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Once plaques intrude into the lumen, the shear stress they are exposed to alters with hitherto unknown consequences for plaque composition. We investigated the relationship between shear stress and strain, a marker for plaque composition, in human coronary arteries. We imaged 31 plaques in coronary arteries with angiography and intravascular ultrasound. Computational fluid dynamics was used to obtain shear stress. Palpography was applied to measure strain. Each plaque was divided into four regions: upstream, throat, shoulder, and downstream. Average shear stress and strain were determined in each region. Shear stress in the upstream, shoulder, throat, and downstream region was 2.55+/-0.89, 2.07+/-0.98, 2.32+/-1.11, and 0.67+/-0.35 Pa, respectively. Shear stress in the downstream region was significantly lower. Strain in the downstream region was also significantly lower than the values in the other regions (0.23+/-0.08% vs. 0.48+/-0.15%, 0.43+/-0.17%, and 0.47+/-0.12%, for the upstream, shoulder, and throat regions, respectively). Pooling all regions, dividing shear stress per plaque into tertiles, and computing average strain showed a positive correlation; for low, medium, and high shear stress, strain was 0.23+/-0.10%, 0.40+/-0.15%, and 0.60+/-0.18%, respectively. Low strain colocalizes with low shear stress downstream of plaques. Higher strain can be found in all other plaque regions, with the highest strain found in regions exposed to the highest shear stresses. This indicates that high shear stress might destabilize plaques, which could lead to plaque rupture.

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Intracoronary thermography is a currently used vulnerable plaque detection method. We studied how catheter design and catheter location influence the temperature readings, and thus its capacity to detect vulnerable plaques. Finite element calculations were performed on geometries representing the coronary artery, the vulnerable plaque and the catheter. Catheter material, diameter and location with respect to the plaque were varied. Both flow and no-flow situations were studied. Maximal lumen wall temperature difference without a catheter (DeltaT=0.12 degrees C, flow=75 cm(3) min(-1)) was considered the reference. Presence of a 1.0mm nitinol catheter right under the plaque increased DeltaT to 0.14 degrees C, whereas a 1.0 mm polyurethane catheter increased DeltaT to 0.51 degrees C. The location at which a thermosensitive element should be placed for most optimal temperature readings during a pullback was shown to lie at the catheter edge for the nitinol catheter and at 1.1mm from the catheter edge for the polyurethane catheter. Temperature readings decreased to background temperature when the catheter was in close proximity but not overlapping the plaque. DeltaT decreased approximately by 70% when a gap of 0.2 mm existed between the catheter and the lumen wall. Occlusion of blood flow increased DeltaT values in all cases, but most pronounced for nitinol catheters. A polyurethane catheter increased the temperature readings, since its heat conductivity is lower than that of blood, which makes it a very good choice for heat source detection. Catheter design can contribute to enhanced temperature readings and thus can enable more optimal vulnerable plaque detection.

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The focal location of atherosclerosis in the vascular tree is correlated with local variations in shear stress. We developed a method to induce defined variations in shear stress in a straight vessel segment of a mouse. To this end, a cylinder with a tapered lumen was placed around the carotid artery, inducing a high shear stress field. Concomitantly, regions of low shear stress and oscillatory shear stress were created upstream and down-stream of the device, respectively. This device was used in mice transgenic for an eNOS3GFP fusion gene. We observed a strong induction of endothelial nitric oxide synthase-green fluorescent protein (eNOS-GFP) mRNA expression in the high shear stress region compared with the other regions (P < .05). Quantification of eNOS-GFP fluorescence or of immunoreactivity to the Golgi complex or to platelet endothelial cell adhesion molecule 1 (PECAM-1) showed an increase in the high shear stress region (P < .05) compared with nontreated carotid arteries. Colocalization of eNOS-GFP with either the Golgi complex or PECAM-1 also responded to alterations of shear stress. In conclusion, we showed a direct response of mRNA and protein expression in vivo to induced variations of shear stress. This model provides the opportunity to study the relationship between shear stress alterations, gene expression, and atherosclerosis.

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The average low shear stress (SS) is known to determine predilection sites of atherosclerotic plaques. However, as plaques encroach into the lumen and thereby increase SS, interpretation of patient-specific data obtained at one moment in time regarding the influence of SS in the generation of atherosclerosis is not straightforward. This study aims to compare two methods of data analysis for the aid of data interpretation: (a) point-wise analysis of the raw data, (b) global analysis: to assess the history related natural SS distribution in coronary arteries by averaging the data in the axial vessel direction. Normal to mildly diseased human coronary arteries were investigated applying a combination of 3-D reconstruction technique and computational fluid dynamics (CFD). Point-wise analysis relating local wall thickness to local SS showed in only 4% of the cases an inverse relationship. In contrast, averaging the data in the axial vessel direction, showed in 38% a significant inverse relation between wall thickness and SS, resulting in an average negative slope of -0.70+/-0.46 mm/Pa. These data suggest that using a geometry guided way of data averaging may reveal history related effects of SS, which in part explains localization of atherosclerotic plaques.

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Intracoronary thermography is a potential vulnerable plaque detection technique of which the development is ongoing. This review discusses the past and present status of this technique from a more fundamental perspective, in which heat generation, heat transfer and heat detection are considered. Details of the presumed heat source, the macrophage clusters in vulnerable, atherosclerotic plaques, are discussed, including their increased energy consumption and heat production values. Heat transfer by ways of conduction, convection by blood flow and radiation are considered in a quantitative way. Ways to detect heat that are currently used are discussed and suggestions for improvement as well as for utilization of unexplored possibilities are given. This review enables interpretation of previously published results and likely also of results to be published in the future.

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Atherosclerotic lesions preferentially localize near side branches or curved vessels. During the last few decades, research has been shown that low or low and oscillating shear stress is associated with plaque location. Despite ample evidence, the precise mechanism is unknown. This is mainly because of a lack of appropriate animal models. We describe two novel methods to study the hypothesis that shear stress acts through endothelial gene expression or shear stress acts through localizing of inflammation. Both literature evidence and own findings support a role for both mechanisms in atherosclerosis.

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Hematocrit is the most important determinant of whole blood viscosity and it affects thrombosis. As hematocrit can be measured accurately in vitro by using an electrical impedance technique, aim of the present study is to investigate the diagnostic potential of using this technique in vivo to continuously monitor hematocrit. Characteristics of a special catheter for in vivo measurement of electrical resistivity in blood in the right atrium are described. In five anesthetized swine hematocrit is monitored continuously with this catheter while different levels of hemoconcentration are induced. In addition, blood viscosity is increased by inducing 'acute phase' reaction the day before surgery, resulting in variable degree of elevated fibrinogen levels in the five swine. Good reproducibility of the resistivity measurements (S.D < 0.01) and excellent correlation between resistivity data in vivo and hematocrit levels in each swine are found (r2 = 0.95-0.99). Furthermore, stepwise regression analysis of data from all swine shows a highly significant contribution also of other important parameters of blood viscosity, such as fibrinogen, total protein and temperature (cumulative r2 = 0.97). Determining hematocrit continuously in vivo by electrical resistivity measurements with a catheter in the right atrium is feasible and these measurements correlate significantly also with other important parameters of blood viscosity.

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PURPOSE: High-precision external beam radiotherapy (EBRT) has been suggested as a potential alternative to endovascular brachytherapy for the treatment of coronary artery in-stent restenosis. The purpose of our study was to investigate and compare different options to define a smallest feasible target volume. METHODS AND MATERIALS: The cardiac motion of 17 coronary artery stents in 17 patients was studied by use of biplane conventional angiography, recorded during breath-hold. Each stent was reconstructed in three dimensions by use of biplane sets of frames covering an entire cardiac cycle. The volume traversed by the stent during the entire or part of the cardiac cycle was determined. Four options to define the stent-traversed volume (STV) as a target for high-precision EBRT were investigated. RESULTS: The mean STV during the entire cardiac cycle was 3.5 cm3; the STV represented less than 1% of the heart volume in all patients. The STV during the diastolic and systolic phase resulted in a mean reduction of 26.6% and 29.1%, respectively, compared with the STV during the entire cardiac cycle. The smallest STV, measured during a 160-ms interval within the cardiac cycle, resulted in a mean maximal reduction of 75.9% compared with the STV during the entire cardiac cycle. CONCLUSIONS: The STV during the entire cardiac cycle represents a small potential target volume for high-precision EBRT. A significant reduction of this target volume is possible in case of definition during a selected interval within the cardiac cycle.

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The true 3-dimensional neointimal thickness distribution in sirolimus-eluting stents was investigated in relation to the shear stress distribution, which was obtained from computational fluid dynamics calculations. Small pits were observed between the stent struts in all patients, and a significant inverse relation between neointimal thickness and shear stress was found, indicating that deeper pits were present in the outside curve of the stented segments.

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BACKGROUND: The composition of an atherosclerotic plaque is considered more important than the degree of stenosis. An unstable lesion may rupture and cause an acute thrombotic reaction. Most of these lesions contain a large lipid pool covered by an inflamed thin fibrous cap. The stress in the cap increases with decreasing cap thickness and increasing macrophage infiltration. Intravascular ultrasound (IVUS) palpography might be an ideal technique to assess the mechanical properties of high-risk plaques. TECHNIQUE: Palpography assesses the local mechanical properties of tissue using its deformation caused by the intraluminal pressure. IN VITRO VALIDATION: The technique was validated in vitro using diseased human coronary and femoral arteries. Especially between fibrous and fatty tissue, a highly significant difference in strain (p = 0.0012) was found. Additionally, the predictive value to identify the vulnerable plaque was investigated. A high-strain region at the lumen-vessel wall boundary has an 88% sensitivity and 89% specificity for identifying such plaques. IN VIVO VALIDATION: In vivo, the technique was validated in an atherosclerotic Yucatan minipig animal model. This study also revealed higher strain values in fatty than fibrous plaques (p < 0.001). The presence of a high-strain region at the lumenplaque interface has a high predictive value to identify macrophages. PATIENT STUDIES: Patient studies revealed high-strain values (1-2%) in thin-cap fibrous atheroma. Calcified material showed low strain values (0-0.2%). With the development of three-dimensional (3-D) palpography, identification of highstrain spots over the full length of a coronary artery becomes available. CONCLUSION: Intravascular palpography is a unique tool to assess lesion composition and vulnerability. The development of 3-D palpography provides a technique that may develop into a clinical tool to identify the high-risk plaque.

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BACKGROUND: Atherosclerosis preferentially develops at average low shear stress (SS) locations. SS-related signaling maintains lumen dimensions by inducing outward arterial remodeling. Prolonged plaque accumulation at low SS predilection locations explains an inverse relation between wall thickness (WT) and SS. No data exist on WT-SS relations when lumen narrowing and loss of compensatory remodeling commence. METHODS AND RESULTS: In 14 patients, an angiographically normal artery (stenosis <50%) was investigated with ANGiography and ivUS (ANGUS) to provide 3D lumen and wall geometry. Selection of segments >5 mm in length, in between side branches, yielded 25 segments in 12 patients. SS at the wall was calculated by computational fluid dynamics. WT smaller than 0.2*lumen diameter was defined as normal. Largest arc of normal WT defined reference cross sections. Lumen area relative to the reference cross sections defined area stenosis (AS). Average segmental AS smaller or greater than 10% defined preserved or narrowed lumen, respectively. Total vessel area relative to the reference defined vascular remodeling (VR). For the preserved lumens (n=11, AS=1.7+/-5.6%, P=NS), axially averaged WT and SS were inversely related (slope, -0.46+/-0.55 mm/Pa, P<0.05) and VR was positive (7+/-9%, P<0.05). Narrowed segments (n=13, 1 excluded, AS=18+/-6%, P<0.05) showed no relation between WT and SS or vascular remodeling. CONCLUSIONS: In patient coronary arteries, the often-reported inverse WT-SS relationship appears restricted to lumen preservation and positive vascular remodeling. Its disappearance with lumen narrowing suggests a growing importance of non-SS-related plaque progression.

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BACKGROUND: Low wall shear stress (WSS) increases neointimal hyperplasia (NH) in vein grafts and stents. We studied the causal relationship between WSS and NH formation in stents by locally increasing WSS with a flow divider (Anti-Restenotic Diffuser, Endoart SA) placed in the center of the stent. METHODS AND RESULTS: In 9 rabbits fed a high-cholesterol diet for 2 months to induce endothelial dysfunction, 18 stents were implanted in the right and left external iliac arteries (1 stent per vessel). Lumen diameters were measured by quantitative angiography before and after implantation and at 4-week follow-up, at which time, macrophage accumulation and interruption of the internal elastic lamina was determined. Cross sections of stent segments within the ARED (S+ARED), outside the ARED (S[minus]ARED), and in corresponding segments of the contralateral control stent (SCTRL) were analyzed. Changes in WSS induced by the ARED placement were derived by computational fluid dynamics. Computational fluid dynamics analysis demonstrated that WSS increased from 0.38 to 0.82 N/m2 in the S+ARED immediately after ARED placement. This augmentation of shear stress was accompanied by (1) lower mean late luminal loss by quantitative angiography ([minus]0.23+/-0.22 versus [minus]0.58+/-0.30 mm, P=0.02), (2) reduction in NH (1.48+/-0.58, 2.46+/-1.25, and 2.36+/-1.13 mm2, P<0.01, respectively, for S+ARED, S[minus]ARED, and SCTRL), and (3) a reduced inflammation score and a reduced injury score. Increments in shear stress did not change the relationship between injury score and NH or between inflammation score and NH. CONCLUSIONS: The newly developed ARED flow divider significantly increases WSS, and this local increment in WSS is accompanied by a local reduction in NH and a local reduction in inflammation and injury. The present study is therefore the first to provide direct evidence for an important modulating role of shear stress in in-stent neointimal hyperplasia.

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The role of shear stress in atherosclerosis has been well documented. However, its role in restenosis was underexposed. In this paper a novel in vivo measuring technique and several of its applications related to restenosis will be described. The technique consists of a combination of 3D reconstruction of blood vessels and computational fluid dynamics (CFD). The 3D imaging techniques use either of 3D intravascular ultrasound (IVUS) as a stand-alone technique or a fusion of biplane angiography and IVUS (ANGUS). CFD is applied in order to relate local shear stress distribution to the morphology of the vessel wall. In the applications of these techniques it will be demonstrated that shear stress plays a role in the prediction of neointimal formation in in-stent restenosis and in vascular remodeling after balloon angioplasty. Attempts to locally increase shear stress by a newly developed flow divider indicate that shear stress reduce in-stent neointimal formation by 50%.

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BACKGROUND: Vascular wall shear stress (WSS) has been implied in the pathogenesis of atherosclerosis and vascular remodeling. Our aim was to calculate WSS after balloon angioplasty and evaluate its predictive value for long-term outcome. METHODS: WSS was calculated proximal to, in, and distal to the lesion after angiographically successful balloon dilatation and at follow-up with the Hagen-Poiseuille formula (WSS = 4 microQ/piR3) in 202 patients. Volumetric blood flow (Q) and lumen radius (R) were derived from Doppler scanning velocities and videodensitometric cross-sectional areas. RESULTS: Postprocedural proximal and in-lesion values were higher in vessels that developed restenosis (n = 72; 1.22 +/- 0.61 N/m2 and 3.61 +/- 2.38 N/m2, respectively) than in those without restenosis (n = 130, 1.05 +/- 0.51 N/m2 and 2.46 +/- 1.39 N/m2, respectively; P <.05). In-lesion WSS was revealed to be predictive of restenosis by means of logistic regression analysis (odds ratio [OR] = 1.42, P <.05), whereas WSS of the proximal segment was associated with an increased rate of target lesion revascularization (OR = 2.33, P <.005). In the multivariate regression model, WSS of the proximal segment was the only independent predictor when entered with known predictors such as diameter stenosis and coronary flow reserve (OR = 2.15, P <.05). CONCLUSIONS: WSS in the lesion after balloon angioplasty is predictive of angiographic restenosis. Moreover, the proximal value is an independent predictor of target lesion revascularization. This study opens perspectives for the on-line use of WSS as a combined parameter of anatomy and physiology to assess the necessity of adjunctive therapy after successful balloon dilatation.

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Three-dimensional reconstructions of 19 coronary artery stents from biplane angiograms were used for measurement of the volume through which the stents traversed during the cardiac cycle. This volume, less than 0.8% of the whole heart volume in all patients, represents a target volume for high-precision radiotherapy to treat coronary artery in-stent restenosis.

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External work, efficiency of energy transfer (EET), and mechanical efficiency (defined as the ratio of external work over myocardial oxygen consumption (MVO2) are reduced in stunned myocardium. We therefore evaluated how inotropic stimulation by dobutamine and the calcium sensitizer EMD 57033 affected the regional stress-strain relationship as, from which contractility (E(es)), external work at the working point (EWwp), maximal external work (EWmax), EETwp (%), and EETmax are determined. Thirty minutes after regional stunning in 11 open chest pigs by two 10-min coronary occlusions separated by 10 min of reperfusion, dobutamine (0.5, 1, and 2 microg x kg(-1) x min(-1)) was infused, after an ample washout period followed by infusion of EMD 57033 (0.05, 0.1, 0.2 mg x kg(-1) x min(-1)). Stunning decreased E(es) (30%), EWwp (56%), EWmax (63%), EETwp (34%), EETmax (33%) and mechanical efficiency (55%), but MVO2 was unaffected. EWwp, EWmax, EETwp, and EETmax increased similarly with the two drugs, whereas MVO2 increased only after dobutamine. Consequently, mechanical efficiency increased linearly with contractility during EMD 57033 infusion but remained constant during infusion of dobutamine.

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