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CLINICAL RESEARCH: CARDIOVASCULAR RISK

Glutathione Peroxidase-1 and Homocysteine for Cardiovascular Risk Prediction

Results from the AtheroGene Study

Renate Schnabel, MD^_*,_*, Karl J. Lackner, MD, Hans J. Rupprecht, MD^_*, Christine Espinola-Klein, MD^_*, Michael Torzewski, MD, Edith Lubos, MD^_*, Christoph Bickel, MD, François Cambien, MD, Laurence Tiret, PhD, Thomas Münzel, MD, FAHA^_* and Stefan Blankenberg, MD^_*

^_* Department of Medicine II, Johannes Gutenberg-University, Mainz, Germany
Department of Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg-University, Mainz, Germany
INSERM U525, Faculté de Médecine Pitié-Salpétrière, Paris, France
Innere Abteilung, Bundeswehrzentralkrankenhaus, Koblenz, Germany

Manuscript received October 30, 2004; revised manuscript received January 25, 2005, accepted February 8, 2005.

^_* Reprint requests and correspondence: Dr. Renate Schnabel, Johannes Gutenberg-University, Cardiology, Langenbeckstrasse 1, Mainz, Rheinland-Pfalz 55131, Germany. (Email: schnabelr{at}gmx.de).

OBJECTIVES: This prospective study was designed to evaluate the effect of joint determination of two important contrary biomarkers—homocysteine and glutathione peroxidase (GPx)-1—on cardiovascular risk stratification.

BACKGROUND: Homocysteine plasma levels have been associated with cardiovascular risk. Experimental data suggest that antioxidative GPx-1 activity modulates cardiovascular risk associated with homocysteine.

METHODS: In 643 patients with coronary artery disease, we performed a prospective study to assess the risk of homocysteine plasma levels and GPx-1 activity on long-term cardiovascular risk with a median follow-up of 7.1 years.

RESULTS: Both homocysteine and GPx-1 were among the strongest univariate predictors of future cardiovascular risk, even after adjustment for cardiovascular confounders. Homocysteine levels were significantly elevated in individuals with future cardiovascular events (15.4 vs. 13.4 µmol/l; p < 0.0001); GPx-1 activity was lower (45.3 ± 13.1 vs. 50.2 ± 11.0 U/g hemoglobin; p < 0.0001). In patients with GPx-1 activity below the median value, homocysteine plasma levels above the median were associated with a 3.2-fold (95% confidence interval 1.8 to 5.6; p < 0.0001) increase in cardiovascular risk, whereas it lost its independent risk prediction in individuals with increased antioxidative capacity, as reflected by high GPx-1 activity. In contrast to single determination, combined assessment revealed a significant increase in the area under the curve of cardiovascular risk predictive models from 0.72, including traditional risk factors to 0.75 and also including homocysteine levels and GPx-1 activity.

CONCLUSIONS: Plasma homocysteine levels and GPx-1 activity are complementary in identifying individuals at high cardiovascular risk. Joint determination of both biomarkers provides substantial information on top of classic risk factors in cardiovascular risk assessment.

Abbreviations and Acronyms   AUC = area under the curve   CAD = coronary artery disease   CI = confidence interval   GPx-1 = glutathione peroxidase-1   HR = hazard ratio   hs-CRP = high-sensitivity C-reactive protein   MI = myocardial infarction   ROS = reactive oxygen species

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