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

Charlotte E. Mills, Virginia Govoni, Luca Faconti, Maria-Linda Casagrande, Steven V. Morant, Hannah Crickmore, Fahad Iqbal, Perry Maskell, Alisha Masani, Elisa Nanino, Andrew J. Webb, J. Kennedy Cruickshank (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)891-902
Number of pages12
JournalBritish Journal of Clinical Pharmacology
Volume86
Issue number5
Early online date13 Dec 2019
DOIs
Publication statusPublished - 17 Apr 2020

Keywords

  • arterial stiffness
  • beetroot juice
  • blood pressure
  • dietary nitrate
  • nitrate–nitrite–NO
  • pathway
  • type 2 diabetes

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    Mills, C. E., Govoni, V., Faconti, L., Casagrande, M-L., Morant, S. V., Crickmore, H., Iqbal, F., Maskell, P., Masani, A., Nanino, E., Webb, A. J., & Cruickshank, J. K. (2020). A randomised, factorial trial to reduce arterial stiffness independently of blood pressure: Proof of concept? The 'VaSera' trial testing dietary nitrate and spironolactone. British Journal of Clinical Pharmacology, 86(5), 891-902. https://doi.org/10.1111/bcp.14194