Folic Acid Improves Endothelial Function in Coronary Artery Disease via Mechanisms Largely Independent of Homocysteine Lowering - Folic Acid Improves Endothelial Function in Coronary Artery Disease via Mechanisms Largely Independent of Homocysteine Lowering

Description:

Folic Acid Improves Endothelial Function in Coronary Artery Disease via Mechanisms Largely Independent of Homocysteine Lowering.

Hypothesis:

An elevated homocysteine is a risk factor for CAD and coronary events and is associated with abnormal arterial endothelial function. This study sought to determine whether folic acid effects arterial endothelial function independent of its ability to lower homocysteine levels.

Study Design

Study Design:

Patients Enrolled: 33
Female: 10

Drug/Procedures Used:

A randomized, double-blind, placebo-controlled study of folic acid (5mg) for 6 weeks in 33 subjects with CAD. Brachial artery endothelial function was determined by flow-mediated dilatation (FMD). The endpoint was the greatest change in diameter within 3 minutes of release of an occluding cuff. FMD was performed at baseline and 2 and 4 hours after the first 5mg dose and 6 weeks after treatment.

Principal Findings:

The groups were compariable in use of anti-ischemic drugs, average age (56 years), 90% were male, and 95% were on lipid-lowering treatment. Pretreatment homocysteine averaged 10.7 umol/L. Two hours after the first 5mg dose of folic acid, FMD increased by 83μm compared to 47μm with the placebo. The FMD at 4 hours increased to 100μm, which was similar to that after 6 weeks of treatment. The homocysteine level did not change acutely after folic acid, but was 23% lower in the folate group at 6 weeks. The change in FMD did not correlate with total or free homocysteine, folate levels, or the level of 5-methyltetrahydrofolate (5-MTHF) at any point of intervention from 2 hours to 6 weeks.

These data suggest that folic acid improves endothelial function in CAD acutely by a mechanism largely independent of homocysteine.

Interpretation:

The 5mg dose of folic acid is 10 fold higher than is generally needed to normalize homocysteine levels. High dose folic acid results in high levels of 5-MTHF, which is a potent intracellular antioxidant that can increase nitric oxide (EDRF) production. The finding is intriguing. As the authors suggest, the studies in progress designed to determine the benefit of lowering homocysteine levels with 0.4mg to 2mg of folic acid may or may not succeed, but regardless will not test the possible added value of high doses.

References:

1. Doshi SN, McDowell IF, Moat SJ, et al. Circulation 2002;105:22-6.

Clinical Topics: Atherosclerotic Disease (CAD/PAD)

Keywords: Coronary Artery Disease, Brachial Artery, Folic Acid, Dilatation, Risk Factors, Nitric Oxide


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