Elevated Wall Shear Stress Research Articles

Axial stent strut angle influences wall shear stress after stent implantation: analysis using 3D computational fluid dynamics models of stent foreshortening

IntroductionThe success of vascular stents in the restoration of blood flow is limited by restenosis. Recent data generated from computational fluid dynamics (CFD) models suggest that the vascular geometry created by an implanted stent causes local alterations in wall shear stress (WSS) that are associated with neointimal hyperplasia (NH). Foreshortening is a potential limitation of stent design that may affect stent performance and the rate of restenosis. The angle created between axially aligned stent struts and the principal direction of blood flow varies with the degree to which the stent foreshortens after implantation.MethodsIn the current investigation, we tested the hypothesis that stent foreshortening adversely influences the distribution of WSS and WSS gradients using time-dependent 3D CFD simulations of normal arteries based on canine coronary artery measurements of diameter and blood flow. WSS and WSS gradients were calculated using conventional techniques in ideal (16 mm) and progressively foreshortened (14 and 12 mm) stented computational vessels.ResultsStent foreshortening increased the intrastrut area of the luminal surface exposed to low WSS and elevated spatial WSS gradients. Progressive degrees of stent foreshortening were also associated with strut misalignment relative to the direction of blood flow as indicated by analysis of near-wall velocity vectors.ConclusionThe current results suggest that foreshortening may predispose the stented vessel to a higher risk of neointimal hyperplasia.

Circumferential vascular deformation after stent implantation alters wall shear stress evaluated with time-dependent 3D computational fluid dynamics models

The success of vascular stents in the restoration of blood flow is limited by restenosis. Recent data generated from computational fluid dynamics (CFD) models suggest that stent geometry may cause local alterations in wall shear stress (WSS) that have been associated with neointimal hyperplasia and subsequent restenosis. However, previous CFD studies have ignored histological evidence of vascular straightening between circumferential stent struts. We tested the hypothesis that consideration of stent-induced vascular deformation may more accurately predict alterations in indexes of WSS that may subsequently account for histological findings after stenting. We further tested the hypothesis that the severity of these alterations in WSS varies with the degree of vascular deformation after implantation. Steady-state and time-dependent simulations of three-dimensional CFD arteries based on canine coronary artery measurements of diameter and blood flow were conducted, and WSS and WSS gradients were calculated. Circumferential straightening introduced areas of high WSS between stent struts that were absent in stented vessels of circular cross section. The area of vessel exposed to low WSS was dependent on the degree of circumferential vascular deformation and axial location within the stent. Stents with four vs. eight struts increased the intrastrut area of low WSS in vessels, regardless of cross-sectional geometry. Elevated WSS gradients were also observed between struts in vessels with polygonal cross sections. The results obtained using three-dimensional CFD models suggest that changes in vascular geometry after stent implantation are important determinants of WSS distributions that may be associated with subsequent neointimal hyperplasia.

Effects of arterial geometry on aneurysm growth: three-dimensional computational fluid dynamics study.

Few researchers have quantified the role of arterial geometry in the pathogenesis of saccular cerebral aneurysms. The authors investigated the effects of parent artery geometry on aneurysm hemodynamics and assessed the implications relative to aneurysm growth and treatment effectiveness. The hemodynamics of three-dimensional saccular aneurysms arising from the lateral wall of arteries with varying arterial curves (starting with a straight vessel model) and neck sizes were studied using a computational fluid dynamics analysis. The effects of these geometric parameters on hemodynamic parameters, including flow velocity, aneurysm wall shear stress (WSS), and area of elevated WSS during the cardiac cycle (time-dependent impact zone), were quantified. Unlike simulations involving aneurysms located on straight arteries, blood flow inertia (centrifugal effects) rather than viscous diffusion was the predominant force driving blood into aneurysm sacs on curved arteries. As the degree of arterial curvature increased, flow impingement on the distal side of the neck intensified, leading to elevations in the WSS and enlargement of the impact zone at the distal side of the aneurysm neck. Based on these simulations the authors postulate that lateral saccular aneurysms located on more curved arteries are subjected to higher hemodynamic stresses. Saccular aneurysms with wider necks have larger impact zones. The large impact zone at the distal side of the aneurysm neck correlates well with other findings, implicating this zone as the most likely site of aneurysm growth or regrowth of treated lesions. To protect against high hemodynamic stresses, protection of the distal side of the aneurysm neck from flow impingement is critical.

Endothelial NOS is main mediator for shear stress-dependent angiogenesis in skeletal muscle after prazosin administration.

The increase of wall shear stress in capillaries by oral administration of the alpha1-adrenergic receptor antagonist prazosin induces angiogenesis in skeletal muscles. Because endothelial nitric oxide synthase (eNOS) is upregulated in response to elevated wall shear stress, we investigated the relevance of eNOS for prazosin-induced angiogenesis in skeletal muscles. Prazosin and/or the NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) were given to C57BL/6 wild-type mice and eNOS-knockout mice for 14 days. The capillary-to-fiber (C/F) ratio and capillary density (CD; no. of capillaries/mm2) were determined in frozen sections from extensor digitorum longus (EDL) muscles of these mice. Immunoblotting was performed to quantify eNOS expression in endothelial cells isolated from skeletal muscles, whereas VEGF (after precipitation with heparin-agarose) and neuronal NOS (nNOS) concentrations were determined in EDL solubilizates. In EDL muscles of C57BL/6 mice treated for 14 days, the C/F ratio was 28% higher after prazosin administration and 11% higher after prazosin and L-NAME feeding, whereas the CD increased by 21 and 13%, respectively. The C/F ratio was highest after day 4 of prazosin treatment and decreased gradually to almost constant values after day 8. Prazosin administration led to elevation of eNOS expression. VEGF levels were lowest at day 4, whereas nNOS values decreased after day 8. In EDL muscles of eNOS-knockout mice, no significant changes in C/F ratio, CD, or VEGF and nNOS expression were observed in response to prazosin administration. Our data suggest that the presence of eNOS is essential for prazosin-induced angiogenesis in skeletal muscle, albeit other signaling molecules might partially compensate for or contribute to this angiogenic activity. Furthermore, subsequent remodeling of the capillary system accompanied by sequential downregulation of VEGF and nNOS in skeletal muscle fibers characterizes shear stress-dependent angiogenesis.

Stent design properties and deployment ratio influence indexes of wall shear stress: a three-dimensional computational fluid dynamics investigation within a normal artery.

Restenosis limits the effectiveness of stents, but the mechanisms responsible for this phenomenon remain incompletely described. Stent geometry and expansion during deployment produce alterations in vascular anatomy that may adversely affect wall shear stress (WSS) and correlate with neointimal hyperplasia. These considerations have been neglected in previous computational fluid dynamics models of stent hemodynamics. Thus we tested the hypothesis that deployment diameter and stent strut properties (e.g., number, width, and thickness) influence indexes of WSS predicted with three-dimensional computational fluid dynamics. Simulations were based on canine coronary artery diameter measurements. Stent-to-artery ratios of 1.1 or 1.2:1 were modeled, and computational vessels containing four or eight struts of two widths (0.197 or 0.329 mm) and two thicknesses (0.096 or 0.056 mm) subjected to an inlet velocity of 0.105 m/s were examined. WSS and spatial WSS gradients were calculated and expressed as a percentage of the stent and vessel area. Reducing strut thickness caused regions subjected to low WSS (<5 dyn/cm(2)) to decrease by approximately 87%. Increasing the number of struts produced a 2.75-fold increase in exposure to low WSS. Reducing strut width also caused a modest increase in the area of the vessel experiencing low WSS. Use of a 1.2:1 deployment ratio increased exposure to low WSS by 12-fold compared with stents implanted in a 1.1:1 stent-to-vessel ratio. Thinner struts caused a modest reduction in the area of the vessel subjected to elevated WSS gradients, but values were similar for the other simulations. The results suggest that stent designs that reduce strut number and thickness are less likely to subject the vessel to distributions of WSS associated with neointimal hyperplasia.

Growth of Intracranial Aneurysms Arised from Curved Vessels under the Influence of Elevated Wall Shear Stress-A Computer Simulation Study

Recent studies have suggested that long standing elevated wall shear stress might degenerate the arterial wall and be involved in the pathogenesis of intracranial aneurysm formation and development. The present study focuses on the interplay between the hemodynamic stresses, arterial wall degeneration and deformation. By constructing a computational model and examining the hypotheses that govern the rules to grow an intracranial aneurysm, we simulate the formation and development of intracranial aneurysms. The high wall shear stress is found to propagate towards the proximal and distal end of the formed aneurysm, which becomes the key factor for the expansion of wall degeneration and aneurysm progression. The development of aneurysm is influenced by the wall shear stress threshold, the Reynolds number and the rate of wall degeneration. Our preliminary results indicate that computer simulation can be used in the study of aneurysm mechanics and yields new insight into the mechanism of aneurysm pathophysiology.

Flow patterns at the stenosed carotid bifurcation: effect of concentric versus eccentric stenosis.

Carotid stenosis severity is a commonly used indicator for assessing risk of stroke. However, the majority of individuals with severe carotid artery disease never suffer a stroke, and strokes can occur even with only mild or moderate stenosis. This suggests local factors (other than stenosis severity) at or near the carotid artery bifurcation may be important in determining stroke risk. In this paper we investigate the effect of stenosis geometry on flow patterns in the stenosed carotid bifurcation, using concentrically and eccentrically stenosed anthropomorphic carotid bifurcation models having identical stenosis severity. Computational simulations and experimental flow visualizations both demonstrate marked differences in flow patterns of concentric and eccentric stenosis models for moderately and severely stenosed cases, respectively. In particular, we identify post-stenotic recirculation zone size and location, and spatial extent of elevated wall shear stress as key factors differing between the two geometries. As these are also rotid plaque more vulnerable to cerebral embolus prokey biophysical factors promoting thrombogenesis, we propose that the stenosed carotid bifurcation geometry--or the induced flow patterns themselves--may provide more specific indicators for those plaques that are vulnerable to enhanced thromboembolic potential, and hence, increased risk of ischemic stroke.

Hemodynamics analyses of arterial expansions with implications to thrombosis and restenosis

It is assumed that critical hemodynamic factors play an important role in the onset, localization and degree of post-operative complications, for example, thrombosis and restenosis. Of special interest are sudden expansion flows, which may occur in straight artery segments such as the common carotid after endarterectomy or end-to-end anastomoses. Sudden expansion geometries are possible origins of early post-operative emboli and significant myointimal hyperplasia resulting in early or late complications. Transient laminar axisymmetric and fully three-dimensional blood flows were simulated employing a validated finite volume code in conjunction with a Runge–Kutta particle tracking technique. Disturbed flow indicators, which may predict the onset of thrombosis and/or restenosis, were identified and employed to evaluate 90°-step and smooth expansion geometries. Smooth expansion geometries have weaker disturbed flow features than step expansion geometries. Specifically, the regions near the expansion wall and the reattachment point are susceptible to both atherosclerotic lesion and thrombi formations as indicated by non-uniform hemodynamic indicators such as near-zero wall shear stress and elevated wall shear stress gradients as well as blood particle accumulation and deposition. A new parameter, the wall shear stress angle deviation (WSSAD) has been introduced, which indicates areas of abnormal endothelial cell morphology and particle wall deposition. In turn, regions of low wall shear stress and high wall shear stress gradients are recognized as susceptible sites for arterial diseases. Thus, it is interesting to note that high WSSAD surface areas cover low wall shear stress, high wall shear stress gradient locations as well as high wall particle deposition. A gradual change in step expansion geometry provides better results in terms of WSSAD values and hence potentially reducing atherosclerosis as well as thrombi formation.

Hemodynamic consequences of stenosis remodeling during coronary angioplasty.

Quantitative hemodynamic assessment during various endovascular interventions including balloon angioplasty is lacking. Translesional pressure drops measured by angioplasty catheters can cause flow blockage and thus lead to inaccurate estimates of preintervention and postintervention flow rates. A new analytical model of the flow rate-pressure drop relation across vascular stenoses is utilized that is nonlinear yet relatively simple in principle, easily applicable in vivo, and compatible with the presence of catheters. The model incorporates in vitro experimental evidence, angiographic data on the dimensions and shapes of coronary arterial stenoses before and after balloon angioplasty, reported translesional pressure gradients, and measurements of coronary flow reserve. Reasonable estimates of mean coronary artery flow rates and translesional pressure drops in the absence of angioplasty catheters are obtained. Prior to angioplasty significant flow restriction across a 68% diameter stenosis exists during hyperemic flow conditions. Following successful balloon dilation, increased minimal cross-sectional area (residual 40% diameter stenosis) results in an improved flow rate-pressure drop relation. Despite minimal flow restriction during hyperemic conditions following angioplasty remodeling, residual luminal constriction leads to elevated wall shear stress levels within the entry region of the stenosis. The flow analysis described may be of clinical utility in evaluating the hemodynamic significance of the anatomic severity of stenoses in coronary and peripheral arteries before and after endovascular therapeutic interventions.

Flow-related responses of intracellular inositol phosphate levels in cultured aortic endothelial cells.

In vitro and in vivo evidence indicates that hemodynamic wall shear stress evokes a diversity of biological responses in vascular endothelial cells, ranging from cell shape changes to alterations in low density lipoprotein receptor expression. The signal transduction mechanisms by which the level of fluid mechanical shear stress is recognized by the endothelial cell and translated into these diverse biological responses remain to be elucidated. The present study focuses on the association between the onset of elevated shear stress and activation of the phosphoinositide signal transduction pathway, as measured by the intracellular release of inositol phosphates, in cultured bovine aortic endothelial cells (BAECs). BAECs were seeded, grown to confluence on large polyester sheets, and preincubated with 0.3 microCi/ml [3H]inositol for 24 hours before insertion in parallel-plate flow chambers for exposure to high shear stress (HS) at 30 dynes/cm2 or low shear stress (LS) at < 0.5 dyne/cm2 for periods ranging from 15 seconds to 24 hours. The induction of HS was associated with an early, transient but significant increase (142%, HS/LS x 100%) in inositol trisphosphate (IP3) measured at 15 seconds of shear stress exposure followed by a major peak in IP3 (189%) observed at 5 minutes after HS onset. After these initial increases, IP3 levels returned to near resting levels within 30 minutes of continued HS exposure and then continued to decline to significantly lower (75%) levels relative to LS-treated cells within 4 hours and remained lower throughout the remainder of the 24-hour HS exposure. LS-treated cells exhibited no significant changes in inositol phosphate levels throughout the 24-hour exposure periods. Exposure of BAECs to shear stress of 60 dynes/cm2 resulted in an approximately fourfold increase in IP3 levels (396%) measured at 5 minutes, almost double the levels measured in cells exposed to 30 dynes/cm2 for 5 minutes. Pretreatment of BAECs for 30 minutes with 5 mM neomycin, an inhibitor of phosphoinositide metabolism, before HS exposure inhibited both the early increases in inositol phosphates and subsequent cell elongation and alignment observed in untreated BAECs simultaneously exposed to HS without inhibiting protein synthesis. These results indicate that the exposure of cultured BAECs to elevated wall shear stress is associated with an early biphasic IP3 increase followed by a resetting of intracellular inositol phosphate concentrations to levels below that observed in static cultured BAECs. Furthermore, neomycin inhibition of this IP3 response to shear stress is associated with an inhibition of one of the major endothelial biological responses to shear stress, i.e., cell shape change and orientation.(ABSTRACT TRUNCATED AT 400 WORDS)

A Numerical Simulation of Flow in a Two-Dimensional End-to-Side Anastomosis Model

In order to understand the possible role that hemodynamic factors may play in the pathogenesis of distal anastomotic intimal hyperplasia, we carried out numerical simulations of the flow field within a two-dimensional 45 degree rigid-walled end-to-side model anastomosis. The numerical code was tested and compared with experimental (photochromic dye tracer) studies using steady and near-sinusoidal waveforms, and agreement was generally very good. Using a normal human superficial femoral artery waveform, numerical simulations indicated elevated instantaneous wall shear stress magnitudes at the toe and heel of the graft-host junction and along the host artery bed. These sites also experienced highly variable wall shear stress behavior over the cardiac cycle, as well as elevated spatial gradients of wall shear stress. These observations provide additional evidence that intimal hyperplasia may be correlated to wall shear stresses over the cardiac cycle, high wall shear stress gradients, or a combination of the three. The limitations of the present work (especially in regard to the two-dimensional nature of the flow simulations) are discussed, and results are compared to previous observations about distal anastomotic intimal hyperplasia.

Increase in endothelial cell density before artery enlargement in flow-loaded canine carotid artery.

To investigate the morphologic basis of blood flow-dependent adaptive vascular enlargement, we quantitated endothelial cell density, dimensions, and structure in canine carotid arteries that were flow-loaded for 4 weeks, i.e., just before the development of significant adaptive enlargement. Increased flow was produced in the right common carotid artery of seven adult beagle dogs by an arteriovenous shunt to the right external jugular vein. The left common carotid artery was used to produce sham-operated controls. Five additional animals were used to produce sham-shunted controls, and two dogs were used as nonoperated controls. The blood flow rate (BFR) and wall shear rate (WSR) were markedly increased immediately after anastomosis in the proximal segment of the shunted artery (BFR = 719 +/- 142 ml/min, WSR greater than 4127 +/- 1002/sec) and after 4 weeks (BFR = 628 +/- 157 ml/min, WSR greater than 2919 +/- 388/sec) compared to the same artery before anastomosis (BFR = 154 +/- 50 ml/min, WSR = 904 +/- 314/sec, p less than 0.01 x 10(-3) for both comparisons) and to the contralateral control artery after 4 weeks (BFR = 365 +/- 110 ml/min, WSR = 2136 +/- 876/sec, p less than 0.01 and p less than 0.05, respectively, compared to the shunted side). In the shunted artery, endothelial cell density was markedly increased (6.15 +/- 0.68 x 10(3) cells/mm2 compared to 3.33 +/- 0.70 x 10(3) cells/mm2 for the controls, p less than 0.001). Endothelial cells on the high flow side were markedly narrowed in both axial and circumferential directions, but were radially thickened; nuclei became prolate-spheroid in shape. On the control side, cells were relatively flat and thin. We conclude that elevated wall shear stress induces an early increase in endothelial cell number and that this increase precedes the development of significant blood flow-dependent vascular enlargement.

Inverse effect of chronically elevated blood flow on atherogenesis in miniature swine

The effect of chronically elevated blood flow on the development of atherosclerosis in miniature swine was studied. Fistulas connecting the right external iliac artery and vein were surgically created in four swine, while three were not fistulated. Pulsed Doppler velocity detection cuffs placed around the abdominal aorta and both iliac arteries of all pigs permitted chronic measurements of blood velocity, blood velocity distributions, and blood flow. All swine were fed an atherogenic diet consisting of 20% beef tallow, 3% cholesterol, and 5% cholic acid for 6 months. This diet elevated the serum cholesterol to values exceeding 500 mg/100 ml. Creation of the arteriovenous fistula (AVF) markedly elevated blood velocity and flow in the abdominal aorta and in the shunted iliac artery. In the shunted animals the aortic blood flow was 42.1 ± 2.0 ml/sec compared with 17.3 ± 1.4 ml/sec in the unshunted swine. The velocity distribution pattern across the vessel was also indicative of an elevated wall shear stress. After 6 months, the animals were killed and the arterial vessels examined macroscopically and microscopically for the presence of atherosclerotic lesions. In the shunted pigs, 17 15% of the lumenal surface was occupied by sudanophilic lesions, whereas 80 8% of the surface was covered by lesions in the unshunted (control) pigs. From these studies, it is apparent that mechanical factors related to blood flow rates can influence the development of atherosclerotic lesions in swine.