A randomised, factorial trial to reduce arterial stiffness independently of blood pressure: Proof of concept? The VaSera trial testing dietary nitrate and spironolactone

Abstract

Aims:To test if spironolactone or dietary nitrate from beetroot juice could reduce arterial stiffness as aortic pulse wave velocity (PWVart), a potential treatment target, independently of blood pressure. Methods:Daily spironolactone (≤50 mg) vs doxazosin (control ≤16 mg) and 70 mL beetroot juice (Beet-It ≤11 mmol nitrate) vs nitrate-depleted juice (placebo; 0 mmol nitrate) were tested in people at risk or with type-2 diabetes using a double-blind, 6-month factorial trial. Vascular indices (baseline, 12, 24 weeks) were cardiac-ankle vascular index (CAVI), a nominally pressure-independent stiffness measure (primary outcome), PWVart secondary, central systolic pressure and augmentation. Analysis was intention-to-treat, adjusted for systolic pressure differences between trial arms.Results: Spironolactone did not reduce stiffness, with evidence for reduced CAVI on doxazosin rather than spironolactone (mean difference [95% confidence interval]; 0.25 [−0.3, 0.5] units, P = .080), firmer for PWVart (0.37 [0.01, 0.7] m/s, P = .045). There was no difference in systolic pressure reduction between spironolactone and doxazosin (0.7 [−4.8, 3.3] mmHg, P = .7). Circulating nitrate and nitrite increased on active vs placebo juice, with central systolic pressure lowered −2.6 [−4.5, − 0.8] mmHg, P = .007 more on the active juice, but did not reduce CAVI, PWVart or peripheral pressure. Change in nitrate and nitrite concentrations were 1.5-fold [1.1-2.2] and 2.2-fold [1.3, 3.6] higher on spironolactone than on doxazosin respectively; both P < .05.Conclusion: Contrary to our hypothesis, in at-risk/type 2 diabetes patients, spironolactone did not reduce arterial stiffness, rather PWVart was lower on doxazosin.Dietary nitrate elevated plasma nitrite, selectively lowering central systolic pressure, observed previously for nitrite.PI statement: The authors confirm that the Principal Investigator for this paper is Professor J.K. Cruickshank and that he had direct clinical responsibility for patients.Clinical trial registration: ISRCTN registry: ISRCTN25003627

Beetroot juice lowers blood pressure and improves endothelial function in pregnant eNOS−/− mice: importance of nitrate‐independent effects

“…In addition, a very recent study (Mills et al . 2020) comparing the effects of nitrate‐containing and nitrate‐depleted ‘placebo’ BRJ in non‐pregnant adults reported no difference in SBP between these arms across the 24‐week intervention period. However, in both of these groups, peripheral BP did decrease by ∼6.5 mmHg compared with baseline SBP.…”

Dietary nitrate and population health: a narrative review of the translational potential of existing laboratory studies

“…Similar effects were also observed when NO 3 − rich beetroot juice was co-ingested alongside folate. In another study, Mills and colleagues [ 70 ] showed that 6 months consumption of NO 3 − -rich beetroot juice (~ 11 mmol/d NO 3 − ) decreased central systolic pressure by − 2.6 mmHg. Likewise, Kapil et al [ 71 ] reported reductions in 24-h systolic and diastolic BP (7.7 and 5.2 mmHg, respectively) and improved endothelial function and arterial stiffness with 4 weeks NO 3 − -rich beetroot juice supplementation (6.4 mmol/d NO 3 − ) with no change after placebo.…”

“…Only a handful of trials have explored the medium-to longer-term effects of NO 3 − consumption (4 weeks to 6 months), usually focusing on BP or endothelial function as an outcome. Whilst not a universal finding [67,68], beneficial effects of medium-to longer-term NO 3 − supplementation protocols have been reported in some trials [69][70][71]. For example, Siervo et al [69] found that 2 months supplementation with NO 3 − -rich beetroot juice (~6.5 mmol/d NO 3 − ) decreased 24-h systolic and diastolic BP by − 10.8 and − 5.4 mmHg, respectively, in a Sub-Saharan African setting.…”

Relationship of Behavioral Risk Factors for Cardiovascular Diseases and Arterial Stiffness in Women of Different Age Groups With Medical Education

“…Пищевые нитраты, содержащиеся в овощах, снижают артериальную ригидность, что связано с их влиянием на эндотелий-зависимую вазодилатацию [10]. Доказано снижение САДао при употреблении овощей, богатых пищевыми нитратами [11]. Наши результаты подтверждают положительное влияние употребления достаточного количества овощей и фруктов на сосудистую жёсткость.…”