J.J. Wentzel

The role of shear stress in the generation of rupture-prone vulnerable plaques

Blood-flow-induced shear stress acting on the arterial wall is of paramount importance in vascular biology. Endothelial cells sense shear stress and largely control its value in a feedback-control loop by adapting the arterial dimensions to blood flow. Nevertheless, to allow for variations in arterial geometry, such as bifurcations, shear stress control is modified at certain eccentrically located sites to let it remain at near-zero levels. In the presence of risk factors for atherosclerosis, low shear stress contributes to local endothelial dysfunction and eccentric plaque build up, but normal-to-high shear stress is atheroprotective. Initially, lumen narrowing is prevented by outward vessel remodeling. Maintenance of a normal lumen and, by consequence, a normal shear stress distribution, however, prolongs local unfavorable low shear stress conditions and aggravates eccentric plaque growth. While undergoing such growth, eccentric plaques at preserved lumen locations experience increased tensile stress at their shoulders making them prone to fissuring and thrombosis. Consequent loss of the plaque-free wall by coverage with thrombus and new tissue may bring shear-stress-controlled lumen preservation to an end. This change causes shear stress to increase, which as a new condition may transform the lesion into a rupture-prone vulnerable plaque. We present a discussion of the role of shear stress, in setting the stage for the generation of rupture-prone, vulnerable plaques, and how this may be prevented.

ANGUS: a new approach to three-dimensional reconstruction of coronary vessels by combined use of angiography and intravascular ultrasound

Current three dimensional (3D) vessel reconstruction using intravascular ultrasound (IVUS) pull back is limited by the lack of information on the real vessel curvatures, because the movement of the catheter is assumed to proceed along a straight path. To overcome this limitation a method (ANGUS) has been developed to combine coronary angiography with data obtained by IVUS. The IVUS data represent a cylindrical stack of cross-sections. A least-square-fit approximation is used to reconstruct the 3D path of the catheter axis from two biplane X-ray images, after which the stack of IVUS contours is wrapped around this 3D catheter centerline. In order to establish the correct rotational position of the stack around the centerline, use is made of landmark which are visible in angiograms, as well as in a simulation of these angiograms derived from the reconstructed 3D contour. The combination of ANGiography and intravascular UltraSound (ANGUS) is promising and provides a unique method of three-dimensional reconstruction of coronary geometry.

Initial stress in biomechanical models of atherosclerotic plaques

Rupture of atherosclerotic plaques is the underlying cause for the majority of acute strokes and myocardial infarctions. Rupture of the plaque occurs when the stress in the plaque exceeds the strength of the material locally. Biomechanical stress analyses are commonly based on pressurized geometries, in most cases measured by in-vivo MRI. The geometry is therefore not stress-free. The aim of this study is to identify the effect of neglecting the initial stress state on the plaque stress distribution. Fifty 2D histological sections (7 patients, 9 diseased coronary artery segments), perfusion fixed at 100 mmHg, were segmented and finite element models were created. The Backward Incremental method was applied to determine the initial stress state and the zero-pressure state. Peak plaque and cap stresses were compared with and without initial stress. The effect of initial stress on the peak stress was related to the minimum cap thickness, maximum necrotic core thickness, and necrotic core angle. When accounting for initial stress, the general relations between geometrical features and peak cap stress remain intact. However, on a patient-specific basis, accounting for initial stress has a different effect on the absolute cap stress for each plaque. Incorporating initial stress may therefore improve the accuracy of future stress based rupture risk analyses for atherosclerotic plaques.

Quantification of plaque volume, shear stress on the endothelium, and mechanical properties of the arterial wall with intravascular ultrasound imaging

Present intravascular echographic imaging (IVUS) is based on either the mechanically rotated single element catheter or the multi-element phased array catheter principle. In both methods the ultrasonic beam is rotated through 360 degrees and the cross-sectional echo image of plaque and wall structures is visualised. A new development based on intravascular ultrasound is calculation of mechanical properties of the arterial wall. In this so-called elastographic approach, high frequency information obtained at identical positions in the arterial wall is compared under systolic and diastolic pressures. Minute shifts in the echo data indicate local compressibility. It thus becomes possible to indicate areas of high or low strain, which correspond to soft and hard material. Three-dimensional information can be obtained if the position of cross sectional slices is recorded with a pull-back device and slices are united into a 3D image. On the basis of such information it has become possible to view stents in 3D, and which interactive software, to calculate automatically plaque volume. With pull-back information only, the artery is reconstructed as a “straight pipe”. Only when the biplane X-ray information is combined with the intravascular pull-back echo information can the true 3D reconstruction of the artery be constructed. Given the true geometric lumen information, it becomes possible, under certain assumptions, to derive the luminal fluid dynamics. From this, shear stress values close to the arterial wall can be evaluated. Under the assumption that low values for local shear stress are areas prone to restenosis, predictions of endangered areas can be made.

Is it safe to implant bioresorbable scaffolds in ostial side-branch lesions? Impact of ‘neo-carina’ formation on main-branch flow pattern. Longitudinal clinical observations

Formation of a neo-carina has been reported after bioresorbable vascular scaffolds (BVS) implantation over side-branches. However, as this neo-carina could protrude into the main-branch, its hemodynamic impact remains unknown. We present two cases of BVS implantation for ostial side-branch lesions, and investigate the flow patterns at follow-up and their potential impact. Computational fluid dynamics analysis was performed, using a 3D mesh created by fusion of 3-dimensional angiogram with optical coherence tomography images. In our first case, mild disturbances were seen when neo-carina did not protrude perpendicularly into the main branch. In the second case, extensive flow re-distribution was observed due to a more pronounced protrusion of the neo-carina. Importantly, these areas of hemodynamic disturbance were observed together with lumen narrowing in a non-stenotic vessel segment. Our case observations highlight the importance of investigating the hemodynamic consequences of BVS implantation in bifurcation lesions and illustrate a novel method to do so inxa0vivo.

Disturbance of 3D velocity profiles induced by an IVUS catheter: evaluation with computational fluid dynamics

New IVUS-based blood velocity profile measurements are under development For these velocity measurements catheter placement in an artery is necessary, but induces disturbances in the native velocity profiles. To what degree the velocity profiles are disturbed by the catheter is studied by computational fluid dynamics. Therefore a straight tube having a catheter inside, is studied for 4 inflow velocities (0.05, 0.1, 0.2, 0.4 m/s) and two catheter positions (in the center and out of the center of the tube). The influence of the catheter size on the velocity profiles is studied as well. Central catheter placement reduced the peak to mean velocity ratio, compared to no catheter inside the tube, by 24%. In contrast, catheter placement out of the center of the tube increased the peak to mean velocity ratio by 14%. These values are independent of the inflow velocities and minimally dependent on changes in catheter size. The shear stress values, however, are dependent on both catheter location and catheter size.

Effect of shear stress alteration on atherosclerotic plaque vulnerability in cholesterol-fed rabbits

Previously, we created an experimental murine model for the induction of vulnerable plaque (VP). Although this murine model offers the opportunity to study the different molecular biological pathways that regulate plaque destabilization, the size of the animals severely limits the use of the model for in vivo diagnostics and percutaneous interventions. This study aimed to create a VP model in the rabbit, based on the murine model, to aid the assessment and development of novel diagnostic and interventional tools. New Zealand white rabbits were fed on a 2% cholesterol diet. After 1 week, a shear stress-altering device was implanted around the right carotid artery. Twelve weeks after cast placement, the carotid artery was isolated and processed for (immuno-)histological analysis to evaluate the presence of a VP phenotype. Atherosclerotic plaques with high lipid and macrophage content, low vascular smooth muscle cell content and intimal neovascularization were located upstream and downstream of the cast. The plaques lacked a significant necrotic core. In conclusion, we were able to create atherosclerotic plaques with a phenotype beyond that of a fatty streak, with a high percentage of lipids and macrophages, a thick cap with some vascular smooth muscle cells and neovascularization. However, as there was only a small necrotic core, the overall phenotype seems less vulnerable as compared to the thin fibrous cap atheroma in patients.

Shear Stress Modulates Plaque Composition in Human Coronary Arteries In Vivo

It is well established that atherosclerotic plaques generally develop in low shear stress regions, including curved arterial segments and bifurcations1. Once these plaques intrude into the lumen, the shear stress they are exposed to alters with hitherto unknown consequences. We hypothesize that in the more advanced stages of the disease, shear stress has an important impact on plaque composition in such a way that high shear stress enhances plaque vulnerability through its biological impact on the endothelium2. We investigated this hypothesis previously by studying the relationship between shear stress and strain, a marker for plaque composition, in human coronary arteries3. In this study, we will extend that study by investigating how shear stress influences changes of strain, and thus plaque composition, over a period of 6 months.Copyright

MRI Based Quantification of Outflow Boundary Conditions for Computational Fluid Dynamics of Stenosed Human Carotid Arteries

Many studies have been performed to investigate the contribution of wall shear stress (WSS) to pathophysiological processes related to atherosclerosis (Groen, et al., 2007; Kaazempur-Mofrad, et al., 2004; Ku, et al., 1985). To investigate these relationships in stenosed human carotid arteries, accurate assessment of WSS is required. WSS can be calculated in vivo by coupling medical imaging and computational fluid dynamics (CFD). However, often patient specific in- and outflow information is unavailable. Therefore flow through the common (CCA), internal (ICA) and external (ECA) carotid artery needs to be estimated. Murray’s law (Murray, 1926) is often used for that purpose, but it is unclear whether this law holds for stenosed arteries. The goal of this study was to determine outflow boundary conditions for WSS calculations in stenosed carotid bifurcations. Therefore we first quantified the flow (Q) in carotid arteries with different degrees of area stenosis using phase-contrast MRI and determined an empirical relation between outflow-ratios and degree of area stenosis. Secondly we compared the estimated flow ratio based on Murray’s law to the ones measured by MRI. Finally we analyzed the influence of the outflow conditions on the calculated WSS using CFD.Copyright

Vascular Remodeling During Atherosclerotic Plaque Build Up Is Controlled by the Plaque Free Part of the Vessel Wall

Glagov et al. observed that positive, compensatory vascular remodeling during plaque build up prevents lumen narrowing until plaque burden, this is the relative plaque area to media bounded area, exceeds a threshold of 40% [1]. Until now it is not clear what mechanism controls the compensatory vascular remodeling during the atherosclerotic plaque build up and what determines absence or limits compensatory vascular remodeling. Plaque burden does not seem to reflect a parameter, which could serve as a limiting step in the known control process in the vascular system. For instance, healthy arteries control vascular remodeling by fluid flow induced shear stress via a number of endothelium dependent pathways [2]. The endothelium at the atherosclerotic plaque side is considered to be dysfunctional [2] and might thereby limit the remodeling process. Since plaques are mostly eccentric, we hypothesize that the healthy part of the artery (or plaque free wall) will respond to changes in shear stress and will determine the capacity of the arteries to remodel up till the moment of complete circumferential involvement of the disease. We investigated whether the size of the plaque free wall contributes to vascular remodeling over a 3 year period using serial intravascular ultrasound measurements by determining 1) the frequency of positive remodeling in segments with varying size of plaque free vessel wall 2) the degree of vascular remodeling for segments with varying size of plaque free vessel wall.Copyright