Mechanical buckling of artery under pulsatile pressure

Tortuosity that often occurs in carotid and other arteries has been shown to be associated with high blood pressure, atherosclerosis, and other diseases. However the mechanisms of tortuosity development are not clear. Our previous studies have suggested that arteries buckling could be a possible mechanism for the initiation of tortuous shape but artery buckling under pulsatile flow condition has not been fully studied. The objectives of this study were to determine the artery critical buckling pressure under pulsatile pressure both experimentally and theoretically, and to elucidate the relationship of critical pressures under pulsatile flow, steady flow, and static pressure. We first tested the buckling pressures of porcine carotid arteries under these loading conditions, and then proposed a nonlinear elastic artery model to examine the buckling pressures under pulsatile pressure conditions. Experimental results showed that under pulsatile pressure arteries buckled when the peak pressures were approximately equal to the critical buckling pressures under static pressure. This was also confirmed by model simulations at low pulse frequencies. Our results provide an effective tool to predict artery buckling pressure under pulsatile pressure.     

Increased venous pressure causes increased thoracic duct pressure in awake sheep.

The lymph from most organs drains through the thoracic duct and into veins in the neck. We hypothesized that increases in neck vein pressure (Pnv) are reflected through the thoracic duct to the lung lymphatic-thoracic duct junction. To test this, we cannulated the lung lymphatics in the direction of flow in four sheep. We advanced each cannula until it entered the thoracic duct. Thus the pressure at the tip of the lymphatic cannula (Px) was the pressure at the outflow of the lung lymphatics. We also placed a balloon into the superior vena cava. One to two days later, we measured Px in the awake sheep as we inflated the balloon and increased Pnv in steps to 25-45 cmH2O. We found no significant differences in Px and Pnv. Furthermore, Px closely followed Pnv after each step increase in Pnv. These results support our hypothesis that increases in Pnv cause increases in the outflow pressure to lung lymphatics.     

Starling forces that oppose filtration after tissue oncotic pressure is increased

We tested the hypothesis that the effective oncotic force that opposes fluid filtration across the microvessel wall is the local oncotic pressure difference across the endothelial surface glycocalyx and not the global difference between the plasma and tissue. In single frog mesenteric microvessels perfused and superfused with solutions containing 50 mg/ml albumin, the effective oncotic pressure exerted across the microvessel wall was not significantly different from that measured when the perfusate alone contained albumin at 50 mg/ml. Measurements were made during transient and steady-state filtration at capillary pressures between 10 and 35 cmH(2)O. A cellular-level model of coupled water and solute flows in the interendothelial cleft showed water flux through small breaks in the junctional strand limited back diffusion of albumin into the protected space on the tissue side of the glycocalyx. Thus oncotic forces opposing filtration are larger than those estimated from blood-to-tissue protein concentration differences, and transcapillary fluid flux is smaller than estimated from global differences in oncotic and hydrostatic pressures.     

Effects of pulsation frequency and endothelial integrity on enhanced arterial transmural filtration produced by pulsatile pressure

The role of the endothelium in regulating transmural fluid filtration into the artery wall under pulsatile pressure and the effects of changes in pulsatile frequency on filtration have received little attention. Previous experiments (Alberding JP, Baldwin AL, Barton JK, and Wiley E. Am J Physiol Heart Circ Physiol 286: H1827-H1835, 2004) demonstrated significantly increased filtration after initial onset of pulsatile pressure compared with that predicted by using parameters measured under steady pressure. To determine the role of the endothelium in this phenomenon, the following experiments were performed on five New Zealand White rabbits (anesthetized with 30 mg/kg pentobarbital sodium). One of each pair of carotid arteries was deendothelialized, and filtration measurements under steady and pulsatile pressure were compared with those made in intact vessels (Alberding JP, Baldwin AL, Barton JK, and Wiley E. Am J Physiol Heart Circ Physiol 286: H1827-H1835, 2004). To determine the effect of increasing pulsatile frequency on arterial filtration, transmural filtration was measured by using pulsatile pressure frequencies of 1 Hz, followed by 2 Hz, in another set of intact arteries (6 arteries and 3 animals). For deendothelialized vessels, the initial increase in filtration after onset of pulsatility was similar to that observed in intact vessels, but the subsequent reduction in filtration was less abrupt. When pulsatile frequency was increased from 1 to 2 Hz in intact arteries, an initial increase in filtration was observed, similar to that obtained after onset of pulsatile pressure subsequent to a steady pressure. The observed responses of arteries to pulsatile pressure, with and without endothelium, or undergoing a frequency change, suggest a dynamic role for the endothelium in regulating transvascular transport in vivo.     

Lack of chemokine signaling through CXCR5 causes increased mortality, ventricular dilatation and deranged matrix during cardiac pressure overload

Rationale

Inflammatory mechanisms have been suggested to play a role in the development of heart failure (HF), but a role for chemokines is largely unknown. Based on their role in inflammation and matrix remodeling in other tissues, we hypothesized that CXCL13 and CXCR5 could be involved in cardiac remodeling during HF.

Objective

We sought to analyze the role of the chemokine CXCL13 and its receptor CXCR5 in cardiac pathophysiology leading to HF.

Methods and Results

Mice harboring a systemic knockout of the CXCR5 (CXCR5^−/−) displayed increased mortality during a follow-up of 80 days after aortic banding (AB). Following three weeks of AB, CXCR5^−/− developed significant left ventricular (LV) dilatation compared to wild type (WT) mice. Microarray analysis revealed altered expression of several small leucine-rich proteoglycans (SLRPs) that bind to collagen and modulate fibril assembly. Protein levels of fibromodulin, decorin and lumican (all SLRPs) were significantly reduced in AB CXCR5^−/− compared to AB WT mice. Electron microscopy revealed loosely packed extracellular matrix with individual collagen fibers and small networks of proteoglycans in AB CXCR5^−/− mice. Addition of CXCL13 to cultured cardiac fibroblasts enhanced the expression of SLRPs. In patients with HF, we observed increased myocardial levels of CXCR5 and SLRPs, which was reversed following LV assist device treatment.

Conclusions

Lack of CXCR5 leads to LV dilatation and increased mortality during pressure overload, possibly via lack of an increase in SLRPs. This study demonstrates a critical role of the chemokine CXCL13 and CXCR5 in survival and maintaining of cardiac structure upon pressure overload, by regulating proteoglycans essential for correct collagen assembly.     

Experimental and numerical study of pulsatile flows through stenosis: wall shear stress analysis.

Different shapes of pulsatile flows through a model of stenosis are experimentally and numerically modeled to validate both methods and to determine the wall shear stress temporal evolution downstream from the stenosis. Two-dimensional velocity measurements are performed in a 75% severity stenosis using a pulsed Doppler ultrasonic velocimeter. Finite element package is employed for the transient numerical simulations. Polynomial method, based on the experimental velocity values, is proposed to determine the wall shear stress temporal evolution. There is a good agreement between the numerical and experimental results. The wall shear stress temporal analysis shows oscillating wall shear stress values during the cycle with high wall shear stress values at the throat of about 120 dyn/cm2, and low values downstream from the stenosis of about - 2.5 dyn/cm2. The key result of the study is that the presence of the stenosis leads the artery to work in a direction which is opposite to the direction of a healthy artery.     

Three-dimensional numerical analysis of pulsatile flow and wall shear stress in the carotid artery bifurcation.

To analyse the pulsatile flow field and the mechanical stresses in a three-dimensional carotid artery bifurcation model, computer simulation is applied. The approximation of the Navier-Stokes equations uses a pressure correction finite element method. Numerical results are presented for axial and secondary flow velocity and wall shear stresses with special emphasis on the fluid dynamics in the carotid sinus. This region is of major interest because it is affected preferentially by lesions. Detailed local flow studies as carried out here should lead to a further insight into the mechanisms of atherogenesis. The flow conditions used in the study were chosen according to Ku et al. (Arteriosclerosis 5, 293-302, 1985). The results of this numerical analysis agree in the essential features with their experimental results.     

Phasic and spatial pressure measurements in a femoral artery branch model for pulsatile flow

Phasic and spatial time-averaged pressure distributions were measured in a 60-deg femoral artery branch model over a large range of branch flow ratios and at physiological Reynolds numbers of about 120 and 700. The results obtained with an in-vivo like flow wave form indicated spatial adverse time average pressure gradients in the branch vicinity which increased in magnitude with branch flow ratio, and the importance of the larger inertial effects at the higher Reynolds numbers. Pressure losses in the branch entrance region were relatively large, and corresponding flow resistances may limit branch flow, particularly at higher Reynolds numbers. The effect of branch flow was to reduce the pressure loss in the main lumen.     

An experimental study of pressure losses in pulsatile flows through rigid and pulsating stenosis

The time-dependent pressure curves of a pulsatile flow across rigid and pulsating stenoses were investigated experimentally in a laboratory simulator of the outflow tract of the heart right ventricle. The experiments were performed within the range of physiological conditions of frequency and flow rate. The experimental setup consisted of a closed flow system which was operated by a pulsatile pump, and a test chamber which enabled checking different modes of stenosis. Rigid constrictions were simulated by means of axisymmetric blunt-ended annular plugs with moderate-to-severe area reductions. The pulsating stenosis consisted of a short starling resistor device operated by a pulsating external pressure which was synchronized by the pulsatile flow. It was found that the shape of the time-dependent pressure curve upstream of the stenosis was different in the case of rigid stenosis than in the pulsating one. Potential clinical applications of the work may relate to diagnosis of the type of stenosis in the congenital heart disease known as Tetralogy of Fallot.     

Vortex generation in pulsatile flow through arterial bifurcation models including the human carotid artery

Visualization experiments were performed to elucidate the complicated flow pattern in pulsatile flow through arterial bifurcations. Human common carotid arteries, which were made transparent, and glass-models simulating Y- and T-shaped bifurcations were used. Pulsatile flow with wave forms similar to those of arterial flow was generated with a piston pump, elastic tube, airchamber, and valves controlling the outflow resistance. Helically recirculating flow with a pattern similar to that of the horseshoe vortex produced around wall-based protuberances in circular tubes was observed in pulsatile flow through all the bifurcations used in the present study. This flow type, which we shall refer to as the horseshoe vortex, has also been demonstrated to occur at the human common carotid bifurcation in steady flow with Reynolds numbers above 100. Time-varying flows also produced the horseshoe vortex mostly during the decelerating phase. Fluid particles of dye solution approaching the bifurcation apex diverged, divided into two directions perpendicularly, and then showed helical motion representing the horseshoe vortex formation. While this helical flow was produced, the stagnation points appeared on the wall upstream of the apex. Their position was dependent upon the flow distribution ratio between the branches in the individual arteries. The region affected by the horseshoe vortex was smaller during pulsatile flow than during steady flow. Lowering the Reynolds number together with the Womersley number weakened the intensity of helical flow. A separation bubble, resulting from the divergence or wall roughness, was observed at the outer or inner wall of the branch vessels and made the flow more complicated.     

A theoretical model for water flux through the artery wall

A two layer model for water flux through the artery is studied using a mathematical model based on the theory for the consolidation of water saturated soils. The matrix is considered to be constituted by two layers with different permeabilities and different elastic constants and the two systems of equations are coupled with the condition of continuity of pressure, total stress, solid displacement and fluid seepage velocity at the interface. The luminal pressure is considered to be harmonic in time. Exact solutions are obtained for displacements and pressures in both the layers. For large consolidation times, large pressure gradients are found to exist near the boundaries and at the interface. The heterogeneous model may not only be useful to understand the mechanics of transport in the physiological system but it will also help the bioengineers to choose proper implant materials to design artificial vascular organs for the purpose of prosthesis.     

Combination of hydrostatic pressure and lacticin 3147 causes increased killing of Staphylococcus and Listeria

The use of hydrostatic pressure and lacticin 3147 treatments were evaluated in milk and whey with a view to combining both treatments for improving the quality of minimally processed dairy foods. The system was evaluated using two foodborne pathogens: Staphylococcus aureus ATCC6538 and Listeria innocua DPC1770. Trials against Staph. aureus ATCC6538 were performed using concentrated lacticin 3147 prepared from culture supernatant. The results demonstrated a more than additive effect when both treatments were used in combination. For example, the combination of 250 MPa (2.2 log reduction) and lacticin 3147 (1 log reduction) resulted in more than 6 logs of kill. Similar results were obtained when a foodgrade powdered form of lacticin 3147 (developed from a spray dried fermentatation of reconstituted demineralized whey powder) was evaluated for the inactivation of L. innocua DPC1770. Furthermore, it was observed that treatment of lacticin 3147 preparations with pressures greater than 400 MPa yielded an increase in bacteriocin activity (equivalent to a doubling of activity). These results indicate that a combination of high pressure and lacticin 3147 may be suitable for improving the quality of minimally processed foods at lower hydrostatic pressure levels.     

Fluid particle motion and Lagrangian velocities for pulsatile flow through a femoral artery branch model

A flow visualization study using selective dye injection and frame by frame analysis of a movie provided qualitative and quantitative data on the motion of marked fluid particles in a 60 degree artery branch model for simulation of physiological femoral artery flow. Physical flow features observed included jetting of the branch flow into the main lumen during the brief reverse flow period, flow separation along the main lumen wall during the near zero flow phase of diastole when the core flow was in the downstream direction, and inference of flow separation conditions along the wall opposite the branch later in systole at higher branch flow ratios. There were many similarities between dye particle motions in pulsatile flow and the comparative steady flow observations.     

A fluid--structure interaction finite element analysis of pulsatile blood flow through a compliant stenotic artery.

A new model is used to analyze the fully coupled problem of pulsatile blood flow through a compliant, axisymmetric stenotic artery using the finite element method. The model uses large displacement and large strain theory for the solid, and the full Navier-Stokes equations for the fluid. The effect of increasing area reduction on fluid dynamic and structural stresses is presented. Results show that pressure drop, peak wall shear stress, and maximum principal stress in the lesion all increase dramatically as the area reduction in the stenosis is increased from 51 to 89 percent. Further reductions in stenosis cross-sectional area, however, produce relatively little additional change in these parameters due to a concomitant reduction in flow rate caused by the losses in the constriction. Inner wall hoop stretch amplitude just distal to the stenosis also increases with increasing stenosis severity, as downstream pressures are reduced to a physiological minimum. The contraction of the artery distal to the stenosis generates a significant compressive stress on the downstream shoulder of the lesion. Dynamic narrowing of the stenosis is also seen, further augmenting area constriction at times of peak flow. Pressure drop results are found to compare well to an experimentally based theoretical curve, despite the assumption of laminar flow.     

Combined effects of pulsatile flow and dynamic curvature on wall shear stress in a coronary artery bifurcation model

A three-dimensional model with simplified geometry for the branched coronary artery is presented. The bifurcation is defined by an analytical intersection of two cylindrical tubes lying on a sphere that represents an idealized heart surface. The model takes into account the repetitive variation of curvature and motion to which the vessel is subject during each cardiac cycle, and also includes the phase difference between arterial motion and blood flowrate, which may be nonzero for patients with pathologies such as aortic regurgitation. An arbitrary Lagrangian Eulerian (ALE) formulation of the unsteady, incompressible, three-dimensional Navier-Stokes equations is employed to solve for the flow field, and numerical simulations are performed using the spectral/hp element method. The results indicate that the combined effect of pulsatile inflow and dynamic geometry depends strongly on the aforementioned phase difference. Specifically, the main findings of this work show that the time-variation of flowrate ratio between the two branches is minimal (less than 5%) for the simulation with phase difference angle equal to 90 degrees, and maximal (51%) for 270 degrees. In two flow pulsatile simulation cases for fixed geometry and dynamic geometry with phase angle 270 degrees, there is a local minimum of the normalized wall shear rate amplitude in the vicinity of the bifurcation, while in other simulations a local maximum is observed.     

RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity

Hyperactivation of the mammalian target of rapamycin (mTOR) pathway can cause malformation of cortical development (MCD) with associated epilepsy and intellectual disability (ID) through a yet unknown mechanism. Here, we made use of the recently identified dominant-active mutation in Ras Homolog Enriched in Brain 1 (RHEB), RHEBp.P37L, to gain insight in the mechanism underlying the epilepsy caused by hyperactivation of the mTOR pathway. Focal expression of RHEBp.P37L in mouse somatosensory cortex (SScx) results in an MCD-like phenotype, with increased mTOR signaling, ectopic localization of neurons, and reliable generalized seizures. We show that in this model, the mTOR-dependent seizures are caused by enhanced axonal connectivity, causing hyperexcitability of distally connected neurons. Indeed, blocking axonal vesicle release from the RHEBp.P37L neurons alone completely stopped the seizures and normalized the hyperexcitability of the distally connected neurons. These results provide new evidence of the extent of anatomical and physiological abnormalities caused by mTOR hyperactivity, beyond local malformations, which can lead to generalized epilepsy.

Hyperactivation of the mTOR pathway can cause cortical malformations and epilepsy. This study reveals that these effects can be uncoupled and that mTOR hyperactivity in a limited set of neurons induces hyperexcitability in non-targeted, healthy neurons, suggesting that it is actually these changes that may underlie mTOR-driven epileptogenesis.     

Reflection coefficients in pulsatile flow through converging junctions and the pressure distribution in a simple loop

Analytical expressions for the reflection coefficients in pulsatile flow through converging junctions are derived by two independent methods and are used to study the effects of wave reflections on the pressure distribution in a simple vascular loop. A simulated physiological situation is used as an example in which the loop is formed by the combination of a bypass and a bypassed vessel, the relative diameter of the latter being varied in order to simulate a narrowing. The results demonstrate how, in the case of a converging junction, the effects of wave reflections on the pressure distribution in one vessel depend on conditions within the vessel itself as well as in the other. The new reflection coefficients take into account this interdependence of flow in the two vessels forming a converging junction, and are shown to be consistent with reflection coefficients commonly used in diverging junctions.     

Bio-medico-mechanical behavior of natural artery blood vessel under constant and variable internal pulsatile pressure flow test in vitro

Studies have been carried out on the bio-medico-mechanical behavior in vitro of natural blood vessel (dogs) under constant and variable internal pulsatile pressure flow. The apparatus designed by us well simulated the arterial system. The studies were made for the case of pressure amplitude kept as constant, of the two-step-multi-duplicated pulsatile pressure and of the fluctuating pressure. For the case of the fluctuating pressure, the strength of the artery becomes considerably lower than those under constant amplitude and two-step-multi-duplicated pulsatile pressure. SEM observations of the inner walls of the artery shows that collagen fibers are more elongated under fluctuating pulsatile pressure flow. In conclusion, in order to avoid the mechanical deterioration of the artery strength, it is useful to keep the pulsatile blood pressure at constant amplitude. Even for the case of the blood pressure fluctuation, it is necessary to manage to keep the blood pressure as near a regular wave as possible, the total number of repeated pulse being equal.     

Thrombin causes increased monocytic-cell adhesion to endothelial cells through a protein kinase C-dependent pathway.

The coagulation protein thrombin has been shown to stimulate multiple endothelial-cell (EC) functions, including production of platelet-derived growth factor and of platelet-activating factor (PAF), and neutrophil adhesion. We have found that thrombin causes increased binding of monocytic cells (U937 cells and normal human monocytes) to cultured EC of various species. Maximum adhesion of monocytes to pig aortic EC occurred 6 h after thrombin treatment and remained elevated through 24 h. Stimulation of adherence by bovine alpha-thrombin was half-maximal at 15 units/ml, and reached a plateau at 50 units/ml. Catalytically inactive thrombin (phenylmethanesulphonyl fluoride-treated) had no effect on monocyte adhesion to EC. Heparin, but not the endotoxin antagonist polymyxin B, suppressed the stimulation of adhesion by thrombin without altering basal adhesion. Two lines of evidence suggested that protein kinase C (PKC) was involved in the intracellular signalling to increase monocyte adhesion to EC. First the PKC activator phorbol 12-myristate 13-acetate (PMA) stimulated monocytic-cell adhesion to EC at a dose consistent with stimulation of PKC (half-maximal response at 1-3 nM) and with a time course similar to that for thrombin stimulation (maximal by 4 h). Diacylglycerol, a physiological activator of PKC, also stimulated U937-cell adhesion to EC. Secondly, H7, a PKC inhibitor, completely blocked stimulation of monocyte adhesion to EC by thrombin or PMA. The structural analogue of H7, HA1004, which preferentially inhibits cyclic-AMP- and cyclic-GMP-dependent protein kinases, had no effect on stimulated monocyte adhesion. The PKC inhibitor also blocked the stimulation of monocyte adhesion to EC by interleukin-1 and endotoxin, but did not alter the basal level of monocyte binding to unstimulated EC. Thrombin stimulation of monocyte adhesion differed from the reported stimulation of neutrophil adhesion by thrombin in that the latter process reached a maximum in minutes rather than hours. In addition, neither PAF itself nor agents known to stimulate PAF production by EC, such as arachidonate and the Ca2+ ionophore A23187, had any effect on monocyte adhesion. These results demonstrate a PKC-dependent cytokine-like action of the coagulation protein thrombin in modulating monocytic-cell adhesion to EC, a phenomenon of potential importance in many pathological and physiological processes.