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

OBJECTIVES We aimed to determine whether intracoronary supplementation will nitric oxide (NO) synthase ca-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 CCBF). 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 (%Delta CBF) at graded doses of intracoronary acetylcholine {1, 3, 10 and. 30 mug/min). Measurements were repeated after intracoronary oo-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 {%Delta CBF <300%, n = 8) and normal (%CBF >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. (J Am Coll Cardiol 2001;38:493-8) (C) 2001 by the American College of Cardiology.