L-Arginine Therapy in Acute Myocardial Infarction: Why the Negative Results? Could It Have Been Prevented?

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 9 No. 1 • January 2006


L-Arginine Therapy in Acute Myocardial Infarction: Why the Negative Results? Could It Have Been Prevented?

A new paper1 reports the results of a clinical trial of 153 patients who were given L-arginine following a first ST-segment-elevation heart attack because of previous studies (cited by the authors) in which arginine improved endothelial function (that is, the dilation of blood vessels caused by nitric oxide) in healthy elderly individuals and patients with vascular disease, as well as improving noninvasive measures of vascular stiffness. This study stopped enrollment at 2.5 years due to excess mortality in the arginine group (there were six deaths among those on arginine, while none of those on placebo died). Moreover, they found no significant change in vascular stiffness or left ventricular ejection fraction. They concluded that “L-arginine should not be recommended following acute myocardial infarction.”

Subjects had a mean age of 60 (13.6 standard deviations) years, with 68% men. Patients were randomly assigned to receive L-arginine (1 gram three times daily for a week, 2 grams three times daily for the next week, and 3 grams three times a day for the third week and thereafter for a total of six months) or placebo.

Those who died were apparently not autopsied. “Two patients were found dead at home without prior symptoms, and two patients died of presumed sepsis.” We don’t really know why those patients died.* Moreover, the sixth death was of a patient taking arginine who “died suddenly 4 months following his acute myocardial infarction and 3 weeks following cessation of study drug.” Any excess arginine would have been gone after one day, let alone three weeks, and hence there is no reason to believe that arginine had anything to do with this.


*iNOS (inducible nitric oxide synthase) is dramatically upregulated in inflammation, and the overproduction of NO can play a role in cell death. See Sedlak and Snyder. Messenger molecules and cell death. JAMA 295(1):85 (2006). We would expect that the choline and vitamin B5 that we have in our arginine formulation would mitigate this, because acetylcholine is anti-inflammatory as well as stimulating desired eNOS (endothelial nitric oxide synthase) activity.


The key to this study’s findings, we believe, is the fact that 96% of the arginine-receiving subjects were taking a statin (97% of those receiving placebo were also on a statin). See our article just above on statin-induced reduction in CoQ10 and selenoproteins. We believe that taking the statin was what caused the negative results with arginine in these patients. It is well known that CoQ10 is an important part of the body’s antioxidant protective mechanisms; it regenerates the tocopheryl radical back to tocopherol, for instance. Selenoproteins (such as glutathione peroxidase) are also important parts of the body’s antioxidant protections. In the presence of arginine and under oxidative conditions, the nitric oxide synthase cofactor tetrahydrobiopterin is oxidized (rather than in its proper reduced condition), which results in the production not of nitric oxide but of superoxide radicals.2,3,4 The problems with reduced CoQ10 and selenoproteins would also affect those on placebo, who were also taking statins, but the additional arginine in the arginine-supplemented subjects would have resulted in a much greater increase in the nitric oxide synthase-produced superoxide radicals. Moreover, nitric oxide radicals react very rapidly with superoxide radicals to form peroxynitrite, a very powerful oxidant.

This problem might have been solved by giving the patients supplements including vitamin C5 (which increases the availability of tetrahydrobiopterin in mice) and folic acid2,2a (which either increases the amount of available tetrahydrobiopterin or actually mimics its effects). It would be very unfortunate if this poorly designed study (none of the effects of statins on antioxidant status were considered) were to discourage the use of L-arginine. However, we do not recommend that those who have recently had heart attacks take L-arginine (even with the addition of vitamin C, folic acid, and CoQ10) until there is more knowledge about the reasons for this study’s results.

References

  1. Schulman et al. L-Arginine therapy in acute myocardial infarction: the Vascular Interaction with Age in Myocardial Infarction (VINTAGE MI) Randomized Clinical Trial. JAMA 293(1):58-64 (2006).
  2. Hyndman et al. Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function. Am J Physiol Heart Circ Physiol 282:H2167-72 (2002). “Tetrahydrobiopterin is a critical cofactor for nitric oxide synthase and maintains this enzyme as a nitric oxide- versus superoxide-producing enzyme. … 5-methyltetrahydrofolate [the physiological form of folic acid] attenuates superoxide production (induced by inhibition of tetrahydrobiopterin synthesis) and improves endothelial function in aortae isolated from tetrahydrobiopterin-deficient rats. We suggest that 5-methyltetrahydrofolate directly interacts with nitric oxide synthase to promote nitric oxide (vs. superoxide) production and improve endothelial function.”
    2a. Gori et al. Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study. Circulation 104:1119-23 (2001). “We think that the effectiveness, low cost, and safety of folic acid supplementation confer direct clinical relevance to our findings.” Subjects were 18 healthy, nonsmoking male volunteers 19 to 32 years of age. They received continuous treatment with nitroglycerin via transdermal patch while receiving either 10 mg/day of oral folic acid or placebo. One of the tests was for forearm blood flow (FBF) in response to an infusion of acetylcholine. “In the placebo group, the mean percent increase in response to the highest infused concentration of acetylcholine was 123% of the baseline FBF, whereas in the folic acid group, it was 583% (p<0.1).”
  3. Vasquez-Vivar et al. The role of tetrahydrobiopterin in superoxide generation from eNOS [endothelial nitric oxide synthase]: enzymology and physiological implications. Free Rad Res 37(2):121-7 (2003). “The pteridine cofactor BH4 [tetrahydrobiopterin] has been shown to critically control eNOS activity. It has been postulated that in disease states, such as diabetes, hypertension, and atherosclerosis, endothelial levels of BH4 are reduced, which correlates with diminished nitric oxide production. Recently, we have shown that activation of eNOS under limited availability of BH4 not only results in low rates of nitric oxide formation but also increases superoxide formation.”
  4. Landmesser et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 111:1201-9 (2003).
  5. d’Uscio et al. Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity. Circ Res 92:88-95 (2003).

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