Expert Review: Acute Coronary Syndrome, Interventional / Cardiac Surgery

Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease

Background

Endothelial nitric oxide synthase (eNOS) plays an important role in maintenance of endothelial function and vascular homeostasis. Tetrahydrobiopterin is an essential cofactor for eNOS. Elevation of endogenous BH4 levels by oral BH4 treatment has been suggested as a possible therapeutic strategy in cardiovascular (CV) disease involving endothelial dysfunction and atherosclerosis.

Knowledge Gap

It is not known whether oral BH4 treatment can improve endothelial function in vivo and ex vivo in patients with coronary artery disease (CAD).

Aim of the Study

The authors assessed the mechanisms of exogenous BH4 regarding vascular function and the oral pharmacokinetics of BH4 in patients with coronary artery disease.

Methods

This was a randomized placebo-controlled study among 49 patients with CAD scheduled for coronary artery bypass surgery (CABG). Patients were randomized to three groups to receive either 400mg or 700mg of BH4 or placebo for two to six weeks before CABG. Vascular function was assessed using magnetic resonance imaging (MRI), brachial artery flow mediated dilatation (FMD) and blood sampling for BH4 levels and markers for endothelial dysfunction before and after treatment. In addition, during CABG, vascular tissue from the saphenous vein and internal mammary artery were obtained to study the vascular effects of BH4 ex vivo.

Results

Regardless of the prescribed dose, oral treatment of BH4 led to marked elevation of BH4 concentrations in plasma and in saphenous veins. However, this augmentation also led to increased levels of BH2, the oxidation product of BH4.

BH2 is unable to exert eNOS cofactor activity. Moreover, BH4 treatment did not lead to improvement of vascular function or superoxide production. In addition, the ex vivo experiments showed that BH4 supplementation lead to rapid oxidation of BH4 to BH2.

Conclusion

Oral BH4 treatment leads to an elevation in total biopterin concentrations in patients with CAD. However, there was no net effect on vascular redox state or endothelial function owing to systemic and vascular oxidation of BH4.

Perspective – Clinical Impact

This study is of importance as the vascular effects of BH4 are studied for the first time in vivo and ex vivo in the same patients. Based on the results showing no net benefit for vascular function in patients with CAD the current therapeutic approach in patients with CV disease to improve endothelial function by oral supplementation of BH4 is questioned.

Future research should target the endogenous BH4/BH2 ratio in human vascular endothelium via a selective increase in absolute BH4 levels, prevention of BH4 oxidation, or increased BH4 recycling. This may be achieved by studying the effects of antioxidant coadministration to prevent systemic and vascular oxidation of exogenous BH4.

 

 

Citation: Circulation 2012 Mar 20;125(11):1356-66. Epub 2012 Feb 7

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