A Pilot Study Characterizing Flow Patterns in the Thoracic Aorta of Patients With Connective Tissue Disease: Comparison to Age- and Gender-Matched Controls via Fluid Structure Interaction.

Prior computational and imaging studies described changes in flow patterns for patients with Marfan syndrome, but studies are lacking for related populations. This pilot study addresses this void by characterizing wall shear stress (WSS) indices for patients with Loeys-Dietz and undifferentiated connective tissue diseases. Using aortic valve-based velocity profiles from magnetic resonance imaging as input to patient-specific fluid structure interaction (FSI) models, we determined local flow patterns throughout the aorta for four patients with various connective tissue diseases (Loeys-Dietz with the native aorta, connective tissue disease of unclear etiology with native aorta in female and male patients, and an untreated patient with Marfan syndrome, as well as twin patients with Marfan syndrome who underwent valve-sparing root replacement). FSI simulations used physiological boundary conditions and material properties to replicate available measurements. Time-averaged WSS (TAWSS) and oscillatory shear index (OSI) results are presented with localized comparison to age- and gender-matched control participants. Ascending aortic dimensions were greater in almost all patients with connective tissue diseases relative to their respective control. Differences in TAWSS and OSI were driven by local morphological differences and cardiac output. For example, the model for one twin had a more pronounced proximal descending aorta in the vicinity of the ductus ligamentum that impacted WSS indices relative to the other. We are optimistic that the results of this study can serve as a foundation for larger future studies on the connective tissue disorders presented in this article.

Towards Automatic Prediction of Outcome in Treatment of Cerebral Aneurysms.

Intrasaccular flow disruptors treat cerebral aneurysms by diverting the blood flow from the aneurysm sac. Residual flow into the sac after the intervention is a failure that could be due to the use of an undersized device, or to vascular anatomy and clinical condition of the patient. We report a machine learning model based on over 100 clinical and imaging features that predict the outcome of wide-neck bifurcation aneurysm treatment with an intrasaccular embolization device. We combine clinical features with a diverse set of common and novel imaging measurements within a random forest model. We also develop neural network segmentation algorithms in 2D and 3D to contour the sac in angiographic images and automatically calculate the imaging features. These deliver 90% overlap with manual contouring in 2D and 83% in 3D. Our predictive model classifies complete vs. partial occlusion outcomes with an accuracy of 75.31%, and weighted F1-score of 0.74.

Angiographic assessment of the efficacy of flow diverter treatment for cerebral aneurysms.

BACKGROUND: The recent growth of neuro-endovascular treatment has rekindled interest in the use of angiographic techniques for flow assessment. Aneurysm treatment with flow diverters is particularly amenable to such analysis. We analyze contrast time-density curves - recorded within aneurysms before (pre) and immediately after (post) flow diverter implantation to estimate six-month treatment outcomes. METHODS: Fifty-six patients with 65 aneurysms were treated with flow diverters at two institutions. A region of interest was drawn around the aneurysm perimeter in image sequences taken both pre and post angiography, and the temporal variation in grayscale intensity within the aneurysm (time-density curve) was recorded. Eleven parameters were quantified from each time-density curve. Aneurysm occlusion status was recorded six months post treatment. The change in parameters from pre to post treatment was statistically evaluated between aneurysm occluded and non-occluded groups. RESULTS: Of the 11 parameters, eight were significantly different before and immediately after flow diversion. Considering the entire data set, none of the parameters was statistically different between the occluded and non-occluded groups. However, subgroup analyses showed that four variables were significantly different between the aneurysm occluded and non-occluded groups. The sensitivity of these variables to predict aneurysm occlusion at six months ranged from 60% to 89%, while the specificity ranged from 55% to 70%. CONCLUSIONS: Device-induced intra-aneurysmal flow alterations quantified by simple aneurysmal time-density curves can potentially be used to predict long-term outcomes of flow diversion. Large multi-center studies will be required to confirm these findings. Patient-to-patient variability in coagulation may need to be incorporated for clinically relevant predictive values.

In vitro angiographic comparison of the flow-diversion performance of five neurovascular stents.

Background and purpose Data differentiating flow diversion properties of commercially available low- and high-porosity stents are limited. This in vitro study applies angiographic analysis of intra-aneurysmal flow to compare the flow-diversion performance of five neurovascular devices in idealized sidewall and bifurcation aneurysm models. Methods Five commercial devices (Enterprise, Neuroform, LVIS, FRED, and Pipeline) were implanted in silicone sidewall and bifurcation aneurysm models under physiological average flow of blood analog fluid. High-speed angiographic images were acquired pre- and post-device implantation and contrast concentration-time curves within the aneurysm were recorded. The curves were quantified with five parameters to assess changes in contrast transport, and thus aneurysm hemodynamics, due to each device. Results Inter-device flow-diversion performance was more easily distinguished in the sidewall model than the bifurcation model. There were no obvious overall statistical trends in the bifurcation parameters but the Pipeline performed marginally better than the other devices. In the sidewall geometry, overall evidence suggests that the LVIS performed better than the Neuroform and Enterprise. The Pipeline and FRED devices were statistically superior to the three stents and Pipeline was superior to FRED in all sidewall parameters evaluated. Conclusions Based on this specific set of experiments, lower-porosity flow diverters perform significantly better in reducing intra-aneurysmal flow activity than higher-porosity stents in sidewall-type geometries. The LVIS device is potentially a better flow diverter than the Neuroform and Enterprise devices, while the Pipeline is potentially better than the FRED.

Hemodynamics of Flow Diverters.

Cerebral aneurysms are pathological focal evaginations of the arterial wall at and around the junctions of the circle of Willis. Their tenuous walls predispose aneurysms to leak or rupture leading to hemorrhagic strokes with high morbidity and mortality rates. The endovascular treatment of cerebral aneurysms currently includes the implantation of fine-mesh stents, called flow diverters, within the parent artery bearing the aneurysm. By mitigating flow velocities within the aneurysmal sac, the devices preferentially induce thrombus formation in the aneurysm within hours to days. In response to the foreign implant, an endothelialized arterial layer covers the luminal surface of the device over a period of days to months. Organization of the intraneurysmal thrombus leads to resorption and shrinkage of the aneurysm wall and contents, eventually leading to beneficial remodeling of the pathological site to a near-physiological state. The devices' primary function of reducing flow activity within aneurysms is corollary to their mesh structure. Complete specification of the device mesh structure, or alternately device permeability, necessarily involves the quantification of two variables commonly used to characterize porous media-mesh porosity and mesh pore density. We evaluated the flow alteration induced by five commercial neurovascular devices of varying porosity and pore density (stents: Neuroform, Enterprise, and LVIS; flow diverters: Pipeline and FRED) in an idealized sidewall aneurysm model. As can be expected in such a model, all devices substantially reduced intraneurysmal kinetic energy as compared to the nonstented case with the coarse-mesh stents inducing a 65-80% reduction whereas the fine-mesh flow diverters induced a near-complete flow stagnation (∼98% reduction). We also note a trend toward greater device efficacy (lower intraneurysmal flow) with decreasing device porosity and increasing device pore density. Several such flow studies have been and are being conducted in idealized as well as patient-derived geometries with the overarching goals of improving device design, facilitating treatment planning (what is the optimal device for a specific aneurysm), and predicting treatment outcome (will a specific aneurysm treated with a specific device successfully occlude over the long term). While the results are generally encouraging, there is poor standardization of study variables between different research groups, and any consensus will only be reached after standardized studies are conducted on collectively large datasets. Biochemical variables may have to be incorporated into these studies to maximize predictive values.

Cardiovascular magnetic resonance imaging-based computational fluid dynamics/fluid-structure interaction pilot study to detect early vascular changes in pediatric patients with type 1 diabetes.

We hypothesized that pediatric patients with type 1 diabetes have cardiac magnetic resonance (CMR) detectable differences in thoracic aortic wall properties and hemodynamics leading to significant local differences in indices of wall shear stress, when compared with age-matched control subjects without diabetes. Pediatric patients with type 1 diabetes were recruited from Children's Hospital of Wisconsin and compared with controls. All underwent morning CMR scanning, 4-limb blood pressure, brachial artery reactivity testing, and venipuncture. Patient-specific computational fluid dynamics modeling with fluid-structure interaction, based on CMR data, determined regional time-averaged wall shear stress (TAWSS) and oscillatory shear index (OSI). Twenty type 1 diabetic subjects, median age 15.8 years (11.6-18.4) and 8 controls 15.4 years (10.3-18.2) were similar except for higher glucose, hemoglobin A1c, and triglycerides for type 1 diabetic subjects. Lower flow-mediated dilation was seen for those with type 1 diabetes (6.5) versus controls (7.8), p = 0.036. For type 1 diabetic subjects, the aorta had more regions with high TAWSS when compared to controls. OSI maps appeared similar. Flow-mediated dilation positively correlated with age at diabetes diagnosis (r = 0.468, p = 0.038) and hemoglobin A1c (r = 0.472, p = 0.036), but did not correlate with aortic distensibility, TAWSS, or OSI. TAWSS did not correlate with any clinical parameter for either group. CMR shows regional differences in aortic wall properties for young diabetic patients. Some local differences in wall shear stress indices were also observed, but a longitudinal study is now warranted.

Quantification of local hemodynamic alterations caused by virtual implantation of three commercially available stents for the treatment of aortic coarctation.

Patients with coarctation of the aorta (CoA) are prone to morbidity including atherosclerotic plaque that has been shown to correlate with altered wall shear stress (WSS) in the descending thoracic aorta (dAo). We created the first patient-specific computational fluid dynamics (CFD) model of a CoA patient treated by Palmaz stenting to date, and compared resulting WSS distributions to those from virtual implantation of Genesis XD and modified NuMED CP stents, also commonly used for CoA. CFD models were created from magnetic resonance imaging, fluoroscopy and blood pressure data. Simulations incorporated vessel deformation, downstream vascular resistance and compliance to match measured data and generate blood flow velocity and time-averaged WSS (TAWSS) results. TAWSS was quantified longitudinally and circumferentially in the stented region and dAo. While modest differences were seen in the distal portion of the stented region, marked differences were observed downstream along the posterior dAo and depended on stent type. The Genesis XD model had the least area of TAWSS values exceeding the threshold for platelet aggregation in vitro, followed by the Palmaz and NuMED CP stents. Alterations in local blood flow patterns and WSS imparted on the dAo appear to depend on the type of stent implanted for CoA. Following confirmation in larger studies, these findings may aid pediatric interventional cardiologists in selecting the most appropriate stent for each patient, and ultimately reduce long-term morbidity following treatment for CoA by stenting.

IN VITRO QUANTIFICATION OF THE SIZE DISTRIBUTION OF INTRASACCULAR VOIDS LEFT AFTER ENDOVASCULAR COILING OF CEREBRAL ANEURYSMS.

PURPOSE: Endovascular coiling of cerebral aneurysms remains limited by coil compaction and associated recanalization. Recent coil designs which effect higher packing densities may be far from optimal because hemodynamic forces causing compaction are not well understood since detailed data regarding the location and distribution of coil masses are unavailable. We present an in vitro methodology to characterize coil masses deployed within aneurysms by quantifying intra-aneurysmal void spaces. METHODS: Eight identical aneurysms were packed with coils by both balloon- and stent-assist techniques. The samples were embedded, sequentially sectioned and imaged. Empty spaces between the coils were numerically filled with circles (2D) in the planar images and with spheres (3D) in the three-dimensional composite images. The 2D and 3D void size histograms were analyzed for local variations and by fitting theoretical probability distribution functions. RESULTS: Balloon-assist packing densities (31±2%) were lower (p=0.04) than the stent-assist group (40±7%). The maximum and average 2D and 3D void sizes were higher (p=0.03 to 0.05) in the balloon-assist group as compared to the stent-assist group. None of the void size histograms were normally distributed; theoretical probability distribution fits suggest that the histograms are most probably exponentially distributed with decay constants of 6-10 mm. Significant (p<=0.001 to p=0.03) spatial trends were noted with the void sizes but correlation coefficients were generally low (absolute r<=0.35). CONCLUSION: The methodology we present can provide valuable input data for numerical calculations of hemodynamic forces impinging on intra-aneurysmal coil masses and be used to compare and optimize coil configurations as well as coiling techniques.

A coupled experimental and computational approach to quantify deleterious hemodynamics, vascular alterations, and mechanisms of long-term morbidity in response to aortic coarctation.

INTRODUCTION: Coarctation of the aorta (CoA) is associated with morbidity despite treatment. Although mechanisms remain elusive, abnormal hemodynamics and vascular biomechanics are implicated. We present a novel approach that facilitates quantification of coarctation-induced mechanical alterations and their impact on vascular structure and function, without genetic or confounding factors. METHODS: Rabbits underwent thoracic CoA at 10weeks of age (~9 human years) to induce a 20mmHg blood pressure (BP) gradient using permanent or dissolvable suture thereby replicating untreated and corrected CoA. Computational fluid dynamics (CFD) was performed using imaging and BP data at 32weeks to quantify velocity, strain and wall shear stress (WSS) for comparison to vascular structure and function as revealed by histology and myograph results. RESULTS: Systolic and mean BP was elevated in CoA compared to corrected and control rabbits leading to vascular thickening, disorganization and endothelial dysfunction proximally and distally. Corrected rabbits had less severe medial thickening, endothelial dysfunction, and stiffening limited to the proximal region despite 12weeks of normal BP (~4 human years) after the suture dissolved. WSS was elevated distally for CoA rabbits, but reduced for corrected rabbits. DISCUSSION: These findings are consistent with alterations in humans. We are now poised to investigate mechanical contributions to mechanisms of morbidity in CoA using these methods.

Computational simulations demonstrate altered wall shear stress in aortic coarctation patients treated by resection with end-to-end anastomosis.

BACKGROUND: Atherosclerotic plaque in the descending thoracic aorta (dAo) is related to altered wall shear stress (WSS) for normal patients. Resection with end-to-end anastomosis (RWEA) is the gold standard for coarctation of the aorta (CoA) repair, but may lead to altered WSS indices that contribute to morbidity. METHODS: Computational fluid dynamics (CFD) models were created from imaging and blood pressure data for control subjects and age- and gender-matched CoA patients treated by RWEA (four males, two females, 15 ± 8 years). CFD analysis incorporated downstream vascular resistance and compliance to generate blood flow velocity, time-averaged WSS (TAWSS), and oscillatory shear index (OSI) results. These indices were quantified longitudinally and circumferentially in the dAo, and several visualization methods were used to highlight regions of potential hemodynamic susceptibility. RESULTS: The total dAo area exposed to subnormal TAWSS and OSI was similar between groups, but several statistically significant local differences were revealed. Control subjects experienced left-handed rotating patterns of TAWSS and OSI down the dAo. TAWSS was elevated in CoA patients near the site of residual narrowings and OSI was elevated distally, particularly along the left dAo wall. Differences in WSS indices between groups were negligible more than 5 dAo diameters distal to the aortic arch. CONCLUSIONS: Localized differences in WSS indices within the dAo of CoA patients treated by RWEA suggest that plaque may form in unique locations influenced by the surgical repair. These regions can be visualized in familiar and intuitive ways allowing clinicians to track their contribution to morbidity in longitudinal studies.