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

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.

Do arterial stiffness and wave reflection underlie cardiovascular risk in ethnic minorities?

Increasing evidence indicates that remarkable differences in cardiovascular risk between ethnic groups cannot be fully explained by traditional risk factors such as hypertension, diabetes or dislipidemia measured in midlife. Therefore, the underlying pathophysiology leading to this "excess risk" in ethnic minority groups is still poorly understood, and one way to address this issue is to shift the focus from "risk" to examine target organs, particularly blood vessels and their arterial properties more directly. In fact, structural and functional changes of the vascular system may be identifiable at very early stages of life when traditional factors are not yet developed. Arterial stiffening, measured as aortic pulse wave velocity, and wave reflection parameters, especially augmentation index, seem to be an important pathophysiological mechanism for the development of cardiovascular disease and predict mortality independent of other risk factors. However, data regarding these arterial indices in ethnic minorities are relatively rare and the heterogeneity between populations, techniques and statistical methods make it difficult to fully understand their role.

Can arterial wave augmentation in young adults help account for variability of cardiovascular risk in different British ethnic groups?

OBJECTIVE: Traditional cardiovascular risk factors do not fully account for ethnic differences in cardiovascular disease. We tested if arterial function indices, particularly augmentation index (AIx), and their determinants from childhood could underlie such ethnic variability among young British adults in the 'DASH' longitudinal study. METHODS: DASH, at http://dash.sphsu.mrc.ac.uk/, includes representative samples of six main British ethnic groups. Pulse wave velocity (PWV) and AIx were recorded using the Arteriograph device at ages 21-23 years in a subsample (n = 666); psychosocial, anthropometric, and blood pressure (BP) measures were collected then and in two previous surveys at ages 11-13 years and 14-16 years. For n = 334, physical activity was measured over 5 days (ActivPal). RESULTS: Unadjusted values and regression models for PWVs were similar or lower in ethnic minority than in White UK young adults, whereas AIx was higher - Caribbean (14.9, 95% confidence interval 12.3-17.0%), West African (15.3, 12.9-17.7%), Indian (15.1, 13.0-17.2%), and Pakistani/Bangladeshi (15.7, 13.7-17.7%), compared with White UK (11.9, 10.2-13.6%). In multivariate models, adjusted for sex, central SBP, height, and heart rate, Indian and Pakistani/Bangladeshi young adults had higher AIx (ß = 3.35, 4.20, respectively, P < 0.01) than White UK with a similar trend for West Africans and Caribbeans but not statistically significant. Unlike PWV, physical activity, psychosocial or deprivation measures were not associated with AIx, with borderline associations from brachial BP but no other childhood variables. CONCLUSION: Early adult AIx, but not arterial stiffness, may be a useful tool for testing components of excess cardiovascular risk in some ethnic minority groups.