Elevated levels of serum nitrite and nitrate, NOx, are associated with increased total and cardiovascular mortality in an 8-year follow-up study

Abstract

Background: Nitric oxide (NO) is one of the key regulators of vascular function. Abnormal NO signalling is linked to various cardiovascular diseases. We studied associations between circulating levels of NO metabolites, nitrite and nitrate (NOx) and total and cardiovascular mortality in a prospective 8-year follow-up cohort study in 1869 patients aged over 55 years.

Materials and methods: The Cox proportional hazard ratio (HR) regression models were adjusted for multiple risk-related variables. Post hoc Kaplan-Meier survival curves were compared by the Log-rank test.

Results: Proportional Cox regression analysis demonstrated that high serum levels of NOx over 70 µmol/L were associated with elevated total mortality (HR 1.4; 95% CI: 1.06-1.80; P = 0.02) and cardiovascular mortality (HR 1.4; 95% CI: 0.98-1.98; P = 0.03) when HR was adjusted for age, sex, smoking and urinary creatinine. Additional adjustments for various mortality-associated baseline comorbidities did not influence associations of elevated NOx with total and cardiovascular mortality. Association of elevated NOx with total mortality persisted in the multivariate regression model combining a number of other characteristics while association of NOx with cardiovascular mortality became non-significant in the multivariate model. Specific subset of patients contributing to these associations was determined by Kaplan-Meier survival analysis indicating that cardiovascular and total mortality were increased in men with high serum levels of NOx over 70 µmol/L (Log-rank test P = 0.01). These associations were not observed in women.

Conclusion: Elevated concentrations of serum NOx over 70 µmol/L can be used to predict mortality in men over 55 years of age.

Keywords: NOx; cardiovascular mortality; nitrate; nitric oxide; nitrite; total mortality.