Christof Karmonik

Quantitation and Localization of Matrix Metalloproteinases and Their Inhibitors in Human Carotid Endarterectomy Tissues

Background—Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) play a central role in arterial wall remodeling, affecting stability of fibrous caps covering atherosclerotic plaques. The objective of this study was to determine the spatial distribution of TIMP mass and MMP mass and activity of carotid endarterectomy (CEA) tissues and relate it to the distribution of atherosclerotic lesions. Methods and Results—Fresh CEA tissues were imaged by multicontrast MRI to generate 3D reconstructions. Tissue segments were cut transversely from the common, bifurcation, internal, and external regions. Segments were subjected to total protein extractions and analyzed by ELISA for MMP-2 and -9 and TIMP-1 and -2 mass and by zymography for gelatinase activity. Segments at or near the bifurcation with highly calcified lesions contained higher MMP levels and activity than segments distant from the bifurcation; highly fibrotic or necrotic plaque contained lower MMP levels and activity and higher TIMP levels. Fatty streak, fibroatheroma with hemorrhage and calcification, and fully occluded lesions were enriched in MMP-2, MMP-9, and TIMP-1 and TIMP-2, respectively. Conclusion—The spatial distribution of MMPs and TIMPs in carotid atherosclerotic lesions is highly heterogeneous, reflecting lesion location, size, and composition. This study provides the first semi-quantitative maps of differential distribution of MMPs and TIMPs over atherosclerotic plaques.

Tetrahedral vs. polyhedral mesh size evaluation on flow velocity and wall shear stress for cerebral hemodynamic simulation

Haemodynamic factors, in particular wall shear stresses (WSSs) may have significant impact on growth and rupture of cerebral aneurysms. Without a means to measure WSS reliably in vivo, computational fluid dynamic (CFD) simulations are frequently employed to visualise and quantify blood flow from patient-specific computational models. With increasing interest in integrating these CFD simulations into pretreatment planning, a better understanding of the validity of the calculations in respect to computation parameters such as volume element type, mesh size and mesh composition is needed. In this study, CFD results for the two most common aneurysm types (saccular and terminal) are compared for polyhedral- vs. tetrahedral-based meshes and discussed regarding future clinical applications. For this purpose, a set of models were constructed for each aneurysm with spatially varying surface and volume mesh configurations (mesh size range: 5119–258, 481 volume elements). WSS distribution on the model wall and point-based velocity measurements were compared for each configuration model. Our results indicate a benefit of polyhedral meshes in respect to convergence speed and more homogeneous WSS patterns. Computational variations of WSS values and blood velocities are between 0.84 and 6.3% from the most simple mesh (tetrahedral elements only) and the most advanced mesh design investigated (polyhedral mesh with boundary layer).

A Computational Fluid Dynamics Study Pre- and Post-Stent Graft Placement in an Acute Type B Aortic Dissection

Purpose: To demonstrate the capability of computational fluid dynamics (CFD) for quantifying hemodynamic forces pretreatment/posttreatment in type B aortic dissection (TB-AD). Methods: From CFD simulations initialized with dynamic magnetic resonance image data, wall shear stress (WSS) and dynamic pressure (dynP) changes post endovascular treatment were quantified. Results: After 1 year follow-up, thoracic aortic segment was completely remodeled, and persistent, nonthrombosed false lumen in the abdominal aorta was noted. Pretreatment, large WSS (>5 Pa) and dynP (>80 Pa) occurred at entrance tear and a stenotic region in the true lumen (TL). Posttreatment, WSS was lower than 3.3 Pa and dynP was lower than 55 Pa in TL, except at proximal end of the stent graft and at reentrance tear. Two focal locations of high dynP existed within the stent graft. Conclusions: Computational fluid dynamics may provide quantitative assessment of hemodynamic wall forces in TB-AD potentially of interest for follow-up examinations.

Blood flow in cerebral aneurysms: Comparison of phase contrast magnetic resonance and computational fluid dynamics - Preliminary experience

PURPOSE Computational fluid dynamics (CFD) simulations are increasingly used to model cerebral aneurysm hemodynamics. We investigated the capability of phase contrast magnetic resonance imaging (pcMRI), guided by specialized software for optimal slice definition (NOVA, Vassol Inc.) as a non-invasive method to measure intra-aneurysmal blood flow patterns in-vivo. In a novel approach, these blood flow patterns measured with pcMRI were qualitatively compared to the ones calculated with CFD. MATERIALS AND METHODS The volumetric inflow rates into three unruptured cerebral aneurysms and the temporal variations of the intra-aneurysmal blood flow patterns were recorded with pcMRI. Transient CFD simulations were performed on geometric models of these aneurysms derived from 3D digital subtraction angiograms. Calculated intra-aneurysmal blood flow patterns were compared at the times of maximum and minimum arterial inflow to the ones measured with pcMRI and the temporal variations of these patterns during the cardiac cycle were investigated. RESULTS In all three aneurysms, the main features of intra-aneurysmal flow patterns obtained with pcMRI consisted of areas with positive velocities components and areas with negative velocities components. The measured velocities ranged from approx. +/- 60 to +/- 100 cm/sec. Comparison with calculated CFD simulations showed good correlation with regard to the spatial distribution of these areas, while differences in calculated magnitudes of velocities were found. CONCLUSION CFD simulations using inflow boundary conditions measured with pcMRI yield main features of intra-aneurysmal velocity patterns corresponding to intra-aneurysmal measurements performed with pcMRI. Thus, pcMRI may become a valuable complementary technique to CFD simulations to obtain in-vivo reference data for the study of aneurysmal hemodynamics. More data is needed to compare and fully explore the capabilities of both methods.

Enhanced MRI relaxivity of Gd3+-based contrast agents geometrically confined within porous nanoconstructs

Gadolinium chelates, which are currently approved for clinical MRI use, provide relaxivities well below their theoretical limit, and they also lack tissue specificity. Recently, the geometrical confinement of Gd(3+) -based contrast agents (CAs) within porous structures has been proposed as a novel, alternative strategy to improve relaxivity without chemical modification of the CA. Here, we have characterized and optimized the performance of MRI nanoconstructs obtained by loading [Gd(DTPA)(H(2) O)](2-) (Magnevist®) into the pores of injectable mesoporous silicon particles. Nanoconstructs with three different pore sizes were studied, and at 60 MHz, they exhibited longitudinal relaxivities of ~24 m m(-1)  s(-1) for 5-10 nm pores and ~10 m m(-1)  s(-1) for 30 - 40 nm pores. No enhancement in relaxivity was observed for larger pores sizes. Using an outer-sphere compound, [GdTTHA](3-) , and mathematical modeling, it was demonstrated that the relaxivity enhancement is due to the increase in rotational correlation times (CA adsorbed on the pore walls) and diffusion correlation times (reduced mobility of the water molecules), as the pore sizes decreases. It was also observed that extensive CA adsorption on the outer surface of the silicon particles negates the advantages offered by nanoscale confinement. Upon incubation with HeLa cells, the nanoconstructs did not demonstrate significant cytotoxicity for up to 3 days post incubation, at different particle/cell ratios. In addition, the nanoconstructs showed complete degradation after 24 h of continuous agitation in phosphate-buffered saline. These data support and confirm the hypothesis that the geometrical confinement of Gd(3+) -chelate compounds into porous structures offers MRI nanoconstructs with enhanced relaxivity (up to 6 times for [Gd(DTPA)(H(2) O)](2-) , and 4 times for [GdTTHA](3-) ) and, potentially, improved stability, reduced toxicity and tissue specificity.

Longitudinal computational fluid dynamics study of aneurysmal dilatation in a chronic DeBakey type III aortic dissection

Computational fluid dynamics, which uses numeric methods and algorithms for the simulation of blood flow by solving the Navier-Stokes equations on computational meshes, is enhancing the understanding of disease progression in type III aortic dissections. To illustrate this, we examined the changes in patient-derived geometries of aortic dissections, which showed progressive false lumen aneurysmal dilatation (26% diameter increase) during follow-up. Total pressure was decreased by 29% during systole and by 34% during retrograde flow. At the site of the highest false lumen dilatation, the temporal average of total pressure decreased from 45 to 22 Pa, and maximal average wall shear stress decreased from 0.9 to 0.4 Pa. These first results in the study of disease progression of type III DeBakey aortic dissection with computational fluid dynamics are encouraging.

Aneurysm volume-to-ostium area ratio: A parameter useful for discriminating the rupture status of intracranial aneurysms

BACKGROUND: Slow or stagnant flow is a hemodynamic feature that has been linked to the risk of aneurysm rupture. OBJECTIVE: To assess the potential value of the ratio of the volume of an aneurysm to the area of its ostium (VOR) as an indicator of intra-aneurysmal slow flow and, thus, in turn, the risk of rupture. METHODS: Using a sample defined from internal databases, a retrospective analysis of aneurysm size, aspect ratio (AR), and VOR was performed on a series of 155 consecutive aneurysms having undergone 3-dimensional digital subtraction angiography as a part of their evaluation. Measurements were obtained from 3-dimensional digital subtraction angiography studies using commercial software. Aneurysm size, AR, and VOR were correlated with rupture status (ruptured or unruptured). A multiple logistic regression model that best correlated with rupture status was generated to evaluate which of these parameters was the most useful to discriminate rupture status. This model was validated using an independent database of 62 consecutive aneurysms acquired outside the retrospective study interval. RESULTS: VOR showed better discrimination for rupture status than did size and AR. The best logistic regression model, which included VOR rather than size or AR, determined rupture status correctly in 80.6% of subjects. The reproducibility calculating AR and VOR was excellent. CONCLUSION: Determination of VOR was easily done and reproducible using widely available commercial equipment. It may be a more robust parameter to discriminate rupture status than AR.

Functional magnetic resonance imaging during urodynamic testing identifies brain structures initiating micturition

PURPOSE Normal voiding in neurologically intact patients is triggered by the release of tonic inhibition from suprapontine centers, allowing the pontine micturition center to trigger the voiding reflex. Supraspinal mechanisms of voluntary voiding in humans are just beginning to be described via functional neuroimaging. We further elucidated brain activity processes during voiding using functional magnetic resonance imaging in normal females to gain better understanding of normal voiding as well as changes that may occur in voiding dysfunction. MATERIALS AND METHODS We screened 13 healthy premenopausal female volunteers using baseline clinic urodynamics to document normal voiding parameters. We then recorded brain activity via functional magnetic resonance imaging and simultaneous urodynamics, including the pressure flow voiding phase. After motion correction of functional magnetic resonance images we performed activation and connectivity analyses in 10 subjects. RESULTS Group analysis revealed consistent activation areas, including regions for motor control (cerebellum, thalamus, caudate, lentiform nucleus, red nucleus, supplementary motor area and post-central gyrus), emotion (anterior/posterior cingulate gyrus and insula), executive function (left superior frontal gyrus) and a focal region in the pons. Connectivity analysis demonstrated strong interconnectivity of the pontine micturition center with many short-range and long-range cortical clusters. CONCLUSIONS Our study is one of the first reports of brain activation centers associated with micturition initiation in normal healthy females. Results show activation of a brain network consisting of regions for motor control, executive function and emotion processing. Further studies are planned to create and validate a model of brain activity during normal voiding in women.

Computational fluid dynamics in patients with continuous-flow left ventricular assist device support show hemodynamic alterations in the ascending aorta

OBJECTIVE Increased use of continuous-flow left ventricular assist devices for long-term mechanical support necessitates a better understanding of hemodynamic changes in the native heart and the ascending aorta. By using patient-specific computational models, correlations of potentially adverse hemodynamic conditions with the orientation of the left ventricular assist device outflow graft and their relationship with aortic insufficiency and ischemic events were investigated. METHODS Computed hemodynamic parameters, including wall shear stress, pressure in the ascending aorta, and dissipation of turbulent energy, were correlated with the orientation of the left ventricular assist device graft outflow in 5 patients (4 with the HeartMate II device [Thoratec Corp, Pleasanton, Calif] and 1 with the HeartWare Ventricular Assist Device [HeartWare Inc, Framingham, Mass]; 3 patients experienced moderate aortic insufficiency, and 2 patients experienced ischemic events). Hemodynamic conditions for aortic insufficiency and ischemic events were differentiated by linear discriminant analysis. RESULTS Positive correlations between left ventricular assist device outflow graft orientation and wall shear stress, pressure, and turbulent energy dissipation in the ascending aorta were found (R(2) > 0.68). Linear discriminant analysis indicated a relationship of the velocity magnitude of retrograde flow toward the aortic root with aortic insufficiency and of the turbulent energy and wall shear stress with ischemic events. CONCLUSIONS Computational fluid dynamic simulations using clinical image data indicate altered hemodynamic conditions after left ventricular assist device implantation. Consequently, the left ventricular assist device outflow graft should be placed so the jet of blood is aimed toward the lumen of the aortic arch to avoid turbulences that will increase wall shear stress and retrograde pressure of the aortic root. Further investigations are warranted to confirm these findings in a larger patient cohort.

Influence of LVAD cannula outflow tract location on hemodynamics in the ascending aorta: a patient-specific computational fluid dynamics approach.

To develop a better understanding of the hemodynamic alterations in the ascending aorta, induced by variation of the cannula outflow position of the left ventricular assist device (LVAD) device based on patient-specific geometries, transient computational fluid dynamics (CFD) simulations using the realizable k-&egr;turbulent model were conducted for two of the most common LVAD outflow geometries. Thoracic aortic flow patterns, pressures, wall shear stresses (WSSs), turbulent dissipation, and energy were quantified in the ascending aorta at the location of the cannula outflow. Streamlines for the lateral geometry showed a large region of disturbed flow surrounding the LVAD outflow with an impingement zone at the contralateral wall exhibiting increased WSSs and pressures. Flow disturbance was reduced for the anterior geometries with clearly reduced pressures and WSSs. Turbulent dissipation was higher for the lateral geometry and turbulent energy was lower. Variation in the position of the cannula outflow clearly affects hemodynamics in the ascending aorta favoring an anterior geometry for a more ordered flow pattern. The new patient-specific approach used in this study for LVAD patients emphasizes the potential use of CFD as a truly translational technique.