A New Risk Factor for Cardiovascular Disease

Abstract & Commentary

Source: Shishehbor MJ, et al. Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. JAMA. 2003;289:1675-1680.

This is a study that examined levels of nitrotyrosine, a specific marker for protein modifications produced by nitric oxide-derived oxidants. Shishehbor and associates studied plasma levels in patients with coronary artery disease (CAD) and determined whether they are modulated by treatment with a HMG CoA-reductase inhibitor (statins). They carried out a case control study and an interventional at 2 tertiary care referral centers. In the case control study, 100 case patients with established CAD and 108 patients with no clinically evident CAD were recruited consecutively. In the interventional study, patients with hypercholesterolemia underwent nutrition and exercise counseling, or when cholesterol levels failed to decrease within 6-8 weeks they were enrolled for 12 weeks to receive 10 mg daily of oral atorvastatin therapy. Thirty-five patients participated in this phase of the trial. Shishehbor et al found that nitrotyrosine levels were significantly higher among patients with CAD. The overall value is 9.1 mmol/mol of nitrotyrosine/tyrosine vs 5.2 mmol/mol in the controls. Patients in the upper quartile of nitrotyrosine had higher odds of CAD as compared to those in the lowest quartile within an adjusted odds ratio of 6.1. The upper quartile of nitrotyrosine levels remained associated with CAD after correction for CRP levels as well as the Framingham Global Risk Score. Statin therapy reduced nitrotyrosine levels significantly by 25%. This was similar in magnitude to the reductions in total cholesterol levels, which were also 25%. This, however, was independent of any changes in lipoproteins or inflammatory markers such as CRP.

Commentary

These findings are of considerable interest. They provide direct evidence that oxidative damage to lipids may play a critical role in the pathogenesis of atherosclerosis. This may be true of both CAD and stroke. There previously has been substantial evidence for nitrotyrosine immunostaining in atherosclerotic plaques. The present report, however, is the first to correctly demonstrate a correlation between plasma levels of nitrotyrosine and risk of CAD. It is of considerable interest that statin treatment significantly reduced the levels of nitrotyrosine. This most likely is due to its anti-inflammatory effects. This suggests that the beneficial effects of statin treatment may be dependent not only on its ability to lower cholesterol but also on its anti-inflammatory activity. Interestingly, the increases in nitrotyrosine appear to be independent of traditional CAD risk factors and CRP levels. Altogether the findings suggest that nitrotyrosine measurements may prove useful in assessing CAD status and for monitoring the anti-inflammatory effects of statins. — M. Flint Beal

Dr. Beal is Professor and Chairman; Department of Neurology; Cornell University Medical College, New York, NY.