Arterial stiffening is a heritable trait associated with arterial dilation but not wall thickening: a longitudinal study in the twins UK cohort.

Aims: Vascular 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 results: Carotid-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. Conclusion: Arterial 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.

Relation of arterial stiffness to left ventricular structure and function in healthy women.

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 <  0.05), but bore no relation to global longitudinal strain. After adjustment for age, body mass index, blood pressure and heart rate, cf-PWV was significantly correlated with RWT, global circumferential strain, apical rotation and LV twist (ß = 0.011, - 0.484, 1.167 and 1.089, respectively, each p ≤  0.05). CONCLUSIONS: In healthy women with a low burden of risk factors, elevated arterial stiffness was intimately interwoven with increased LV twisting even before LV dysfunction becomes clinically evident.

Paradoxical normoxia-dependent selective actions of inorganic nitrite in human muscular conduit arteries and related selective actions on central blood pressures.

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<0.001). Nitrite (0.087-87 µmol/min) displayed conduit artery selectivity similar to that of glyceryl trinitrate (0.013-4.4 nmol/min) over resistance arterioles. Nitrite dose-dependently increased local cGMP production at the dose of 2.6 µmol/min by 1.1 pmol·min(-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<0.0001, and P=0.0006, respectively) but was inhibited under hypoxia (P<0.0001) and hyperoxia (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.

Endothelial function does not relate to haemoglobin or serum erythropoietin concentrations and these do not explain the gender difference in endothelial function in healthy middle-aged men and women.

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 < 0·001). However, in a multivariable model, incorporating sex and other confounding factors, FMD was independently negatively correlated only with age, male sex and systolic blood pressure: standardized regression coefficients -0·21 (P < 0·01), -0·17 (P < 0·05) and -0·20 (P < 0·05) respectively and not with [Hb]. Similarly, when the analysis was restricted to men or to postmenopausal women, there was no significant relationship between FMD and Hb. There was no significant correlation between FMD and EPO on either univariate analysis in the whole group, in each sex, or in multivariate analysis. CONCLUSION: These results suggest that in healthy middle-aged subjects, FMD is not influenced by [Hb] or EPO and these do not contribute to the gender difference in FMD.

Effects of neuronal nitric oxide synthase on human coronary artery diameter and blood flow in vivo.

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 micromol/min) reduced basal coronary blood flow by 34.1+/-5.2% (n=10; P<0.01) and epicardial coronary diameter by 3.6+/-1.2% (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 micromol/min) also reduced basal coronary flow (by 22.3+/-5.3%; n=8; P<0.01) but, in contrast to SMTC, inhibited substance P-induced increases in flow (P<0.01). In healthy volunteers, local infusion of SMTC (0.2 micromol/min) reduced radial artery blood flow by 36.0+/-6.4% (n=10; P=0.03) but did not affect flow-mediated dilatation (P=0.55). In contrast, N(G)-monomethyl-L-arginine (2 micromol/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 approximately 80% (P<0.01). 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.

Effects of Inhibition of Nitric Oxide Synthase on Muscular Arteries During Exercise: Nitric Oxide Does Not Contribute to Vasodilation During Exercise or in Recovery.

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 NG-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<0.01), increased peripheral vascular resistance (by 7.0±1.4 mmHg per L/min, P<0.001), mean arterial blood pressure (by 8.9±3.5 mmHg, P<0.05), and blunted an increase in femoral artery diameter that occurred immediately before exercise (change in diameter: 0.14±0.04 versus 0.32±0.06 mm after l-NMMA and placebo, P<0.01). During/after exercise 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.

Hemodynamic Mechanism of the Age-Related Increase in Pulse Pressure in Women.

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 <40 years to 44.2±13.8 mm Hg in those >70 years (means±SD; P<0.001), an increase explained almost entirely by the concomitant increase in aortic pulse wave velocity. Pulse pressure, at the second pressure peak ( P2, usually equal to peak central pulse pressure) increased to a greater extent with age: from 29.1±7.8 mm Hg for those <40 years to 60.2±20.5 mm Hg for those >70 years ( P<0.001). The ratio of 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<0.001) in parallel with an age-related increase in stroke volume and body mass index. These results suggest that the age-related change in central pulse wave morphology is driven mainly by an increase in arterial stiffening and altered pattern of ventricular ejection.

Impaired postprandial endothelial function depends on the type of fat consumed by healthy men.

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.

Assessment of endothelial function: comparison of the pulse wave response to beta 2-adrenoceptor stimulation with flow mediated dilatation.

AIMS: 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). METHODS: 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). RESULTS: 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, P < 0.01 and 4.2 +/- 0.6 vs. 7.5 +/- 0.8%, P < 0.02 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, P < 0.01) and had 88% sensitivity and 79% specificity to detect abnormal (FMD < 4%). CONCLUSIONS: 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.

Vascular dysfunction and reduced circulating endothelial progenitor cells in young healthy UK South Asian men.

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 microU/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.

Measurement of pulse wave velocity using pulse wave Doppler ultrasound: comparison with arterial tonometry.

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).

Maternal diet during pregnancy and carotid intima-media thickness in children.

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. CONCLUSIONS: Lower maternal energy intake during pregnancy may increase the susceptibility to atherogenesis of the child.

Blood Pressure in Healthy Humans Is Regulated by Neuronal NO Synthase.

NO is physiologically generated by endothelial and neuronal NO synthase (nNOS) isoforms. Although nNOS was first identified in brain, it is expressed in other tissues, including perivascular nerves, cardiac and skeletal muscle. Increasing experimental evidence suggests that nNOS has important effects on cardiovascular function, but its composite effects on systemic hemodynamics in humans are unknown. We undertook the first human study to assess the physiological effects of systemic nNOS inhibition on basal hemodynamics. Seventeen healthy normotensive men aged 24±4 years received acute intravenous infusions of an nNOS-selective inhibitor, S-methyl-l-thiocitrulline, and placebo on separate occasions. An initial dose-escalation study showed that S-methyl-l-thiocitrulline (0.1-3.0 µmol/kg) induced dose-dependent changes in systemic hemodynamics. The highest dose of S-methyl-l-thiocitrulline (3.0 µmol/kg over 10 minutes) significantly increased systemic vascular resistance (+42±6%) and diastolic blood pressure (67±1 to 77±3 mm Hg) when compared with placebo (both P<0.01). There were significant decreases in heart rate (60±4 to 51±3 bpm; P<0.01) and left ventricular stroke volume (59±6 to 51±6 mL; P<0.01) but ejection fraction was unaltered. S-methyl-l-thiocitrulline had no effect on radial artery flow-mediated dilatation, an index of endothelial NOS activity. These results suggest that nNOS-derived NO has an important role in the physiological regulation of basal systemic vascular resistance and blood pressure in healthy humans.

[Digital pulse wave analyzing method in evaluating arterial compliance based on population study in Chinese 415 adults].

OBJECTIVE: To explore the reliability and validity of digital pulse wave analyzing method in evaluating arterial compliance in population-based study. METHODS: All 415 adults (132 men and 283 women) aged 20 to 86 years old were selected from urban (220 persons) and rural (195 persons) areas, respectively by a stratified randomly sampling method. Arterial compliance, evaluated by stiffness index (SI), was measured by using digital pulse wave analyzing method from the Pulse trace machine (Micro medical, London), and the SI value was determined accordingly. RESULTS: In the study on both repeatability and stability, there was a perfect correlation between the frequent measurements for one individual either on one occasion or on two 40-days-apart occasions. The SI values were not significantly different between the urban and the rural, men and women. Multiple stepwise regressions showed that systolic blood pressure and age were positively correlated with SI value, respectively (both P values were less than 0.001). The correlation kept unchanged after taking account of gender, BMI and heart rate. The mean SI values for people aged 20 to 29, 30 to 39, 40 to 49, 50 to 59 and > or = 60 were 7.35, 8.84, 10.41, 10.95 and 12.01 m/s (P < 0.01), respectively. CONCLUSIONS: Both systolic blood pressure and age should be contributed as the main influencing factors of arterial compliance. Digital pulse wave analyzing method is a preferable measurement in evaluating arterial compliance in population-based study due to its better repeatability and stability.

Association of Cross-Sectional and Longitudinal Change in Arterial Stiffness With Gene Expression in the Twins UK Cohort.

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 (ß=0.19, P=0.008) and collagen type IV α 1 (ß=0.32, P<0.0001). Gene transcripts most closely related to change in carotid distensibility during the follow-up period were endothelial nitric oxide synthase (ß=-0.20, P=0.005), angiotensin-converting enzyme (ß=-0.15, P=0.035), and B-cell CLL/lymphoma11B (ß=0.18, P=0.010). Expression levels of angiotensin-converting enzyme also related to progression in carotid diameter (ß=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.

Microbubbles shunting via a patent foramen ovale impair endothelial function.

OBJECTIVES: Exposure 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. DESIGN: Patients 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. SETTING: St Thomas' Hospital in London. PARTICIPANTS: Patients 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 MEASURES: Change in brachial artery flow-mediated dilatation. RESULTS: In 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 < 0.005 vs. corresponding change in flow-mediated dilatation during control study). There was no significant change in flow-mediated dilatation for patent foramen ovale- patients at either visit. CONCLUSION: These 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.

Dominance of the forward compression wave in determining pulsatile components of blood pressure: similarities between inotropic stimulation and essential hypertension.

Pulsatile components of blood pressure may arise from forward (ventricular generated) or backward wave travel in the arterial tree. The objective of this study was to determine the relative contributions of forward and backward waves to pulsatility. We used wave intensity and wave separation analysis to determine pulsatile components of blood pressure during inotropic and vasopressor stimulation by dobutamine and norepinephrine in normotensive subjects and compared pulse pressure components in hypertensive (mean±SD, 48.8±11.3 years; 165±26.6/99±14.2 mm Hg) and normotensive subjects (52.2±12.6 years; 120±14.2/71±8.2 mm Hg). Dobutamine (7.5 µg/kg per minute) increased the forward compression wave generated by the ventricle and increased pulse pressure from 36.8±3.7 to 59.0±3.4 mm Hg (mean±SE) but had no significant effect on mean arterial pressure or the midsystolic backward compression wave. By contrast, norepinephrine (50 ng/kg per minute) had no significant effect on the forward compression wave but increased the midsystolic backward compression wave. Despite this increase in the backward compression wave, and an increase in mean arterial pressure, norepinephrine increased central pulse pressure less than dobutamine (increases of 22.1±3.8 and 7.2±2.8 mm Hg for dobutamine and norepinephrine, respectively; P<0.02). An elevated forward wave component (mean±SE, 50.4±3.4 versus 35.2±1.8 mm Hg, in hypertensive and normotensive subjects, respectively; P<0.001) accounted for approximately two thirds of the total difference in central pulse pressures between hypertensive and normotensive subjects. Increased central pulse pressure during inotropic stimulation and in essential hypertension results primarily from the forward compression wave.

Cardiovascular remodeling relates to elevated childhood blood pressure: Beijing Blood Pressure Cohort Study.

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 6-18 years old were followed over 24 years 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 6-11 years, and 1.6 (1.1-2.4) in middle adulthood for those aged 12-18 years. CONCLUSIONS: Children with elevated BP from 6 years old have accelerated remodeling on both cardiac and arterial system in early or middle adulthood.

Progression of central pulse pressure over 1 decade of aging and its reversal by nitroglycerin a twin study.

OBJECTIVES: The goal of this study was to examine the progression of central arterial pulse pressure (cPP) in women and the degree to which this can be reversed by nitrovasodilation. BACKGROUND: cPP can be partitioned into height of the first systolic shoulder (P1), generated by a forward pressure wave and related to arterial stiffness, and augmentation pressure (AP), thought to be influenced by pressure wave reflection from muscular arteries and/or aortic reservoir. METHODS: Using a longitudinal cohort design, cPP, P1, and AP were estimated (using the SphygmoCor System [AtCor Medical Pty Ltd., West Ryde, Australia]) in 411 female twins over a mean follow-up of 10.8 years. In a subsample (n = 42), cPP, arterial stiffness (using pulse wave velocity [PWV]) and arterial diameters (using ultrasonography) were measured before and after nitroglycerin administration (400 µg s/l). RESULTS: cPP increased more than peripheral pulse pressure (10.3 and 9.2 mm Hg, respectively; p < 0.0001). In women <60 years of age at follow-up, AP contributed more to the increase in cPP than did P1 (increases of 6.5 ± 6.4 mm Hg and 4.2 ± 7.8 mm Hg, respectively). P1 was significantly positively correlated to PWV (p < 0.0001); AP was correlated to aorto-femoral tapering (p < 0.0001) but not PWV. Nitroglycerin reduced cPP by 10.0 ± 6.0 mm Hg (p < 0.0001), equivalent to a decade of aging. The reduction in cPP was entirely explained by a decrease in AP, with no significant change in P1 or PWV but an increase in large artery diameters of 4% to 18% (p < 0.0001). CONCLUSIONS: Age-related widening of cPP is driven in large part by an increase in AP, which can be reversed by selective dilation of muscular arteries, independent of PWV.

Regulation of vascular tone and pulse wave velocity in human muscular conduit arteries: selective effects of nitric oxide donors to dilate muscular arteries relative to resistance vessels.

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 <9%). By contrast, for comparable actions on resistance vessels, nitroglycerine and nitroprusside but not brain natriuretic peptide had powerful actions to dilate the radial artery (dilations of 31.3 ± 3.6%, 23.6 ± 3.1%, and 9.8 ± 2.0% for nitroglycerine, nitroprusside, and brain natriuretic peptide, respectively). Changes in pulse wave velocity followed those in arterial diameter irrespective of the signaling pathway used to modulate arterial tone (R=-0.89, P<0.05). Basal tone in human muscular arteries is relatively unaffected by α-adrenergic or calcium-channel blockade, but is functionally or directly antagonized by NO donors. The differential response to NO donors suggests that there is potential to manipulate the downstream pathway to confer greater specificity for large arteries with a resultant decrease in pressure wave reflection and systolic blood pressure.