Biomedical subjects

J M Tarbell

Publications and source records attributed to J M Tarbell.

At least 19 recordsLinked to original sources

PubMed2006

Mechanotransduction and the glycocalyx.

Endothelial cells (ECs) line all blood vessel walls and are exposed to the mechanical forces of blood flow which modulate their function and play a role in vascular regulation, remodelling and disease. The principal mechanical forces sensed by ECs are the shear stress of flowing blood on their apical surface, and the circumferential stress resisting blood pressure, which induces stretch in the cell body. 'Mechanotransduction' refers to the mechanisms by which these forces are transduced into biomolecular responses of the cells. Given the importance of endothelial mechanotransduction in cardiovascular physiology and pathology, numerous research efforts have been dedicated to identifying the mechanosensory component(s) of ECs. This review focuses on mechanotransduction of shear stress by ECs and considers the evidence in support of the surface glycocalyx acting as a mechanotransducer.

Animals↗

PubMed2005

A computational study of flow in a compliant carotid bifurcation-stress phase angle correlation with shear stress.

The present study presents a three-dimensional, unsteady supercomputer simulation of the coupled fluid-solid interaction problem associated with flow through a compliant model of the bifurcation of the common carotid artery into the internal and external carotid arteries. The fluid wall shear stress (WSS) and solid circumferential stress/strain (CS) are computed and analyzed for the first time using the complex ratio of CS to WSS (CS/WSS). This analysis reveals a large negative phase angle between CS and WSS (stress phase angle--SPA) on the outer wall of the carotid sinus where atherosclerotic plaques are localized. This finding is consistent with other measurements and computations of the SPA in coronary arteries and the aortic bifurcation that show large negative SPA correlating with sites of plaque location and in vitro studies of endothelial cells showing that large negative SPA induces pro-atherogenic gene expression and metabolite release profiles.

Animals↗

PubMed2001

Integrating particle image velocimetry and laser Doppler velocimetry measurements of the regurgitant flow field past mechanical heart valves.

This study investigates the transient regurgitant flow downstream of a prosthetic heart valve using both laser Doppler velocimetry (LDV) and particle image velocimetry (PIV). Until now, LDV has been the more commonly used tool in investigating the flow characteristics associated with mechanical heart valves. The LDV technique allows point-by-point velocity measurements and provides enough information about the temporal variations in the flow. The main drawback of this technique is the time consuming nature of the data acquisition process in order to assess an entire flow field area. The PIV technique, on the other hand, allows measurement of the entire flow field in space in a plane at a given instant. In this study, PIV with spatial resolution of 0 (1 mm) and LDV with a temporal resolution of 0 (1 ms) were used to measure the regurgitant flow proximal to the Björk-Shiley monostrut (BSM) valve in the mitral position. With PIV, the ability to measure 2 velocity components over an entire plane simultaneously provides a very different insight into the flow field compared to a more traditional point-to-point technique like LDV. In this study, a picture of the effects of occluder motion on the fluid flow in the atrial chamber is interpreted using an integration of PIV and LDV measurements. Specifically, fluid velocities in excess of 3.0 m/s were recorded in the pressure-driven jet during valve closure, and a 1.5 m/s sustained regurgitant jet was observed on the minor orifice side. Additionally, the effects of the impact and subsequent rebound of the occluder on the flow also were clearly recorded in spatial and temporal detail by the PIV and LDV measurements, respectively. The PIV results provide a visually intuitive way of interpreting the flow while the LDV data explore the temporal variations and trends in detail. This analysis is an integrated flow description of the effects of valve closure and leakage on the pulsatile regurgitation flow field past a tilting-disc mechanical heart valve (MHV). It further reinforces the hypothesis that the planar flow visualization techniques, when integrated with traditional point-to point techniques, provide significantly more insight into the complex pulsatile flow past MHVs.

Blood Flow Velocity↗

PubMed2001

Fenestral pore size in the internal elastic lamina affects transmural flow distribution in the artery wall.

Interstitial flow through the subendothelial intima and media of an artery wall was simulated numerically to investigate the water flow distribution through fenestral pores which affects the wall shear stress on smooth muscle cells right beneath the internal elastic lamina (IEL). A two-dimensional analysis using the Brinkman model of porous media flow was performed. It was observed that the hydraulic permeability of the intimal layer should be much greater than that of the media in order to predict a reasonable magnitude for the pressure drop across the subendothelial intima and IEL (about 23 mostly at a 70 mm Hg luminal pressure). When Ki was set equal to the value in the media, this pressure drop was unrealistically high. Furthermore, the higher value of Ki produced a nearly uniform distribution of water flow through a simple array of fenestral pores all having the same diameters (1.2 microm), whereas when Ki was set at the value in the media, the flow distribution through fenestral pores was highly nonuniform and nonphysiologic. A deformable intima model predicted a nonuniform flow distribution at high pressure (180 mm Hg). Damage to the IEL was simulated by introducing a large fenestral pore (up to 17.8 microm) into the array. A dramatic increase in flow through the large pore was observed implying an altered fluid mechanical environment on the smooth muscle cells near the large pore which has implications for intimal hyperplasia and atherosclerosis. The model also predicted that the fluid shear stress on the bottom surface of an endothelial cell is on the order of 10 dyne/cm2, a level which can affect cell function.

Animals↗

PubMed2001

A biphasic, anisotropic model of the aortic wall.

A biphasic, anisotropic elastic model of the aortict wall is developed and compared to literature values of experimental measurements of vessel wall radii, thickness, and hvdraulic conductivity as a function of intraluminal pressure. The model gives good predictions using a constant wall modulus for pressures less than 60 mmHg, but requires a strain-dependent modulus for pressures greater than this. In both bovine and rabbit aorta, the tangential modulus is found to be approximately 20 times greater than the radial modulus. These moduli lead to predictions that, when perfused in a cylindrical geometry, the aortic volume and its specific hydraulic coonductivity are relatively independent of perfusion pressure, in agreement with experimental measurements. M, the parameter that relates specific hydraulic conductivy, to tissue dilation, is found to be a positive quantity correcting a previous error in the literature.

Animals↗

PubMed2001

Shear stress regulates occludin content and phosphorylation.

Previous studies determined that shear stress imposed on bovine aortic endothelial cell (BAEC) monolayers increased the hydraulic conductivity (L(P)); however, the mechanism by which shear stress increases L(P) remains unknown. This study tested the hypothesis that shear stress regulates paracellular transport by altering the expression and phosphorylation state of the tight junction protein occludin. The effect of shear stress on occludin content was examined by Western blot analysis. Ten dyn/cm(2) significantly reduced occludin content in a time-dependent manner such that after a 3 h exposure to shear, occludin content decreased to 44% of control. Twenty dyn/cm(2) decreased occludin content to 50% of control and increased L(P) by 4.7-fold after 3 h. Occludin expression and L(P) depend on tyrosine kinase activity because erbstatin A (10 microM) attenuated both the shear-induced decrease in occludin content and increase in L(P). Shear stress increased occludin phosphorylation after 5 min, 15 min, and 3 h exposures. The shear-induced increase in occludin phosphorylation was attenuated with dibutyryl (DB) cAMP (1 mM), a reagent previously shown to reverse the shear-induced increase in L(P). We conclude that shear stress rapidly (< or = 5 min) increases occludin phosphorylation and significantly decreases the expression of occludin over 1-4 h. Alterations in the occludin phosphorylation state and occludin total content are potential mechanisms by which shear stress increases L(P).

Animals↗

PubMed2001

Laser Doppler velocimetry and flow visualization studies in the regurgitant leakage flow region of three mechanical mitral valves.

Streak line flow visualization and laser Doppler velocimetry (LDV) were conducted in the regurgitant leakage flow region of 3 mechanical heart valve types: CarboMedics, Medtronic Hall, and St. Jude Medical. Streak line flow visualization identified regions of high regurgitant flow, and LDV measurements were focused on those locations. Maximum regurgitant flow velocities after valve closure ranged from 0.7 to 2.6 m/s, and maximum Reynolds shear stress after valve closure ranged from 450 to 3,600 dyne/cm2. These data indicate that leakage flows can generate turbulent jets with elevated Reynolds stresses even in bileaflet valves.

Blood Flow Velocity↗

PubMed2000

Effect of vascular endothelial growth factor on cultured endothelial cell monolayer transport properties.

Vascular endothelial growth factor (VEGF) is a potent enhancer of microvascular permeability in vivo. To date, its effects on hydraulic conductivity (L(p)) and diffusive albumin permeability (P(e)) of endothelial monolayers have not been thoroughly assessed in vitro. We hypothesized that VEGF affects endothelial transport properties differently depending on vessel location and endothelial phenotype. Using three well-established endothelial cell culture models-human umbilical vein endothelial cells (HUVECs), bovine aortic endothelial cells (BAECs), and bovine retinal microvascular cells (BRECs)-grown on porous, polycarbonate filters we were able to produce baseline transport properties characteristic of restrictive barriers. Our results show 3.1-fold and 5.7-fold increases in endothelial L(p) for BAEC and BREC monolayers, respectively, at the end of 3 h of VEGF (100 ng/ml) exposure. HUVECs, however, showed no significant alteration in L(p) after 3 h (100 ng/ml) or 24 h (25 ng/ml) of incubation with VEGF even though they were responsive to the inflammatory mediators, thrombin (1 U/ml; 27-fold increase in L(p) in 25 min) and bradykinin (10 microM; 4-fold increase in L(p) in 20 min). Protein kinase C (PKC) and nitric oxide (NO) are downstream effectors of VEGF signaling. BAEC L(p) was responsive to activation of NO (SNAP) and PKC (PMA), whereas these agents had no effect in altering HUVEC L(p). Moreover, BAECs exposed to the PKC inhibitor, staurosporine (50 ng/ml), exhibited significant attenuation of VEGF-induced increase in L(p), but inhibition of nitric oxide synthase (NOS) with L-NMMA (100 microM) had no effect in altering the VEGF-induced increase in L(p). These data provide strong evidence that in BAECs, the VEGF-induced increase in L(p) is mediated by a PKC-dependent mechanism. Regarding diffusive albumin P(e), at the end of 3 h, BAECs and BRECs showed 6.0-fold and 9. 9-fold increases in P(e) in response to VEGF (100 ng/ml), whereas VEGF had no significant effect after 3 h (100 ng/ml) or 24 h (25 ng/ml) in changing HUVEC P(e). In summary, these data indicate that VEGF affects endothelial transport properties differently depending on the vessel type and that differences in cell signaling pathways underlie the differences in VEGF responsiveness.

Animals↗

PubMed2000

Fluid dynamics of a pediatric ventricular assist device.

The number of pediatric patients requiring some form of mechanical circulatory assistance is growing throughout the world because of new surgical procedures and the success of pediatric cardiac transplantation. However, the salvage rate for those patients requiring circulatory support may be as low as 25%. Despite the fact that Penn State's 70 cc pneumatic ventricular assist device has been used with a success rate of over 90% in more than 250 patients worldwide, efforts to scale down the pump have encountered difficulties. Animal experiments with a 15 cc version were unsuccessful, with explanted pumps showing extensive thrombus deposition within the pumping chamber. The materials used to fabricate the smaller pump as well as the basic operating principles are identical to the successful adult-sized version. It is therefore believed that reducing the size of the pump altered the internal flow field, and that fluid dynamic factors were responsible for the high degree of thrombus observed with the implanted devices. A dimensional analysis was conducted that revealed significant differences in both Reynolds (Re) and Strouhal (St) numbers between the successful and unsuccessful pumps. Two component laser Doppler velocimetry was then used to characterize the internal flow field quantitatively. Comparison with data from the 70 cc pump showed a reduction in wall shear stress and turbulence levels in the 15 cc pump that would yield an environment conducive to clot formation.

Adult↗

PubMed2000

Effect of shear stress on the hydraulic conductivity of cultured bovine retinal microvascular endothelial cell monolayers.

The shear stress of flowing blood on endothelial cells increases water transport (hydraulic conductivity, Lp) in several vascular beds in vivo and has been hypothesized to play a role in elevating vascular transport in ocular diseases such as diabetic retinopathy. The purpose of this study is to determine the response of Lp to varying levels of shear stress using an in vitro model of the blood-retinal barrier: bovine retinal endothelial cells (BRECs) grown on polycarbonate filters. The study also addresses the role of nitric oxide (NO) and other downstream effectors in mediating shear-induced changes in water transport. A step change in shear stress of 10 dyn/cm(2) did not produce a significant change in Lp over 3 hours, whereas a 20 dyn/cm(2) step change elevated Lp by 14.6-fold relative to stationary controls at the end of 3h of shear exposure. 20 dyn/cm( 2) of shear stress stimulated the endothelial monolayers to release nitric oxide in a biphasic manner and incubation of the BRECs with a nitric oxide synthase (NOS) inhibitor, L-NMMA, significantly attenuated the shear-induced Lp response. These experiments demonstrate that NO is a key signaling molecule in the pathway linking shear stress and Lp in BRECs. A widely studied pathway downstream of NO involves the activation of guanylate cyclase (GC), guanosine 3', 5' -- cyclic monophosphate (cGMP) and protein kinase G (PKG). It was observed that incubation of BRECs with the GC inhibitor, LY83583 (10 microM) or the PKG inhibitor, KT5823 (1 microM) did not significantly alter the shear-induced Lp response. Also the cGMP analogue, 8-br-cGMP (1mM), did not affect the baseline Lp over 4h. These results demonstrate that shear stress elevates hydraulic conductivity in BRECs through a signaling mechanism that involves NO but not the GC/cGMP/PKG pathway.

Alkaloids↗

PubMed2000

Numerical simulation of oxygen mass transfer in a compliant curved tube model of a coronary artery.

Arterial wall transport of blood-borne oxygen is essential for superficial arterial wall metabolism. The unique geometry and hemodynamics of coronary arteries curved over the heart surface may alter the O2 transport pattern and lead to abnormalities of O2 tension at the inner wall (epicardial surface) which may contribute to atherogenesis. This study focused on O2 transport in a compliant model of a curved coronary artery. A three-dimensional finite element model with moving boundaries was setup to simulate physiological flow and O2 transport in coronary arteries. The full Navier-Stokes equations and the coupled conservation of species equation were solved simultaneously for typical coronary flow characteristics (aspect ratio=10, diameter variation=6%, mean Reynolds number= 150, unsteadiness parameter=3, Schmidt number=2,700). The results indicate a large difference in O2 wall flux (Sherwood number [Sh]) between the outside (Sh about 55) and inside (Sh about 2) walls and imply that O2 transport at the inner wall could be limited by the fluid phase.

Animals↗

PubMed2000

Flow visualization in mechanical heart valves: occluder rebound and cavitation potential.

High density particle image velocimetry, with spatial resolution of O(1 mm), was used to measure the effect of occluder rebound on the flow field near a Bjork-Shiley Monostrut tilting-disk mitral valve. The ability to measure two velocity components over an entire plane simultaneously provides a very different insight into the flow compared to the more traditional point to point techniques (like Laser Doppler Velocimetry) that were utilized in previous investigations of the regurgitant flow. A picture of the effects of occluder rebound on the fluid flow in the atrial chamber is presented. Specifically, fluid velocities in excess of 1.5 m/s traveling away from the atrial side were detected 3 mm away from the valve seat in the local low pressure region created by the occluder rebound on the major orifice side where cavitation has been observed. This analysis is the first spatially detailed flow description of the effects of occluder rebound on the flow field past a tilting-disk mechanical heart valve and further reinforces the hypothesis that the rebound effect plays a significant role in the formation of cavitation, which has been implicated in the hemolysis and wear associated with tilting-disk valves in vivo.

Biomedical Engineering↗

PubMed2000

The osmotic swelling characteristics of cardiac valve prostheses.

Several types of mechanical cardiac prostheses have been constructed with Delrin occluders, a material that is subject to osmotic swelling. The leaftets are designed to expand to specific tolerances when immersed in blood. The synthetic blood analogs commonly used in vitro contain hydrophilic compounds that can alter the osmotic expansion of the Delrin occluders. A static leak test chamber was employed to illustrate the effects of various test fluids on the sustained regurgitation phase of Delrin valves.

Equipment Failure Analysis↗

PubMed2000

Observation and quantification of gas bubble formation on a mechanical heart valve.

Clinical studies using transcranial Doppler ultrasonography in patients with mechanical heart valves (MHV) have detected gaseous emboli. The relationship of gaseous emboli release and cavitation on MHV has been a subject of debate in the literature. To study the influence of cavitation and gas content on the formation and growth of stable gas bubbles, a mock circulatory loop, which employed a Medtronic-Hall pyrolytic carbon disk valve in the mitral position, was used. A high-speed video camera allowed observation of cavitation and gas bubble release on the inflow valve surfaces as a function of cavitation intensity and carbon dioxide (CO2) concentration, while an ultrasonic monitoring system scanned the aortic outflow tract to quantify gas bubble production by calculating the gray scale levels of the images. In the absence of cavitation, no stable gas bubbles were formed. When gas bubbles were formed, they were first seen a few milliseconds after and in the vicinity of cavitation collapse. The volume of the gas bubbles detected in the aortic track increased with both increased CO2 and increased cavitation intensity. No correlation was observed between O2 concentration and bubble volume. We conclude that cavitation is an essential precursor to stable gas bubble formation, and CO2, the most soluble blood gas, is the major component of stable gas bubbles.

Carbon Dioxide↗

PubMed2000

Numerical simulation of pulsatile flow in a compliant curved tube model of a coronary artery.

The endothelial cells (ECs) lining a blood vessel wall are exposed to both the wall shear stress (WSS) of blood flow and the circumferential strain (CS) of pulsing artery wall motion. These two forces and their interaction are believed to play a role in determining remodeling of the vessel wall and development of arterial disease (atherosclerosis). This study focused on the WSS and CS dynamic behavior in a compliant model of a coronary artery taking into account the curvature of the bending artery and physiological radial wall motion. A three-dimensional finite element model with transient flow and moving boundaries was set up to simulate pulsatile flow with physiological pressure and flow wave forms characteristic of the coronary arteries. The characteristic coronary artery curvature and flow conditions applied to the simulation were: aspect ratio (lambda) = 10, diameter variation (DV) = 6 percent, mean Reynolds number (Re) = 150, and unsteadiness parameter (alpha) = 3. The results show that mean WSS is about 50 percent lower on the inside wall than the outside wall while WSS oscillation is stronger on the inside wall. The stress phase angle (SPA) between CS and WSS, which characterizes the dynamics of the mechanical force pattern applied to the endothelial cell layer, shows that CS and WSS are more out of phase in the coronaries than in any other region of the circulation (-220 deg on the outside wall, -250 deg on the inside wall). This suggests that in addition to WSS, SPA may play a role in localization of coronary atherosclerosis.

Animals↗

PubMed2000

Interstitial flow through the internal elastic lamina affects shear stress on arterial smooth muscle cells.

Interstitial flow through the tunica media of an artery wall in the presence of the internal elastic lamina (IEL), which separates it from the subendothelial intima, has been studied numerically. A two-dimensional analysis applying the Brinkman model as the governing equation for the porous media flow field was performed. In the numerical simulation, the IEL was modeled as an impermeable barrier to water flux, except for the fenestral pores, which were uniformly distributed over the IEL. The tunica media was modeled as a heterogeneous medium composed of a periodic array of cylindrical smooth muscle cells (SMCs) embedded in a fiber matrix simulating the interstitial proteoglycan and collagen fibers. A series of calculations was conducted by varying the physical parameters describing the problem: the area fraction of the fenestral pore (0. 001-0.036), the diameter of the fenestral pore (0.4-4.0 microm), and the distance between the IEL and the nearest SMC (0.2-0.8 microm). The results indicate that the value of the average shear stress around the circumference of the SMC in the immediate vicinity of the fenestral pore could be as much as 100 times greater than that around an SMC in the fully developed interstitial flow region away from the IEL. These high shear stresses can affect SMC physiological function.

Arteries↗

PubMed2000

Effect of fluid flow on smooth muscle cells in a 3-dimensional collagen gel model.

A 3D collagen gel model was developed to simulate interstitial fluid flow and to assess the importance of this flow on the biochemical production rates of vascular smooth muscle cells (SMCs). Rat aortic SMCs were suspended in type I collagen, and the gel was supported by nylon fibers that allowed a 9-cm length of the SMC-gel model to withstand 90 cm H(2)O differential pressure over a 6-hour period without significant compaction. Up to 1 dyne/cm(2) shear stress on the suspended SMCs could be induced by the pressure-driven interstitial flow. The suspended SMCs were globular, had a diameter of approximately 10 microm, and were distributed uniformly throughout the gel. The collagen fibers formed a network that was connected randomly with the surface of SMCs and nylon fibers. The diameter of the collagen fibers was approximately 100 nm, and the concentration of collagen was 2.5 mg/mL. Using these parameters, fiber matrix theory predicted a Darcy permeability coefficient (K:(p)) of 1.22x10(-)(8) cm(2), which was close to the measured value of K:(p). The production rates of prostaglandin (PG) I(2) and PGE(2) were used as markers of biochemical responsiveness of SMCs to fluid shear stress. Both PGI(2) and PGE(2) production rates under 1 dyne/cm(2) shear stress were significantly elevated relative to static (no-flow) controls. The production rates, however, were approximately 10 times lower than observed when the same cells were plated on collagen-treated glass slides (2D model) and exposed to the same level of shear stress by use of a rotating disk apparatus. The results indicate that interstitial flow can affect SMC biology and that SMCs are more quiescent in 3D cultures than in 2D cultures. The 3D collagen gel model should be useful for future studies of interstitial flow effects on SMC function.

Animals↗

PubMed2000

Shear-induced increase in hydraulic conductivity in endothelial cells is mediated by a nitric oxide-dependent mechanism.

This study addresses the role of nitric oxide (NO) and its downstream mechanism in mediating the shear-induced increase in hydraulic conductivity (L(p)) of bovine aortic endothelial cell monolayers grown on porous polycarbonate filters. Direct exposure of endothelial monolayers to 20-dyne/cm(2) shear stress induced a 4. 70+/-0.20-fold increase in L(p) at the end of 3 hours. Shear stress (20 dyne/cm(2)) also elicited a multiphasic NO production pattern in which a rapid initial production was followed by a less rapid, sustained production. In the absence of shear stress, an exogenous NO donor, S-nitroso-N-acetylpenicillamine, increased endothelial L(p) 2.23+/-0.14-fold (100 micromol/L) and 4.8+/-0.66-fold (500 micromol/L) at the end of 3 hours. In separate experiments, bovine aortic endothelial cells exposed to NO synthase inhibitors, N(G)-monomethyl-L-arginine and N(G)-nitro-L-arginine methyl ester, exhibited significant attenuation of shear-induced increase in L(p) in a dose-dependent manner. Inhibition of guanylate cyclase (GC) with LY-83,583 (1 micromol/L) or protein kinase G (PKG) with KT5823 (1 micromol/L) failed to attenuate the shear-induced increase in L(p). Furthermore, direct addition of a stable cGMP analogue, 8-bromo-cGMP, had no effect in altering baseline L(p), indicating that the GC/cGMP/PKG pathway is not involved in shear stress-NO-L(p) response. Incubation with iodoacetate (IAA), a putative inhibitor of glycolysis, dose-dependently increased L(p). Addition of IAA at levels that did not affect baseline L(p) greatly potentiated the response of L(p) to 20-dyne/cm(2) shear stress. Finally, both shear stress-induced and IAA-induced increases in L(p) could be reversed with the addition of dibutyryl cAMP. However, additional metabolic inhibitors, 2 deoxyglucose (10 mmol/L) and oligomycin (1 micromol/L), or reactive oxygen species scavengers, deferoxamine (1 mmol/L) and ascorbate (10 mmol/L), failed to alter shear-induced increases in L(p). Our results show that neither the NO/cGMP/PKG pathway nor a metabolic pathway mediates the shear stress-L(p) response. An alternate mechanism downstream from NO that is sensitive to IAA must mediate this response.

Alkaloids↗