Carotid plaque vulnerability: a positive feedback between hemodynamic and biochemical mechanisms.

BACKGROUND AND PURPOSE: Rupture of atherosclerotic plaques is one of the main causes of ischemic strokes. The aim of this study was to investigate carotid plaque vulnerability markers in relation to blood flow direction and the mechanisms leading to plaque rupture at the upstream side of carotid stenoses. METHODS: Frequency and location of rupture, endothelial erosion, neovascularization, and hemorrhage were determined in longitudinal sections of 80 human carotid specimens. Plaques were immunohistochemically analyzed for markers of vulnerability. Plaque geometry was measured to reconstruct shape profiles of ruptured versus stable plaques and to perform computational fluid dynamics analyses. RESULTS: In 86% of ruptured plaques, rupture was observed upstream. In this region, neovascularization and hemorrhage were increased, along with increased immunoreactivity of vascular endothelial and connective tissue growth factor, whereas endothelial erosion was more frequent downstream. Proteolytic enzymes, mast cell chymase and cathepsin L, and the proapoptotic protein Bax showed significantly higher expression upstream as compared with the downstream shoulder of atherosclerotic lesions. Comparison of geometric profiles for ruptured and stable plaques showed increased longitudinal asymmetry of fibrous cap and lipid core thickness in ruptured plaques. The specific geometry of plaques ruptured upstream induced increased levels of shear stress and increased pressure drop between the upstream and the downstream plaque shoulders. CONCLUSIONS: Vulnerability of the upstream plaque region is associated with enhanced neovascularization, hemorrhage, and cap thinning induced by proteolytic and proapoptotic mechanisms. These processes are reflected in structural plaque characteristics, analyses of which could improve the efficacy of vascular diagnostics and prevention.

Grid computing for detailed hemodynamics-simulation-based planning of endovascular interventions.

Detailed numerical simulations of blood flow in arteries with various malformations and its conjugate loads on the vessel walls have been a research topic for specialized medical and engineering communities over decades. The present state of computing resources and software allows access to these elaborate diagnostic and research tools to a broad user circle and even to integrate them into clinical workflows. To tap the full potential of hemodynamic simulations, a Grid-based "virtual vessel surgery" application has been developed and deployed as part of the image processing module of the MediGRID project of the German Federal Ministry of Education and Science (BMBF). The very resource-intensive parts of that application, including not only the numerical simulation itself, but also automated data pre- and post-processing and visualization are implemented and are made available through the MediGRID portal. Some highly interactive workflow steps of the application are left at the user site but automated - via a specially developed Web interface - to a degree allowing intuitive, fast interaction and seamless integration with the Grid components. Standard middleware provided by D-Grid is used throughout. The complete workflow is implemented into the grid and can in principle be carried out using no external software. It was applied to real vessel data with a stenosis and an aneurysm, respectively.

[Numerical simulations of pulsating flow in intracranial blood vessels with aneurysms using Lattice Boltzmann methods]. / Numerische Simulation pulsierender Strömungen in Blutgefässen des Gehirns mit Aneurysmen mittels Lattice-Boltzmann-Verfahren.

A major prerequisite for successful planning and control of the medical treatment of blood vessels with stenoses or aneurysms is the detailed knowledge of the individual situation in the damaged vessels. Modern tomography methods provide good spatial resolution, so that vessel walls as well as prostheses can be easily and rapidly identified. However, the mechanical loads of the walls remain largely unknown. In the past few years, tomography data have been used for spatial and temporal simulations of the blood flow in such vessels and to predict the mechanical loads of the vessel walls. The methodologies used so far, however, involve elaborate grid generation and simulation steps, most often relying on commercial software suited for engineering projects. These require specific knowledge and experience in mechanics and numerical simulation, and are therefore inappropriate for clinical applications. It is now shown, by example of an intracranial aneurysm, that employing a Lattice Boltzmann method for the flow simulation allows to avoid all mentioned drawbacks and to simulate blood flows in a fast and simple way that is also appropriate for clinical use. The practical relevance of such simulations will be enhanced by a better understanding of the correlations between pathology and specific mechanical loads. The paper discusses also some aspects of fluid mechanics that are relevant for the study of aneurysms.

Second-order structure function scaling derivation from the Euler and magnetohydrodynamic equations.

An anomalous scaling paradigm that has recently come to be canonical has two features limiting its range of applicability: The driving and driven fields are separated dyamically and the driving field statistics is prescribed, in terms of the (inertial subrange) scaling of its second-order structure functions and of white-noise statistics in time. Then the spectrum of scaling exponents for the driven field, scalar or vector, depends parametrically on the driving. Here, the coupling of turbulent vorticity to the driving velocity field is considered. Using simple approximations and no white-noise statistics assumption, equations are derived for the evolution of two-point second-order correlations. The turbulent magnetohydrodynamic (MHD) case is treated in an analogous fashion. In the neutral case, the kinematic coupling between vorticity and velocity leads to a unique prediction for the scaling exponent of the second-order structure functions of the two turbulent fields. The velocity scaling exponent estimate is zeta(2)=3(1/2)-1 approximately equal to 0.732, i.e., close to experimental data. Unlike Kolmogorov scaling, this result is systematically derived from the Euler equations. The analogous scaling of MHD fields is now treated beyond the dynamo theory approximation. In contrast to the uniqueness found in the neutral case, predicted MHD scalings depend on one parameter, similar to the "plasma beta" parameter beta(T) relating kinetic to magnetic energy. The nature of predicted dependence of inertial-range scaling exponents on beta(T) agrees with an observed dichotomy between high-beta(T) and low-beta(T) turbulence regimes.

Shear stress preconditioning modulates endothelial susceptibility to circulating TNF-alpha and monocytic cell recruitment in a simplified model of arterial bifurcations.

OBJECTIVE: Atherosclerotic plaque formation results from a combination of local shear stress patterns and inflammatory processes. This study investigated the endothelial response to shear stress in combination with the inflammatory cytokine TNF-alpha in a simplified model of arterial bifurcation. METHODS: Human umbilical vein endothelial cells (ECs) were exposed to laminar or non-uniform shear stress in bifurcating flow-through slides, followed by stimulation with TNF-alpha. To study cell adhesion, ECs were perfused with medium containing THP-1 monocytic cells. Endothelial protein expression was determined by immunofluorescence. RESULTS: Adhesion of monocytic cells to unstimulated ECs was nearly undetectable under laminar shear stress and was slightly increased under non-uniform shear stress. Exposure of ECs to non-uniform shear stress in combination with TNF-alpha induced a 12-fold increase in monocytic cell recruitment and a significant induction of endothelial E-selectin and VCAM-1 expression. Both these effects were prevented in ECs exposed to laminar shear stress. The significant differences in TNF-alpha-induced monocytic cell recruitment and adhesion molecule expression between laminar and non-uniform shear stress regions were abolished in the absence of shear stress preconditioning. Simvastatin (1 micromol/L) suppressed the non-uniform shear stress- and TNF-alpha-induced increase in monocytic cell adhesion by about 30% via inhibition of VCAM-1 expression. Resveratrol, the active component of red wine, inhibited the expression of both VCAM-1 and E-selectin, and reduced monocytic cell recruitment by 50% at 20 micromol/L. CONCLUSIONS: Non-uniform shear stress induces endothelial susceptibility to circulating TNF-alpha and adhesion of monocytic cells. Interference with this process may inhibit inflammatory response in atherosclerosis-prone regions.