Pulsatile Nature Of Blood Flow Research Articles

Considerations of Blood Properties, Outlet Boundary Conditions and Energy Loss Approaches in Computational Fluid Dynamics Modeling

Despite recent development of computational fluid dynamics (CFD) research, analysis of computational fluid dynamics of cerebral vessels has several limitations. Although blood is a non-Newtonian fluid, velocity and pressure fields were computed under the assumptions of incompressible, laminar, steady-state flows and Newtonian fluid dynamics. The pulsatile nature of blood flow is not properly applied in inlet and outlet boundaries. Therefore, we present these technical limitations and discuss the possible solution by comparing the theoretical and computational studies.

Impact of flow pulsatility on arterial drug distribution in stent-based therapy

Drug-eluting stents reside in a dynamic fluid environment where the extent to which drugs are distributed within the arterial wall is critically modulated by the blood flowing through the arterial lumen. Yet several factors associated with the pulsatile nature of blood flow and their impact on arterial drug deposition have not been fully investigated. We employed an integrated framework comprising bench-top and computational models to explore the factors governing the time-varying fluid dynamic environment within the vasculature and their effects on arterial drug distribution patterns. A custom-designed bench-top framework comprising a model of a single drug-eluting stent strut and a poly-vinyl alcohol-based hydrogel as a model tissue bed simulated fluid flow and drug transport under fully apposed strut settings. Bench-top experiments revealed a relative independence between drug distribution and the factors governing pulsatile flow and these findings were validated with the in silico model. Interestingly, computational models simulating suboptimal deployment settings revealed a complex interplay between arterial drug distribution, Womersley number and the extent of malapposition. In particular, for a stent strut offset from the wall, total drug deposition was sensitive to changes in the pulsatile flow environment, with this dependence increasing with greater wall displacement. Our results indicate that factors governing pulsatile luminal flow on arterial drug deposition should be carefully considered in conjunction with device deployment settings for better utilization of drug-eluting stent therapy.

Pulsatile blood flow in human bone assessed by laser-Doppler flowmetry and the interpretation of photoplethysmographic signals

Human bone blood flow, mean blood speed and the number of moving red blood cells were assessed (in arbitrary units), as a function of time, during one cardiac cycle. The measurements were obtained non-invasively on five volunteers by laser-Doppler flowmetry at large interoptode spacing. The investigated bones included: patella, clavicle, tibial diaphysis and tibial malleolus. As hypothesized, we found that in all bones the number of moving cells remains constant during cardiac cycles. Therefore, we concluded that the pulsatile nature of blood flow must be completely determined by the mean blood speed and not by changes in blood volume (vessels dilation). Based on these results, it is finally demonstrated using a mathematical model (derived from the radiative transport theory) that photoplethysmographic (PPG) pulsations observed by others in the literature, cannot be generated by oscillations in blood oxygen saturation, which is physiologically linked to blood speed. In fact, possible oxygen saturation changes during pulsations decrease the amplitude of PPG pulsations due to specific features of the PPG light source. It is shown that a variation in blood oxygen saturation of 3% may induce a negative change of ∼1% in the PPG signal. It is concluded that PPG pulsations are determined by periodic ‘positive’ changes of the reduced scattering coefficient of the tissue and/or the absorption coefficient at constant blood volume. No explicit experimental PPG measurements have been performed. As a by-product of this study, an estimation of the arterial pulse wave velocity obtained from the analysis of the blood flow pulsations give a value of 7.8 m s−1 (95% confidence interval of the sample mean distribution: [6.7, 9.5] m s−1), which is perfectly compatible with data in the literature. We hope that this note will contribute to a better understanding of PPG signals and to further develop the domain of the vascular physiology of human bone.

Microfluidic artificial “vessels” for dynamic mechanical stimulation of mesenchymal stem cells

Cells in the cardiovascular system are constantly exposed to complex mechanical stimulation due to the pulsatile nature of blood flow and the haemodynamic forces that are key to the regulation of vascular development, remodeling and pathophysiology. Mechanical stretch can also modulate the differentiation of stem cells toward vascular cell lineages (i.e., vascular smooth muscle cells), and represent a critical factor in vascular tissue engineering. Here we report on the development of a microchip platform that can emulate several key aspects of the vascular mechanical environment, such as cyclic stimulation and circumferential strain. This chip consists of an array of microfluidic channels with widths ranging from 20 to 500 micrometers. These channels are covered by suspended deformable membranes, on which cells are cultured and stimulated by cyclic circumferential strain of up to 20% via hydrodynamic actuation of the fluid in the microfluidic channels, thereby mimicking the biomechanical conditions of small blood vessels. We show that human mesenchymal stem cells (MSCs) can be cultured and continuously stimulated by cyclic stretch over a period of 7 days with no evidence of device fatigue or performance degradation. We observed localization and alignment of MSCs when mechanical stretch is larger than 10%, indicating the importance of mechanical stimulation in modulating cellular behavior. We further demonstrated simultaneous detection of proteins in multiple signaling pathways, including SMAD1/SMAD2 and canonical Wnt/β-catenin. This microchip represents a generic and versatile platform for high-throughput and rapid screening of cellular responses, including signal transduction cascades, in response to mechanical cues. The system emulates the physiological conditions of blood vessels and other tissues that are subject to cyclic strain, and may have a wide range of applications in the fields of stem cell mechanobiology, vascular tissue engineering, and other areas of regenerative medicine.

Vascular Responses to Shear Stress: The Involvement of Mechanosensors in Endothelial Cells

Shear stress, the frictional drag on the endothelium from blood flow, is a major determinant of vascular physi- ology and pathology. Due to the pulsatile nature of blood flow, blood vessels are subjected to significant variations in me- chanical forces. Endothelial cells situated at the interface between blood and the vessel wall play a crucial role in detecting and responding to the mechanical forces generated by shear stress. Multiple sensing mechanisms are used by endothelial cells to detect changes in mechanical forces, leading to the activation of signaling networks. This review attempts to bring together recent findings on the mechanosensors present in the endothelial cells, and the regulation of endothelium-derived vasoactive autacoid production by shear stress.

The Importance of Velocity Acceleration to Flow-Mediated Dilation

The validity of the flow-mediated dilation test has been questioned due to the lack of normalization to the primary stimulus, shear stress. Shear stress can be calculated using Poiseuille's law. However, little attention has been given to the most appropriate blood velocity parameter(s) for calculating shear stress. The pulsatile nature of blood flow exposes the endothelial cells to two distinct shear stimuli during the cardiac cycle: a large rate of change in shear at the onset of flow (velocity acceleration), followed by a steady component. The parameter typically entered into the Poiseuille's law equation to determine shear stress is time-averaged blood velocity, with no regard for flow pulsatility. This paper will discuss (1) the limitations of using Posieuille's law to estimate shear stress and (2) the importance of the velocity profile—with emphasis on velocity acceleration—to endothelial function and vascular tone.

Cellular and molecular effects of mechanical stretch on vascular cells and cardiac myocytes

Cells in the cardiovascular system are permanently subjected to mechanical forces due to the pulsatile nature of blood flow and shear stress, created by the beating heart. These haemodynamic forces play an important role in the regulation of vascular development, remodelling, wound healing and atherosclerotic lesion formation. Mechanical stretch can modulate several different cellular functions in VSMCs (vascular smooth muscle cells). These functions include, but are not limited to, cell alignment and differentiation, migration, survival or apoptosis, vascular remodelling, and autocrine and paracrine functions. Laminar shear stress exerts anti-apoptotic, anti-atherosclerotic and antithrombotic effects on ECs (endothelial cells). Mechanical stretch of cardiac myocytes can modulate growth, apoptosis, electric remodelling, alterations in gene expression, and autocrine and paracrine effects. The aim of the present review is primarily to summarize the cellular and molecular effects of mechanical stretch on vascular cells and cardiac myocytes, emphasizing the molecular mechanisms underlying the regulation. Knowledge of the impact of mechanical stretch on the cardiovascular system is vital to the understanding of the pathogenesis of cardiovascular diseases, and is also crucial to provide new insights into the prevention and therapy of cardiovascular diseases.

Statins, Central Blood Pressure, and Blood Pressure Amplification

It is well established that blood pressure (BP) differs markedly between peripheral (brachial) and central arteries (aorta).1 As the pressure wave travels distally from the heart, mean BP and diastolic BP decrease slightly (1 to 2 mmHg), but a gradual and significant increase of systolic BP (SBP) and pulse pressure (PP) occurs. This phenomenon is called BP amplification.1 The development of commercially available devices for the assessment of central BP has boosted this field of clinical research.1–3 Numerous studies have shown the close pathophysiological connection between central BP and cardiovascular diseases1–4 and have highlighted the ability of central BP to provide complementary data on cardiovascular risk beyond that provided by brachial BP.2–6 Article p 53 In the present issue of Circulation,7 data from the Conduit Artery Function Evaluation-Lipid-Lowering Arm (CAFE-LLA, a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial [ASCOT]l8,9) on the effect of statins on central BP is presented. Before commenting on the available data, we briefly summarize the pathophysiology of PP amplification. Finally, we discuss potential strategies based on central hemodynamics that will hopefully improve cardiovascular risk assessment and reduction. As a consequence of the pulsatile nature of blood flow and of the presence of arterial stiffness/diameter gradient along the arterial tree, pressure wave reflections arise at various sites of the arterial bed.1 The backward-traveling reflected wave sums up with the forward-traveling wave, forming the actual pressure waveform (Figure 1a). Whereas in healthy young subjects the average aortic SBP is 100 to 110 mm Hg, at the same time the brachial SBP is amplified substantially and reaches 120 to 130 mm Hg.10 This difference of 10 to 30 mm Hg expresses the amplification of the SBP (Figure 1a).1,10 Because DBP is practically steady between the aorta and …

A power-law model of blood flow through a tapered overlapping stenosed artery

A mathematical model of non-Newtonian blood flow through a tapered stenotic artery is considered. The non-Newtonian model chosen is characterized by the generalized power-law model incorporating the effect of tapering due to the pulsatile nature of blood flow. The flow is assumed to be unsteady, laminar, two-dimensional and axisymmetric. The governing equations of motion in terms of the viscous shear stress in the cylindrical coordinate system are solved numerically using a finite difference scheme. Numerical results obtained for the positive taper angle show that the blood flow characteristics such as the axial velocity profiles, flow rate and wall shear stress have lower values, while the resistive impedances have higher values than the Newtonian model.

Cyclic strain-mediated matrix metalloproteinase regulation within the vascular endothelium: a force to be reckoned with

The vascular endothelium is a dynamic cellular interface between the vessel wall and the bloodstream, where it regulates the physiological effects of humoral and biomechanical stimuli on vessel tone and remodeling. With respect to the latter hemodynamic stimulus, the endothelium is chronically exposed to mechanical forces in the form of cyclic circumferential strain, resulting from the pulsatile nature of blood flow, and shear stress. Both forces can profoundly modulate endothelial cell (EC) metabolism and function and, under normal physiological conditions, impart an atheroprotective effect that disfavors pathological remodeling of the vessel wall. Moreover, disruption of normal hemodynamic loading can be either causative of or contributory to vascular diseases such as atherosclerosis. EC-matrix interactions are a critical determinant of how the vascular endothelium responds to these forces and unquestionably utilizes matrix metalloproteinases (MMPs), enzymes capable of degrading basement membrane and interstitial matrix molecules, to facilitate force-mediated changes in vascular cell fate. In view of the growing importance of blood flow patterns and mechanotransduction to vascular health and pathophysiology, and considering the potential value of MMPs as therapeutic targets, a timely review of our collective understanding of MMP mechanoregulation and its impact on the vascular endothelium is warranted. More specifically, this review primarily summarizes our current knowledge of how cyclic strain regulates MMP expression and activation within the vascular endothelium and subsequently endeavors to address the direct and indirect consequences of this on vascular EC fate. Possible relevance of these phenomena to vascular endothelial dysfunction and pathological remodeling are also addressed.

Effects of uniaxial cyclic strain on adipose-derived stem cell morphology, proliferation, and differentiation

Cells and tissues in vivo are subjected to various forms of mechanical forces that are essential to their normal development and functions. The arterial blood vessel wall is continuously exposed to mechanical stresses such as pressure, strain, and shear due to the pulsatile nature of blood flow. Vascular smooth muscle cells (SMCs) populate the media of blood vessels and play important roles in the control of vasoactivity and the remodeling of the vessel wall. It is well documented that the phenotype and functions of vascular SMCs are not only regulated by chemical factors such as transforming growth factor-beta(1) (TGF-beta(1)), but also by mechanical factors such as uniaxial strain. The purpose of our study was to explore the effects of TGF-beta(1) alone or in combination with uniaxial cyclic strain on adipose-derived stem cell (ASC) morphology, proliferation, and differentiation. Low passage ASCs were stimulated with 10% strain at 1 Hz for 7 days, with or without TGF-beta(1). Cyclic strain inhibited proliferation, and caused alignment of the cells and of the F-actin cytoskeleton perpendicular to the direction of strain. Strain alone resulted in a decrease in the expression of early SMC markers alpha-SMA and h (1)-calponin. While the response of SMCs and other progenitor cells such as bone marrow stromal cells to mechanical forces has been extensively studied, the roles of these forces on ASCs remain unexplored. This work advances our understanding of the mechanical regulation of ASCs.

Molecular mechanisms of the vascular responses to haemodynamic forces

Blood vessels are permanently subjected to mechanical forces in the form of stretch, encompassing cyclic mechanical strain due to the pulsatile nature of blood flow and shear stress. Significant variations in mechanical forces, of physiological or physiopathological nature, occur in vivo. These are accompanied by phenotypical modulation of smooth muscle cells and endothelial cells, producing structural modifications of the arterial wall. In all the cases, vascular remodelling can be allotted to a modification of the tensional strain or shear, and underlie a trend to reestablish baseline mechanical conditions. Vascular cells are equipped with numerous receptors that allow them to detect and respond to the mechanical forces generated by pressure and shear stress. The cytoskeleton and other structural components have an established role in mechanotransduction, being able to transmit and modulate tension within the cell via focal adhesion sites, integrins, cellular junctions and the extracellular matrix. Mechanical forces also initiate complex signal transduction cascades, including nuclear factor-kappaB and mitogen-activated protein kinase pathways, leading to functional changes within the cell.

Roles of Hemodynamic Forces in Vascular Cell Differentiation

The pulsatile nature of blood flow is a key stimulus for the modulation of vascular cell differentiation. Within the vascular media, physiologic stress is manifested as cyclic strain, while in the lumen, cells are subjected to shear stress. These two respective biomechanical forces influence the phenotype and degree of differentiation or proliferation of smooth muscle cells and endothelial cells within the human vasculature. Elucidation of the effect of these mechanical forces on cellular differentiation has led to a surge of research into this area because of the implications for both the treatment of atherosclerotic disease and the future of vascular tissue engineering. The use of mechanical force to directly control vascular cell differentiation may be utilized as an invaluable engineering tool in the future. However, an understanding of the role of hemodynamics in vascular cell differentiation and proliferation is critical before application can be realized. Thus, this review will provide a current perspective on the latest research and controversy behind the role of hemodynamic forces for vascular cell differentiation and phenotype modulation. Furthermore, this review will illustrate the application of hemodynamic force for vascular tissue engineering and explicate future directions for research.

Mechano-active tissue engineering of vascular smooth muscle using pulsatile perfusion bioreactors and elastic PLCL scaffolds

Blood vessels are subjected in vivo to mechanical forces in a form of radial distention, encompassing cyclic mechanical strain due to the pulsatile nature of blood flow. Vascular smooth muscle (VSM) tissues engineered in vitro with a conventional tissue engineering technique may not be functional, because vascular smooth muscle cells (VSMCs) cultured in vitro typically revert from a contractile phenotype to a synthetic phenotype. In this study, we hypothesized that pulsatile strain and shear stress stimulate VSM tissue development and induce VSMCs to retain the differentiated phenotype in VSM engineering in vitro. To test the hypothesis, rabbit aortic smooth muscle cells (SMCs) were seeded onto rubber-like elastic, three-dimensional PLCL [poly(lactide- co-caprolactone), 50:50] scaffolds and subjected to pulsatile strain and shear stress by culturing them in pulsatile perfusion bioreactors for up to 8 weeks. As control experiments, VSMCs were cultured on PLCL scaffolds statically. The pulsatile strain and shear stress enhanced the VSMCs proliferation and collagen production. In addition, a significant cell alignment in a direction radial to the distending direction was observed in VSM tissues exposed to radial distention, which is similar to that of native VSM tissues in vivo, whereas VSMs in VSM tissues engineered in the static condition randomly aligned. Importantly, the expression of SM α-actin, a differentiated phenotype of SMCs, was upregulated by 2.5-fold in VSM tissues engineered under the mechano-active condition, compared to VSM tissues engineered in the static condition. This study demonstrates that tissue engineering of VSM tissues in vitro by using pulsatile perfusion bioreactors and elastic PLCL scaffolds leads to the enhancement of tissue development and the retention of differentiated cell phenotype.

Cellular mechanics and gene expression in blood vessels

Blood vessels are permanently subjected to mechanical forces in the form of stretch, encompassing cyclic mechanical strain due to the pulsatile nature of blood flow, and shear stress. Alterations in stretch or shear stress invariably produce transformations in the vessel wall that will aim to accommodate the new conditions and to ultimately restore basal levels of tensile stress and shear stress. Vascular cells are equipped with numerous receptors that allow them to detect and respond to the mechanical forces generated by pressure and shear stress. The cytoskeleton and other structural components have an established role in mechanotransduction, being able to transmit and modulate tension within the cell via focal adhesion sites, integrins, cellular junctions and the extracellular matrix. Beyond the structural modifications incurred, mechanical forces can also initiate complex signal transduction cascades leading to functional changes within the cell. Many intracellular pathways, including the MAP kinase cascade, are activated by flow or stretch and initiate, via sequential phosphorylations, the activation of transcription factors and subsequent gene expression.

Fractal dimensions of laser doppler flowmetry time series

Laser Doppler flowmetry (LDF) provides a non-invasive method of assessing cutaneous perfusion. As the microvasculature under the probe is not defined the measured flux cannot be given absolute units, but the technique has nevertheless proved valuable for assessing relative changes in perfusion in response to physiological stress. LDF signals normally show pronounced temporal variability, both as a consequence of the pulsatile nature of blood flow and local changes in dynamic vasomotor activity. The aim of the present study was to investigate the use of methods of nonlinear analysis in characterizing temporal fluctuations in LDF signals. Data were collected under standardised conditions from the forearm of 16 normal subjects at rest, during exercise and on recovery. Surrogate data was then generated from the original time series by phase randomization. Dispersional analysis demonstrated that the LDF data was fractal with two distinct scaling regions, thus allowing the calculation of a fractal dimension which decreased significantly from 1.23 ± 0.09 to 1.04 ± 0.02 during exercise. By contrast, dispersional analysis of the surrogate data showed no scaling region.

Hypertensive effects of methoxamine on arterial mechanics in rats: analysis based on exponentially tapered T-tube model

Methoxamine, a specific α 1-selective adrenoceptor agonist, has proven to be useful in the treatment of hypotension, especially hypotension due to failure of the sympathetic nervous system. This study is to explore the vascular dynamic response to methoxamine in Wistar–Kyoto rats, based on the exponentially tapered T-tube model. The pulsatile aortic pressure and flow signals before and after the administration of methoxamine (0.025 mg/kg) were measured by a high-fidelity pressure sensor and electromagnetic flow probe, respectively. Hemodynamic parameters, such as aortic characteristic impedance, wave transit time, and arterial load compliance, were inferred from the aortic pressure and flow signals to describe the pulsatile nature of blood flow in the vasculature. The hypertensive effects of methoxamine on the static components of ventricular afterload were characterized by (1) little change in cardiac output, (2) a decrease in heart rate and (3) an increase in aortic pressure and total peripheral resistance. As for the pulsatile components of ventricular afterload, no significant changes in aortic characteristic impedance and wave transit time were observed, suggesting that the distensibility of the aorta was not altered in rats after the administration of methoxamine. In contrast, there was a significant drop in arterial load compliance mainly due to the elevated arterial blood pressure in methoxamine-treated rats. In conclusion, methoxamine at the dose of 0.025 mg/kg has a greater effect on peripheral resistance vessels than on Winkessel vessels in the rat systemic circulation.

A novel flow-suppression technique using tailored RF pulses.

The pulsatile nature of blood flow makes zipper-like artifacts along the coding direction in the two-dimensional Fourier transform NMR image. So far, spatial presaturation, one of the correction methods, is known to be effective in eliminating flow artifacts when the Fourier spin echo acquisition is employed. However, this method requires an additional RF pulse and a spoiling gradient for presaturation. Described in this paper is a new flow suppression technique, based on spin dephasing, using a set of tailored RF pulses. The proposed method does not require additional saturation RF pulses or spoiling gradient pulses, making it advantageous over other methods. In addition, the method is relatively robust to flow velocity. The proposed technique is equivalent to the existing flow saturation technique except that the elimination of the flow component is achieved by a pair of tailored 90-180 degrees RF pulses in the spin echo sequence. The principle of the proposed method is the creation of a linear phase gradient within the slice along the slice selection direction for the moving material by use of two opposing quadratic phase RF pulses, i.e., 90 degrees and 180 degrees RF pulses with opposing quadratic phase distributions. That is to say, all the spins of the moving materials along the slice selection direction become dephased. Therefore, no observable signal is generated. Computer simulations and experimental results obtained using a 2.0-T whole-body imaging system on both a phantom and a human volunteer are also presented.

Excitation of resonators by blood flow in arteries

Resonators are known to exist in human arteries. These include aneurysms and weakened sections of the arterial wall. The present paper gives a quantitative theory of how such resonators are excited under physiological conditions. Considered mechanisms of excitation include turbulence and flutter. The pulsatile nature of blood flow is taken into account, as are the flexible walls of arteries. The time‐varying frequency, bandwidth, and amplitude of such resonances are related to parameters that characterize the cardiovascular system. [Work supported by the William E. Leonhard endowment to Penn State Univ. The author acknowledges the advice of A. D. Pierce.]

Ventricular volumes determined from indicator dilution curves

A bolus of indicator substance injected into a ventricle or an atrium will be diluted in a stepwise manner according to the pulsatile nature of bloodflow. Provided the indicator is dispersed immediately and uniformly in the ventricle or atrium the time course of the indicator can be predicted. Dilution curves recorded in three dog experiments demonstrate a stepwise change of the indicator concentration in the ascending aorta following a bolus injection into the left atrium. The information thus retrieved is entered into equations describing the mathematical model in order to calculate the distribution volumes of the indicator in the left atrium and ventricle.