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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 ± 0.15 and 2.28 ± 0.17) than in individuals in Nigeria (4.09 ± 0.26, both P

Thiazide diuretics have been the cornerstone of hypertension treatment for >5 decades. Most recent European and American guidelines recommend both thiazide‐type and thiazide‐like diuretics as first‐line drugs for all patients with hypertension. In contrast, diuretics are not regarded as first‐line treatment in the UK and in patients who are to be initiated on a diuretic treatment, thiazide‐like molecules, such as chlortalidone and indapamide are the preferred option. This review examines the prescribing trend of the 4 most commonly prescribed thiazide diuretics for the treatment of hypertension in the UK. Prescription cost analysis data were obtained for both 2010 and 2016/2017 for each region of the UK to analyse the impact of the 2011 National Institute for Health and Care Excellence hypertension guidelines on the trend in thiazide diuretic prescribing. Overall, the prescriptions of thiazide diuretics declined over the years. Bendroflumethiazide is the most commonly prescribed diuretic in the UK and despite some geographical differences, thiazide‐type diuretics are more widely used than thiazide‐like. The use of indapamide increased significantly between 2010 and 2016/2017 while chlortalidone was rarely employed. Of the many factors affecting trends in prescriptions, clinical inertia, treatment adherence, availability of the products and the lack of fixed dose combinations may play a role.

Background Black African/African-Caribbean individuals with hypertension (BH) are at greater risk of heart failure than those of white European ethnicity (WH). The mechanisms underlying this dissimilarity remain poorly understood. Purpose To investigate the influence of ethnicity on left ventricular (LV) remodelling using multi-parametric cardiovascular magnetic resonance (CMR). Methods BH (n=44), WH (n=38) and healthy-volunteers (HV; n=25, 5 of black ethnicity) underwent comprehensive CMR. The exam included: i) Arterial Stiffness/Afterload pulse-wave-velocity (PWV), aortic elastance (Ea) and systemic vascular resistance (SVR) by phase-contrast velocity-encoding imaging; ii) Ventricular remodelling/Function LV and right ventricular (RV) volumes, mass, ejection fraction (EF), LV peak-filling rate by short-axis cine images; myocardial strains were measured by feature tracking; iii) Left atrial (LA) remodelling/Function volumes and functions by long-axis cine images; iv) Tissue characterisation: extracellular volume by pre/post-contrast T1-mapping and late gadolinium enhancement (LGE) for interstitial and replacement myocardial fibrosis, respectively. Multivariate linear regression models were developed to investigate how LV remodelling associates with ethnicity, arterial afterload, including elastance (Ea) and stiffness [PW], and SVR. Models were adjusted for age, gender, body-mass-index, LV volumes or function and LA volumes. Results Subject characteristics are summarised in the Table. PWV and Ea and SVR were greater in hypertensives, particularly in BH, than HV; this was paralleled by higher LV mass, interventricular septum thickness (IVS), LA volumes but lower LV-EF. These findings were confirmed after adjusting for age. On the Model-1, IVS was associated with Ea (β=0.335, P=0.008) and black ethnicity (β=0.226, P=0.019) but not with SVR or PWV. For each increment of Ea there was a similar increase of IVS in BH and WH (P=0.602 for interaction), however BH had greater IVS than WH at each Ea value (Figure, fully-adjusted Model-1). On Model-2, LV end-diastolic volume was associated with Ea (β=−0.268, P=0.001), SVR (β=−0.319, P=0.019) but not with PWV or ethnicity. However, the inverse relation between LV size and Ea was significantly attenuated in BH (P=0.039 for interaction), (Figure, fully-adjusted Model-2). On model-3, LV-EF was associated with Ea (β=0.223, P=0.009) but not with ethnicity, PWV or SVR. LV-EF reduction for each Ea increment was similar for BH and WH (P=0.597 for interaction). Conclusion BH and WH show a distinctive LV remodelling phenotype. BH had a greater susceptibility to hypertrophy and an attenuated reduction of chamber size in response to arterial afterload. Further research to disentangle the genetic and environmental factors underlying these ethnic group-specific differences is utterly required. Funding Acknowledgement Type of funding sources: None. Figure 1Table 1

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.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.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 (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.

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 p = 0.012). eGCSS was positively correlated with ACR (p p

Aim: Different to inhibitory drugs of the renin-angiotensin-aldosterone system (RAAS), diuretics are known to decrease blood pressure (BP) and stimulate renin release by the kidneys. Despite plasma aldosterone (PA) level is mostly regulated by the 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 randomized-controlled trials investigating the effects of diuretic therapy on PA and its correlation with change in potassium and BP. Methods: Three databases were searched: MEDLINE, EMBASE and The Cochrane Central Register of Controlled Trials (CENTRAL). Titles were firstly screened by title and abstract for relevancy before full-text articles were assessed for eligibility according to a pre-defined inclusion/exclusion criteria. Results: A total of 1139 articles were retrieved of which 45 met the pre-specified inclusion/exclusion criteria. The average standardised difference in mean PA change was similar for all classes of diuretic (mean, 95% CI); thiazide/thiazide-like 0.304 (0.169, 0.440), loop 0.927 (0.37, 1.49), MRA/potassium-sparing 0.264 (0.174, 0.355) and combination 0.466 (0.142, 0.789), Q = 6.475, P = 0.091. In subjects previously untreated with another antihypertensive, there was a significant relationship between PA change 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 between-class heterogeneity. Change in PA is not related with potassium but correlates to the change in BP in subjects previously untreated with another antihypertensive medication.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dr Georgiopoulos was supported by the Onassis Foundation under the special grant & support program for scholars" association members Introduction – Black Afro-Caribbean hypertensives (BAHs) are exposed to a higher risk of heart failure (HF) than white hypertensives (WHs). Arterial afterload is higher in BAHs due to increased arterial stiffness and vascular volume; BAHs develop more often left ventricular (LV) hypertrophy, dilatation and systolic dysfunction than WHs. However, it is unclear whether other racial differences concur to the more pronounced LV remodelling in BAHs. Methods – This cross-sectional study included hypertensive patients undergoing cardiovascular magnetic resonance for their clinical work-up (1.5T Aera Siemens-Healthcare). Clinical history and haemodynamic parameters were collected in all participants; a subset of patients had complete bio-humoral assay of the renin-angiotensin-aldosterone system (RAAs). Arm cuff pressure was measured during CMR. The CMR protocol included: i) Arterial afterload / LV arterial-coupling - pulse-wave-velocity (PWV), aortic (Ea) and LV elastance (Ees) by aorta anatomic and phase-contrast velocity-encoding imaging; ii) ventricular remodelling and function - LV and right ventricular (RV) volumes, mass, EF, LV peak-filling rate by short-axis cine images; global circumferential and longitudinal strains by cine feature tracking; iii) left atrial (LA) remodelling volumes and reservoir, conduit and booster functions by long-axis cine images; iv) tissue characterisation: T2 and pre/post-contrast T1 relaxation times, extracellular volume (ECV) by single mid-ventricular short-axis T1/T2-mapping. Results – 34 BAHs and 35 WHs (52 ± 12 vs 45 ± 14 years, P Conclusion – BAHs have heightened LV remodelling than WHs because of racial predisposition to develop hypertrophy which also encompasses derangements in RAAs. Altogether, these findings may account for the greater risk for HF in BAHs than WHs.

Selection of antihypertensive treatment according to self-defined ethnicity is recommended by some guidelines but might be better guided by individual genotype rather than ethnicity or race. We compared the extent to which variation in blood pressure response across different ethnicities may be explained by genetic factors: genetically defined ancestry and gene variants at loci known to be associated with blood pressure. We analyzed data from 5 trials in which genotyping had been performed (n=4696) and in which treatment responses to β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blocker, thiazide or thiazide-like diuretic and calcium channel blocker were available. Genetically defined ancestry for proportion of African ancestry was computed using the 1000 genomes population database as a reference. Differences in response to the thiazide diuretic hydrochlorothiazide, the β-blockers atenolol and metoprolol, the angiotensin-converting enzyme inhibitor lisinopril, and the angiotensin receptor blocker candesartan were more closely associated to genetically defined ancestry than self-defined ethnicity in admixed subjects. A relatively small number of gene variants related to loci associated with drug-signaling pathways ( KCNK3, SULT1C3, AMH, PDE3A, PLCE1, PRKAG2 ) with large effect size (−3.5 to +3.5 mm Hg difference in response per allele) and differing allele frequencies in black versus white individuals explained a large proportion of the difference in response to candesartan and hydrochlorothiazide between these groups. These findings suggest that a genomic precision medicine approach can be used to individualize antihypertensive treatment within and across populations without recourse to surrogates of genetic structure such as self-defined ethnicity.

Supplemental Digital Content is available in the text., 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

Purpose Heat stress exacerbates post-exercise hypotension (PEH) and cardiovascular disturbances from elevated body temperature may contribute to exertion-related incapacity. Mast cell degranulation and muscle mass are possible modifiers, though these hypotheses lack practical evidence. This study had three aims: (1) to characterise pre–post-responses in histamine and mast cell tryptase (MCT), (2) to investigate relationships between whole body muscle mass (WBMM) and changes in blood pressure post-marathon, (3) to identify any differences in incapacitated runners. Methods 24 recreational runners were recruited and successfully completed the 2019 Brighton Marathon (COMPLETION). WBMM was measured at baseline. A further eight participants were recruited from incapacitated runners (COLLAPSE). Histamine, MCT, blood pressure, heart rate, body temperature and echocardiographic measures were taken before and after exercise (COMPLETION) and upon incapacitation (COLLAPSE). Results In completion, MCT increased by nearly 50% from baseline (p = 0.0049), whereas histamine and body temperature did not vary (p > 0.946). Systolic (SBP), diastolic (DBP) and mean (MAP) arterial blood pressures and systemic vascular resistance (SVR) declined (p $$\Delta $$ Δ SBP (r = − 0.43, p = 0.046). For collapse versus completion, there were significant elevations in MCT (1.77 ± 0.25 μg/L vs 1.18 ± 0.43 μg/L, p = 0.001) and body temperature (39.8 ± 1.3 °C vs 36.2 ± 0.8 °C, p p = 0.107) and significantly lower MAP, DBP and SVR (p Conclusion These data support the hypothesis that mast cell degranulation is a vasodilatory mechanism underlying PEH and exercise associated collapse. The magnitude of PEH is inversely proportional to the muscle mass and enhanced by concomitant body heating.

Aim To test if 6 months' intervention with dietary nitrate and spironolactone could affect carotid subclinical atherosclerosis and stiffness, respectively, versus 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 was analysed by modified intention to treat and using mixed-model effect, adjusted for confounders. Results 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 versus placebo juice significantly lowered CIMT [-0.06 (95% Confidence Interval -0.12, -0.01), p=0.034], an overall difference of ~8% relative to baseline; but had no effect on carotid diameter (CD) or carotid stiffness (CS). Doxazosin appeared to reduce CS from baseline [-0.34 (-0.62, -0.06)] however, no difference was detected versus spironolactone [-0.15 (-0.46, 0.16)]. No differences were detected between spironolactone or doxazosin on CIMT and CD. Conclusion 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.

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.

Heat stress exacerbates post-exercise hypotension (PEH) and cardiovascular disturbances from elevated body temperature may contribute to exertion-related incapacity. Mast cell degranulation and muscle mass are possible modifiers, though these hypotheses lack practical evidence. This study had three aims: (1) to characterise pre-post-responses in histamine and mast cell tryptase (MCT), (2) to investigate relationships between whole body muscle mass (WBMM) and changes in blood pressure post-marathon, (3) to identify any differences in incapacitated runners.24 recreational runners were recruited and successfully completed the 2019 Brighton Marathon (COMPLETION). WBMM was measured at baseline. A further eight participants were recruited from incapacitated runners (COLLAPSE). Histamine, MCT, blood pressure, heart rate, body temperature and echocardiographic measures were taken before and after exercise (COMPLETION) and upon incapacitation (COLLAPSE).In completion, MCT increased by nearly 50% from baseline (p = 0.0049), whereas histamine and body temperature did not vary (p 0.946). Systolic (SBP), diastolic (DBP) and mean (MAP) arterial blood pressures and systemic vascular resistance (SVR) declined (p 0.019). WBMM negatively correlated with Δ SBP (r = - 0.43, p = 0.046). For collapse versus completion, there were significant elevations in MCT (1.77 ± 0.25 μg/L vs 1.18 ± 0.43 μg/L, p = 0.001) and body temperature (39.8 ± 1.3 °C vs 36.2 ± 0.8 °C, p 0.0001) with a non-significant rise in histamine (9.6 ± 17.9 μg/L vs 13.7 ± 33.9 μg/L, p = 0.107) and significantly lower MAP, DBP and SVR (p 0.033).These data support the hypothesis that mast cell degranulation is a vasodilatory mechanism underlying PEH and exercise associated collapse. The magnitude of PEH is inversely proportional to the muscle mass and enhanced by concomitant body heating.

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.

Background: Effects of afterload and blood pressure (BP) on pulse wave velocity (PWV) have been investigated using vasoactive drugs but effects of cardiac pre-load have not previously been studied. Methods: Transient mechanical reduction of cardiac pre-load (lower limb venous occlusion, LVO) and expansion of cardiac pre-load (intravenous infusion of 2 litres of saline solution, SST) were performed in patients with hypertension. BP, carotid-femoral PWV (Sphygmocor, AtCor Medical, Asutralia), cardiac stroke volume (SV) and total peripheral resistance (TPR) derived by transthoracic echocardiography were recorded during LVO and SST. Peak flow velocity in superior vena cava (SVCx) was used to asses change in pre-load. Results: 35 subjects were studied. SVCx decreased during LVO (n = 20) by mean (95% confidence-intervals) 7.6 (2.8–11.6) cm/s and increased during SST (n = 15) by 7.1 (−0.3–14.6) cm/s. LVO produced a small but significant reduction in mean arterial BP (MAP) of 1.5 (0.0–3.1) mmHg and SV of 6.7 (2.2–11.3) mL; while TPR and PWV increased by 236.9 (51.7–422.1) dynes-sec/cm5 and 0.7 (0.3–1.1) m/s respectively. SST produced a decrease of MAP of 4.3 (0.4–8.0) mmHg while SV increased by 4.8 (0.7–9.1) mL. TPR and PWV were reduced by 255.7 (15.4–490.5) dynes-sec/cm5 and 0.7 (0.1–1.0) m/s, respectively. All p < 0.05. Conclusion: Modulation of cardiac pre-load affect PWV beyond the effects on afterload and BP. The reciprocal changes of BP, PWV, SV and TPR could be explained by a role of the autonomic nervous system in the regulation of vascular tone in response to change of pre-load.

AIMS: The aims of the present study were to explore whether a long‐term intervention with dietary nitrate [(NO(3) (−)), 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.

Background Effects of short‐term interventions on large‐artery stiffness assessed by pulse wave velocity ( PWV ) have mainly been explained by concomitant changes in blood pressure ( BP ). However, lower body negative pressure, which increases sympathetic activity and has other hemodynamic effects, has a specific effect on PWV in healthy volunteers. Methods and Results We examined effects of lower‐limb venous occlusion ( LVO ), a similar intervention to lower‐body negative pressure that reduces BP but increases sympathetic activity and device‐guided breathing ( DGB ), which reduces both BP and sympathetic activity, on PWV in patients with essential hypertension (n=70 after LVO , n=45 after DGB and LVO in random order). The short‐acting calcium channel antagonist nifedipine was used as a control for changes in BP . LVO produced a small but significant reduction in mean arterial pressure of 1.8 (95% CI 0.3–3.4) mm Hg. Despite this, aortic and carotid‐femoral PWV increased during LVO by 0.8 (0.2–1.4) m/s and 0.7 (0.3–1.05) m/s, respectively. DGB reduced PWV by 1.2 (0.9–1.4) m/s, to a greater extent than did nifedipine 10 mg (reduction of 0.7 [0.1–1.3] m/s, P DGB ). This occurred despite a greater decrease in BP with nifedipine compared with DGB . Conclusions Arterial stiffness can be modulated independently of BP over the short term. The mechanism could involve alterations in sympathetic activity or other as yet uncharacterized effects of LVO and DGB .

Selection of antihypertensive treatment according to self-defined ethnicity is recommended by some guidelines but might be better guided by individual genotype rather than ethnicity or race. We compared the extent to which variation in blood pressure response across different ethnicities may be explained by genetic factors: genetically defined ancestry and gene variants at loci known to be associated with blood pressure. We analyzed data from 5 trials in which genotyping had been performed (n=4696) and in which treatment responses to β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blocker, thiazide or thiazide-like diuretic and calcium channel blocker were available. Genetically defined ancestry for proportion of African ancestry was computed using the 1000 genomes population database as a reference. Differences in response to the thiazide diuretic hydrochlorothiazide, the β-blockers atenolol and metoprolol, the angiotensin-converting enzyme inhibitor lisinopril, and the angiotensin receptor blocker candesartan were more closely associated to genetically defined ancestry than self-defined ethnicity in admixed subjects. A relatively small number of gene variants related to loci associated with drug-signaling pathways (KCNK3, SULT1C3, AMH, PDE3A, PLCE1, PRKAG2) with large effect size (-3.5 to +3.5 mm Hg difference in response per allele) and differing allele frequencies in black versus white individuals explained a large proportion of the difference in response to candesartan and hydrochlorothiazide between these groups. These findings suggest that a genomic precision medicine approach can be used to individualize antihypertensive treatment within and across populations without recourse to surrogates of genetic structure such as self-defined ethnicity.

Aim 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 (≤50mg) versus doxazosin (control ≤16mg) and 70mL beetroot juice (‘Beet-It’ ≤11mmol nitrate) versus nitrate-depleted juice (placebo; 0mmol 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), pulse wave velocity (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 intervals]; 0.25[-0.3, 0.5] units, p=0.080), firmer for PWVart (0.37[0.01, 0.7] ms-1, p=0.045). There was no difference in systolic pressure reduction between spironolactone and doxazosin (0.7[-4.8, 3.3]mmHg, p=0.7). Circulating nitrate and nitrite increased on active versus placebo juice, with central systolic pressure lowered -2.6[-4.5, - 0.8]mmHg, p=0.007 more on the active juice, but did not reduce CAVI, PWVart, nor 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

Background: Epidemiological and animal studies suggest the potential of dietary nitrate (NO 3−) to inhibit atherogenesis. Spironolactone may improve arterial stiffness. We tested if 6 months’ intervention with dietary nitrate and spironolactone could affect carotid subclinical atherosclerosis and stiffness versus placebo/doxazosin, to control for blood pressure (BP), in a population with or at risk of type 2 diabetes [1]. Methods: A subgroup of participants in our double-blind, randomized-controlled, factorial VaSera trial were randomized to nitrate-containing beetroot juice or nitrate-depleted juice, and spironolactone or doxazosin. Ultrasound for carotid diameter (CD, mm) and intima-media thickness (CIMT, mm) was performed at baseline, 3- and 6-months. Carotid stiffness (CS, m/s) was estimated from aortic pulse pressure (Arteriograph®) and carotid lumen area. Data was analysed by modified intention-to-treat and mixed-model effect, adjusted for confounders. Results: 93 participants had a baseline evaluation; 86% had follow-up data. No statistical interactions occurred between the juice and drug arms. BP was similar between the juices and between the drugs. CIMT was significantly lower following nitrate-containing, compared with placebo juice [−0.06 (95% Confidence Interval −0.12, −0.01), p = 0.022], with no effect on CD. CS reduction was similar between juices [−0.38(−0.67, −0.10) with placebo, −0.13 (−0.42, 0.16) with active juice] and the drugs [−0.30(−0.58, −0.02) with doxazosin, −0.21(−0.51, 0.09), with spironolactone]. No differences were detected between spironolactone or doxazosin on CIMT and CD. Conclusion: 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.

Obstructive Sleep Apnoea (OSA) is a breathing disorder characterized by narrowing of the upper airway that impairs normal ventilation during sleep. OSA is a highly prevalent condition which is associated with several Cardiovascular (CV) risk factors and CV diseases. Despite this clear association, Randomized Controlled Trials (RCTs) have provided equivocal data that treatment of sleep apnoea can improve CV outcomes regardless of its ability to reduce blood pressure. Here, we critically review the evidence that supports role of OSA as a risk factor for increased arterial stiffness which represents an early manifestation of vascular damage often preceding major CV events. Additionally, we examined evidence from interventional RCTs to assess if treatment of OSA by continuous positive airway pressure can affect arterial stiffness measured as carotid-femoral pulse wave velocity. Overall, a large body of evidence supports the role of OSA as a risk factor for increased arterial stiffness and several pathophysiological mechanisms, including activation of the autonomic nervous system, may help to explain the link between breathing disorders and vascular alterations (here mainly examined as functional properties). Whether the causal relationship between OSA and vascular damage exists or is mostly explained by confounders and whether OSA treatment can improve vascular stiffening is still debated.

Objective: Blood pressure (BP) can be divided into steady state (mean arterial pressure, MAP) and pulsatile (pulse pressure, PP) components that are differentially associated with target organ damage and cardiovascular events. Here, we tested the effects of non-pharmacological interventions that reduce sympathetic activity (SA) and cardiac pre-load on MAP and PP. Material and Methods: Pulse-wave analysis of the radial artery (SphygmoCor, AtCor Medical, Sydney, Australia), calibrated from 3 consecutive readings of brachial BP, was used for the evaluation of central PP and MAP. Measurements were obtained before and after supervised device-guided paced breathing (DGB), and bilateral lower limb venous occlusion (LVO, performed non-invasively using thigh cuffs), in random order. DGB reduces SA whereas LVO produces an acute reduction in pre-load. High resolution heart rate variability (HRV) as log-ratio of low-frequency/high-frequency range (LF/HF),( Schiller Medilog AR12plus, United States) was used to assess the effects of DGB on SA, while reduction of pre-load was evaluated by inferior vena cava diameter (IVCd) measured with cardiac ultrasound. Results: Thirty six HT patients (16 female) age (mean±SD) 46±12 years, BP 144.8±17.7/88.2±10.3 mmHg were studied. DGB decreased log LF/HF from 0.306±0.27 to 0.171±0.3 and LVO decreased IVCd from 15.16±3.96 mm to 12.39±3.43mm. Reduction of brachial BP was greater during DGB compared to LVO: (mean (95% confidence interval)):-9.7(-11.6,-7.8) mmHg vs -3.8(-5.8,-1.7) mmHg for systolic BP and -4.1(-5.6,-2.5) mmHg vs 1.1(-0.1, 2.2) mmHg for diastolic BP, respectively ( P . Effects of DGB and LVO were similar on PP: -3.5(-4.8,-2.3) mmHg for DBG and -3.1(-5.5,-0.7) mmHg for LVO, P>0.1. MAP reduction was significant only during DBG (-6.4 (-8.1,-4.7) mmHg) compared to LVO (-1.2 (-2.7, 0.1) mmHg, P between the interventions. Conclusion: Reducing sympathetic activity via DGB decreases both steady state and pulsatile components of BP whereas pre-load reduction selectively decreases PP. Depending on individual BP components, interventions targeting sympathetic activity and/or pre-load might be used to personalized treatment.

Objective:Arterial stiffness (AS) measured as carotid-femoral pulse wave velocity (cfPWV) is an important determinant of cardiovascular risk closely related to brachial blood pressure (BP). Whether it can be changed independently of BP in the short term is uncertain but recent observations suggest t

The aims of the present study were to explore whether a long-term intervention with dietary nitrate [(NOA 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.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 mSix 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.

PURPOSE OF REVIEW To provide an overview of available evidence of the relationship between birth weight and future hypertension development. RECENT FINDINGS Fetal programming plays a significant role in future hypertension. Both low and high birth weight are able to influence weight gain during childhood, adult weight and blood pressure values during childhood and adulthood. To date, an increasing amount of evidence is available especially for the relationship between low birth weight and hypertension, supported also by pathophysiological studies. SUMMARY In the era of personalized medicine, the possibility to reduce cardiovascular risk before or soon after birth and intervene on risk factors during childhood is appealing and promising for the future.