Development and validation of implantable sensors for monitoring function of prosthetic heart valves:<Emphasis Type="Italic">in vitro</Emphasis> studies

The development of a ‘smart’ heart valve prosthesis, with the intrinsic ability to monitor thrombus formation, mechanical failure and local haemodynamics and to relay this information externally, would be of significant help to clinicians. The first step towards such a valve is development of the sensors and examination of whether sensor output provides predictive information on function. Custom-made piezo-electric sensors were mounted onto the housing of mechanical valves with various layers of simulated thrombus and bioprosthetic valves with normal and stiffened leaflets. Sensor output was examined using joint time-frequency analysis. Sensors were able to detect leaflet opening and closing with high fidelity for all types of valve. The frequency content of the closing sounds for the mechanical valves contained several peaks between 100 Hz and 10 kHz, whereas closing sounds for the bioprosthetic valve contained energy in a lower frequency range (<1 kHz). A frequency peak of 47±15 Hz was seen for the normal bioprosthetic valve; this peak increased to 115±12 Hz for the valve with visibly stiffened leaflets. Total low-frequency (80–3500 Hz) energy content diminished predictably with increasing levels of thrombus for the mechanical valves. Lastly, closing sound intensity correlated well with closing pressure dynamics (dp/dt) (y=190x−443; r=0.90), indicating that the sensors also provide information on haemodynamics. These studies provide initial evidence regarding the use of embedded sensors to detect prosthetic valve function. Efforts to encapsulate these sensors with telemetry into a custom valve are currently underway.     

A three-dimensional analysis of flow in the pivot regions of an ATS bileaflet valve

Bileaflet heart valves are currently the most commonly implanted type of mechanical prosthetic valve, because of their low transvalvular pressure drop, centralised flow and durability. However, in common with all mechanical heart valves, implanted bileaflet valves show an inherent tendency for blood clot formation at the valve site. Fluid dynamical phenomena associated with blood clotting are elevated blood shear stresses and regions of persistent blood recirculation, particularly when both occur together. Using three-dimensional CFD modelling, combined with enlarged scale experimental modelling, we investigated the blood flow through the ATS bileaflet valve during forward flow, with particular attention to the leaflet pivot regions. Recirculating regions were found both within and downstream of the valve housing ring. Qualitative assessment of the entire cardiac cycle suggested that recirculating blood within the housing ring will be washed away whilst the valve is closed, but as with all bileaflet valve designs recirculating blood downstream of the valve may have a residence time much longer than one cardiac cycle.     

保留相同瓣下结构比较不同人工瓣膜下游湍流剪应力的差异

背景：保留瓣下结构可引起瓣膜下游血流受阻,目前有关保留瓣下结构不同人工瓣膜下游血流受阻情况的定量研究尚不深入。 目的：比较保留相同瓣下结构、不同类型人工瓣膜下游血流动力学性能的优劣。 方法：按常规二尖瓣置换方法,在全麻气管插管体外循环下建立标准的猪二尖瓣置换模型。按未保留瓣下结构、保留后瓣瓣下结构以及保留全瓣瓣下结构3种术式处理猪的二尖瓣及其瓣下结构,置换的瓣膜类型为单叶机械瓣膜、双叶机械瓣膜和生物瓣膜。采用多普勒超声结合计算机图像分析技术,对猪保留相同瓣下结构的不同类型的人工瓣膜下游湍流剪应力进行体内定量实验。 结果与结论：未保留瓣下结构的单叶双叶机械人工瓣膜下游血流动力学性能相当,均较生物瓣膜差。保留相同瓣下结构的不同类型人工瓣膜置换后其下游的血流动力学性能以生物瓣膜最佳,双叶机械瓣膜次之,单叶瓣膜最差。     

6-Month aortic valve implantation of an off-the-shelf tissue-engineered valve in sheep

Diseased aortic valves often require replacement, with over 30% of the current aortic valve surgeries performed in patients who will outlive a bioprosthetic valve. While many promising tissue-engineered valves have been created in the lab using the cell-seeded polymeric scaffold paradigm, none have been successfully tested long-term in the aortic position of a pre-clinical model. The high pressure gradients and dynamic flow across the aortic valve leaflets require engineering a tissue that has the strength and compliance to withstand high mechanical demand without compromising normal hemodynamics. A long-term preclinical evaluation of an off-the-shelf tissue-engineered aortic valve in the sheep model is presented here. The valves were made from a tube of decellularized cell-produced matrix mounted on a frame. The engineered matrix is primarily composed of collagen, with strength and organization comparable to native valve leaflets. In vitro testing showed excellent hemodynamic performance with low regurgitation, low systolic pressure gradient, and large orifice area. The implanted valves showed large-scale leaflet motion and maintained effective orifice area throughout the duration of the 6-month implant, with no calcification. After 24 weeks implantation (over 17 million cycles), the valves showed no change in tensile mechanical properties. In addition, histology and DNA quantitation showed repopulation of the engineered matrix with interstitial-like cells and endothelialization. New extracellular matrix deposition, including elastin, further demonstrates positive tissue remodeling in addition to recellularization and valve function. Long-term implantation in the sheep model resulted in functionality, matrix remodeling, and recellularization, unprecedented results for a tissue-engineered aortic valve.     

Daily transient discontinuation of extracorporeal LVAD to prevent thromboembolism of mechanical aortic valve prosthesis

Patients with mechanical aortic valves are generally contraindicated for left ventricular assist device (LVAD) insertion because the prosthetic valve often becomes fixed in closed position. A 41-year-old woman with mechanical aortic valve prosthesis experienced sudden chest pain and developed cardiogenic shock. A paracorporeal pulsatile LVAD and a monopivot centrifugal pump as a right VAD (RVAD) were implanted. The mechanical aortic valve was intentionally left in place. Soon after the operation, LVAD support was discontinued daily for few seconds to allow the mechanical aortic valve to open and to avoid thrombus formation. The patient was successfully weaned off RVAD and received anticoagulation therapy with warfarin. On postoperative day 141, she was transferred to a university hospital where a HeartMate II LVAD was implanted, and the aortic valve was successfully replaced with a bioprosthetic valve. The patient is currently awaiting heart transplantation.     

Three-Dimensional Fluid-Structure Interaction Simulation of Bileaflet Mechanical Heart Valve Flow Dynamics

The wall shear stress induced by the leaflet motion during the valve-closing phase has been implicated with thrombus initiation with prosthetic valves. Detailed flow dynamic analysis in the vicinity of the leaflets and the housing during the valve-closure phase is of interest in understanding this relationship. A three-dimensional unsteady flow analysis past bileaflet valve prosthesis in the mitral position is presented incorporating a fluid-structure interaction algorithm for leaflet motion during the valve-closing phase. Arbitrary Lagrangian-Eulerian method is employed for incorporating the leaflet motion. The forces exerted by the fluid on the leaflets are computed and applied to the leaflet equation of motion to predict the leaflet position. Relatively large velocities are computed in the valve clearance region between the valve housing and the leaflet edge with the resulting relatively large wall shear stresses at the leaflet edge during the impact-rebound duration. Negative pressure transients are computed on the surface of the leaflets on the atrial side of the valve, with larger magnitudes at the leaflet edge during the closing and rebound as well. Vortical flow development is observed on the inflow (atrial) side during the valve impact-rebound phase in a location central to the leaflet and away from the clearance region where cavitation bubbles have been visualized in previously reported experimental studies.     

The Influence of Valve Leaflet Stiffness Variability on Aortic Wall Shear Stress

Aortic stenosis is a common cardiac condition that impacts the aorta’s hemodynamics downstream of the affected valve. We sought to better understand how non-uniform stiffening of a stenotic aortic valve would affect the wall shear stress (WSS) experienced by the walls of the aorta and the residence time near the valve. Several experimental configurations were created by individually stiffening leaflets of a polymer aortic valve. These configurations were mounted inside an in vitro experimental setup. Digital particle image velocimetry (DPIV) was used to measure velocity profiles inside a model aorta. The DPIV results were used to estimate the WSS and residence time. Our analysis suggests that leaflet asymmetry greatly affects the amount of WSS by vectoring the systolic jet and stiffened leaflets have an increased residence time. This study indicates that valve leaflets with different stiffness conditions can have a more significant impact on wall shear stress than stenosis caused by the uniform increase in all three leaflets (and the subsequent increased systolic velocity) alone. This finding is promising for creating customizable (patient-specific) prosthetic heart valves tailored to individual patients.

     

Dynamic particle image velocimetry flow analysis of the flow field immediately downstream of bileaflet mechanical mitral prostheses

New dynamic particle image velocimetry (PIV) technology was applied to the study of the flow field associated with prosthetic heart valves. Four bileaflet prostheses, the St. Jude Medical (SJM) valve, the On-X valve with straight leaflets, the Jyros (JR) valve, and the Edwards MIRA (MIRA) valve with curved leaflets, were tested in the mitral position under pulsatile flow conditions to find the effect of the leaflet shape and overall valve design on the flow field, particularly in terms of the turbulent stress distribution, which may influence hemolysis, platelet activation, and thrombus formation. Comparison of the time-resolved flow fields associated with the opening, accelerating, peak, and closing phases of the diastolic flow revealed the effects of the leaflet shape and overall valve design on the flow field. Anatomically and antianatomically oriented bileaflet valves were also compared in the mitral position to study the effects of the orientation on the downstream flow field. The experimental program used a dynamic PIV system utilizing a high-speed, high-resolution video camera to map the true time-resolved velocity field inside the simulated ventricle. Based on the experimental data, the following general conclusions can be made. High-resolution dynamic PIV can capture true chronological changes in the velocity and turbulence fields. In the vertical measuring plane that passes the centers of both the aortic and mitral valves (A-A section), bileaflet valves show clear and simple circulatory flow patterns when the valve is installed in the antianatomical orientation. The SJM, the On-X, and the MIRA valves maintain a relatively high velocity through the central orifice. The curved leaflets of the JR valve generate higher velocities with a divergent flow during the accelerating and peak flow phases when the valve is installed in the anatomical orientation. In the velocity field directly below the mitral valve and normal to the previous measuring plane (B-B section), where characteristic differences in valve design on the three-dimensional flow should be visible, the symmetrical divergent nature of the flow generated by the two inclined half-disks installed in the antianatomical orientation was evident. The SJM valve, with a central downward flow near the valve, is contrasted with the JR valve, which has a peripherally strong downward circulation with higher turbulent stresses. The On-X valve has a strong central downward flow attributable to its large opening angle and flared inlet shape. The MIRA valve also has a relatively strong downward central flow. The MIRA valve, however, diverts the flow three-dimensionally due to its peripherally curved leaflets.     

Echocardiographic characteristics of transprosthetic blood peak velocity in the Sorin Bicarbon bileaflet prosthetic heart valve

The Bicarbon prosthetic heart valve with two curved leaflets is designed so that the blood flows through the three orifices are parallel jets of equal size. This study was conducted to confirm that the Bicarbon valve functions clinically as designed. Forty-three patients underwent valve replacement with the Bicarbon valve. Forty-eight Bicarbon valves were implanted: 25 valves in the mitral position and 23 in the aortic position. Peak blood flow velocity through the three prosthetic orifices was measured postoperatively by Doppler echocardiography. The three flow jets through the prosthesis were parallel. The velocity through the lateral orifice was 2.33±0.38 m/min, and the velocity through the central orifice was 2.14±0.43 m/min at the aortic position (P>0.05). The velocity through the lateral orifice was 1.72±0.06 m/min at the mitral position, and that through the central orifice was 1.73±0.06 m/min (P>0.05). Serum lactic acid dehydrogenase values were also lower than those of patients or whom another bileaflet prosthesis had been implanted. The results confirm that the Bicarbon prosthetic heart valve performs clinically as designed, producing three parallel blood flow jets with equal flow velocity.     

New J-3 flexible-leaflet polyurethane heart valve prosthesis with improved hydrodynamic performance.

The aim of this new three-leaflet valve development was to design a leaflet with minimum membrane stresses during performance. This is achieved by manufacturing the valve leaflets shaped almost flat in a medium opening position. Thus, the leaflets have two stable positions, one with maximum opening area and the other with favorable stress distribution in the closed position. The transition between the two end positions is achieved through a two-dimensional rolling motion without buckling and with minimum membrane stresses (bulge forces). The manufacturing technique is dip-coating in polyurethane. Hydrodynamic evaluation of the J-3 valve in steady and pulsatile flow showed minimum pressure drop compared to other commercially available valves. Laser-Doppler-anemometry studies indicated very low shear stresses in the flow field downstream of the valve. In durability tests prototypes have reached lifetimes of up to 17 years. In conclusion, the J-3 valve shows superior hydrodynamic performance thereby reducing potential thrombus formation. Minimization of stresses within the valve leaflets through design could reduce calcification.     

A Comparison of Flow Field Structures of Two Tri-Leaflet Polymeric Heart Valves

Polymeric heart valves have the potential to reduce thrombogenic complications associated with current mechanical valves and overcome fatigue-related problems experienced by bioprosthetic valves. In this in vitro study, the velocity fields inside and downstream of two different prototype tri-lealfet polymeric heart valves were studied. Experiments were conducted on two 23 mm prototype polymeric valves, provided by AorTech Europe, having open or closed commissure designs and leaflet thickness of 120 and 80 m, respectively. A two-dimensional LDV system was used to measure the velocity fields in the vicinity of the two valves under simulated physiological conditions. Both commissural design and leaflet thickness were found to affect the flow characteristics. In particular, very high levels of Reynolds shear stress of 13,000 dynes/cm² were found in the leakage flow of the open commisure design. Maximum leakage velocities in the open and closed designs were 3.6 m/s and 0.5 m/s respectively; the peak forward flow velocities were 2.0 m/s and 2.6 m/s, respectively. In both valve designs, shear stress levels exceeding 4,000 dyne/cm² were observed at the trailing edge of the leaflets and in the leakage and central orifice jets during peak systole. Additionally, regions of low velocity flow conducive to thrombus formation were observed in diastole. The flow structures measured in these experiments are consistent with the location of thrombus formation observed in preliminary animal experiments.     

Time-resolved PIV technique for high temporal resolution measurement of mechanical prosthetic aortic valve fluid dynamics

Prosthetic heart valves (PHVs) have been used to replace diseased native valves for more than five decades. Among these, mechanical PHVs are the most frequently implanted. Unfortunately, these devices still do not achieve ideal behavior and lead to many complications, many of which are related to fluid mechanics. The fluid dynamics of mechanical PHVs are particularly complex and the fine-scale characteristics of such flows call for very accurate experimental techniques. Adequate temporal resolution can be reached by applying time-resolved PIV, a high-resolution dynamic technique which is able to capture detailed chronological changes in the velocity field. The aim of this experimental study is to investigate the evolution of the flow field in a detailed time domain of a commercial bileaflet PHV in a mock-loop mimicking unsteady conditions, by means of time-resolved 2D Particle Image Velocimetry (PIV). The investigated flow field corresponded to the region immediately downstream of the valve plane. Spatial resolution as in "standard" PIV analysis of prosthetic valve fluid dynamics was used. The combination of a Nd:YLF high-repetition-rate double-cavity laser with a high frame rate CMOS camera allowed a detailed, highly temporally resolved acquisition (up to 10000 fps depending on the resolution) of the flow downstream of the PHV. Features that were observed include the non-homogeneity and unsteadiness of the phenomenon and the presence of large-scale vortices within the field, especially in the wake of the valve leaflets. Furthermore, we observed that highly temporally cycle-resolved analysis allowed the different behaviors exhibited by the bileaflet valve at closure to be captured in different acquired cardiac cycles. By accurately capturing hemodynamically relevant time scales of motion, time-resolved PIV characterization can realistically be expected to help designers in improving PHV performance and in furnishing comprehensive validation with experimental data on fluid dynamics numeric modelling.     

Characterizing the Collagen Fiber Orientation in Pericardial Leaflets Under Mechanical Loading Conditions

When implanted inside the body, bioprosthetic heart valve leaflets experience a variety of cyclic mechanical stresses such as shear stress due to blood flow when the valve is open, flexural stress due to cyclic opening and closure of the valve, and tensile stress when the valve is closed. These types of stress lead to a variety of failure modes. In either a natural valve leaflet or a processed pericardial tissue leaflet, collagen fibers reinforce the tissue and provide structural integrity such that the very thin leaflet can stand enormous loads related to cyclic pressure changes. The mechanical response of the leaflet tissue greatly depends on collagen fiber concentration, characteristics, and orientation. Thus, understating the microstructure of pericardial tissue and its response to dynamic loading is crucial for the development of more durable heart valve, and computational models to predict heart valves' behavior. In this work, we have characterized the 3D collagen fiber arrangement of bovine pericardial tissue leaflets in response to a variety of different loading conditions under Second-Harmonic Generation Microscopy. This real-time visualization method assists in better understanding of the effect of cyclic load on collagen fiber orientation in time and space.     

Mechanisms of the in vivo inhibition of calcification of bioprosthetic porcine aortic valve cusps and aortic wall with triglycidylamine/mercapto bisphosphonate

Heart valve replacements fabricated from glutaraldehyde (Glut)-crosslinked heterograft materials, porcine aortic valves or bovine pericardium, have been widely used in cardiac surgery to treat heart valve disease. However, these bioprosthetic heart valves often fail in long-term clinical implants due to pathologic calcification of the bioprosthetic leaflets, and for stentless porcine aortic valve bioprostheses, bioprosthetic aortic wall calcification also typically occurs. Previous use of the epoxide-based crosslinker, triglycidyl amine (TGA), on cardiac bioprosthetic valve materials demonstrated superior biocompatibility, mechanics, and calcification resistance for porcine aortic valve cusps (but not porcine aortic wall) and bovine pericardium, vs. Glut-prepared controls. However, TGA preparation did not completely prevent long-term calcification of cusps or pericardium. Herein we report further mechanistic investigations of an added therapeutic component to this system, 2-mercaptoethylidene-1,1-bisphosphonic acid (MABP), a custom synthesized thiol bisphosphonate, which has previously been shown in a preliminary report to prevent bioprosthetic heterograft biomaterial calcification when used in combination with initial TGA crosslinking for 7 days. In the present studies, we have further investigated the effectiveness of MABP in experiments that examined: (1) The use of MABP after optimal TGA crosslinking, in order to avoid any competitive interference of MABP-reactions with TGA during crosslinking; (2) Furthermore, recognizing the importance of alkaline phosphatase (ALP) in the formation of dystrophic calcific nodules, we have investigated the hypothesis that the mechanism by which MABP primarily functions is through the reduction of ALP activity. Results from cell-free model systems, cell culture studies, and rat subcutaneous implants, show that materials functionalized with MABP after TGA crosslinking have reduced ALP activity, and in vivo have no significant calcification in long-term implant studies. It is concluded that bioprosthetic heart valves prepared in this fashion are compelling alternatives for Glut-prepared bioprostheses.     

Dynamic Simulation of Bioprosthetic Heart Valves Using a Stress Resultant Shell Model

It is a widely accepted axiom that localized concentration of mechanical stress and large flexural deformation is closely related to the calcification and tissue degeneration in bioprosthetic heart valves (BHV). In order to investigate the complex BHV deformations and stress distributions throughout the cardiac cycle, it is necessary to perform an accurate dynamic analysis with a morphologically and physiologically realistic material specification for the leaflets. We have developed a stress resultant shell model for BHV leaflets incorporating a Fung-elastic constitutive model for in-plane and bending responses separately. Validation studies were performed by comparing the finite element predicted displacement and strain measures with the experimentally measured data under physiological pressure loads. Computed regions of stress concentration and large flexural deformation during the opening and closing phases of the cardiac cycle correlated with previously reported regions of calcification and/or mechanical damage on BHV leaflets. It is expected that the developed experimental and computational methodology will aid in the understanding of the complex dynamic behavior of native and bioprosthetic valves and in the development of tissue engineered valve substitutes.     

Fluid Dynamic Assessment of Three Polymeric Heart Valves Using Particle Image Velocimetry

Polymeric heart valves have the potential to reduce thrombogenic complications associated with current mechanical valves and overcome fatigue-related problems experienced by bioprosthetic valves. In this paper we characterize the in vitro velocity and Reynolds Shear Stress (RSS) fields inside and downstream of three different prototype trileaflet polymeric heart valves. The fluid dynamic differences are then correlated with variations in valve design parameters. The three valves differ in leaflet thickness, ranging from 80 to 120 μm, and commisural design, either closed, opened, or semi-opened. The valves were subjected to aortic flow conditions and the velocity measured using three-dimensional stereo Particle Image Velocimetry. The peak forward flow phase in the three valves was characterized by a strong central orifice jet of approximately 2 m/s with a flat profile along the trailing edge of the leaflets. Leakage jets, with principle RSS magnitudes exceeding 4,500 dyn/cm², were observed in all valves with larger leaflet thicknesses and also corresponded to larger leakage volumes. Additional leakage jets were observed at the commissural region of valves with the open and the semi-open commissural designs. The results of the present study indicate that commissural design and leaflet thickness influence valve fluid dynamics and thus the thrombogenic potential of trileaflet polymeric valves.     

Dynamic particle image velocimetry study of the aortic flow field of contemporary mechanical bileaflet prostheses

The characteristics of mechanical bileaflet valves, the leaflets of which open at the outside first, differ significantly from those of natural valves, whose leaflets open at the center first, and this fact affects the flow field down-stream of the valves. The direction of jet-type flows, which is influenced by this difference in valve features, and the existence of the sinus of Valsalva both affect the flow field inside the aorta in different ways, depending on the valve design. There may also be an influence on the coronary circulation, the entrance to which resides inside the sinus of Valsalva. A dynamic particle image velocimetry (PIV) study was conducted to analyze the influence of the design of prosthetic heart valves on the aortic flow field. Three contemporary bileaflet prostheses, the St. Jude Medical (SJM) valve, the On-X valve (with straight leaflets), and the MIRA valve (with curved leaflets), were tested inside a simulated aorta under pulsatile flow conditions. A dynamic PIV system was employed to analyze the aortic flow field resulting from the different valve designs. The two newer valves, the On-X and the MIRA valves, open more quickly than the SJM valve and provide a wider opening area when the valve is fully open. The SJM valve's outer orifices deflect the flow during the accelerating flow phase, whereas the newer designs deflect the flow less. The flow through the central orifice of the SJM valve has a lower velocity compared to the newer designs; the newer designs tend to have a strong flow through all orifices. The On-X valve generates a simple jet-type flow, whereas the MIRA valve (with circumferentially curved leaflets) generates a strong but three-dimensionally diffuse flow, resulting in a more complex flow field downstream of the aortic valve. The clinically more adapted 180 degrees orientation seems to provide a less diffuse flow than the 90 degrees orientation does. The small differences in leaflet design in the bileaflet valves generate noticeable differences in the aortic flow; the newer valves show strong flows through all orifices.     

A synthetic three-leaflet valve.

To increase durability and decrease calcification tendencies, the reduction of mechanical leaflet stress is of prime importance. In order to achieve this for a three-leaflet valve, the leaflets of a new design of prosthesis (the J-3) are manufactured in a medium open, almost flat shaped position, whereby the stent posts are expanded by a cone-shaped mold. Owing to this design, the leaflets have stable closed and open positions, the transition succeeds with low opening pressure. Valves are manufactured by dip-coating in polyurethane. Hydrodynamic evaluation of this polyurethane valve shows minimum pressure drop and very low energy losses compared with other commercially available valves. Very low shear stresses in the flow field downstream of the valve are observed by laser-Doppler-anemometry. In durability tests, prototypes have reached lifetimes equivalent to 17 years. For comparative testing of durability and biocompatibility, six bioprostheses and seven J-3 valves were implanted in mitral position of growing Jersey calves. While animal tests are encouraging, they also reveal necessary manufacturing improvements.     

An unusual complication associated with the Carpentier-Edwards porcine bioprosthesis

Primary tissue failure of bioprosthetic heart valves refers primarily to calcification of the leaflets of the bioprosthesis. A 75 year old patient underwent reoperation 15 years after mitral valve replacement with a Carpentier-Edwards porcine bioprosthesis. The extracted bioprosthetic valve was found to have one prolapsed leaflet and a small amount of calcification on all three leaflets without tear or perforation. The two commissures suspending the prolapsed leaflet were detached, causing mitral valve regurgitation.     

Retraction of bioprosthetic heart valve cusps: a cause of wide-open regurgitation in right-sided heart valves

Most failures of bioprosthetic heart valves in children are due to stenosis secondary to thrombus, calcific deposits, or tissue ingrowth. Valve failures due to regurgitation typically involve cuspal detachment, tears, or perforations. We present four cases of prosthetic valve regurgitation in children caused by cuspal retraction without stenosis and describe the morphologic findings related to the valves at autopsy or explantation. A mononuclear cell and giant cell response to the cusps of the valve was a striking finding in one patient.