Author + information
- Christos Rammos, MD,
- Ulrike B. Hendgen-Cotta, PhD,
- Julia Sobierajski, MD,
- Andrea Bernard, MSc,
- Malte Kelm, MD and
- Tienush Rassaf, MD∗ ()
- Department of Medicine, Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, University Hospital Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany
- ↵∗Department of Medicine, Division of Cardiology, Pulmonary and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty, Moorenstrasse 5, D-40225 Düsseldorf, Germany
To the Editor:
The average human life span increases continuously and with it the percentage of sexagenarians and older people. Aging deteriorates vascular integrity, characterized by endothelial dysfunction and increasing vascular stiffness. The latter jointly precede and entail incident systolic blood pressure (SBP), with an increase in cardiovascular morbidity and mortality (1). Strategies to attenuate the aging process are sparse. Studies such as the DASH (Dietary Approaches to Stop Hypertension) trial have demonstrated that certain dietary patterns may influence blood pressure (2). The micronutrient inorganic nitrate, abundant in vegetables, acutely lowered diastolic blood pressure (DBP) in healthy young volunteers and improved vascular remodeling in animals (3,4). We here sought to investigate the effects of daily dietary supplementation with inorganic nitrate on vascular function in older adults.
Elderly volunteers without history, signs, or symptoms of cardiovascular disease, although with moderate cardiovascular risk (mean [SD]; HeartScore 4.7 [2.7]; age 63  years), were included in a randomized, placebo-controlled double-blind trial. Study procedures were in accordance with the Declaration of Helsinki and the Heinrich-Heine University Düsseldorf Institutional Ethics Committee. Volunteers gave informed consent and were treated daily with dietary nitrate supplementation (sodium nitrate 150 μmol/kg body weight, dissolved in drinking water; dose equivalent to a portion (300 g) of spinach). The study comprised 11 volunteers (7 men; mean age 63  years; body mass index 24  kg/m2; cholesterol 238  mg/dl; HeartScore 4.7 [2.5]) receiving sodium nitrate for 4 weeks, compared with controls (sodium chloride 150 μmol/kg body weight; 10 volunteers: 6 men, mean age 63  years; body mass index 26  kg/m2; cholesterol 219  mg/dl; HeartScore 4.7 [3.1]); no difference was seen between groups. Measurements were taken at baseline and 1 day after the last intake of nitrate or placebo. Paired 2-tailed Student t test was used for statistical analyses within the groups; unpaired Student t test was used for comparing the groups on change from baseline.
To evaluate effects on endothelial function, we assessed flow-mediated dilation of the brachial artery and carotid intima-media thickness (IMT) (Vivid i ultrasound, GE Healthcare, Munich, Germany) (5). Dietary nitrate supplementation improved endothelial function modestly, with no effect in controls (nitrate group: flow-mediated dilation 6.0% [0.8%] to 6.5% [0.8%], p = 0.004; controls: 6.0% [0.8%], p = 0.97; unpaired p = 0.0058) (Fig. 1). The impact of dietary nitrate on vascular stiffness was evaluated by measures of aortic stiffness and pressure pulsatility, namely pulse wave velocity and augmentation index (at 75 beats/min) derived from arterial applanation tonometry (SphygmoCor, AtCor Medical, Meinerzhagen, Germany). Vascular stiffness only improved in nitrate-supplemented volunteers (pulse wave velocity for nitrate group 10.2 [2.0] to 9.0 [1.8] m/s, p = 0.006; controls: 9.2 [2.6] to 9.6 [2.7] m/s, p = 0.148; unpaired: p = 0.002); augmentation index at 75 beats/min for nitrate group: 23.4 [6.5] to 19.9 [9.3], p = 0.012; controls: 25.3 [6.0] to 25.5 [5.9], p = 0.85; unpaired p = 0.029) (Fig. 1).
These vascular changes suggest an impact on blood pressure. SBP was measured twice noninvasively using a standard sphygmomanometer. Remarkably, 1 day after the last intake of nitrate, a reduction in systolic pressure from 137  to 129  mm Hg (p = 0.008) was observed in older adults with mild hypertension, with no effect in controls (138  to 136  mm Hg; p = 0.71; unpaired p = 0.037) (Fig. 1). Of note, DBP, heart rate, and IMT remained unchanged (DBP in nitrate group 80  to 79  mm Hg, p = 0.39; controls 83  to 81  mm Hg, p = 0.51; unpaired p = 0.89; HR for nitrate group 65  to 66  beats/min, p = 0.59; controls: 62  to 62  beats/min, p = 0.73; unpaired p = 0.33; IMT in nitrate group 0.77 [0.08] to 0.77 [0.08] mm, p = 0.3; controls 0.76 [0.1] to 0.76 [0.09] mm, p = 0.5; unpaired p = 0.88).
Dietary nitrate supplementation increased plasma nitrite and nitrate levels as measured by high-performance liquid chromatography (5), with no differences in controls (nitrite in nitrate group 85  to 330  nM, p = 0.005; controls 99  to 111  nM, p = 0.4; unpaired p = 0.005; nitrate in nitrate group 32  to 263  μM, p = 0.002; controls 31  to 40  μM, p = 0.06; unpaired p = 0.001).
Mechanistically, nitrate and nitrite can be viewed as stable storage pools for nitric oxide (NO)-like bioactivity. Nitrate is initially bioactivated via reduction to nitrite by symbiotic bacteria in the oral cavity. Nitrite then undergoes conversion to NO by numerous enzymatic as well as nonenzymatic processes in blood and tissue (3–5). A role for nitrite and especially NO has been suggested for the regulation and modulation of blood flow, endothelial function, and blood pressure. The nutritional aspects of the vasculoprotective effects of nitrite and nitrate are intriguing because nitrate and nitrite are abundant in our everyday diet. Major dietary sources of nitrite and nitrate are green leafy vegetables. Long-term effects are unknown but likely include adaptive and regenerative processes.
Dietary supplementation with inorganic nitrate improves endothelial dysfunction and vascular stiffness and reduces SBP in the elderly with moderately increased cardiovascular risk. These prognostic relevant outcome measures have been shown to predict cardiovascular events in older adults. Our findings provide evidence that dietary modulation with micronutrients improves vascular dysfunction. This might prevent or delay development of essential hypertension and have an impact on the deleterious sequelae and clinical outcome in an aging population. (Effects of Dietary Nitrate on Age-Related Vascular Function; NCT01729234).
Please note: This study was supported by grants from the German Research Foundation (DFG) to Dr Rassaf (RA969/4-2). Dr Rassaf is a Heisenberg professor funded by the DFG grant RA969/7-2. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation