Stability and function of glycosaminoglycans in porcine bioprosthetic heart valves

Glycosaminoglycans (GAGs) are important structural and functional components in native aortic heart valves and in glutaraldehyde (Glut)-fixed bioprosthetic heart valves (BHVs). However, very little is known about the fate of GAGs within the extracellular matrix of BHVs and their contribution to BHV longevity. BHVs used in heart valve replacement surgery have limited durability due to mechanical failure and pathologic calcification. In the present study we bring evidence for the dramatic loss of GAGs from within the BHV cusp structure during storage in saline and both short- and long-term Glut fixation. In order to gain insight into role of GAGs, we compared properties of fresh and Glut-fixed porcine heart valve cusps before and after complete GAG removal. GAG removal resulted in significant morphological and functional tissue alterations, including decreases in cuspal thickness, reduction of water content and diminution of rehydration capacity. By virtue of this diminished hydration, loss of GAGs also greatly increased the "with-curvature" flexural rigidity of cuspal tissue. However, removal of GAGs did not alter calcification potential of BHV cups when implanted in the rat subdermal model. Controlling the extent of pre-implantation GAG degradation in BHVs and development of improved GAG crosslinking techniques are expected to improve the mechanical durability of future cardiovascular 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.     

Flow in Prosthetic Heart Valves: State-of-the-Art and Future Directions

Since the first successful implantation of a prosthetic heart valve four decades ago, over 50 different designs have been developed including both mechanical and bioprosthetic valves. Today, the most widely implanted design is the mechanical bileaflet, with over 170,000 implants worldwide each year. Several different mechanical valves are currently available and many of them have good bulk forward flow hemodynamics, with lower transvalvular pressure drops, larger effective orifice areas, and fewer regions of forward flow stasis than their earlier-generation counterparts such as the ball-and-cage and tilting-disc valves. However, mechanical valve implants suffer from complications resulting from thrombus deposition and patients implanted with these valves need to be under long-term anti-coagulant therapy. In general, blood thinners are not needed with bioprosthetic implants, but tissue valves suffer from structural failure with, an average life-time of 10–12 years, before replacement is needed. Flow-induced stresses on the formed elements in blood have been implicated in thrombus initiation within the mechanical valve prostheses. Regions of stress concentration on the leaflets during the complex motion of the leaflets have been implicated with structural failure of the leaflets with bioprosthetic valves. In vivo and in vitro experimental studies have yielded valuable information on the relationship between hemodynamic stresses and the problems associated with the implants. More recently, Computational Fluid Dynamics (CFD) has emerged as a promising tool, which, alongside experimentation, can yield insights of unprecedented detail into the hemodynamics of prosthetic heart valves. For CFD to realize its full potential, however, it must rely on numerical techniques that can handle the enormous geometrical complexities of prosthetic devices with spatial and temporal resolution sufficiently high to accurately capture all hemodynamically relevant scales of motion. Such algorithms do not exist today and their development should be a major research priority. For CFD to further gain the confidence of valve designers and medical practitioners it must also undergo comprehensive validation with experimental data. Such validation requires the use of high-resolution flow measuring tools and techniques and the integration of experimental studies with CFD modeling.     

Current developments and future prospects for heart valve replacement therapy

Valve replacement is the most common surgical treatment in patients with advanced valvular heart disease. Mechanical and bio-prostheses have been the traditional heart valve replacements in these patients. However, currently the heart valves for replacement therapy are imperfect and subject patients to one or more ongoing risks, including thrombosis, limited durability, and need for re-operations due to the lack of growth in pediatric populations. Furthermore, they require an open heart surgery, which is risky for elderly and young children who are too weak or ill to undergo major surgery. This article reviews the current state of the art of heart valve replacements in light of their potential clinical applications. In recent years polymeric materials have been widely studied as potential prosthetic heart valve material being designed to overcome the clinical problems associated with both mechanical and bio-prosthetic valves. The review also addresses the advances in polymer materials, tissue engineering approaches, and the development of percutaneous valve replacement technology and discusses the future prospects in these fields.     

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.     

Electrospun bioresorbable heart valve scaffold for tissue engineering

Currently marketed mechanical or biological prosthetic heart valves are regarded as valid substitutes for native heart valves suffering from degenerative pathologies. These devices require strict follow-up due to dysfunctions or post-surgical complications. Potential drawbacks of these medical devices are calcification, tearing of the cusps, thromboembolism and hemolysis. In this context, a tissue engineering approach offers a promising alternative scenario. In this paper, a trileaflet poly(epsilon-caprolactone) (PCL) heart valve scaffold prototype has been manufactured by electrospinning technique using a custom-made rotating target. Process parameters were selected in order to achieve suitable microstructure and mechanical performance. The electrospun heart valve prototype was functionally characterized by means of a pulse duplicator in order to evaluate the mechanical/hydraulic response to the imposed testing conditions. Leaflets synchronously opened in the ejection phase and the proper apposition of the leaflets prevented high leakage volumes in the diastolic phase. This preliminary study suggests a successful perspective for the proposed approach in designing a novel tissue engineered bioresorbable heart valve.     

Artificial valves “up to date” in Japan

We have many choices when selecting artificial valves for valve replacement surgery. It is necessary to know the characteristics of the various prosthetic valves to make an appropriate decision for each valvular heart disease patient. In this review paper, we describe the features and benefits of the artificial valves available in Japan. Standard and new generation bioprostheses and mechanical prostheses are reviewed. The new technology of the catheter-delivery heart valve is also mentioned in this paper.     

Noninvasive detection of mechanical prosthetic heart valve disorder

Auscultation is a widely used efficient technique by cardiologists for detecting the heart conditions. Since the mechanical prosthetic heart valves are widely used today, it is important to develop a simple and efficient method to detect abnormal mechanical valves. In this paper, the mechanical prosthetic heart valve sounds are analyzed by using different power spectral density (PSD) estimation techniques. To improve the classification accuracy of heart sounds, we propose two different feature extraction schemes, i.e., a modified local discriminant bases (LDB) scheme and a Hilbert-Huang Transform (HHT)-based scheme. A database of 150 heart sounds is used in this study and an average classification accuracy of 97.3% is achieved for both the two feature extraction schemes, when a generic linear discriminant analysis (LDA) classifier is used in the classification stage.     

Phonographic detection of mechanical heart valve thrombosis

The formation of thrombotic deposits affects the functionality of mechanical prosthetic heart valves; as a consequence, mechanical valves thrombosis needs early diagnosis to prevent thromboembolic events. This paper compares the acoustic signals produced by two commercial bileaflet mechanical heart valves in the closing phase to detect the presence of thrombi. The closing sounds were recorded in vitro by means of a phonocardiographic device under different hydrodynamic conditions. Thrombotic deposits of different weight and shape were applied onto the valve leaflet and the annular housing, until the movement of one leaflet was completely blocked. From the acoustic signals, the corresponding spectra were calculated and four diagnostic frequency bands were identified: their comparison allowed detecting malfunctioning valves because of the presence of thrombotic formations.     

Hydrodynamics of a Newly China-Made Jiuling Bileaflet Heart Valve Prostheses

INTRODUCTION　　 Implantation of heart valve substitute has become the standard treatment forend-stage valvular heart disease since the1 960 s.There are two different types ofmechanical heart valve in widespread use at present,the tilting disc valve and t…     

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。     

Phonocardiogram spectral analysis simulator of mitral valve prostheses.

Spectral analysis of sounds produced in vitro by mitral valve prostheses placed in a specially designed flow simulator has been carried out using a short-time Fourier representation of the recorded signal. Time variations of power spectra are displayed as a three-dimensional plot. Sounds produced by three types of valves, namely ball and cage, tilting disk and porcine valves, were analysed. Each valve type produced a characteristic spectrogram, and, for a given valve, spectrograms were reproducible to within a margin of 5 dB. The simulator may be used to detect structural deficiencies and functional abnormalities of prosthetic heart valves. In addition to quantifying the noise level of mechanical valves, the system may be used for quality control purposes to identify faulty valves.     

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.     

人造机械瓣心音的分析研究

在一些致命性心脏病的诊断中,心音听诊是最有效也是应用得最成功的手段之一.鉴于目前机械瓣的使用非常普遍,研究简单有效的机械瓣病变判别方法对于临床诊断来讲具有重要意义.运用希尔波特-黄变换(HHT),针对不同的机械瓣心音进行分析,并设计一种基于Hilbert边界谱特征的提取方法,结合线性判别分析(LDA),对不同的机械瓣心音进行分类.同时,与基于局部最优基特征的分类器分类结果进行比较.分析结果表明,机械瓣心音的各阶Hilbert边界谱具有非常明显不同的分布,基于HHT的分类器识别率达到了97.3％,较基于局部最优基特征分类器的识别率(91.3％)更高.对于人造机械瓣心音而言,HHT是一种有效的分析处理手段.     

Beat to beat analysis of mechanical heart valves by means of return map

Three mechanical heart valves (two bileaflet prostheses and a tilting one) were investigated in a basic hardware setup in order to evaluate with a hydrophone their opening and closing action in time and in amplitude of each beat. The recorded signal was then segmented into the series of cycles xi(t) having a temporal duration equal to the working period imposed on the valve. Two return maps were defined, in order to evaluate the degree of dispersion of the resulting scatter plot: (i) the amplitude map xi(t) versus xi+1(t); (ii) the delay map for the closure of the valve within each beat versus the successive ones. To evaluate the results obtained, two indices were proposed based on both the degree of dispersion and the deviation of the regression line of the resulting scatter plot with respect to the bisector of the map plane. The tilting disc valve showed a lower degree of dispersion, both in the amplitude signal and in the closure time delays, with respect to the other two bileaflet heart valves. The methodology proposed here could be regarded as an alternative non-invasive tool to investigate the dynamic behaviour of prosthetic heart valves, especially in the case of their suspected failure.     

Tri-layered elastomeric scaffolds for engineering heart valve leaflets

Tissue engineered heart valves (TEHVs) that can grow and remodel have the potential to serve as permanent replacements of the current non-viable prosthetic valves particularly for pediatric patients. A major challenge in designing functional TEHVs is to mimic both structural and anisotropic mechanical characteristics of the native valve leaflets. To establish a more biomimetic model of TEHV, we fabricated tri-layered scaffolds by combining electrospinning and microfabrication techniques. These constructs were fabricated by assembling microfabricated poly(glycerol sebacate) (PGS) and fibrous PGS/poly(caprolactone) (PCL) electrospun sheets to develop elastic scaffolds with tunable anisotropic mechanical properties similar to the mechanical characteristics of the native heart valves. The engineered scaffolds supported the growth of valvular interstitial cells (VICs) and mesenchymal stem cells (MSCs) within the 3D structure and promoted the deposition of heart valve extracellular matrix (ECM). MSCs were also organized and aligned along the anisotropic axes of the engineered tri-layered scaffolds. In addition, the fabricated constructs opened and closed properly in an ex vivo model of porcine heart valve leaflet tissue replacement. The engineered tri-layered scaffolds have the potential for successful translation towards TEHV replacements.     

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.     

Physical principles of the Edinburgh prosthetic heart valve

A new type of prosthetic heart valve, at present under development, has been designed according to a set of general assumptions, here made explicit, concerning the interaction of flowing blood with artificial structures. On these assumptions, it is shown that the characteristics desirable in a prosthetic heart valve are supplied by a form of butterfly valve in which an occluder, capable of rotation about a nearly diametral axis in a smooth-bore housing, rapidly assumes a low-drag position aligned with the forward flow and closes rapidly on flow reversal. These desiderata, not furnished by conventional butterfly valves, are achieved in the Edinburgh design, in which an occluder of suitable aerofoil shape is mounted pivotally in a housing of conical or similarly divergent bore. Certain forms of carbon are suitable materials of construction. Preliminary data forin vivo (canine) performance are given for Edinburgh valves fabricated from graphite coated with pyrolytic carbon.     

Endothelial retention and phenotype on carbonized cardiovascular implant surfaces

Heart valve disease is an increasing clinical burden for which there is no effective treatment outside of prosthetic replacement. Over the last 20 years, clinicians have increasingly preferred the use of biological prosthetics to mechanical valves despite their superior durability because of the lifelong anticoagulation therapy that is required. Mechanical valve surface engineering has largely focused on being as non-thrombogenic as possible, but despite decades of iteration has had insufficient impact on the anticoagulation burden. In this study, we systematically evaluate the potential for endothelialization of the pyrolytic carbon surface used in mechanical valves. We compared adsorbed adhesion ligand type (collagen I, fibronectin, laminin, and purified adhesion domain fragments GFOGER and FN_7-10) and concentration on endothelial adhesion rates and adhesion strength on Medtronic-Hall prosthetic valve surfaces. Regardless of ligand type or concentration, endothelial adhesion strengthening was insufficient for their intended ultra-high shear stress environment. We then hypothesized that microfabricated trenches would reduce shear stress to tolerable levels while maintaining endothelial access to the flow stream, thereby promoting a confluent and anticoagulant endothelial monolayer. Computational fluid dynamics simulations predicted an empirical relationship of channel width, depth, and spacing that would maintain interior surface shear stress within tolerable levels. Endothelial cells seeded to confluence in these channels retained a confluent monolayer when exposed to 600 dyn/cm² shear stress for 48 h regardless of applied adhesive ligand. Furthermore, sheared EC expressed a mature anti-coagulant profile, including endothelial nitric oxide synthase (eNOS), VE-cadherin, and significantly downregulated plasminogen activator inhibitor-1 (PAI-1). As a final test, channeled pyrolytic carbon surfaces with confluent EC reduced human platelet adhesion 1000-fold over pyrolytic carbon alone. These results advance a promising biohybrid approach to enable active moderation of local coagulative response in mechanical heart valves, which could significantly extend the utility of this important treatment for heart valve disease.