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In JoVE (1)
Other Publications (15)
- Journal of Biomechanical Engineering
- Journal of Biomechanical Engineering
- American Journal of Physiology. Heart and Circulatory Physiology
- The Journal of Biological Chemistry
- Annals of Biomedical Engineering
- Medical Image Computing and Computer-assisted Intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention
- Journal of Magnetic Resonance Imaging : JMRI
- Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
- Journal of Biomechanical Engineering
- American Journal of Physiology. Heart and Circulatory Physiology
- Arteriosclerosis, Thrombosis, and Vascular Biology
- American Heart Journal
- Circulation
Articles by Don P. Giddens in JoVE
JoVE Clinical and Translational Medicine
A Model of Disturbed Flow-Induced Atherosclerosis in Mouse Carotid Artery by Partial Ligation and a Simple Method of RNA Isolation from Carotid Endothelium
1Department of Medicine, Division of Cardiology, Emory University, 2Coulter Department of Biomedical Engineering, Georgia Tech and Emory University, 3Department of Bioinspired Science, Ewha Womans University
This describes a partial carotid ligation surgery, which causes disturbed flow conditions and subsequent atherosclerosis development (in two weeks) with intraplaque neo-vascularization (in four weeks) in the mouse common carotid artery. We also describe a novel method of RNA isolation from the carotid intima, providing high purity endothelial RNA.
Other articles by Don P. Giddens on PubMed
Relative Contribution of Wall Shear Stress and Injury in Experimental Intimal Thickening at PTFE End-to-side Arterial Anastomoses
Intimal hyperplastic thickening (IHT) is a frequent cause of prosthetic bypass graft failure. Induction and progression of IHT is thought to involve a number of mechanisms related to variation in the flow field, injury and the prosthetic nature of the conduit. This study was designed to examine the relative contribution of wall shear stress and injury to the induction of IHT at defined regions of experimental end-to-side prosthetic anastomoses.
Effects of Wall Motion and Compliance on Flow Patterns in the Ascending Aorta
Helical flows have been observed in the ascending aorta in vivo, and geometric curvature has been suggested to be a major contributing factor. We employed magnetic resonance imaging (MRI) and velocity mapping to develop a computational model to examine the effects of curvature and also wall compliance and movement upon flow patterns. In the computational model, MRI-derived geometry and velocities were imposed as boundary conditions, which included both radial expansion-contraction and translational motion of the wall. The computed results were in agreement with the MR data only when full wall motion was included in the model, suggesting that the flow patterns observed in the ascending aorta arise not only from geometric curvature of the arch but also from the motion of the aorta resulting from its attachment to the beating heart.
Role of Xanthine Oxidoreductase and NAD(P)H Oxidase in Endothelial Superoxide Production in Response to Oscillatory Shear Stress
Oscillatory shear stress occurs at sites of the circulation that are vulnerable to atherosclerosis. Because oxidative stress contributes to atherosclerosis, we sought to determine whether oscillatory shear stress increases endothelial production of reactive oxygen species and to define the enzymes responsible for this phenomenon. Bovine aortic endothelial cells were exposed to static, laminar (15 dyn/cm2), and oscillatory shear stress (+/-15 dyn/cm2). Oscillatory shear increased superoxide (O2.-) production by more than threefold over static and laminar conditions as detected using electron spin resonance (ESR). This increase in O2*- was inhibited by oxypurinol and culture of endothelial cells with tungsten but not by inhibitors of other enzymatic sources. Oxypurinol also prevented H2O2 production in response to oscillatory shear stress as measured by dichlorofluorescin diacetate and Amplex Red fluorescence. Xanthine-dependent O2*- production was increased in homogenates of endothelial cells exposed to oscillatory shear stress. This was associated with decreased xanthine dehydrogenase (XDH) protein levels and enzymatic activity resulting in an elevated ratio of xanthine oxidase (XO) to XDH. We also studied endothelial cells lacking the p47phox subunit of the NAD(P)H oxidase. These cells exhibited dramatically depressed O2*- production and had minimal XO protein and activity. Transfection of these cells with p47phox restored XO protein levels. Finally, in bovine aortic endothelial cells, prolonged inhibition of the NAD(P)H oxidase with apocynin decreased XO protein levels and prevented endothelial cell stimulation of O2*- production in response to oscillatory shear stress. These data suggest that the NAD(P)H oxidase maintains endothelial cell XO levels and that XO is responsible for increased reactive oxygen species production in response to oscillatory shear stress.
Oscillatory Shear Stress Stimulates Endothelial Production of O2- from P47phox-dependent NAD(P)H Oxidases, Leading to Monocyte Adhesion
Arterial regions exposed to oscillatory shear (OS) in branched arteries are lesion-prone sites of atherosclerosis, whereas those of laminar shear (LS) are relatively well protected. Here, we examined the hypothesis that OS and LS differentially regulate production of O2- from the endothelial NAD(P)H oxidase, which, in turn, is responsible for their opposite effects on a critical atherogenic event, monocyte adhesion. We used aortic endothelial cells obtained from C57BL/6 (MAE-C57) and p47phox-/- (MAE-p47-/-) mice, which lack a component of NAD(P)H oxidase. O2- production was determined by dihydroethidium staining and an electron spin resonance using an electron spin trap methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine. Chronic exposure (18 h) to an arterial level of OS (+/- 5 dynes/cm2) increased O2- (2-fold) and monocyte adhesion (3-fold) in MAE-C57 cells, whereas chronic LS (15 dynes/cm2, 18 h) significantly decreased both monocyte adhesion and O2- compared with static conditions. In contrast, neither LS nor OS were able to induce O2- production and monocyte adhesion to MAE-p47-/-. Treating MAE-C57 with a cell-permeable superoxide dismutase compound, polyethylene glycol-superoxide dismutase, also inhibited OS-induced monocyte adhesion. In addition, over-expressing p47phox in MAE-p47-/- restored OS-induced O2- production and monocyte adhesion. These results suggest that chronic exposure of endothelial cells to OS stimulates O2- and/or its derivatives produced from p47phox-dependent NAD(P)H oxidase, which, in turn, leads to monocyte adhesion, an early and critical atherogenic event.
Blood Flow in Major Blood Vessels-modeling and Experiments
Although primarily motivated by an interest in atherosclerosis, modeling of arterial blood flow is also important to an understanding of congenital effects and to improvements in therapeutics. A variety of methods are available to estimate the flow field in living arteries, each with its own advantages and limitations. Tradeoffs must be made among the realism of the technique, spatial resolution, geometric fidelity, and the reliability of assumed wall mechanical properties. Once the velocity field is obtained, each differentiation, to obtain wall shear or its spatial or temporal derivatives, adds additional uncertainty into the results, demanding cautious interpretation. A distinction is made between "macro" and "micro" levels of flow structure detail: macro level structure is relatively coarse and more descriptive of the flow field, pressure, and shear distribution than the cellular response; the micro approach tries to relate a more local hemodynamic description to vascular pathology. The applications of each, and the interactions between them, are described. Issues related to these approaches, including the use of clinical data, animal experimentation, the role of cell and organ culture, and in vivo flow measurement, are briefly discussed. The summary closes with a list of recommendations for future developments in this area.
Harmonic Skeleton Guided Evaluation of Stenoses in Human Coronary Arteries
This paper presents a novel approach that three-dimensionally visualizes and evaluates stenoses in human coronary arteries by using harmonic skeletons. A harmonic skeleton is the center line of a multi-branched tubular surface extracted based on a harmonic function, which is the solution of the Laplace equation. This skeletonization method guarantees smoothness and connectivity and provides a fast and straightforward way to calculate local cross-sectional areas of the arteries, and thus provides the possibility to localize and evaluate coronary artery stenosis, which is a commonly seen pathology in coronary artery disease.
Characterization of Coronary Atherosclerotic Plaque Using Multicontrast MRI Acquired Under Simulated in Vivo Conditions
To compare coronary atherosclerotic plaque characterization using multicontrast MRI on: 1) freshly excised vessels under simulated in vivo conditions, and 2) preserved vessels.
3D Modeling of Patient-specific Geometries of Portal Veins Using MR Images
In this note, we present an approach for developing patient-specific 3D models of portal veins to provide geometric boundary conditions for computational fluid dynamics (CFD) simulations of the blood flow inside portal veins. The study is based on MRI liver images of individual patients to which we apply image registration and segmentation techniques and inlet and outlet velocity profiles acquired using PC-MRI in the same imaging session. The portal vein and its connected veins are then extracted and visualized in 3D as surfaces. Image registration is performed to align shifted images between each breath-hold when the MRI images are acquired. The image segmentation method first labels each voxel in the 3D volume of interest by using a Bayesian probability approach, and then isolates the portal veins via active surfaces initialized inside the vessel. The method was tested with two healthy volunteers. In both cases, the main portal vein and its connected veins were successfully modeled and visualized.
Hemodynamic Shear Stresses in Mouse Aortas: Implications for Atherogenesis
The hemodynamic environment is a determinant of susceptibility to atherosclerosis in the vasculature. Although mouse models are commonly used in atherosclerosis studies, little is known about local variations in wall shear stress (WSS) in the mouse and whether the levels of WSS are comparable to those in humans. The objective of this study was to determine WSS values in the mouse aorta and to relate these to expression of gene products associated with atherosclerosis.
Automatic Plaque Characterization Employing Quantitative and Multicontrast MRI
Multicontrast magnetic resonance imaging (MRI) has shown promise in identifying and characterizing atherosclerotic plaques. One of the limitations of this technique is the lack of a practical automated plaque characterization scheme. In the current study, a prior-information-enhanced clustering (PIEC) technique that utilizes both multicontrast MR images and quantitative T(2) maps is proposed to characterize atherosclerotic plaque components automatically. The PIEC algorithm was assessed on computationally simulated images and multicontrast MRI data of coronary arteries. Multicontrast (T(1)-, T(2)-, partial T(2)-, and proton density-weighted) MR images were acquired from freshly excised human coronary arteries using a 4.7T small-animal scanner. The T(2) distribution for each plaque constituent was measured by exponentially fitting the signal from multiple MR images with different TEs and the same TR. The calculated T(2) distributions were used as the a priori information and combined with the Fuzzy C-Means (FCM)-based clustering algorithm to characterize plaque constituents. The proposed PIEC technique appears to be a promising algorithm for accurate automated plaque characterization.
Choice of in Vivo Versus Idealized Velocity Boundary Conditions Influences Physiologically Relevant Flow Patterns in a Subject-specific Simulation of Flow in the Human Carotid Bifurcation
Accurate fluid mechanics models are important tools for predicting the flow field in the carotid artery bifurcation and for understanding the relationship between hemodynamics and the initiation and progression of atherosclerosis. Clinical imaging modalities can be used to obtain geometry and blood flow data for developing subject-specific human carotid artery bifurcation models. We developed subject-specific computational fluid dynamics models of the human carotid bifurcation from magnetic resonance (MR) geometry data and phase contrast MR velocity data measured in vivo. Two simulations were conducted with identical geometry, flow rates, and fluid parameters: (1) Simulation 1 used in vivo measured velocity distributions as time-varying boundary conditions and (2) Simulation 2 used idealized fully-developed velocity profiles as boundary conditions. The position and extent of negative axial velocity regions (NAVRs) vary between the two simulations at any given point in time, and these regions vary temporally within each simulation. The combination of inlet velocity boundary conditions, geometry, and flow waveforms influences NAVRs. In particular, the combination of flow division and the location of the velocity peak with respect to individual carotid geometry landmarks (bifurcation apex position and the departure angle of the internal carotid) influences the size and location of these reversed flow zones. Average axial wall shear stress (WSS) distributions are qualitatively similar for the two simulations; however, instantaneous WSS values vary with the choice of velocity boundary conditions. By developing subject-specific simulations from in vivo measured geometry and flow data and varying the velocity boundary conditions in otherwise identical models, we isolated the effects of measured versus idealized velocity distributions on blood flow patterns. Choice of velocity distributions at boundary conditions is shown to influence pathophysiologically relevant flow patterns in the human carotid bifurcation. Although mean WSS distributions are qualitatively similar for measured and idealized inlet boundary conditions, instantaneous NAVRs differ and warrant imposing in vivo velocity boundary conditions in computational simulations. A simulation based on in vivo measured velocity distributions is preferred for modeling hemodynamics in subject-specific carotid artery bifurcation models when studying atherosclerosis initiation and development.
In Vivo Assessment of Blood Flow Patterns in Abdominal Aorta of Mice with MRI: Implications for AAA Localization
Abdominal aortic aneurysms (AAA) localize in the infrarenal aorta in humans, while they are found in the suprarenal aorta in mouse models. It has been shown previously that humans experience a reversal of flow during early diastole in the infrarenal aorta during each cardiac cycle. This flow reversal causes oscillatory wall shear stress (OWSS) to be present in the infrarenal aorta of humans. OWSS has been linked to a variety of proatherogenic and proinflammatory factors. The presence of reverse flow in the mouse aorta is unknown. In this study we investigated blood flow in mice, using phase-contrast magnetic resonance (PCMR) imaging. We measured blood flow in the suprarenal and infrarenal abdominal aorta of 18 wild-type C57BL/6J mice and 15 apolipoprotein E (apoE)-/- mice. Although OWSS was not directly evaluated, results indicate that, unlike humans, there is no reversal of flow in the infrarenal aorta of wild-type or apoE-/- mice. Distensibility of the mouse aortic wall in both the suprarenal and infrarenal segments is higher than reported values for the human aorta. We conclude that normal mice do not experience the reverse flow in the infrarenal aorta that is observed in humans.
An in Vivo Murine Model of Low-magnitude Oscillatory Wall Shear Stress to Address the Molecular Mechanisms of Mechanotransduction--brief Report
Current understanding of shear-sensitive signaling pathways has primarily been studied in vitro largely because of a lack of adequate in vivo models. Our objective was to develop a simple and well-characterized murine aortic coarctation model to acutely alter the hemodynamic environment in vivo and test the hypothesis that endothelial inflammatory protein expression is acutely upregulated in vivo by low-magnitude oscillatory wall shear stress (WSS).
Localization of Culprit Lesions in Coronary Arteries of Patients with ST-segment Elevation Myocardial Infarctions: Relation to Bifurcations and Curvatures
Although culprit lesions in ST-segment elevation myocardial infarction (STEMI) cluster in the proximal coronary arteries, their relationship to bifurcations and curvatures, where blood flow is disturbed, is unknown. We hypothesized that (a) culprit lesions localize to disturbed flow distal to bifurcations and curvatures and (b) the distribution of culprit lesions in the left (LCA) and right coronary arteries (RCA) and resulting infarct size are related to the location of bifurcations and curvatures.
Coronary Artery Wall Shear Stress is Associated with Progression and Transformation of Atherosclerotic Plaque and Arterial Remodeling in Patients with Coronary Artery Disease
Experimental studies suggest that low wall shear stress (WSS) promotes plaque development and high WSS is associated with plaque destabilization. We hypothesized that low-WSS segments in patients with coronary artery disease develop plaque progression and high-WSS segments develop necrotic core progression with fibrous tissue regression.
