Tetrahydrobiopterin improves endothelial dysfunction in coronary microcirculation in patients without epicardial coronary artery disease

OBJECTIVES We aimed to determine whether intracoronary supplementation with nitric oxide (NO) synthase co-factor tetrahydrobiopterin (BH4) improves NO-dependent coronary microvascular dilation in patients with coronary risk factors but no significant organic stenosis. BACKGROUND Impaired coronary microvascular dilator reserve attributable to endothelial dysfunction plays an important role in the regulation of coronary blood flow (CBF). METHODS Fifteen patients were measured for CBF (Doppler-wire and quantitative coronary angiography). Stimulated release of NO in the coronary microcirculation was evaluated by percent increase in CBF (%ΔCBF) at graded doses of intracoronary acetylcholine (1, 3, 10 and 30 μg/min). Measurements were repeated after intracoronary co-infusion of BH4 (4 mg/min) and acetylcholine. RESULTS The patients were divided into two groups on the basis of CBF responses to acetylcholine: those with “diminished” (%ΔCBF <300%, N = 8) and “normal” (%ΔCBF >300%, N = 7) flow responses. Tetrahydrobiopterin significantly (p < 0.0001) improved acetylcholine-induced increases in CBF in patients with diminished flow responses, but exerted no effect in those with normal flow responses. Among the 15 studied patients, the magnitude of flow improvement by BH4 was inversely correlated with baseline flow responses (p < 0.02). Microvascular dilator response to direct NO donor (isosorbide dinitrate) was not affected by BH4. CONCLUSIONS We demonstrated for the first time that intracoronary BH4 improved acetylcholine-induced microvascular dilator responses in patients with endothelial dysfunction in vivo. Thus, supplementation with BH4 may be a novel therapeutic means to increase NO availability for patients with coronary microvascular disease.