Simulation of the effect of hemolysis on thrombosis in blood-contacting medical devices.

Heart failure, broadly characterized by the gradual decline of the ability of the heart to maintain adequate blood flow throughout the body's vascular network of veins and arteries, is one of the leading causes of death worldwide. Mechanical Circulatory Support is one of the few available alternative interventions for late-stage heart failure with reduced ejection fraction. A ventricular assist device is surgically implanted and connected to the left and or right heart ventricles to provide additional bloodflow, off-loading the work required by the heart to maintain circulation. Modern mechanical circulatory support devices generate non-physiological flow conditions that can lead to the damage and rupture of blood cells (hemolysis), and the formation of blood clots (thrombosis), which pose severe health risks to the patient. It is essential to improve prediction tools for blood damage to reduce the risk of hemolysis and thrombosis. A simulation-based approach examines the interaction between hemolysis and thrombosis. Incompressible finite-volume computational fluid dynamics simulations are executed on an open-hub axial flow ventricular assist device. A continuum model of thrombosis and the intrinsic coagulation process is extended to include the effect of hemolysis. The model accounts for the effect of activation of platelets by shear stress, paracrine signaling, adhesion, and hemoglobin and ADP released during hemolysis. The effect of hemolysis with thrombosis is modelled by accounting for the hyper-adhesivity of von-Willebrand Factor on extracellular hemoglobin, and the increased rate of platelet activation induced by ADP release. Thrombosis is assessed at varying inflow rates and rotor speeds, and cases are executed where thrombosis is affected by ADP release and Hb-induced hyper-adhesivity. It is found that there is a non-negligible effect from hemolysis on thrombosis across a range of rotor speeds, and that hyperadhesivity plays a dominant role in thrombus formation in the presence of hemolysis.

Deformable mock stenotic artery with a lipid pool.

The comparison, evaluation, and optimization of new techniques, models, or algorithms often require the use of realistic deformable test phantoms. The purpose of this paper is to present a multilayer deformable test specimen mimicking an atherosclerotic coronary artery, suitable for mechanical testing and intravascular imaging. Mock arteries were constructed in three phases using two molds: building a first layer of polyvinyl alcohol (PVA) cryogel, adding a lipid pool and building a second layer of PVA cryogel. To illustrate the deformation of the mock arteries, one has been placed in a custom-made bath, axially stretched then inflated while acquiring intravascular ultrasound (IVUS) images. The resulting specimen presents a progressing lumen narrowing of 25% in cross-sectional area at the peak and a lipid pool. The average inner gel layer is about 0.4 mm thick and the outer about 0.6 mm. The dimensions are of the same order as clinical observations, the first gel layer mimicking the intima-media and the second layer the adventitia. In the sequence of IVUS images, the different components of the mock artery are visible and differentiable. The variation in diameter of the segmented contours is presented for a specific specimen subjected to intraluminal pressure. This double-layer stenotic mock artery is approximately the size of a human coronary artery, has a lipid inclusion, can withstand relative large deformation, suitable for (intravascular) ultrasound imaging, and has customizable geometry and wall material parameters.

3D flow study in a mildly stenotic coronary artery phantom using a whole volume PIV method.

Blood flow dynamics has an important role in atherosclerosis initiation, progression, plaque rupture and thrombosis eventually causing myocardial infarction. In particular, shear stress is involved in platelet activation, endothelium function and secondary flows have been proposed as possible variables in plaque erosion. In order to investigate these three-dimensional flow characteristics in the context of a mild stenotic coronary artery, a whole volume PIV method has been developed and applied to a scaled-up transparent phantom. Experimental three-dimensional velocity data was processed to estimate the 3D shear stress distributions and secondary flows within the flow volume. The results show that shear stress reaches values out of the normal and atheroprotective range at an early stage of the obstructive pathology and that important secondary flows are also initiated at an early stage of the disease. The results also support the concept of a vena contracta associated with the jet in the context of a coronary artery stenosis with the consequence of higher shear stresses in the post-stenotic region in the blood domain than at the vascular wall.

The influence of composition and location on the toughness of human atherosclerotic femoral plaque tissue.

The toughness of femoral atherosclerotic tissue is of pivotal importance to understanding the mechanism of luminal expansion during cutting balloon angioplasty (CBA) in the peripheral vessels. Furthermore, the ability to relate this parameter to plaque composition, pathological inclusions and location within the femoral vessels would allow for the improvement of existing CBA technology and for the stratification of patient treatment based on the predicted fracture response of the plaque tissue to CBA. Such information may lead to a reduction in clinically observed complications, an improvement in trial results and an increased adoption of the CBA technique to reduce vessel trauma and further endovascular treatment uptake. This study characterises the toughness of atherosclerotic plaque extracted from the femoral arteries of ten patients using a lubricated guillotine cutting test to determine the critical energy release rate. This information is related to the location that the plaque section was removed from within the femoral vessels and the composition of the plaque tissue, determined using Fourier Transform InfraRed spectroscopy, to establish the influence of location and composition on the toughness of the plaque tissue. Scanning electron microscopy (SEM) is employed to examine the fracture surfaces of the sections to determine the contribution of tissue morphology to toughness. Toughness results exhibit large inter and intra patient and location variance with values ranging far above and below the toughness of healthy porcine arterial tissue (Range: 1330-3035 for location and 140-4560J/m(2) for patients). No significant difference in mean toughness is observed between patients or location. However, the composition parameter representing the calcified tissue content of the plaque correlates significantly with sample toughness (r=0.949, p<0.001). SEM reveals the presence of large calcified regions in the toughest sections that are absent from the least tough sections. Regression analysis highlights the potential of employing the calcified tissue content of the plaque as a preoperative tool for predicting the fracture response of a target lesion to CBA (R(2)=0.885, p<0.001). STATEMENT OF SIGNIFICANCE: This study addresses a gap in current knowledge regarding the influence of plaque location, composition and morphology on the toughness of human femoral plaque tissue. Such information is of great importance to the continued improvement of endovascular treatments, particularly cutting balloon angioplasty (CBA), which require experimentally derived data as a framework for assessing clinical cases and advancing medical devices. This study identifies that femoral plaque tissue exhibits large inter and intra patient and location variance regarding tissue toughness. Increasing calcified plaque content is demonstrated to correlate significantly with increasing toughness. This highlights the potential for predicting target lesion toughness which may lead to an increased adoption of the CBA technique and also further the uptake of endovascular treatment.

Simultaneous determination of aortic valve area by the Gorlin formula and by transesophageal echocardiography under different transvalvular flow conditions. Evidence that anatomic aortic valve area does not change with variations in flow in aortic stenosis.

OBJECTIVES: The purpose of this study was to determine the impact of changes in flow on aortic valve area (AVA) as measured by the Gorlin formula and transesophageal echocardiographic (TEE) planimetry. BACKGROUND: The meaning of flow-related changes in AVA calculations using the Gorlin formula in patients with aortic stenosis remains controversial. It has been suggested that flow dependence of the calculated area could be due to a true widening of the orifice as flow increases or to a disproportionate flow dependence of the formula itself. Alternatively, anatomic AVA can be measured by direct planimetry of the valve orifice with TEE. METHODS: Simultaneous measurement of the planimetered and Gorlin valve area was performed intraoperatively under different hemodynamic conditions in 11 patients. Left ventricular and ascending aortic pressures were measured simultaneously after transventricular and aortic punctures. Changes in flow were induced by dobutamine infusion. Using multiplane TEE, AVA was planimetered at the level of the leaflet tips in the short-axis view. RESULTS: Overall, cardiac output, stroke volume and transvalvular volume flow rate ranged from 2.5 to 7.3 liters/min, from 43 to 86 ml and from 102 to 306 ml/min, respectively. During dobutamine infusion, cardiac-output increased by 42% and mean aortic valve gradient by 54%. When minimal flow was compared with maximal flow, the Gorlin area varied from (mean +/- SD) 0.44 +/- 0.12 to 0.60 +/- 0.14 cm2 (p < 0.005). The mean change in Gorlin area under different flow rates was 36 +/- 32%. Despite these changes, there was no significant change in the planimetered area when minimal flow was compared with maximal flow. The mean difference in planimetered area under different flow rates was 0.002 +/- 0.01 cm2 (p = 0.86). CONCLUSIONS: By simultaneous determination of Gorlin formula and TEE planimetry valve areas, we showed that acute changes in transvalvular volume flow substantially altered valve area calculated by the Gorlin formula but did not result in significant alterations of the anatomic valve area in aortic stenosis. These results suggest that the flow-related variation in the Gorlin AVA is due to a disproportionate flow dependence of the formula itself and not a true change in valve area.

Biocompatibility aspects of new stent technology.

Stent implantation represents a major step forward since the introduction of coronary angioplasty. As indications continue to expand, better understanding of the early and late biocompatibility issues appears critical. Persisting challenges to the use of intracoronary stents include the prevention of early thrombus formation and late neointima development. Different metals and designs have been evaluated in animal models and subsequently in patients. Polymer coatings have been proposed to improve the biocompatibility of metallic stents or to serve as matrix for drug delivery and they are currently undergoing clinical studies. The promises of a biodegradable stent have not yet been fulfilled although encouraging results have recently been reported. Continuous low dose-rate brachytherapy combining the scaffolding effect of the stent with localized radiation therapy has witnessed the development and early clinical testing of radioactive stents. The combined efforts of basic scientists and clinicians will undoubtedly contribute to the improvement of stent biocompatibility in the future.

In vitro response of human and porcine vascular cells exposed to high dose-rate gamma-irradiation.

AIM: The objective of this study was to compare the in vitro response of human and pig endothelial cells, smooth muscle cells and fibroblasts exposed to conventional high dose-rate gamma-irradiation. MATERIALS AND METHODS: Clonogenic cell survival and growth responses were obtained after irradiation of plateau-phase cells with a 60Co source at a dose-rate of 1.5 Gy/min. DNA single-strand breaks were also evaluated using an alkaline filter elution technique. RESULTS: Overall, both the pig and human cell lines showed a similar response to conventional high dose-rate irradiation. Using clonogenic assays, the human aortic smooth muscle cell line was more sensitive than the fibroblast and endothelial cell lines, whereas the pig endothelial cell line was more sensitive than smooth muscle cells and fibroblasts. Shortly after irradiation (10 days) there was a temporary growth arrest, which was similar for endothelial, smooth muscle cells and fibroblasts with doses above 6 Gy. There was also a non-linear, dose-dependent growth delay up to 4 weeks after irradiation. This effect was also consistent between the different cell lines. Using alkaline filter elution, there was no significant difference in relative elution between endothelial cells, smooth muscle cells and fibroblasts, indicating similar DNA damage among the different cell lines. CONCLUSION: The in vitro response of human and pig endothelial cells, smooth muscle cells and fibroblasts exposed to high dose-rate irradiation appeared similar. The pig model seems well suited to evaluate the short- and long-term effects of ionizing radiation in the prevention of restenosis after vessel injury.

Study of catheter designs and drug mixing processes using 2D steady numerical simulations.

The effectiveness of substance delivery through catheters is an important issue in interventional radiology, especially for infusion therapies where the pharmacokinetic advantage of local intra-arterial drug administration has been firmly established. In principle, the procedure is used to provide appropriate local concentrations while maintaining low systemic values so as to minimise the global effect and toxicity of the intervention. However, poor drug mixing may produce excessive local concentrations potentially damaging for the surrounding tissues and may lead to unsuccessful therapies. These phenomena have been observed in the infusion therapies of liver cancers through the hepatic artery and with brain tumour therapies through the carotid artery. Many aspects of the drug delivery methodology have been explored in order to determine the infusion conditions that would provide optimal mixing: the catheter tip design is considered one of the most important characteristics to be investigated for this purpose. Interestingly, it turns out that angiographic procedures could also benefit from this, because better mixing properties are associated with designs that provide potentially less harmful flow conditions such as jets, whipping and recoil of the catheter on the vascular wall. A 2D steady numerical model is proposed, to simulate the main physical processes occurring during catheter substance infusion: blood dynamics is taken into account with the Navier-Stokes equations and substance dispersion by the flowing blood with the advection-diffusion equation. The model is used to evaluate mixing properties of certain catheter designs in different flow conditions. In particular, two types of side hole catheter are compared in the context of water bath injection and in the context of vessel injection. The simulations suggest that the improved mixing reported with water bath experiments would not be maintained in the clinical context of arterial circulation.

Large-displacement 3D structural analysis of an aortic valve model with nonlinear material properties.

Grafts used in aortic valve-sparing procedures should ideally not only reproduce the geometry of the natural aortic root but also its material properties. Indeed, a number of studies using the finite element method have shown the importance of the natural sinus shape of the root in the functioning of the normal aortic valve, and the relative increase in stresses due to the replacement of the valve by a stiffer synthetic graft. Because of the wide range in experimentally measured values of aortic wall and leaflet material properties, studies by different research groups have incorporated very different material properties in their models. The aim of the present study was to investigate the influence of material properties on aortic wall displacements, and to determine which material properties would most closely match reported experimental data. Two geometrically accurate 3D models corresponding to the closed and open valve configurations were created in Pro/Engineer CAD software. Loads corresponding to systolic and diastolic pressures were specified and large-displacement structural analyses were carried out using the ANSYS package. Results have indicated that the closest match to experiments using isotropic material properties occurred for a Young's modulus of about 2000 KPa. Nonlinear models based on experimental stress-strain curves have shown similar displacements, but altered strain distribution patterns and significantly lower stresses. These results suggest that an accurate comparison of potential new graft models would have to be made with natural aortic valve models incorporating nonlinear material behavior.

[Use of ionizing radiation to prevent restenosis in interventional cardiology]. / Utilisation des radiations ionisantes pour la prévention de la resténose en cardiologie interventionnelle.

Recently, the use of ionizing radiations has received much interest as a new treatment tool to reduce restenosis after angioplasty or stent implantation. There are two main approaches for delivering endovascular radiation: one is based on gamma or beta sources with very high activities to deliver locally through a catheter the dose in a limited period of time. The other approach is based on a stent rendered radioactive for long exposure and continuous low-dose rate treatment. External radiation is also contemplated but indications seem more oriented towards the peripheral vascular system. After a brief introduction to fundamentals of radiobiology, radiation physics and radioprotection, we review the experimental data which have led to large ongoing multicenter trials. The results of these trials involving more than 2000 patients will be available in the next few years and will allow to better define the risk/benefit ratio of this potentially new indication for radiotherapy.

The effect of aortic wall and aortic leaflet stiffening on coronary hemodynamic: a fluid-structure interaction study.

Pathologies of the aortic valve such as aortic sclerosis are thought to impact coronary blood flow. Recent clinical investigations have observed simultaneous structural and hemodynamic variations in the aortic valve and coronary arteries due to regional pathologies of the aortic valve. The goal of the present study is to elucidate this observed and yet unexplained phenomenon, in which a local pathology in the aortic valve region could potentially lead to the initiation or progression of coronary artery disease. Results revealed a considerable impact on the coronary flow, velocity profile, and consequently shear stress due to an increase in the aortic wall or aortic leaflet stiffness and thickness which concur with clinical observations. The cutoff value of 0.75 for fractional flow reserve was reached when the values of leaflet thickness and aortic wall stiffness were approximately twice and three times their normal value, respectively. Variations observed in coronary velocity profiles as well as wall shear stress suggest a possible link for the initiation of coronary artery disease.

Improvement of aortic valve stenosis by ApoA-I mimetic therapy is associated with decreased aortic root and valve remodelling in mice.

BACKGROUND AND PURPOSE: We have shown that infusions of apolipoprotein A-I (ApoA-I) mimetic peptide induced regression of aortic valve stenosis (AVS) in rabbits. This study aimed at determining the effects of ApoA-I mimetic therapy in mice with calcific or fibrotic AVS. EXPERIMENTAL APPROACH: Apolipoprotein E-deficient (ApoE(-/-) ) mice and mice with Werner progeria gene deletion (Wrn(Δhel/Δhel) ) received high-fat diets for 20 weeks. After developing AVS, mice were randomized to receive saline (placebo group) or ApoA-I mimetic peptide infusions (ApoA-I treated groups, 100 mg·kg(-1) for ApoE(-/-) mice; 50 mg·kg(-1) for Wrn mice), three times per week for 4 weeks. We evaluated effects on AVS using serial echocardiograms and valve histology. KEY RESULTS: Aortic valve area (AVA) increased in both ApoE(-/-) and Wrn mice treated with the ApoA-I mimetic compared with placebo. Maximal sinus wall thickness was lower in ApoA-I treated ApoE(-/-) mice. The type I/III collagen ratio was lower in the sinus wall of ApoA-I treated ApoE(-/-) mice compared with placebo. Total collagen content was reduced in aortic valves of ApoA-I treated Wrn mice. Our 3D computer model and numerical simulations confirmed that the reduction in aortic root wall thickness resulted in improved AVA. CONCLUSIONS AND IMPLICATIONS: ApoA-I mimetic treatment reduced AVS by decreasing remodelling and fibrosis of the aortic root and valve in mice.

Therapeutic vascular compliance change may cause significant variation in coronary perfusion: a numerical study.

In some pathological conditions like aortic stiffening and calcific aortic stenosis (CAS), the microstructure of the aortic root and the aortic valve leaflets are altered in response to stress resulting in changes in tissue thickness, stiffness, or both. This aortic stiffening and CAS are thought to affect coronary blood flow. The goal of the present paper was to include the flow in the coronary ostia in the previous fluid structure interaction model we have developed and to analyze the effect of diseased tissues (aortic root stiffening and CAS) on coronary perfusion. Results revealed a significant impact on the coronary perfusion due to a moderate increase in the aortic wall stiffness and CAS (increase of the aortic valve leaflets thickness). A marked drop of coronary peak velocity occurred when the values of leaflet thickness and aortic wall stiffness were above a certain threshold, corresponding to a threefold of their normal value. Consequently, mild and prophylactic treatments such as smoking cessation, exercise, or diet, which have been proven to increase the aortic compliance, may significantly improve the coronary perfusion.

A three-layer model for buckling of a human aortic segment under specific flow-pressure conditions.

Human aortas are subjected to large mechanical stresses because of blood flow pressurization and through contact with the surrounding tissue. It is essential that the aorta does not lose stability by buckling with deformation of the cross-section (shell-like buckling) (i) for its proper functioning to ensure blood flow and (ii) to avoid high stresses in the aortic wall. A numerical bifurcation analysis employs a refined reduced-order model to investigate the stability of a straight aorta segment conveying blood flow. The structural model assumes a nonlinear cylindrical orthotropic laminated composite shell composed of three layers representing the tunica intima, media and adventitia. Residual stresses because of pressurization are evaluated and included in the model. The fluid is formulated using a hybrid model that contains the unsteady effects obtained from linear potential flow theory and the steady viscous effects obtained from the time-averaged Navier-Stokes equations. The aortic segment loses stability by divergence with deformation of the cross-section at a critical flow velocity for a given static pressure, exhibiting a strong subcritical behaviour with partial or total collapse of the inner wall. Preliminary results suggest directions for further study in relation to the appearance and growth of dissection in the aorta.

Polyvinyl alcohol cryogel: optimizing the parameters of cryogenic treatment using hyperelastic models.

The PVA gels obtained by freezing/thawing cycles of PVA solutions, also called cryogels, exhibit non-linear elastic behavior and can mimic, within certain limits, the behavior of biological soft tissues such as arterial tissue. Several authors have investigated the effects of cryogenic processing parameters on the Young's modulus. However, an elastic modulus does not describe the non-linearity of the cryogel's stress-strain response. This study examines the non-linear elastic response of PVA cryogel under uniaxial tension and investigates how processing parameters such as the concentration, the number of thermal cycles, and the thawing rate affect this response. The relationship between the coefficients of the material model and the processing parameters was interpolated to find the set of parameters that would best approximate the elastic response of healthy porcine coronary arteries under uniaxial tension.

Effects of low-dose-rate beta-irradiation on vascular smooth muscle cells: comparison with high-dose-rate exposure.

PURPOSE: Radiation therapy is undergoing extensive preclinical and clinical testing as a new tool to reduce restenosis after vessel injury. To date, however, no definite dose threshold has been identified after radioactive stent implantation. In this study, we compared the in vitro response of pig vascular smooth muscle cells (SMC) to conventional high-dose-rate (HDR) irradiation with the response to continuous low-dose rate (LDR) that could result from exposure to a radioactive stent. MATERIALS AND METHODS: Catheter-based radiotherapy delivers single doses at HDR whereas radioactive stents use a continuous LDR approach. Single doses in excess of 10 Gy have clearly shown a reduction in neointima formation and negative vessel remodeling in several animal models. Because dose rate is an important parameter modulating the overall biological response to ionizing radiation, we have compared the in vitro response of pig aortic SMC at conventional HDR (1.5 Gy/min) and at LDR (0.675 Gy/h). RESULTS: SMC showed significant repair of sublethal DNA damage and about twice the dose was necessary at the LDR to produce the same effect as that seen at the HDR. CONCLUSION: In vitro SMC exhibit a significant dose-rate effect that indicates that radioactive stents could deliver the dose at a sufficiently high dose rate to compensate for cell proliferation while at the same time the total dose should be increased to account for sublethal damage repair. This finding has important implications for the design of a radioactive stent.

A novel realistic three-layer phantom for intravascular ultrasound imaging.

Intravascular ultrasound (IVUS) is an imaging modality that experienced a tremendous development over the last 20 years. Phantoms for IVUS are rare and poorly documented. The aim of this paper is to propose an original IVUS phantom that has geometries and specular textures closer to those of coronary arteries than conventional tube-like phantoms. The proposed phantom has a three-layer aspect, reproducing the intima, media and adventitia that compose the arterial wall. It is made of an agar-based compound, with water, glycerol and cellulose particles. Fourteen phantoms were quantified using IVUS. Six phantoms were evaluated by both photomacroscopy and IVUS. There was an excellent correlation between phantom dimensions evaluated by photomacroscopy and the nominal values (mold dimensions). The IVUS quantification of the phantom was closely correlated to the measurements obtained by photomacroscopy. These results demonstrate that a multilayer phantom, with known and reproducible dimensions and with realistic geometric and echographic properties has been developed.

A method for matching the refractive index and kinematic viscosity of a blood analog for flow visualization in hydraulic cardiovascular models.

In this work, we propose a simple method to simultaneously match the refractive index and kinematic viscosity of a circulating blood analog in hydraulic models for optical flow measurement techniques (PIV, PMFV, LDA, and LIF). The method is based on the determination of the volumetric proportions and temperature at which two transparent miscible liquids should be mixed to reproduce the targeted fluid characteristics. The temperature dependence models are a linear relation for the refractive index and an Arrhenius relation for the dynamic viscosity of each liquid. Then the dynamic viscosity of the mixture is represented with a Grunberg-Nissan model of type 1. Experimental tests for acrylic and blood viscosity were found to be in very good agreement with the targeted values (measured refractive index of 1.486 and kinematic viscosity of 3.454 milli-m2/s with targeted values of 1.47 and 3.300 milli-m2/s).

Reliability of mechanical and phased-array designs for serial intravascular ultrasound examinations--animal and clinical studies in stented and non-stented coronary arteries.

BACKGROUND: Both mechanical and multi-element intravascular ultrasound designs have potential advantages and limitations that may impact on their value for clinical and research purposes. Determination of the reproducibility of measurements is critical before a given system can be used in studies such as regression of atherosclerosis trials. METHODS: We performed serial intravascular ultrasound imaging with catheters using mechanical and phased-array designs in stented and non-stented coronary arteries in dogs and in patients. RESULTS: Both systems correlated well for areas (r > or = 0.90, p < 0.0001) and diameters (r > or = 0.84. p < 0.0001) in dogs and in patients. There was a slight difference between multi-element and mechanical designs for measurements of area (mean difference in dogs and in patients: -0.24 and 0.96 mm2, p < 0.055) and diameter (-0.08 and 0.16 mm, p < 0.0001). The reproducibility of the multi-element system for reanalysis of the same frames and for analysis of serial pullbacks was similar to the same measurements with the mechanical system (r > or = 0.96 for all measurements). The differences in absolute and relative variability between the mechanical and phased-array designs, both for reanalysis of same frames and serial pullbacks, were very small. CONCLUSIONS: Although multi-element and mechanical intravascular ultrasound designs are not strictly interchangeable, their similar reproducibility and the small differences in measurements demonstrate that both designs are acceptable alternatives for trials of regression of atherosclerosis. Determination of the variability for serial pullbacks of both designs was also important to assess the statistical power of such trials.

Development of coronary aneurysm after cutting balloon angioplasty: assessment by intracoronary ultrasound.

We report the case of a coronary aneurysm observed 6 mo after cutting balloon angioplasty complicated by a mild perforation. Intravascular ultrasound allowed characterization of the malformation as a true aneurysm. The clinical course was uneventful.