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Tissue reactions to epoxy-crosslinked porcine heart valves post-treated with detergents or a dicarboxylic acid.

Calcification limits the long-term durability of xenograft glutaraldehyde (GA)-crosslinked heart valves. Previously, a study in rats showed that epoxy-crosslinked heart valves reduced lymphocyte reactions to the same extent as the GA-crosslinked control and induced a similar foreign-body response and calcification reaction. The present study was aimed at reducing the occurrence of calcification of epoxy-crosslinked tissue. Two modifications were carried out and their influence on cellular reactions and the extent of calcification after 8 weeks' implantation in weanling rats was evaluated. First, epoxy-crosslinked valves were post-treated with two detergents to remove cellular elements, phospholipids and small soluble proteins, known to act as nucleation sites for calcification. The second approach was to study the effect of the impaired balance between negatively and positively charged amino acids by an additional crosslinking step with a dicarboxylic acid. The detergent treatment resulted in a washed-out appearance of especially the cusp tissue. With the dicarboxylic acid, both the cusps and the walls had a limited washed-out appearance. The wall also demonstrated some detachment of the subendothelium. After implantation, both detergent and dicarboxylic acid post-treatment histologically resulted in reduced calcification at the edges of cusps and walls. However, total amounts of calcification, measured by atomic emission spectroscopy, were not significantly reduced. Data concerning the presence of lymphocytes varied slightly, but were in the same range as the GA-crosslinked control, i.e., clearly reduced compared with a noncrosslinked control. It is concluded that both the double detergent and the dicarboxylic acid post-treatment of epoxy-crosslinked heart valve tissue do not represent a sound alternative in the fabrication of heart valve bioprostheses.

Animals↗

Fluid dynamic models as a guide to determine prosthetic heart valve diameter.

The diameter of prosthetic heart valves is usually chosen according to the anatomic annulus size as determined during open-heart surgery. Therefore, this approach does not take into account the dimensional changes induced by heart pathology and surgical procedures. In addition, current practice fails to consider the variations of heart dimensions due to hemodynamic improvement following valve replacement. Here we suggest a method to determine the appropriate prosthesis diameter according to the hemodynamic features of the patient, to its kind of activity, and to the type of prosthesis. Assuming that the pressure drop across a valve can be calculated as delta p = apv 2/2, and considering the variation of blood flow with time and its change induced by frequency, it is possible to obtain the relationship between pressure drop and prosthetic valve diameter. The results obtained with this analytical method have been plotted on diagrams which allow the graphical determination of the proper valve diameter.

Aortic Valve↗

In vitro endothelialization of bioprosthetic heart valves provides a cell monolayer with proliferative capacities and resistance to pulsatile flow.

OBJECTIVES: Degeneration of bioprosthetic heart valves has been suggested to be at least partly an immunogenic reaction toward the xenogeneic tissue. An autologous endothelial lining has been proposed to overcome this problem. We examined in vitro endothelialization of such tissue and retention of endothelial cells after exposure to flow resembling the in vivo situation. METHODS: Cultured human saphenous vein endothelial cells were used to in vitro endothelialize photo-oxidized bioprosthetic heart valves. The endothelialized valves were mounted in a specially designed flow device, creating a pulsatile flow through the valve. Maintenance of a confluent cell layer and deposition of basement membrane markers were determined with immunohistochemical labeling. RESULTS: Labeling of the main components of the basement membrane, laminin and collagen type IV, was verified within 6 hours after in vitro endothelialization. Under static conditions, 4-mm wide denudations were completely re-endothelialized in 4 days, which was similar to the growth rate on gelatin-coated cell culture plastic, which served as a control material. After exposure of endothelialized valves to pulsatile flows for 24 hours (80 beats/min, 3.4 L/min), there were minimal cell losses from the bioprostheses. The cell layer adapted to the pulsatile flow, as verified by rearrangement of morphology and intracellular stress fibers. CONCLUSIONS: This study shows the feasibility of in vitro endothelialization of photo-oxidized bioprosthetic heart valves. The cells are able to withstand a pulsatile flow in vitro, to develop basement membrane-like structures, and to re-endothelialize denuded areas. This technology may be used to enhance the performance of bioprosthetic heart valve prostheses.

Basement Membrane↗

[Anticoagulation in patients with heart valve replacement in pregnancy].

Oral anticoagulants are the drugs of first choice for an effective anticoagulation after mechanical and biological heart valve replacement. Patients with mechanical heart valves are anticoagulated life long, whereas biological prostheses are anticoagulated for 3 months postoperatively in the case of sinus rhythm. Life-long anticoagulation in biological heart valve replacement is indicated if atrial fibrillation or dilatation of the left atrium or peripheral arterial embolism are present. During pregnancy oral anticoagulants are contraindicated in the first trimester. Heparins are effective alternatives for anticoagulation during this period. However, the dose of heparin has to be adjusted according to the activated partial thromboplastin time, which should be 1.5-fold prolonged. Low-molecular-weight heparins may be an alternative due to improved pharmacokinetics. Neither unfractionated nor low-molecular-weight heparin cross the placenta.

Anticoagulants↗

[Low intensity anticoagulation therapy after mechanical heart valve replacement].

OBJECTIVE: To investigate the proper anticoagulation intensity in patients after mechanical heart valve replacement in china. METHODS: The anticoagulation therapy intensity and the complications in 480 patients after mechanical heart valve replacement were studied. RESULTS: The follow-up rate was 89.17%, the total patient-years (Pty) was 2,110.04 years, the mean oral import warfarin dosage was (2.81 +/- 0.95) mg/day, and native warfarin dosage (2.38 +/- 0.46) mg/day. The mean PTR value of 2 116 samples was 1.43 +/- 0.26, and the INR value of 1 195 samples was 1.63 +/- 0.49. The total hemorrhage rate was 4.60% Pty, and the hemorrhage death rate was 0.38% Pty. The PTR and INR values were higher in the hemorrhage group than in the no-hemorrhage group. (t = 1.816, P < 0.05; t = 2.407, P < 0.01). The thromboembolism rate was 0.66% Pty, and the thromboembolism death rate was 0.05% Pty. There were 15 pregnancies in 14 women patients and no malformed newborns were found. CONCLUSIONS: The most important complication of anticoagulation therapy after mechanical heart valve replacement is hemorrhage in china; The proper anticoagulation intensities of this group are INR 1.5-2.0 and PTR 1.3-1.5. It is beneficial to adopt the low intensity anticoagulation therapy for decreasing the death rate from hemorrhage, protecting pregnant women and newborns from hemorrhage and malformation, and improving the life qualities of the patients.

Adolescent↗

Fluid dynamics of the CarboMedics kinetic bileaflet prosthetic heart valve.

OBJECTIVE: To compare hydrodynamic characteristics of a new bileaflet heart valve, the CarboMedics kinetic cardiac valve prosthesis, with those of a St. Jude Medical (SJM) heart valve. METHODS: Hydrodynamic characteristics were determined in the mitral and aortic positions of a Vivitro Systems pulse duplicator for size 23 Kinetic aortic values, size 23 SJM aortic valves, size 29 Kinetic mitral valves and size 29 SJM mitral valves. Test conditions were 72 beats per min with cardiac outputs of 2, 5 and 7 l/min. Values of forward flow pressure drop (delta P), regurgitant and energy loss were determined for each valve. The test results for the two valve designs were compared by valve size. RESULTS: The test results show that both the size 23 and size 29 Kinetic valves have 8-14% lower delta P values and 5-10% greater effective orifice area (EOA) values. The size 29 Kinetic mitral valve has a 1-2 ml lower regurgitant volume, while the size 23 Kinetic aortic valve has a 0.5 ml greater regurgitant volume than the corresponding SJM values. These factors combine to provide a 5-10% lower energy loss for size 23 Kinetic aortic valves and a 15-25% lower energy loss for size 29 Kinetic mitral valves over the cardiac cycle than for corresponding sizes of SJM valves. CONCLUSIONS: The Kinetic valve's fluid dynamics are superior to equivalent sizes of SJM valves. This is especially impressive considering that the tissue annulus diameters for Kinetic valves are approximately 0.5 mm less than equivalent size SJM valves. The primary reasons for the superior hydrodynamic performance of Kinetic valves are (1) the larger orifices which result in lower forward flow delta P values and (2) the opening angles, which have been customized for each valve size to minimize energy loss.

Aortic Valve↗

Osteopontin is associated with bioprosthetic heart valve calcification in humans.

Calcification of non-osseous tissues such as heart valves or vessels is a major concern in clinical practice. The exact mechanism is still unknown. Numerous studies have shown that mineral deposits of crystalline hydroxyapatite within these tissues were associated with increased non-collagenous protein content. More recently osteopontin was found to be associated with calcification in living tissues such as vessels and native human aortic valves. The aim of this study was to determine whether or not non-collagenous proteins can also be found in non-living tissues such as glutaraldehyde-pretreated porcine valves after implantation in humans. Thirty-eight glutaraldehyde pretreated porcine bioprostheses were studied: 16 not implanted and 22 after 11 years of implantation in the aortic and mitral valve position in humans. In areas of calcification vizualized by Von Kossa staining and microradiography, immunostaining using polyclonal antibodies against calcium-binding proteins showed osteopontin positive staining and no staining for osteocalcin, bone sialoprotein or osteonectin. In uncalcified areas and in non-implanted values, staining for osteopontin or other calcium-binding proteins was negative. Western blot analysis of macroscopically calcified and uncalcified areas showed that several proteins were adsorbed in implanted values and confirmed the presence of osteopontin in the calcified areas, while no immunolabelling was found in non-calcified areas, in uncalcified valves and in non-implanted valves. Thus the presence of osteopontin in the calcified areas of bioprosthetic heart valves implanted in human indicates that this protein is associated with bioprosthetic valvular calcification. Since these values are made of non-living connective tissue, and no cell immunostained for osteopontin was found around the calcified area, this suggests that a non-cellular mediated mechanism involving protein adsorption may play a role in bioprosthetic valvular calcification.

Bioprosthesis↗

[Anticoagulation of pregnant women with mechanical heart valve prostheses].

Patients with a mechanical heart valve prosthesis (MHVP) are usually anticoagulated with oral anticoagulants (OAC) to prevent thromboembolic complications. Considering the paucity of published data, the management of women with MHVP of childbearing age, who wish to become pregnant, still remains difficult and complicated. OAC may cause embryopathy during the first trimester, while neurologic complications, stillbirth and fetal death may appear during the second and third trimester. While the application of unfractionated heparin (UFH) in pregnant patients with MHVP may fail to prevent thromboembolic complications even with therapeutic dosage, only little is known about the application of body weight adjusted therapeutic dosages of low molecular weight heparin (LMWH). We report on 8 female patients, 7 with MHVP, one with atrial fibrillation, who were treated with LMWH during the whole pregnancy. No malformations or major bleeding complications were observed, no valve thrombosis or thromboembolic complications occurred. Three patients developed moderate heart failure during the third trimester, which resolved after treatment. In three patients, cesarean section was necessary, while the other five patients delivered spontaneously. Therefore, anticoagulation with body weight adjusted LMWH seems to be an alternative, safe and efficient treatment for pregnant women with MHVP. Prospective, randomized studies are needed to further evaluate this new therapeutic approach. The underlying heart disease represents a serious comorbid condition that requires continuous interdisciplinary monitoring.

Administration, Oral↗

Comparison of fondaparinux, low molecular-weight heparin and unfractionated heparin in preventing thrombus formation on mechanical heart valves: results of an in-vitro study.

BACKGROUND AND AIM OF THE STUDY: The study aim was to investigate the efficacy of three different anticoagulants in preventing thrombus formation on mechanical heart valves, using an in-vitro system. METHODS: Blood samples (470 ml) were taken from young and healthy male volunteers and anticoagulated with unfractionated heparin (UFH; n=18), low molecular-weight heparin (LMWH; n=18) or fondaparinux (n=16). Bileaflet mechanical heart valves were placed in a new device--the 'Thrombosis Tester'--and exposed in a continuous circulation at a rate of 80 beats per min to the anticoagulated blood samples for a total exposure time of 60 min. Results for thrombus weight were skewed distributed and presented as log-transformed values. RESULTS: The weight of each valve was measured before and after 1 h of perfusion; subsequent mean (+/-SD) thrombus weights were 0.739 +/- 0.573 g for UFH, 0.789 +/- 0.099 g for LMWH, and 0.934 +/- 0.145 g for fondaparinux (p = 0.397 for comparison of all groups by ANOVA). Electron microscopy showed concordant results with regard to thrombus formation on heart valve surfaces. CONCLUSION: Fondaparinux and LMWH were as effective as UFH in preventing thrombus formation on mechanical heart valves in vitro. The 'Thrombosis Tester' proved to be a new, unique instrument for investigating the ability of anticoagulants to prevent valve thrombosis on mechanical heart valves under in-vitro conditions.

Anticoagulants↗

Application of an unstructured grid algorithm to artificial heart valve simulations.

The time varying flow pattern in the vicinity of mechanical heart valves (MHV) is fairly complex: it involves multiple passages and moving leaflets. The numeric simulation of unsteady flows in these multiple passages with moving boundaries presents a major challenge to computational fluid dynamics (CFD). Two major difficulties in the numeric simulation of MHV flows are 1) the generation of a body fitted grid within the multipassage device and 2) moving leaflets. The conventional finite difference and finite volume scheme obtained by using a structured grid have serious deficiencies in these applications. To fit the grid lines with the various angles of the moving MHV, the grid may often become too skewed for accurate numeric solution. To overcome these deficiencies, significant effort and attention should be placed on the grid generation and moving grid scheme. We present an unstructured moving grid finite volume method for heart valve simulations. The Navier-Stokes equations are discretized on a general tetrahedral mesh by using a finite volume scheme. With this scheme, the mesh can be automatically generated with any commercial software. The method is applied to a tilting disk (Medtronic Hall 29mm, Medtronic, Inc., Minneapolis, MN) heart valve, and results are compared with that of the steady flow solutions. Significant differences between steady and unsteady flow solutions are observed.

Algorithms↗

Seven-and-a-half years clinical experience with the CarboMedics prosthetic heart valve.

Seven and a half year clinical experience with the CarboMedics prosthetic heart valve is presented. A total of 287 valves were inserted in 277 patients. The first 132 patients were followed in a prospective, and the remaining 145 patients in a partly prospective and partly retrospective manner. The follow up was 98.9% complete with a total of 1,055 patient-years. Actuarial survival at 7.5 years was 74.0% +/- 3.5% overall; 76.0% +/- 4.3% for single aortic, 75.0% +/- 6.5% for single mitral and 76.0% +/- 11.4% for double valve replacements. The actuarial rates of freedom from complications were as follows: valve thrombosis 99.6% +/- 0.4%, embolism 96.0% +/- 1.7%, and anticoagulant-related bleeding 88.0% +/- 2.4%. There was no hemolysis, prosthetic valve dysfunction, or structural deterioration. The linearized rates per 100 patients-years were as follows: valve thrombosis 0.09 (mitral 0.30); embolism 0.75 (aortic 0.31, mitral 1.80); anticoagulant related bleeding 2.84; paravalvular leakage overall 0.19 (aortic 0.31); prosthetic valve endocarditis 0.19 (aortic 0.31). Over a 7.5-year time frame, the CarboMedics prosthetic heart valve has been highly reliable with a low incidence of valve related complications.

Adolescent↗

The influence of manufacturing methods on the function and performance of a synthetic leaflet heart valve.

There is considerable interest in polyurethane synthetic leaflet heart valves for both ventricular assist devices and direct implantation in the body. Two different manufacturing methods, thermal forming, and dip casting, of the leaflets have been investigated. There were only small differences in the hydrodynamic function of the valves made by the two methods. However, the durability of dip cast valves was far superior to the thermally formed film fabricated leaflets, with all of the dip cast valves reaching 160 million cycles without failure. This study indicates that a correctly designed and manufactured polyurethane synthetic leaflet heart valve has the potential for long-term implantation in the body.

Evaluation Studies as Topic↗

Comparison of the cross-linking characteristics of porcine heart valves fixed with glutaraldehyde or epoxy compounds.

The concerns about currently available bioprosthetic heart valves are calcification, long-term durability, and functional and hemodynamic performance. These concerns are all more or less related to the cross-linking reagents, glutaraldehyde or formaldehyde, used in fixing bioprostheses. To address these concerns, the authors undertook the development of a porcine heart valve cross-linked with an epoxy compound. This study compared the cross-linking characteristics, shrink temperature, and moisture content of porcine heart valves fixed with epoxy compounds or glutaraldehyde. Two types of epoxy compounds, Denacol EX-313 and EX-810, or a 0.625% glutaraldehyde were used to fix the porcine aortic valves procured from a slaughter house. Samples of each group were removed at various elapsed fixation times. The shrink temperature and moisture content of the valvular leaflet and distinct layers of aortic wall of each sample were measured. Fresh porcine aortic valve was used as a control. It was found that the shrink temperature of the glutaraldehyde leaflet was the highest, whereas the moisture content of the EX-313 leaflet was the greatest among the three test groups. No significant difference in shrink temperature was observed among the epoxy compound fixed inner, middle, outer, and entire aortic walls. This implied that the cross-linking density of the epoxy compound valve was uniform throughout the entire aortic wall. The same also was observed for the glutaraldehyde fixed aortic wall.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

[Mechanical aspects of the development of artificial heart valves].

The development of an antithrombogenic coating permits a hybrid design for artificial heart valves. A substrate material optimized for its application is coated to meet the electrochemical requirements of improved hemocompatibility. But future progress in artificial heart valves requires an improvement in design as well as of the material. The basis of both aspects is the determination of such fundamental mechanical properties as the elasticity and plasticity of the valve ring and the deformation and fraction behaviour of the occluder. Analytical and numerical calculations of various different models result in different requirements for the substrate of ring and occluder. A combination of high elastic temper and low resistance to flow requires a ring material with a Young's modulus of 40 GPa or more, and a 0.2% proof stress to (Young's modulus)2/3 ratio of 0.3 MPa1/3. The best occluder materials should have a Young's modulus of more than 50 GPa and a flexural strength of at least 800 MPa. On the basis of these criteria, a heart valve consisting of a TiA15Fe2,5 ring and occluders made partially stabilized zirconia is introduced.

Biomechanical Phenomena↗

Low-molecular-weight heparin in pregnant women with prosthetic heart valves.

BACKGROUND AND AIM OF THE STUDY: Low-molecular-weight heparin (LMWH) is considered a recommended anticoagulation option in pregnant women with prosthetic heart valves. However, few data are available regarding the efficacy and safety of LMWH in this setting. METHODS: In 1999, the authors' institution developed a standardized anticoagulation protocol for pregnant women with prosthetic heart valves, which included LMWH administered between six and 12 weeks' gestation, and after 36 weeks, with prespecified target levels, and additional low-dose aspirin. Herein is presented the initial experience using this anticoagulation regimen. RESULTS: Among five women with prosthetic heart valves treated with LMWH during part of their pregnancy, four had uneventful pregnancies while one suffered a coronary artery embolus. A review is provided of the current state of knowledge regarding anticoagulation in pregnancy, with emphasis placed on the importance of strict monitoring of anticoagulation levels. CONCLUSION: Given the drawbacks of other forms of anticoagulation, and within the constraints of available data, LMWH appears--when administered with caution--to be an acceptable alternative in pregnant women with prosthetic heart valves.

Adult↗

In vitro endothelialization of commercially available heart valve bioprostheses with cultured adult human cells.

The possibility of improving the performance of heart valve bioprostheses by preendothelialization with autologous cells has been suggested. In this study we used cultured adult human vein endothelial cells to endothelialize cusps isolated from commercially available porcine valve bioprostheses. We also describe a method for primary endothelialization of the intact heart valve bioprosthesis. After detoxification of the glutaraldehyde, the cusps or valves were seeded at high density with cultured cells. To obtain an even distribution on the intact valve bioprosthesis, a device was designed which permits application of cells from different directions during rotation. Evaluation was performed by hematoxylin-eosin staining, scanning electron microscopy and immunohistochemistry of the von Willebrand factor and the human basement membrane constituent collagen IV. The endothelial cells were vital-stained during culture by the addition to the culture medium of carbocyanine dye. This made it possible to verify that the endothelium was derived from culture. A confluent lining of cultured endothelial cells in close proximity to a de novo formed basement membrane was observed on the isolated cusps 7 days after seeding. The intact heart valve bioprosthesis showed an even distribution of seeded cells with areas of cells spreading to confluency as evaluated after 24 h. However, 7 days after seeding only unspread and probably dead cells were observed.

Bioprosthesis↗