Construction of a physical model of the human carotid artery based upon in vivo magnetic resonance images

A method is described for construction of an in vitro flow model based on in vivo measurements of the lumen geometry of the human carotid bifurcation. A large-scale physical model of the vessel lumen was constructed using fused deposition modeling (a rapid prototyping technique) based on magnetic resonance (MR) images of the carotid bifurcation acquired in a healthy volunteer. The lumen negative was then used to construct a flow model for experimental studies that examined the hemodynamic environment of subject-specific geometry and flow conditions. The physical model also supplements physician insight into the three-dimensional geometry of the arterial segment, complementing the two-dimensional images obtained by MR. Study of the specific geometry and flow conditions in patients with vascular disease may contribute to our understanding of the relationship between their hemodvnamic environment and conditions that lead to the development and progression of arterial disease.     

Variability of 3D arterial geometry and dynamics,and its pathologic implications

Geometric parameters and features vary within the vasculature. Furthermore, at any given anatomic site, there are substantial variations in geometry among individuals. These variations can contribute to a corresponding variability in the hemodynamic environment and, to the extent that hemodynamics affects the atherosclerotic process, the progress of vascular disease. Measurements of the geometry and wall morphometry of post-mortem human coronary arteries demonstrate a relationship between these variables that supports the notion that geometric variations can contribute to a corresponding variability in the local rate of progression of arterial disease. The dynamic geometry of the coronary arteries also varies from site to site and among individuals, and this variability too may play a role in the epidemiology of coronary artery disease.     

Spontaneous hemodynamic oscillations during human sleep and sleep stage transitions characterized with near-infrared spectroscopy

Understanding the interaction between the nervous system and cerebral vasculature is fundamental to forming a complete picture of the neurophysiology of sleep and its role in maintaining physiological homeostasis. However, the intrinsic hemodynamics of slow-wave sleep (SWS) are still poorly known. We carried out 30 all-night sleep measurements with combined near-infrared spectroscopy (NIRS) and polysomnography to investigate spontaneous hemodynamic behavior in SWS compared to light (LS) and rapid-eye-movement sleep (REM). In particular, we concentrated on slow oscillations (3-150 mHz) in oxy- and deoxyhemoglobin concentrations, heart rate, arterial oxygen saturation, and the pulsation amplitude of the photoplethysmographic signal. We also analyzed the behavior of these variables during sleep stage transitions. The results indicate that slow spontaneous cortical and systemic hemodynamic activity is reduced in SWS compared to LS, REM, and wakefulness. This behavior may be explained by neuronal synchronization observed in electrophysiological studies of SWS and a reduction in autonomic nervous system activity. Also, sleep stage transitions are asymmetric, so that the SWS-to-LS and LS-to-REM transitions, which are associated with an increase in the complexity of cortical electrophysiological activity, are characterized by more dramatic hemodynamic changes than the opposite transitions. Thus, it appears that while the onset of SWS and termination of REM occur only as gradual processes over time, the termination of SWS and onset of REM may be triggered more abruptly by a particular physiological event or condition. The results suggest that scalp hemodynamic changes should be considered alongside cortical hemodynamic changes in NIRS sleep studies to assess the interaction between the autonomic and central nervous systems.     

Hemodynamics of the mouse abdominal aortic aneurysm

The abdominal aortic aneurysm (AAA) is a significant cause of death and disability in the Western world and is the subject of many clinical and pathological studies. One of the most commonly used surrogates of the human AAA is the angiotensin II (Ang II) induced model used in mice. Despite the widespread use of this model, there is a lack of knowledge concerning its hemodynamics; this study was motivated by the desire to understand the fluid dynamic environment of the mouse AAA. Numerical simulations were performed using three subject-specific mouse models in flow conditions typical of the mouse. The numerical results from one model showed a shed vortex that correlated with measurements observed in vivo by Doppler ultrasound. The other models had smaller aneurysmal volumes and did not show vortex shedding, although a recirculation zone was formed in the aneurysm, in which a vortex could be observed, that elongated and remained attached to the wall throughout the systolic portion of the cardiac cycle. To link the hemodynamics with aneurysm progression, the remodeling that occurred between week one and week two of the Ang II infusion was quantified and compared with the hemodynamic wall parameters. The strongest correlation was found between the remodeled distance and the oscillatory shear index, which had a correlation coefficient greater than 0.7 for all three models. These results demonstrate that the hemodynamics of the mouse AAA are driven by a strong shear layer, which causes the formation of a recirculation zone in the aneurysm cavity during the systolic portion of the cardiac waveform. The recirculation zone results in areas of quiescent flow, which are correlated with the locations of the aneurysm remodeling.     

Atherogenesis: hemodynamics, vascular geometry, and the endothelium

The evidence for a hemodynamic involvement and possible mechanisms by which hemodynamic-related events could influence the arterial wall, and in particular the vascular endothelium, are reviewed and used to speculate on the role of fluid mechanics in atherogenesis and specifically in lesion localization. The evidence presented suggests that it is vascular geometry, and the way it influences the local detailed flow properties, which is the primary determinant of a hemodynamic effect on the arterial wall and in the initiation of atherosclerosis.     

Mesoscopic simulations of systolic flow in the human abdominal aorta

The complex nature of blood flow in the human arterial system is still gaining more attention, as it has become clear that cardiovascular diseases localize in regions of complex geometry and complex flow fields. In this article, we demonstrate that the lattice Boltzmann method can serve as a mesoscopic computational hemodynamic solver. We argue that it may have benefits over the traditional Navier-Stokes techniques. The accuracy of the method is tested by studying time-dependent systolic flow in a 3D straight rigid tube at typical hemodynamic Reynolds and Womersley numbers as an unsteady flow benchmark. Simulation results of steady and unsteady flow in a model of the human aortic bifurcation reconstructed from magnetic resonance angiography, are presented as a typical hemodynamic application.     

Comparison of the mutations induced by p-benzoquinone, a benzene metabolite, in human and mouse cells

Benzene is one of the chemicals widely contaminating the environment. Benzene is suggested to be a human leukemogen. When benzene is absorbed in the human body, it is metabolized firstly in the liver and subsequently in the bone marrow where it provokes initiation of leukemia. In the present study, we analyzed mutations induced by p-benzoquinone (p-BQ), a benzene metabolite, in human cells using a shuttle vector plasmid pMY189, and compared frequencies, types and spectra of the mutations with those of the mutations previously revealed in mouse cells using a similar plasmid pNY200. We found that p-BQ induces mutations in human and mouse cells at similar frequencies but with different types of mutagenesis. The proportion of tandem base mutations was significantly lower in human cells than in mouse cells. Most base substitutions were induced in G:C base pairs in both human and mouse cells. However, the proportion of G:C-->C :G transversion is significantly higher in human cells. These findings indicate that the p-BQ-induced DNA damage in human and mouse cells is processed in a different manner, and that extrapolation of mice findings on experimental benzene carcinogenesis to human cancer risk assessment should be conducted carefully.     

An efficient full space-time discretization method for subject-specific hemodynamic simulations of cerebral arterial blood flow with distensible wall mechanics

A computationally inexpensive mathematical solution approach using orthogonal collocations for space discretization with temporal Fourier series is proposed to compute subject-specific blood flow in distensible vessels of large cerebral arterial networks. Several models of wall biomechanics were considered to assess their impact on hemodynamic predictions. Simulations were validated against in vivo blood flow measurements in six human subjects. The average root-mean-square relative differences were found to be less than 4.3% for all subjects with a linear elastic wall model. This discrepancy decreased further in a viscoelastic Kelvin-Voigt biomechanical wall. The results provide support for the use of collocation-Fourier series approach to predict clinically relevant blood flow distribution and collateral blood supply in large portions of the cerebral circulation at reasonable computational costs. It thus opens the possibility of performing computationally inexpensive subject-specific simulations that are robust and fast enough to predict clinical results in real time on the same day.     

Effects of exercise on endothelium and endothelium/smooth muscle cross talk: role of exercise-induced hemodynamics

Physical activity, exercise training, and fitness are associated with decreased cardiovascular risk. In the context that a risk factor "gap" exists in the explanation for the beneficial effects of exercise on cardiovascular disease, it has recently been proposed that exercise generates hemodynamic stimuli which exert direct effects on the vasculature that are antiatherogenic. In this review we briefly introduce some of the in vitro and in vivo evidence relating exercise hemodynamic modulation and vascular adaptation. In vitro data clearly demonstrate the importance of shear stress as a potential mechanism underlying vascular adaptations associated with exercise. Supporting this is in vivo human data demonstrating that exercise-mediated shear stress induces localized impacts on arterial function and diameter. Emerging evidence suggests that exercise-related changes in hemodynamic stimuli other than shear stress may also be associated with arterial remodeling. Taken together, in vitro and in vivo data strongly imply that hemodynamic influences combine to orchestrate a response to exercise and training that regulates wall stress and peripheral vascular resistance and contributes to the antiatherogenic impacts of physical activity, fitness, and training.     

Measurement in vitro of pulsatile arterial diameter using a helium-neon laser

A noncontacting in vitro measurement of pulsatile arterial diameter using a scanning optical micrometer is described. The major component of this system is a He-Ne laser whose beam scans the pulsating artery to be measured. The laser micrometer was integrated into a pulsatile perfusion apparatus that imposed various hemodynamic conditions on excised canine vessels. The laser system reliably tracked the pulsating arterial diameter at a particular longitudinal site as well as at various increments in the presence of an experimentally created stenosis. The He-Ne laser measured the radial motion of canine arteries and various vascular substitutes anastomosed in an end-to-end fashion. From these novel measurements, calculations were made of arterial compliance and bending stress, two biomechanical parameters that are implicated as potential causes of anastomotic intimal hyperplasia and graft failure. Although this device is inherently limited to in vitro use, it is a potentially useful instrument for vascular physiology and biophysics.     

Interaction of glycated human serum albumin with endothelial cells in a hemodynamic environment: structural and functional correlates

Advanced glycation end products (AGEs) are known to be involved in the pathogenesis of several diseases, in particular diabetes, via signaling through their receptor. Numerous studies have been carried out on protein-sugar interactions at very high concentrations of the latter. The objective of this investigation was to determine the effects of nonenzymatic glycation induced by reducing sugars on the secondary structure of human serum albumin (HSA) under different physiological conditions and to correlate that with expression of RAGE (receptor for advanced glycation end products) on HUVECs (human umbilical vein endothelial cells) in a controlled hemodynamic environment. Our results indicate that RAGE expression is shear stress modulated and that glycated HSA enhances the expression further. The secondary structure of AGE-HSA derived from glucose at 20 mM contains higher α-helical content and elicits maximum expression of the receptor. The effect of shear stress at 10 dynes cm(-2) is independent of AGE-HSA.     

Quantitative models of the rat pulmonary arterial tree morphometry applied to hypoxia-induced arterial remodeling.

Little is known about the constituent hemodynamic consequences of structural changes that occur in the pulmonary arteries during the onset and progression of pulmonary arterial remodeling. Many disease processes are known to be responsible for vascular remodeling that leads to pulmonary arterial hypertension, cor pulmonale, and death. Histology has been the primary tool for evaluating pulmonary remodeling, but it does not provide information on intact vascular structure or the vessel mechanical properties. This study is an extension of our previous work in which we developed an alternative imaging technique to evaluate pulmonary arterial structure. The lungs from Sprague-Dawley rats were removed, perfusion analysis was performed on the isolated lungs, and then an X-ray contrast agent was used to fill the arterial network for imaging. The lungs were scanned over a range of intravascular pressures by volumetric micro-computed tomography, and the arterial morphometry was mapped and measured in the reconstructed isotropic volumes. A quantitative assessment of hemodynamic, structural, and biomechanical differences between rats exposed for 21 days to hypoxia (10% O(2)) or normoxia (21.0% O(2)) was performed. One metric, the normalized distensibility of the arteries, is significantly (P < 0.001) larger [0.025 +/- 0.0011 (SE) mmHg(-1)] (n = 9) in normoxic rats compared with hypoxic [0.015 +/- 0.00077 (SE) mmHg(-1)] (n = 9). The results of the study show that these models can be applied to the Sprague-Dawley rat data and, specifically, can be used to differentiate between the hypoxic and the control groups.     

Nontraumatic aortic blood flow sensing by use of an ultrasonic esophageal probe.

The measurement of blood velocity fields, volume flow, and arterial wall motion in the descending thoracic aorta provides essential hemodynamic information for both research and clinical diagnosis. The close proximity of the esophagus to the aorta in the dog makes it possible to obtain such data nonsurgically using an ultrasonic esophageal probe; however, the accuracy of such a probe is limited if the angle between the sound beam and the flow axis, known as the Doppler angle, is not precisely known. By use of a pulsed Doppler velocity meter (PUDVM) and a triangulation procedure, accurate empirical measurement of the Doppler angle has been obtained, allowing quantification of blood velocity scans across the aorta. Volume flow is obtained by integration of blood velocity profiles and arterial wall motion is measured with an ultrasonic echo tracking device. Accuracy of the probe was substantiated by comparison with ultrasonic and electromagnetic implanted flow cuff measurements. Use of the probe in measurement of blood velocity, volume flow and arterial wall motion at various locations along the 8- and 10-cm length of the descending thoracic aorta in adult beagle dogs is detailed. The simplicity, accuracy, and nontraumatic aspect of the technique should allow increasing use of such a probe in numerous research and clinical applications.     

Proteome analysis of conditioned medium from mouse embryonic fibroblast feeder layers which support the growth of human embryonic stem cells

Human embryonic stem (ES) cells are pluripotent cells with the potential to differentiate into a variety of cell types, which could be used for cell transplantation therapies as well as drug discovery studies. However, the large-scale culture of undifferentiated human ES cells is currently limited by their dependency on mouse embryonic fibroblast feeder layers. The proteomics approach was employed to characterize the environment that supports the growth of undifferentiated human ES cells and to identify factors critical for their independent growth. Conditioned medium from mouse embryonic fibroblast feeder layers, STO cell line, was concentrated and subjected to analyses by two-dimensional electrophoresis mass spectrometry. In total, 136 unique protein species were identified which included some that are known to participate in cell growth and differentiation, extracellular matrix formation and remodeling, in addition to the unexpected but interesting finding of many nominally intracellular proteins. This approach has thus revealed the complexity of the environment provided by the feeder cells and provides a useful starting point for future studies. Moreover, candidates from the initial list of identified proteins can be further investigated for their effects on the growth and differentiation of human ES cells in a defined culture environment.     

Mechanical Testing of Mouse Carotid Arteries: from Newborn to Adult

The large conducting arteries in vertebrates are composed of a specialized extracellular matrix designed to provide pulse dampening and reduce the work performed by the heart. The mix of matrix proteins determines the passive mechanical properties of the arterial wall¹. When the matrix proteins are altered in development, aging, disease or injury, the arterial wall remodels, changing the mechanical properties and leading to subsequent cardiac adaptation². In normal development, the remodeling leads to a functional cardiac and cardiovascular system optimized for the needs of the adult organism. In disease, the remodeling often leads to a negative feedback cycle that can cause cardiac failure and death. By quantifying passive arterial mechanical properties in development and disease, we can begin to understand the normal remodeling process to recreate it in tissue engineering and the pathological remodeling process to test disease treatments.Mice are useful models for studying passive arterial mechanics in development and disease. They have a relatively short lifespan (mature adults by 3 months and aged adults by 2 years), so developmental³ and aging studies⁴ can be carried out over a limited time course. The advances in mouse genetics provide numerous genotypes and phenotypes to study changes in arterial mechanics with disease progression⁵ and disease treatment⁶. Mice can also be manipulated experimentally to study the effects of changes in hemodynamic parameters on the arterial remodeling process⁷. One drawback of the mouse model, especially for examining young ages, is the size of the arteries. We describe a method for passive mechanical testing of carotid arteries from mice aged 3 days to adult (approximately 90 days). We adapt a commercial myograph system to mount the arteries and perform multiple pressure or axial stretch protocols on each specimen. We discuss suitable protocols for each age, the necessary measurements and provide example data. We also include data analysis strategies for rigorous mechanical characterization of the arteries.     

Fluid–structure interaction (FSI) simulation for studying the impact of atherosclerosis on hemodynamics,arterial tissue remodeling,and initiation risk of intracranial aneurysms

The biomechanical and hemodynamic effects of atherosclerosis on the initiation of intracranial aneurysms (IA) are not yet clearly discovered. Also, studies for the observation of hemodynamic variation due to atherosclerotic stenosis and its impact on arterial remodeling and aneurysm genesis remain a controversial field of vascular engineering. The majority of studies performed are relevant to computational fluid dynamic (CFD) simulations. CFD studies are limited in consideration of blood and arterial tissue interactions. In this work, the interaction of the blood and vessel tissue because of atherosclerotic occlusions is studied by developing a fluid and structure interaction (FSI) analysis for the first time. The FSI presents a semi-realistic simulation environment to observe how the blood and vessels' structural interactions can increase the accuracy of the biomechanical study results. In the first step, many different intracranial vessels are modeled for an investigation of the biomechanical and hemodynamic effects of atherosclerosis in arterial tissue remodeling. Three physiological conditions of an intact artery, the artery with intracranial atherosclerosis (ICAS), and an atherosclerotic aneurysm (ACA) are employed in the models with required assumptions. Finally, the obtained outputs are studied with comparative and statistical analyses according to the intact model in a normal physiological condition. The results show that existing occlusions in the cross-sectional area of the arteries play a determinative role in changing the hemodynamic behavior of the arterial segments. The undesirable variations in blood velocity and pressure throughout the vessels increase the risk of arterial tissue remodeling and aneurysm formation.

     

Catheterization of the Carotid Artery and Jugular Vein to Perform Hemodynamic Measures,Infusions and Blood Sampling in a Conscious Rat Model

The success of a small animal model to study critical illness is, in part, dependent on the ability of the model to simulate the human condition. Intra-tracheal inoculation of a known amount of bacteria has been successfully used to reproduce the pathogenesis of pneumonia which then develops into sepsis. Monitoring hemodynamic parameters and providing standard clinical treatment including infusion of antibiotics, fluids and drugs to maintain blood pressure is critical to simulate routine supportive care in this model but to do so requires both arterial and venous vascular access. The video details the surgical technique for implanting carotid artery and common jugular vein catheters in an anesthetized rat. Following a 72 hr recovery period, the animals will be re-anesthetized and connected to a tether and swivel setup attached to the rodent housing which connects the implanted catheters to the hemodynamic monitoring system. This setup allows free movement of the rat during the study while continuously monitoring pressures, infusing fluids and drugs (antibiotics, vasopressors) and performing blood sampling.     

Expression of hair-related keratins in a soft epithelium: subpopulations of human and mouse dorsal tongue keratinocytes express keratin markers for hair-, skin- and esophageal-types of differentiation

The dorsal surfaces of mammalian tongues are covered with numerous projections known as filiform papillae whose morphology varies in different species. Using a panel of monoclonal antibodies to keratins as probes, we have established that, in both human and mouse, the interpapillary epithelia express mainly the "esophageal-type" keratins, while the papillary epithelia express "skin-type" keratins as well as some keratins reacting with a monoclonal antibody (AE13) to hair keratins. The AE13-reactive proteins of the mouse were found to be very similar to those of authentic mouse hair keratins. However, the corresponding protein of human tongue appears to be different from all known human keratins. This protein has a MW of 51K; it is relatively acidic; it is sulfhydryl-rich, as revealed by iodoacetic acid-induced charge and apparent size shift; it shares an epitope with all the known acidic human hair keratins; and it is associated with keratin fibrils in vivo. This protein may therefore be regarded as a novel type I "hard" keratin. These data establish that mammalian dorsal tongue epithelia can be divided into at least three compartments that undergo mainly "esophageal-", "skin-" and "hair"-types of differentiation. Different keratin filaments, e.g., those of the esophageal- and hair-types, exhibit strikingly different degrees of lateral aggregation, which can potentially account for the different physical strength and rigidity of various cellular compartments. Our data also suggest the possibility that variations in papillary structure in human and mouse may arise from different spatial arrangements of specific keratinocytes, and/or from the expression of specialized hair-related keratins.     

Hemodynamic indices versus gastric tonometric measurements for prognosis of hemorrhagic shock: a porcine model

The aim of the study reported here was to assess the prognostic value of gastric tonometry and its implications in the initial phases of hemorrhagic shock. Hemorrhagic shock was induced by use of femoral arterial bleeding in 12 hybrid swine under general anesthesia. Approximately 30% of the circulating blood volume was removed, until mean arterial pressure of 45 mmHg was reached. The shock conditions were observed over a limited period (90 min) by comparing traditional hemodynamic parameters with gastric tonometric measurements and tissue oxygenation. After a shock period of 90 min without pharmacologic treatment, blood was collected in acid-citrate dextrose-treated bags and was reinfused via the right femoral vein. At the end of the experiment, seven animals had good hemodynamic recovery on reinfusion (group A), whereas values in five animals deceased in the same phase (group B). Hemodynamic and gastric tonometric results were compared between survivors and nonsurvivors. Intravascular volume restoration and reduction of systemic vascular resistance (SVR) enabled the animals of group A to maintain standard ventricular kinetics and recover in terms of splanchnic regional flow. In addition, increase in intramucosal gastric pH (pHi), decrease in the pH-gap (pHa-Hi), and progressive restoration in gastric wall tissue oxygenation (PtO2) also were observed. These results suggest that useful diagnostic and therapeutic indications can be obtained by acquisition of simple hemodynamic measurements at the beginning of the shock period. On the basis of results of statistical analysis, only mean arterial pressure and SVR were good indicators of shock development, whereas pHi was not a significant factor in this experimental model.