High-dose folic acid acutely improves coronary vasodilator function in patients with coronary artery disease

Abstract

Objectives: We investigated the acute effect of orally administered high-dose folic acid on coronary dilator function in humans.

Background: Folic acid and its active metabolite, 5-methyltetrahydrofolate, increase endothelium-dependent vasodilation in human peripheral circulation. However, the acute effect on coronary circulation is not known.

Methods: Fourteen patients with ischemic heart disease, age 62 +/- 12 years (mean +/- SD), were enrolled in a double-blind, placebo-controlled crossover trial. Basal and adenosine-stimulated myocardial blood flow (MBF) were determined by positron emission tomography, and myocardial flow reserve was calculated. Each patient was studied after ingestion of placebo and after ingestion of 30 mg folic acid. Myocardial zones were prospectively defined physiologically as "normal" versus "abnormal" on the basis of MBF response to adenosine 140 microg/kg/min (normal = MBF >1.65 ml/min/g). Abnormal and normal zones were analyzed separately in a patient-based analysis.

Results: Folate was associated with a reduction in mean arterial pressure (100 +/- 12 mm Hg vs. 96 +/- 11 mm Hg, placebo vs. folate, p < 0.03). Despite the fall in mean arterial pressure, folic acid significantly increased the MBF dose response to adenosine (p < 0.001 using analysis of variance) in abnormal zones, whereas MBF in normal zones did not change. In abnormal segments, folic acid increased peak MBF by 49% (1.45 +/- 0.59 ml/min/g vs. 2.16 +/- 1.01 ml/min/g, p < 0.02). Furthermore, folate increased dilator reserve by 83% in abnormal segments (0.77 +/- 0.59 vs. ml/min/g 1.41 +/- 1.08 ml/min/g, placebo vs. folate, p < 0.05), whereas dilator reserve in normal segments remained unchanged (2.00 +/- 0.61 ml/min/g vs. 2.12 +/- 0.69 ml/min/g, placebo vs. folate, p = NS).

Conclusions: The data demonstrate that high-dose oral folate acutely lowers blood pressure and enhances coronary dilation in patients with coronary artery disease.

Figure 1

Effect of high-dose folate on mean arterial pressure (MAP). Resting MAP was measured. Individual responses are shown, and group mean data (± SD) are depicted by the thick line. Folate significantly reduced MAP (100 ± 3 mm Hg vs. 96 ± 2 mm Hg, placebo vs. folate, p < 0.03).

Figure 2

Effect of high-dose folate on peak (adenosine-stimulated) myocardial blood flow (MBF). Peak adenosine-stimulated MBF was measured in abnormal zones. Individual responses are shown, and group mean data are depicted by the thick line. Folate significantly increased peak MBF (1.45 ± 0.59 ml/min/g vs. 2.16 ± 1.01 ml/min/g, mean ± SD, placebo vs. folate, p < 0.02).

Figure 3

Effect of high-dose folate on coronary dilator reserve. Dilator reserve was measured in normal (WNL) and abnormal (ABNL) regions. Mean data and standard error bars are depicted. Folate increased dilator reserve by ~83% in abnormal segments (0.72 ± 0.60 ml/min/g vs. 1.31 ± 1.08 ml/min/g, mean ± SD, placebo vs. folate, p < 0.05), whereas dilator reserve in normal segments remained unchanged (2.00 ± 0.61 ml/min/g vs. 2.12 ± 0.69 ml/min/g, placebo vs. folate, p = NS). Open bars = placebo; solid bars = folate.

Figure 4

Effect of high-dose folate on peak flow ratio. The ratio for peak myocardial blood flow, in abnormal relative to normal segments, is shown for each patient. Group mean data are depicted by the thick line. Folate increased the ratio of flow in abnormal segments relative to normal segments (0.54 ± 0.17 vs. 0.75 ± 0.24, mean ± SD, placebo vs. folate, p < 0.01).