Dietary Nitrate and the Epidemiology of Cardiovascular Disease: Report From a National Heart, Lung, and Blood Institute Workshop

Ahluwalia, Amrita; Gladwin, Mark T.; Coleman, Gary D.; Hord, Norman G.; Howard, George; Kim‐Shapiro, Daniel B.; Lajous, Martín; Larsen, Filip J.; Lefer, David J.; McClure, Leslie A.; Nolan, Bernard T.; Pluta, Ryszard; Schechter, Alan N.; Wang, Chia‐Yih; Ward, Mary H.; Harman, Jane

doi:10.1161/jaha.116.003402

Cited by 76 publications

(70 citation statements)

References 121 publications

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“…A 2010 International Agency for Research on Cancer report concluded that "Ingested nitrate or nitrite under conditions that results in endogenous nitrosation is probably carcinogenic to humans (Group 2A)" (7). These conditions, however, are likely to be to the result of complex interactions between the amount of nitrate and nitrite consumed, stomach acidity, intakes of nutrients likely to decrease the potential for nitrosation (polyphenols, vitamin C, and vitamin E), smoking status, and medical conditions that would in all probability increase nitrosation (41).…”

Section: Discussionmentioning

confidence: 99%

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Association of dietary nitrate with atherosclerotic vascular disease mortality: a prospective cohort study of older adult women

Blekkenhorst

Bondonno

Lewis

et al. 2017

The American Journal of Clinical Nutrition

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Background: Nitrate-rich vegetables lower blood pressure and improve endothelial function in humans. It is not known, however, whether increased consumption of nitrate-rich vegetables translates to a lower risk of atherosclerotic vascular disease (ASVD) mortality. Objective: The objective was to investigate the association of nitrate intake from vegetables with ASVD mortality. Design: A total of 1226 Australian women aged 70-85 y without prevalent ASVD and/or diabetes were recruited in 1998 and were studied for 15 y. We assessed demographic and ASVD risk factors at baseline (1998), and we used a validated food-frequency questionnaire to evaluate dietary intake. Nitrate intake from vegetables was calculated by use of a newly developed comprehensive database. The primary outcome was any death attributed to ASVD ascertained by using linked data that were provided via the Western Australian Data Linkage system. We used Cox proportional hazards modeling to examine the association between nitrate intake and ASVD mortality before and after adjustment for lifestyle and cardiovascular disease risk factors. Conclusions: Nitrate intake from vegetables was inversely associated with ASVD mortality independent of lifestyle and cardiovascular disease risk factors in this population of older adult women without prevalent ASVD or diabetes. These results support the concept that nitrate-rich vegetables may reduce the risk of age-related ASVD mortality. This trial was registered at www. anzctr.org.au as ACTRN12617000640303.

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Section: Discussionmentioning

confidence: 99%

“…With the discovery of the enterosalivary nitrate-nitrite-NO pathway, clinical focus has shifted to the possible beneficial effects of dietary nitrate from vegetables (4,41). In the study population, an w30 mg/d-higher nitrate intake from vegetables was associated with a 21% lower risk of ASVD mortality.…”

Section: Discussionmentioning

confidence: 99%

Association of dietary nitrate with atherosclerotic vascular disease mortality: a prospective cohort study of older adult women

Blekkenhorst

Bondonno

Lewis

et al. 2017

The American Journal of Clinical Nutrition

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“…Methemogobinemia becomes clinically significant when baseline levels of metHgb (1–3%) rise to 5–12%, with cyanosis and fatal toxicity occurring at levels between 30–50%[153]. Early concerns of infant exposures led to current regulations limiting nitrate content in water to 44 mg/L[154,155], although more recent evidence in both infants and adults suggests that exceptionally high concentrations of nitrite (and well beyond the <75mg nitrite necessary to achieve blood pressure effects) would be necessary to pose a significant threat to safety[25,51,72,113,155–158]. Similarly, little evidence exists to suggest that chronic nitrate or nitrite consumption are directly carcinogenic in humans[159,160].…”

Section: Safety Of Inorganic Nitrate and Nitritementioning

confidence: 99%

“…Similarly, little evidence exists to suggest that chronic nitrate or nitrite consumption are directly carcinogenic in humans[159,160]. However, in certain settings nitrite can form nitrous acid via the N-nitrosation pathway in the stomach, which then reacts with dietary amines and amides to form powerful alkylating, and carcinogenic, N-nitroso compounds[155,161,162]. Indeed, nitrites in combination with dietary amines or amides, such as in red and cured meats, have been linked to stomach and several other cancers[155,157,160,163–166].…”

Section: Safety Of Inorganic Nitrate and Nitritementioning

confidence: 99%

Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health

Koch

Gladwin

Freeman

et al. 2017

Free Radical Biology and Medicine

145

127

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Recent insights into the bioactivation and signaling actions of inorganic, dietary nitrate and nitrite now suggest a critical role for the microbiome in the development of cardiac and pulmonary vascular diseases. Once thought to be the inert, end-products of endothelial-derived nitric oxide (NO) heme-oxidation, nitrate and nitrite are now considered major sources of exogenous NO that exhibit enhanced vasoactive signaling activity under conditions of hypoxia and stress. The bioavailability of nitrate and nitrite depend on the enzymatic reduction of nitrate to nitrite by a unique set of bacterial nitrate reductase enzymes possessed by specific bacterial populations in the mammalian mouth and gut. The pathogenesis of pulmonary hypertension (PH), obesity, hypertension and CVD are linked to defects in NO signaling, suggesting a role for commensal oral bacteria to shape the development of PH through the formation of nitrite, NO and other bioactive nitrogen oxides. Oral supplementation with inorganic nitrate or nitrate-containing foods exert pleiotropic, beneficial vascular effects in the setting of inflammation, endothelial dysfunction, ischemia-reperfusion injury and in pre-clinical models of PH, while traditional high-nitrate dietary patterns are associated with beneficial outcomes in hypertension, obesity and CVD. These observations highlight the potential of the microbiome in the development of novel nitrate- and nitrite-based therapeutics for PH, CVD and their risk factors.

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“…Under normal conditions, these contribute about equally to NO homeostasis 16. The mammalian nitrate‐nitrite‐NO pathway is involved in the regulation of blood flow and blood pressure, cell signaling, and tissue responses to hypoxia 17. During aging and hypoxia/ischemia, the highly oxygen‐dependent NOSs become less effective in generating NO, in contrast to the nitrate‐nitrite‐NO pathway, in which NO formation from nitrite reduction in tissues is enhanced during hypoxia and low pH 18.…”

Section: Introductionmentioning

confidence: 99%

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

Conley

Roberts

Sharpton

et al. 2017

Molecular Nutrition Food Res

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ScopeStudies suggest diets rich in fruit and vegetables reduce bone loss, although the specific compounds responsible are unknown. Substrates for endogenous nitric oxide (NO) production, including organic nitrates and dietary nitrate, may support NO production in age‐related conditions, including osteoporosis. We investigated the capability of dietary nitrate to improve NO bioavailability, reduce bone turnover and loss.Methods and resultsSix‐month‐old Sprague Dawley rats [30 ovariectomized (OVX) and 10 sham‐operated (sham)] were randomized into three groups: (i) vehicle (water) control, (ii) low‐dose nitrate (LDN, 0.1 mmol nitrate/kg bw/day), or (iii) high‐dose nitrate (HDN, 1.0 mmol nitrate/kg bw/day) for three weeks. The sham received vehicle. Serum bone turnover markers; bone mass, mineral density, and quality; histomorphometric parameters; and fecal microbiome were examined. Three weeks of LDN or HDN improved NO bioavailability in a dose‐dependent manner. OVX resulted in cancellous bone loss, increased bone turnover, and fecal microbiome changes. OVX increased relative abundances of Firmicutes and decreased Bacteroideceae and Alcaligenaceae. Nitrate did not affect the skeleton or fecal microbiome.ConclusionThese data indicate that OVX affects the fecal microbiome and that the gut microbiome is associated with bone mass. Three weeks of nitrate supplementation does not slow bone loss or alter the fecal microbiome in OVX.

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Dietary Nitrate and the Epidemiology of Cardiovascular Disease: Report From a National Heart, Lung, and Blood Institute Workshop

Cited by 76 publications

References 121 publications

Association of dietary nitrate with atherosclerotic vascular disease mortality: a prospective cohort study of older adult women

Association of dietary nitrate with atherosclerotic vascular disease mortality: a prospective cohort study of older adult women

Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

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