Investigation and management of young-onset hypertension: British and Irish hypertension society position statement.

National and international hypertension guidelines recommend that adults with young-onset hypertension (aged <40 years at diagnosis) are reviewed by a hypertension specialist to exclude secondary causes of hypertension and optimise therapeutic regimens. A recent survey among UK secondary care hypertension specialist physicians highlighted variations in the investigation of such patients. In this position statement, the British and Irish Hypertension Society seek to provide clinicians with a practical approach to the investigation and management of adults with young-onset hypertension. We aim to ensure that individuals receive consistent and high-quality care across the UK and Ireland, to highlight gaps in the current evidence, and to identify important future research questions.

Influence of Blood Pressure Reduction on Pulse Wave Velocity in Primary Hypertension: A Meta-Analysis and Comparison With an Acute Modulation of Transmural Pressure.

BACKGROUND: Increased arterial stiffness and pulse wave velocity (PWV) of the aorta and large arteries impose adverse hemodynamic effects on the heart and other organs. Antihypertensive treatment reduces PWV, but it is unknown whether this results from an unloading of stiffer elements in the arterial wall or is due to an alternate functional or structural change that might differ according to class of antihypertensive drug. METHODS: We performed a systematic review and meta-analysis of the effects of different antihypertensive drug classes and duration of treatment on PWV with and without adjustment for change in mean arterial blood pressure (BP; study 1) and compared this to the change in PWV after an acute change in transmural pressure, simulating an acute change in BP (study 2). RESULTS: A total of 83 studies involving 6200 subjects were identified. For all drug classes combined, the reduction of PWV was 0.65 (95% CI, 0.46-0.83) m/s per 10 mm Hg reduction in mean arterial BP, a change similar to that induced by an acute change in transmural pressure in a group of hypertensive subjects. When adjusted for change in mean arterial BP, the reduction in PWV after treatment with beta-blockers or diuretics was less than that after treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists or calcium channel antagonists. CONCLUSIONS: Reduction in PWV after antihypertensive treatment is largely explained by the reduction in BP, but there are some BP-independent effects. These might increase over time and contribute to better outcomes over the long term, but this remains to be demonstrated in long-term clinical trials.

Effects of potassium supplementation on plasma aldosterone: a systematic review and meta-analysis in humans.

OBJECTIVES: Effects of potassium supplementation on blood pressure (BP) may be offset by an increase in plasma aldosterone. The magnitude of potassium-dependent regulation of aldosterone secretion in humans is not fully characterized; it is not clear whether this is mediated by activation of the renin-angiotensin-aldosterone system (RAAS), as a result of a reduction in BP or other mechanisms. We performed a systematic review and meta-analysis of clinical trials assessing effects of potassium on plasma aldosterone and renin in adult individuals. METHODS: This was carried out in accordance with PRISMA guidelines. Three databases were searched: MEDLINE, EMBASE and CENTRAL. Titles were firstly screened by title and abstract for relevance before full-text articles were assessed for eligibility. The keywords used included "aldosterone", "potassium" and "RAAS". RESULTS: 6395 articles were retrieved and after title/abstract screening, 123 full-text articles were assessed for eligibility. Thirty-six met the prespecified inclusion/exclusion criteria (of which 18/36 also reported systolic BP). Potassium supplementation caused a significant decrease in systolic BP (mean difference [95% CI] -3.69 mmHg [-4.91, -2.46], P < 0.001) and increase in serum potassium (+0.37 [0.23, 0.52] mmol/l, P < 0.001). There was an increase in plasma aldosterone (standardized difference 0.426 [0.299, 0.553], P < 0.001) but not in plasma renin activity. Meta-regression showed a significant positive correlation between change in plasma aldosterone and change in serum potassium (P < 0.001). CONCLUSIONS: Potassium supplementation increases plasma aldosterone concentrations, which correlates with the increase in serum potassium concentration which does not appear to be mediated by an increase in plasma renin activity.

Ethnicity differences in geometric remodelling and myocardial composition in hypertension unveiled by cardiovascular magnetic resonance.

AIMS: Hypertensive patients of African ancestry (Afr-a) have higher incidences of heart failure and worse clinical outcomes than hypertensive patients of European ancestry (Eu-a), yet the underlying mechanisms remain misunderstood. This study investigated right (RV) and left (LV) ventricular remodelling alongside myocardial tissue derangements between Afr-a and Eu-a hypertensives. METHODS AND RESULTS: 63 Afr-a and 47 Eu-a hypertensives underwent multi-parametric cardiovascular magnetic resonance. Biventricular volumes, mass, function, mass/end-diastolic volume (M/V) ratios, T2 and pre-/post-contrast T1 relaxation times, synthetic extracellular volume, and myocardial fibrosis (MF) were measured. 3D shape modelling was implemented to delineate ventricular geometry. LV and RV mass (indexed to body-surface-area) and M/V ratio were significantly greater in Afr-a than Eu-a hypertensives (67.1 ± 21.7 vs. 58.3 ± 16.7 g/m2, 12.6 ± 3.48 vs. 10.7 ± 2.71 g/m2, 0.79 ± 0.21 vs. 0.70 ± 0.14 g/mL, and 0.16 ± 0.04 vs. 0.13 ± 0.03 g/mL, respectively; P < 0.03). Afr-a patients showed greater basal interventricular septum thickness than Eu-a patients, influencing LV hypertrophy and RV cavity changes. This biventricular remodelling was associated with prolonged T2 relaxation time (47.0 ± 2.2 vs. 45.7 ± 2.2 ms, P = 0.005) and higher prevalence (23% vs. 4%, P = 0.001) and extent of MF [2.3 (0.6-14.3) vs. 1.6 (0.9-2.5) % LV mass, P = 0.008] in Afr-a patients. Multivariable linear regression showed that modifiable cardiovascular risk factors and greater end-diastolic volume, but not ethnicity, were independently associated with greater LV mass. CONCLUSION: Afr-a hypertensives had distinctive biventricular remodelling, including increased RV mass, septal thickening and myocardial tissue abnormalities compared with Eu-a hypertensives. From this study, modifiable cardiovascular risk factors and ventricular geometry, but not ethnicity, were independently associated with greater LV myocardial mass.

Adult hypertension referral pathway and therapeutic management: British and Irish Hypertension Society position statement.

In the UK, most adults with hypertension are managed in Primary Care. Referrals to Secondary Care Hypertension Specialists are targeted to patients in whom further investigations are likely to change management decisions. In this position statement the British and Irish Hypertension Society provide clinicians with a framework for referring patients to Hypertension Specialists. Additional therapeutic advice is provided to optimise patient management whilst awaiting specialist review. Our aim is to ensure that referral criteria to Hypertension Specialists are consistent across the UK and Ireland to ensure equitable access for all patients.

Diagnosis and management of primary hyperaldosteronism in patients with hypertension: a practical approach endorsed by the British and Irish Hypertension Society.

Alongside the lack of homogeneity among international guidelines and consensus documents on primary hyperaldosteronism, the National UK guidelines on hypertension do not provide extensive recommendations regarding the diagnosis and management of this condition. Local guidelines vary from area to area, and this is reflected in the current clinical practice in the UK. In an attempt to provide support to the clinicians involved in the screening of subjects with hypertension and clinical management of suspected cases of primary hyperaldosteronism the following document has been prepared on the behalf of the BIHS Guidelines and Information Service Standing Committee. Through remote video conferences, the authors of this document reviewed an initial draft which was then circulated among the BIHS Executive members for feedback. A survey among members of the BIHS was carried out in 2022 to assess screening strategies and clinical management of primary hyperaldosteronism in the different regions of the UK. Feedback and results of the survey were then discussed and incorporated in the final document which was approved by the panel after consensus was achieved considering critical review of existing literature and expert opinions. Grading of recommendations was not performed in light of the limited available data from properly designed randomized controlled trials.

Impaired ß 2 -adrenergic endothelium-dependent vasodilation in patients previously hospitalized with coronavirus disease 2019.

AIM: The pulse wave response to salbutamol (PWRS) - change in augmentation index (AIx) - provides a means to assess endothelial vasodilator function in vivo . Endothelial dysfunction plays a relevant role in the pathogenesis of hypertension and cardiovascular disease and appears to underlie many of the complications of coronavirus disease 2019 (COVID-19). However, to what degree this persists after recovery is unknown. METHODS: Individuals previously hospitalized with COVID-19, those recovered from mild symptoms and seronegative controls with well known risk factors for endothelial dysfunction were studied. To assess the involvement of nitric oxide-cyclic guanosine monophosphate pathway (NO-cGMP) on PWRS, sildenafil was also administrated in a subsample. RESULTS: One hundred and one participants (60 men) aged 47.8 ±â€Š14.1 (mean ±â€ŠSD) years of whom 33 were previously hospitalized with COVID-19 were recruited. Salbutamol had minimal effect on haemodynamics including blood pressure and heart rate. It reduced AIx in controls ( n  = 34) and those recovered from mild symptoms of COVID-19 ( n  = 34) but produced an increase in AIx in those previously hospitalized: mean change [95% confidence interval] -2.85 [-5.52, -0.188] %, -2.32 [-5.17,0.54] %, and 3.03 [0.06, 6.00] % for controls, those recovered from mild symptoms and those previously hospitalized, respectively ( P  = 0.001). In a sub-sample ( n  = 22), sildenafil enhanced PWRS (change in AIx 0.05 [-2.15,2.24] vs. -3.96 [-7.01. -2.18], P  = 0.006) with no significant difference between hospitalized ( n  = 12) and nonhospitalized participants ( n  = 10). CONCLUSIONS: In patients previously hospitalized with COVID-19, there is long-lasting impairment of endothelial function as measured by the salbutamol-induced stimulation of the NO-cGMP pathway that may contribute to cardiovascular complications.

A pilot study to evaluate the erythrocyte glycocalyx sensitivity to sodium as a marker for cellular salt sensitivity in hypertension.

Supressed plasma renin in patients with primary hypertension is thought to be an indirect marker of sodium-induced volume expansion which is associated with more severe hypertension and hypertension-mediated organ damage. A novel test for erythrocyte glycocalyx sensitivity to sodium (eGCSS) has been proposed as a direct measure of sodium-induced damage on erythrocyte surfaces and a marker of sensitivity of the endothelium to salt in humans. Here we explore if eGCSS relates to plasma renin and other clinical and biochemical characteristics in a cohort of patients with primary hypertension. Hypertensive subjects (n = 85, 54% male) were characterised by blood biochemistry (including plasma renin/aldosterone), urine analysis for albumin-creatinine ratio (ACR), 24-h urine sodium/potassium excretion. eGCSS was measured using a commercially available kit. Correlations between eGCSS and clinical and biochemical characteristics were explored using Spearman's correlation coefficient and characteristics compared across tertiles of eGCSS. eGCSS was inversely correlated with renin (p < 0.05), with renin 17.72 ± 18 µU/l in the highest tertile of eGCSS compared to 84.27 ± 146.5 µU/l in the lowest (p = 0.012). eGCSS was positively correlated with ACR (p < 0.01), with ACR 7.37 ± 15.29 vs. 1.25 ± 1.52 g/mol for the highest vs. lowest tertiles of eGCSS (p < 0.05). eGCSS was not correlated with other clinical characteristics or biochemical measures. These results suggests that sodium retention in hypertension characterised by a low-renin state is associated with cell membrane damage reflected by eGCSS. This may contribute to the hypertension-mediated organ damage and the excess mortality associated with sodium overload and "salt sensitivity".

Sensitivity and Reproducibility of Inferior Vena Cava Diameter and Superior Vena Cava Flow Velocity Measurements to Changes in Cardiac Preload in Subjects with Hypertension.

Objectives: We investigated the sensitivity and reproducibility of inferior vena cava (IVC) diameters and superior vena cava (SVC) flow velocities in detecting changes in cardiac preload in clinically euvolemic subjects with hypertension. Methods: Measurements were obtained during passive leg raising (PLR) and lower limb venous occlusion (LVO), interventions which respectively transiently increase and decrease cardiac preload. Measurements were made in 36 subjects and repeated on two separate occasions to examine reproducibility. Results: During PLR, there was no significant change in IVC diameters, but peak flow velocity of the SVC S wave increased by 6.5 (95% confidence interval 1.6-11.3) cm/s (P = 0.01). During LVO, IVC diameter in expiration decreased by 3.2 (1.7-4.7) mm and the SVC S wave decreased by 9.7 (4.4-14.7) cm/s (P < 0.001). Venae cavae-derived indices can be used to assess changes in preload within the physiological range in euvolemia. Conclusions: Despite suboptimal reproducibility of baseline measurements, high agreeability between the changes in IVC diameter and SVC flow after LVO suggests that these indices can be used to monitor changes in cardiac preload.

Effect of diuretics on plasma aldosterone and potassium in primary hypertension: A systematic review and meta-analysis.

AIM: By contrast with drugs inhibiting the renin-angiotensin-aldosterone system (RAAS), diuretics stimulate renin release by the kidneys. Although plasma aldosterone (PA) is thought to be mainly regulated by RAAS activity, serum potassium has been shown to be an important factor in animal models and humans. Here we perform a systematic review and meta-analysis of randomised controlled trials (RCT) in hypertension investigating the effects of diuretic therapy on PA and the correlation of change in PA with that of potassium and blood pressure (BP). METHODS: Three databases were searched: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). Titles were first screened by title and abstract for relevance before full-text articles were assessed for eligibility according to a predefined inclusion/exclusion criteria. RESULTS: A total of 1139 articles were retrieved, of which 42 met the prespecified inclusion/exclusion criteria. The average standardised difference in mean PA was similar for all classes of diuretic: thiazide/thiazide-like 0.299 (95% confidence interval [CI] 0.150, 0.447), loop 0.927 (0.37, 1.49), MRA/potassium-sparing 0.265 (0.173, 0.357) and combination 0.466 (0.137, 0.796), Q = 6.33, P = .097. In subjects untreated with another antihypertensive, there was a significant relationship between change in PA and change in systolic BP but no relationship with the change in potassium. CONCLUSION: In RCTs of diuretic therapy in hypertension, there is an increase in PA with all classes of diuretic and no significant between-class heterogeneity. Change in PA is not related with potassium but correlates with the change in BP in subjects untreated with another antihypertensive medication.

Hypertension and heart failure with preserved ejection fraction: position paper by the European Society of Hypertension.

Hypertension constitutes a major risk factor for heart failure with preserved ejection fraction (HFpEF). HFpEF is a prevalent clinical syndrome with increased cardiovascular morbidity and mortality. Specific guideline-directed medical therapy (GDMT) for HFpEF is not established due to lack of positive outcome data from randomized controlled trials (RCTs) and limitations of available studies. Although available evidence is limited, control of blood pressure (BP) is widely regarded as central to the prevention and clinical care in HFpEF. Thus, in current guidelines including the 2018 European Society of Cardiology (ESC) and European Society of Hypertension (ESH) Guidelines, blockade of the renin-angiotensin system (RAS) with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers provides the backbone of BP-lowering therapy in hypertensive patients. Although superiority of RAS blockers has not been clearly shown in dedicated RCTs designed for HFpEF, we propose that this core drug treatment strategy is also applicable for hypertensive patients with HFpEF with the addition of some modifications. The latter apply to the use of spironolactone apart from the treatment of resistant hypertension and the use of the angiotensin receptor neprilysin inhibitor. In addition, novel agents such as sodium-glucose co-transporter-2 inhibitors, currently already indicated for high-risk patients with diabetes to reduce heart failure hospitalizations, and finerenone represent promising therapies and results from ongoing RCTs are eagerly awaited. The development of an effective and practical classification of HFpEF phenotypes and GDMT through dedicated high-quality RCTs are major unmet needs in hypertension research and calls for action.

First-Phase Ejection Fraction, a Measure of Preclinical Heart Failure, Is Strongly Associated With Increased Mortality in Patients With COVID-19.

Presence of heart failure is associated with a poor prognosis in patients with coronavirus disease 2019 (COVID-19). The aim of the present study was to examine whether first-phase ejection fraction (EF1), the ejection fraction measured in early systole up to the time of peak aortic velocity, a sensitive measure of preclinical heart failure, is associated with survival in patients hospitalized with COVID-19. A retrospective outcome study was performed in patients hospitalized with COVID-19 who underwent echocardiography (n=380) at the West Branch of the Union Hospital, Wuhan, China and in patients admitted to King's Health Partners in South London, United Kingdom. Association of EF1 with survival was performed using Cox proportional hazards regression. EF1 was compared in patients with COVID-19 and in historical controls with similar comorbidities (n=266) who had undergone echocardiography before the COVID-19 pandemic. In patients with COVID-19, EF1 was a strong predictor of survival in each patient group (Wuhan and London). In the combined group, EF1 was a stronger predictor of survival than other clinical, laboratory, and echocardiographic characteristics including age, comorbidities, and biochemical markers. A cutoff value of 25% for EF1 gave a hazard ratio of 5.23 ([95% CI, 2.85-9.60]; P<0.001) unadjusted and 4.83 ([95% CI, 2.35-9.95], P<0.001) when adjusted for demographics, comorbidities, hs-cTnI (high-sensitive cardiac troponin), and CRP (C-reactive protein). EF1 was similar in patients with and without COVID-19 (23.2±7.3 versus 22.0±7.6%, P=0.092, adjusted for prevalence of risk factors and comorbidities). Impaired EF1 is strongly associated with mortality in COVID-19 and probably reflects preexisting, preclinical heart failure.

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

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.

Effect of diuretics on plasma renin activity in primary hypertension: A systematic review and meta-analysis.

AIMS: Plasma renin activity (PRA) is regarded as a marker of sodium and fluid homeostasis in patients with primary hypertension. Whether effects of diuretics on PRA differ according to class of diuretic, whether diuretics lead to a sustained increase in PRA, and whether changes in PRA relate to those in blood pressure (BP) is unknown. We performed a systematic review and meta-analysis of trials investigating the antihypertensive effects of diuretic therapy in which PRA and/or other biomarkers of fluid homeostasis were measured before and after treatment. METHODS: Three databases were searched: MEDLINE, EMBASE and The Cochrane Central Register of Controlled Trials. Titles were firstly screened by title and abstract for relevancy before full-text articles were assessed for eligibility according to a predefined inclusion/exclusion criteria. RESULTS: A total of 1684 articles were retrieved of which 61 met the prespecified inclusion/exclusion criteria. PRA was measured in 30/61 studies. Diuretics led to a sustained increase in PRA which was similar for different classes of diuretic (standardised mean difference [95% confidence interval] 0.481 [0.362, 0.601], 0.729 [0.181, 1.28], 0.541 [0.253, 0.830] and 0.548 [0.159, 0.937] for thiazide, loop, mineralocorticoid receptor antagonists/potassium-sparing and combination diuretics respectively, Q = 0.897, P = .826), and did not relate to the average decrease in blood pressure. CONCLUSION: In antihypertensive drug trials, diuretics lead to a sustained increase in average PRA, which is similar across different classes of diuretic and unrelated to the average reduction in blood pressure.

Post-exertional increase in first-phase ejection fraction in recreational marathon runners.

OBJECTIVES: Running a marathon has been equivocally associated with acute changes in cardiac performance. First-phase ejection fraction is a novel integrated echocardiographic measure of left ventricular contractility and systo-diastolic coupling which has never been studied in the context of physical activity. The aim of this study was to assess first-phase ejection fraction following recreational marathon running along with standard echocardiographic indices of systolic and diastolic function.Design and participants: Runners (n = 25, 17 males), age (mean ± standard deviation) 39 ± 9 years, were assessed before and immediately after a marathon race which was completed in 4 h, 10 min ± 47 min. MAIN OUTCOME MEASURES: Central hemodynamics were estimated with applanation tonometry; cardiac performance was assessed using standard M-mode two-dimensional Doppler, tissue-doppler imaging and speckle-tracking echocardiography. First-phase ejection fraction was calculated as the percentage change in left ventricular volume from end-diastole to the time of peak aortic blood flow. RESULTS: Conventional indices of systolic function and cardiac performance were similar pre- and post-race while aortic systolic blood pressure decreased by 9 ± 8 mmHg (P < 0.001) and first-phase ejection fraction increased by approximately 48% from 16.3 ± 3.9% to 22.9 ± 2.5% (P < 0.001). The ratio of left ventricular transmitral Doppler early velocity (E) to tissue-doppler imaging early annular velocity (e') increased from 5.1 ± 1.8 to 6.2 ± 1.3 (P < 0.01). CONCLUSION: In recreational marathon runners, there is a marked increase in first-phase ejection fraction after the race despite no other significant change in cardiac performance or conventional measure of systolic function. More detailed physiological studies are required to elucidate the mechanism of this increase.

Differences in hypertension phenotypes between Africans and Europeans: role of environment.

OBJECTIVES: Hypertension phenotypes differ between Africans and Europeans, with a greater prevalence of low renin salt-sensitive hypertension and greater predisposition to adverse cardiac remodelling in Africans. To elucidate the roles of inheritance and environment in determining hypertension phenotypes in sub-Saharan Africans and white-Europeans, we compared phenotypes in white individuals in the UK (n = 132) and in African individuals in the UK (n = 158) and Nigeria (n = 179). METHODS: Biochemistry, blood pressure, left ventricular structure (echocardiography) and 24-h urinary collections of sodium and potassium were measured. RESULTS: Twenty-four-hour urinary sodium/potassium ratio was lower in individuals living in Europe (both African and white: 2.32 ±â€Š0.15 and 2.28 ±â€Š0.17) than in individuals in Nigeria (4.09 ±â€Š0.26, both P < 0.001) reflecting proportionately higher potassium intake in Europeans (African or white) than African residents. Plasma renin was lower in Africans irrespective of residency than white Europeans, but aldosterone was higher in Africans in Europe than those in Africa (466.15 ±â€Š32.95 vs. 258.60 ±â€Š17.42 pmol/l, P < 0.001). Left ventricular mass index adjusted for blood pressure and other confounders was greatest in Africans in Europe (103.27 ±â€Š2.32 g/m) compared with those in Africa (89.28 ±â€Š1.98 g/m) or white Europeans (86.77 ±â€Š2.63 g/m, both P < 0.001). CONCLUSION: Despite a similar low renin state in African origin individuals living in Europe and Africa, a higher aldosterone level, possibly related to higher potassium intake or other environmental factors, may contribute to greater cardiac remodelling in Africans in Europe.

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.