Relation of arterial geometry to luminal narrowing and histologic markers for plaque vulnerability: the remodeling paradox.

OBJECTIVE: To relate local arterial geometry with markers that are thought to be related to plaque rupture. BACKGROUND: Plaque rupture often occurs at sites with minor luminal stenosis and has retrospectively been characterized by colocalization of inflammatory cells. Recent studies have demonstrated that luminal narrowing is related with the mode of atherosclerotic arterial remodeling. METHODS: We obtained 1,521 cross section slices at regular intervals from 50 atherosclerotic femoral arteries. Per artery, the slices with the largest and smallest lumen area, vessel area and plaque area were selected for staining on the presence of macrophages (CD68), T-lymphocytes (CD45RO), smooth muscle cells (alpha-actin) and collagen. RESULTS: Inflammation of the cap or shoulder of the plaque was observed in 33% of all cross sections. Significantly more CD68 and CD45RO positive cells, more atheroma, less collagen and less alpha-actin positive staining was observed in cross sections with the largest plaque area and largest vessel area vs. cross sections with the smallest plaque area and smallest vessel area, respectively. No difference in the number of inflammatory cells was observed between cross sections with the largest and smallest lumen area. CONCLUSION: Intraindividually, pathohistologic markers previously reported to be related to plaque vulnerability were associated with a larger plaque area and vessel area. In addition, inflammation of the cap and shoulder of the plaque was a common finding in the atherosclerotic femoral artery.

Collateral ability of the circle of Willis in patients with unilateral internal carotid artery occlusion: border zone infarcts and clinical symptoms.

BACKGROUND AND PURPOSE: The circle of Willis is regarded as the major source of collateral flow in patients with severe carotid artery disease. The purpose of the present study was to assess whether the presence of border zone infarcts is related to the collateral ability of the circle of Willis in symptomatic (transient ischemic attack, minor stroke) and asymptomatic patients with unilateral occlusion of the internal carotid artery (ICA). METHODS: Fifty-one patients (35 symptomatic, 16 asymptomatic) and 53 control subjects were investigated. Patients had unilateral occlusion of the ICA and contralateral ICA stenosis between 0% and 69%. The directions of flow, on the side of the ICA occlusion, and the size of the component vessels in the circle of Willis were investigated with MR angiography. RESULTS: On average, 92% of the patients without border zone infarcts (n=26) had willisian collateral flow compared with 60% of patients with border zone infarcts (n=25; P<0.05). This increase in collateral flow was caused by the high prevalence of collateral flow via the posterior communicating artery in patients without border zone infarcts (50% versus 12%; P<0.05). No statistically significant relation was found between the pattern of collateral flow via the circle of Willis and the presence of clinical symptoms. Nevertheless, asymptomatic patients with ICA occlusion demonstrated an increased diameter of the anterior communicating artery (P<0.05). CONCLUSIONS: In patients with unilateral ICA occlusion, the presence of collateral flow via the posterior communicating artery in the circle of Willis is associated with a low prevalence of border zone infarcts. Asymptomatic patients with an ICA occlusion do not have an increased collateral function of the circle of Willis.

Perivascular nerves of the human basal cerebral arteries: II. Changes in aging and Alzheimer's disease.

In the present study the intrinsic nerve plexuses of the basal cerebral arteries, derived from aged non-Alzheimer's and aged Alzheimer's disease patients were quantified and compared. A previous study described and quantified nerve density on similar arteries from healthy middle-aged patients. Whole-mount preparations of various segments of the basal cerebral arteries were stained for protein gene product 9.5. The deep nerve plexuses, located at the adventitial-medial border, were quantified by image analysis. Transverse cryostat sections were stained for various markers and quantified. Measurements on whole mounts demonstrated that nerve densities were highest in the posterior communicating artery and in the postcommunicating part of the posterior cerebral artery (PCA) for both aged and Alzheimer's groups. Statistical comparison showed a tendency toward decreased nerve density with aging, which was significant for the internal carotid artery, precommunicating part of the PCA, and the anterior choroidal artery in both non-Alzheimer's and Alzheimer's aged groups. In addition, in Alzheimer's patients nerve density was significantly lower in the precommunicating part of the anterior cerebral artery compared with the healthy aged group. Measurements on sections confirmed the tendency to decreased innervation with aging. It is concluded that densities of deep perivascular nerves of human basal cerebral arteries are subject to localized changes caused by aging and Alzheimer's disease.

Perivascular nerves of the human basal cerebral arteries: I. Topographical distribution.

In the present study the topographical distribution of the intrinsic nerve plexuses of the basal cerebral arteries in humans was quantified and the relation between vessel diameter and nerve density was investigated. Whole-mount preparations of various segments of the basal cerebral arteries from middle-aged patients were stained for protein gene product (PGP) 9.5. The deep nerve plexuses, located at the adventitial-medial border, were quantified by image analysis. Confocal scanning laser microscopy was used to study nerve plexuses throughout the adventitia. Transverse cryostat sections were stained for PGP 9.5, tyrosine hydroxylase and neurofilament, and quantified. The results showed a three-layered configuration of the adventitial nerves. Measurements on whole-mounts demonstrated that nerve densities were highest in the posterior communicating artery (PCom), and next highest in the proximal parts of the posterior cerebral artery (PCA) and anterior choroidal artery. There appeared to be no clear relation between nerve density and vessel diameter. The measurements on sections confirmed the high nerve densities in the PCom and PCA. Tyrosine hydroxylase- and neurofilament-immunoreactivities appeared to demonstrate separate subpopulations of the overall nerve plexuses, representing sympathetic and, possibly, sensory fibers, respectively. Densities of both subgroups generally followed those of PGP 9.5-immunoreactive nerves. Transmission electron microscopy suggested motor function of the deep nerve plexuses. The results indicate a stronger neuronal influence on this part of the cerebral circulation than hitherto reported. It is concluded that human basal cerebral arteries display a topographical distribution of deep perivascular nerves, and that nerve density is determined by locality rather than by vascular diameter.

Middle cerebral artery occlusion in Wistar and Fischer-344 rats: functional and morphological assessment of the model.

Cerebral infarction volume after occlusion of a short proximal segment of the middle cerebral artery (MCA) is reported to be different in Wistar compared to Fischer-344 (F344) rats, in both size and variability. Knowledge about the cause of these differences might enable us to explain and perhaps reduce the variation in infarct volume and create a reproducible model of focal cerebral ischemia in the rat. We investigated in Wistar and F344 rats both the effect of occlusion of a long proximal MCA segment on cerebral infarction volume, visualized by magnetic resonance imaging and histology, and the morphology of the major cerebral arteries. Occlusion of a long proximal MCA segment resulted in a striatal and a small cortical infarction in Wistar and a striatal and sizable cortical infarction in F344 rats (as is the case after occlusion of a short proximal MCA segment). In Wistar rats, however, occlusion of a long proximal MCA segment strongly reduced the variability in infarction volume in comparison to occlusion of a small proximal MCA segment. Analysis of the morphology of the major cerebral arteries showed a significantly higher number of proximal side branches of the long proximal MCA segment in Wistar rates than in F344 rats. We conclude that after short-segment proximal MCA occlusion, extreme variability in cerebral infarction volume in Wistar rats compared to F344 rats may be attributable to a significantly greater number of proximal MCA side branches in Wistar rats than in F344 rats.

Is plaque formation in the common carotid artery representative for plaque formation and luminal stenosis in other atherosclerotic peripheral arteries? A post mortem study.

The atherosclerotic carotid artery is easily accessible for non-invasive duplex investigation. The aim of the present post mortem study was to examine whether plaque accumulation and luminal stenosis in the common carotid artery is representative for atherosclerotic plaque accumulation and luminal stenosis in other peripheral arteries. A total of 3765 cross-sections were obtained at regular intervals from 240 arteries (24 individuals). Five types of peripheral arteries were investigated: common carotid, femoral, common iliac, external iliac and renal arteries. In each cross-section, the lumen area, vessel area, plaque area and maximal plaque thickness was measured. For each location, the percentage luminal stenosis and relative plaque area was calculated. Relative plaque area was defined as the percentage of the vessel area which was occupied by plaque. Weak correlations (r=0.41-0.59) were observed between percentage relative plaque area or maximal plaque thickness in the common carotid artery and percentage relative plaque area in other peripheral arteries. Neither plaque accumulation nor luminal stenosis in the common carotid artery correlated with the percentage luminal stenosis in other peripheral arteries (P > 0.05). We conclude that plaque area in the common carotid artery is weakly correlated with plaque area and not correlated with luminal stenosis in other peripheral arteries.

Impact of local atherosclerotic remodeling on the calculation of percent luminal narrowing.

The choice of the reference site in order to calculate percent luminal narrowing mainly depends on which diagnostic tool is used for examination. In intravascular ultrasound or histology, the local area encompassed by the internal elastic lamina (IEL) area is used as a reference. However, the local IEL area, and thereby the reference value, may have been altered by atherosclerotic remodeling. In the present study we examined the impact of local arterial remodeling on the calculation of luminal narrowing. Forty-five human femoral arteries were analyzed, 32 postmortem and 20 in vivo, by intravascular ultrasound. Cross sections were examined every 0.5 cm over an arterial segment length of 10 to 15 cm. In each cross section we measured the lumen area and the IEL area. Two reference areas were used to calculate percent luminal narrowing: (1) the lumen area in the cross section that contained the least amount of plaque (distant reference); and (2) the local IEL area (local reference). In each cross section, the IEL area was expressed as percent of the IEL area in the cross section that contained the least amount of plaque (relative IEL area). Using the distant reference, we found that less luminal narrowing was observed for cross sections with a relative IEL area > 100% (indicating compensatory enlargement) than for those with a relative IEL area < 100% (indicating shrinkage), whereas percent luminal narrowing calculated using the local reference hardly differed between cross section with a relative IEL area > 100% and < 100%. Thus, arterial wall remodeling makes the local IEL area an unreliable reference for calculation of percent luminal narrowing. The calculated percent luminal narrowing using a distant, nondiseased reference site reflects the actual change of the luminal area more accurately.

Rat middle cerebral artery occlusion by an intraluminal thread compromises collateral blood flow.

We compared in Wistar rats collateral blood flow through leptomeningeal anastomoses after middle cerebral artery occlusion using craniotomy ('extravasal occlusion'), which results in a small volume of cerebral infarction, and after intraluminal thread occlusion ('intravasal occlusion'), which produces a large volume of cerebral infarction. Simultaneous laser-Doppler flowmetry with two probes placed on the cerebral cortex was used to measure and compare collateral blood flow. Extravasal occlusion caused a cortical blood flow reduction along a gradient in lateral direction, whereas blood flow reduction after intravasal occlusion was more uniformly distributed. It is concluded that permanent intravasal occlusion compromises collateral blood flow and therefore may not be a suitable model for measuring the ability of pharmacotherapeutic agents, if any, to improve collateral blood flow acutely after middle cerebral artery occlusion. The two models can be useful for testing drugs on parenchymal neuroprotective properties. Thereby, the intraluminal technique is preferred because of the possibility to study reperfusion damage when transient occlusion is applied.

Collateral hemodynamics after middle cerebral artery occlusion in Wistar and Fischer-344 rats.

We investigated whether the difference in infarction volume after occlusion of a long proximal segment of the middle cerebral artery between Wistar and Fischer-344 rats, is caused by differences in collateral blood flow rate through leptomeningeal anastomoses. In view of the retrograde direction of collateral blood flow into the middle cerebral artery territory, we developed parasagittal laser-Doppler flowmetry. Using this method two laser-Doppler probes are placed on the cerebral cortex: probe 1 is placed near the anastomoses between the middle- and anterior cerebral artery, probe 2 is placed 2 mm further away from these anastomoses than probe 1. We found in both rat strains a comparable relation between the areas under the curve of the signal measured by both laser-Doppler probes for 2 h after middle cerebral artery occlusion. This relation is considered to be a measurement of the collateral blood flow rate into the middle cerebral artery territory through leptomeningeal anastomoses after middle cerebral artery occlusion. We conclude that collateral blood flow for the two strains were essentially similar for the initial 2 h after MCA occlusion. Although these collateral blood flows could have been different at a later time, it is unlikely that the interstrain difference in cerebral infarction volume between Wistar and Fischer-344 rats after proximal middle cerebral artery occlusion is caused by an apparent interstrain difference in the magnitude of collateral blood flow rate through leptomeningeal anastomoses. The parasagittal laser-Doppler flowmetry technique we developed for these experiments is currently successfully used in our laboratory to evaluate the efficacy of hemodynamically active pharmacotherapeutical agents in raising the collateral blood flow rate into the middle cerebral artery territory after middle cerebral artery occlusion.

Relationships between masticatory muscle cross-section and skull shape.

Cross-sectional areas of the masseter, temporalis and medial, and lateral pterygoid muscles were determined in 16 subjects by means of computer tomography. In each subject three scans were made, intersecting the thickest part of the muscles at right angles to the fiber direction. The masseter and medial pterygoid muscles are large in persons with brachycephalic skulls, short faces, and a small jaw angle. The cross-sectional areas of the temporalis and lateral pterygoid muscles showed no correlation with facial dimensions.

Normal direct multiplanar CT anatomy of the orbit with correlative anatomic cryosections.

This article presents high-resolution thin-section in vivo CT scans of the normal orbit, scanned directly in the transverse, coronal, and sagittal planes, compared with correlative anatomic cryosections of fresh frozen cadaver specimens. The techniques used are described.

Variability of the territories of the major cerebral arteries.

Recent morphological and functional studies on the circle of Willis suggest that the areas of supply of the six major cerebral arteries show a considerable variation in distribution, in contrast to the relatively consistent pattern generally accepted; therefore, the cortical and intracerebral distribution of the territories of these arteries was investigated in 25 unfixed human brains obtained at routine autopsy. The six major cerebral arteries were simultaneously injected under the same pressure with different-colored Araldite F mixtures under standardized conditions to obtain the most realistic territorial distribution. The cortical boundaries were examined and recorded in relation to the cerebral gyri and sulci, and the territories of the anterior, middle, and posterior cerebral arteries were analyzed and compared. The intracerebral distribution of these territories was investigated after the injected brains were cut in parallel slices. The variability of the territories of these arteries was much larger than generally described in the literature. Twenty-six variations in the territory of the anterior cerebral artery, 17 variations in the area of the middle cerebral artery, and 22 variations in the area of the posterior cerebral artery were found in the cortex of 50 hemispheres. Intracerebrally, the anterior, middle, and posterior cerebral arteries contributed in varying degrees to the blood supply of the lobar white matter, the internal capsule, the caudate nucleus, and the lentiform nucleus. The large variation in the area in which the cortical and intracerebral boundaries between these territories was located was demonstrated by illustrating the minimum and maximum extent of each. The results are compared with prior findings, and their implications for both experimental model studies and clinical practice are discussed.

Mathematical models of the flow in the basilar artery.

The flow in the basilar artery arises from the merging of the flows from the two vertebral arteries. This study deals with the question whether a parabolic (Poiseuille) profile will have been established before the basilar artery divides into both posterior cerebral arteries. The inlet length (that is, the downstream distance needed for the flow to become approximately equal to the limiting Poiseuille flow) and velocity profiles have been computed from two- and three-dimensional mathematical models in which flow pulsatility and vessel wall distensibility have been neglected and the complex geometry of the junction has been taken into account in a simplified form. The results show that the flow at the end of the basilar artery is far from being parabolic and that an asymmetry in the entrance flow will be carried along towards the end of the basilar artery, thus affecting flows in the circle of Willis.

A mathematical model of the flow in the circle of Willis.

A mathematical model of the flow in the circle of Willis has been designed and the effects of (a) the large anatomical variation of the communicating arteries and (b) physiological changes of the resistances of the vertebral arteries have been studied. The influence of the posterior perforating arteries on the flow in the posterior communicating arteries has been investigated as well, with special attention being paid to the possible occurrence of a 'dead point'. In the model, the influence of diameters of the communicating arteries on the flow in the afferent vessels and the segments of the circle turns out to be considerable, especially in the range of the anatomical variation of the diameters. Within this range flow reductions due to an increased resistance of the vertebral artery will be compensated for by the system. Assuming that the values and ratios of the peripheral resistances are within the physiological range, a dead point is not to be expected in the flow in the posterior communicating arteries.

A mathematical model of the flow in the posterior communicating arteries.

This paper reports on a mathematical model designed to study the hemodynamics of one posterior communicating artery and its afferent and efferent vessels. The variables in the model are the diameter of the posterior communicating artery, the resistance in the vertebral artery and the ratio of the two peripheral resistances. In the model, the "posterior communicating artery" exhibits a compensatory capacity, as defined in the introduction, which appears to be independent of its diameter. The fluxes in the efferent vessels are dominated by the peripheral resistances.

Analysis of flow and vascular resistance in a model of the circle of Willis.

A very simple model of the flow in the circle of Willis is described in this paper. Disregarding pulsatility and vessel wall elasticity, fluxes in all segments of the circle of Willis and its afferent and efferent vessels are calculated by applying the Poiseuille-Hagen formula. Comparison with the fluxes calculated numerically from a more sophisticated mathematical model, including pulsatility, vessel wall elasticity and nonlinear effects, revealed only very slight differences. In short, fluxes in the afferent vessels and the segments of the circle of Willis are influenced by any change of resistance within the network, whereas the fluxes in the efferent segments are dominated by the efferent resistance distribution. However, a great advantage of the present simple model is that it offers the possibility of an analytical approach which yields both an easy sensitivity analysis of parameters and an insight into the mechanisms that govern the flow in a network like the circle of Willis. It can be concluded that these mechanisms are similar to the principles of the Wheatstone bridge, known from electrical circuit theory.

The influence of the angle of confluence on the flow in a vertebro-basilar junction model.

In earlier work, it was demonstrated that the flow in models of the vertebro-basilar junction is highly three-dimensional and the geometry exerts a strong influence on the hemodynamics. The morphology of the vertebro-basilar junction is very variable amongst individuals. In a study of 85 human vertebro-basilar junctions, the angle between the vertebral arteries varied between 10 and 160 degrees. To determine how the flow is influenced by this geometrical parameter, the flow is studied both experimentally, with laser Doppler velocimetry, and numerically, with a finite element package. A series of junction models is used with a range of confluence angles (45, 85 and 125 degrees). It appears that the angle of confluence has a strong influence on the structure and strength of the secondary flow field. The secondary velocities persist far downstream. Furthermore, near the apex, a region with low velocities is present. The larger the confluence angle is, the larger this region is, and even backflow may occur. In addition, the occurrence of atherosclerotic plaques in 85 human vertebro-basilar junctions is studied. Only one preferential location was found: the apex, the other plaques seem to be randomly distributed. The magnitude of the confluence angle of junctions with sharp-edged apices has a significant influence (p = 0.006) on the occurrence of a plaque at the apex. Apparently, a large confluence angle is a geometrical risk factor for atherosclerosis.

Linear and nonlinear one-dimensional models of pulse wave transmission at high Womersley numbers.

The accuracy of nonlinear and linear one-dimensional models in describing pulse wave propagation in a uniform cylindrical viscoelastic tube, with Womersley's parameter alpha equal to 7.6 at 1 Hz, was evaluated. To this end calculations of wave propagation using these models were compared with the experimentally determined propagation of the pressure wave in the tube. The experimentally generated pressure pulse had an amplitude of 9.0 kPa and caused a relative radius change of about 17%. The static pressure vs cross-sectional area relation was found to be nonlinear for these pressure changes. Maximum fluid velocity was about 2.9 ms-1, while the phase velocity was about 5.4 ms-1. The radius change and the ratio of fluid and phase velocities violated the linear model assumptions. The nonlinear model with viscous fluid friction modelled on the basis of Poiseuille's law and treating the tube wall as purely elastic, underestimated the damping of the pulse wave and predicted the formation of shock waves, which were not found experimentally. In the linear models, the viscous friction of the blood was modelled according to either Poiseuille's law or Womersley's theory and the tube wall was treated as either linearly elastic or linearly viscoelastic. A description of the viscous friction of the blood based on Poiseuille's law underestimated damping. Disregarding the viscoelasticity of the tube wall resulted in an underestimation of both phase velocity and damping. In spite of the nonlinearity of the system, the linear viscoelastic Womersley model described the pulse wave propagation satisfactorily.

Computation of steady three-dimensional flow in a model of the basilar artery.

The flow in the basilar artery arises from the merging of the flows from the two vertebral arteries. To study the flow phenomena in the basilar artery, computations have been performed using a finite element (FE) method. We consider steady flow in a geometrically symmetric confluence. For simplicity, channels with a rectangular cross-section have been used. Both symmetric and asymmetric flow cases have been considered. The results show that for the Reynolds number of interest the flow downstream of the junction is highly three-dimensional, and that the flow at the end of the basilar artery, where it splits again, will not be fully developed. The computed phenomena have been confirmed by laser Doppler velocity measurements.

Numerical simulation of blood flow in an artery with two successive bends.

Blood flow in an artery with two successive bends is simulated by a finite-element computation of steady flow of a Newtonian viscous fluid through a rigid tube having the same shape as a specific part of the femoral artery. Notwithstanding the fact that the bends in the model geometry are rather gentle, the axial and secondary flow patterns, computed for a range of values of the Reynolds number Re, show strong and complicated three-dimensional flow effects. In particular, the flow pattern in the second bend for relatively small values of Re (Re < 240) turns out to be drastically different from that for larger Re-values.