Cardiac valve replacement: a bioengineering approach

The second most common major heart operation in the western world is valve replacement. Any one of the four heart valves may become either so stenotic or regurgitant that it needs to be replaced in order to restore normal heart function. Although replacement surgery of dysfunctional heart valves has a very high success rate, it can provide the surgeon with a difficult decision regarding the choice of a suitable prosthesis for the individual patient. Over the years many different types of artificial heart valves have been devised. Surgeons typically deal with a heart valve replacement by installing a mechanical prosthesis or by using a bioprosthetic valve, hand-crafted from animal tissue. Least commonly, valves can be taken from human organ donors. Mechanical valve substitutes have a long fatigue life but the central flow occluders often induce blood cell trauma. Tissue substitutes have an unimpeded central orifice when open, cause minimal cell damage but have a relatively short fatigue life, especially in children where calcification may be a major problem. More recently alternative materials, such as polyurethane, have been used in artificial heart valve design while the new concept of tissue-engineering has enhanced the prospects towards an ideal cardiac valve replacement. Today's artificial valves are designed with a better understanding of the cardiovascular system with the aid of computers. Advances in computer software have allowed simulations of fluid flows through valve substitutes, both in cardiac flow simulators and the heart itself.     

Increased risk for double valve replacement with tissue and mechanical prostheses

We wanted to determine whether there is any advantage of using a mitral tissue valve, when aortic and mitral valves are simultaneously replaced. We placed a tissue valve in the mitral position and a mechanical valve in the aortic position in 22 cases (combined group). In 31 other double valve replacements, mechanical prostheses were chosen for both positions (mechanical group). The mean follow-up time for the combined group was 8.9 years, and that for the mechanical group was 7.2 years. The 10-year survival rate and freedom from thromboembolism at 10 years were not different in the two groups. Treatment-related hemorrhage was seen in 3 patients of the combined group alone. Five patients among the combined group underwent reoperation because of bioprosthetic dysfunction, and the rate of freedom from reoperation at 10 years was 75 ±12%. The rate of freedom from all complications at 10 years was 43±11% for the combined group and 70±8% for the mechanical group. We find no advantage in mixing aortic mechanical and mitral tissue valves when performing double valve replacement.     

Origin and appearance of HITS induced by prosthetic heart valves: an in vitro study

Patients with mechanical heart valve prostheses show significantly enhanced numbers of HITS detected by transcranial Doppler ultrasound. In order to assess the origin of HITS formation, an in vitro study was set out to quantify valve induced microemboli for mechanical and bioprosthetic valves under various circulatory conditions by means of Ultrasound-Doppler-Sonography. At the same time the influence of CO2 partial pressure on HITS rate vas investigated. It can be summarised that for mechanical heart valve prostheses a strong correlation exists between left ventricular dp/dtmax and the detected HITS rates. It was also demonstrated that a bioprosthesis generates significantly less HITS than a mechanical valve. The origin of HITS is gaseous since the tests were carried out using a cell-free filtered water-glycerol test fluid. The HITS rate could be increased by increasing the amount of dissolved gas within the test fluid. The results support the hypothesis that cavitation is the key factor in the appearance of gaseous microemboli at heart valve prostheses.     

Bioprosthetic heart valves: modes of failure

Valve replacement started in 1960, with the surgeon now having a significant variety of prosthetic heart valves from which to choose. These valves are broadly divided into mechanical heart valves (MHV) and bioprosthetic heart valves (BHV). Improvements in the performance and ease of usage of BHV without the need for anticoagulant therapy are among the desired features of BHV and hence the increasingly preferred choice over their mechanical counterparts. However, with increased use the post-implantation complications have become more apparent, and these include: calcification, cusp tears, pannus growth, infective endocarditis, valve thrombosis and other factors specific to valve type. In this review we describe these complications in order to bring awareness among surgeons, clinicians and pathologists. Diagnosis, treatment and preventive measures, if taken in a timely manner, can help reduce their impact and further enhance the quality of life of patients with prosthetic heart valves.     

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.     

Controlled release of diphosphonates from synthetic polymers to inhibit calcification

Calcification is the most frequent cause of the failure of bioprosthetic heart valves fabricated from glutaraldehyde pretreated porcine aortic valves or bovine pericardium. Formulation and evaluation of controlled-release drug delivery system to inhibit bioprosthetic heart valve calcification is reviewed.     

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.     

Replacement of the left-side valves of an implanted total artificial heart

The MagScrew total artificial heart (TAH) is under development. Despite its anticipated durability and reliability, the possibility of a bioprosthetic valve malfunction exists. As a result, the potential for valve replacement surgery, instead of device replacement, would be desirable after a TAH implant. In two of our 90-day animal experiments, we successfully replaced the left-side valves through a left thoracotomy opposite to the right-sided incision site for the initial TAH implant. The results of these cases suggest that the left-side valves could also be replaced through a left thoracotomy approach in humans. To confirm the ability to access the left-side valves in humans, four human cadaver studies were performed with the use of a mock pump designed for human application. This report describes the operative techniques for left-side valve replacement in animals and discusses the advantages of a left thoracotomy in clinical situations, based on results from the human cadaver studies.     

The evolution of bioprosthetic heart valve design and its impact on durability.

Bioprosthetic heart valves have evolved over the years into remarkably useful and predictable devices. During this process, a number of specific designs have come and gone, and a few have remained. Many design changes were successful, and many were not. This article will describe the successes and failures of the various bioprosthetic valve designs and will detail the specific reasons why a particular design change succeeded or failed to improve bioprosthetic valve performance.     

Scaffolds for tissue engineering of cardiac valves

Tissue engineered heart valves offer a promising alternative for the replacement of diseased heart valves avoiding the limitations faced with currently available bioprosthetic and mechanical heart valves. In the paradigm of tissue engineering, a three-dimensional platform – the so-called scaffold – is essential for cell proliferation, growth and differentiation, as well as the ultimate generation of a functional tissue. A foundation for success in heart valve tissue engineering is a recapitulation of the complex design and diverse mechanical properties of a native valve. This article reviews technological details of the scaffolds that have been applied to date in heart valve tissue engineering research.     

Cardiovascular implant calcification: a survey and update.

Calcification of cardiovascular prosthetic implants is a common and important problem. This review provides an update based upon the Conference on Cardiovascular Implant Calcification held as part of the 13th World Congress of the International Society for Heart Research, 1989. A variety of cardiovascular prostheses are affected clinically by calcification, including bioprosthetic heart valves, aortic homografts and trileaflet polymeric valve prostheses. In addition, experimental studies have demonstrated calcification of artificial heart devices in ventricular assist systems in long-term calf studies. The pathophysiology of this disease process is incompletely understood. A common element between the various types of cardiovascular implant calcification is the localization of calcific deposits to devitalized cells and membranous debris. Prevention of cardiovascular implant calcification by either biomaterial modifications or regional drug therapy (controlled release) is being investigated.     

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.     

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.     

一种新型抗钙化处理的人工生物瓣膜流体力学性能

目的 评价一种新型生物瓣膜的体外流体力学性能,并与传统生物瓣膜及机械瓣膜进行比较.方法 将测试瓣膜分成三组:新型生物瓣组(GA SOB处理牛心包瓣),传统生物瓣组(单纯GA处理牛心包瓣),机械瓣组(双叶瓣),每组分别选21号、25号、29号三种型号,采用清华大学TH-1200脉动流测试仪,按照ISO5840瓣膜检测标准进行流体性能检测,包括跨瓣压差、返流量、返流百分比及有效开口面积,并进行组间的分析、比较.结果 新型生物瓣膜的前向流跨瓣压差较传统生物瓣小17%～30%,较机械瓣小23%～50%;新型生物瓣的有效开口面积较传统生物瓣和机械瓣分别大13%～37%和36%～50%;新型生物瓣的返流量较传统生物瓣大1.2～2.0 mL,约3%～6%;较机械瓣小0.9～2.8mL,约1.3%～5%.结论 新型人工生物瓣膜具有良好的血流动力学性能.     

Polymeric heart valves for surgical implantation,catheter-based technologies and heart assist devices

Efficient function and long-term durability without the need for anticoagulation, coupled with the ability to be accommodated in many different types of patient, are the principal requirements of replacement heart valves. Although the clinical use of valves appeared to have remained steady for several decades, the evolving demands for the elderly and frail patients typically encountered in the developed world, and the needs of much younger and poorer rheumatic heart disease patients in the developing world have now necessitated new paradigms for heart valve technologies and associated materials. This includes further consideration of durable elastomeric materials. The use of polymers to produce flexible leaflet valves that have the benefits of current commercial bioprosthetic and mechanical valves without any of their deficiencies has been held desirable since the mid 1950s. Much attention has been focused on thermoplastic polyurethanes in view of their generally good physico-chemical properties and versatility in processing, coupled with the improving biocompatibility and stability of recent formulations. Accelerated in vitro durability of between 600 and 1000 million cycles has been achieved using polycarbonate urethanes, and good resistance to degradation, calcification and thrombosis in vivo has been shown with some polysiloxane-based polyurethanes. Nevertheless, polymeric valves have remained relegated to use in temporary ventricular assist devices for bridging heart failure patients to transplantation. Some recent studies suggest that there is a greater degree of instability in thermoplastic materials than hitherto believed so that significant challenges remain in the search for the combination of durability and biocompatibility that would allow polymeric valves to become a clinical reality for surgical implantation. Perhaps more importantly, they could become candidates for use in situations where minimally invasive transcatheter procedures are used to replace diseased valves. Being amenable to relatively inexpensive mass production techniques, the attainment of this goal could benefit very large numbers of patients in developing and emerging countries who currently have no access to treatment for rheumatic heart disease that is so prevalent in these areas. This review discusses the evolution and current status of polymeric valves in wide-ranging circumstances.     

A 10-year comparison of explanted Hancock-II and Carpentier-Edwards supraannular bioprostheses.

BACKGROUND: Bioprosthetic heart valves are more frequently being used in valve replacement procedures today. Although second-generation bioprosthetic valves have improved functionality over their first-generation counterparts, they still often fail due to primary tissue degeneration. METHODS: This study examines two second-generation porcine valves after surgical explantation, the Hancock-II (HAN; Medtronic Heart Valve Division, Irvine, CA, USA) and the Carpentier-Edwards supraannular (CE-SAV; Baxter Healthcare Corporation, now Edwards LifeSciences, Irvine, CA, USA), with special attention to morphological/histological changes and reasons for valve failure. A total of 98 HAN and 65 CE-SAV valves were explanted and seen over a 10-year period. RESULTS: CE-SAV valves had a longer average implant duration than HAN valves (13.9+/-3.9 years vs. 10.0+/-5.1 years). Compared with HAN valves, CE-SAV valves also had a higher incidence of stent deformation (41.5% vs. 14.3%), calcification (75.4% vs. 54.1%), and pannus (100% vs. 91.8%). CONCLUSIONS: The greater degenerative changes seen with CE-SAV valves over HAN valves may be due to the longer implant duration of CE-SAV valves in this series. To our knowledge, the present study is the first direct morphological comparison of these two valve models.     

A 44-year experience of prosthetic heart valve implantation at Niigata University Hospital

Based on a single hospital experience of heart valve implantation from 1965 to 2009, the superiority of prosthetic heart valves including Starr-Edwards caged ball valves, Omniscience aortic tilting disc valves, and St. Jude Medical bileaflet valves are reviewed. This review discusses the prominent antithrombogenicity of the Starr-Edwards model 1200 aortic prosthesis under selected conditions, the relatively rarely thrombosed (despite its decreased opening angle) Omniscience aortic valve, the long-term outcomes 10 as well as 30 years after St. Jude Medical valve replacement, and finally the latest results on the significance of patient-aortic prosthesis mismatch in relation to myocardial hypertrophy. The findings described here should be considered in further investigations of cardiac valve prostheses.     

Crosslinking of decellularized porcine heart valve matrix by procyanidins

Heart valve diseases have a significant high mortality, and the valve replacement using glutaraldehyde crosslinked porcine heart valves is one of the main curing techniques. But its application is limited due to poor durability, calcification of the valves and immunogenic reactions. The aim of this study was to evaluate the crosslinking effect of procyanidins on porcine heart valve matrix. After crosslinking of the decellularized porcine aortic heart valves by procyanidins, the tensile strength, the in vitro enzymatic degradation resistance, procyanidins release from the crosslinked materials and the cytotoxicity of procyanidins to heart valvular interstitial cells were examined. The results showed that the tensile strength of procyanidins crosslinked valve matrix was higher than that of glutaraldehyde crosslinked valve matrix. Valve matrix crosslinked by 10 mg/ml procyanidins could be stored in D-Hanks solution for at least 45 days without any decline in ultimate tensile strength and maintained the elasticity as the fresh valves. Furthermore, procyanidins was found to release when the crosslinked tissue stored in D-Hanks solution. The release rate was high during the first 4 days and then dramatically decreased thereafter. During releasing phase, the concentration of procyanidins was no toxicity to heart valve interstitial cells. In vitro enzymatic degradation revealed that crosslinked matrix could resist the enzymatic hydrolysis, and the resistant capacity was approximately the same as glutaraldehyde crosslinked valve matrix. This study shows that procyanidins can crosslink porcine heart valves effectively without toxicity. Our results suggested that this method might be a useful approach for preparation of bioprosthetic heart valve.     

Autopsy-determined causes of death following heart valve replacement

The pathological findings and the principal cause of death were reviewed in 275 patients with 345 heart valve prostheses. Rheumatic fever necessitated valve replacement in 73% of these patients. Tissue valves bore significantly fewer and scantier thrombi than did the mechanical prostheses. Patients with these two groups of valves showed no significant difference with regard to the incidence of infarction of systemic organs. Patients with prostheses showed infarcts of the spleen, brain, and heart more often than did nonoperated controls with valvular disease. Among the mechanical valves, patients with Starr-Edwards valves showed the highest incidence of fatal thromboembolism. Prosthesis-related problems formed the biggest single cause of death in the 275 patients with valve prostheses. The mechanical valve group, which formed 82% of the total, had prosthesis-related problems as the prime cause of death; in the tissue valve group this complication ranked third in importance after unknown causes and diseases unrelated to valve surgery. Analysis of the valve-related causes of death showed that thrombosis and infection of the prosthesis were more important in the mechanical valves, whereas structural failure was more common with the tissue valves. Prosthesis-related fatal complications were present in 13% of the patients who died within 30 days postoperatively and in 61% of those who died later.     

Novel "biomechanical" polymeric valve prostheses with special design for aortic and mitral position: a future option for pediatric patients?

In children, systemic heart valve replacement with bioprostheses is associated with accelerated valve degeneration, and mechanical prostheses require permanent anticoagulation. Novel "biomechanical" polymeric valve prostheses ("bio" = flexible, "mechanical" = synthetic), solely made of polycarbonate urethane (PCU), were tested in vitro and in a growing animal (calf) model with the aim of improved durability without permanent anticoagulation. The trileaflet aortic prosthesis has diminished pressure loss and reduced stress and strain peaks. The asymmetric bileaflet mitral valve mimics natural nonaxial inflow. The valves underwent long-term in vitro testing and in vivo testing in growing calves for 20 weeks [mitral (7), aortic (7)] with comparison to different commercial bioprostheses [mitral (7), aortic (2)]. In vitro durability of PCU valves was proved up to 20 years. Survival of PCU valves versus bioprostheses was 7 versus 2 mitral and 5 versus 0 aortic valves, respectively. Two animals with PCU aortic valves died of pannus overgrowth causing left ventricular outflow tract obstruction. Degeneration and calcification were mild (mitral) and moderate (aortic) in PCU valves but were severe in biological valves. There was no increased thrombogenicity of the PCU valves compared to bioprostheses. The novel polymeric valve prostheses revealed superior durability compared to current bioprostheses in growing animal model without permanent anticoagulation and thus, may be a future option for pediatric patients.