Impact of dietary nitrate on age‐related diastolic dysfunction

Abstract

Aims Diastolic dysfunction is highly prevalent, and ageing is the main contributor due to impairments in active cardiac relaxation, ventriculo‐vascular stiffening, and endothelial dysfunction. Nitric oxide (NO) affects cardiovascular functions, and NO bioavailability is critically reduced with ageing. Whether replenishment of NO deficiency with dietary inorganic nitrate would offer a novel approach to reverse age‐related cardiovascular alterations was not known. Methods and results A dietary nitrate supplementation was applied to young (6 month) and old (20 month) wild‐type mice for 8 weeks and compared with controls. High‐resolution ultrasound, pressure–volume catheter techniques, and isolated heart measurements were applied to assess cardiac diastolic and vascular functions. Cardiac manganese‐enhanced magnetic resonance imaging was performed to study the effects of dietary nitrate on myocyte calcium handling. In aged mice with preserved systolic function, dietary nitrate supplementation improved LV diastolic function, arterial compliance, and coronary flow reserve. Mechanistically, improved cardiovascular functions were associated with an accelerated cardiomyocyte calcium handling and augmented NO/cyclic guanosine monophosphate/protein kinase G signalling, while enhanced nitrate reduction was related to age‐related differences in the oral microbiome. Conclusion Dietary inorganic nitrate reverses age‐related LV diastolic dysfunction and improves vascular functions. Our results highlight the potential of a dietary approach in the therapy of age‐related cardiovascular alterations.

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

“…For example, one study demonstrated that nitrate supplementation offers net decrease in oxygen cost (V O2 , mL/kg/min) during moderate and heavy submaximal exercise in healthy adults[127], an effect that over 14 studies have confirmed with reduced V O2 and increased work capacity in response to nitrate during submaximal exercise in healthy individuals[128,129] (reviewed in:[130,131]) and in certain chronic diseases[127,132]. Additionally, in the setting of heart failure and cardiomyopathy, dietary nitrate improves left ventricular function in mice[133] and overall cardiac contractility and exercise performance in humans[134–137], suggesting the critical potential of exploiting the oral microbiome to enhance functional outcomes in patients via mechanisms spanning from improved mitochondrial function to increased vascular and cardiac performance[138]. …”

Randomised, double-blind, placebo-controlled study investigating the effects of inorganic nitrate on vascular function, platelet reactivity and restenosis in stable angina: protocol of the NITRATE-OCT study

“…In healthy volunteers and patients with cardiovascular disease dietary nitrate, in the form of beetroot juice, causes dose-dependent rises in circulating nitrite levels associated with improvement in endothelial dysfunction, and suppressed platelet reactivity assessed ex vivo 23–2527 Furthermore, there have now been several studies in patients demonstrating the benefits of inorganic nitrate, administered either through the use of nitrate-rich beetroot juice or through provision of a nitrate salt dose, with respect to improvements in maximal oxygen consumption and diastolic function in heart failure28 29 as well as reduction in platelet reactivity and improvements in endothelial function in patients with hypercholesterolaemia25 that importantly could have direct relevance for patients with angina undergoing elective intervention.…”

Cardiac aging and the fountain of youth

“…In this issue of the Journal, Rammos and colleagues report the results of an impressive array of experiments suggesting that this dream of reversing cardiac aging might not be as mythical as we had once believed. The authors treated young and old wild‐type mice with inorganic nitrate for 8 weeks.…”

“…Coronary endothelium‐dependent vasodilation assessed in Langendorff preparations was impaired in old animals compared with young, and similarly was improved with nitrate despite no effect in the young animals. Arterial stiffness increases as part of normal aging, and nitrate supplementation reduced blood pressure and aortic stiffness in old but not young animals, suggesting that vascular aging might also be targeted by this approach …”

“…To explore the mechanisms underlying these benefits from nitrate, the authors then evaluated in vivo calcium handling using an elegant manganese‐enhanced magnetic resonance imaging (MRI) technique . This revealed diminished entry of calcium through the L‐type calcium channel in the hearts of old animals compared with young animals, which was improved with nitrate supplementation.…”