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Mehdi H. Shishehbor, DO; Ronnier J. Aviles, MD; Marie-Luise Brennan, PhD; Xiaoming Fu, MS; Marlene Goormastic, MPH; Gregory L. Pearce, MS; Noyan Gokce, MD; John F. Keaney, Jr, MD; Marc S. Penn, MD, PhD; Dennis L. Sprecher, MD; Joseph A. Vita, MD; Stanley L. Hazen, MD, PhD

JAMA. 2003;289:1675-1680.

Context  Formation of nitric oxide–derived oxidants may serve as a mechanism linking inflammation to development of atherosclerosis. Nitrotyrosine, a specific marker for protein modification by nitric oxide–derived oxidants, is enriched in human atherosclerotic lesions and low-density lipoprotein (LDL) recovered from human atheroma.

Objectives  To determine whether systemic levels of nitrotyrosine are associated with the prevalence of coronary artery disease (CAD) and are modulated by hydroxymethylglutaryl coenzyme-A reductase inhibitor (statin) therapy.

Design, Setting, and Patients  A case-control and interventional study at 2 urban tertiary-care referral centers; recruitment for each was from June 1, 2001, until January 1, 2002. For 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, participants aged 21 years or older with hypercholesterolemia (LDL cholesterol 130 mg/dL [3.5 mmol/L]) underwent nutrition and exercise counseling. Those whose levels did not decrease with 6 to 8 weeks were enrolled in the study (n = 35). For 12 weeks, they received 10 mg/d of oral atorvastatin therapy.

Main Outcome Measures  In the case-control study, the association between systemic levels of protein-bound nitrotyrosine, CAD risk, and presence of CAD. In the interventional study, the change in nitrotyrosine, lipoprotein, and C-reactive protein (CRP) levels.

Results  Nitrotyrosine levels were significantly higher among patients with CAD (median 9.1 µmol/mol [interquartile range, 4.8-13.8 µmol/mol] tyrosine vs 5.2 µmol/mol [interquartile range, 2.2-8.4 µmol/mol]; P<.001). Patients in the upper quartile of nitrotyrosine (29%; P<.001) had a higher odds of CAD compared with those in the lowest quartile (unadjusted odds ratio, 6.1; 95% confidence interval, 2.6-14.0; P<.001). In multivariate models adjusting for Framingham Global Risk Score and CRP, upper quartiles of nitrotyrosine remained associated with CAD (odds ratio, 4.4; 95% confidence interval, 1.8-10.6; P<.001). Statin therapy reduced nitrotyrosine levels significantly (25%; P<.02) with a magnitude similar to reductions in total cholesterol levels (25%; P<.001) and LDL particle number (29%; P<.001) yet were independent of alterations in lipoproteins and inflammatory markers like CRP.

Conclusions  The findings from this preliminary study indicate that nitrotyrosine levels are associated with the presence of CAD and appear to be modulated by statin therapy. These results suggest a potential role for nitric oxide–derived oxidants as inflammatory mediators in CAD and may have implications for atherosclerosis risk assessment and monitoring of anti-inflammatory actions of statins.

Author Affiliations: Departments of Cell Biology (Drs Shishehbor, Aviles, Brennan, Penn, Sprecher, and Hazen and Ms Fu), Cardiovascular Medicine (Drs Aviles, Penn, Sprecher, and Hazen and Ms Goormastic and Mr Pearce) and the Center for Cardiovascular Diagnostics and Prevention (Drs Shishehbor, Aviles, Brennan, Penn, Sprecher, and Hazen and Ms Goormastic), the Cleveland ClinicFoundation, Cleveland, Ohio; and Evans Department of Medicine (Drs Gokce, Keaney, and Vita), Boston University School of Medicine, Boston, Mass.

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