Mapping vascular response to in vivo Hemodynamics: application to increased flow at the basilar terminus

Hemodynamic forces play critical roles in vascular pathologies such as atherosclerosis, aneurysms, and stenosis. However, detailed relationships between the specific in vivo hemodynamic microenvironment and vascular responses leading to the triggering or exacerbation of pathological remodeling of the vessel remain elusive. We have developed a hemodynamics-biology co-mapping technique that enables in situ correlation between the in vivo blood flow field and vascular changes secondary to hemodynamic insult. The hemodynamics profile is obtained from computational fluid dynamics simulation within the vascular geometry reconstructed from three-dimensional in vivo images, whereas the vascular response is obtained from histology or immunohistochemistry on harvested vascular tissue. The hemodynamics field is virtually sectioned in the histological slicing planes and digitally co-mapped with the histological images, thereby enabling correlation of the specific local vascular responses with the inciting hemodynamic stresses. We demonstrate application of this technique to rabbit basilar terminus subjected to elevated flow. Morphological changes at the basilar terminus 5 days after the flow increase were co-mapped with the initial wall shear stress and wall shear stress gradient distributions, from which localization of destructive remodeling in a specific hemodynamic zone was noticed. This method paves the way for further investigations to determine the connection between in vivo mechanical stimuli and biological responses, such as initiation of aneurysmal remodeling.     

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.     

Compound Ex Vivo and In Silico Method for Hemodynamic Analysis of Stented Arteries

Hemodynamic factors such as low wall shear stress have been shown to influence endothelial healing and atherogenesis in stent-free vessels. However, in stented vessels, a reliable quantitative analysis of such relations has not been possible due to the lack of a suitable method for the accurate acquisition of blood flow. The objective of this work was to develop a method for the precise reconstruction of hemodynamics and quantification of wall shear stress in stented vessels. We have developed such a method that can be applied to vessels stented in or ex vivo and processed ex vivo. Here we stented the coronary arteries of ex vivo porcine hearts, performed vascular corrosion casting, acquired the vessel geometry using micro-computed tomography and reconstructed blood flow and shear stress using computational fluid dynamics. The method yields accurate local flow information through anatomic fidelity, capturing in detail the stent geometry, arterial tissue prolapse, radial and axial arterial deformation as well as strut malapposition. This novel compound method may serve as a unique tool for spatially resolved analysis of the relationship between hemodynamic factors and vascular biology. It can further be employed to optimize stent design and stenting strategies.     

Fluid shear stress and the vascular endothelium: for better and for worse

As blood flows, the vascular wall is constantly subjected to physical forces, which regulate important physiological blood vessel responses, as well as being implicated in the development of arterial wall pathologies. Changes in blood flow, thus generating altered hemodynamic forces are responsible for acute vessel tone regulation, the development of blood vessel structure during embryogenesis and early growth, as well as chronic remodeling and generation of adult blood vessels. The complex interaction of biomechanical forces, and more specifically shear stress, derived by the flow of blood and the vascular endothelium raise many yet to be answered questions:How are mechanical forces transduced by endothelial cells into a biological response, and is there a "shear stress receptor"?Are "mechanical receptors" and the final signaling pathways they evoke similar to other stimulus-response transduction systems?How do vascular endothelial cells differ in their response to physiological or pathological shear stresses?Can shear stress receptors or shear stress responsive genes serve as novel targets for the design of diagnostic and therapeutic modalities for cardiovascular pathologies?The current review attempts to bring together recent findings on the in vivo and in vitro responses of the vascular endothelium to shear stress and to address some of the questions raised above.     

Numerical simulations of pulsatile flow in an end-to-side anastomosis model

A potential interaction between the local hemodynamics and the artery wall response has been suggested for vascular graft failure by intimal hyperplasia (IH). Among the various hemodynamic factors, wall shear stress has been implicated as the primary factor responsible for the development of IH. In order to explore the role of hemodynamics in the formation of IH in end-to-side anastomosis, computational fluid dynamics is employed. To validate the numerical simulations, comparisons with existing experimental data are performed for both steady and pulsatile flows. Generally, good agreement is observed with the velocity profiles whereas some discrepancies are found in wall shear stress (WSS) distributions. Using the same end-to-side anastomosis geometry, numerical simulations are extended using a femoral artery waveform to identify the possible role of unsteady hemodynamics. In the current simulations, Carreau-Yasuda model is used to account for the non-Newtonian nature of blood. Computations indicated a disturbed flow field at the artery-graft junction leading to locally elevated shear stresses on the vascular wall. Furthermore, the shear stress distribution followed the same behavior with oscillating magnitude over the entire flow cycle. Thus, distal IH observed in end-to-side artery-graft models may be caused by the fluctuations in WSS's along the wall.     

Computation of hemodynamics in the left coronary artery with variable angulations

The purpose of this study was to investigate the hemodynamic effect of variations in the angulations of the left coronary artery, based on simulated and realistic coronary artery models. Twelve models consisting of four realistic and eight simulated coronary artery geometries were generated with the inclusion of left main stem, left anterior descending and left circumflex branches. The simulated models included various coronary artery angulations, namely, 15°, 30°, 45°, 60°, 75°, 90°, 105° and 120°. The realistic coronary angulations were based on selected patient's data with angles ranging from narrow angles of 58° and 73° to wide angles of 110° and 120°. Computational fluid dynamics analysis was performed to simulate realistic physiological conditions that reflect the in vivo cardiac hemodynamics. The wall shear stress, wall shear stress gradient, velocity flow patterns and wall pressure were measured in simulated and realistic models during the cardiac cycle. Our results showed that a disturbed flow pattern was observed in models with wider angulations, and wall pressure was found to reduce when the flow changed from the left main stem to the bifurcated regions, based on simulated and realistic models. A low wall shear stress gradient was demonstrated at left bifurcations with wide angles. There is a direct correlation between coronary angulations and subsequent hemodynamic changes, based on realistic and simulated models. Further studies based on patients with different severities of coronary artery disease are required to verify our results.     

Rapid three-dimensional segmentation of the carotid bifurcation from serial MR images

The current trend in computational hemodynamics is to employ realistic models derived from ex vivo or in vivo imaging. Such studies typically produce a series of images from which the lumen boundaries must first be individually extracted (i.e., two-dimensional segmentation), and then serially reconstructed to produce the three-dimensional lumen surface geometry. In this paper, we present a rapid three-dimensional segmentation technique that combines these two steps, based on the idea of an expanding virtual balloon. This three-dimensional technique is demonstrated in application to finite element meshing and CFD modeling of flow in the carotid bifurcation of a normal volunteer imaged with black blood MRI. Wall shear stress patterns computed using a mesh generated with the three-dimensional technique agree well with those computed using a mesh generated from conventional two-dimensional segmentation and serial reconstruction. In addition to reducing the time required to extract the lumen surface from hours to minutes, our approach is easy to learn and use and requires minimal user intervention, which can potentially increase the accuracy and precision of quantitative and longitudinal studies of hemodynamics and vascular disease.     

Effects of sodium nitroprusside in aortic stenosis associated with severe heart failure: pressure-volume loop analysis using a numerical model

In the recently published clinical study [Use of Nitroprusside in Left Ventricular Dysfunction and Obstructive Aortic Valve Disease (UNLOAD)], sodium nitroprusside (SNP) improved cardiac function in patients with severe aortic stenosis (AS) and left ventricular (LV) systolic dysfunction. We explored the possible mechanisms of these findings using a series of numerical simulations. A closed-loop lumped parameters model that consists of 24 differential equations relating pressure and flow throughout the circulation was used to analyze the effects of varying hemodynamic conditions in AS. Hemodynamic data from UNLOAD study subjects were used to construct the initial simulation. Systemic vascular resistance (SVR), heart rate, and aortic valve area were directly entered into the model while end-systolic and end-diastolic pressure-volume (P-V) relationships were adjusted using previously published data to match modeled and observed end-systolic and end-diastolic pressures and volumes. Initial simulation of SNP treatment by a reduction of SVR was not adequate. To obtain realistic model hemodynamics that reliably reproduce SNP treatment effects, we performed a series of simulations while simultaneously changing end-systolic elastance (E(es)), end-systolic volume at zero pressure (V(0)), and diastolic P-V shift. Our data indicate that either an E(es) increase or V(0) decrease is necessary to obtain realistic model hemodynamics. In five patients, we corroborated our findings by using the model to duplicate individual P-V loops obtained before and during SNP treatment. In conclusion, using a numerical model, we identified ventricular function parameters that are responsible for improved hemodynamics during SNP infusion in AS with LV dysfunction.     

Analysis of early embryonic great-vessel microcirculation in zebrafish using high-speed confocal μPIV

In the developing cardiovascular system, hemodynamic vascular loading is critical for angiogenesis and cardiovascular adaptation. Normal zebrafish embryos with transgenically-labeled endothelial and red blood cells provide an excellent in vivo model for studying the fluid-flow induced vascular loading. To characterize the developmental hemodynamics of early embryonic great-vessel microcirculation in the zebrafish embryo, two complementary studies (experimental and numerical) are presented. Quantitative comparison of the wall shear stress (WSS) at the first aortic arch (AA1) of wild-type zebrafish embryos during two consecutive developmental stages is presented, using time-resolved confocal micro-particle image velocimetry (μPIV). Analysis showed that there was significant WSS difference between 32 and 48 h post-fertilization (hpf) wild-type embryos, which correlates with normal arch morphogenesis. The vascular distensibility of the arch wall at systole and the acceleration/deceleration rates of time-lapse phase-averaged streamwise blood flow curves were also analyzed. To estimate the influence of a novel intermittent red-blood cell (RBC) loading on the endothelium, a numerical two-phase, volume of fluid (VOF) flow model was further developed with realistic in vivo conditions. These studies showed that near-wall effects and cell clustering increased WSS augmentation at a minimum of 15% when the distance of RBC from arch vessel wall was less than 3 μm or when RBC cell-to-cell distance was less than 3 μm. When compared to a smooth wall, the WSS augmentation increased by a factor of ~1.4 due to the roughness of the wall created by the endothelial cell profile. These results quantitatively highlight the contribution of individual RBC flow patterns on endothelial WSS in great-vessel microcirculation and will benefit the quantitative understanding of mechanotransduction in embryonic great vessel biology, including arteriovenous malformations (AVM).     

Structural Adaptation and Heterogeneity of Normal and Tumor Microvascular Networks

Relative to normal tissues, tumor microcirculation exhibits high structural and functional heterogeneity leading to hypoxic regions and impairing treatment efficacy. Here, computational simulations of blood vessel structural adaptation are used to explore the hypothesis that abnormal adaptive responses to local hemodynamic and metabolic stimuli contribute to aberrant morphological and hemodynamic characteristics of tumor microcirculation. Topology, vascular diameter, length, and red blood cell velocity of normal mesenteric and tumor vascular networks were recorded by intravital microscopy. Computational models were used to estimate hemodynamics and oxygen distribution and to simulate vascular diameter adaptation in response to hemodynamic, metabolic and conducted stimuli. The assumed sensitivity to hemodynamic and conducted signals, the vascular growth tendency, and the random variability of vascular responses were altered to simulate ‘normal’ and ‘tumor’ adaptation modes. The heterogeneous properties of vascular networks were characterized by diameter mismatch at vascular branch points (d³_var) and deficit of oxygen delivery relative to demand (O_2def). In the tumor, d³_var and O_2def were higher (0.404 and 0.182) than in normal networks (0.278 and 0.099). Simulated remodeling of the tumor network with ‘normal’ parameters gave low values (0.288 and 0.099). Conversely, normal networks attained tumor-like characteristics (0.41 and 0.179) upon adaptation with ‘tumor’ parameters, including low conducted sensitivity, increased growth tendency, and elevated random biological variability. It is concluded that the deviant properties of tumor microcirculation may result largely from defective structural adaptation, including strongly reduced responses to conducted stimuli.     

Regulation of maternal and fetal hemodynamics by heme oxygenase in mice

Heme oxygenase (HMOX) regulates vascular tone and blood pressure through the production of carbon monoxide (CO), a vasodilator derived from the heme degradation pathway. During pregnancy, the maternal circulation undergoes significant adaptations to accommodate the hemodynamic demands of the developing fetus. Our objective was to investigate the role of HMOX on maternal and fetal hemodynamics during pregnancy in a mouse model. We measured and compared maternal tissue and placental HMOX activity and endogenous CO production, represented by excreted CO and carboxyhemoglobin levels, during pregnancy (Embryonic Days 12.5-15.5) to nonpregnant controls. Micro-ultrasound was used to monitor maternal abdominal aorta diameters as well as blood flow velocities and diameters of fetal umbilical arteries. Tin mesoporphyrin, a potent HMOX inhibitor, was used to inhibit HMOX activity. Changes in maternal vascular tone were monitored by tail cuff blood pressure measurements. Effects of HMOX inhibition on placental structures were assessed by histology. We showed that maternal tissue and placental HMOX activity and CO production were significantly elevated during pregnancy. When HMOX in the placenta was inhibited, maternal and fetal hemodynamics underwent significant changes, with maternal blood pressures increasing. We concluded that increases in maternal tissue and placental HMOX activity contribute to the regulation of peripheral vascular resistance and therefore are important for the maintenance of normal maternal vascular tone and fetal hemodynamic functions during pregnancy.     

A numerical study of blood flow patterns in anatomically realistic and simplified end-to-side anastomoses.

PURPOSE: Recently, some numerical and experimental studies of blood flow in large arteries have attempted to accurately replicate in vivo arterial geometries, while others have utilized simplified models. The objective of this study was to determine how much an anatomically realistic geometry can be simplified without the loss of significant hemodynamic information. METHOD: A human femoral-popliteal bypass graft was used to reconstruct an anatomically faithful finite element model of an end-to-side anastomosis. Nonideal geometric features of the model were removed in sequential steps to produce a series of successively simplified models. Blood flow patterns were numerically computed for each geometry, and the flow and wall shear stress fields were analyzed to determine the significance of each level of geometric simplification. RESULTS: The removal of small local surface features and out-of-plane curvature did not significantly change the flow and wall shear stress distributions in the end-to-side anastomosis. Local changes in arterial caliber played a more significant role, depending upon the location and extent of the change. The graft-to-host artery diameter ratio was found to be a strong determinant of wall shear stress patterns in regions that are typically associated with disease processes. CONCLUSIONS: For the specific case of an end-to-side anastomosis, simplified models provide sufficient information for comparing hemodynamics with qualitative or averaged disease locations, provided the "primary" geometric features are well replicated. The ratio of the graft-to-host artery diameter was shown to be the most important geometric feature. "Secondary" geometric features such as local arterial caliber changes, out-of-plane curvature, and small-scale surface topology are less important determinants of the wall shear stress patterns. However, if patient-specific disease information is available for the same arterial geometry, accurate replication of both primary and secondary geometric features is likely required.     

Adaptation to mechanical load determines shape and properties of heart and circulation: the CircAdapt model

With circulatory pathology, patient-specific simulation of hemodynamics is required to minimize invasiveness for diagnosis, treatment planning, and followup. We investigated the advantages of a smart combination of often already known hemodynamic principles. The CircAdapt model was designed to simulate beat-to-beat dynamics of the four-chamber heart with systemic and pulmonary circulation while incorporating a realistic relation between pressure-volume load and tissue mechanics and adaptation of tissues to mechanical load. Adaptation was modeled by rules, where a locally sensed signal results in a local action of the tissue. The applied rules were as follows: For blood vessel walls, 1) flow shear stress dilates the wall and 2) tensile stress thickens the wall; for myocardial tissue, 3) strain dilates the wall material, 4) larger maximum sarcomere length increases contractility, and 5) contractility increases wall mass. The circulation was composed of active and passive compliances and inertias. A realistic circulation developed by self-structuring through adaptation provided mean levels of systemic pressure and flow. Ability to simulate a wide variety of patient-specific circumstances was demonstrated by application of the same adaptation rules to the conditions of fetal circulation followed by a switch to the newborn circulation around birth. It was concluded that a few adaptation rules, directed to normalize mechanical load of the tissue, were sufficient to develop and maintain a realistic circulation automatically. Adaptation rules appear to be the key to reduce dramatically the number of input parameters for simulating circulation dynamics. The model may be used to simulate circulation pathology and to predict effects of treatment.     

Spatial phenotyping of the endocardial endothelium as a function of intracardiac hemodynamic shear stress

Despite substantial evidence for the central role of hemodynamic shear stress in the functional integrity of vascular endothelial cells, hemodynamic and molecular regulation of the endocardial endothelium lining the heart chambers remains understudied. We propose that regional differences in intracardiac hemodynamics influence differential endocardial gene expression leading to phenotypic heterogeneity of this cell layer. Measurement of intracardiac hemodynamics was performed using 4-dimensional flow MRI in healthy humans (n=8) and pigs (n=5). Local wall shear stress (WSS) and oscillatory shear indices (OSI) were calculated in three distinct regions of the LV – base, mid-ventricle (midV), and apex. In both the humans and pigs, WSS values were significantly lower in the apex and midV relative to the base. Additionally, both the apex and midV had greater oscillatory shear indices (OSI) than the base. To investigate regional phenotype, endocardial endothelial cells (EEC) were isolated from an additional 8 pigs and RNA sequencing was performed. A false discovery rate of 0.10 identified 1051 differentially expressed genes between the base and apex, and 321 between base and midV. Pathway analyses revealed apical upregulation of genes associated with translation initiation. Furthermore, tissue factor pathway inhibitor (TFPI; mean 50-fold) and prostacyclin synthase (PTGIS; 5-fold), genes prominently associated with antithrombotic protection, were consistently upregulated in LV apex. These spatio-temporal WSS values in defined regions of the left ventricle link local hemodynamics to regional heterogeneity in endocardial gene expression.     

Large Negative Stress Phase Angle (SPA) attenuates nitric oxide production in bovine aortic endothelial cells

Hemodynamics plays an important role in cardiovascular physiology and pathology. Pulsatile flow (Q), pressure (P), and diameter (D) waveforms exert wall shear stress (WSS), normal stress, and circumferential strain (CS) on blood vessels. Most in vitro studies to date have focused on either WSS or CS but not their interaction. Recently, we have shown that concomitant WSS and CS affect EC biochemical response modulated by the temporal phase angle between WSS and CS (stress phase angle, SPA). Large negative SPA has been shown to occur in regions of the circulation where atherosclerosis and intimal hyperplasia are prevalent. Here, we report that nitric oxide (NO) biochemical secretion was significantly decreased in response to a large negative SPA of -180 deg with respect to an SPA of 0 degrees in bovine aortic endothelial cells (BAEC) at 5 h. A new hemodynamic simulator for the study of the physiologic SPA was used to provide the hemodynamic conditions of pro-atherogenic (SPA = -180 deg) and normopathic (SPA = 0 deg) states. The role of complex hemodynamics in vascular remodeling, homeostasis, and pathogenesis can be advanced by further assessment of the hypothesis that a large negative SPA is pro-atherogenic.     

Pulsatile flow in an end-to-side vascular graft model: comparison of computations with experimental data

Various hemodynamic factors have been implicated in vascular graft intimal hyperplasia, the major mechanism contributing to chronic failure of small-diameter grafts. However, a thorough knowledge of the graft flow field is needed in order to determine the role of hemodynamics and how these factors affect the underlying biological processes. Computational fluid dynamics offers much more versatility and resolution than in vitro or in vivo methods, yet computations must be validated by careful comparison with experimental data. Whereas numerous numerical and in vitro simulations of arterial geometries have been reported, direct point-by-point comparisons of the two techniques are rare in the literature. We have conducted finite element computational analyses for a model of an end-to-side vascular graft and compared the results with experimental data obtained using laser-Doppler velocimetry. Agreement for velocity profiles is found to be good, with some clear differences near the recirculation zones during the deceleration and reverse-flow segments of the flow waveform. Wall shear stresses are determined from velocity gradients, whether by computational or experimental methods, and hence the agreement for this quantity, while still good, is less consistent than for velocity itself from the wall shear stress numerical results, we computed four variables that have been cited in the development of intiimal hyperplasia-the time-averaged wall shear stress, an oscillating shear index, and spatial and temporal wall shear stress gradients in order to illustrate the versatility of numerical methods. We conclude that the computational approach is a valid alternative to the experimental approach for quantitative hemodynamic studies. Where differences in velocity were found by the two methods, it was generally attributed to the inability of the numerical method to model the fluid dynamics when flow conditions are destabilizing. Differences in wall shear, in the absence of destabilizing phenomena, were more likely to be caused by difficulties in calculating wall shear from relatively low resolution in vitro data.     

Response of Various Conduit Arteries in Tachycardia- and Volume Overload-Induced Heart Failure

Although hemodynamics changes occur in heart failure (HF) and generally influence vascular function, it is not clear whether various HF models will affect the conduit vessels differentially or whether local hemodynamic forces or systemic factors are more important determinants of vascular response in HF. Here, we studied the hemodynamic changes in tachycardia or volume-overload HF swine model (created by either high rate pacing or distal abdominal aortic-vena cava fistula, respectively) on carotid, femoral, and renal arteries function and molecular expression. The ejection fraction was reduced by 50% or 30% in tachycardia or volume-overload model in four weeks, respectively. The LV end diastolic volume was increased from 65±22 to 115±78 ml in tachycardia and 67±19 to 148±68 ml in volume-overload model. Flow reversal was observed in diastolic phase in carotid artery of both models and femoral artery in volume-overload model. The endothelial function was also significantly impaired in carotid and renal arteries of tachycardia and volume-overload animals. The endothelial dysfunction was observed in femoral artery of volume-overload animals but not tachycardia animals. The adrenergic receptor-dependent contractility decreased in carotid and femoral arteries of tachycardia animals. The protein expressions of NADPH oxidase subunits increased in the three arteries and both animal models while expression of MnSOD decreased in carotid artery of tachycardia and volume-overload model. In conclusion, different HF models lead to variable arterial hemodynamic changes but similar vascular and molecular expression changes that reflect the role of both local hemodynamics as well as systemic changes in HF.