Plasma Nitrate and Incidence of Cardiovascular Disease and All‐Cause Mortality in the Community: The Framingham Offspring Study

Abstract

BackgroundNitrate is a dietary component as well as an endogenously formed metabolite and source of the signaling molecule nitric oxide. Harmful as well as beneficial effects of nitrate have been advocated. Data regarding the prognostic relevance of plasma nitrate are limited. The aim of this study was to evaluate the prospective association of plasma nitrate with cardiovascular disease (CVD) and all‐cause mortality.Methods and ResultsWe assayed plasma nitrate in 2855 Framingham Offspring Study participants (mean age 59 years, 54% women) by gas chromatography–mass spectrometry and evaluated its association with all‐cause mortality and incident CVD. On follow‐up (median 17.3 years), 775 participants died and 522 developed new‐onset CVD (of 2546 participants free of CVD at baseline). In multivariable models adjusting for standard risk factors, plasma nitrate was associated with an increased risk of death in participants (hazard ratio per unit increase in log‐nitrate 1.21; 95% confidence interval, 1.04–1.40 [P=0.015]). The strength of the association was attenuated by additional adjustment for estimated glomerular filtration rate (hazard ratio, 1.16; 95% confidence interval, 1.00–1.35 [P=0.057]). In contrast, no evidence was found for an association of plasma nitrate with incident CVD (multivariable‐adjusted hazard ratio per unit increase log‐nitrate 1.08; 95% confidence interval, 0.89–1.31 [P=0.42]).ConclusionsIn our prospective community‐based investigation, a higher plasma nitrate concentration was associated with all‐cause mortality but not with incident CVD. The association of nitrate with mortality may at least in part be attributable to its association with renal function.

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

“…Our findings are very similar to a recently published Framingham Offspring Study that demonstrated association between elevated plasma levels of nitrate with total mortality and lack of association with incident cardiovascular disease . The study did not report the data on cardiovascular mortality and associations of NOx levels with mortality were not assessed in men or women separately …”

“…25 Our findings are very similar to a recently published Framingham Offspring Study that demonstrated association between elevated plasma levels of nitrate with total mortality and lack of association with incident cardiovascular disease. 26 The study did not report the data on cardiovascular mortality and associations of NOx levels with mortality were not assessed in men or women separately. 26 In general, serum levels of NOx are a steady-state sum of various dynamic processes including excretion of NOx from the body, oxidation of endogenous NO into NOx and dietary consumption of NOx.…”

“…26 The study did not report the data on cardiovascular mortality and associations of NOx levels with mortality were not assessed in men or women separately. 26 In general, serum levels of NOx are a steady-state sum of various dynamic processes including excretion of NOx from the body, oxidation of endogenous NO into NOx and dietary consumption of NOx. 27 Thus, serum NOx levels integrate these metabolic processes and are associated with various pathologies.…”

Inorganic Nitrate: Marker or Mediator of Mortality?

“…For those with 4 or more cardiovascular risk factors, the plasma nitrate concentration was 35±4 μmol/L and plasma nitrite concentration was 171±29 nmol/L (both P <0.001). This higher plasma nitrate concentration with increasing numbers of cardiovascular risk factors appears to be similar to the findings by Maas et al . With increasing numbers of cardiovascular risk factors, plasma nitrite appears to be lower.…”

“…In this issue of JAHA , the examination by Maas et al of plasma nitrate and incidence of cardiovascular disease and all‐cause mortality from the Framingham Offspring Study is the largest data set using a robust measure of plasma nitrate performed to date, with a median follow‐up of 17.3 years …”