- Email: [email protected]
Effects of Carotid Artery Stenting on Arterial Geometry
Effects of Carotid Artery Stenting on Arterial Geometry Alexey V Kamenskiy, PhD, Iraklis I Pipinos, MD, PhD, Yuris A Dzenis, PhD, Jai Bikhchandani, MD, Prateek K Gupta, MD, Nick Phillips, BS, Syed A Jaffar Kazmi, MD, Jason N MacTaggart, MD The role of carotid artery stenting (CAS) for the treatment of carotid artery disease continues to evolve, despite higher stroke and restenosis risks for CAS compared with conventional open endarterectomy. Understanding the effects of CAS on arterial geometry, which strongly influence hemodynamics and wall mechanics, can assist in better stratifying the inherent risk of CAS to individual patients. STUDY DESIGN: Fifteen consecutive patients undergoing CAS had pre- and post-stenting CT angiograms. These images were used to reconstruct the 3-dimensional geometries of the bilateral carotid arteries from their origin to the skull base. Quantitative assessment of the carotid bifurcation angle, cross-sectional area, tortuosity and artery length, were compared pre- and poststenting. Plaque volume and calcification were also measured. Mathematical models were devised to determine the mechanisms of CAS-induced geometric changes, and their mechanical and hemodynamic significances. RESULTS: Major and moderate changes in arterial tortuosity and elongation were seen in 5 (33%) patients. Characteristics most associated with the development of CAS-induced geometric changes were stenoses located in the internal carotid artery distal to the carotid bulb, circumferential distribution of plaque, and plaque calcification. Modeling did not demonstrate substantial alterations in wall shear stress due to geometric changes, but did show considerable increases in arterial wall axial stress. CONCLUSIONS: Cartoid artery stenting can produce geometric changes to the artery that promote favorable conditions for complications and recurrent disease. Patients with circumferential, highly calcified plaques that are located relatively distal in the internal carotid artery are most likely to have post-stenting geometric changes. (J Am Coll Surg 2013;217:251e262. 2013 by the American College of Surgeons) BACKGROUND:
Stroke is the third most common cause of death and the leading cause of disability in the United States,1 with carotid bifurcation atherosclerotic disease being one of the most common correctable culprits. In addition to medical therapies, 2 procedures are used to treat carotid artery stenosisdopen carotid endarterectomy (CEA) and carotid artery stenting (CAS). Traditionally, CEA has been the gold standard for management of both symptomatic and asymptomatic high-grade carotid artery stenosis, and original indications for CAS were limited to anatomically and physiologically high-risk patients.1 However, the minimally invasive nature, shorter procedure and patient-recovery times, and expanded pool of physicians capable of performing the procedure, have popularized CAS beyond its original indications.1-3 Recent data comparing CAS with CEA demonstrate that CAS is associated with increased risks of postprocedural clinically silent ischemic brain lesions, shortterm (30-day) and long-term (>6 months) stroke, and
Disclosure Information: Nothing to disclose. This work was supported in part by NIH grant R01AG034995, and by grants from the Nebraska Research Initiative Nanofiber Core Facility, the National Science Foundation, the University of Nebraska-Lincoln/ University of Nebraska Medical Center Engineering for Medicine initiative, and the Charles and Mary Heider Fund for Excellence in Vascular Surgery. Presented at the American College of Surgeons 98th Annual Clinical Congress, Chicago, IL, October 2012. Received December 27, 2012; Revised February 13, 2013; Accepted March 22, 2013. From the Departments of Surgery (Kamenskiy, Pipinos, MacTaggart) and Pathology and Microbiology (Kazmi), University of Nebraska Medical Center, Department of Surgery, Creighton University Medical Center (Bikhchandani), Omaha, Departments of Mechanical and Materials Engineering (Dzenis) and Biological Systems Engineering (Phillips), University of Nebraska-Lincoln, Lincoln, NE, and Department of Surgery, University of Wisconsin Hospital and Clinics, Madison, WI (Gupta). Correspondence address: Alexey V Kamenskiy, PhD or Jason N MacTaggart, MD, Department of Surgery, 985182 Nebraska Medical Center, Omaha, NE 68198-5182. email: [email protected] or [email protected]
ª 2013 by the American College of Surgeons Published by Elsevier Inc.
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Abbreviations and Acronyms
CAS CCA CEA 3D ECA HMM-1 ICA NASCET
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
carotid artery stenting common carotid artery carotid endarterectomy 3-dimensional external carotid artery Hemodynamic Mathematical Model internal carotid artery North American Symptomatic Carotid Endarterectomy Trial PMM-II ¼ Parametric Mathematical Model WSS ¼ wall shear stress
restenosis,4 which points to the need for the development of methods that can identify the subsets of patients at increased risk for complications after CAS. This goal cannot be achieved without a sound understanding of the changes that CAS introduces to the geometry, hemodynamics, and wall mechanics of the treated carotid. Few computational studies describing potential changes to the blood flow after CAS have been performed,5,6 yet a comprehensive analysis of the actual stented carotid is still missing, even though some investigators occasionally report kinks in the internal carotid artery (ICA) after CAS and their potential contribution to restenosis.2,7 The objective of our analysis was to study the effects of CAS on the geometry, hemodynamics, and mechanics of the carotid artery, and to identify the conditions that can result in severe changes after CAS.
METHODS The research protocol was approved by our Institutional Review Board. Fifteen consecutive male patients who subsequently underwent CAS were included in the study. All patients had unilateral CAS done between 2007 and 2010. Computer reconstructions of 3-dimensional arterial geometry Preoperative and 15 11 month follow-up CT angiograms of patients’ arteries were obtained using 64channel scanner Brilliance 64 (Philips Medical Systems). The patients were imaged in the supine position during inspiration breath hold. Computed tomography angiography images were taken with an axial slice thickness of 1 mm. Resolution of each image was 512 512 pixels (pixel size 0.488 mm). The bilateral carotid arteries were reconstructed from the aortic arch to the skull base using Mimics v15 software (Materialize). In addition to the stented artery, we also analyzed the contralateral carotid to ensure that the observed changes in the treated artery after CAS were
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not due to variations in the position of the head on the pre- and post-CAS CT angiograms. This comparison demonstrated no changes in the contralateral artery post-stenting. Arterial, plaque, and stent contours were semi-automatically segmented using a combination of thresholding and region growing techniques. Segmentation was performed under the supervision of a vascular surgeon who assisted the algorithm by correcting the segments of the automatically detected boundary that were partially obscured by the periadventitial fat or the atherosclerotic plaque, or were ill-defined due to poor contrast. For each carotid with CAS, 4 different segmentations (ie, flow lumen, outer wall border, plaque, and stent) were obtained to quantify cross-sectional area, plaque volume, degree of stenosis, and other parameters. An additional fifth segmentation was performed for the calcified plaques to measure the percent of calcium in the plaque volume. For brevity, the contralateral control artery was reconstructed using a single segmentation that included the flow lumen and the plaque. Assessment of carotid artery stentinginduced geometric changes Changes in the carotid geometry after CAS were identified by comparing preoperative and postoperative CT scans for differences in the 3-dimensional (3D) shape, bifurcation angle, cross-sectional area of the lumen, tortuosity, and ICA elongation. The bifurcation angle was calculated as the angle between the common carotid artery (CCA)-ICA and CCA-external carotid artery (ECA) centerlines in the 3D space.8 The area of the lumen was measured for each CCA-ICA cross-section in the plane perpendicular to the arterial centerline. Assessment of area instead of the conventional radius allowed us to account for the noncircular shape of the cross-section, which was particularly important in the highly stenotic irregular lumina. In addition, it allowed estimation of the actual degree of stenosis by calculating the ratio of the flow lumen area to the area of the entire arterial cross-section. Tortuosity (fractional increase in length of the tortuous vessel relative to a perfectly straight path) of the arterial centerlines was calculated as T ¼ 1 D/C, where D is the linear (shortest) distance between the 2 points, and C is the distance between the same points along the arterial centerline. T was calculated for 2 arterial segments: the stented bifurcation (Tstent), and the distal ICA (Tdistal). The first segment started at the proximal end of the stent and ended at its distal end; and the second segment started at the distal end of the stent and ended at the skull base. Calculation of the 2 tortuosities allowed separate estimations of the amount of straightening produced by
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the deployed stent, and kinking of the distal ICA post intervention. Elongation of the distal ICA was calculated as the increase in the length of the centerline segment starting from the take off of the ICA and ending at the skull base. Both elongation and tortuosity were measured using the centerlines of the arteries with outer wall boundary (pink colored in Fig. 1). This allowed us to avoid overestimation of the length that comes from perturbations of the flow lumen centerline in the heavily diseased regions (red colored in Fig. 1). Hemodynamic significance of carotid artery stentinginduced changes: Hemodynamic Mathematical Model The Hemodynamic Mathematical Model (HMM-I) was created for the carotid artery with the most severe CASinduced changes in tortuosity and ICA elongation. This model was then used to assess the hemodynamic significance of the observed geometric changes. HMM-I was intentionally built “idealized,” that is, with smoothly varied circular cross-sections and uniform wall thickness. This allowed study of the isolated influence of CASinduced tortuosity and elongation, and avoided hemodynamic effects from irregularities in luminal contours and nonuniform wall thickness. Cross-sectional diameters were conceived as circles with areas equivalent to the actual CT measurements. Arterial wall of uniform thickness was created by expanding the contours in both preoperative and postoperative carotids. Our simulations accounted for the interaction between the blood flow and the arterial wall and used Finite Element software (ADINA v8.8 R&D). Details of model development, solution algorithms, and assessment of model accuracy can be found elsewhere.9 Briefly, we constructed fine tetrahedral meshes that closely matched the
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blood flow and arterial wall of the preoperative and postoperative arterial geometries. Continuity and the full Navier-Stokes equations in Arbitrary Lagrangian Eulerian formulation (to account for the moving boundary) were solved for the blood flow. Blood was modeled as a nonNewtonian fluid described by the Carreau constitutive law.10 Boundary conditions for the blood flow included catheter pressure waveform measurements in the CCA and duplex derived pulsatile flow velocities in the ICA and ECA, both based on previously published human in vivo data.11,12 Because the stented segment of the cervical carotid artery is a fraction of the total length of the evaluated artery, the inlet (level of the CCA at take off from either the brachiocephalic or the arch) and outlet (level of entry of the ICA in the skull) boundary conditions had minimal influence on the flow in the bifurcation.13 The momentum conservation equation in the Lagrangian description for large displacements and large strains was solved for the arterial wall. The carotid tissue was realistically modeled as a nonlinear hyperelastic anisotropic material with strain energy taken in the Holzapfel-Gasser-Ogden form.14 The constitutive model parameters for the arterial wall were determined from our experimental data representing the average human carotid artery.15 The stent was simulated by assigning Nitinol properties16 at 37 C to the stented region of the artery, mimicking the rigidity of the bifurcation post intervention. We note that, in reality, the complex mesh geometry of the stent impacts the nature of the blood flow at its interface with the carotid wall. However, it is likely that the influence of the stent struts/carotid wall interplay on the flow distal to the stent (that is of interest in this study) is not very significant. Obviously, additional studies and explicit models of the blood flow through the stent struts are required to verify this speculation. Full coupling between the blood flow and the
Figure 1. Carotid arteries with large amounts of calcium in the atherosclerotic plaques. Volume of calcium is given as percentage of the total plaque volume. Internal carotid artery flow is colored in red. External carotid artery flow is not visualized.
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arterial wall was achieved by imposing the compatibility of displacements, equilibrium of tractions, and no-slip conditions on the interface. The hemodynamic significance of the changes produced by CAS was assessed by calculating the wall shear stress (WSS; magnitude of the fluid tangential traction vector). Although WSS is not the only hemodynamic factor known for its involvement in pathogenesis,9 it is perhaps the most commonly used one when studying flow in arteries.17-19 Low WSS (<0.4 Pa) is known to stimulate an atherogenic phenotype in the carotid wall, and physiological and elevated shear (values >1 to 2 Pa18 but <40 Pa20) induce endothelial quiescence and an atheroprotective gene expression profile.18,21 Calculation of WSS involved multiplication of the dynamic blood viscosity with the velocity gradient projected onto the luminal surface and calculated in the direction of local vu unit surface normal nbs as ss ¼ m , where ss is the vb ns vu WSS, m is the variable blood viscosity and is the vb ns velocity gradient in the direction of surface normal. In addition to WSS, we estimated the axial stress in the arterial wall that resulted from CAS-induced ICA elongation. High mechanical stress can damage the arterial wall, which can promote migratory and proliferative responses of vascular smooth muscle cells and can eventually result in restenosis.22,23 Identification of morphological conditions that result in carotid artery stentinginduced changes and development of Parametric Mathematical Model Pearson product-moment correlation coefficients were calculated to establish correlations between the datasets of patients’ age, stenosis severity, preoperative bifurcation angle, change in bifurcation angle after CAS, plaque total volume, plaque calcium, pre-CAS tortuosity, change in tortuosity after CAS, and CAS-induced ICA elongation. Pearson coefficient is used to measure the strength of linear association between two paired variables, and it is computed as the ratio of the covariance to the product of the standard deviations. Datasets that were found to have the strongest correlation (highest absolute values of Pearson’s coefficient) with CAS-induced tortuosity and elongation were further analyzed in detail using the Parametric Mathematical Model (PMM-II). The Parametric Mathematical Model possessed higher spatial resolution than HMM-I, but focused on the smaller segment of the arterial bifurcation. To ensure that the results obtained by our PMM-II model were
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not specific to a particular patient, we developed the model using the mean carotid artery geometry,8 mean arterial wall,15 and atherosclerotic plaque24 properties. Both the arterial wall and the plaque were assumed to be homogeneous, and were modeled with nonlinear hyperelastic anisotropic Holzapfel-Gasser-Ogden constitutive strain energy potentials.14 We note that although the assumption of plaque homogeneity can be quite strong, the data on plaque properties are scarcely available in the literature. Finite Element simulations used the same steps and procedures described here for the HMM-I. A 3D Nitinol stent was deployed in the PMM-II, mimicking the actual endovascular procedure. First, the stent was compressed radially, simulating the loading of the device into the delivery system. After that, the stent inside the delivery system sheath was placed into the target lesion and the sheath was removed, allowing the stent to deploy gradually, opening from the distal to the proximal end. Simple nonpenetrating frictionless contact was assumed between the arterial wall and the stent.
RESULTS Fifteen consecutive male patients (age 67 9 years old) undergoing CAS were included in the study. The carotid stenosis was symptomatic in 6 and asymptomatic in 9 patients. The stenosis produced a mean 82% 9% diameter reduction of the ICA as determined per North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria25 using CT angiography. None of these patients had previous open or endovascular carotid interventions. None of the patients died or had stroke or transient ischemic attack after CAS. Ev3 Prote´ge´ tapered stents were used in 6 patients, Boston Scientific Wallstents were used in 7 patients, and Abbott Vascular Acculink tapered stents were used in 2 patients. Due to the variety of stents used in these series, and the small number of patients in our study, the effect of the stent design on the outcomes measured was not assessed. Such effects have been evaluated previously in works by Holzapfel and colleagues26 and Conti and colleagues.6 Computer reconstructions of 3-dimensional arterial geometry Preoperative and postoperative 3D reconstructions of both left and right carotid arteries were obtained for all 15 patients. Plaque volume (in mm3) measured in all patients is presented in Table 1. Fraction of calcium in each plaque is presented as a percentage of the total plaque volume. Plaques with high fractions of calcium are plotted in Figure 1. Calcium constituted a mean of only 8% 9% of the total plaque volume.
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Table 1. Patient
Vtotal, mm3 VCa, %
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Atherosclerotic Plaque Volume and Fraction of Calcium in Each Plaque for Patients 1 to 15 1
2
3
4
5
6
7
495 13
851 20
266 0
354 4
589 8
376 0
811 0
Patient no. 8 9
932 30
1,333 9
10
11
12
13
14
15
Mean
1,797 1
959 14
479 0
594 3
1,066 15
794 0
780 8
Vtotal, total plaque volume; VCa, fraction of calcium in the total plaque volume.
Assessment of carotid artery stentinginduced geometric changes The mean bifurcation angle before CAS was 27 12 degrees, with a range of 5 to 53 degrees. After CAS, the angle decreased to 22 9 degrees and range decreased to 10 to 45 degrees, neither were statistically significant (p ¼ 0.124). In 2 patients, the bifurcation angle increased, and in another 2 it was unchanged; however, 3 of these 4 patients had preoperative bifurcation angles significantly more narrow than average. The changes in bifurcation angles (Da, degrees) after CAS for all patients are given in Table 2. Cross-sectional area of the lumen before and after CAS for all patients is plotted in Figure 2. Graphs represent the change in lumen area along the CCA-ICA arterial axis as one progresses from proximal to distal (shown in bright red in Fig. 3). Small fluctuations characterize irregularity of the lumen and steep drops indicate either stenosis or position of the stent end. Each graph was normalized to the area at the most proximal CCA site to ensure proper comparison of preoperative and postoperative segmentations. Table 3 contains comparisons of stenosis severity measured before CAS using the conventional NASCET25 method, and the ratio of lumen areas described here. Comparison of measurements shows that NASCET, on average, underestimated the stenosis by 11% 11% (p < 0.01) with the largest underestimation by 38% (patient no. 15) and overestimation by 10% (patient no. 13). Underestimation of stenosis by NASCET method should be expected, as the arterial centerline is rarely perpendicular to the imaging plane. In addition, the small diameter of the distal ICA compared with the size of the bulb can substantially affect the NASCET ratio and result in gross underestimation, as was observed in patient no. 15. After CAS actual stenosis severity improved in 80% of patients (p < 0.01) showing a mean 17% 11% increase
in cross-sectional area (measured in the most narrow location) at the time of follow-up. In 20% of patients (no. 1, 2, and 9), the stenosis was the same as before stenting, although intra-procedural angiography and immediate post-procedural ultrasound evaluation after CAS demonstrated <10% residual stenosis. Typically, the most severe stenoses before and after CAS were observed slightly distal to the take off of the ECA. After CAS, stenosis was also common at the distal end of the stent (eg, no. 11, 14, and 15). Although follow-up CTAs were performed at variable time points post stenting, no correlation was observed between the time of follow-up and stenosis severity after CAS (Pearson ¼ 0.02). In roughly half (47%) of our patients, the lumen of the distal ICA became larger after CAS. In the other 8 patients it was unchanged or slightly decreased, as can be seen in patients no. 3, 8 and 9. Tortuosity of the stented bifurcation (Tstent) decreased in 80% of patients after CAS (p ¼ 0.013) by a mean DTstent ¼ 0.02 0.03 (range 0.09 to 0.01). The straightening of the artery was followed by kinking of the distal ICA after CAS (p ¼ 0.282). On average, Tdistal increased by Tdistal ¼ 0.02 0.03 (range 0.01 to 0.11) which was the same amount Tstent decreased after CAS. This, however, does not mean that the overall tortuosity of the artery from the proximal stent end to the skull base remained unchanged because tortuosity is (by definition) calculated relative to a specific distance. Values of DTdistal are summarized in Table 2. The change in distal ICA tortuosity was appreciable in only 33% of the patients (DTdistal ¼ 0.020.11). Arteries of those patients are presented in Figure 3 (lower panel). Special attention should be given to patient no. 2, as this artery demonstrated the most severe change (DTdistal ¼ 0.11) among all patients. After CAS, the distal ICA elongated in 67% of patients (p ¼ 0.012; Table 2). Although overall
Table 2. Change in Bifurcation Angle, Distal Internal Carotid Artery Tortuosity, and Internal Carotid Artery Elongation in Patients after Carotid Artery Stenting Change
1
2
3
4
5
6
Patient no. 7 8
9
Da, degrees 10 5 2 2 15 0 5 7 23 DTdistal 0.01 0.11 0.01 0.01 0.01 0.01 0.01 0.03 0.03 DL, mm 1 6 1 1 1 0 1 3 2
10
11
12
13
14
15
Mean
5 0 0
4 0.01 1
6 0 0
1 0.01 1
0 0.02 2
3 0.02 1
5 0.02 1
Da, bifurcation angle; DL, internal carotid artery elongation; DTdistal, distal internal carotid artery tortuosity.
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Figure 2. Change in cross-sectional area of the lumen along the common carotid artery (CCA)-internal carotid artery (ICA) axis before (red) and after (blue) carotid artery stenting. Segments of the artery that correspond to the graphs are plotted in Figure 1 with bright red color. Distance between the peaks in the graphs is given in millimeters. Measurements were normalized to the proximal CCA area to ensure adequate comparison of preoperative and postoperative segmentations. ECA, external carotid artery.
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Figure 3. Carotid arteries with and without carotid artery stenting (CAS)induced changes in tortuosity. Left geometry is pre-CAS, right is post-CAS. Bright red color represents the flow, blue color represents the stent.
elongation of the entire ICA was rather small, elongations within the stented region of the artery were significant and inhomogeneous. These elongations were calculated by aligning the proximal portions of the preCAS and post-CAS area-over-the-length graphs (that were strikingly similar) and calculating the distance between the peaks in the stented and distal regions (see Fig. 2, graphs 2, 8, and 9). A distal shift in a peak indicates CAS induced axial stretch. In patient no. 2, for example, the change in elongation ranged from 5 to 21 mm. Interestingly, the segment that showed a 21-mm elongation corresponded to the most severe
stenosis and the largest concentration of calcium in the plaque of this patient (see Fig. 1, patient no. 2). Hemodynamic and mechanical significance of carotid artery stentinginduced changes We used HMM-I to evaluate the hemodynamic significance of CAS-induced ICA tortuosity (DTdistal) and elongation (DL) for patient no. 2, who demonstrated the most severe changes. The influence of tortuosity was assessed by comparing pre- and post-CAS WSS (Pa) contours presented in Figure 4. These contours show that CAS improved the
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Table 3. Stenosis Severity Measured before Carotid Artery Stenting Using Conventional North American Symptomatic Carotid Endarterectomy Trial Method and the Ratio of Cross-Sectional Areas Variable
Stenosis NASCET Stenosis actual
Patient no. 8 9
1
2
3
4
5
6
7
70
80
90
95
90
75
80
80
77
97
92
96
95
97
97
99
10
11
12
13
14
15
Mean
85
80
90
80
90
90
60
82
92
95
97
96
80
95
98
93
NASCET, North American Symptomatic Carotid Endarterectomy Trial.
hemodynamics in the carotid bulb by decreasing the area of low shear (<0.4 Pa18) as much as 6-fold. Note that location of low WSS area corresponds to the largest stenosis in the artery both before and after CAS. Despite low shear being present in the carotid bulb, the ICA kink (the cause of high tortuosity) possesses normal physiologic shear. The influence of ICA elongation was evaluated by estimating the axial stress resulting from CAS-induced axial stretch. Estimation was done using the biaxial experimental data on the mechanical properties of the human carotid arteries.15 These data suggest that an axial stretch of 1.125 to 1.525 (which corresponds to 5-mm and 21-mm elongations of the 40-mm stented segment) results in axial stress of approximately 50 kPa to 1 to 2 MPa. To put these numbers into perspective, stage II hypertension (160 mmHg) roughly translates into 100 kPa of circumferential engineering stress as estimated by the simple Laplace law. Although circumferential and axial stresses are different, for illustrative purposes one can appreciate that the circumferential stress due to hypertension is at least 10-fold smaller than the axial stress induced by CAS in patient no. 2. Identification of morphological conditions that result in carotid artery stentinginduced changes Pearson product-moment correlation coefficients calculated between the datasets of patients age, stenosis severity, preoperative bifurcation angle, change in bifurcation angle after CAS, plaque total volume, plaque calcium, pre-CAS tortuosity, change in tortuosity after CAS, and CASinduced ICA elongation are presented in Figure 5. Pearson’s coefficient in the range of 0 to 0.25 indicate no correlation (colored in gray), values of 0.25 to 0.5 show moderate correlation (colored in yellow), and values of 0.5 to 1 show strong correlation between the datasets (colored in red). Analysis of correlations demonstrated that senior patients had more tortuous arteries (Pearson ¼ 0.640) with larger plaques (Pearson ¼ 0.569). Severely stenosed arteries had smaller bifurcation angles (Pearson ¼ 0.476), and they were less likely to change this angle after CAS
(Pearson ¼ 0.620). Tortuous arteries had larger plaques (Pearson ¼ 0.633) and their bifurcation angle was more likely to change after CAS (Pearson ¼ 0.497). Arteries with highly calcified plaques were more likely to become longer (ie, stretch axially, Pearson ¼ 0.642) and more tortuous (Pearson ¼ 0.512) after CAS. Interestingly, no correlation was found between the size of the plaque and the amount of calcium in it (Pearson ¼ 0.218). Size of the plaque was also not correlated with either CAS-induced tortuosity (Pearson ¼ 0.146) or elongation (Pearson ¼ 0.195). Finally, the amount of
Figure 4. Three-dimensional distributions of temporal mean wall shear stress (WSS) (Pa) in carotid artery before (left) and after (right) carotid artery stenting as predicted by Hemodynamic Mathematical Model. Magenta color represents atherogenic WSS <0.4 Pa.14 Arterial wall is removed for better visualization.
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Variable Age Actual stenosis Pre-CAS bifurcation angle Change in bifurcation angle after CAS Plaque total volume Plaque calcium Pre-CAS tortuosity Change in distal ICA tortuosity after CAS ICA Elongation after CAS
Age
Actual stenosis
pre-CAS bifurcation angle
Change in bifurcation angle after CAS
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Plaque, total volume
Plaque calcium
pre-CAS tortuosity
Change in distal ICA tortuosity after CAS
1 -0.278 -0.078
1 -0.476
1
0.129
-0.620
0.689
1
0.569 -0.192 0.640
-0.050 0.260 -0.327
0.076 -0.251 0.274
0.247 -0.156 0.497
1 0.218 0.633
1 -0.051
1
-0.387
0.208
0.160
0.054
0.146
0.512
0.042
1
-0.361
0.241
0.064
0.011
0.195
0.642
0.057
0.980
259
ICA Elongation after CAS
1
Figure 5. Pearson product-moment correlation coefficients calculated for various datasets. Values in the range 0 to 0.25 indicate no correlation (gray), values 0.25 to 0.5 show moderate correlation (yellow), and values 0.5 to 1 show strong correlation (red). Correlation between any datasets of A and B is located on the intersection of the row A and a corresponding column B. Positive values indicate direct relation, and negative values indicate inverse relation. CAS, carotid artery stenting; ICA, internal carotid artery.
time elapsed after CAS (ie, time of the follow-up CT scan) had no effect on either elongation (Person ¼ 0.187) or tortuosity (Pearson ¼ 0.136). The analysis summarized in Figure 5 shows that the high amount of calcium in the patient’s plaque was the most reliable indicator of CAS-induced tortuosity (DTdistal) and ICA elongation (DL). To identify the mechanism of how stiff calcified plaque promotes elongation of the distal ICA after CAS, we used PMM-II with 2 types of atherosclerotic plaques: soft and stiff (calcified). Properties of both plaque types were determined from the experimental mechanical testing of human plaques.24 The stent modeled in PMM-II was the tapered EV3 Prote´ge´ 10/7 40. This stent was used in 3 of 5 patients with CAS-induced changes, including patient no. 2 with largest DTdistal and DL. Results of modeling with PMMII are presented in Figure 6. The left panel demonstrates the influence of plaque stiffness on DL. During deployment, the articulated tapered section of the stent anchored the plaque and pushed the artery distally. Soft plaque was less resistant to stent deployment, which resulted in larger lumen and an axial elongation of only 1.5 mm after CAS. Stiff calcified plaque on the other hand constrained the radial expansion of the stent, which resulted in severe stent deformation, smaller lumen, and a 3 times larger axial extension of 4.7 mm. The influence of the deployment site on DL was evaluated by moving the stent proximally and distally. Plaque properties were set up as average between soft and stiff.24 Results of modeling are presented in the right panel of Figure 6. Proximal stent deployment resulted in ICA elongation of only 1.9 mm. When the stent was deployed distally, DL increased 2-fold to 4 mm via the same plaque anchoring mechanism described here. We note again that plaque was assumed homogeneous in these simulations.
In reality, however, plaque inhomogeneity, and particularly variations in location and amount of calcium in it, can produce substantial inhomogeneity in the axial stretch. This, for example, was found from the analysis of the CT angiography scans of patient no. 2 described here (stretch of 1.125 to 1.525 within the stented region). Distal deployment also produced abrupt changes in the lumen area at the ends of the stent, caused by the larger diameter of the device compared with the artery. This correlates with steep slopes of the area-over-the-length curves presented in Figure 2. Analysis of stress distributions in these areas using PMM-II showed that the distal end of the stent imposed substantial circumferential stress in the ICA. This stress was in the order of several hundred kPa, several times larger than the one estimated at the stage II hypertension mentioned previously.
DISCUSSION Despite the recent progress in device and technique refinements aimed at making CAS safer,27 most randomized controlled clinical trials report that CAS is still associated with an increased risk of periprocedural, intermediate and long-term complications.4,28 However, certain patients do appear to benefit from CAS over CEA.29 It is therefore vital to develop criteria for identifying patients who are at the greater risk with CAS. Patient-specific risk factors that were earlier reported to be associated with complications include age, sex, altered levels of high-density lipoprotein cholesterol, hyperglycemia, and renal insufficiency.27 These systemic risk factors are the same for both CAS and CEA, but they do not explain more frequent adverse events with CAS or the occurrence of unilateral complications in patients with bilateral repair.30,31 In this study, we attempted to
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Figure 6. Results of parametric modeling with Parametric Mathematical Model showing Ev3 Prote´ge´ tapered 10/7 40 mm stent deployed in the 8.5/5.5 mm artery with severe stenosis. The left panel shows the influence of plaque stiffness, and the right panel shows the influence of deployment location on the post-stenting internal carotid artery elongation DL.
identify other localized arterial factors that can stratify the inherent risk specific to CAS. Our results suggest that circumferential highly calcified plaques that involve >1 cm of the proximal ICA can result in higher predisposition of the artery to adverse geometric, hemodynamic, and mechanic changes after CAS. In addition, it appears that highly calcified plaques limit the ability of the stent to deform the abnormal portion of the artery and, therefore, the deformation is transferred to the nondiseased portion, usually located distally. In addition, the less calcified (and the more deformable) the plaque, the less geometric change occurs. We have shown that severe axial extension of the ICA produced by the high stiffness of the plaque, is accompanied by axial stress that can damage the arterial wall.20 Arterial wall damage has been shown to lead to cell migratory and proliferative responses, platelet deposition, and development of restenosis.22,23 Although these findings and associations are mostly speculative, and in vitro experimentation and rigorous clinical study are required for verification, the knowledge of the described mechanisms can be of critical importance to both clinicians and stent manufacturers. To the best of our knowledge, these mechanisms have not yet been described in the literature. Other effects of CAS revealed by our study included straightening of the carotid bifurcation by decreasing the bifurcation angle and increasing the tortuosity of the distal ICA. The increase in ICA tortuosity might be due to a combination of factors. First, it might be a direct consequence of CAS-induced elongation of the stented region, which adds overall length to the artery. Second, increased flow after CAS can result in lengthening of the artery distally as part of the compensatory adaptation
to restore the multiaxial stress state toward homeostatic equilibrium.32 This mechanism has been described by Lehman and colleagues33 in rabbit cerebral arteries, and was confirmed by Sho and colleagues34 in rabbit carotid arteries and by Humphrey and colleagues32 in carotid arteries of a mouse. Additional studies are warranted to elucidate this mechanism in humans and to determine its relation to CAS. Strong correlations were established between patient age, tortuosity, plaque volume, stenosis severity, and bifurcation angle. Results of mathematical modeling demonstrated that stent deployment location was equally important as the composition of the plaque. Distal deployment resulted in high circumferential stress in the ICA at the distal end of the stent. Similar to axial stress, high circumferential stress can also promote injury and possibly restenosis. This speculation is supported by clinical observations of Lal and colleagues,24 who reported that most frequently restenosis occurs at the ends of the stent. This information suggests that tapered stents are likely preferable to nontapered stents because they produce less circumferential stress distally. However, the shape of the taper likely also plays an important role, and it is possible that gradual taper can be preferential to the step taper because the latter can anchor the plaque during deployment. This result also speaks for the importance of careful selection of both the proximal and the distal diameters of the tapered stent to avoid oversizing. Despite the significance of increased axial stress from CAS-induced elongation, the extra ICA length per se did not produce what is known to be pathogenic WSS,18 and the temporal mean of WSS in the kinked ICA was within the atheroprotective range (values >1 to 2 Pa18 but <40 Pa20). If the kink in the ICA was
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produced at the expense of the proximal CCA length (ie, by the distal movement of the bifurcation after CAS), this would not have resulted in what we define as hemodynamically and mechanically significant changes. This, however, was not the case because both the length of the proximal CCA and the position of bifurcation (on both repaired and contralateral sides) were the same before and after CAS. We speculate that low atherogenic values of WSS could potentially be present in the curved artery if the kink is severe enough and the flow is slow enough to result in WSS of <0.4 Pa.18 As these conditions can be produced by head rotation, which can change arterial geometry and alter the WSS patterns,35 the importance of simultaneous analysis of the contralateral control carotid becomes apparent. From fluid mechanics we know that when a channel curves, velocity is greater along the outside wall of the curvature than along the inside wall. This results in velocity profile being skewed toward the outer wall of the curvature, with the fluid near the inner wall moving at relatively low velocities and smaller WSS.21,36,37 Experimentally, low WSS is linked to increased monocyte recruitment, increased vasoconstriction and paracrine growth stimulation of vessel wall constituents, increased oxidative stress, and increased apoptosis and cellular turnover18dall thought to be potential players in development of arterial disease. Clinically, it is known that sharp kinks in the elongated ICA can obstruct the blood flow and some suggest that kinks might also be associated with atherogenesis.38 This points to the need for a more detailed study investigating the effect of different kink severities on pathophysiology.
CONCLUSIONS Despite the small cohort of patients selected for this study, we were able to identify statistically significant geometric changes to the ICA after CAS in 33% of the patients. Twenty percent of the patients we evaluated (and 40% of patients with CAS-induced changes) demonstrated hemodynamically substantial recurrent stenosis at the time of follow-up with CT angiography. These results pose a question of whether CAS can reliably reduce the severity of stenosis, or whether its main effect is based on plaque trapping and stabilization behind the stent. This points to the need for a larger engineeringassisted clinical study that could verify our findings of CAS-induced geometric, hemodynamic, and mechanical effects on a larger, more diverse patient population, allowing a more powerful analysis including and in relation to the types and sizes of stents used, time elapsed from the procedure, and other parameters. Although
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CAS-induced changes identified in this study were statistically significant, the reproducibility of our findings in a larger patient population is key to establishing their true clinical significance. Author Contributions Study conception and design: Kamenskiy, Pipinos, Dzenis, Bikhchandani, MacTaggart Acquisition of data: Kamenskiy, Pipinos, Bikhchandani Analysis and interpretation of data: Kamenskiy, Pipinos, Dzenis, Bikhchandani, Gupta, Phillips, Kazmi, MacTaggart Drafting of manuscript: Kamenskiy, Pipinos, Dzenis, Bikhchandani, Gupta, Phillips, Kazmi, MacTaggart Critical revision: Kamenskiy, Pipinos, Dzenis, Bikhchandani, Gupta, Phillips, Kazmi, MacTaggart Acknowledgment: The authors wish to acknowledge Mark Pemberton for his help with data collection. REFERENCES 1. Bates ER, Babb JD, Casey DE, et al. ACCF/SCAI/SVMB/ SIR/ASITN 2007 clinical expert consensus document on carotid stenting: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (ACCF/SCAI/SVMB/SIR/ASITN Clinical Expert Consensus Document. J Am Coll Cardiol 2007;49:126e170. 2. Berkefeld J, Turowski B, Dietz A, et al. Recanalization results after carotid stent placement. AJNR Am J Neuroradiol 2002; 23:113e120. 3. Nallamothu BK, Gurm HS, Ting HH, et al. Operator experience and carotid stenting outcomes in Medicare beneficiaries. JAMA 2011;306:1338e1343. 4. Arya S, Pipinos II, Garg N, et al. Carotid endarterectomy is superior to carotid angioplasty and stenting for perioperative and long-term results. Vasc Endovasc Surg 2011;45:490e498. 5. Cebral J, Lo¨hner R, Soto O, et al. Patient-specific simulation of carotid artery stenting using computational fluid dynamics. Med Image Comput Comput Assist Interv 2001;2208: 153e160. 6. Conti M, Van Loo D, Auricchio F, et al. Impact of carotid stent cell design on vessel scaffolding: a case study comparing experimental investigation and numerical simulations. J Endovasc Ther 2011;18:397e406. 7. Vitek JJ, Roubin GS, Al-Mubarek N, et al. Carotid artery stenting: technical considerations. AJNR Am J Neuroradiol 2000;21:1736e1743. 8. Kamenskiy AV, MacTaggart JN, Pipinos I, et al. Threedimensional geometry of the human carotid artery. J Biomech Eng 2012;134:64502. 9. Kamenskiy AV, MacTaggart JN, Pipinos II, et al. Hemodynamically motivated choice of patch angioplasty for the performance of carotid endarterectomy. Ann Biomed Eng 2013;41: 263e278. 10. Johnston BM, Johnston PR, Corney S, Kilpatrick D. NonNewtonian blood flow in human right coronary arteries: steady state simulations. J Biomech 2004;37:709e720.
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11. Kamenskiy AV, Dzenis YA, MacTaggart JN, et al. Nonlinear mechanical behavior of the human common, external and internal carotid arteries in vivo. J Surg Res 2012;176: 329e336. 12. Kamenskiy AV, Dzenis YA, MacTaggart J, et al. In vivo threedimensional blood velocity profile shapes in the human common, internal and external carotid arteries. J Vasc Surg 2011;54:P1011eP1020. 13. Moyle KR, Antiga L, Steinman DA. Inlet conditions for image-based CFD models of the carotid bifurcation: is it reasonable to assume fully developed flow? J Biomech Eng 2006;128:371e379. 14. Holzapfel GA, Gasser TC, Ogden RW. A new constitutive framework for arterial wall mechanics and a comparative study of material models. J Elast 2000;61:1e48. 15. Kamenskiy AV, Pipinos II, MacTaggart J, et al. Comparative analysis of the biaxial mechanical behavior of carotid wall tissue and biological and synthetic materials used for carotid patch angioplasty. J Biomech Eng 2011;133:111008. 16. Kleinstreuer C, Li Z, Basciano CA, et al. Computational mechanics of nitinol stent grafts. J Biomech 2008;41: 2370e2378. 17. Milner JS, Moore JA, Rutt BK, Steinman DA. Hemodynamics of human carotid artery bifurcations: computational studies with models reconstructed from magnetic resonance imaging of normal subjects. J Vasc Surg 1998;28:143e156. 18. Malek AM, Alper SL, Izumo S. Hemodynamics shear stress and its role in atherosclerosis. JAMA 1999;282[21]:2035e2042. 19. Chatzizisis YS, Coskun AU, Jonas M, et al. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol 2007;49:2379e2393. 20. Humphrey JD. Cardiovascular Solid Mechanics: Cells, Tissues, and Organs. New York: Springer; 2002. 21. Ku DN, Giddens DP. Pulsatile flow in a model carotid bifurcation. Arteriosclerosis 1983;3:31e39. 22. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362[6423]:801e809. 23. Clowes AW, Reidy MA, Clowes MM. Mechanisms of stenosis after arterial injury. Lab Invest 1983;49:208e215. 24. Kamenskiy AV. Coupled hemodynamics and mechanics of the repaired human carotid artery. PhD Dissertation. University of Nebraska-Lincoln. December 2009. AAI3386755. Available at: http://digitalcommons.unl.edu/dissertations/AAI3386755. 25. Fox AJ. How to measure carotid stenosis. Radiology 1993;186: 316e318.
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26. Holzapfel GA, Stadler M, Gasser TC. Changes in the mechanical environment of stenotic arteries during interaction with stents: computational assessment of parametric stent designs. Trans ASME 2005;127:166e180. 27. Ross CB, Yancey AE, Byrnes KR, et al. Late outcomes of carotid artery stenting: a critical review. Am Surg 2011;77: 1117e1130. 28. Bangalore S, Kumar S, Wetterslev J, et al. Carotid artery stenting vs carotid endarterectomy: meta-analysis and diversityadjusted trial sequential analysis of randomized trials. Arch Neurol 2011;68:172e184. 29. Brott T, Hobson R. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010;363: 11e23. 30. AbuRahma AF, Robinson PA, Saiedy S, et al. Prospective randomized trial of bilateral carotid endarterectomies: primary closure versus patching. Stroke 1999;30:1185e1189. 31. Ballotta E, Renon L, Da Giau G, et al. A prospective randomized study on bilateral carotid endarterectomy: patching versus eversion. Ann Surg 2000;232:119e125. 32. Humphrey JD, Eberth JF, Dye WW, Gleason RL. Fundamental role of axial stress in compensatory adaptations by arteries. J Biomech 2009;42:1e8. 33. Lehman RM, Owens GK, Kassell NF, Hongo K. Mechanism of enlargement of major cerebral collateral arteries in rabbits. Stroke 1991;22:499e504. 34. Sho E, Nanjo H, Sho M, et al. Arterial enlargement, tortuosity, and intimal thickening in response to sequential exposure to high and low wall shear stress. J Vasc Surg 2004;39: 601e612. 35. Glor FP, Ariff B, Hughes AD, et al. Influence of head position on carotid hemodynamics in young adults. Am J Physiol Heart Circ Physiol 2004;287:H1670eH1681. 36. Lal BK, Kaperonis EA, Cuadra S, et al. Patterns of in-stent restenosis after carotid artery stenting: classification and implications for long-term outcome. J Vasc Surg 2007;46: 833e840. 37. Krams R, Wentzel JJ, Oomen JA, et al. Evaluation of endothelial shear stress and 3D geometry as factors determining the development of atherosclerosis and remodeling in human coronary arteries in vivo. Combining 3D reconstruction from angiography and IVUS (ANGUS) with computational fluid dyna. Arterioscler Thromb Vasc Biol 1997;17: 2061e2065. 38. Berguer R, Kieffer E. Surgery of the Arteries to the Head. New York: Springer-Verlag; 1992.
Stroke is the third most common cause of death and the leading cause of disability in the United States,1 with carotid bifurcation atherosclerotic disease being one of the most common correctable culprits. In addition to medical therapies, 2 procedures are used to treat carotid artery stenosisdopen carotid endarterectomy (CEA) and carotid artery stenting (CAS). Traditionally, CEA has been the gold standard for management of both symptomatic and asymptomatic high-grade carotid artery stenosis, and original indications for CAS were limited to anatomically and physiologically high-risk patients.1 However, the minimally invasive nature, shorter procedure and patient-recovery times, and expanded pool of physicians capable of performing the procedure, have popularized CAS beyond its original indications.1-3 Recent data comparing CAS with CEA demonstrate that CAS is associated with increased risks of postprocedural clinically silent ischemic brain lesions, shortterm (30-day) and long-term (>6 months) stroke, and
Disclosure Information: Nothing to disclose. This work was supported in part by NIH grant R01AG034995, and by grants from the Nebraska Research Initiative Nanofiber Core Facility, the National Science Foundation, the University of Nebraska-Lincoln/ University of Nebraska Medical Center Engineering for Medicine initiative, and the Charles and Mary Heider Fund for Excellence in Vascular Surgery. Presented at the American College of Surgeons 98th Annual Clinical Congress, Chicago, IL, October 2012. Received December 27, 2012; Revised February 13, 2013; Accepted March 22, 2013. From the Departments of Surgery (Kamenskiy, Pipinos, MacTaggart) and Pathology and Microbiology (Kazmi), University of Nebraska Medical Center, Department of Surgery, Creighton University Medical Center (Bikhchandani), Omaha, Departments of Mechanical and Materials Engineering (Dzenis) and Biological Systems Engineering (Phillips), University of Nebraska-Lincoln, Lincoln, NE, and Department of Surgery, University of Wisconsin Hospital and Clinics, Madison, WI (Gupta). Correspondence address: Alexey V Kamenskiy, PhD or Jason N MacTaggart, MD, Department of Surgery, 985182 Nebraska Medical Center, Omaha, NE 68198-5182. email: [email protected] or [email protected]
ª 2013 by the American College of Surgeons Published by Elsevier Inc.
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Abbreviations and Acronyms
CAS CCA CEA 3D ECA HMM-1 ICA NASCET
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
carotid artery stenting common carotid artery carotid endarterectomy 3-dimensional external carotid artery Hemodynamic Mathematical Model internal carotid artery North American Symptomatic Carotid Endarterectomy Trial PMM-II ¼ Parametric Mathematical Model WSS ¼ wall shear stress
restenosis,4 which points to the need for the development of methods that can identify the subsets of patients at increased risk for complications after CAS. This goal cannot be achieved without a sound understanding of the changes that CAS introduces to the geometry, hemodynamics, and wall mechanics of the treated carotid. Few computational studies describing potential changes to the blood flow after CAS have been performed,5,6 yet a comprehensive analysis of the actual stented carotid is still missing, even though some investigators occasionally report kinks in the internal carotid artery (ICA) after CAS and their potential contribution to restenosis.2,7 The objective of our analysis was to study the effects of CAS on the geometry, hemodynamics, and mechanics of the carotid artery, and to identify the conditions that can result in severe changes after CAS.
METHODS The research protocol was approved by our Institutional Review Board. Fifteen consecutive male patients who subsequently underwent CAS were included in the study. All patients had unilateral CAS done between 2007 and 2010. Computer reconstructions of 3-dimensional arterial geometry Preoperative and 15 11 month follow-up CT angiograms of patients’ arteries were obtained using 64channel scanner Brilliance 64 (Philips Medical Systems). The patients were imaged in the supine position during inspiration breath hold. Computed tomography angiography images were taken with an axial slice thickness of 1 mm. Resolution of each image was 512 512 pixels (pixel size 0.488 mm). The bilateral carotid arteries were reconstructed from the aortic arch to the skull base using Mimics v15 software (Materialize). In addition to the stented artery, we also analyzed the contralateral carotid to ensure that the observed changes in the treated artery after CAS were
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not due to variations in the position of the head on the pre- and post-CAS CT angiograms. This comparison demonstrated no changes in the contralateral artery post-stenting. Arterial, plaque, and stent contours were semi-automatically segmented using a combination of thresholding and region growing techniques. Segmentation was performed under the supervision of a vascular surgeon who assisted the algorithm by correcting the segments of the automatically detected boundary that were partially obscured by the periadventitial fat or the atherosclerotic plaque, or were ill-defined due to poor contrast. For each carotid with CAS, 4 different segmentations (ie, flow lumen, outer wall border, plaque, and stent) were obtained to quantify cross-sectional area, plaque volume, degree of stenosis, and other parameters. An additional fifth segmentation was performed for the calcified plaques to measure the percent of calcium in the plaque volume. For brevity, the contralateral control artery was reconstructed using a single segmentation that included the flow lumen and the plaque. Assessment of carotid artery stentinginduced geometric changes Changes in the carotid geometry after CAS were identified by comparing preoperative and postoperative CT scans for differences in the 3-dimensional (3D) shape, bifurcation angle, cross-sectional area of the lumen, tortuosity, and ICA elongation. The bifurcation angle was calculated as the angle between the common carotid artery (CCA)-ICA and CCA-external carotid artery (ECA) centerlines in the 3D space.8 The area of the lumen was measured for each CCA-ICA cross-section in the plane perpendicular to the arterial centerline. Assessment of area instead of the conventional radius allowed us to account for the noncircular shape of the cross-section, which was particularly important in the highly stenotic irregular lumina. In addition, it allowed estimation of the actual degree of stenosis by calculating the ratio of the flow lumen area to the area of the entire arterial cross-section. Tortuosity (fractional increase in length of the tortuous vessel relative to a perfectly straight path) of the arterial centerlines was calculated as T ¼ 1 D/C, where D is the linear (shortest) distance between the 2 points, and C is the distance between the same points along the arterial centerline. T was calculated for 2 arterial segments: the stented bifurcation (Tstent), and the distal ICA (Tdistal). The first segment started at the proximal end of the stent and ended at its distal end; and the second segment started at the distal end of the stent and ended at the skull base. Calculation of the 2 tortuosities allowed separate estimations of the amount of straightening produced by
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the deployed stent, and kinking of the distal ICA post intervention. Elongation of the distal ICA was calculated as the increase in the length of the centerline segment starting from the take off of the ICA and ending at the skull base. Both elongation and tortuosity were measured using the centerlines of the arteries with outer wall boundary (pink colored in Fig. 1). This allowed us to avoid overestimation of the length that comes from perturbations of the flow lumen centerline in the heavily diseased regions (red colored in Fig. 1). Hemodynamic significance of carotid artery stentinginduced changes: Hemodynamic Mathematical Model The Hemodynamic Mathematical Model (HMM-I) was created for the carotid artery with the most severe CASinduced changes in tortuosity and ICA elongation. This model was then used to assess the hemodynamic significance of the observed geometric changes. HMM-I was intentionally built “idealized,” that is, with smoothly varied circular cross-sections and uniform wall thickness. This allowed study of the isolated influence of CASinduced tortuosity and elongation, and avoided hemodynamic effects from irregularities in luminal contours and nonuniform wall thickness. Cross-sectional diameters were conceived as circles with areas equivalent to the actual CT measurements. Arterial wall of uniform thickness was created by expanding the contours in both preoperative and postoperative carotids. Our simulations accounted for the interaction between the blood flow and the arterial wall and used Finite Element software (ADINA v8.8 R&D). Details of model development, solution algorithms, and assessment of model accuracy can be found elsewhere.9 Briefly, we constructed fine tetrahedral meshes that closely matched the
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blood flow and arterial wall of the preoperative and postoperative arterial geometries. Continuity and the full Navier-Stokes equations in Arbitrary Lagrangian Eulerian formulation (to account for the moving boundary) were solved for the blood flow. Blood was modeled as a nonNewtonian fluid described by the Carreau constitutive law.10 Boundary conditions for the blood flow included catheter pressure waveform measurements in the CCA and duplex derived pulsatile flow velocities in the ICA and ECA, both based on previously published human in vivo data.11,12 Because the stented segment of the cervical carotid artery is a fraction of the total length of the evaluated artery, the inlet (level of the CCA at take off from either the brachiocephalic or the arch) and outlet (level of entry of the ICA in the skull) boundary conditions had minimal influence on the flow in the bifurcation.13 The momentum conservation equation in the Lagrangian description for large displacements and large strains was solved for the arterial wall. The carotid tissue was realistically modeled as a nonlinear hyperelastic anisotropic material with strain energy taken in the Holzapfel-Gasser-Ogden form.14 The constitutive model parameters for the arterial wall were determined from our experimental data representing the average human carotid artery.15 The stent was simulated by assigning Nitinol properties16 at 37 C to the stented region of the artery, mimicking the rigidity of the bifurcation post intervention. We note that, in reality, the complex mesh geometry of the stent impacts the nature of the blood flow at its interface with the carotid wall. However, it is likely that the influence of the stent struts/carotid wall interplay on the flow distal to the stent (that is of interest in this study) is not very significant. Obviously, additional studies and explicit models of the blood flow through the stent struts are required to verify this speculation. Full coupling between the blood flow and the
Figure 1. Carotid arteries with large amounts of calcium in the atherosclerotic plaques. Volume of calcium is given as percentage of the total plaque volume. Internal carotid artery flow is colored in red. External carotid artery flow is not visualized.
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arterial wall was achieved by imposing the compatibility of displacements, equilibrium of tractions, and no-slip conditions on the interface. The hemodynamic significance of the changes produced by CAS was assessed by calculating the wall shear stress (WSS; magnitude of the fluid tangential traction vector). Although WSS is not the only hemodynamic factor known for its involvement in pathogenesis,9 it is perhaps the most commonly used one when studying flow in arteries.17-19 Low WSS (<0.4 Pa) is known to stimulate an atherogenic phenotype in the carotid wall, and physiological and elevated shear (values >1 to 2 Pa18 but <40 Pa20) induce endothelial quiescence and an atheroprotective gene expression profile.18,21 Calculation of WSS involved multiplication of the dynamic blood viscosity with the velocity gradient projected onto the luminal surface and calculated in the direction of local vu unit surface normal nbs as ss ¼ m , where ss is the vb ns vu WSS, m is the variable blood viscosity and is the vb ns velocity gradient in the direction of surface normal. In addition to WSS, we estimated the axial stress in the arterial wall that resulted from CAS-induced ICA elongation. High mechanical stress can damage the arterial wall, which can promote migratory and proliferative responses of vascular smooth muscle cells and can eventually result in restenosis.22,23 Identification of morphological conditions that result in carotid artery stentinginduced changes and development of Parametric Mathematical Model Pearson product-moment correlation coefficients were calculated to establish correlations between the datasets of patients’ age, stenosis severity, preoperative bifurcation angle, change in bifurcation angle after CAS, plaque total volume, plaque calcium, pre-CAS tortuosity, change in tortuosity after CAS, and CAS-induced ICA elongation. Pearson coefficient is used to measure the strength of linear association between two paired variables, and it is computed as the ratio of the covariance to the product of the standard deviations. Datasets that were found to have the strongest correlation (highest absolute values of Pearson’s coefficient) with CAS-induced tortuosity and elongation were further analyzed in detail using the Parametric Mathematical Model (PMM-II). The Parametric Mathematical Model possessed higher spatial resolution than HMM-I, but focused on the smaller segment of the arterial bifurcation. To ensure that the results obtained by our PMM-II model were
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not specific to a particular patient, we developed the model using the mean carotid artery geometry,8 mean arterial wall,15 and atherosclerotic plaque24 properties. Both the arterial wall and the plaque were assumed to be homogeneous, and were modeled with nonlinear hyperelastic anisotropic Holzapfel-Gasser-Ogden constitutive strain energy potentials.14 We note that although the assumption of plaque homogeneity can be quite strong, the data on plaque properties are scarcely available in the literature. Finite Element simulations used the same steps and procedures described here for the HMM-I. A 3D Nitinol stent was deployed in the PMM-II, mimicking the actual endovascular procedure. First, the stent was compressed radially, simulating the loading of the device into the delivery system. After that, the stent inside the delivery system sheath was placed into the target lesion and the sheath was removed, allowing the stent to deploy gradually, opening from the distal to the proximal end. Simple nonpenetrating frictionless contact was assumed between the arterial wall and the stent.
RESULTS Fifteen consecutive male patients (age 67 9 years old) undergoing CAS were included in the study. The carotid stenosis was symptomatic in 6 and asymptomatic in 9 patients. The stenosis produced a mean 82% 9% diameter reduction of the ICA as determined per North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria25 using CT angiography. None of these patients had previous open or endovascular carotid interventions. None of the patients died or had stroke or transient ischemic attack after CAS. Ev3 Prote´ge´ tapered stents were used in 6 patients, Boston Scientific Wallstents were used in 7 patients, and Abbott Vascular Acculink tapered stents were used in 2 patients. Due to the variety of stents used in these series, and the small number of patients in our study, the effect of the stent design on the outcomes measured was not assessed. Such effects have been evaluated previously in works by Holzapfel and colleagues26 and Conti and colleagues.6 Computer reconstructions of 3-dimensional arterial geometry Preoperative and postoperative 3D reconstructions of both left and right carotid arteries were obtained for all 15 patients. Plaque volume (in mm3) measured in all patients is presented in Table 1. Fraction of calcium in each plaque is presented as a percentage of the total plaque volume. Plaques with high fractions of calcium are plotted in Figure 1. Calcium constituted a mean of only 8% 9% of the total plaque volume.
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Table 1. Patient
Vtotal, mm3 VCa, %
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Atherosclerotic Plaque Volume and Fraction of Calcium in Each Plaque for Patients 1 to 15 1
2
3
4
5
6
7
495 13
851 20
266 0
354 4
589 8
376 0
811 0
Patient no. 8 9
932 30
1,333 9
10
11
12
13
14
15
Mean
1,797 1
959 14
479 0
594 3
1,066 15
794 0
780 8
Vtotal, total plaque volume; VCa, fraction of calcium in the total plaque volume.
Assessment of carotid artery stentinginduced geometric changes The mean bifurcation angle before CAS was 27 12 degrees, with a range of 5 to 53 degrees. After CAS, the angle decreased to 22 9 degrees and range decreased to 10 to 45 degrees, neither were statistically significant (p ¼ 0.124). In 2 patients, the bifurcation angle increased, and in another 2 it was unchanged; however, 3 of these 4 patients had preoperative bifurcation angles significantly more narrow than average. The changes in bifurcation angles (Da, degrees) after CAS for all patients are given in Table 2. Cross-sectional area of the lumen before and after CAS for all patients is plotted in Figure 2. Graphs represent the change in lumen area along the CCA-ICA arterial axis as one progresses from proximal to distal (shown in bright red in Fig. 3). Small fluctuations characterize irregularity of the lumen and steep drops indicate either stenosis or position of the stent end. Each graph was normalized to the area at the most proximal CCA site to ensure proper comparison of preoperative and postoperative segmentations. Table 3 contains comparisons of stenosis severity measured before CAS using the conventional NASCET25 method, and the ratio of lumen areas described here. Comparison of measurements shows that NASCET, on average, underestimated the stenosis by 11% 11% (p < 0.01) with the largest underestimation by 38% (patient no. 15) and overestimation by 10% (patient no. 13). Underestimation of stenosis by NASCET method should be expected, as the arterial centerline is rarely perpendicular to the imaging plane. In addition, the small diameter of the distal ICA compared with the size of the bulb can substantially affect the NASCET ratio and result in gross underestimation, as was observed in patient no. 15. After CAS actual stenosis severity improved in 80% of patients (p < 0.01) showing a mean 17% 11% increase
in cross-sectional area (measured in the most narrow location) at the time of follow-up. In 20% of patients (no. 1, 2, and 9), the stenosis was the same as before stenting, although intra-procedural angiography and immediate post-procedural ultrasound evaluation after CAS demonstrated <10% residual stenosis. Typically, the most severe stenoses before and after CAS were observed slightly distal to the take off of the ECA. After CAS, stenosis was also common at the distal end of the stent (eg, no. 11, 14, and 15). Although follow-up CTAs were performed at variable time points post stenting, no correlation was observed between the time of follow-up and stenosis severity after CAS (Pearson ¼ 0.02). In roughly half (47%) of our patients, the lumen of the distal ICA became larger after CAS. In the other 8 patients it was unchanged or slightly decreased, as can be seen in patients no. 3, 8 and 9. Tortuosity of the stented bifurcation (Tstent) decreased in 80% of patients after CAS (p ¼ 0.013) by a mean DTstent ¼ 0.02 0.03 (range 0.09 to 0.01). The straightening of the artery was followed by kinking of the distal ICA after CAS (p ¼ 0.282). On average, Tdistal increased by Tdistal ¼ 0.02 0.03 (range 0.01 to 0.11) which was the same amount Tstent decreased after CAS. This, however, does not mean that the overall tortuosity of the artery from the proximal stent end to the skull base remained unchanged because tortuosity is (by definition) calculated relative to a specific distance. Values of DTdistal are summarized in Table 2. The change in distal ICA tortuosity was appreciable in only 33% of the patients (DTdistal ¼ 0.020.11). Arteries of those patients are presented in Figure 3 (lower panel). Special attention should be given to patient no. 2, as this artery demonstrated the most severe change (DTdistal ¼ 0.11) among all patients. After CAS, the distal ICA elongated in 67% of patients (p ¼ 0.012; Table 2). Although overall
Table 2. Change in Bifurcation Angle, Distal Internal Carotid Artery Tortuosity, and Internal Carotid Artery Elongation in Patients after Carotid Artery Stenting Change
1
2
3
4
5
6
Patient no. 7 8
9
Da, degrees 10 5 2 2 15 0 5 7 23 DTdistal 0.01 0.11 0.01 0.01 0.01 0.01 0.01 0.03 0.03 DL, mm 1 6 1 1 1 0 1 3 2
10
11
12
13
14
15
Mean
5 0 0
4 0.01 1
6 0 0
1 0.01 1
0 0.02 2
3 0.02 1
5 0.02 1
Da, bifurcation angle; DL, internal carotid artery elongation; DTdistal, distal internal carotid artery tortuosity.
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Figure 2. Change in cross-sectional area of the lumen along the common carotid artery (CCA)-internal carotid artery (ICA) axis before (red) and after (blue) carotid artery stenting. Segments of the artery that correspond to the graphs are plotted in Figure 1 with bright red color. Distance between the peaks in the graphs is given in millimeters. Measurements were normalized to the proximal CCA area to ensure adequate comparison of preoperative and postoperative segmentations. ECA, external carotid artery.
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Figure 3. Carotid arteries with and without carotid artery stenting (CAS)induced changes in tortuosity. Left geometry is pre-CAS, right is post-CAS. Bright red color represents the flow, blue color represents the stent.
elongation of the entire ICA was rather small, elongations within the stented region of the artery were significant and inhomogeneous. These elongations were calculated by aligning the proximal portions of the preCAS and post-CAS area-over-the-length graphs (that were strikingly similar) and calculating the distance between the peaks in the stented and distal regions (see Fig. 2, graphs 2, 8, and 9). A distal shift in a peak indicates CAS induced axial stretch. In patient no. 2, for example, the change in elongation ranged from 5 to 21 mm. Interestingly, the segment that showed a 21-mm elongation corresponded to the most severe
stenosis and the largest concentration of calcium in the plaque of this patient (see Fig. 1, patient no. 2). Hemodynamic and mechanical significance of carotid artery stentinginduced changes We used HMM-I to evaluate the hemodynamic significance of CAS-induced ICA tortuosity (DTdistal) and elongation (DL) for patient no. 2, who demonstrated the most severe changes. The influence of tortuosity was assessed by comparing pre- and post-CAS WSS (Pa) contours presented in Figure 4. These contours show that CAS improved the
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Table 3. Stenosis Severity Measured before Carotid Artery Stenting Using Conventional North American Symptomatic Carotid Endarterectomy Trial Method and the Ratio of Cross-Sectional Areas Variable
Stenosis NASCET Stenosis actual
Patient no. 8 9
1
2
3
4
5
6
7
70
80
90
95
90
75
80
80
77
97
92
96
95
97
97
99
10
11
12
13
14
15
Mean
85
80
90
80
90
90
60
82
92
95
97
96
80
95
98
93
NASCET, North American Symptomatic Carotid Endarterectomy Trial.
hemodynamics in the carotid bulb by decreasing the area of low shear (<0.4 Pa18) as much as 6-fold. Note that location of low WSS area corresponds to the largest stenosis in the artery both before and after CAS. Despite low shear being present in the carotid bulb, the ICA kink (the cause of high tortuosity) possesses normal physiologic shear. The influence of ICA elongation was evaluated by estimating the axial stress resulting from CAS-induced axial stretch. Estimation was done using the biaxial experimental data on the mechanical properties of the human carotid arteries.15 These data suggest that an axial stretch of 1.125 to 1.525 (which corresponds to 5-mm and 21-mm elongations of the 40-mm stented segment) results in axial stress of approximately 50 kPa to 1 to 2 MPa. To put these numbers into perspective, stage II hypertension (160 mmHg) roughly translates into 100 kPa of circumferential engineering stress as estimated by the simple Laplace law. Although circumferential and axial stresses are different, for illustrative purposes one can appreciate that the circumferential stress due to hypertension is at least 10-fold smaller than the axial stress induced by CAS in patient no. 2. Identification of morphological conditions that result in carotid artery stentinginduced changes Pearson product-moment correlation coefficients calculated between the datasets of patients age, stenosis severity, preoperative bifurcation angle, change in bifurcation angle after CAS, plaque total volume, plaque calcium, pre-CAS tortuosity, change in tortuosity after CAS, and CASinduced ICA elongation are presented in Figure 5. Pearson’s coefficient in the range of 0 to 0.25 indicate no correlation (colored in gray), values of 0.25 to 0.5 show moderate correlation (colored in yellow), and values of 0.5 to 1 show strong correlation between the datasets (colored in red). Analysis of correlations demonstrated that senior patients had more tortuous arteries (Pearson ¼ 0.640) with larger plaques (Pearson ¼ 0.569). Severely stenosed arteries had smaller bifurcation angles (Pearson ¼ 0.476), and they were less likely to change this angle after CAS
(Pearson ¼ 0.620). Tortuous arteries had larger plaques (Pearson ¼ 0.633) and their bifurcation angle was more likely to change after CAS (Pearson ¼ 0.497). Arteries with highly calcified plaques were more likely to become longer (ie, stretch axially, Pearson ¼ 0.642) and more tortuous (Pearson ¼ 0.512) after CAS. Interestingly, no correlation was found between the size of the plaque and the amount of calcium in it (Pearson ¼ 0.218). Size of the plaque was also not correlated with either CAS-induced tortuosity (Pearson ¼ 0.146) or elongation (Pearson ¼ 0.195). Finally, the amount of
Figure 4. Three-dimensional distributions of temporal mean wall shear stress (WSS) (Pa) in carotid artery before (left) and after (right) carotid artery stenting as predicted by Hemodynamic Mathematical Model. Magenta color represents atherogenic WSS <0.4 Pa.14 Arterial wall is removed for better visualization.
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Variable Age Actual stenosis Pre-CAS bifurcation angle Change in bifurcation angle after CAS Plaque total volume Plaque calcium Pre-CAS tortuosity Change in distal ICA tortuosity after CAS ICA Elongation after CAS
Age
Actual stenosis
pre-CAS bifurcation angle
Change in bifurcation angle after CAS
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Plaque, total volume
Plaque calcium
pre-CAS tortuosity
Change in distal ICA tortuosity after CAS
1 -0.278 -0.078
1 -0.476
1
0.129
-0.620
0.689
1
0.569 -0.192 0.640
-0.050 0.260 -0.327
0.076 -0.251 0.274
0.247 -0.156 0.497
1 0.218 0.633
1 -0.051
1
-0.387
0.208
0.160
0.054
0.146
0.512
0.042
1
-0.361
0.241
0.064
0.011
0.195
0.642
0.057
0.980
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ICA Elongation after CAS
1
Figure 5. Pearson product-moment correlation coefficients calculated for various datasets. Values in the range 0 to 0.25 indicate no correlation (gray), values 0.25 to 0.5 show moderate correlation (yellow), and values 0.5 to 1 show strong correlation (red). Correlation between any datasets of A and B is located on the intersection of the row A and a corresponding column B. Positive values indicate direct relation, and negative values indicate inverse relation. CAS, carotid artery stenting; ICA, internal carotid artery.
time elapsed after CAS (ie, time of the follow-up CT scan) had no effect on either elongation (Person ¼ 0.187) or tortuosity (Pearson ¼ 0.136). The analysis summarized in Figure 5 shows that the high amount of calcium in the patient’s plaque was the most reliable indicator of CAS-induced tortuosity (DTdistal) and ICA elongation (DL). To identify the mechanism of how stiff calcified plaque promotes elongation of the distal ICA after CAS, we used PMM-II with 2 types of atherosclerotic plaques: soft and stiff (calcified). Properties of both plaque types were determined from the experimental mechanical testing of human plaques.24 The stent modeled in PMM-II was the tapered EV3 Prote´ge´ 10/7 40. This stent was used in 3 of 5 patients with CAS-induced changes, including patient no. 2 with largest DTdistal and DL. Results of modeling with PMMII are presented in Figure 6. The left panel demonstrates the influence of plaque stiffness on DL. During deployment, the articulated tapered section of the stent anchored the plaque and pushed the artery distally. Soft plaque was less resistant to stent deployment, which resulted in larger lumen and an axial elongation of only 1.5 mm after CAS. Stiff calcified plaque on the other hand constrained the radial expansion of the stent, which resulted in severe stent deformation, smaller lumen, and a 3 times larger axial extension of 4.7 mm. The influence of the deployment site on DL was evaluated by moving the stent proximally and distally. Plaque properties were set up as average between soft and stiff.24 Results of modeling are presented in the right panel of Figure 6. Proximal stent deployment resulted in ICA elongation of only 1.9 mm. When the stent was deployed distally, DL increased 2-fold to 4 mm via the same plaque anchoring mechanism described here. We note again that plaque was assumed homogeneous in these simulations.
In reality, however, plaque inhomogeneity, and particularly variations in location and amount of calcium in it, can produce substantial inhomogeneity in the axial stretch. This, for example, was found from the analysis of the CT angiography scans of patient no. 2 described here (stretch of 1.125 to 1.525 within the stented region). Distal deployment also produced abrupt changes in the lumen area at the ends of the stent, caused by the larger diameter of the device compared with the artery. This correlates with steep slopes of the area-over-the-length curves presented in Figure 2. Analysis of stress distributions in these areas using PMM-II showed that the distal end of the stent imposed substantial circumferential stress in the ICA. This stress was in the order of several hundred kPa, several times larger than the one estimated at the stage II hypertension mentioned previously.
DISCUSSION Despite the recent progress in device and technique refinements aimed at making CAS safer,27 most randomized controlled clinical trials report that CAS is still associated with an increased risk of periprocedural, intermediate and long-term complications.4,28 However, certain patients do appear to benefit from CAS over CEA.29 It is therefore vital to develop criteria for identifying patients who are at the greater risk with CAS. Patient-specific risk factors that were earlier reported to be associated with complications include age, sex, altered levels of high-density lipoprotein cholesterol, hyperglycemia, and renal insufficiency.27 These systemic risk factors are the same for both CAS and CEA, but they do not explain more frequent adverse events with CAS or the occurrence of unilateral complications in patients with bilateral repair.30,31 In this study, we attempted to
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Figure 6. Results of parametric modeling with Parametric Mathematical Model showing Ev3 Prote´ge´ tapered 10/7 40 mm stent deployed in the 8.5/5.5 mm artery with severe stenosis. The left panel shows the influence of plaque stiffness, and the right panel shows the influence of deployment location on the post-stenting internal carotid artery elongation DL.
identify other localized arterial factors that can stratify the inherent risk specific to CAS. Our results suggest that circumferential highly calcified plaques that involve >1 cm of the proximal ICA can result in higher predisposition of the artery to adverse geometric, hemodynamic, and mechanic changes after CAS. In addition, it appears that highly calcified plaques limit the ability of the stent to deform the abnormal portion of the artery and, therefore, the deformation is transferred to the nondiseased portion, usually located distally. In addition, the less calcified (and the more deformable) the plaque, the less geometric change occurs. We have shown that severe axial extension of the ICA produced by the high stiffness of the plaque, is accompanied by axial stress that can damage the arterial wall.20 Arterial wall damage has been shown to lead to cell migratory and proliferative responses, platelet deposition, and development of restenosis.22,23 Although these findings and associations are mostly speculative, and in vitro experimentation and rigorous clinical study are required for verification, the knowledge of the described mechanisms can be of critical importance to both clinicians and stent manufacturers. To the best of our knowledge, these mechanisms have not yet been described in the literature. Other effects of CAS revealed by our study included straightening of the carotid bifurcation by decreasing the bifurcation angle and increasing the tortuosity of the distal ICA. The increase in ICA tortuosity might be due to a combination of factors. First, it might be a direct consequence of CAS-induced elongation of the stented region, which adds overall length to the artery. Second, increased flow after CAS can result in lengthening of the artery distally as part of the compensatory adaptation
to restore the multiaxial stress state toward homeostatic equilibrium.32 This mechanism has been described by Lehman and colleagues33 in rabbit cerebral arteries, and was confirmed by Sho and colleagues34 in rabbit carotid arteries and by Humphrey and colleagues32 in carotid arteries of a mouse. Additional studies are warranted to elucidate this mechanism in humans and to determine its relation to CAS. Strong correlations were established between patient age, tortuosity, plaque volume, stenosis severity, and bifurcation angle. Results of mathematical modeling demonstrated that stent deployment location was equally important as the composition of the plaque. Distal deployment resulted in high circumferential stress in the ICA at the distal end of the stent. Similar to axial stress, high circumferential stress can also promote injury and possibly restenosis. This speculation is supported by clinical observations of Lal and colleagues,24 who reported that most frequently restenosis occurs at the ends of the stent. This information suggests that tapered stents are likely preferable to nontapered stents because they produce less circumferential stress distally. However, the shape of the taper likely also plays an important role, and it is possible that gradual taper can be preferential to the step taper because the latter can anchor the plaque during deployment. This result also speaks for the importance of careful selection of both the proximal and the distal diameters of the tapered stent to avoid oversizing. Despite the significance of increased axial stress from CAS-induced elongation, the extra ICA length per se did not produce what is known to be pathogenic WSS,18 and the temporal mean of WSS in the kinked ICA was within the atheroprotective range (values >1 to 2 Pa18 but <40 Pa20). If the kink in the ICA was
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produced at the expense of the proximal CCA length (ie, by the distal movement of the bifurcation after CAS), this would not have resulted in what we define as hemodynamically and mechanically significant changes. This, however, was not the case because both the length of the proximal CCA and the position of bifurcation (on both repaired and contralateral sides) were the same before and after CAS. We speculate that low atherogenic values of WSS could potentially be present in the curved artery if the kink is severe enough and the flow is slow enough to result in WSS of <0.4 Pa.18 As these conditions can be produced by head rotation, which can change arterial geometry and alter the WSS patterns,35 the importance of simultaneous analysis of the contralateral control carotid becomes apparent. From fluid mechanics we know that when a channel curves, velocity is greater along the outside wall of the curvature than along the inside wall. This results in velocity profile being skewed toward the outer wall of the curvature, with the fluid near the inner wall moving at relatively low velocities and smaller WSS.21,36,37 Experimentally, low WSS is linked to increased monocyte recruitment, increased vasoconstriction and paracrine growth stimulation of vessel wall constituents, increased oxidative stress, and increased apoptosis and cellular turnover18dall thought to be potential players in development of arterial disease. Clinically, it is known that sharp kinks in the elongated ICA can obstruct the blood flow and some suggest that kinks might also be associated with atherogenesis.38 This points to the need for a more detailed study investigating the effect of different kink severities on pathophysiology.
CONCLUSIONS Despite the small cohort of patients selected for this study, we were able to identify statistically significant geometric changes to the ICA after CAS in 33% of the patients. Twenty percent of the patients we evaluated (and 40% of patients with CAS-induced changes) demonstrated hemodynamically substantial recurrent stenosis at the time of follow-up with CT angiography. These results pose a question of whether CAS can reliably reduce the severity of stenosis, or whether its main effect is based on plaque trapping and stabilization behind the stent. This points to the need for a larger engineeringassisted clinical study that could verify our findings of CAS-induced geometric, hemodynamic, and mechanical effects on a larger, more diverse patient population, allowing a more powerful analysis including and in relation to the types and sizes of stents used, time elapsed from the procedure, and other parameters. Although
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CAS-induced changes identified in this study were statistically significant, the reproducibility of our findings in a larger patient population is key to establishing their true clinical significance. Author Contributions Study conception and design: Kamenskiy, Pipinos, Dzenis, Bikhchandani, MacTaggart Acquisition of data: Kamenskiy, Pipinos, Bikhchandani Analysis and interpretation of data: Kamenskiy, Pipinos, Dzenis, Bikhchandani, Gupta, Phillips, Kazmi, MacTaggart Drafting of manuscript: Kamenskiy, Pipinos, Dzenis, Bikhchandani, Gupta, Phillips, Kazmi, MacTaggart Critical revision: Kamenskiy, Pipinos, Dzenis, Bikhchandani, Gupta, Phillips, Kazmi, MacTaggart Acknowledgment: The authors wish to acknowledge Mark Pemberton for his help with data collection. REFERENCES 1. Bates ER, Babb JD, Casey DE, et al. ACCF/SCAI/SVMB/ SIR/ASITN 2007 clinical expert consensus document on carotid stenting: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (ACCF/SCAI/SVMB/SIR/ASITN Clinical Expert Consensus Document. J Am Coll Cardiol 2007;49:126e170. 2. Berkefeld J, Turowski B, Dietz A, et al. Recanalization results after carotid stent placement. AJNR Am J Neuroradiol 2002; 23:113e120. 3. Nallamothu BK, Gurm HS, Ting HH, et al. Operator experience and carotid stenting outcomes in Medicare beneficiaries. JAMA 2011;306:1338e1343. 4. Arya S, Pipinos II, Garg N, et al. Carotid endarterectomy is superior to carotid angioplasty and stenting for perioperative and long-term results. Vasc Endovasc Surg 2011;45:490e498. 5. Cebral J, Lo¨hner R, Soto O, et al. Patient-specific simulation of carotid artery stenting using computational fluid dynamics. Med Image Comput Comput Assist Interv 2001;2208: 153e160. 6. Conti M, Van Loo D, Auricchio F, et al. Impact of carotid stent cell design on vessel scaffolding: a case study comparing experimental investigation and numerical simulations. J Endovasc Ther 2011;18:397e406. 7. Vitek JJ, Roubin GS, Al-Mubarek N, et al. Carotid artery stenting: technical considerations. AJNR Am J Neuroradiol 2000;21:1736e1743. 8. Kamenskiy AV, MacTaggart JN, Pipinos I, et al. Threedimensional geometry of the human carotid artery. J Biomech Eng 2012;134:64502. 9. Kamenskiy AV, MacTaggart JN, Pipinos II, et al. Hemodynamically motivated choice of patch angioplasty for the performance of carotid endarterectomy. Ann Biomed Eng 2013;41: 263e278. 10. Johnston BM, Johnston PR, Corney S, Kilpatrick D. NonNewtonian blood flow in human right coronary arteries: steady state simulations. J Biomech 2004;37:709e720.
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26. Holzapfel GA, Stadler M, Gasser TC. Changes in the mechanical environment of stenotic arteries during interaction with stents: computational assessment of parametric stent designs. Trans ASME 2005;127:166e180. 27. Ross CB, Yancey AE, Byrnes KR, et al. Late outcomes of carotid artery stenting: a critical review. Am Surg 2011;77: 1117e1130. 28. Bangalore S, Kumar S, Wetterslev J, et al. Carotid artery stenting vs carotid endarterectomy: meta-analysis and diversityadjusted trial sequential analysis of randomized trials. Arch Neurol 2011;68:172e184. 29. Brott T, Hobson R. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010;363: 11e23. 30. AbuRahma AF, Robinson PA, Saiedy S, et al. Prospective randomized trial of bilateral carotid endarterectomies: primary closure versus patching. Stroke 1999;30:1185e1189. 31. Ballotta E, Renon L, Da Giau G, et al. A prospective randomized study on bilateral carotid endarterectomy: patching versus eversion. Ann Surg 2000;232:119e125. 32. Humphrey JD, Eberth JF, Dye WW, Gleason RL. Fundamental role of axial stress in compensatory adaptations by arteries. J Biomech 2009;42:1e8. 33. Lehman RM, Owens GK, Kassell NF, Hongo K. Mechanism of enlargement of major cerebral collateral arteries in rabbits. Stroke 1991;22:499e504. 34. Sho E, Nanjo H, Sho M, et al. Arterial enlargement, tortuosity, and intimal thickening in response to sequential exposure to high and low wall shear stress. J Vasc Surg 2004;39: 601e612. 35. Glor FP, Ariff B, Hughes AD, et al. Influence of head position on carotid hemodynamics in young adults. Am J Physiol Heart Circ Physiol 2004;287:H1670eH1681. 36. Lal BK, Kaperonis EA, Cuadra S, et al. Patterns of in-stent restenosis after carotid artery stenting: classification and implications for long-term outcome. J Vasc Surg 2007;46: 833e840. 37. Krams R, Wentzel JJ, Oomen JA, et al. Evaluation of endothelial shear stress and 3D geometry as factors determining the development of atherosclerosis and remodeling in human coronary arteries in vivo. Combining 3D reconstruction from angiography and IVUS (ANGUS) with computational fluid dyna. Arterioscler Thromb Vasc Biol 1997;17: 2061e2065. 38. Berguer R, Kieffer E. Surgery of the Arteries to the Head. New York: Springer-Verlag; 1992.