Endothelial function may play a more important role than lipoproteins in the pathogenesis of atherosclerosis—if dietary nitrate improves endothelial function, correcting nutrient deficiencies may be addressing the heart of the evolution of CVD.
Velmurugan S, Gan JM, Rathod KS, et al. Dietary nitrate improves vascular function in patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled study. Am J Clin Nutr. 2016;103(1):25-38.
Randomized, double-blind, placebo-controlled parallel study; participants were randomly assigned 1:1 to receive either 250 mL naturally nitrate-rich beetroot juice or placebo nitrate-depleted beetroot juice once a day for 6 weeks.
Sixty-nine nonsmoking, nondiabetic, otherwise healthy hypercholesterolemic men and women aged 18 to 80 years old, with body mass index (BMI) (in kg/m2 ) from 18.5 to 40 were recruited (final full data sets available from 65 participants). Inclusion criteria included a total serum cholesterol concentration > 6.0 mmol/L (232 mg/dL) or any elevation of low-density lipoprotein cholesterol (LDL-C) or triglycerides with a QRISK 2 (cardiovascular disease risk calculator; National Health Service) score >15%. All participants were expected to be free from any use of statins or other cholesterol-lowering medication for at least 2 months before screening.
Study Parameters Assessed
- Flow-mediated dilatation
- Platelet reactivity
- Arterial pulse wave velocity
- Pulse wave analysis
- Nitric oxide metabolite concentrations
The primary endpoint was the absolute percentage change in ultrasound flow-mediated dilation (FMD) at 6 weeks from baseline.
Secondary endpoints included the following measures:
- Within-group comparison of the FMD response at baseline and at 6 weeks
- Assessment of the change at 6 weeks from baseline of platelet reactivity
- Arterial pulse wave velocity and pulse wave analysis
- Changes in nitric oxide metabolite concentrations
- Changes in salivary microbiome composition
Dietary nitrate resulted in an absolute increase in the FMD response of 1.1%, equating to a 24% improvement from baseline, with a worsening of 0.3% in the placebo group (P<0.001).
When compared to the placebo group, the study found the nitrate group had small but significant improvements in the following measures:
- Aortic pulse wave velocity: decrease of 0.22 m/s [95% confidence interval (CI): -0.4 to -0.3], showing a trend (P=0.06) to improvement
- Platelet-monocyte aggregates: 7.6% reduction in in the nitrate group, compared with a 10.1% increase in the placebo group (P=0.004)
- Stimulated P-selectin expression: statistically significant reductions (P<0.05); no significant changes in unstimulated expression
In addition, the nitrate treatment altered the salivary microbiome, while the placebo did not (P<0.01). Finally, no adverse effects of dietary nitrate were detected in the treatment group.
How best to evaluate risk and optimize preventive strategies in cardiovascular disease (CVD) continues to be a complicated and poorly agreed upon grouping of opinions and approaches.1 This problem may, in part, be due to an overemphasis on the measurement and modification of cholesterol-related biomarkers.1 In particular, LDL-C and related markers remain a primary focus of risk assessment and treatment targeting. Yet, providing further proof for the lack of reliability in this strategy, the most recent treatment guidelines have abandoned more stringent aspects of these goals due to lack of evidence for improved outcomes.2
Perhaps then, at least to some extent, focusing our attention on standard risk calculation, along with treating basic lipid-related markers, can lead to an incomplete overall approach.
Focusing our attention on standard risk calculation, along with treating basic lipid-related markers, can lead to an incomplete overall approach.
Flow-mediated dilation (FMD), a method used for assessing endothelial function, along with more advanced biomarker tests such as high sensitivity C-reactive protein (hs-CRP), lipoprotein-associated phospholipase A2 (Lp-PLA2), asymmetric dimethylarginine (ADMA) and others represent a core group of newer, less proven options that could help round out a more complete picture.
Certainly, the process of atherogenesis is complicated and multifactorial, and lipid-related markers do play a role. After all, some of the initiating steps in the process of atherosclerosis would not technically be possible without the presence of an atherogenic, cholesterol-carrying molecule in the vascular wall.3 However, statistical analyses have shown excess dependence on these markers may lead to many CVD cases being missed until it is too late.4
In fact, endothelial dysfunction, the primary process assessed via FMD measured in our current study, is proven to be present well before other signs of atherosclerosis and may be the watershed event through which all other accepted risk factors for CVD have their effects.5
Furthermore, in-depth analysis of the entire process reveals the role of atherogenic lipoproteins, while important, may be a secondary one, whereas certain nutrient deficiencies, and subsequent increased vulnerability to vascular injury and/or increased vulnerability to endothelial dysfunction, may be playing the primary role.6-7
Therefore, it seems entirely appropriate to consider assessment and treatment strategies that move beyond this focus on lipid management, and begin to address the process of atherosclerosis at its earliest stages, and from as many angles as possible. One way may be increasing nitrate intake, including from these nitrate-rich foods:8
- Butter leaf lettuce
- Spring greens
- Beet greens
- Oak leaf lettuce
- Swiss chard
The evidence would thus far suggest that assessing and optimizing vascular health and function would be paramount for garnering the best results possible.