Dietary nitrate prevents progression of carotid subclinical atherosclerosis through blood pressure‐independent mechanisms in patients with or at risk of type 2 diabetes mellitus

Abstract

To test if 6 months' intervention with dietary nitrate and spironolactone could affect carotid subclinical atherosclerosis and stiffness, respectively, vs. placebo/ doxazosin, to control for blood pressure (BP).Methods: A subgroup of participants in our double-blind, randomized-controlled, factorial VaSera trial had carotid imaging. Patients with hypertension and with/at risk of type 2 diabetes were randomized to active nitrate-containing beetroot juice or placebo nitrate-depleted juice, and spironolactone or doxazosin. Vascular ultrasound for carotid diameter (CD, mm) and intima-media thickness (CIMT, mm) was performed at baseline, 3-and 6-months. Carotid local stiffness (CS, m/s) was estimated from aortic pulse pressure (Arteriograph) and carotid lumen area. Data were analysed by modified intention to treat and using mixed-model effect, adjusted for confounders.Results: In total, 93 subjects had a baseline evaluation and 86% had follow-up data.No statistical interactions occurred between the juice and drug arms and BP was similar between the juices and between the drugs. Nitrate-containing vs. placebo juice significantly lowered CIMT (À0.06 [95% confidence interval À0.12, À0.01], P = .034), an overall difference of $8% relative to baseline; but had no effect on CD or CS. Doxazosin appeared to reduce CS from baseline (À0.34 [À0.62, À0.06]) however, no difference was detected vs. spironolactone (À0.15 [À0.46, 0.16]). No differences were detected between spironolactone or doxazosin on CIMT and CD. Conclusions:Our results show that 6 months' intervention with dietary nitrate influences vascular remodelling, but not carotid stiffness or diameter. Neither spironolactone nor doxazosin had a BP-independent effect on carotid structure and function.

Effects of beetroot juice supplementation on vascular functional and structural changes in aged mice

“…The aged mice used in this study also showed pronounced medial thickening without affecting the lumen diameter, implying the occurrence of outward hypertrophic remodeling. As BRJ supplementation has beneficial effects on vascular wall thickening (Morselli et al, 2021;Tawa et al, 2021Tawa et al, , 2022, we expected that age-related vascular remodeling would also be suppressed in this study. However, BRJ supplementation did not reverse the medial thickening observed in aged mice.…”

Dietary Nitrate from Plant Foods: A Conditionally Essential Nutrient for Cardiovascular Health

“…Furthermore, most trials were conducted with healthy participants. For this reason, the effectiveness of nitrate supplementation for those presenting with cardiovascular disease risk factors such as hypertension and hypercholesterolemia remains unclear, although evidence suggests that nitrate improves vascular function, stabilizes atherosclerotic plaques and decreases cardiac fibrosis in humans and animal models [ 76 , 84 , 104 , 105 ]. Finally, most participants included in studies on nitrate supplementation were male.…”

“Every beet you take”: lowering systolic blood pressure and improving vascular function/exercise capacityviathe dietary nitrate–nitrite–NO pathway in patients with COPD

“…Mainly outside of COPD, several meta-analyses have confirmed BP-lowering effects of inorganic nitrate: with 1-15 days' intervention (16 studies, 254 participants) a significant SBP decrease, ~-4 mmHg (15), and 1-6 weeks' intervention (13 studies, 325 participants) for clinic BP measurements: SBP -4.1 mmHg (95% CI: -6.1, -2.2) and DBP -2.0 mmHg (95% CI: -3.0, -0.9), though not significant for ambulatory and/or home BP monitoring (16). Subsequent longer/larger studies include the 'Vasera' study, a double-blind, randomised controlled study in 126 patients with hypertension and with/at risk of, type 2 diabetes, using daily beetroot juice shots (active nitrate-containing versus identical nitrate-depleted placebo) for 6 months found that whilst nitrate had no effect on large artery (aortic) stiffness (primary outcome) (17), nitrate lowered central/aortic systolic BP by ~2.6 mmHg ( 18), decreased left-ventricular volumes (19), and decreased CIMT by ~8% (20). Sundqvist et al, randomised 231 patients with clinic SBP 130-159 mmHg to 5 weeks' of either low nitrate vegetables + placebo pills, low-nitrate vegetables + nitrate (300 mg) pills, or green leafy vegetables (300 mg nitrate) + placebo pills but found no effect on 24h ambulatory SBP (primary endpoint) (21).…”