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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

Abstract 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: 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

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

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

Backward traveling waves, an important determinant of central haemodynamics, are usually regarded as being due to reflections from discontinuities in the arterial tree. However, consideration of a single tube model of the arterial with a single site of reflection shows that a backward pressure wave may be generated by elastic recoil of large arteries, in which case the magnitude of the backward wave is proportional to that of the forward wave. A 55-segment 1-D model of the arterial which allows reflection as a continuum along the arterial tree and, for a given prescribed aortic flow, generates physiological aortic pulse waveforms was used to examine the relation of the backward to forward pressure waves in 4107 “virtual subjects” with arterial parameters spanning the physiological range. Backward pressure wave was closely correlated with the forward wave (R = 0.931, P < 0.001). Clinical data was obtained by carotid tonometry and aortic Doppler sonography during modulation of cardiovascular function in healthy volunteers (n = 13, age 46.5 ± 10.1 years with inotropic, vasopressor and vasodilator drugs (dobutamine, norepinephrine phentolamine and nitroglycerin). The magnitude of backward pressure was highly correlated with forward pressure over a range 5–15 mmHg (R = 0.824, P < 0.001) with a constant ratio of backward to forward wave magnitude except during treatment with nitroglycerin, a vasodilator known to be highly selective for large muscular arteries. These numerical and experimental data suggest that backward pressure waves can be generated by elastic recoil of large arteries independent of pressure wave reflection and this effect dominates in human physiology.

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

Background: Arterial calcification may lead to regional variation in distension imposing stresses on the arterial wall that predispose to plaque rupture. The objective of this study was to use a novel speckle tracking method to investigate regional motion of the carotid wall and to determine whether this relates to subclinical disease. Methods and results: Measurements were obtained on 256 subjects from the Twins UK cohort (mean ± SD age 62±10.2 years). The left carotid was imaged for an assessment of plaque and calcification. Speckle-tracking was then used to measure regional circumferential strain of the left common carotid in 6 separate 60° segments of the circumference of the arterial wall in a plaque free plane of the common carotid approximately 1 cm proximal to the bifurcation. Regional variation in circumferential strain around the circumference of the arterial wall was characterized by the standard deviation of circumferential strain and that of the time from onset of systole to peak circumferential strain in each segment. Spatio-temporal variation in circumferential strain characterized by variation in the time to peak circumferential strain was associated with age and presence of calcified plaque (regression coefficients 0.73 units/year and 14.2 increase for presence of calcified plaque, each P

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).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

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 flowmediated 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. [ABSTRACT FROM AUTHOR]

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 mmHg) and normotensive subjects (52.2±12.6 years; 120±14.2/71±8.2 mmHg). 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 mmHg (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 2 2 .1±3.8 and 7.2±2.8 mmHg for dobutamine and norepinephrine, respectively; P<0.02). An elevated forward wave component (mean±SE, 50.4±3.4 versus 35.2±1.8 mmHg, 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. [ABSTRACT FROM AUTHOR]

The article examines the relative specificity of vasodilator drugs for radial artery and forearm resistance vessels during intrabrachial arterial infusion. The nitric oxide (NO) donors, were compared with the a-adrenergic antagonist phentolamine, calcium-channel antagonist verapamil and hyrdralazine. The differential response to NO donors suggests that there is potential to manipulate the downstream pathway to confer greater specificity for large arteries.

Flow-mediated dilation of the brachial or radial artery in response to transient hyperaemic flow, the most widely used test of endothelial function, is only manifest after flow decays back to baseline. We examined whether this dissociation of flow and diameter might be explained by a reduction in transmural pressure generated by high flow. Studies were performed in healthy subjects 20 to 55 years of age. Flow-mediated dilation was measured in the radial artery using a standard protocol and after flow interruption at peak hyperemia during brachial artery infusion of saline and the NO synthase inhibitor N(G)-monomethyl-L-arginine (8 μmol/min). Flow interruption 20 seconds after cuff release (during high flow but no dilatation) produced an immediate increase in radial artery diameter of 5.36±2.12%, inhibited by N(G)-monomethyl-L-arginine to 1.09±0.67% (n=8; P<0.001). Mean intra-arterial radial blood pressure and, hence, transmural pressure fell after cuff release by a mean of 26±1.8 mm Hg (n=6; P<0.0001) at the time of peak hyperemic flow. Modulation of transmural pressure within the brachial artery by cuff inflation around the artery demonstrated that this fall is sufficient to reduce arterial diameter by an amount similar to flow-mediated dilation. These results suggest that flow-dependent, NO-dependent dilation is offset by a flow-induced fall in local arterial pressure and, hence, in transmural pressure. Shear related NO release is likely to play a greater role in the short-term regulation of arterial tone than that suggested by flow-mediated dilation. [ABSTRACT FROM AUTHOR]

Aims To assess the reproducibility of the digital pulse wave response to β2-adrenoreceptor stimulation and to determine if an attenuated response to β2-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 (ΔRI) of the digital volume pulse in response to salbutamol (SALB, 5 µg min−1 i.v) and to nitroglycerin (NTG, 5 µg min−1 i.v) was used to assess endothelium-dependent (ΔRISALB) and endothelium-independent (ΔRINTG) pressure wave reflection. ΔRISALB 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 ΔRISALB between two visits was −0.2%, with SD of the difference 4.9%. Both ΔRISALB 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 ΔRISALB and FMD, respectively), whereas ΔRINTG and NTGD were similar in the two groups. ΔRISALB 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 β2-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. [ABSTRACT FROM AUTHOR]