Tetrahydrobiopterin restores impaired coronary microvascular dysfunction in hypercholesterolaemia

Abstract

Purpose

Tetrahydrobiopterin (BH₄) is an essential co-factor for the synthesis of nitric oxide (NO), and BH₄ deficiency may cause impaired NO synthase (NOS) activity. We studied whether BH₄ deficiency contributes to the coronary microcirculatory dysfunction observed in patients with hypercholesterolaemia.

Methods

Myocardial blood flow (MBF; ml min⁻¹ g⁻¹) was measured at rest, during adenosine-induced (140 μg kg⁻¹ min⁻¹ over 7 min) hyperaemia (mainly non-endothelium dependent) and immediately after supine bicycle exercise (endothelium-dependent) stress in ten healthy volunteers and in nine hypercholesterolaemic subjects using ¹⁵O-labelled water and positron emission tomography. Measurements were repeated 60 min later, after intravenous infusion of BH₄ (10 mg kg⁻¹ body weight over 30 min). Adenosine-induced hyperaemic MBF is considered to represent (near) maximal flow. Flow reserve utilisation was calculated as the ratio of exercise-induced to adenosine-induced hyperaemic MBF and expressed as percent to indicate how much of the maximal (adenosine-induced) hyperaemia can be achieved by bicycle stress.

Results

BH₄ increased exercise-induced hyperaemia in controls (2.96±0.58 vs 3.41±0.73 ml min⁻¹ g⁻¹, p<0.05) and hypercholesterolaemic subjects (2.47±0.78 vs 2.70±0.72 ml min⁻¹ g⁻¹, p<0.01) but had no influence on MBF at rest or during adenosine-induced hyperaemia in controls (4.52±1.10 vs 4.85±0.45 ml min⁻¹ g⁻¹, p=NS) or hypercholesterolaemic subjects (4.86±1.18 vs 4.53±0.93 ml min⁻¹ g⁻¹, p=NS). Flow reserve utilisation remained unchanged in controls (70±17% vs 71±19%, p=NS) but increased significantly in hypercholesterolaemic subjects (53±15% vs 66±14%, p<0.05).

Conclusion

BH₄ restores flow reserve utilisation of the coronary microcirculation in hypercholesterolaemic subjects, suggesting that BH₄ deficiency may contribute to coronary microcirculatory dysfunction in hypercholesterolaemia.