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

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Franca Morselli, Luca Faconti, Charlotte E Mills, Steven Morant, Philip J Chowienczyk, Joshua Au Yeung, Alessandro Cavarape, J Kennedy Cruickshank, Andrew J Webb

Original languageEnglish
Pages (from-to)4726-4736
Number of pages11
JournalBritish Journal of Clinical Pharmacology
Volume87
Issue number12
Early online date13 May 2021
DOIs
E-pub ahead of print13 May 2021
PublishedDec 2021

Bibliographical note

Funding Information: The authors would like to thank the research nurses at Clinical Research Facility at St Thomas' Hospital for their assistance in running the study, as well as the study participants. We also thank Karen McNeill for managing the blinding and randomization of the interventions, and Suzanne Barrett, who worked as research administrator. The work was funded by Fukuda Denshi, Tokyo, Japan. We acknowledge internal infrastructure financial support from King's College London British Heart Foundation Centre; National Institute for Health Research (NIHR), Clinical Research Facility at Guy's & St Thomas' NHS Foundation Trust, NIHR Biomedical Research Centre, based at Guy's and St Thomas' NHS Foundation Trust, and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Publisher Copyright: © 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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Abstract

Aims: 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 (−0.06 [95% confidence interval −0.12, −0.01], 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 (−0.34 [−0.62, −0.06]) however, no difference was detected vs. spironolactone (−0.15 [−0.46, 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.

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