Tetrahydrobiopterin restores impaired coronary microvascular dysfunction in hypercholesterolaemia

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 mug 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 O-15-labelled water and positron emission tomography. Measurements were repeated 60 min later, after intravenous infusion of BH4 (10 mg k(g)-(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.