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We examined the influence of arterial stiffening and ventricular ejection dynamics on the age-related increase in central pulse pressure. A total of 2033 women aged 18 to 91 years from the Twins UK cohort were studied. Aortic flow and central blood pressure were measured by Doppler sonography and carotid tonometry, respectively. Measured values of central pulse pressure were compared with values predicted from aortic pulse wave velocity and ventricular ejection characteristics. Central pulse pressure at the first shoulder ( P1 ) increased with age from 29.2±8.0 in those 70 years (means±SD; P P2 , usually equal to peak central pulse pressure) increased to a greater extent with age: from 29.1±7.8 mm Hg for those 70 years ( P P2/P1 closely mirrored the ratio of ejection volume to ejection velocity at corresponding time points, and the proportionately greater increase in P2 compared with P1 was explained by increased ventricular ejection up to the time of P2 . This increased from 52.5±13.1 to 59.3±17.8 mL ( P

Background Basal release of nitric oxide ( NO ) from the vascular endothelium regulates the tone of muscular arteries and resistance vasculature. Effects of NO on muscular arteries could be particularly important during exercise when shear stress may stimulate increased NO synthesis. Methods and Results We investigated acute effects of NO synthase inhibition on exercise hemodynamics using N G ‐monomethyl‐ l ‐arginine ( l ‐ NMMA ), a nonselective NO synthase ‐inhibitor. Healthy volunteers (n=10, 5 female, 19–33 years) participated in a 2‐phase randomized crossover study, receiving l ‐ NMMA (6 mg/kg, iv over 5 minutes) or placebo before bicycle exercise (25–150 W for 12 minutes). Blood pressure, cardiac output (measured by dilution of soluble and inert tracers) and femoral artery diameter were measured before, during, and after exercise. At rest, l ‐ NMMA reduced heart rate (by 16.2±4.3 bpm relative to placebo, P P P l ‐ NMMA and placebo, P l ‐ NMMA had no significant effect on peripheral resistance, cardiac output, or on femoral artery diameter. Conclusions These results suggest that NO plays little role in modulating muscular artery function during exercise but that it may mediate changes in muscular artery tone immediately before exercise.

We investigated whether expression of genes previously implicated in arterial stiffening associates with cross-sectional and longitudinal measures of arterial stiffness. Women from the Twins UK cohort (n=470, aged 39–81 years) had gene expression in lymphoblastoid cell lines measured using an Illumina microarray. Arterial stiffness was measured by carotid-femoral pulse wave velocity and carotid distensibility. A subsample (n=121) of women had repeat vascular measures after a mean±SD follow-up of 4.3±1.4 years. Associations of arterial phenotypes with gene expression levels were examined for 52 genes identified from previous association studies. The gene transcript most closely associated with pulse wave velocity in cross-sectional analysis was ectonucleotide pyrophosphatase/phosphodiesterase ( P =0.012). Pleiotropic genetic effects accounted for 14% of the phenotypic correlation between ectonucleotide pyrophosphatase/phosphodiesterase expression and pulse wave velocity. Progression of pulse wave velocity during the follow-up period best related to expression of ectonucleotide pyrophosphatase/phosphodiesterase (β=0.19, P =0.008) and collagen type IV α 1 (β=0.32, P P =0.005), angiotensin-converting enzyme (β=–0.15, P =0.035), and B-cell CLL/lymphoma11B (β=0.18, P =0.010). Expression levels of angiotensin-converting enzyme also related to progression in carotid diameter (β=0.21, P =0.012). Expression levels of ectonucleotide pyrophosphatase/phosphodiesterase, involved in arterial calcification, and collagen type IV α 1, involved in collagen formation, correlate with aortic stiffening. These genes may be functional mediators of arterial stiffening.

Background Interactions between the left ventricular (LV) and the arterial system, (ventricular-arterial coupling) are key determinants of cardiovascular function. However, most of studies covered multiple cardiovascular risk factors, which also contributed to the morphological and functional changes of LV. The aim of this study was to examine the relationship between arterial stiffness and LV structure and function in healthy women with a low burden of risk factors. Methods Healthy women from the Twins UK cohort (n = 147, mean age was 54.07 ± 11.90 years) were studied. Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (cf-PWV). LV structure and function were assessed by two-dimensional speckle tracking echocardiography. Results cf-PWV was significantly associated with most measures of LV geometry and function, including relative wall thickness (RWT), E/e’ ratio, global circumferential and radial strain, apical rotation and LV twist (each p

Background— Inorganic nitrite dilates small resistance arterioles via hypoxia-facilitated reduction to vasodilating nitric oxide. The effects of nitrite in human conduit arteries have not been investigated. In contrast to nitrite, organic nitrates are established selective dilators of conduit arteries. Methods and Results— We examined the effects of local and systemic administration of sodium nitrite on the radial artery (a muscular conduit artery), forearm resistance vessels (forearm blood flow), and systemic hemodynamics in healthy male volunteers (n=43). Intrabrachial sodium nitrite (8.7 μmol/min) increased radial artery diameter by a median of 28.0% (25th and 75th percentiles, 25.7% and 40.1%; P −1 ·100 mL −1 tissue (95% confidence interval, 0.5–1.8). Nitrite-induced radial artery dilation was enhanced by administration of acetazolamide (oral or intra-arterial) and oral raloxifene ( P =0.0248, P P =0.0006, respectively) but was inhibited under hypoxia ( P P =0.0006) compared with normoxia. Systemic intravenous administration of sodium nitrite (8.7 μmol/min) dilated the radial artery by 10.7% (95% confidence interval, 6.8–14.7) and reduced central systolic blood pressure by 11.6 mm Hg (95% confidence interval, 2.4–20.7), augmentation index, and pulse wave velocity without changing peripheral blood pressure. Conclusions— Nitrite selectively dilates conduit arteries at supraphysiological and near-physiological concentrations via a normoxia-dependent mechanism that is associated with cGMP production and is enhanced by acetazolamide and raloxifene. The selective central blood pressure–lowering effects of nitrite have therapeutic potential to reduce cardiovascular events.

AimsVascular ageing is characterized by arterial stiffening, dilation, and arterial wall thickening. We investigated the extent to which these changes are related and their heritability during 5 year follow-up in the Twins UK cohort.Methods and resultsCarotid-femoral pulse wave velocity (PWVcf), carotid diameter, carotid distensibility, and carotid intima-media thickness (IMT) were measured in 762 female twins (mean age 57.9 ± 8.6 years) at two time-points over an average follow-up of 4.9 ± 1.5 years. Magnetic resonance imaging (MRI) was performed in a sub-sample of 38 women to measure aortic pulse wave velocity (PWVaorta), diameter, and wall thickness. Heritability of changes in arterial wall properties was estimated using structural equation modelling. Annual increases in PWVcf, carotid diameter, distensibility, and IMT were 0.139 m/s, 0.028 mm, −0.4 kPa−1, and 0.011 mm per year, respectively. In regression analysis, predictors of progression in PWVcf included age, mean arterial pressure (MAP), and heart rate (HR) at baseline, and progression in MAP, HR, and body mass index (BMI). Predictors of progression in IMT included progression in MAP, BMI, and triglyceride levels. Progression of PWV and distensibility correlated with progression in carotid diameter but not with IMT. Heritability of progression of PWVcf, diameter, and IMT was 55%, 21%, and 8%, respectively. In a sub-sample of women that underwent MRI, aortic wall thickness increased by 0.19 mm/year, but aortic wall thickening was not correlated with an increase in lumen diameter or PWVaorta.ConclusionArterial stiffening, as measured by PWVcf, and dilation are heritable but independent of arterial wall thickening. Genetic and cardiovascular risk factors contribute differently to progression of PWV and IMT.

Background/objectives There are few studies investigating the long-term association between childhood blood pressure (BP) and adult cardiovascular remodeling. We seek to examine the effect of elevated childhood BP on cardiovascular remodeling in early or middle adulthood. Methods We used the "Beijing BP Cohort Study", where 1259 subjects aged 6–18years old were followed over 24years from childhood (1987) to early or middle adulthood (2011). Anthropometric measures and BP were obtained at baseline and follow-up examinations. Carotid–femoral pulse wave velocity (cfPWV), carotid intima-media thickness (cIMT), and left ventricular mass index (LVMI) were measured to assess cardiovascular remodeling in early or middle adulthood. Multiple logistic regression models were used to assess the odds ratio (OR) and 95% confidence interval (CI) for cardiovascular remodeling. Results 82 out of 384 children with elevated BP (21.4%) had adult hypertension. Compared to those with normal BP, children with elevated BP were at 2.1 times (95% CI: 1.4–3.1) likely to develop hypertension in early or middle adulthood. Compared to those with normal BP, children with elevated BP were at higher OR of developing high cfPWV (OR=1.8, 95% CI=1.3–2.4), high cIMT (1.4, 1.0–1.9), or high LVMI (1.4, 1.0–1.9) in early or middle adulthood. The ORs for remodeling (for any measures) were 1.4 (0.9–2.0) in early adulthood for children age 6–11years, and 1.6 (1.1–2.4) in middle adulthood for those aged 12–18years. Conclusions Children with elevated BP from 6years old have accelerated remodeling on both cardiac and arterial system in early or middle adulthood.

Background Haemoglobin scavenges nitric oxide, and a previous study has shown a negative association between flow-mediated vasodilation (FMD), a measure of nitric oxide (NO)-dependent vasomotor function and haemoglobin concentrations [Hb]. Circulating erythropoietin (EPO) is also negatively associated with [Hb] and could influence availability of NO. The purpose of this study was to examine the association of FMD with [Hb] and EPO concentrations and to determine whether these contribute to the sex difference in FMD. FMD (by high-resolution ultrasound), [Hb], circulating immunoreactive EPO and cardiovascular risk factors were measured in 317 healthy middle-aged men and women (183 women, 33 premenopausal, mean age ± SD, 55 ± 6·8 years) participating in a dietary study. Results In the whole mixed-sex group, FMD was negatively correlated with [Hb] (R = −0·23, P

Objectives Our aim was to examine the relationship of arterial stiffness to measures of atherosclerosis, arterial calcification, and bone mineral density (BMD); the heritability of these measures; and the degree to which they are explained by common genetic influences. Background Arterial stiffening relates to arterial calcification, but this association could result from coexistent atherosclerosis. A reciprocal relationship between arterial stiffening/calcification and BMD could explain the association between cardiovascular morbidity and osteoporosis. Methods We examined, in 900 women from the Twins UK cohort, the relationship of carotid-femoral pulse wave velocity (cfPWV) to measures of atherosclerosis (carotid intima-media thickening; carotid/femoral plaque), calcification (calcified plaque [CP]; aortic calcification by computed tomography, performed in subsample of 40 age-matched women with low and high cfPWV), and BMD. Results The cfPWV independently correlated with CP but not with intima-media thickness or noncalcified plaque. Total aortic calcium, determined by computed tomography, was significantly greater in subjects with high cfPWV (median Agatston score 450.4 compared with 63.2 arbitrary units in subjects with low cfPWV, p = 0.001). There was no independent association between cfPWV and BMD. Adjusted heritability estimates of cfPWV and CP were 0.38 (95% confidence interval: 0.19 to 0.59) and 0.61 (95% confidence interval: 0.04 to 0.83), respectively. Shared genetic factors accounted for 92% of the observed correlation (0.38) between cfPWV and CP. Conclusions These results suggest that the association between increased arterial stiffness and the propensity of the arterial wall to calcify is explained by a common genetic etiology and is independent of noncalcified atheromatous plaque and independent of BMD.

Background: Pulse wave velocity (PWV) is independent predictor of cardiovascular outcomes. Antihypertensive treatment reduces PWV, but it is unknown whether this results from an unloading of stiffer elements in the arterial wall or a structural change in the wall. Methods: To distinguish between these effects we performed a systematic review and meta-regression analysis of effects of different drug classes and durations of antihypertensive treatment on the relationship between reduction in PWV and that in mean arterial pressure (MAP). We compared this to the variation in PWV during an acute modulation of aortic transmural pressure (TMP) by respiratory manoeuvres, simulating a change in MAP in patients with essential hypertension. Results: We identified 99 trials on 6,703 hypertensive individuals in total (average age and treatment duration were 56 ± 9.4 years and 21.6 ± 17.9 weeks, respectively). Reduction in PWV was strongly associated with that in MAP, PWV falling by 0.7 m/s per 10 mmHg fall in MAP (95% CI 0.5 – 0.86 m/s, p < 0.001). However, reduction in PWV was independent of drug class or duration of treatment. Change in PWV during respiratory manoeuvres was related to TMP with a similar relation to that observed in the meta-regression analysis: 0.94 m/s per 10 mmHg change in TMP (95% CI 0.34 – 1.54 m/s, p

Objectives: Patients with rheumatoid arthritis (RA) have increased cardiovascular mortality. Tumour necrosis factor α (TNFα)-blocking therapy has been shown to reduce RA disease activity measures and joint damage progression. Some observational studies suggest that TNFα blockade reduces mortality and incidence of first cardiovascular events. The mechanisms contributing to these outcomes are unclear. This study assessed the effects of infliximab treatment on vascular stiffness and structure in patients with RA. Methods: A post hoc analysis of longitudinal data from a randomised placebo controlled study evaluated the effect of infliximab on vascular assessments. 26 patients received intravenous infliximab (3 mg/kg) at weeks 0, 2, 6 and every 8 weeks thereafter to week 54. Patients were followed up to 56 weeks of infliximab therapy with assessments of RA disease activity, cardiovascular risk factors, vascular stiffness (pulse wave velocity (PWV)), carotid intima media thickness (CIMT) and carotid artery plaque (CAP). Univariate analyses of changes over time by repeated measures analysis of variance (ANOVA) were followed by multivariate time-series regression analysis (TSRA) if changes were seen. Results: PWV was significantly lower (better) after 56 weeks of treatment with infliximab (ANOVA p

Postprandial lipemia impairs endothelial function possibly via an oxidative stress mechanism. A stearic acid-rich triacylglycerol (TAG) (shea butter) results in a blunted postprandial increase in plasma TAG compared with an oleic acid-rich TAG; however, its acute effects on endothelial function and oxidative stress are unknown. A randomized crossover trial (n = 17 men) compared the effects of 50 g fat, rich in stearic acid [shea butter blend (SA)] or oleic acid [high oleic sunflower oil (HO)], on changes in endothelial function [brachial artery flow-mediated dilatation (FMD)], arterial tone [pulse wave analysis (PWA), and carotid-femoral pulse wave velocity (PWV(c-f))], and oxidative stress (plasma 8-isoprostane F2alpha) at fasting and 3 h following the test meals. The postprandial increase in plasma TAG was lower (66% lower incremental area under curve) following the SA meal [28.3 (9.7, 46.9)] than after the HO meal [83.4 (57.0, 109.8); P < 0.001] (geometric means with 95% CI, arbitary units). Following the HO meal, there was a decrease in FMD [-3.0% (-4.4, -1.6); P < 0.001] and an increase in plasma 8-isoprostane F2alpha [10.4ng/L (3.8, 16.9); P = 0.005] compared with fasting values, but no changes followed the SA meal. The changes in 8-isoprostane F2alpha and FMD differed between meals and were 14.0 ng/L (6.4, 21.6; P = 0.001) and 1.75% (0.10, 3.39; P = 0.02), respectively. The reductions in PWA and PWV c-f did not differ between meals. This study demonstrates that a stearic acid-rich fat attenuates the postprandial impairment in endothelial function compared with an oleic acid-rich fat and supports the hypothesis that postprandial lipemia impairs endothelial function via an increase in oxidative stress.

Arterial calcification leading to increased arterial stiffness, a powerful risk factor for cardiovascular disease, may underlie the association of osteoporosis with cardiovascular disease in postmenopausal women. Osteoprotegerin (OPG), an indirect inhibitor of osteoclastogenesis, may be involved in arterial calcification. We examined relationships between calcification of subclinical atherosclerotic plaque and arterial stiffness with bone mineral density (BMD) and OPG in a group of 54 postmenopausal women referred for routine osteoporosis screening by dual-energy X-ray absorptiometric scanning of the lumbar spine and hip. Presence of calcified and noncalcified plaque in carotid and femoral arteries was examined using ultrasonography. Pulse wave velocity (PWV), a measure of arterial stiffness, was determined by sequential tonometry over the carotid and femoral region. Fifty-nine percent of osteoporotic women had calcified (echogenic) plaque at one or more sites compared with 42% and 20% for women with osteopenia and normal BMD, respectively (P = 0.04). There was a significant negative correlation between PWV and hip BMD (r = -0.35, P = 0.01), which remained significant when age, mean arterial pressure, and serum lipids were taken into account (P = 0.05). No significant relationships were observed between serum concentrations of OPG and lumbar spine or total hip BMD or with the number of arterial sites with calcified or noncalcified plaque. However, there was a strong correlation between OPG and PWV (r = 0.44, P = 0.001), which remained significant when adjusted for age (P = 0.01). These findings suggest that decreased BMD is associated with arterial calcification and stiffening and raise the possibility that OPG is a marker of arterial stiffening, independent of any association with BMD.

Pulse wave velocity (PWV), the speed of propagation of arterial pressure waves through the arterial tree, is related to arterial stiffness and is an important prognostic marker for cardiovascular events. In clinical practice PWV is commonly determined by arterial tonometry, with a noninvasive pressure sensor applied sequentially over carotid and femoral arteries. The electrocardiogram (ECG) is used as a timing reference to determine the time delay or "transit time" between the upstroke of carotid and femoral pulse waveforms. Commercially available vascular ultrasound scanners provide a pulsed wave (PW) Doppler velocity signal, which should allow determination of carotid-femoral transit time and hence PWV. We compared carotid-femoral PWV measured by tonometry and by PW Doppler ultrasound (Seimens, Apsen scanner with 7 MHz linear transducer) in asymptomatic subjects (n = 62, 26 male, aged 21 to 72 y). To test for intra-subject and inter-observer variation, ten subjects were scanned by one observer on two occasions 2 wk apart and by two observers on same day. PWV by tonometry ranged from 5.3 to 15.0 m/s. There was no significant difference between mean values of PWV obtained by the two techniques (mean difference: 0.3 m/s, standard deviation of difference: 1.5 m/s), which were closely correlated (r = 0.83). The coefficient of variation for repeated measures on the same subject by the same observer was 10.1% and the inter-observer coefficient of variation was 5.8%. These results suggest a commercial ultrasound scanner can be used to measure PWV, giving results that are reproducible and closely correlated with those obtained by arterial tonometry. (E-mail: ben_yu.jiang@kcl.ac.uk).

Objective To overall evaluate the change of global cardiac systolic performance and diastolic filling in hypovoleamia by LBNP. Methods 10 healthy male subjects were placed in a standard LBNP chamber. Baseline haemodynamic and echocardiographic measure- ments were made after a period of least 10 min resting supine within the chamber. Pressure was then decreased to -10,-20 and -30 mmHg, with each pressure maintained for 15 min. The indices offour transvalvular and SVC flow were measured using Doppler echocardiography. Results The results showed that S wave, Re wave, and VTI of SVC progressively decreased with increasing LBNP. At -30 mmHg stage, S wave decreased by 35.4 %(change of 0.21+0.03 m/s, P P −1 at -30 mmHg LBNP, P P P P P Conclusion Doppler indices changes in different LBNP stage can roughly reflect the degree of hypovoleamia caused by blood volume redistribution. The indices of Doppler echocardiography are more sensitive than traditional physiological indexes in evaluating cardiovascular responses of LBNP. Echocardiography techniques overall can evaluate the global cardiac function including systolic performance and diastolic filling.

Objectives— The objective of this study was to examine determinants of excess coronary artery disease risk in UK South Asians, more prevalent in this population than UK Caucasians, by examining differences in risk factors, vascular function, and endothelial progenitor cells (EPCs). Methods and Results— 24 South Asian and 25 Caucasian healthy age-matched nonsmoking men were studied. Vascular function was assessed by flow-mediated and GTN brachial artery dilatation and blood flow responses to infusion of ACh, SNP, and L-NMMA. EPC number and function were measured by flow cytometry (CD34, CD133, and KDR positive cells), and CFU/migration assays. Traditional risk factors and anthropometric measurements were similar in the groups. South Asians had higher fasting insulin levels (6.01 versus 3.62 μU/mL; P =0.02). South Asians had lower FMD (6.9 versus 8.5%; P =0.003), L-NMMA response (0.8 versus 1.3 mL/min/100 mL; P =0.03), mean SNP response (9.5±0.6 versus 11.6±0.6; P =0.02), EPC number (0.046±0.005% versus 0.085±0.009%; P =< 0.001), and CFU ability (CFU 4.29±1.57 versus 18.86±4.00; P =0.005). EPC number was the strongest predictor of FMD. Ethnicity was the strongest predictor of EPC number. Conclusions— Healthy South Asian men are more insulin resistant, and demonstrate endothelial dysfunction and reduced EPC number and function compared with Caucasians. These abnormalities may contribute to their increased CAD risk.

Rheumatoid arthritis (RA) is associated with increased cardiovascular disease (CVD) risk that has been attributed to endothelial dysfunction and inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase (COX)-2 inhibitors have been shown in some studies to improve endothelial function in subjects without RA. The aim of this study was to investigate the effects of COX inhibition on endothelial function in patients with RA.Patients with RA (n = 37) were randomized to receive a 2-week course of either indomethacin (75 mg bd), rofecoxib (12.5 mg bd), or placebo in a double-blind study. Endothelial function was measured using flow-mediated dilation (FMD) of the brachial artery in response to reactive hyperaemia. Arterial stiffness was also assessed using pulse wave analysis (PWA) through the measurement of the aortic augmentation index (AIx). Measurements of vascular function and inflammatory markers were taken before and at the end of the treatment period.There were no significant differences in changes in FMD, AIx, blood pressure (BP), serum creatinine, erythrocyte sedimentation rate (ESR), or high-sensitivity C-reactive protein (hsCRP) between groups. However, compared with the other treatment groups, there was a tendency for systolic BP to decrease in the placebo group (p = 0.063) and for creatinine to increase in the indomethacin and rofecoxib groups after treatment (p = 0.054).This study suggests that COX inhibition by indomethacin or rofecoxib do not improve endothelial function in patients with RA.

Objective— Autopsy studies show that intimal lipid accumulations in arteries are often present at birth, suggesting that the prenatal environment plays a role in the pathogenesis of atherosclerosis. In animal models, a restricted or unbalanced maternal diet during gestation can influence susceptibility to atherosclerosis, but the relation in humans between maternal diet during pregnancy and atherogenesis is unknown. Methods and Results— We measured carotid intima–media thickness (IMT) in 216 nine-year-old children whose mothers had participated in a study of nutrition during pregnancy. IMT was greater in boys, in children who were heavier, in those with higher systolic blood pressure, and in those who took less exercise. Increased IMT was associated with a lower maternal energy intake in early ( P =0.029) or late ( P =0.006) pregnancy, after adjustment for these factors. Mean IMT of children whose mothers were in the lowest quarter of the distribution of energy intake in late pregnancy was 0.027 mm (95% confidence interval, 0.004 to 0.049) greater than that of those whose mothers were in the highest quarter of the distribution. Conclusion— Lower maternal energy intake during pregnancy may increase the susceptibility to atherogenesis of the child.

Background: Nitroglycerin (NTG) reduces cardiac pre-load and after-load through venodilation and arterial dilation respectively but the relative contributions of these effects to reduction in myocardial wall stress is unknown. Methods: We estimated myocardial wall stress from transthoracic echocardiographic imaging of the left ventricle (LV) and LV pressure estimated from carotid tonometry during systole. Nineteen subjects aged 43.3 ± 2.7 (mean ± SE) years were studied before and 7–12 min after NTG (400 ìg sublingually). Carotid pressure calibrated by mean and diastolic blood pressure (BP) was used to calculate time-varying LV wall stress from endocardial and epicardial volumes obtained from Tomtec wall tracking analysis. The relative contributions of reductions in systolic pressure and in LV volumes and to overall reduction in LV wall stress were calculated assuming that volume or pressures after NTG were identical to baseline values. Results: NTG decreased peak LV stress (pre: 387±22; post: 329±22kdynes/cm2, P

Purpose/ background/ objectives: People with or at risk of Type II diabetes (T2DM) are at increased risk of vascular disease and arterial stiffness (AS). We hypothesized that spironolactone and dietary nitrate (beetroot juice) separately and together would reduce AS, measured as cardiac-ankle vascular index (CAVI Fukuda Denshi, Japan mainly BP-independent) or aortic pulse wave velocity (PWV). Methods: 126 (60% T2DM) were randomized, double-blind to spironolactone (≤50mg) or doxazosin (control ≤16mg) and active/ placebo juice (≤9/0mmol) daily. AS and echocardiographic measures (on a subgroup) were performed. Intention-to-treat analysis adjusted for between-group blood pressure (BP) change over time was performed using SAS. Results: Change in (Δ)BP was not different between spironolactone and doxazosin (mean -6.7mmHg), nor between the juices. ΔCAVI was marginally reduced on doxazosin compared to spironolactone (−0.11[−0.30,0.08] vs. 0.14[−0.06,0.34] units, p=0.080) but more for aortic PWV (−0.44 [−0.69,−0.20] vs. −0.07 [−0.32,0.18]ms−2, p=0.04). Dietary nitrate had no impact, but did rise in plasma. Spironolactone improved Δrelative wall thickness vs. doxazosin (0.01[−0.02,−0.0], p

Introduction: Myocardial wall stress (MWS) is thought to be the mechanical stimulus to ventricular hypertrophy (1,2). The objective of this study was to examine the effect of exercise on time-varying MWS (3). Methods: Twelve subjects, aged 42.0 ± 16.8 (mean ± SD) years, systolic blood pressure (BP) (128 ± 11mmHg), were studied before and during peak bicycle exercise (85% of target heart rate). We estimated MWS from 3D transthoracic echocardiographic imaging of the left ventricle (LV) and LV pressure was derived from carotid tonometry during systole. Carotid pressure calibrated by mean and diastolic BP was used to calculate time-varying LV wall stress from endocardial and epicardial volumes obtained from Philips 3DQ analysis package. Time of onset relaxation (TOR) was defined as percentage of time to peak wall stress to ejection duration. Results: There was a significant reduction in peak and mean MWS during exercise (rest 435.3±25.3 VS exercise 385.9±22.5, p=0.001 and 387.3±24.2 VS 368.7±19.6 kdynes/cm2, p=0.016), despite significant increase in systolic BP (128±3 VS 210±6 mmHg, p

Arterial tone in muscular conduit arteries may influence pressure wave reflection through changes in diameter and pulse wave velocity. We examined the relative specificity of vasodilator drugs for radial artery and forearm resistance vessels during intrabrachial arterial infusion. The nitric oxide (NO) donors, nitroglycerine and nitroprusside, and brain natriuretic peptide were compared with the α-adrenergic antagonist phentolamine, calcium-channel antagonist verapamil, and hydralazine. Radial artery diameter was measured by high resolution ultrasound, forearm blood flow by strain gauge plethysmography, and pulse wave velocity by pressure recording cuffs placed over the distal brachial and radial arteries. Norepinephrine was used to constrict the radial artery to generate a greater range of vasodilator tone when examining pulse wave velocity. Despite dilating resistance vasculature, phentolamine and verapamil had little effect on radial artery diameter (mean dilation R =−0.89, P

Although a high intake of some flavonoid subclasses may reduce cardiovascular disease mortality, data regarding the in vivo mechanisms of action are limited.We examined associations between habitual flavonoid intakes and direct measures of arterial stiffness, central blood pressure, and atherosclerosis.In a cross-sectional study of 1898 women aged 18-75 y from the TwinsUK registry, intakes of total flavonoids and their subclasses (flavanones, anthocyanins, flavan-3-ols, polymers, flavonols, and flavones) were calculated from validated food-frequency questionnaires by using an updated and extended USDA database. Direct measures of arterial stiffness and atherosclerosis included central systolic blood pressure (cSBP), central diastolic blood pressure, mean arterial pressure (MAP), augmentation index, pulse wave velocity (PWV), and intima-media thickness.In multivariate analyses, a higher anthocyanin intake was associated with significantly lower cSBP (mean ± SE: -3.0 ± 1.4 mm Hg for quintile 5 compared with quintile 1; P-trend = 0.02), MAP (-2.3 ± 1.2 mm Hg for quintile 5 compared with quintile 1; P-trend = 0.04), and PWV (-0.4 ± 0.2 m/s for quintile 5 compared with quintile 1; P-trend = 0.04), whereas a higher flavone intake was associated with a lower PWV (-0.4 ± 0.2 m/s for quintile 5 compared with quintile 1; P-trend = 0.04). Although a higher wine and berry intake was associated with a lower PWV, no associations were observed for total and other flavonoid subclasses.These data, which include direct measures of arterial stiffness and thickness, suggest that higher intake of anthocyanins and flavones are inversely associated with lower arterial stiffness. The intakes of anthocyanins associated with these findings could be incorporated into the diet by the consumption of 1-2 portions of berries daily and are, therefore, relevant for public health strategies to reduce cardiovascular disease risk.

Background: Within the general population, levels of C-reactive protein (CRP) are positively associated with atherosclerotic cardiovascular disease (CVD). Whether CRP is causally implicated in atherogenesis or is the results of atherosclerosis is disputed. A role of CRP to protect endothelium-derived nitric oxide (EDNO) has been suggested. We examined the association of CRP with EDNO-dependent vasomotor function and subclinical measures of atherosclerosis and arteriosclerosis in patients with raised CRP resulting from rheumatoid arthritis (RA).Methodology/Principal Findings: Patients with RA (n = 59) and healthy control subjects (n = 123), underwent measures of high sensitivity CRP, flow-mediated dilation (FMD, dependent on EDNO), intima-media thickness (IMT, a measure of subclinical atherosclerosis) and aortic pulse wave velocity (PWV, a measure of arteriosclerosis). IMT and PWV were elevated in patients with RA compared to controls but FMD was similar in the two groups. In patients with RA, IMT and PWV were not correlated with CRP but FMD was positively independently correlated with CRP (P

Background— Nitric oxide (NO)–mediated local regulation of vascular tone is considered to involve endothelial NO synthase (eNOS). However, we recently reported that human forearm basal microvascular tone in vivo is tonically regulated by neuronal NO synthase (nNOS), in contrast to an acetylcholine-stimulated reduction in tone, which is eNOS dependent. Here, we investigated the in vivo effects of an nNOS-selective inhibitor, S-methyl- l -thiocitrulline (SMTC), on the human coronary circulation and on flow-mediated dilatation in the forearm. Methods and Results— In patients with angiographically normal coronary arteries, intracoronary infusion of SMTC (0.625 μmol/min) reduced basal coronary blood flow by 34.1±5.2% (n=10; P P =0.02) but had no effect on increases in flow evoked by intracoronary substance P (20 pmol/min). The nonselective NOS inhibitor N G -monomethyl- l -arginine (25 μmol/min) also reduced basal coronary flow (by 22.3±5.3%; n=8; P P P =0.03) but did not affect flow-mediated dilatation ( P =0.55). In contrast, N G -monomethyl- l -arginine (2 μmol/min) infusion reduced radial blood flow to a similar degree (by 39.7±11.8%; P =0.02) but also inhibited flow-mediated dilatation by ≈80% ( P Conclusions— These data indicate that local nNOS-derived NO regulates basal blood flow in the human coronary vascular bed, whereas substance P–stimulated vasodilatation is eNOS mediated. Thus, nNOS and eNOS have distinct local roles in the physiological regulation of human coronary vascular tone in vivo.

To assess the reproducibility of the digital pulse wave response to beta(2)-adrenoreceptor stimulation and to determine if an attenuated response to beta(2)-adrenoceptor stimulation is associated with impaired flow mediated dilatation (FMD).Subjects (n = 20) with endothelial dysfunction (ED), were compared with healthy control subjects (n = 20). Change in reflection index (Delta RI) of the digital volume pulse in response to salbutamol (SALB, 5 microg min(-1) i.v) and to nitroglycerin (NTG, 5 microg min(-1) i.v) was used to assess endothelium-dependent (Delta RI(SALB)) and endothelium-independent (Delta RI(NTG)) pressure wave reflection. Delta RI(SALB) was assessed on two occasions to examine reproducibility. High resolution ultrasound of the brachial artery was used to measure FMD and also dilation to NTG (NTGD).The mean difference in Delta RI(SALB) between two visits was -0.2%, with SD of the difference 4.9%. Both Delta RI(SALB) and FMD were impaired in subjects with ED compared with values in control subjects (5.0 +/- 0.7 vs. 11.3 +/- 1.2%, mean values +/- SEM, P0.01 and 4.2 +/- 0.6 vs. 7.5 +/- 0.8%, P0.02 for Delta RI(SALB) and FMD, respectively), whereas Delta RI(NTG) and NTGD were similar in the two groups. Delta RI(SALB) was correlated with FMD (r = 0.44, P0.01) and had 88% sensitivity and 79% specificity to detect abnormal (FMD4%).The pulse wave response to a beta(2)-adrenoceptor agonist correlates with FMD and has high sensitivity and specificity in detecting abnormal endothelial function as defined by FMD. However, FMD is the preferred test to detect effects of interventions on endothelial function.

Black Africans have a higher incidence of cardiovascular disease than white Europeans. We explored potential mechanisms of this excess risk by assessing endothelium function, inflammatory status (C-reactive protein), oxidative stress (isoprostane-F2α), and plasma asymmetrical dimethyl arginine (ADMA; an endogenous competitive inhibitor of NO synthase) in each ethnic group. Thirty healthy black Africans and 28 well-matched white European male subjects were studied (mean age±SE: 32.2±0.9 and 29.2±1.2 years, respectively; P =0.07). High-resolution ultrasound was used to assess vascular function in the brachial artery by measuring flow mediated dilatation ([percentage of change]; endothelium-dependent function) and glyceryltrinitrate dilatation ([percentage of change]; endothelium-independent function). Blood pressure, fasting lipids, glucose, and estimated glomerular filtration rate levels were similar in both groups. There was no difference in C-reactive protein (black Africans: 0.8±0.1 mg/L; white Europeans: 0.6±0.1 mg/L; P =0.22), isoprostane-F2α (black Africans: 42.9±1.5 pg/mL; white Europeans: 39.2±1.5 pg/mL; P =0.23), and leptin (black Africans: 64.1±10.2 ng/mL; white Europeans: 47.8±9.8 ng/mL; P =0.37) levels between the 2 ethnic groups. However, compared with white Europeans, plasma ADMA levels were significantly higher in black Africans (0.34±0.02 μmol/L and 0.25±0.03 μmol/L; P =0.03). There was no difference in the percentage of glyceryltrinitrate dilatation ( P =0.7), but the percentage of flow-mediated dilatation was significantly lower in black Africans (black Africans: 5.2±0.3; white Europeans: 6.3±0.4; P =0.02). In a stepwise multiple regression model, ADMA level was the only independent determinant of flow-mediated dilatation ( P =0.02). In turn, race was the only independent determinant of ADMA levels ( P =0.03). Our findings indicate that circulating ADMA levels are significantly higher in healthy black African males than in white European males. This may contribute to the lower NO bioavailability and higher incidence of cardiovascular disease seen in black Africans.

ObjectivesExposure to intravascular microbubbles after diving and during medical procedures alters endothelial function. The aim of this study was to investigate whether a patent foramen ovale altered forearm endothelial function by facilitating microbubbles transfer.DesignPatients attended on two separate visits, at least seven days apart receiving agitated saline or no active intervention in random order. On both days, flow-mediated dilatation of the brachial artery was measured using vascular ultrasound. On the intervention visit, agitated saline was injected and the passage of microbubbles into the arterial circulation was confirmed by echocardiography. Serial flow-mediated dilatation measurements were made after agitated saline and at the same time points after no intervention.SettingSt Thomas’ Hospital in London.ParticipantsPatients with a patent foramen ovale (PFO+n = 14, 9 male, mean ± SD age 42.2 ± 10.5 years) and patients without a patent foramen ovale (PFO− n = 10, 7 male, mean ± SD age 49.4 ± 18.4 years) were recruited.Main outcome measuresChange in brachial artery flow-mediated dilatation.ResultsIn patent foramen ovale + patients, flow-mediated dilatation did not change significantly on the control day but after agitated saline reduced by 2.3 ± 0.3%, 20 minutes after bubble injection ( P ConclusionThese results suggest that the presence of a patent foramen ovale facilitated impairment of endothelial function acutely by the transfer of microbubbles into the arterial circulation. As a patent foramen ovale is a common condition, this may be relevant to microbubbles exposure in medical procedures and in decompression illness.

Introduction: Nitroglycerin (NTG) has a particularly marked action to reduce augmentation pressure (cAP), attributed to a reduction in timing or amplitude of pressure wave reflection. However, a recent study suggests that cAP is determined in large part by ventricular contraction/relaxation dynamics. We examined whether the reduction in cAP induced by NTG is associated with a change in left ventricular (LV) systolic function. Methods: We estimated myocardial wall stress from transthoracic echocardiographic imaging of the LV and LV pressure estimated from carotid tonometry during systole. Eighteen subjects aged 43.0±11.9 (mean ± SD) years were studied before and 7-12 min after NTG (400 μg sublingually). Carotid pressure calibrated by mean and diastolic blood pressure was used to calculate time-varying LV wall stress from endocardial and epicardial volumes obtained from wall tracking analysis. Tissue Doppler Imaging (TDI) S wave (a measure of LV systolic function) was measured at the basal mitral annulus from an echocardiographic 4-chamber view. Results: NTG decreased cAP from 16.3±3.6 to 4.5±2.9mmHg (means±SEM, P

OBJECTIVE Exercise blood pressure is elevated in conditions associated with endothelial dysfunction. To determine whether this is a causal association, we examined the effects of endothelial dysfunction induced by methionine loading, on exercise blood pressure. DESIGN Healthy subjects (18-63 years) participated in randomized, double-blind, cross-over studies receiving methionine and placebo on separate occasions before exercise. METHODS In study 1 (n = 32), subjects received placebo and methionine 100 mg/kg 4 h before exercise and, in study 2 (n = 11), placebo and methionine 200 mg/kg (given as 100 mg 20 and 12 h before exercise). A further study confirmed that methionine 100 mg/kg impaired brachial artery flow-mediated dilation. Blood pressure was measured by mercury sphygmomanometry at rest and during low workload bicycle ergometry. RESULTS Plasma homocysteine increased after methionine compared to placebo (22.5 +/- 1.2 versus 7.7 +/- 0.7 mumol/l in study 1, and 50.2 +/- 7.6 versus 12.8 +/- 0.7 mumol/l in study 2, means +/- SE, each P < 0.0001). In both studies resting systolic and diastolic blood pressures and the increases in systolic blood pressure during exercise were similar after methionine and placebo. By contrast, exercise diastolic blood pressure responses (measured as the change from resting values) increased more after methionine than after placebo. In study 1, diastolic blood pressure responses increased relative to placebo by 3.5 +/- 1.0, 3.7 +/- 1.0 and 2.4 +/- 1.0 mmHg at 50, 75 and 100 W, respectively (P < 0.01). In study 2, diastolic blood pressure responses increased by 4.9 +/- 1.0, 5.4 +/- 2.1 and 6.1 +/- 1.1 mmHg at 50, 75 and 100 W, respectively (P < 0.001). CONCLUSION Endothelial dysfunction produced by methionine loading is associated with an increased exercise diastolic blood pressure response.

OBJECTIVE. Epidemiologic studies have shown associations between impaired fetal growth and risk for coronary heart disease in adults. The underlying mechanisms are unknown. We investigated whether restricted intrauterine growth affects cardiac structure. METHODS. We performed echocardiography on 216 9-year-old children who were measured previously at birth. The diameter of the coronary left and right main branches was derived from the widest dimension; total coronary artery diameter was calculated by adding the diameters of the left and right coronary arteries. Aortic root diameter, left atrial diameter, left ventricular diameter, left ventricular outflow tract diameter, and left ventricular mass were measured. RESULTS. On average, children who had weighed less at birth had a smaller total coronary artery diameter, aortic root diameter, and left ventricular outflow tract diameter after adjustment for gender, gestational age, current height and weight, and maternal height and prepregnant weight. For each SD increase in birth weight, total coronary diameter rose by 0.10 mm, log aortic root diameter rose by 1.5%, and log left ventricular outflow tract diameter rose by 1.6%. CONCLUSION. Impaired fetal growth may have long-term effects on cardiac structure. This may help to explain why adults whose birth weight was low are at greater risk for coronary heart disease.

Background. Organic nitrates (e.g. nitroglycerin) are highly selective dilators of muscular conduit arteries. By contrast, the endogenous inorganic nitrite anion (NO2−) is thought to be a hypoxia-dependent dilator of small resistance arterioles, via its reduction to vasodilating nitric oxide (NO) by deoxyhaemoglobin. Objective. To establish selectivity of nitrite for resistance versus conduit arteries. Methods and Results A series of forearm blood flow (FABF) studies were performed in healthy volunteers. Intra-brachial sodium nitrite (8.7 μmol/min) markedly increased radial artery diameter (assessed using ultrasound) by 37.6 ± 9.7% (P < 0.001), with HbO2 ∼99%. Furthermore, nitrite (0.087–87 μmol/min) displayed similar selectivity as nitroglycerin (0.003–1 μg/min) for conduit arteries, compared to resistance arterioles (FABF). Intravenous administration of sodium nitrite (8.7 μmol/min) dilated the contralateral radial artery by 10.7 ± 1.8% (P < 0.01) and lowered central systolic blood pressure (BP) by ~12mmHg from 98.3 ± 12.3 to 86.7 ± 15.1 mmHg (P = 0.02) without any change in peripheral BP; nitrite also reduced augmentation index and pulse wave velocity. In contrast to nitrite’s effects on FABF, induction of hypoxia (breathing 12% O2) paradoxically inhibited nitrite-induced dilatation of the radial artery to a similar extent as hyperoxia/ breathing 100% O2 (both P < 0.001 compared to normoxia). Conclusions. Contrary to expectation, inorganic nitrite is a normoxia-dependent selective conduit artery dilator with similar selectivity to nitroglycerin. A specific advantage of nitrite is that it lacks the problems of development of tolerance and endothelial dysfunction, which limit the efficacy of organic nitrates. The selective central BP-lowering effects of nitrite have therapeutic potential to reduce cardiovascular events.

To what degree elevated pulsatile components of blood pressure arise from a primary interaction of ventricular contraction with the impedance of the arterial tree or from more complex phenomena involving backward wave travel in the arterial tree is unknown. We used wave intensity analysis to explore the haemodynamic basis for elevated pulsatile components of blood pressure in 20 hypertensive subjects (47.4± 13.4 years, 158.5±27.7/98.7±14.2 mmHg, means ± SD) compared to 20 normotensive controls (52.2±12.3 years, 108.7±12.2/71.8±7.7 mmHg, means ± SD). Secondly we used dobutamine and norepinephrine as inodilators and vasoconstrictors in normotensive subjects to examine the contributions of ventricular contractility and peripheral vasoconstriction to waves disproportionately elevated in hypertensive compared to normotensive subjects. An elevated central pulse pressure in hypertensive subjects was accounted primarily by the forward wave component (50.4±3.4 vs 35.2±1.8 mmHg, P < 0.001) but the backward wave also contributed significantly (8.9±1.7 vs 1.6±0.4 mmHg, P < 0.002) and was a particularly important component of augmentation pressure (13.5±3.6 vs 0.3±0.6 mmHg, P < 0.01). The forward component arose from the primary forward compression wave (FCW) and the backward component from a backward compression wave (BCW). The BCW/FCW intensity was greater in hypertensive compared to normotensive subjects and in normotensive subjects could be increased by norepinephrine but not by dobutamine. Increased pulse pressure in hypertension results primarily from the FCW but the BCW provides a significant contribution to pulse pressure components particularly augmentation pressure.

Our aim was to examine the relative contributions of the first systolic shoulder (P1) and augmentation pressure (DeltaP(aug)) to central pulse pressure (cPP), their relation to central arterial stiffness (pulse wave velocity [PWV]) and arterial diameters, and their respective heritability estimates.cPP is augmented above P1 by DeltaP(aug) due to pressure waves reflected from the periphery of the circulation.Women (n = 496) from the Twins UK adult twin registry (112 monozygotic, 135 dizygotic pairs) age 21 to 81 years were studied. cPP, P1, and DeltaP(aug) were estimated using the SphygmoCor system (Atcor, West Ryde, Australia) from transformed radial waveforms. Carotid-femoral PWV was measured using the same system. Aortic and femoral artery diameters were measured by ultrasonography. Heritability was estimated using structural equation modeling.P1 and DeltaP(aug) accounted for 22% and 76%, respectively, of the variance in cPP. After adjustment for mean arterial pressure and heart rate, P1 strongly independently positively correlated with PWV (standardized regression coefficient, beta = 0.4, p0.0001), whereas DeltaP(aug) did not independently correlate with PWV but independently negatively correlated with the ratio of the diameter of the femoral to that of the abdominal aorta (beta = -0.12, p0.001). Estimates of heritability (h(2)) of cPP, PWV, P1, and DeltaP(aug) were 0.43, 0.34, 0.31, and 0.62, respectively, after adjustment for mean arterial pressure and heart rate.These results suggest that, in women, DeltaP(aug) is highly heritable, is associated with the ratio of distal to proximal arterial diameters, and, independent of PWV, is a major determinant of cPP.