Cardiac effects of 6 months' dietary nitrate and spironolactone in patients with hypertension and with/at risk of type 2 diabetes, in the factorial design, double‐blind, randomized controlled VaSera trial

Abstract

Aims The aims of the present study were to explore whether a long‐term intervention with dietary nitrate [(NO3−), a potential tolerance‐free source of beneficial vasoactive nitric oxide] and spironolactone (to oppose aldosterone's potential deleterious cardiovascular effects) improve cardiac structure/function, independently of blood pressure (BP), in patients with/at risk of type 2 diabetes (a population at risk of heart failure). Methods A subsample of participants in our double‐blind, randomized, factorial‐design intervention (VaSera) trial of active beetroot juice as a nitrate source (≤11.2 mmol) or placebo (nitrate depleted) beetroot juice, and either ≤50 mg spironolactone or ≤16 mg doxazosin (control), had transthoracic cardiac ultrasounds at baseline (n = 105), and at 3 months and 6 months (n = 87) after the start of the intervention. Analysis was by modified intent‐to‐treat. Results Nitrate‐containing juice (n = 40) decreased left ventricular (LV) end‐diastolic volume {−6.3 [95% confidence interval (CI) –11.1, –1.6] ml} and end‐systolic volume [−3.2 (95% CI −5.9, –0.5) ml], and increased end‐diastolic mass/volume ratio [+0.04 (95% CI 0.00, 0.07)], relative to placebo juice (n = 47). Spironolactone (n = 44) reduced relative wall thickness compared with doxazosin (n = 43) [−0.01 (95% CI −0.02, –0.00)]. Although spironolactone reduced LV mass index relative to baseline [−1.48 (95% CI −2.08, –0.88) g m–2.7], there was no difference vs. doxazosin [−0.85 (95% CI −1.76, 0.05) g m–2.7]. Spironolactone also decreased the E/A ratio [−0.12 (95% CI −0.19, –0.04)] and increased S′ (a tissue‐Doppler systolic function index) by 0.52 (95% CI 0.05, 1.0) cm s–1. BP did not differ between the juices, or between the drugs. Conclusions Six months' dietary nitrate decreased LV volumes ~5%, representing new, sustained, BP‐independent benefits on cardiac structure, extending mechanisms characterized in preclinical models of heart failure. Spironolactone's effects on cardiac remodelling and systolic–diastolic function, although confirmatory, were independent of BP.

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

“…Having diabetes on doxazosin in the trial was a particular aggravating factor . Whilst the change in PWVart and the borderline change in CAVI could be related to changes in cardiac function, our echocardiographic data do not suggest that as the ejection fraction, and global longitudinal strain, which is a well‐established marker of systolic function, were similar between the 2 drugs in our study; however, S′ (a tissue‐Doppler systolic function index) was increased by spironolactone vs doxazosin. Thus, while our data suggest that we have shown proof of concept that PWVart can be reduced independent of BP change, we have not shown that it is independent of cardiac functional change.…”

“…Left ventricular mass also changed, probably in response to the decreased BP. In our study, we found that left ventricular mass index between the 2 active BP drugs was not significant . Here, 71% patients were on prior anti‐hypertensive medication of many types, and the 62% with T2DM generally on metformin and other glucocentric agents.…”

Comment on ‘Cardiac effects of 6 months' dietary nitrate and spironolactone in patients with hypertension and with/at risk of type 2 diabetes, in the factorial design, double‐blind, randomised controlled VaSera trial’ by Faconti et al.

“…They showed that, whereas spironolactone and doxazosin both equally reduced the systolic blood pressure (SBP), supplementation with nitrate does not improve the antihypertensive effects of these drugs. However, nitrate improved cardiac remodelling complications suggesting that the beneficial effects of nitrate are independent on blood pressure lowering effects [2]. This study provides clinical evidence that supports the idea that dietary nitrate may be a useful therapeutic approach to treat cardiomyopathies given that it seems to provide additional beneficial effects to antihypertensive drugs.…”

“…Our group has compelling data demonstrating that sustained blood pressure lowering effect of nitrate and nitrite are dependent on NO and S-nitrosothiol formation in the stomach [5]. While Faconti et al [2] showed interesting effects of nitrate, we would like to point out that we have recently shown that treatment with oral nitrite protected against hypertensioninduced cardiomyocyte hypertrophy by mechanisms that are independent of blood pressure lowering effects of nitrite [7]. In our study, a low dose of nitrite induced antioxidant effects in the heart of hypertensive animals which negatively modulated the mTOR signalling, a common promoter of cardiac hypertrophy that stimulates protein synthesis.…”

“…Hypertension and diabetes are leading risk factors for cardiovascular complications and frequently occur together [1]. Faconti et al [2] evaluated if the administration of beetroot juice, as a source of dietary nitrate, in patients with hypertension and with/at risk of type 2 diabetes mellitus would improve the effects of the antihypertensive drugs spironolactone and doxazosin. They showed that, whereas spironolactone and doxazosin both equally reduced the systolic blood pressure (SBP), supplementation with nitrate does not improve the antihypertensive effects of these drugs.…”