Comparison of brachial artery pressure and derived central pressure in the measurement of abdominal aortic aneurysm distensibility.

OBJECTIVE: AAA distensibility (Ep, beta) may predict growth and risk of rupture. However, distensibility measurements based on brachial rather than central pressure may be inaccurate. Our aim was to compare AAA distensibility using non-invasive brachial and derived central aortic pressure. DESIGN: brachial and central pressures were measured prospectively by automated sphygmomanometry (Omron) and pulse wave analysis (SphygmoCor) respectively. AAA distensibility was calculated using brachial (Ep(b), beta(b)) and central (Ep(c), beta(c)) pressures by ultrasonic echo-tracking (Diamove). Twenty-eight patients (18 males) were selected on a first come basis from a larger study of AAA patients. There were no exclusion criteria, so 54% had cardiac dysfunction (MI, angina) and 14% were hypertensive (BP >140/90 mmHg). RESULTS: median (IQR) age was 74 (70-77) years, median AAA (IQR) diameter was 44 (40-51) mm. Central and brachial systolic pressures were significantly different, [140 (121-153) vs 144 (130-164) mmHg respectively, p < or =0.01]. Central and brachial diastolic pressures were not significantly different [76 (72-86) vs 76 (71-86) mmHg respectively, p=0.5]. Ep(c)(3.0, [2.2-4.9]) and beta(c)(22.2 [15.5-33.2]) were significantly lower than Ep(b)(3.6, [2.4-5.1] 10(5)Nm(-2)) and beta(b)(24.7 [17.1-33.0] a.u., all p < 0.001. Brachial and central derived distensibility remained significantly different after adjusting for age and diameter (p<0.001). CONCLUSION: the use of brachial pressure leads to a small, systematic overestimate of Ep (18%) and beta (11%) independent of age and AAA diameter. This systematic error will not bias follow-up of changes in distensibility.

Adrenomedullin (ADM) in the human forearm vascular bed: effect of neutral endopeptidase inhibition and comparison with proadrenomedullin NH2-terminal 20 peptide (PAMP).

AIMS: To compare the haemodynamic responses of proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (ADM) in the forearm vascular bed of healthy male volunteers, and to investigate the role of neutral endopeptidase (NEP) in the metabolism of ADM. METHODS: On two separate occasions, ADM (1-30 pmol x min(-1)) and PAMP (100-3000 pmol x min(-1)) were infused into the brachial artery of eight male subjects, and forearm blood flow (FBF) assessed using venous occlusion plethysmography. In a second study, eight male subjects received the same doses of ADM, co-infused with either the NEP inhibitor thiorphan (30 nmol x min(-1)) or the control vasoconstrictor noradrenaline (120 pmol x min(-1)), on separate occasions. Both studies were conducted in a double-blind, randomized manner. RESULTS: ADM and PAMP produced a dose-dependent increase in FBF (P < or = 0.002). Based on the dose producing a 50% increase in FBF, ADM was approximately 60 times more potent than PAMP. Thiorphan and noradrenaline produced similar reductions in FBF of 14 +/- 4% (mean +/- s.e. mean) and 22 +/- 6%, respectively (P = 0.4). However, the area under the dose-response curve was significantly greater during co-infusion of ADM with thiorphan than with noradrenaline (P = 0.028), as was the maximum increase in FBF ratio (2.1 +/- 1.0 vs 1.2 +/- 0.2; P = 0.030). CONCLUSIONS: ADM and PAMP both produce a local dose-related vasodilatation in the human forearm, but PAMP is approximately 60 times less potent than ADM. In addition, NEP inhibition potentiates the haemodynamic effects of ADM. These findings suggest that PAMP may not play a role in the physiological regulation of blood flow. However, in pathophysiological conditions such as hypertension and heart failure, NEP inhibition may exert a beneficial effect by increasing the biological activity of ADM.

Effects of acute methionine loading and vitamin C on endogenous fibrinolysis, endothelium-dependent vasomotion and platelet aggregation.

We assessed forearm blood flow and plasma fibrinolytic factors in eight healthy males who received unilateral brachial artery infusions of the endothelium-dependent vasodilator, substance P, and the endothelium-independent vasodilator, sodium nitroprusside. These measurements, together with platelet aggregation studies, were performed on four occasions after double-blind randomized ingestion of placebo, methionine (0.1 mg/kg), vitamin C (2 g) and methionine plus vitamin C. Blood flow and platelet aggregation responses were unaffected by methionine loading. Substance P caused dose-dependent increases in plasma tissue plasminogen activator (t-PA) antigen (from 3.0+/-0.1 to 4.7+/-0.4 ng/ml; P<0.001) and activity (from 1.2+/-0.2 to 4.2+/-0.4 i.u./ml; P<0.001), which were augmented during acute methionine loading (4.7+/-0.4 to 5.6+/-0.5 ng/ml and 4.2+/-0.4 to 5.5+/-0.9 i.u./ml respectively; P

Changes in the derived central pressure waveform and pulse pressure in response to angiotensin II and noradrenaline in man.

Peripheral pulse pressure provides a surrogate measure of arterial stiffness. Analysis of the central pressure waveform allows assessment of central pulse pressure and arterial stiffness. The aim of the present study was to assess the effect of vasoconstrictor drugs on pulse pressure amplification and arterial stiffness in vivo. Eight healthy male subjects (mean age 30 years) received an infusion of angiotensin II (1, 3, 6 and 10 ng kg(-1) min(-1)), noradrenaline (10, 30, 60 and 100 ng kg(-1) min(-1)) and matching placebo, in random order, on separate occasions. Peripheral blood pressure and cardiac index were recorded non-invasively. Pulse wave analysis was used to determine augmentation index (AIx), which provides a measure of systemic arterial stiffness, aortic stiffness and central arterial pressure. Infusion of both active drugs resulted in a significant increase in peripheral mean arterial pressure (PMAP), peripheral vascular resistance, AIx, aortic stiffness and central pulse pressure, but only angiotensin II reduced cardiac index. Peripheral pulse pressure was unaffected by infusion of angiotensin II but increased with noradrenaline, which also produced a greater reduction in pulse pressure amplification than angiotensin II. However, the linear relationship of PMAP with both AIx and aortic stiffness did not differ significantly between drugs. These results demonstrate that intravenous infusion of angiotensin II and noradrenaline increase aortic and systemic arterial stiffness. Despite a similar effect on both parameters, for a given change in PMAP, the two drugs had divergent effects on peripheral pulse pressure and pulse pressure amplification. These data reveal that assessment of peripheral pulse pressure does not always reliably predict changes in central pulse pressure or arterial stiffness.

A novel S-nitrosothiol (RIG200) causes prolonged relaxation in dorsal hand veins with damaged endothelium.

BACKGROUND: Reduced nitric oxide bioavailability caused by endothelial dysfunction or damage is a contributory factor in the initiation and progression of a number of cardiovascular diseases. Delivery of exogenous nitric oxide is an attractive therapeutic option, but current agents lack selectivity for areas of endothelial damage. We tested the hypothesis that a novel nitric oxide donor drug, N-(S-nitroso-N-acetylpenicillamine)-2-amino-2-deoxy-1,3,4,6-tetra-O-acet yl-P-glucopyranose [RIG200], which has selective effects in endothelium-denuded isolated arteries in vitro, would exert similar effects in dorsal hand veins with experimentally damaged endothelium in vivo. METHODS: Venodilator responses to sodium nitroprusside and RIG200 were compared in two groups of healthy volunteers (age range, 18 to 63 years; n = 7 for each group) in norepinephrine 70% maximum effective concentration (EC70) preconstricted hand veins with use of the Aellig technique. In this doubleblind study, subjects were randomly assigned to receive either sodium nitroprusside or RIG200 (infusions of 0.06 and 6 nmol/min into the hand vein) before and 2 days after 15 minutes of local venous irription with distilled water. Endothelial function was assessed in all subjects on both visits with use of the endothelium-dependent vasodilator acetylcholine (1 nmol/min). RESULTS: Irrigation of hand veins with distilled water abolished endothelium-dependent dilatation in response to acetylcholine in both study groups (n = 14) but did not affect the amplitude or duration of responses to the conventional nitric oxide donor sodium nitroprusside (P = .87; n = 7). However, responses to RIG200 were significantly prolonged during the washout phase (30 minutes) in veins after water irrigation (P = .02; n = 7). CONCLUSION: These studies confirm that RIG200 has prolonged effects in veins with damaged endothelium, a characteristic that might be exploited therapeutically to target nitric oxide delivery to damaged blood vessels.

Increased augmentation index and systolic stress in type 1 diabetes mellitus.

Type 1 diabetes mellitus is associated with endothelial dysfunction and increased arterial stiffness, both of which may contribute to the excess cardiovascular mortality in such patients. Arterial stiffening increases pulse wave velocity and wave reflection, which augments central systolic pressure and stress. Using the non-invasive technique of pulse wave analysis, we investigated aortic augmentation and central pressure in 35 patients with type 1 diabetes and 35 matched controls. Peripheral pulse waveforms were recorded from the radial artery. Central aortic waveforms were then generated, and augmentation index (AIx), ascending aortic pressure and tension time index (TTI), a measure of systolic load, were calculated. Peripheral and central blood pressure did not differ between the two groups. AIx was significantly elevated in the diabetic patients compared with controls (7.1+/-1.6% vs. 0.4+/-2.0%; p=0.01), as was the TTI (2307+/-51 mmHg x s x min(-1) vs. 2010+/-61 mmHg. s x min(-1); p<0.001). Estimated pulse wave velocity was also higher in the diabetic group. Type 1 diabetes is associated with an increased AIx and rate of wave travel, indicating enhanced wave reflection and increased systemic arterial stiffness, and elevation of the TTI. Such haemodynamic effects may contribute to the increased left ventricular mass and risk of cardiovascular disease associated with type 1 diabetes mellitus.

The influence of heart rate on augmentation index and central arterial pressure in humans.

Arterial stiffness is an important determinant of cardiovascular risk. Augmentation index (AIx) is a measure of systemic arterial stiffness derived from the ascending aortic pressure waveform. The aim of the present study was to assess the effect of heart rate on AIx. We elected to use cardiac pacing rather than chronotropic drugs to minimize confounding effects on the systemic circulation and myocardial contractility. Twenty-two subjects (13 male) with a mean age of 63 years and permanent cardiac pacemakers in situ were studied. Pulse wave analysis was used to determine central arterial pressure waveforms, non-invasively, during incremental pacing (from 60 to 110 beats min-1), from which AIx and central blood pressure were calculated. Peripheral blood pressure was recorded non-invasively from the brachial artery. There was a significant, inverse, linear relationship between AIx and heart rate (r = -0.76; P < 0.001). For a 10 beats min-1 increment, AIx fell by around 4 %. Ejection duration and heart rate were also inversely related (r = -0. 51; P < 0.001). Peripheral systolic, diastolic and mean arterial pressure increased significantly during incremental pacing. Although central diastolic pressure increased significantly with pacing, central systolic pressure did not. There was a significant increase in the ratio of peripheral to central pulse pressure (P < 0.001), which was accounted for by the observed change in central pressure augmentation. These results demonstrate an inverse, linear relationship between AIx and heart rate. This is likely to be due to alterations in the timing of the reflected pressure wave, produced by changes in the absolute duration of systole. Consideration of wave reflection and aortic pressure augmentation may explain the lack of rise in central systolic pressure during incremental pacing despite an increase in peripheral pressure.

Photoplethysmographic assessment of pulse wave reflection: blunted response to endothelium-dependent beta2-adrenergic vasodilation in type II diabetes mellitus.

OBJECTIVES: We sought to determine whether a simple index of pressure wave reflection may be derived from the digital volume pulse (DVP) and used to examine endothelium-dependent vasodilation in patients with type II diabetes mellitus. BACKGROUND: The DVP exhibits a characteristic notch or inflection point that can be expressed as percent maximal DVP amplitude (IP(DVP)). Nitrates lower IP(DVP), possibly by reducing pressure wave reflection. Response of IP(DVP) to endothelium-dependent vasodilators may provide a measure of endothelial function. METHODS: The DVP was recorded by photoplethysmography. Albuterol (salbutamol) and glyceryl trinitrate (GTN) were administered locally by brachial artery infusion or systemically. Aortic pulse wave transit time from the root of the subclavian artery to aortic bifurcation (T(Ao)) was measured by simultaneous Doppler velocimetry. RESULTS: Brachial artery infusion of drugs producing a greater than threefold increase in forearm blood flow within the infused limb was without effect on IP(DVP), whereas systemic administration of albuterol and GTN produced dose-dependent reductions in IP(DVP). The time between the first and second peak of the DVP correlated with T(Ao) (r = 0.75, n = 20, p < 0.0001). The effects of albuterol but not GTN on IP(DVP) were attenuated by N(G)-monomethyl-L-arginine. The IP(DVP) response to albuterol (400 microg by inhalation) was blunted in patients with type II diabetes mellitus as compared with control subjects (fall 5.9 +/- 1.8% vs. 11.8 +/- 1.8%, n = 20, p < 0.02), but that to GTN (500 microg sublingually) was preserved (fall 18.3 +/- 1.2% vs. 18.6 +/- 1.9%, p = 0.88). CONCLUSIONS: The IP(DVP) is influenced by pressure wave reflection. The effects of albuterol on IP(DVP) are mediated in part through the nitric oxide pathway and are impaired in patients with type II diabetes.

Oral vitamin C reduces arterial stiffness and platelet aggregation in humans.

Atherosclerosis is associated with stiffening of conduit arteries and increased platelet activation, partly as a result of reduced bioavailability of nitric oxide (NO), a mediator that normally has a variety of protective effects on blood vessels and platelets. Increased levels of oxygen free radicals are a feature of atherosclerosis that contributes to reduced NO bioavailability and might lead to increased arterial stiffness and platelet activation. Vitamin C is a dietary antioxidant that inactivates oxygen free radicals. This placebo-controlled, double-blind, randomized study was designed to establish whether acute oral administration of vitamin C (2 g), would reduce arterial stiffness and in vitro platelet aggregation in healthy male volunteers. Plasma vitamin C concentrations increased from 42+/-8 to 104+/-8 microM at 6 h after oral administration, and were associated with a significant reduction in augmentation index, a measure of arterial stiffness (by 9.6+/-3.0%; p = 0.016), and ADP-induced platelet aggregation (by 35+/-13%; p = 0.046). There was no change in these parameters after placebo. Vitamin C, therefore, appears to have beneficial effects, even in healthy subjects. The mechanism responsible is likely to involve protection of NO from inactivation by oxygen free radicals, but this requires confirmation. If similar effects are observed in patients with atherosclerosis or risk factors, vitamin C supplementation might prove an effective therapy in cardiovascular disease.