L-arginine and heart disease

Townsend Letter for Doctors and Patients, June, 2006 by Alan R. Gaby

One hundred-fifty-three patients (mean age, 60.3 years) who had had a first acute myocardial infarction three to 21 days previously were randomly assigned to receive, in double-blind fashion, L-arginine or placebo for six months. The dose of L-arginine was 1 g three times a day for the first week, 2 g three times a day for the second week, and 3 g three times a day thereafter. Six participants (8.6%) in the L-arginine group died during the study period vs. none in the placebo group (p = 0.01). Because of safety concerns, the study was terminated prematurely.

Comment: As a precursor to nitric oxide, L-arginine functions as a vasodilator and improves endothelial function, effects that might be beneficial for patients with heart disease. In previous studies, L-arginine supplementation increased exercise tolerance and improved quality of life in patients with congestive heart failure and in those with angina pectoris. It is surprising, therefore, that the present study showed an increase in mortality from L-arginine supplementation in patients with a recent myocardial infarction.

The results of this study might be explained by a fundamental, though often overlooked, principle of nutrition: that nutrients function in the body as a team and that administration of large doses of a single nutrient will in some instances cause biochemical imbalances, with potentially adverse effects. I have pointed out previously that supplementation with high doses of pure alpha-tocopherol (vitamin E) depletes another important cardioprotective component of the "vitamin E complex" (gamma-tocopherol), and that a deficiency of gamma-tocopherol might explain why treatment with high-dose alpha-tocopherol increased the risk of developing heart failure in one study. If that is the case, then "mixed tocopherols" (the form in which vitamin E occurs in food) would be expected to be both safer and more effective than alpha-tocopherol for the prevention and treatment of cardiovascular disease.

A similar mechanism might be in operation with respect to L-arginine. While nitric oxide produced from L-arginine has a number of beneficial effects on the cardiovascular system, it is also a highly unstable molecule that promotes the formation of reactive oxidants such as peroxynitrite. Peroxynitrite and other nitric oxide-derived oxidants appear to be inflammatory mediators that promote the development of atherosclerosis. Interestingly, the compound that has been shown most clearly to scavenge reactive nitrogen compounds is gamma-tocopherol. Moreover, in the process of quenching nitric oxide-derived oxidants, gamma-tocopherol is converted to 5-nitro-gamma-tocopherol, an apparently inactive metabolite.

Thus, as with high-dose alpha-tocopherol, high-dose L-arginine might deplete gamma-tocopherol, potentially reversing the beneficial cardiovascular effects of L-arginine. Based on the results of the present study, it is probably not a good idea to recommend large doses of L-arginine for people who have had a recent myocardial infarction. If L-arginine is being used to treat angina or heart failure, it should be administered as part of a comprehensive nutritional program, including supplementation with mixed tocopherols.

Schulman SP, et al. L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA. 2006;295:58-64.