Discovery of the role of wall shear in atherosclerosis.

The suggestion was made in the 1870s that mechanical irritation of the arterial wall is a cause of atherosclerosis, because the changes were chiefly found at points "exposed to the full stress and impact of the blood." The mechanical damage theory persisted until well into the 20th century when, with interest increasing in multidisciplinary research, two fluid mechanical proposals were advanced for the patchy distribution of the lesions. One advocated high- and the other low-wall shear. Arterial wall shear stress levels appeared, however, insufficiently high to damage the endothelium. In contrast, examination of cadaver human arteries, combined with flow studies in models and casts of arteries, implied that the lesions occurred preferentially in regions expected to experience low-wall shear; a mechanism, involving arterial wall lipid metabolism and shear-dependent blood-wall mass transport, was suggested to account for that distribution. These proposals helped stimulate extensive investigation of arterial fluid mechanics/mass transport and vascular biology/pathology, revealing mechanisms that may explain the now widely confirmed preferred occurrence of atherosclerosis in low wall shear regions in adult human beings.

The Effect of Arterial Curvature on Blood Flow in Arterio-Venous Fistulae: Realistic Geometries and Pulsatile Flow.

Arterio-Venous Fistulae (AVF) are regarded as the "gold standard" method of vascular access for patients with End-Stage Renal Disease (ESRD) who require haemodialysis. However, up to 60% of AVF do not mature, and hence fail, as a result of Intimal Hyperplasia (IH). Unphysiological flow and oxygen transport patterns, associated with the unnatural and often complex geometries of AVF, are believed to be implicated in the development of IH. Previous studies have investigated the effect of arterial curvature on blood flow in AVF using idealized planar AVF configurations and non-pulsatile inflow conditions. The present study takes an important step forwards by extending this work to more realistic non-planar brachiocephalic AVF configurations with pulsatile inflow conditions. Results show that forming an AVF by connecting a vein onto the outer curvature of an arterial bend does not, necessarily, suppress unsteady flow in the artery. This finding is converse to results from a previous more idealized study. However, results also show that forming an AVF by connecting a vein onto the inner curvature of an arterial bend can suppress exposure to regions of low wall shear stress and hypoxia in the artery. This finding is in agreement with results from a previous more idealized study. Finally, results show that forming an AVF by connecting a vein onto the inner curvature of an arterial bend can significantly reduce exposure to high WSS in the vein. The results are important, as they demonstrate that in realistic scenarios arterial curvature can be leveraged to reduce exposure to excessively low/high levels of WSS and regions of hypoxia in AVF. This may in turn reduce rates of IH and hence AVF failure.

Automated classification of peripheral distal by-pass geometries reconstructed from medical data.

Abnormal haemodynamic conditions are implicated in the development of anastomotic myointimal hyperplasia (MIH). However, these conditions are difficult to determine in vivo, prompting research using ex vivo idealised models. To relate the understanding gained in idealised geometries to anatomically correct conditions we have investigated a reproducible approach to classify in vivo distal graft anastomoses and their inter-patient variability. In vivo distal anastomotic geometries were acquired by magnetic resonance (MR) angiography from 13 patients who had undergone infrageniculate autologous venous by-pass surgery. On average, the images were acquired 2 weeks post-operatively. Five patients also underwent repeat examinations 2 to 7 weeks later. For each geometry, the surface of the arterial lumen is represented by the zero level set of an implicit function constructed from radial basis functions that minimise curvature. The three-dimensional binary image created from the interpolated surface is processed using a skeletonisation algorithm to obtain the centreline of each branch in the geometry. This allows for the measurement of the branching angles between straight line approximations of the centrelines of each vessel, averaging them over a characteristic length of each anastomosis. The main finding in the application of the proposed classification methodology to this set of patients is that the spectrum of anastomoses can be reduced to a small subset of cases characterised by two angles: the angle between the graft and the plane of the host artery and the angle between the graft and the proximal branch of the artery.

Uptake of 125I albumin by the endothelial surface of the isolated dog common carotid artery: effect of certain physical factors and metabolic inhibitors.

A study has been made, under transient conditions, of the uptake of 125I albumin by the endothelial surface of isolated dog carotid arteries. Effective rate constants were determined and the apparent activation energy was calculated to be about 13 kcal/mol in the range 25-37 degrees C. Label uptake was not significantly altered by the presence of 1 mmol/1 potassium cyanide or 10 mmol/1 iodoacetate in the incubating medium, or by the absence of substrate from it, consistent with the process being primarily passive. It appeared that the label entered the wall mainly by other routes than the endothelial inter-cell clefts.

Influence of heart rate and vasoactive drugs on blood flow patterns at the canine ilio-femoral bifurcation.

OBJECTIVE: The aim was to study the effects of altered heart rate and vasoactive drugs on the blood velocity patterns in the region of an arterial bifurcation. METHODS: Blood velocity profiles were measured in an exposed iliofemoral bifurcation of paced dogs using a pulsed Doppler ultrasound velocimeter with high temporal and spatial resolution. RESULTS: Decrease of the heart rate from 120 beats.min-1 (2 Hz) to 60 beats.min-1 (1 Hz) increased the peak forward velocity (30%), the peak reverse velocity (20%), and the duration of reverse flow (25%). Each drug caused qualitatively similar changes in velocity patterns at both heart rates. The systemic administration of angiotensin II reduced peak forward velocity (-26% at 2 Hz and -33% at 1 Hz) and forward flow duration (-15% at 1 Hz), the peak reverse velocity (-30% at 1 Hz), and reverse flow duration (-20% at 2 Hz and -28% at 1 Hz). Glyceryl trinitrate also reduced the peak forward velocity (-19% at both 2 and 1 Hz) but prolonged forward flow duration (28% at 2 Hz and 17% at 1 Hz) and that of reverse flow (45% at 2 Hz and 24% at 1 Hz), and also decreased the degree of oscillation (-16% at 2 Hz). Barnidipine hydrochloride (a calcium channel antagonist) also increased the duration of forward flow (48% at 1 Hz) and of reverse flow (31% at 2 Hz) but reduced the peak reverse velocity (-29% at 1 Hz) and flow oscillation (-22% at 2 Hz and 20% at 1 Hz). CONCLUSIONS: These dramatic changes in the pattern of blood flow, including alterations in the amplitudes and durations of the different phases of the flow cycle, are expected to have important consequences on the shear dependent responses of endothelial cells in the region of the bifurcation.

The effect of in-plane arterial curvature on blood flow and oxygen transport in arterio-venous fistulae.

Arterio-Venous Fistulae (AVF) are the preferred method of vascular access for patients with end stage renal disease who need hemodialysis. In this study, simulations of blood flow and oxygen transport were undertaken in various idealized AVF configurations. The objective of the study was to understand how arterial curvature affects blood flow and oxygen transport patterns within AVF, with a focus on how curvature alters metrics known to correlate with vascular pathology such as Intimal Hyperplasia (IH). If one subscribes to the hypothesis that unsteady flow causes IH within AVF, then the results suggest that in order to avoid IH, AVF should be formed via a vein graft onto the outer-curvature of a curved artery. However, if one subscribes to the hypothesis that low wall shear stress and/or low lumen-to-wall oxygen flux (leading to wall hypoxia) cause IH within AVF, then the results suggest that in order to avoid IH, AVF should be formed via a vein graft onto a straight artery, or the inner-curvature of a curved artery. We note that the recommendations are incompatible-highlighting the importance of ascertaining the exact mechanisms underlying development of IH in AVF. Nonetheless, the results clearly illustrate the important role played by arterial curvature in determining AVF hemodynamics, which to our knowledge has been overlooked in all previous studies.

Effect of vasoactive agents and applied stress on the albumin space of excised rabbit carotid arteries.

Experiments were undertaken on excised rabbit common carotid arteries to assess whether the distribution volume for radioactively labelled albumin is influenced by smooth muscle tone or externally applied stress. In arteries at relaxed length and zero transmural pressure, the distribution volume in the media was reduced by noradrenaline at concentrations exceeding 10(-9) M and increased by both sodium nitrite and isosorbide dinitrate at concentrations exceeding 10(-4) M. The distribution volume was lower in both the media and adventitia of segments at in vivo length pressurized with air to prevent convection through the wall, than in segments at relaxed length and zero transmural pressure. Noradrenaline decreased and sodium nitrite increased the medial distribution volume of the tracer in these air-pressurized segments. The vasoactive agents did not change the [51Cr]EDTA space in vessels at relaxed length and zero transmural pressure, although there were small alterations of medial water content. Transient conditions raise interpretative difficulties because of uncertainty about endothelial permeability and time-dependent changes of wall properties. The changes of the distribution volume for labelled albumin are thought to reflect changes in the properties of the interstitium.

Effect of noradrenaline, sodium nitrite and isosorbide dinitrate on albumin transport in the wall of the excised rabbit common carotid artery.

The effects of noradrenaline (NA), sodium nitrite (NaNO2) and isosorbide dinitrate (ISDN) on the steady state distribution of 125I-labelled albumin in the wall of excised rabbit common carotid arteries were studied. The vessels were incubated in Tyrodes solution either at relaxed length and zero transmural pressure (non-pressurized) or at in vivo length and a transmural pressure of 70 mm Hg (pressurized). Label was applied in the same concentration at both the luminal and outer surfaces. The mean medial uptake in pressurized vessels was greater after treatment with 10(-7) M NA than after additional treatment with either 10(-3) M NaNO2 or 10(-3) M ISDN. The opposite was found for non-pressurized vessels. The medial uptake by NA-treated pressurized vessels was greater than that by NA-treated non-pressurized vessels, while the reverse was found for NaNO2- or ISDN-treated vessels. We conclude that the different patterns of uptake seen in these vessels results from the relative effects of externally applied stress (elongation and pressurization), smooth muscle tone and convection through the wall, on the properties of the interstitium, and possibly from the effects of the vasoactive agents on endothelial permeability.

Diffusion coefficients for protein molecules in blood serum.

A new technique is described for the measurement of the self-diffusion coefficients of protein macromolecules in solution. The method makes use of the phenomenon of Taylor dispersion of a solute introduced into a solvent flowing in the laminar regime through a tube of circular section. Results are reported for the self-diffusion coefficient of cholesterol associated with lipoprotein molecules in dogs' serum at pH 7.4 in the temperature range 18-37 degrees C. The diffusivity of bovine serum albumin in serum has also been studied as a function of temperature at pH 7.4 and 4.7. In the more basic solution, measurements of the diffusivity as a function of protein concentration substantially agree with earlier work. For all the systems studied the diffusivity varies rapidly with temperature. The pH of the solution, in the case of bovine serum albumin, also has a significant effect on the diffusivity of the macromolecule. The latter observation is related to the amount of water bound to the protein molecule in solution.

Net albumin transport across the wall of the rabbit common carotid artery perfused in situ.

We have studied the transport of radioactively labelled albumin in the rabbit common carotid artery perfused in situ at 100 cm H2O luminal pressure in the anaesthetized living animal, assessing the distribution of concentration across the wall by means of sequential frozen sectioning. We have compared the findings with those of experiments in which we have attempted to saturate the wall with label. Our findings support the belief that there is a net transport of macromolecules across the arterial wall. They show in addition that the wall is inhomogeneous. The distribution volume for label is greater in the adventitia than the media, which appears to offer a larger resistance. The transport process is seemingly dominantly diffusional.

Effect of positive external pressure on calf volume and local venous haemodynamics.

The pressure external to the calf was increased suddenly in 11 normal subjects and the resulting change in calf volume (considered to be mainly a change of calf vein blood volume) was followed using a mercury-in-rubber strain gauge. For a small increase of pressure the volume decreased exponentially and increased linearly when the pressure was suddenly released. A simple theory was developed which treats the calf veins as a single volume with a single compliance and a single outflow resistance. Using the theory, the following average results were obtained from measured values: effective venous compliance 1-1%kPa (SD 0.3); effective venous outflow resistance 3.8 s kPa/% (SD 1-3); and total flow into the veins from themicrocirculation 0.054%/s (SD 0.020) (% refers to a change in volume expressed as a percentage of the initial volume of the calf). The significance of the findings is considered with special reference to the occurrence of calf vein thrombosis.

Factors influencing arterial wall mass transport.

Arterial wall mass transport has particularly attracted attention because it may be implicated in the development of arterial disease, including arteriosclerosis. A short review is presented of the structure of the arterial wall and of studies of mass transport within it. Recent findings confirm that mass transport occurs across the entire arterial wall apparently from the lumen to the adventitial lymphatics. Evidence has emerged of inhomogeneity of the distribution volume for extracellular tracers in different layers of the wall. An attempt is made to interpret results which indicate that distension per se of arteries and increase of medial smooth muscle tone tend to compact the medial interstitium whereas pressure driven convection across the wall tends to expand that tissue. These findings imply a potentially important role of endothelial permeability, smooth muscle tone and luminal pressure in influencing solute transport in the wall and wall transport properties.

Parallel-plate flow chamber for studies of 3D flow-endothelium interaction.

Flow induced shear stress influences vascular cellular biology and pathophysiology in numerous ways. Previous in vitro studies on interactions between flow and endothelial cells using parallel-plate flow chambers involve two-dimensional flows, whereas flows in larger vessels are commonly three-dimensional. We have constructed a parallel plate flow chamber with a backward facing step aligned oblique to the axis of the chamber. Flow visualisation by steady injection of ink through a hypodermic tube reveals swirling flow in the recirculation region downstream of the step. At given angles of the step, theta; (to the axis of the chamber), the pitch of the swirl and the width of the separation region, as measured in the direction perpendicular to the step, increase with the Reynolds number (Re). On the other hand, at given values of Re, reduction of theta; results in increases in the swirl pitch but decreases in the width of the separation zone. Furthermore, clearance time of ink from the separation region is shorter with an oblique step than a perpendicular one at given Re. Computer simulation confirms the 3D swirling flow created by the oblique step and provides detailed distribution of wall shear stresses in the flow chamber.

Combined MR imaging and numerical simulation of flow in realistic arterial bypass graft models.

We report methods for (a) transforming a three-dimensional geometry acquired by magnetic resonance angiography (MRA) in vivo, or by imaging a model cast, into a computational surface representation, (b) use of this to construct a three dimensional numerical grid for computational fluid dynamic (CFD) studies, and (c) use of the surface representation to produce a stereo-lithographic replica of the real detailed geometry, at a scale convenient for detailed magnetic resonance imaging (MRI) flow studies. This is applied to assess the local flow field in realistic geometry arterial bypass grafts. Results from a parallel numerical simulation and MRI measurement of flow in an aorto-coronary bypass graft with various inlet flow conditions demonstrate the strong influence of the graft inlet waveform on the perianastomotic flow field. A sinusoidal and a multi harmonic coronary flow waveform both with a mean Reynolds number (Re) of 100 and a Womersley parameter of 2.7 were applied at the graft inlet. A weak axial flow separation region just distal to the toe was found in sinusoidal flow near end deceleration (Re = 25). At the same location and approximately the same point in the cycle (Re = 30) but in coronary flow, the axial flow separation was stronger and more spatially pronounced. No axial flow separation occurred in steady flow for Re = 100. Numerical predictions indicate a region in the vicinity of the suture line (where there is a local narrowing of the graft) with a wall shear magnitude in excess of five times that associated with fully developed flow at the graft inlet.

A helical PTFE arteriovenous access graft to swirl flow across the distal anastomosis: results of a preliminary clinical study.

Intimal hyperplasia develops preferentially in regions where the blood flow is stagnant and wall shear stress low. The small amplitude helical geometry of the SwirlGraft was designed to ensure physiological-type swirling flow, and thus suppress the triggers. We report the first conceptual testing of the SwirlGraft. Primary, assisted primary and secondary patency rates at 6 months in 20 patients were 57.9+/-11.4%, 84.4+/-8.3% and 100+/-0.0%. There was angiographic evidence of reduction of helical geometry in a proportion of the grafts. The helical graft is associated with high assisted primary and secondary patency. Elaboration of the surgical implantation techniques and an improved SwirlGraft design can be expected to exploit the advantages of the helical concept.