for at least 8 weeks with on-going therapy with no adverse effects. Response to folic acid may however also be dependent on particular genetic polymorphisms in eNOS 11 , with carriers of an insertion, which influences NO production, being more likely to respond to folic acid in our studies 11 . Importantly, folate also prevents tolerance to nitrates in the systemic circulation. 12 Limited data suggest an effect of folic acid on the pulmonary vasculature via eNOS. In both human pulmonary artery endothelial cells and murine pulmonary arteries exposed to hypoxia, folic acid reverses uncoupling of eNOS and restores NO production. 13 Pulmonary hypertension also occurs in children with cobalamin-C deficiency 14, 15 and total plasma homocyst(e)ine is elevated in individuals with primary pulmonary hypertension, 16 supporting a role for folic acid metabolism in development of pulmonary hypertension.

In combination, these data suggest high doses of folic acid may have a beneficial effect on pulmonary perfusion or the treatment of pulmonary hypertension, both directly and by enhancing the effectiveness of iNO or by preventing tachyphylaxis to iNO (via its enhancement of NO bioavailability and reduction in degradation), at least in some patients, with minimal risk of adverse consequences. Although folate could have an effect in a variety of situations in which pulmonary hypertension occurs, during the current COVID-19 outbreak it may be of specific benefit in patients with hypoxaemia associated with severe pneumonia in whom iNO therapy is being considered. We hypothesise that in these patients, folic acid, 5-10 mg administered orally (or the equivalent dose, 50-100 mcg, of the active form 5-methyltetrahydrofolate intravenously, if the oral route is unavailable) will: 1) rapidly improve hypoxaemia due to pulmonary hypertension and 2) prevent tachyphylaxis to iNO therapy.

Testing these hypotheses could initially occur in a case series of patients affected by severe COVID-19 pneumonia in whom iNO is being considered. As the effect in the systemic circulation occurs within two hours 9 , improvement in hypoxia would be expected over a similar time-frame in individuals, if it is effective. To assess an impact on tachyphylaxis to iNO, the effect of the addition of oral folate 5 mg daily to the length of time that iNO was required and dose requirements over time could be assessed. If there was any evidence of benefit from individual cases or a case series, then a formal randomised controlled trial over a short time period would establish effectiveness.

Being physicians fortunate enough to live in countries that have been less affected by severe COVID-19 disease, we are not in a position to test these hypotheses ourselves, but submit the idea to the medical community in case it does prove to have some benefit for some patients, as an adjunctive therapy with very low risk even when given for longer periods. 

Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management

Inhalation of Nitric Oxide in the Treatment of Severe Acute Respiratory Syndrome: A Rescue Trial in Beijing

Clinical Characterization of 162 COVID-19 patients in Israel: Preliminary Report from a Large Tertiary Center

Folic acid reverts dysfunction of endothelial nitric oxide synthase

Role of folic acid in nitric oxide bioavailability and vascular endothelial function

Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering

5-methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia

Folate and vitamin B6 rapidly normalize endothelial dysfunction in children with type 1 diabetes mellitus

Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo

A NOS3 polymorphism determines endothelial response to folate in children with type 1 diabetes or obesity

Folic Acid Prevents Nitroglycerin-Induced Nitric Oxide Synthase Dysfunction and Nitrate Tolerance

Folic Acid Promotes Recycling of Tetrahydrobiopterin and Protects Against Hypoxia-Induced Pulmonary Hypertension by Recoupling Endothelial Nitric Oxide Synthase

Cobalamin C Defect Presenting With Isolated Pulmonary Hypertension

Reversible pulmonary arterial hypertension in cobalamin-dependent cobalamin C disease due to a novel mutation in the MMACHC gene

Association between hyperhomocysteinemia and primary pulmonary hypertension