Lesion Geometry Research Articles

Changing Views of the Biomechanics of Vulnerable Plaque Rupture: A Review

This review examines changing perspectives on the biomechanics of vulnerable plaque rupture over the past 25 years from the first finite element analyses (FEA) showing that the presence of a lipid pool significantly increases the local tissue stress in the atheroma cap to the latest imaging and 3D FEA studies revealing numerous microcalcifications in the cap proper and a new paradigm for cap rupture. The first part of the review summarizes studies describing the role of the fibrous cap thickness, tissue properties, and lesion geometry as main determinants of the risk of rupture. Advantages and limitations of current imaging technologies for assessment of vulnerable plaques are also discussed. However, the basic paradoxes as to why ruptures frequently did not coincide with location of PCS and why caps >65 μm thickness could rupture at tissue stresses significantly below the 300 kPa critical threshold still remained unresolved. The second part of the review describes recent studies in the role of microcalcifications, their origin, shape, and clustering in explaining these unresolved issues including the actual mechanism of rupture due to the explosive growth of tiny voids (cavitation) in local regions of high stress concentration between closely spaced microinclusions oriented along their tensile axis.

Estudio de la eliminación de arritmias cardíacas mediante el uso de la modelización matemática

Mathematical modeling is a fast and low cost tool used as a first approach to solve certain problems in real contexts. In this paper we present an example of how a real clinical problem, in the context of cardiac surgery, can be simulated and responded to through mathematical models. Specifically, the resolution of these models, which are based on a coupled electric-thermal problem, allows us to assess in detail the temperature distribution and the geometry of the thermal lesion created in the ventricular wall after radiofrequency ablation in order to eliminate cardiac arrhythmias.

SU-E-CAMPUS-I-05: Optical Based Elastography Method for Breast Tumor Detection

Purpose: In this research, we present an optical based elastography device which can be used for practical medical diagnostic experiments for measuring stiffness and geometry of lesion. Methods: The optical elastography incorporates an optical waveguide sensing probe unit, a light source unit, a camera unit, and a computer unit. The optical method of total internal reflection phenomenon in an optical waveguide is adapted for the tissue elasticity measurement principle. The light sources are attached along the edges of the waveguide and illuminates at a critical angle to totally reflect the light within the waveguide. Once the waveguide is deformed due to the stiff inclusion, it causes the trapped light to change the critical angle and diffuse outside the waveguide. The scattered light is captured by a camera. From elastography images, we developed a novel method to estimate that size, depth, and elasticity of the embedded lesion using 3-D finite element-model-based forward algorithm, and neural-network based inversion algorithm. Results: The proposed elasticity characterization device and method were validated by the realistic tissue phantom with inclusions to emulate the tumors. The phantom was made of a silicone composite having a Youngs modulus of approximately 5kPa. The inclusion was made using another silicone composite; the stiffness of which was higher than the surrounding tissue phantom. The Youngs modulus of each inclusion was 120kPa, which is for fibrous tissue at 5% pre-compression with loading frequency of 4.0Hz. The experimental results showed that, the proposed characterization method estimated the size, depth, and Youngs modulus of a tissue inclusion within 0.16mm, 0.18mm, and 0.66kPa relative errors, respectively. Conclusion: An elastography device using the total internal reflection principle and its algorithms were designed and experimentally evaluated. The work presented in this research is the initial step towards early detection of malignant breast tumors.

Effects of Open‐Irrigated Radiofrequency Ablation Catheter Design on Lesion Formation and Complications: In Vitro Comparison of 6 Different Devices

Open-irrigated radiofrequency ablation catheters with slight differences in tip architecture are widely used, although limited comparative data are available. The purpose of this study was to compare the lesion size and potential complications produced by commercially available open-irrigated catheters in an in vitro porcine heart model. Six catheters were tested (Biosense Webster Thermocool, Boston Scientific Open irrigated, St. Jude CoolPath, St. Jude CoolPath Duo, Biosense Webster Thermocool SF, St. Jude Cool Flex) at 20 and 35 W power-control, under 2 different blood flows (0.1 and 0.5 m/s) and at 2 target durations (30 and 60 seconds). A total of 601 lesions were made in 26 in vitro preparations. The tip temperature profile showed significant differences between the catheters (P < 0.001) with the Thermocool SF registering the lowest. Only the surface diameter and the depth at maximum diameter of the lesion were influenced by the design of the ablation electrode. The lesion volume did not show significant differences between catheters for any power, application duration or blood flow condition. Char and pops occurred more often at 35 W with only slight differences between the catheters. Tip design of the 6 different irrigated catheters does not affect the lesion total volume, although a slight difference in lesion geometry in terms of surface diameter and depth at maximum diameter is present. The catheters show a slight different in vitro safety profile.

Image-based Modeling and Characterization of RF Ablation Lesions in Cardiac Arrhythmia Therapy.

In spite of significant efforts to enhance guidance for catheter navigation, limited research has been conducted to consider the changes that occur in the tissue during ablation as means to provide useful feedback on the progression of therapy delivery. We propose a technique to visualize lesion progression and monitor the effects of the RF energy delivery using a surrogate thermal ablation model. The model incorporates both physical and physiological tissue parameters, and uses heat transfer principles to estimate temperature distribution in the tissue and geometry of the generated lesion in near real time. The ablation model has been calibrated and evaluated using ex vivo beef muscle tissue in a clinically relevant ablation protocol. To validate the model, the predicted temperature distribution was assessed against that measured directly using fiberoptic temperature probes inserted in the tissue. Moreover, the model-predicted lesions were compared to the lesions observed in the post-ablation digital images. Results showed an agreement within 5°C between the model-predicted and experimentally measured tissue temperatures, as well as comparable predicted and observed lesion characteristics and geometry. These results suggest that the proposed technique is capable of providing reasonably accurate and sufficiently fast representations of the created RF ablation lesions, to generate lesion maps in near real time. These maps can be used to guide the placement of successive lesions to ensure continuous and enduring suppression of the arrhythmic pathway.

Effect of the Spiroiminodihydantoin (Sp) Lesion on Nucleosome Stability

The chemical integrity of the DNA is constantly being modified covalently by endogenous and exogenous agents. If not repaired, these DNA lesions play a critical role in carcinogenic and ageing processes of the cell. Though lesions occur throughout the genome, the low redox potential of the guanine bases make them particularly vulnerable to oxidants. One of the major base lesions formed on DNA is 8-oxo-7,8-dihydroguanine (8-oxo-G). Once formed, this lesion can be further oxidized to the enantiomeric spiroiminodihydantoin (Sp) lesion. These Sp lesions are highly mutagenic, leading to G→T and G→C transversion mutations.DNA lesions can alter the binding of critical transcription factors and chromatin components. Here, we explore how the presence of the Sp lesion affects the binding of histone proteins to form nucleosomes. Histone proteins are isolated from chicken erythrocytes, and 146 bp DNA duplexes synthesized with single, enantiomerically-pure Sp lesions placed site-specifically around the center of the sequence. Histone proteins are exchanged onto our target DNA, and the binding of the histones to the DNA is assessed by gel shift to yield changes in free energy of nucleosome formation relative to unmodified control DNA.Our results indicate that although nucleosomes are formed on all 146-mer duplexes, nucleosome stability decreases measurably when a single Sp lesion is present. Both Sp enantiomers bind more weakly than the control, but the two enantiomers do not bind identically. These enantiospecific differences may play a key role in the process of DNA repair. Placement of the lesion within the sequence also has an effect upon binding thermodynamics, potentially reflecting conflicting pressures exerted by the lesion geometry and the bent DNA geometry necessary for protein binding. These findings suggest that formation of the Sp lesion could have dramatic effects on DNA packaging and expression.

Abstract 19280: Computational Fluid Dynamics Predicts Correlations between Transluminal Contrast and Pressure Gradients in Models of Stenosed Arteries

Background: Recent computed tomography coronary angiography (CTCA) studies have noted the presence of transluminal contrast gradients (TCG) in stenosed arteries but the mechanism and significance of TCG is unknown. Objective: Use computational fluid dynamics (CFD) modeling to determine mechanisms of contrast dispersion and correlate TCG to transstenotic pressure gradient (TPG) in models of stenosed coronary arteries. Methods: Simulations of flow and contrast dispersion in simple 2-dimensional models of coronary stenosis were carried out. Models with symmetric and asymmetric stenosis of varying severities (25%-75%) were employed. Key parameters including Reynolds and Womersley numbers were also varied. Simulations predict the variations of flow, pressure and contrast concentration in arterial models. Data from the simulations was analyzed to generate correlations between and contrast dispersion patterns and TPG with increasing stenosis severity. For extracting transluminal correlations, pressure and contrast concentration are averaged across the cross-section of the lumen and the contrast gradient is normalized by the maximum concentration at the inlet of the model. Results: Simulations predict the variations of flow, pressure and contrast concentration in arterial models (see figure). The data shows a direct but nonlinear correlation between TCG and TPG. A comparison of contrast dispersion in symmetric and one-sided stenoses also indicates that the correlation between TCG and TPG is sensitive to lesion geometry; the TCG for a symmetric lesion correlates to a higher TPG than a one-sided lesion. Conclusions: The current result is the first direct evidence that TCG may encode for vessel hemodynamics and that lesion geometry also modulates this relationship. CFD modeling provides data for determining important mechanistic insights into TCG and may be used to “decode” flow resistance from CTCA exams.

Hydrogels derived from central nervous system extracellular matrix

Biologic scaffolds composed of extracellular matrix (ECM) are commonly used repair devices in preclinical and clinical settings; however the use of these scaffolds for peripheral and central nervous system (CNS) repair has been limited. Biologic scaffolds developed from brain and spinal cord tissue have recently been described, yet the conformation of the harvested ECM limits therapeutic utility. An injectable CNS-ECM derived hydrogel capable of in vivo polymerization and conformation to irregular lesion geometries may aid in tissue reconstruction efforts following complex neurologic trauma. The objectives of the present study were to develop hydrogel forms of brain and spinal cord ECM and compare the resulting biochemical composition, mechanical properties, and neurotrophic potential of a brain derived cell line to a non-CNS-ECM hydrogel, urinary bladder matrix. Results showed distinct differences between compositions of brain ECM, spinal cord ECM, and urinary bladder matrix. The rheologic modulus of spinal cord ECM hydrogel was greater than that of brain ECM and urinary bladder matrix. All ECMs increased the number of cells expressing neurites, but only brain ECM increased neurite length, suggesting a possible tissue-specific effect. All hydrogels promoted three-dimensional uni- or bi-polar neurite outgrowth following 7 days in culture. These results suggest that CNS-ECM hydrogels may provide supportive scaffolding to promote in vivo axonal repair.

Evaluation of a Novel Cryoablation System: In vivo Testing in a Chronic Porcine Model

Cryoablation is commonly used at present in the surgical treatment of atrial fibrillation (AF). However, there have been few studies examining the efficacy of the commonly used ablation devices. This report compares the efficacy of two cryoprobes in creating transmural endocardial lesions on the beating heart in a porcine model for chronic AF. In six Hanford miniature swine, the right atrial appendage and the inferior vena cava were isolated using a bipolar radiofrequency clamp to create areas of known conduction block. A connecting ablation line was performed endocardially via a purse string with the novel malleable 10-cm Cryo1 probe for 2 minutes at -40°C. Additional ablation lines were created with the Cryo1 and the 3.5-cm 3011 Maze Linear probe on the right and the left atrial wall. Epicardial activation mapping was performed before and immediately after ablation as well as 14 days postoperatively. Histologic examination was performed 14 days postoperatively. Transmural lesions were confirmed in 83/84 cross-sections (99%) for the Cryo1 probe and in 40/41 cross-sections (98%) for the 3011 Maze Linear probe. There was no difference between the devices in lesion width (mean ± SD, Cryo1, 10.7 ± 3.5 mm; 3011, 10.0 ± 3.9 mm; P = 0.31), lesion depth (Cryo1, 4.5 ± 1.7 mm; 3011, 4.6 ± 1.5 mm; P = 0.74), or atrial wall thickness (Cryo1, 4.5 ± 1.8 mm; 3011, 4.7 ± 1.7 mm; P = 0.74). There was a conduction delay across the right atrial ablation line (20 ± 2 milliseconds vs 51 ± 8 milliseconds, P < 0.001) that remained unchanged at 14 days (51 ± 8 milliseconds vs 52 ± 10 milliseconds, P = 0.88). The Cryo1 probe created transmural lesions on the beating heart, resulting in sustained conduction delay. Both probes had a similar performance in lesion geometry in this chronic animal model.

Evaluation of a novel cryoablation system: in vivo testing in a chronic porcine model.

Cryoablation is commonly used at present in the surgical treatment of atrial fibrillation (AF). However, there have been few studies examining the efficacy of the commonly used ablation devices. This report compares the efficacy of two cryoprobes in creating transmural endocardial lesions on the beating heart in a porcine model for chronic AF. In six Hanford miniature swine, the right atrial appendage and the inferior vena cava were isolated using a bipolar radiofrequency clamp to create areas of known conduction block. A connecting ablation line was performed endocardially via a purse string with the novel malleable 10-cm Cryo1 probe for 2 minutes at -40°C. Additional ablation lines were created with the Cryo1 and the 3.5-cm 3011 Maze Linear probe on the right and the left atrial wall. Epicardial activation mapping was performed before and immediately after ablation as well as 14 days postoperatively. Histologic examination was performed 14 days postoperatively. Transmural lesions were confirmed in 83/84 cross-sections (99%) for the Cryo1 probe and in 40/41 cross-sections (98%) for the 3011 Maze Linear probe. There was no difference between the devices in lesion width (mean ± SD, Cryo1, 10.7 ± 3.5 mm; 3011, 10.0 ± 3.9 mm; P = 0.31), lesion depth (Cryo1, 4.5 ± 1.7 mm; 3011, 4.6 ± 1.5 mm; P = 0.74), or atrial wall thickness (Cryo1, 4.5 ± 1.8 mm; 3011, 4.7 ± 1.7 mm; P = 0.74). There was a conduction delay across the right atrial ablation line (20 ± 2 milliseconds vs 51 ± 8 milliseconds, P < 0.001) that remained unchanged at 14 days (51 ± 8 milliseconds vs 52 ± 10 milliseconds, P = 0.88). The Cryo1 probe created transmural lesions on the beating heart, resulting in sustained conduction delay. Both probes had a similar performance in lesion geometry in this chronic animal model.

Histopathologic Characterization of Chronic Radiofrequency Ablation Lesions for Pulmonary Vein Isolation

This study describes the histopathologic and electrophysiological findings in patients with recurrence of atrial fibrillation (AF) after pulmonary vein (PV) isolation who underwent a subsequent surgical maze procedure. The recovery of PV conduction is commonly responsible for recurrence of AF after catheter-based PV isolation. Twelve patients with recurrent AF after acutely successful catheter-based antral PV isolation underwent a surgical maze procedure. Full-thickness surgical biopsy specimens were obtained from the PV antrum in areas of visible endocardial scar. Before biopsy, intraoperative epicardial electrophysiological recordings were taken from each PV using a circular mapping catheter. Twenty-two PVs were biopsied from the 12 patients 8 ± 11 months after ablation. Eleven of the 22 specimens (50%) revealed transmural scar, and 11 (50%) showed viable myocardium with or without scar. Each biopsy specimen demonstrated evidence of injury, most commonly endocardial thickening (n = 21 [95%]) and fibrous scar (n = 18 [82%]). Seven of the 22 specimens (32%) showed conduction block at surgery. Transmural scar was more likely to be seen in the biopsy specimens from the PVs with conduction block than in specimens from the PVs showing reconnection. However, viable myocardium alone or mixed with scar was seen in 2 specimens from PVs with conduction block. PVs showing electrical reconnection after catheter-based antral ablation frequently reveal anatomic gaps or nontransmural lesions at the sites of catheter ablation. Nontransmural lesions are noted in some PVs with persistent conduction block, suggesting that lesion geometry may influence PV conduction. The histological findings show that nontransmural ablation can produce a dynamic cellular substrate with features of reversible injury. Delayed recovery from injury may explain late recurrences of AF after PV isolation.

Impact of Irrigation Flow Rate on Tissue Temperature Profile and Lesion Geometry in an Ovine Thigh Muscle Radio-frequency Ablation Model

Impact of Irrigation Flow Rate on Tissue Temperature Profile and Lesion Geometry in an Ovine Thigh Muscle Radio-frequency Ablation Model

Conductance catheter measurements of lumen area of stenotic coronary arteries: theory and experiment

An injection of saline solution is required for the measurement of vessel lumen area using a conductance catheter. The injection of room temperature saline to displace blood in a vessel inevitably involves mass and heat transport and electric field conductance. The objective of the present study is to understand the accuracy of conductance method based on the phenomena associated with the saline injection into a stenotic blood vessel. Computational fluid dynamics were performed to simulate flow and its relation to transport and electric field in a stenotic artery for two different sized conductance catheters (0.9 and 0.35 mm diameter) over a range of occlusions [56-84% cross-sectional area (CSA) stenosis]. The results suggest that the performance of conductance catheter is dependent on catheter size and severity of stenosis more significantly for 0.9 mm than for 0.35 mm catheter. Specifically, the time of detection of 95% of injected saline solution at the detection electrodes was shown to range from 0.67 to 3.7 s and 0.82 to 0.94 s for 0.9 mm and 0.35 mm catheter, respectively. The results also suggest that the detection electrodes of conductance catheter should be placed outside of flow recirculation region distal to the stenosis to minimize the detection time. Finally, the simulations show that the accuracy in distal CSA measurements, however, is not significantly altered by whether the position of detection electrodes is inside or outside of recirculation zone (error was within 12% regardless of detection electrodes position). The results were experimentally validated for one lesion geometry and the simulation results are within 8% of actual measurements. The simulation of conductance catheter injection method may lead to further optimization of device and method for accurate sizing of diseased coronary arteries, which has clinical relevance to percutaneous intervention.

Morphology of coronary artery lesions assessed by virtual histology intravascular ultrasound tissue characterization and fractional flow reserve

Fractional flow reserve (FFR) is an index of the physiological significance of a coronary stenosis. Patients who have lesions with a FFR of >0.80, even optimally treated with medication, have however a MACE rate ranging from 8 to 21%. Coronary plaques at high risk of rupture and clinical events can be also identified by virtual histology intravascular ultrasound (IVUS-VH) as plaques with high amount of necrotic core (NC) abutting the lumen. Aim of this exploratory study was to investigate whether the geometry and composition of lesions with FFR≤0.80 were different from their counterparts. Fifty-five consecutive patients in whom FFR was clinically indicated on a moderate angiographic lesion, received also an imaging investigation on the same lesion with IVUS-VH. Data on plaque geometry and composition was analyzed. Patients were subdivided in two groups according to the value of FFR (> or ≤0.80). Lesions with a FFR≤0.80 (n=17) showed a slightly larger plaque burden than those with FFR>0.80 (n=38) (54.6±0.7% vs. 51.7±0.7% P=0.1). In addition, they tend to have less content of necrotic core than their counterparts (14.2±8% vs. 19.2±10.2%, P=0.08). No difference was found in the distribution of NC-rich plaques (fibroatheroma and thin-capped fibroatheroma) between groups (82% in FFR≤0.80 vs. 79% in FFR>0.80, P=0.5). Although FFR≤0.80 lesions have larger plaque size, they do not differ in composition from the ones with FFR>0.80. Further exploration in a large prospective study is needed to study whether the lesions with FFR>0.80 that are NC rich are the ones associated with the presence of clinical events at follow-up.

Optical coherence tomography for guidance in bifurcation lesion treatment

Optical coherence tomography (OCT) has higher resolution than IVUS (approximately 10 times), with the potential to precisely measure lumen diameters in the variable geometry of a bifurcational lesion and to identify superficial lipid laden plaques and calcium, relevant to confirm the severity of the lumen obstruction before treatment and guide location and diameter of the stent. In addition, OCT produces fewer strut-induced artifacts and offers precise evaluation of strut apposition in a real-life clinical setting. The increase in the speed of image acquisition consequent to the introduction of frequency domain OCT allows rapid pull-back at a speed of 2 cm/sec, minimising the amount of contrast required to clear blood during image acquisition, with an average injection of 10-18 ml required for the maximal length currently available of 5.6 cm. This allows serial OCT acquisitions, typically before treatment if the lesion is not very severe and flow is expected to be present around the OCT catheter, after predilatation and to assess and guide stent expansion. Repeated OCT examinations at follow-up may help to detect presence and characteristics of strut coverage, a potential predictor of late stent thrombosis. These applications are of particular interest in the context of bifurcational lesion treatment because this condition is still associated with a higher number of malapposed stent struts and frequent impairment of stent expansion, explaining the higher incidence of stent thrombosis and restenosis. In this article, all potential applications of OCT for bifurcational lesion treatment are explored. The use of OCT to characterise plaque components, and to optimise stent expansion and strut apposition are first discussed in detail. The conclusion of the article highlights some future research and technological developments that promise to expand the role of OCT further still.

GPR application to the structural control of historical buildings: two case studies in Rome, Italy

ABSTRACTPreservation of historical buildings requires particular care, as any intervention must not alter or damage the style, structure or contents of the edifice. In order to properly plan the restoration of a building, non‐destructive techniques can be used extensively to detect structural elements and weaknesses. Ground‐penetrating radar (GPR) is particularly well adapted to this type of work, as the method is non‐invasive, rapid and provides high‐resolution images of contrasting subsurface materials.In the present work we show the successful application of the GPR technique to the investigation of two historical buildings that differ in age, structure and geometry.The first case is the GPR detection of fractures and internal lesions in the architrave of the Porticus Octaviae, a partially restored Roman building. The second case uses GPR in the important Zuccari Palace to determine the internal structure above vaulted ceilings that host a series of 16th century frescos. Both buildings are located in downtown Rome, Italy.These examples show that GPR can give detailed, non‐invasive data that describe the state of conservation of historical buildings. In particular, this technique can produce fundamental information for the restorers (e.g., location, dimension and geometry of the structural lesions) that will help them develop the best possible protection plan, retrieving quantitative information about the location and the dimension of the lesions as well as the thickness of the different layers.

Radiofrequency Endothelial Ablation Prevents Recanalization after Endovascular Coil Occlusion: In Vitro and in Vivo Assessment

Coil embolization of intracranial aneurysms may be followed by recurrences. Radiofrequency (RF) ablation of the endothelium may prevent recanalization after coil embolization. The authors performed in vitro experiments in chicken meat and egg white models to investigate the thermal distribution and geometry of lesions created with RF applied through standard coils alone or by using a prototype RF electrode inserted in a coil or a mass of coils. A mathematic model was designed to predict perianeurysmal isotherm lesions by using the bio-heat equation. In an in vivo coil arterial occlusion model (six dogs), the authors compared angiographic and pathologic results of coil embolization (n = 8) with those of coil embolization preceded by RF ablation (n = 7) by using a cardiac electrode at 1 month. Current coils offer high impedance (400 Omega) at high current frequencies and are damaged by RF transmission. A dedicated electrode generated reproducible lesions, but contact with coils interferes with lesion reproducibility. When the coil mass was used, a uniform RF lesion that conformed to the coil mass shape was produced. The mathematic model predicted a uniform heat distribution within 1 mm from the coil mass periphery. Arterial coil embolization led to occlusion followed by recanalization (n = 8), whereas RF ablation (20-30 W for 60 seconds) prevented recanalization in all coil-occluded arteries (P < .001, chi(2) test). Pathologic findings helped confirm complete arterial occlusion with RF ablation. One animal developed brachial plexus injury with excessive levels of RF ablation. RF ablation can prevent recanalization after coil occlusion-at least in the arterial model. Modifications of coils, dedicated neurovascular electrodes, and technique optimization remain necessary before considering a clinical application.

Invasive Cortical Stimulation to Promote Recovery of Function After Stroke

Residual motor deficits frequently linger after stroke. Search for newer effective strategies to promote functional recovery is ongoing. Brain stimulation, as a means of directing adaptive plasticity, is appealing. Animal studies and Phase I and II trials in humans have indicated safety, feasibility, and efficacy of combining rehabilitation and concurrent invasive cortical stimulation. However, a recent Phase III trial showed no advantage of the combination. We critically review results of various trials and discuss the factors that contributed to the distinctive result. Regarding cortical stimulation, it is important to determine the (1) location of peri-infarct representations by integrating multiple neuroanatomical and physiological techniques; (2) role of other mechanisms of stroke recovery; (3) viability of peri-infarct tissue and descending pathways; (4) lesion geometry to ensure no alteration/displacement of current density; and (5) applicability of lessons generated from noninvasive brain stimulation studies in humans. In terms of combining stimulation with rehabilitation, we should understand (1) the principle of homeostatic plasticity; (2) the effect of ongoing cortical activity and phases of learning; and (3) that subject-specific intervention may be necessary. Future cortical stimulation trials should consider the factors that may have contributed to the peculiar results of the Phase III trial and address those in future study designs.

Biomechanical Regulation of Endothelium-dependent Events Critical for Adaptive Remodeling

Alterations in hemodynamic shear stress acting on the vascular endothelium are critical for adaptive arterial remodeling. The molecular mechanisms regulating this process, however, remain largely uncharacterized. Here, we sought to define the responses evoked in endothelial cells exposed to shear stress waveforms characteristic of coronary collateral vessels and the subsequent paracrine effects on smooth muscle cells. A lumped parameter model of the human coronary collateral circulation was used to simulate normal and adaptive remodeling coronary collateral shear stress waveforms. These waveforms were then applied to cultured human endothelial cells (EC), and the resulting differences in EC gene expression were assessed by genome-wide transcriptional profiling to identify genes distinctly regulated by collateral flow. Analysis of these transcriptional programs identified several genes to be differentially regulated by collateral flow, including genes important for endothelium-smooth muscle interactions. In particular, the transcription factor KLF2 was up-regulated by the adaptive remodeling coronary collateral waveform, and several of its downstream targets displayed the expected modulation, including the down-regulation of connective tissue growth factor. To assess the effect of endothelial KLF2 expression on smooth muscle cell migration, a three-dimensional microfluidic assay was developed. Using this three-dimensional system, we showed that KLF2-expressing EC co-cultured with SMC significantly reduce SMC migration compared with control EC and that this reduction can be rescued by the addition of exogenous connective tissue growth factor. Collectively, these results demonstrate that collateral flow evokes distinct EC gene expression profiles and functional phenotypes that subsequently influence vascular events important for adaptive remodeling.

Determination of Wall Tension in Cerebral Artery Aneurysms by Numerical Simulation

Cerebral artery aneurysms rupture when wall tension exceeds the strength of the wall tissue. At present, risk-assessment of unruptured aneurysms does not include evaluation of the lesions shape, yet clinical experience suggests that this is of importance. We aimed to develop a computational model for simulation of fluid-structure interaction in cerebral aneurysms based on patient specific lesion geometry, with special emphasis on wall tension. An advanced isogeometric fluid-structure analysis model incorporating flexible aneurysm wall based on patient specific computed tomography angiogram images was developed. Variables used in the simulation model were retrieved from a literature review. The simulation results exposed areas of high wall tension and wall displacement located where aneurysms usually rupture. We suggest that analyzing wall tension and wall displacement in cerebral aneurysms by numeric simulation could be developed into a novel method for individualized prediction of rupture risk.