A mechanistic model of acute platelet accumulation in thrombogenic stenoses.

Thrombosis on an atherosclerotic lesion can cause heart attack or stroke. Thrombosis may be triggered by plaque rupture or erosion, creating a thrombogenic stenosis. To measure and model this situation, collagen-coated stenoses have been exposed to nonanticoagulated blood in a baboon ex vivo shunt. The maximum rate of platelet accumulation, measured using a gamma camera, was highest in the throat region of moderate and severe stenoses, and increased with increasing stenosis severity. A species transport model of platelet accumulation was developed, which included mechanisms of convection, shear-enhanced diffusion, near-wall platelet concentration, and a kinetic model of platelet activation and aggregation. The model accurately reproduced the average spatial pattern and time rate of platelet accumulation in the upstream and throat regions of the stenosis, where shear-enhanced diffusivity increased platelet transport in the stenosis throat. Downstream of the throat where flow is complicated by recirculation, the model computed a transport-limited region with lower than measured platelet accumulation, suggesting that fluid-phase platelet activation may significantly affect both transport and adhesion rates in the poststenotic region. This model may provide an initial quantitative estimate of the likelihood of occlusive thrombus in individual patients due to plaque erosion, artery spasm, incomplete angioplasty, or plaque rupture.

Antithrombotic effects of ionic and non-ionic contrast media in nonhuman primates.

Thromboembolic complications have been attributed to the use of radiographic contrast media (CM) during interventional procedures for arterial revascularization. However, due to the low frequency of adverse events, comparisons between different CM have been difficult to perform, although it has been suggested that ionic (vs. non-ionic) CM may be associated with fewer thrombotic events. The present study was undertaken using well-characterized baboon thrombosis models in order to compare different CM under physiologically relevant and controlled conditions of blood flow, exposure time, and CM concentration. Three CM were studied: ioxaglate, iohexol, and iodixanol. CM were locally infused into the proximal segment of femoral arteriovenous shunts. Palmaz-Schatz stents (4 mm i.d.) and expanded tubular segments (9 mm i.d.), which exhibited venous-type flow recirculation and stasis, were deployed into the shunts distally. Saline was infused in identical control studies. Blood flow was maintained at 100 ml/min. Thrombosis was measured over a blood exposure period of 2 hours by gamma camera imaging of 111In-platelets and by gamma counting of deposited 125I-fibrin. CM concentrations within the flowfield were predicted using computational fluid dynamics. At infusion rates of 0.1 and 0.3 ml/min, the low-osmolar ionic CM ioxaglate reduced both platelet and fibrin deposition on the stents by 75-80% (p <0.005), while both iohexol and iodixanol reduced platelet deposition by 30-50% (p <0.05). In the regions of low shear flow, ioxaglate (0.3 ml/min) also reduced platelet deposition significantly (by 52% vs. control results; p <0.05). Thus the three agents evaluated--ioxaglate, iohexol, and iodixanol--all produced anticoagulant and antiplatelet effects and were inherently antithrombotic in vivo. The most striking effects were seen with the low osmolarity, ionic contrast agent ioxaglate.

Reduced thrombus formation by hyaluronic acid coating of endovascular devices.

Biocompatible stent coatings may alleviate problems of increased (sub)acute thrombosis after stent implantation. Hyaluronic acid (HA), a ubiquitous, nonsulfated glycosaminoglycan, inhibits platelet adhesion and aggregation and prolongs bleeding when administered systemically. However, the effects of immobilized HA for reducing stent platelet deposition in vivo are unknown. We therefore quantified the antithrombotic effects of coating stainless steel stents and tubes with HA using an established baboon thrombosis model under physiologically relevant blood flow conditions. HA-coated and uncoated (control) stents (3.5 mm in diameter, n=32) and stainless steel tubes (4.0 mm in diameter, n=18) were deployed into exteriorized arteriovenous shunts of conscious, nonanticoagulated baboons. Accumulation of (111)In-radiolabeled platelets was quantified by continuous gamma-camera imaging during a 2-hour blood exposure period. HA coating resulted in a significant reduction in platelet deposition in long (4 cm) tubes (0.24+/-0.15 x 10(9) versus 6.12+/-0.49 x 10(9) platelets; P<0.03), short (2 cm) stainless steel tubes (0.18+/-0.06 x 10(9) versus 3.03+/-0.56 x 10(9) platelets; P<0.008), and stents (0.82+/-0.20 x 10(9) versus 1.83+/-0. 23 x 10(9) platelets; P<0.02) compared with uncoated control devices. Thus, HA coating reduces platelet thrombus formation on stainless steel stents and tubes in primate thrombosis models. These results indicate that immobilized HA may represent an attractive strategy for improving the thromboresistance of endovascular devices.

Boundary layer drug delivery using a helical catheter.

BACKGROUND: A catheter-based approach for local endovascular drug delivery has been developed. The catheter is deployed percutaneously, while the end of the catheter is in the form of a helix that is placed just proximal to the vascular site to be treated. The helices are in contact with the vessel wall. A number of small holes is drilled in the coils of the catheter through which drug is infused, so that the infused drug remains within the blood fluid 'boundary layer' adjacent to the vessel wall. This approach is expected to be highly efficient for administration of antithrombotic and antiproliferative agents that target processes leading to vascular occlusion, heart attacks, and strokes. METHODS: The helical catheter was qualitatively evaluated using optical dye density measurements of Evans blue dye infused using an in vitro steady flow system under a physiologic range of conditions. To further demonstrate the efficiency of the technique, its capacity to inhibit thrombosis was evaluated in a baboon thrombosis model. The catheter was inserted into a femoral arteriovenous shunt (blood flow rate = 100 ml/min) and placed proximal to a segment of highly thrombogenic Dacron vascular graft (4.0 mm i.d.). Integrelin (an inhibitor of platelet glycoprotein IIb/IIIa; doses: 0.25-1.0 microg/min) and hirudin (an antithrombin; doses: 10-100 microg/min) were used to inhibit thrombus formation. RESULTS: Experimental flow visualization studies demonstrated that high concentrations of the infused Evans blue dye were retained near the vessel wall. In the animal experiments, platelet deposition on the Dacron graft surface was reduced by 82-97% (Integrelin) and 68-92% (hirudin) over 1-2 h of blood exposure. The local antithrombotic effects produced were found to be 200-fold and 30-fold more efficient than systemic administration of the same agents. CONCLUSIONS: Local drug infusion using the helical catheter approach can achieve high drug concentration levels at target sites, may avoid systemic effects, and can reduce cost of therapy by reducing total drug requirements.

A novel method for efficient drug delivery.

Local delivery of anti-thrombotic and anti-restenotic drugs is desired to achieve high concentrations of agents which may be rapidly degraded systemically or which exhibit very short half-lives in vivo. In this article, the operating characteristics of a novel local drug delivery method are described and its effectiveness demonstrated computationally and experimentally. Computational models used a finite volume method to determine the concentration field. Optical dye density measurements of Evans blue in saline were performed in an in vitro steady flow system. Modeling parameters were kept in the physiologic range. Experimental flow visualization studies demonstrated high concentrations of infusate near the vessel wall. Computational studies predicted high, clinically significant drug concentrations along the wall downstream of the infusion device. When the radial infusion velocity is large (infusion flow rate, Qinf>0.5% of the main flow rate, Q), the wall concentration of the infused drug remains high, e.g., levels are greater than 80% of the infusate concentration 5 cm downstream of the infusion device. At lower infusion rates (Qinf<0.001Q), the drug concentration at the wall decreases exponentially with axial distance to less than 25% of the infusate concentration 5 cm downstream of the infusion device, although therapeutic drug levels are still readily maintained. The near wall drug concentration is a function of flow conditions, infusion rate, and the drug diffusivity. Good agreement was obtained between computational and experimental concentration measurements. Flow simulation and experimental results indicate that the technique can effectively sustain high local drug concentrations for inhibition of thrombosis and vascular lesion formation.

Improved measurement of pressure gradients in aortic coarctation by magnetic resonance imaging.

OBJECTIVES: This study evaluated whether magnetic resonance imaging (MRI) and magnetic resonance (MR) phase velocity mapping could provide accurate estimates of stenosis severity and pressure gradients in aortic coarctation. BACKGROUND: Clinical management of aortic coarctation requires determination of lesion location and severity and quantification of the pressure gradient across the constricted area. METHODS: Using a series of anatomically accurate models of aortic coarctation, the laboratory portion of this study found that the loss coefficient (K), commonly taken to be 4.0 in the simplified Bernoulli equation delta P = KV2, was a function of stenosis severity. The values of the loss coefficient ranged from 2.8 for a 50% stenosis to 4.9 for a 90% stenosis. Magnetic resonance imaging and MR phase velocity mapping were then used to determine coarctation severity and pressure gradient in 32 patients. RESULTS: Application of the new severity-dependent loss coefficients found that pressure gradients deviated from 1 to 17 mm Hg compared with calculations made with the commonly used value of 4.0. Comparison of MR estimates of pressure gradient with Doppler ultrasound estimates (in 22 of 32 patients) and with catheter pressure measurements (in 6 of 32 patients) supports the conclusion that the severity-based loss coefficient provides improved estimates of pressure gradients. CONCLUSIONS: This study suggests that MRI could be used as a complete diagnostic tool for accurate evaluation of aortic coarctation, by determining stenosis location and severity and by accurately estimating pressure gradients.

A scaling law for wall shear rate through an arterial stenosis.

Atherosclerosis of the human arterial system produces major clinical symptoms when the plaque advances to create a high-grade stenosis. The hemodynamic shear rates produced in high-grade stenoses are important in the understanding of atheromatous plaque rupture and thrombosis. This study was designed to quantify the physiologic stress levels experienced by endothelial cells and platelets in the region of vascular stenoses. The steady hemodynamic flow field was solved for stenoses with percent area reductions of 50, 75, and 90 percent over a range of physiologic Reynolds numbers (100-400). The maximum wall shear rate in the throat region can be shown to vary by the square root of the Reynolds number. The shear rate results can be generalized to apply to a range of stenosis lengths and flow rates. Using dimensions typical for a human carotid or coronary artery, wall shear rates were found to vary from a maximum of 20,000 s-1 upstream of the throat to a minimum of -630 s-1 in the recirculation zone for a 90 percent stenosis. An example is given which illustrates how these values can be used to understand the relationship between hemodynamic shear and platelet deposition.

Accuracy of velocity and shear rate measurements using pulsed Doppler ultrasound: a comparison of signal analysis techniques.

An experimental investigation was instituted to evaluate the performance of Doppler ultrasound signal processing techniques for measuring fluid velocity under well-defined flow conditions using a 10-MHz multigated pulsed ultrasound instrument. Conditions of fully developed flow in a rigid, circular tube were varied over a Reynolds number range between 500 and 8000. The velocity across the tube was determined using analog and digital zero crossing detectors and three digital spectrum estimators. Determination of the Doppler frequency from analog or digital zero crossing detectors gave accurate velocity values for laminar and moderately turbulent flow away from the wall (0.969 less than or equal to r less than or equal to 0.986). Three digital spectrum estimators, Fast Fourier Transform, Burg autoregressive method, and minimum variance method, were slightly more accurate than the zero crossing detector (0.984 less than or equal to r less than or equal to 0.994), especially at points close to the walls and with higher levels of turbulence. Steep velocity gradients and transit-time-effects from high velocities produced significantly larger errors in velocity measurement. Wall shear rate estimates were most precise when calculated using the position of the wall and two velocity points. The calculated wall shears were within 20%-30% of theoretically predicted values.

Evaluation of magnetic resonance velocimetry for steady flow.

Whole body magnetic resonance (MR) imaging has recently become an important diagnostic tool for cardiovascular diseases. The technique of magnetic resonance phase velocity encoding allows the quantitative measurement of velocity for an arbitrary component direction. A study was initiated to determine the ability and accuracy of MR velocimetry to measure a wide range of flow conditions including flow separation, three-dimensional secondary flow, high velocity gradients, and turbulence. A steady flow system pumped water doped with manganese chloride through a variety of test sections. Images were produced using gradient echo sequences on test sections including a straight tube, a curved tube, a smoothly converging-diverging nozzle, and an orifice. Magnetic resonance measurements of laminar and turbulent flows were depicted as cross-sectional velocity profiles. MR velocity measurements revealed such flow behavior as spatially varying velocity, recirculation and secondary flows over a wide range of conditions. Comparisons made with published experimental laser Doppler anemometry measurements and theoretical calculations for similar flow conditions revealed excellent accuracy and precision levels. The successful measurement of velocity profiles for a variety of flow conditions and geometries indicate that magnetic resonance imaging is an accurate, non-contacting velocimeter.