Device Thrombogenicity Emulator (DTE) − Design optimization methodology for cardiovascular devices: A study in two bileaflet MHV designs

Patients who receive prosthetic heart valve (PHV) implants require mandatory anticoagulation medication after implantation due to the thrombogenic potential of the valve. Optimization of PHV designs may facilitate reduction of flow-induced thrombogenicity and reduce or eliminate the need for post-implant anticoagulants. We present a methodology entitled Device Thrombogenicty Emulator (DTE) for optimizing the thrombo-resistance performance of PHV by combining numerical and experimental approaches. Two bileaflet mechanical heart valves (MHV) designs, St. Jude Medical (SJM) and ATS, were investigated by studying the effect of distinct flow phases on platelet activation. Transient turbulent and direct numerical simulations (DNS) were conducted, and stress loading histories experienced by the platelets were calculated along flow trajectories. The numerical simulations indicated distinct design dependent differences between the two valves. The stress loading waveforms extracted from the numerical simulations were programmed into a hemodynamic shearing device (HSD), emulating the flow conditions past the valves in distinct ‘hot-spot’ flow regions that are implicated in MHV thrombogenicity. The resultant platelet activity was measured with a modified prothrombinase assay, and was found to be significantly higher in the SJM valve, mostly during the regurgitation phase. The experimental results were in excellent agreement with the calculated platelet activation potential. This establishes the utility of the DTE methodology for serving as a test bed for evaluating design modifications for achieving better thrombogenic performance for such devices.     

Platelet activation of mechanical versus bioprosthetic heart valves during systole

Thrombus formation is a major concern for recipients of mechanical heart valves (MHVs), which requires them to take anticoagulant drugs for the rest of their lives. Bioprosthetic heart valves (BHVs) do not require life-long anticoagulant therapy but deteriorate after 10–15 years. The thrombus formation is initiated by the platelet activation which is thought to be mainly generated in MHVs by the flow through the hinge and the leakage flow during the diastole. However, our results show that the activation in the bulk flow during the systole phase might play an essential role as well. This is based on our results obtained by comparing the thrombogenic performance of a MHV and a BHV (as control) in terms of shear induced platelet activation under exactly the same conditions. Three different mathematical activation models including linear level of activation, damage accumulation, and Soares model are tested to quantify the platelet activation during systole using the previous simulations of the flow through MHV and BHV in a straight aorta under the same physiologic flow conditions. Results indicate that the platelet activation in the MHV at the beginning of the systole phase is slightly less than the BHV. However, at the end of the systole phase the platelet activation by the bulk flow for the MHV is several folds (1.41, 5.12, and 2.81 for linear level of activation, damage accumulation, and Soares model, respectively) higher than the BHV for all tested platelet activation models.     

A novel mathematical model of activation and sensitization of platelets subjected to dynamic stress histories

Blood recirculating devices, such as ventricular assist devices and prosthetic heart valves, are burdened by thromboembolic complications requiring complex and lifelong anticoagulant therapy with its inherent hemorrhagic risks. Pathologic flow patterns occurring in such devices chronically activate platelets, and the optimization of their thrombogenic performance requires the development of flow-induced platelet activation models. However, existing models are based on empirical correlations using the well-established power law paradigm of constant levels of shear stress during certain exposure times as factors for mechanical platelet activation. These models are limited by their range of application and do not account for other relevant phenomena, such as loading rate dependence and platelet sensitization to high stress conditions, which characterize the dynamic flow conditions in devices. These limitations were addressed by developing a new class of phenomenological stress-induced platelet activation models that specifies the rate of platelet activation as a function of the entire stress history and results in a differential equation that can be directly integrated to calculate the cumulative levels of activation. The proposed model reverts to the power law under constant shear stress conditions and is able to describe experimental results in response to a diverse range of highly dynamic stress conditions found in blood recirculating devices. The model was tested in vitro under emulated device flow conditions and correlates well with experimental results. This new model provides a reliable and robust mathematical tool that can be incorporated into computational fluid dynamic studies in order to optimize design, with the goal of improving the thrombogenic performance of blood recirculating devices.     

Velocity and turbulence measurements past mitral valve prostheses in a model left ventricle

Thrombogenesis and hemolysis have both been linked to the flow dynamics past heart valve prostheses. To learn more about the particular flow dynamics past mitral valve prostheses in the left ventricle under controlled experimental conditions, an in vitro study was performed. The experimental methods included velocity and turbulent shear stress measurements past caged-ball, tilting disc, bileaflet, and polyurethane trileaflet mitral valves in an acrylic rigid model of the left ventricle using laser Doppler anemometry. The results indicate that all four prosthetic heart valves studied create at least mildly disturbed flow fields. The effect of the left ventricular geometry on the flow development is to produce a stabilizing vortex which engulfs the entire left ventricular cavity, depending on the orientation of the valve. The measured turbulent shear stress magnitudes for all four valves did not exceed the reported value for hemolytic damage. However, the measured turbulent shear stresses were near or exceeded the critical shear stress reported in the literature for platelet lysis, a known precursor to thrombus formation.     

A numerical analysis of the backflow between the leaflets of a St Jude Medical cardiac valve prosthesis

Clinically significant, unexplained hemolysis has been reported to occur in St Jude Medical (SJM) cardiac valve prostheses. The leakage phase of backflow is identified as having the most hemolytic potential, when compared with the other phases of the cardiac cycle. A two-dimensional, laminar, constant fluid property finite element analysis (FEA) is used to calculate the peak shear stress obtained in the flow through the narrow slit formed by the closed leaflets of an idealized size 29 mm (tissue annulus diameter) SJM cardiac valve prosthesis, during the leakage phase of backflow. The flow geometry was such that the simple laminar flow theory (SLFT) could be used to model the flow through the region of peak shear stresses with reasonable accuracy. The SLFT predicts that the maximum shear stress depends upon the thickness of the clearance space and the average velocity through that space. These results suggest that the magnitude of the peak shear stress is of the order of 700-1000 Pa for a duration of the order of 0.5-0.4 ms for pressure drops across the valve of 150-300 torr. This suggests that hemolysis is possible for certain unfortunate combinations of clearances and pressure conditions. However, further research is needed before this flow phenomenon can be associated with the reported clinical hemolysis.     

Two-component laser velocimeter measurements downstream of heart valve prostheses in pulsatile flow

Elevated turbulent shear stresses resulting from disturbed blood flow through prosthetic heart valves can cause damage to red blood cells and platelets. The purpose of this study was to measure the turbulent shear stresses occurring downstream of aortic prosthetic valves during in-vitro pulsatile flow. By matching the indices of refraction of the blood analog fluid and model aorta, correlated, simultaneous two-component laser velocimeter measurements of the axial and radial velocity components were made immediately downstream of two aortic prosthetic valves. Velocity data were ensemble averaged over 200 or more cycles for a 15-ms window opened at peak systolic flow. The systolic duration for cardiac flows of 8.4 L/min was 200 ms. Ensemble-averaged total shear stress levels of 2820 dynes/cm2 and 2070 dynes/cm2 were found downstream of a trileaflet valve and a tilting disk valve, respectively. These shear stress levels decreased with axial distance downstream much faster for the tilting disk valve than for the trileaflet valve.     

Computational simulations of flow dynamics and blood damage through a bileaflet mechanical heart valve scaled to pediatric size and flow

Despite pressing needs, there are currently no FDA approved prosthetic valves available for use in the pediatric population. This study is performed for predictive assessment of blood damage in bileaflet mechanical heart valves (BMHVs) with pediatric sizing and flow conditions. A model of an adult-sized 23 mm St. Jude Medical (SJM) Regent^™ valve is selected for use in simulations, which is scaled in size for a 5-year old child and 6-month old infant. A previously validated lattice-Boltzmann method (LBM) is used to simulate pulsatile flow with thousands of suspended platelets for cases of adult, child, and infant BMHV flows. Adult BMHV flows demonstrate more disorganized small-scale flow features, but pediatric flows are associated with higher fluid shear stresses. Platelet damage in the pediatric cases is higher than in adult flow, highlighting thrombus complication dangers of pediatric BMHV flows. This does not necessarily suggest clinically important differences in thromboembolic potential. Highly damaged platelets in pediatric flows are primarily found far downstream of the valve, as there is less flow recirculation in pediatric flows. In addition, damage levels are well below expected thresholds for platelet activation. The extent of differences here documented between the pediatric and adult cases is of concern, demanding particular attention when pediatric valves are designed and manufactured. However, the differences between the pediatric and adult cases are not such that development of pediatric sized valves is untenable. This study may push for eventual approval of prosthetic valves resized for the pediatric population. Further studies will be necessary to determine the validity and potential thrombotic and clinical implications of these findings.     

Free emboli formation in the wake of bi-leaflet mechanical heart valves and the effects of implantation techniques

The high incidence of thromboembolic complications of mechanical heart valves (MHV), primarily due to platelet activation by contact with foreign surfaces and by non-physiological flow patterns past the valve, still limits their success as permanent implants. The latter include elevated shear and turbulent stresses and shed vortices formed in the wake of the valve's leaflets during the deceleration phase, potentially entrapping activated and aggregated platelets. It is hypothesized that these flow patterns induce the formation of free emboli which are the source of cerebrovascular microemboli associated with MHV. Implicit to this hypothesis is that free emboli formation will be affected by the implantation technique employed and the valve orientation, as those will alter the flow characteristics past the valve and the interaction of the platelets with the flow. In this study, numerical simulations of turbulent pulsatile flow past a St. Jude Medical bi-leaflet MHV were conducted. Platelet shear histories were calculated along pertinent turbulent platelet trajectories, and the effect of a misaligned valve on platelet activation was quantified and compared to that of an aligned valve. It demonstrated that the combination of a tilted valve and subannularly sutured pledgets had an explicit detrimental effect on platelet activation, with the following entrapment of the platelets within the shed vortices of the wake leading to a significant increase of the thromboembolic potential of the valve. This numerical model depicted a viable course for free emboli formation, and indicated how the implantation technique may enhance the risk of cardioembolism.     

Experimental technique of measuring dynamic fluid shear stress on the aortic surface of the aortic valve leaflet

Aortic valve (AV) calcification is a highly prevalent disease with serious impact on mortality and morbidity. The exact cause and mechanism of the progression of AV calcification is unknown, although mechanical forces have been known to play a role. It is thus important to characterize the mechanical environment of the AV. In the current study, we establish a methodology of measuring shear stresses experienced by the aortic surface of the AV leaflets using an in vitro valve model and adapting the laser Doppler velocimetry (LDV) technique. The valve model was constructed from a fresh porcine aortic valve, which was trimmed and sutured onto a plastic stented ring, and inserted into an idealized three-lobed sinus acrylic chamber. Valve leaflet location was measured by obtaining the location of highest back-scattered LDV laser light intensity. The technique of performing LDV measurements near to biological surfaces as well as the leaflet locating technique was first validated in two phantom flow systems: (1) steady flow within a straight tube with AV leaflet adhered to the wall, and (2) steady flow within the actual valve model. Dynamic shear stresses were then obtained by applying the techniques on the valve model in a physiologic pulsatile flow loop. Results show that aortic surface shear stresses are low during early systole (<5 dyn/cm2) but elevated to its peak during mid to late systole at about 18-20 dyn/cm2. Low magnitude shear stress (<5 dyn/cm2) was observed during early diastole and dissipated to zero over the diastolic duration. Systolic shear stress was observed to elevate only with the formation of sinus vortex flow. The presented technique can also be used on other in vitro valve models such as congenitally geometrically malformed valves, or to investigate effects of hemodynamics on valve shear stress. Shear stress data can be used for further experiments investigating effects of fluid shear stress on valve biology, for conditioning tissue engineered AV, and to validate numerical simulations.     

Comparison of hinge microflow fields of bileaflet mechanical heart valves implanted in different sinus shape and downstream geometry

The characterization of the bileaflet mechanical heart valves (BMHVs) hinge microflow fields is a crucial step in heart valve engineering. Earlier in vitro studies of BMHV hinge flow at the aorta position in idealized straight pipes have shown that the aortic sinus shapes and sizes may have a direct impact on hinge microflow fields. In this paper, we used a numerical study to look at how different aortic sinus shapes, the downstream aortic arch geometry, and the location of the hinge recess can influence the flow fields in the hinge regions. Two geometric models for sinus were investigated: a simplified axisymmetric sinus and an idealized three-sinus aortic root model, with two different downstream geometries: a straight pipe and a simplified curved aortic arch. The flow fields of a 29-mm St Jude Medical BMHV with its four hinges were investigated. The simulations were performed throughout the entire cardiac cycle. At peak systole, recirculating flows were observed in curved downsteam aortic arch unlike in straight downstream pipe. Highly complex three-dimensional leakage flow through the hinge gap was observed in the simulation results during early diastole with the highest velocity at 4.7 m/s, whose intensity decreased toward late diastole. Also, elevated wall shear stresses were observed in the ventricular regions of the hinge recess with the highest recorded at 1.65 kPa. Different flow patterns were observed between the hinge regions in straight pipe and curved aortic arch models. We compared the four hinge regions at peak systole in an aortic arch downstream model and found that each individual hinge did not vary much in terms of the leakage flow rate through the valves.     

Numerical and experimental investigations of pulsatile blood flow pattern through a dysfunctional mechanical heart valve

Around 250,000 heart valve replacements are performed every year around the world. Due their higher durability, approximately 2/3 of these replacements use mechanical prosthetic heart valves (mainly bileaflet valves). Although very efficient, these valves can be subject to valve leaflet malfunctions. These malfunctions are usually the consequence of pannus ingrowth and/or thrombus formation and represent serious and potentially fatal complications. Hence, it is important to investigate the flow field downstream of a dysfunctional mechanical heart valve to better understand its impact on blood components (red blood cells, platelets and coagulation factors) and to improve the current diagnosis techniques. Therefore, the objective of this study will be to numerically and experimentally investigate the pulsatile turbulent flow downstream of a dysfunctional bileaflet mechanical heart valve in terms of velocity field, vortex formation and potential negative effect on blood components. The results show that the flow downstream of a dysfunctional valve was characterized by abnormally elevated velocities and shear stresses as well as large scale vortices. These characteristics can predispose to blood components damage. Furthermore, valve malfunction led to an underestimation of maximal transvalvular pressure gradient, using Doppler echocardiography, when compared to numerical results. This could be explained by the shifting of the maximal velocity towards the normally functioning leaflet. As a consequence, clinicians should try, when possible, to check the maximal velocity position not only at the central orifice but also through the lateral orifices. Finding the maximal velocity in the lateral orifice could be an indication of valve dysfunction.     

The influence of the leaflets' curvature on the flow field in two bileaflet prosthetic heart valves

A successful mechanical prosthetic heart valve design is the bileaflet valve, which has been implanted for the first time more than 20 years ago. A key feature of bileaflet valves is the geometry of the two leaflets, which can be very important in determining the flow field. Laser Doppler anemometry (LDA) was used to perform an accurate study of the velocity and turbulence shear stress peak values (TSS(max)) fields at four distances from the valve plane. TSS(max) is a relevant parameter to assess the risk of hemolysis and platelet activation associated to the implantation of a prosthetic device, continuously interacting with blood. Two bileaflet valves were tested: the St. Jude HP and the Sorin Bicarbon, of the same nominal size (19mm). The former has flat leaflets, whereas the latter's leaflets have a cylindrical surface. A high regime (CO: 6l/min) was imposed, in order to test the two valves at maximum Reynolds number and consequent turbulence generation. The flat-leaflet design of the St. Jude generates a TSS field constant with distance; on the contrary, the Bicarbon's shear stress field undergoes an evident development, with an unexpected central peak at a distance comparable to the valve's dimensions (21mm). The two bileaflet valves tested, although very similar in design, behave very differently as for their turbulence properties. In particular, the concept of curved wake leads to conclude that the curvature of the leaflets' surface must be identified as an important parameter, which deserves careful attention in PHV design and development.     

Turbulence characteristics downstream of bileaflet aortic valve prostheses

This study was focused on a series of in vitro tests on the turbulent flow characteristics of three bileaflet aortic valves: St. Jude Medical (SJM), CarboMedics (CM), and Edwards Tekna (modified Duromedics, DM). The flow fields of the valves were measured in a pulsatile flow model with a laser-Doppler anemometer (LDA) at the aortic sinus area downstream of the valves. The heart rate was set at 70 beats per minute, the cardiac output was maintained at 5 liters per minute, and the aortic pressure wave forms were kept within the physiological range. Cycle-resolved analysis was applied to obtain turbulence data, including mean velocity, Reynolds stresses, autocorrelation coefficients, energy spectral density functions, and turbulence scales. The Reynolds shear stresses of all three valves induced only minor damage to red blood cells, but directly damaged the platelets, increasing the possibility of thrombosis. The smallest turbulence length scale, which offers a more reliable estimate of the effects of turbulence on blood cell damage, was three times the size of red blood cells and five times the size of platelets. This suggests that there is more direct interaction with the blood cells, thus causing more damage.     

In vitro pulsatile flow velocity and shear stress measurements in the vicinity of mechanical mitral heart valve prostheses

A three beam laser Doppler anemometer system was used to study the flow fields created by various types of mitral heart valve prostheses under physiological pulsatile flow conditions. The prosthetic valves studied were: Beall caged disc valve, Bjork-Shiley tilting disc valve, Medtronic-Hall tilting disc valve and St. Jude bileaflet valve. The results indicate that all four prosthetic valve designs studied create very disturbed flow fields with elevated turbulent shear stresses and regions of flow separation and/or stagnation. The observed elevated turbulent shear stresses could cause sublethal and/or lethal damage to red cells and platelets. The regions of flow separation and/or stagnation, could lead to thrombus formation and/or tissue overgrowth on the valve structure, as observed on clinically recovered prosthetic valves.     

Two-dimensional color-mapping of turbulent shear stress distribution downstream of two aortic bioprosthetic valves in vitro.

Since artificial heart valve related complications such as thrombus formation, hemolysis and calcification are considered related to flow disturbances caused by the inserted valve, a thorough hemodynamic characterization of heart valve prostheses is essential. In a pulsatile flow model, fluid velocities were measured one diameter downstream of a Hancock Porcine (HAPO) and a Ionescu-Shiley Pericardial Standard (ISPS) aortic valve. Hot-film anemometry (HFA) was used for velocity measurements at 41 points in the cross-sectional area of the ascending aorta. Three-dimensional visualization of the velocity profiles, at 100 different instants during one mean pump cycle, was performed. Turbulence analysis was performed as a function of time by calculating the axial turbulence energy within 50 ms overlapping time windows during the systole. The turbulent shear stresses were estimated by using the correlation equation between Reynolds normal stress and turbulent (Reynolds) shear stress. The turbulent shear stress distribution was visualized by two-dimensional color-mapping at different instants during one mean pump cycle. Based on the velocity profiles and the turbulent shear stress distribution, a relative blood damage index (RBDI) was calculated. It has the feature of combining the magnitude and exposure time of the estimated shear stresses in one index, covering the entire cross-sectional area. The HAPO valve showed a skewed jet-type velocity profile with the highest velocities towards the left posterior aortic wall. The ISPS valve revealed a more parabolic-shaped velocity profile during systole. The turbulent shear stresses were highest in areas of high or rapidly changing velocity gradients. For the HAPO valve the maximum estimated turbulent shear stress was 194 N m-2 and for the ISPS valve 154 Nm-2. The RBDI was the same for the two valves. The turbulent shear stresses had magnitudes and exposure times that might cause endothelial damage and sublethal or lethal damage to blood corpuscules. The RBDI makes comparison between different heart valves easier and may prove important when making correlation with clinical observations.     

Computational simulation of hemodynamic-driven growth and remodeling of embryonic atrioventricular valves

Embryonic heart valves develop under continuous and demanding hemodynamic loading. The particular contributions of fluid pressure and shear tractions in valve morphogenesis are difficult to decouple experimentally. To better understand how fluid loads could direct valve formation, we developed a computational model of avian embryonic atrioventricular (AV) valve (cushion) growth and remodeling using experimentally derived parameters for the blood flow and the cushion stiffness. Through an iterative scheme, we first solved the fluid loads on the axisymmetric AV canal and cushion model geometry. We then applied the fluid loads to the cushion and integrated the evolution equations to determine the growth and remodeling. After a set time of growth, we updated the fluid domain to reflect the change in cushion geometry and resolved for the fluid forces. The rate of growth and remodeling was assumed to be a function of the difference between the current stress and an isotropic homeostatic stress state. The magnitude of the homeostatic stress modulated the rate of volume addition during the evolution. We found that the pressure distribution on the AV cushion was sufficient to generate leaflet-like elongation in the direction of flow, through inducing tissue resorption on the inflow side of cushion and expansion on the outflow side. Conversely, shear tractions minimally altered tissue volume, but regulated the remodeling of tissue near the cushion surface, particular at the leading edge. Significant shear and circumferential residual stresses developed as the cushion evolved. This model offers insight into how natural and perturbed mechanical environments may direct AV valvulogenesis and provides an initial framework on which to incorporate more mechano-biological details.     

The congenital bicuspid aortic valve can experience high-frequency unsteady shear stresses on its leaflet surface

The bicuspid aortic valve (BAV) is a common congenital malformation of the aortic valve (AV) affecting 1% to 2% of the population. The BAV is predisposed to early degenerative calcification of valve leaflets, and BAV patients constitute 50% of AV stenosis patients. Although evidence shows that genetic defects can play a role in calcification of the BAV leaflets, we hypothesize that drastic changes in the mechanical environment of the BAV elicit pathological responses from the valve and might be concurrently responsible for early calcification. An in vitro model of the BAV was constructed by surgically manipulating a native trileaflet porcine AV. The BAV valve model and a trileaflet AV (TAV) model were tested in an in vitro pulsatile flow loop mimicking physiological hemodynamics. Laser Doppler velocimetry was used to make measurements of fluid shear stresses on the leaflet of the valve models using previously established methodologies. Furthermore, particle image velocimetry was used to visualize the flow fields downstream of the valves and in the sinuses. In the BAV model, flow near the leaflets and fluid shear stresses on the leaflets were much more unsteady than for the TAV model, most likely due to the moderate stenosis in the BAV and the skewed forward flow jet that collided with the aorta wall. This additional unsteadiness occurred during mid- to late-systole and was composed of cycle-to-cycle magnitude variability as well as high-frequency fluctuations about the mean shear stress. It has been demonstrated that the BAV geometry can lead to unsteady shear stresses under physiological flow and pressure conditions. Such altered shear stresses could play a role in accelerated calcification in BAVs.     

Unsteady effects on the flow across tilting disk valves

The present study simulates numerically the flow across two-dimensional tilting disk models of mechanical heart valves. The time-dependent Navier-Stokes equations are solved to assess the importance of unsteady effects in the fully open position of the valve. Flow cases with steady or physiological inflow conditions and with fixed or moving valves are solved. The simulations lead into mixed conclusions. It is obvious that steady inflow cases that account for vortex shedding only cannot model realistic physiological cases. In cases with imposed physiological inflow, the details of the flow field for fixed and moving valves might differ in the fully open position as well, although the gross features are quite similar. The fixed valve case consistently results in safe estimations of several critical quantities such as the axial force, the maximal shear stress on the valve, or the transvalvular pressure drop. Thus, fixed valve simulations can provide useful information for the design of prosthetic heart valves, as long as the properties in the fully open position only are sought.     

Turbulent shear stress measurements in the vicinity of aortic heart valve prostheses

A two dimensional laser Doppler anemometer system has been used to measure the turbulent shear fields in the immediate downstream vicinity of a variety of mechanical and bioprosthetic aortic heart valves. The measurements revealed that all the mechanical valves studied, created regions of elevated levels of turbulent shear stress during the major portion of systole. The tissue bioprostheses also created elevated levels of turbulence, but they were confined to narrow regions in the bulk of the flow field. The newer generation of bioprostheses create turbulent shear stresses which are considerably lower than those created by the older generation tissue valve designs. All the aortic valves studied (mechanical and tissue) create turbulent shear stress levels which are capable of causing sub-lethal and/or lethal damage to blood elements.