Tubular heart valves: a new tissue prosthesis design--preclinical evaluation of the 3F aortic bioprosthesis.

BACKGROUND: It was hypothesized that native heart valves function as if they were simple tubes with sides that collapse when external pressure is applied. Because "form follows function," this hypothesis could theoretically be confirmed by implanting a simple tube into the anatomic position of any native heart valve and documenting that under the same anatomic constraints and physiologic conditions as the native valve, the tube would assume the form of that native valve. If the hypothesis were thus proved, it would follow that a tissue valve based on a tubular design would have superior flow dynamics and stress distribution and would therefore be expected to outlast currently available tissue valves. Such a tubular tissue valve, the 3F Aortic Bioprosthesis (3F Therapeutics, Inc, Lake Forest, Calif) was designed and tested in vitro against a commercially available stentless aortic bioprosthesis. METHODS: With the use of state-of-the-art testing equipment, some of which had to be developed especially to test this truly stentless bioprosthesis in vitro, transvalvular gradients, effective orifice areas, degree of transvalvular laminar flow, finite element analysis of the distribution of leaflet stress, and accelerated wear testing for long-term durability were evaluated for the new 3F Aortic Bioprosthesis in comparison with the St Jude Medical Toronto SPV aortic bioprosthesis (St Jude Medical, Inc, St Paul, Minn). RESULTS: The valve gradients were lower and the effective orifice areas were greater for the 3F Aortic Bioprosthesis at all valve sizes and under all test conditions, including cardiac outputs ranging from 2.0 to 7.0 L/min, mean perfusion pressures from 40 to 200 mm Hg, and aortic compliances of 4% and 16%. The transvalvular flow across the 3F Aortic Bioprosthesis in vitro was qualitatively smooth, with a minimum of surrounding vortices. Maximum stress occurred in the belly of the leaflets of the 3F Aortic Bioprosthesis, with minimum stress at the commissural posts. The 3F Aortic Bioprosthesis was superior to the Toronto SPV valve in accelerated wear tests. CONCLUSIONS: These in vitro studies show that a tissue aortic valve designed on the basis of the proved engineering principle that form follows function has better hemodynamics, flow dynamics, stress distribution, and durability when compared under identical in vitro conditions with an excellent commercially available tissue aortic valve.

Fluid dynamics of venous valve closure.

In vitro experiment was performed on a stented bovine jugular vein valve (VV, 14 mm I.D. x 2 cm long) and a stentless bovine jugular vein valve conduit (10 mm I.D. x 6 cm long) in a hydraulic flow loop with a downstream oscillatory pressure source to mimic respiratory changes. Simultaneous measurements were made on the valve opening area, conduit and sinus diameter changes using a specially designed laser optic system. Visualization of flow fields both proximal and distal to the venous valve, and the valve opening area were simultaneously recorded by using two video cameras. Laser Doppler anemometer surveys were made at three cross sections: the valve inlet, the valve exist, and 2 cm downstream of the venous valve to quantity flow reflux at valve closure. The experiment confirmed that the VV is a pressure-operated rather than a flow-driven device and that little or no reflux is needed to close the valve completely. The experiment further demonstrated that the VV sinus expands rapidly against back pressure, a critical character to consider in venous prosthesis design.

In vitro pulsatile flow evaluation of a stentless porcine aortic bioprosthesis.

Suboptimal hemodynamic performance, tissue calcification, and limitation in long-term durability have been encountered clinically after aortic valve replacement with currently available bioprostheses. It is believed that some of these problems may be caused, directly or indirectly, by the stents of the bioprostheses. To address these deficiencies, the authors undertook the development of the Edwards Prima Stentless Bioprosthesis. This study was designed to evaluate the hemodynamic performance of the Edwards Prima Stentless Bioprosthesis in a pulse duplicator system. The stented Carpentier-Edwards Porcine Bioprosthesis (Baxter Healthcare Corp., Irvine, CA), which has been used in United States clinics for more than 10 years, was used as a control device. The flow fields in the vicinity of the test bioprostheses were inspected with color Doppler flow mapping. The transvalvular pressure gradients were measured invasively with a catheter and calculated with the Doppler determined velocity using a simplified Bernoulli equation. Additionally, the leakage volumes were determined with an electromagnetic flowmeter. In the Doppler flow mapping study, during systole, a central flow was observed distal to the stentless and stented bioprostheses. The central flow distal to the stentless bioprosthesis was broader than that observed distal to its stented counterpart. During diastole, no regurgitation was detected by color Doppler flow mapping in either the stentless or stented groups. The Doppler determined transvalvular pressure gradients correlated well with those measured by catheter (r = 0.990). Moreover, it was learned that the transvalvular pressure gradients of the stentless bioprosthesis were less than those of its stented counterpart, especially for the smaller sizes.(ABSTRACT TRUNCATED AT 250 WORDS)

The closing velocity of mechanical heart valve leaflets.

The closing motion of the occluder leaflets in bileaflet type mechanical heart valves (MHV) was monitored with a laser sweeping technique. The angular displacements of the leaflets were registered with precision of 0.2 microsecond steps. Experimental measurements were made using five 29 mm Edwards-Duromedics including three original specification (EDOS) and two modified specification (EDMS), and two 29 mm St Jude Medical MHVs. The testing valve was installed in the mitral position of a physiologic pulsatile mock circulatory flow loop using water-glycerine solution as the testing fluid. Each valve was tested by: (1) direct mounting the valve on metal washers, and (2) mounting the valve with its sewing ring. Experiments were carried out at pulse rates of 70, 90, and 120 beats min-1, with the corresponding cardiac output of 5, 6, and 7.5 litres min-1, and maximum left ventricular pressure gradients (dp/dt) of 1,800, 3,000 and 5,600 mm Hg s-1, respectively. The maximum leaflet closing velocity of each of the tested valve types are presented. The difference in leaflet closing movements between the direct rigid mounting and the sewing ring mounting are discussed. The details of the laser sweeping technique are presented.

Characterization of a polyepoxy compound fixed porcine heart valve bioprosthesis.

Concerns with the currently available bioprostheses are calcification, long-term durability, and suboptimal hemodynamic performance. It is well known that these concerns are all more or less related to the cross-linking reagent, glutaraldehyde or formaldehyde, used in fixing bioprostheses. To address these concerns, we undertook the development of a porcine bioprosthesis fixed with a polyepoxy compound. In the development of this polyepoxy compound valve, it was found that the porcine leaflets fixed with polyepoxy compound were softer and more pliable than those fixed with glutaraldehyde. In this study, a special microtoming technique was developed to section the biological tissue so that the fixation uniformity in distinct layers of porcine aortic wall could be characterized. The fixation index and the denaturation temperature measurements in distinct layers of aortic walls showed that the cross-linking density was uniform throughout the entire aortic wall for the polyepoxy compound fixed porcine valve. It was also noted that the fixation index of the polyepoxy compound fixed aortic wall (91.5 +/- 0.5, n = 3) was not significantly different from that of its valvular leaflet (90.6 +/- 0.8, n = 3). Similarly, the denaturation temperature of the polyepoxy compound fixed aortic wall (80.4 +/- 0.9 degrees C, n = 5) was statistically comparable to that of its valvular leaflet (79.0 +/- 0.5 degrees C, n = 5). The results of this study indicated that polyepoxy compound can adequately fix the entire porcine aortic wall as well as its valvular leaflets.(ABSTRACT TRUNCATED AT 250 WORDS)

Fixation of bioprosthetic tissues with monofunctional and multifunctional polyepoxy compounds.

Collagen from a native tissue is fixed with a polyepoxy compound (PC) for use as a new biologic prosthetic material. Prior studies have shown that this biomaterial has comparable properties with collagen fixed with glutaraldehyde (GA), and thus has great promise for biomedical applications. A prior kinetic study indicated that the reaction between the functional groups of collagen and the multifunctional epoxy EX-313 is a 2.5th-order reaction. The purpose of this study was to understand the mechanism of the amino acid-PC reactions in a fixation process. Bovine arteries were fixed with a monofunctional PC (EX-131) and a multifunctional PC (EX-313) as a function of fixation time. A sequential fixation with a second fixative was used to identify the available remaining reactive sites from a prior fixation. The denaturation temperature (Td) was measured on each sample. Because the denaturation temperature is a direct indication of crosslinking of individual amino acids with the fixative, the increase in Td of a subsequent fixation may be indicative of the available remaining amino acids. The fixation index was measured on each sample to reflect the increase of fixation completion in a sequential fixation process. The fixation index and crosslink data also revealed that the reactive amino acids for EX-131 and EX-313 may not be exactly the same. The data in this study suggest that a monofunctional fixative can pre-react with the amino acids of collagen to effectively block further fixation of collagen with a second fixative. This amino acid masking may be associated with collagen branching. Collagen branching and its effect on denaturation temperature are described.

A newly developed porcine heart valve bioprosthesis fixed with an epoxy compound. An experimental evaluation.

Concerns with currently available bioprostheses are calcification, long-term durability, and functional and hemodynamic performance. It has been well known that these concerns are all more or less related to the fixatives, glutaraldehyde or formaldehyde, used in preserving bioprostheses. To address these concerns, we undertook the development of a porcine bioprosthesis fixed with an epoxy compound. It was discovered that the porcine leaflets fixed with the epoxy compound appeared more natural than those preserved with glutaraldehyde. The performance of this newly developed epoxy compound bioprosthesis (three samples) was evaluated in a juvenile sheep model. The results were compared to those of its glutaraldehyde counterpart (three samples). Two-dimensional echocardiographic inspection of the valvular leaflet motion indicated that the epoxy compound leaflets were more pliable than their glutaraldehyde counterparts. In addition, the epoxy compound valve appeared to open more widely than the glutaraldehyde valve. Color Doppler flow mapping demonstrated that the blood flow distal to the epoxy compound valve was slightly broader than that observed distal to the glutaraldehyde valve. Moreover, at retrieval, less calcium and pannus ingrowth were observed in the epoxy compound valve than its glutaraldehyde counterpart. The results of this preliminary evaluation indicated that the performance of this newly developed epoxy compound valve was at least equivalent to its glutaraldehyde counterpart, if not better.

Neural net-bootstrap hybrid methods for prediction of complications in patients implanted with artificial heart valves.

A novel hybrid methodology for prediction of valve related complications in patients with implanted artificial heart valves is discussed. Artificial neural networks provided a mechanism for prediction of postoperative valve-related deaths based on preoperative patient information and valve parameters. Then bootstrap methodology was applied for estimating prediction errors and maximizing prediction accuracy. Data from a clinical trial with 10 years of follow-up on 789 patients implanted with Carpentier-Edwards Pericardial Bioprosthesis were used. A random subset of the data was reserved for validation of the final outcome. The remaining patients' records were repeatedly divided into two groups, using resampling strategy provided by the bootstrap methodology. One of the groups was used for training the neural net and the other one for testing the trained network and determining error rates. Patient information, such as sex, age, NYHA class and anticoagulation therapy, as well as valve parameters, such as size and the date of implant were used as the network inputs. Calculated error rates were then used for assessing the distribution of the error, further optimization of the neural network, and constructing confidence intervals for the error rates. Thus, reliable statistical estimation was obtained on the prediction accuracy. Additionally this new hybrid methodology allowed us to optimize the neural network even further, raising the accuracy of prediction to 78%.

Hemodynamic evaluation of a bioprosthetic venous prosthesis.

PURPOSE: A prosthetic venous valve must be biocompatible and nonthrombogenic and function in the venous circulation. Biocompatibility and thrombogenicity of our prosthesis have been examined in prior animal experiments, and 91% of valve conduits including early prototypes are patent at 3 weeks. However, evaluation of valve function is much more difficult in animals; therefore in this study the function of excised valves was evaluated ex vivo. METHODS: Nine bovine jugular vein conduits, each with one bileaflet venous valve, were harvested and placed in a venous flow simulator. Flows and pressures were adjusted to mimic human respiratory and hydrostatic variations. Each valve and conduit was tested for variations in valve diameter and sinus expansion in response to flow. Valve opening and closing times and valve competence were measured in response to pressure changes. After testing, each specimen was glutaraldehyde fixed and assessed a second time. RESULTS: Valve orifice area increased in response to flow in both fresh and fixed tissues. Maximum valve orifice area was reduced by fixation (27.7%) at full flows (p < 0.05). Valve sinus dimensions increased in response to increased pressure until maximum expansion was achieved (33 mm Hg). This was reduced 15.3% in fixed tissue (p < 0.05). Valve opening times (at < 1 mm Hg gradient) were slightly longer in fixed compared with fresh tissue (0.43 +/- 0.09 vs 0.41 +/- 0.13 second; p < 0.05). Valve closing times were comparable in both states (0.43 +/- 0.08 vs 0.49 +/- 0.07 second). Three fresh and seven fixed specimens that were subjected to 287 mm Hg back pressure exhibited minimal reflux. CONCLUSIONS: Size and availability make the bovine jugular vein valve an ideal venous valve substitute. Glutaraldehyde fixation renders the tissue biocompatible and nonthrombogenic while preserving anatomic integrity and leaflet strength and flexibility. Mounted and stented in a sewing sleeve, this prosthesis could represent the first generally applicable clinical solution to chronic venous insufficiency and venous hypertension.

Prediction of valve-related complications for artificial heart valves using adaptive neural networks: a preliminary study.

A novel approach to the prediction of valve-related complications in patients with implanted artificial heart valves is discussed. Adaptive artificial neural networks were used to identify patients at high risk of valve-related events based on preoperative data. Data from a clinical trial on 789 subjects with Carpentier-Edwards pericardial bioprostheses were used. Patients' records were divided into two groups, one of which was used for training the neural network and the other for testing the trained network and determining error rates. Patient information such as age, sex, NYHA class and anticoagulation therapy, as well as valve information such as size and the date of implant, were used as the network inputs. The neural net had a single output variable indicating the risk that an individual patient would develop a valve-related complication resulting in death. The results show that a trained neural network was able to predict valve-related deaths in the specified time interval of 1981-1991 with a high degree of accuracy. The neural network was also successful in classifying patients into high and low risk categories.

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)

A comparative study of complement activation by Denaflex, Bioflow, and BioPolyMeric vascular grafts.

This study was performed to evaluate the degree of complement activation by three bovine arterial graft materials: Bioflow (Bio-Vascular Inc., a bovine artery fixed with dialdehyde starch), BioPolyMeric (St. Jude Medical Inc., a collagen conduit of bovine arterial origin, tanned with glutaraldehyde and covered with a Dacron mesh), and Denaflex (Baxter Edwards CVS Division, a bovine artery fixed with polyepoxy compounds). The grafts were rinsed by following the manufacturer's recommended procedures and thereafter incubated with normal human serum. CH50 assays were performed on the serum after incubation, and the percentage of complement activation for each sample was calculated relative to its control serum. The results indicated that the BioPolyMeric grafts activated the most complement, with about a 48% decrease in the CH50. The BioPolyMeric graft is composed of an outer polyester mesh and an inner collagenous tubing, exhibiting a nonreversible negative surface charge. After the polyester mesh was removed, the BioPolyMeric graft showed the highest complement activation in this study, suggesting that the glutaraldehyde fixed graft is more prone to complement activation than either the polyepoxy compound or dialdehyde starch fixed grafts. The complement fragment, C5a, generated during complement activation is strongly chemotactic for polymorphonuclear leukocytes and monocytes, which likely play early and long-lasting roles in regulating tissue reaction to the implanted graft.

Cavitation threshold with respect to dP/dt: evaluation in 29 mm bileaflet, pyrolitic carbon heart valves.

A total of 15 bileaflet mechanical heart valves were studied in a pulse duplicator at the Helmholtz Institute (Aachen, Germany) under conditions approximating first, a physiological pressure curve and subsequently, a sinusoidal pressure curve. In this study Edwards-Duromedics valves of the modified specification were compared with the earlier version of the Edwards-Duromedics valve as well as with St. Jude Medical valves. Each valve was tested at a series of nine (9) conditions. At each condition, without altering the valve installation or the systemic conditions, each valve was filmed by two separate video systems: the Helmholtz Institute strobe light system and a high speed video recording system. All data, as recorded by each system, was then independently analyzed by both of the two contributing groups and subsequently compared. In this manner, it was possible to objectively verify not only the consistency of the data obtained, but to also determine the relative reliability of the methods for cavitation threshold detection.

Evaluation of collagen modification and surface properties of a bovine artery via polyepoxy compound fixation.

Collagen of bovine internal thoracic artery (BITA) was treated with glutaraldehyde (GA) or polyepoxy compounds (PC). This study was to evaluate the surface properties as a result of tissue tanning reaction with PC. The fixation resulted in a significant reduction of available lysine, histidine, and other amino acid residues in PC fixed grafts as compared to fresh pre-fixed arteries. Among them, the lysine (Lys) content was reduced by about 80%, indicating that PC reactions mainly involve with Lys residues. Both PC and GA treatment led to crosslinking as evidenced by the increase in the denaturation temperature. The critical surface tension and the Fourier Transform Infrared Spectrum (FTIR) on a pre-implant and its 96 days explant were evaluated and found to be similar. The FTIR analysis of a pre-implant and the 96 day explant indicated that there was no lipid deposition.

A preliminary study of the fixation mechanism of collagen reaction with a polyepoxy fixative.

A new biomaterial has been developed by fixing native collagens with a polyepoxy compound (PC) fixative. Prior studies have shown that this biomaterial has comparable properties as compared to collagen fixed with glutaraldehyde (GA) and thus has a great promise for use as an implantable bioprosthesis. The purpose of this study was to understand the mechanism of the amino acids-PC reactions in the fixation process. Bovine arteries were fixed with PC under various pH, concentration and temperature conditions as a function of fixation time. Individual amino acid components in the fresh and the fixed arteries were assayed using a Beckman amino acid analyzer to determine the degree of tanning. The denaturation temperature (Td) was also measured on each sample. Since the denaturation temperature is a direct indication of cross-linking of individual amino acids with the fixative, the difference in the degree of tanning for the same increase in Td may be indicative of the quantity of the masked, non-cross-linked amino acids. The fixation reaction data indicated that not all amino acids were cross-linked upon contacting the PC fixative. Masking appeared to be more substantial with a fixation at higher pH values.

Development and evaluation of a pliable biological valved conduit. Part II: Functional and hemodynamic evaluation.

Many congenital cardiac malformations may require a valved conduit for the reconstruction of the right ventricular outflow tract. In spite of many endeavors made in the last 25 years, the clinical results of right ventricular outflow tract reconstruction with currently available valved conduits are still not satisfactory. Specific problems encountered clinically include suboptimal hemodynamic performance, conduit kinking or compression, and fibrous peeling from the luminal surface. To address these deficiencies, we undertook the development of a biological valved conduit: a bovine external jugular vein graft with a retained native valve cross-linked with a diglycidyl ether (DE). This study, using a canine model, was to evaluate the functional and hemodynamic performance of this newly developed valved conduit. Three 14 mm conduits, implanted as bypass grafts, right ventricle to pulmonary artery, were evaluated. The evaluation was conducted with a noninvasive color Doppler flow mapping system at pre-implantation, immediately post implantation, one- and three-months post implantation, and prior to retrieval (five-months post implantation). The two-dimensional tomographic inspection of the leaflet motion at various periods post implantation showed that the valvular leaflets in the DE treated conduit was quite pliable. No cardiac failure or valvular dysfunction was observed in any of the studied cases. The color Doppler flow mapping study demonstrated that the valve in the DE treated conduit was competent, with no conduit kinking or compression observed in any of the three cases. The spectral Doppler velocity study evidenced that the transvalvular pressure gradients of the DE treated conduit were minimal as compared to those of the currently available conduits. In conclusion, from the functional and hemodynamic performance points of view, this newly developed valved conduit is superior to those currently available.

Evaluation of epoxy ether fixed bovine arterial grafts for mutagenic potential.

Two epoxy ether compounds [glycerol polyglycidyl ether (Denacol EX-313) and ethylene glycol diglycidyl ether (Denacol EX-810)] are under consideration as alternatives to glutaraldehyde for use in the processing of an arterial graft. The two are utilized as cross-linking and sterilant agents, respectively. Epoxy resins are multifunctional alkylating agents, and bifunctional alkylating epoxide solutions are known to be mutagenic. The correlation between mutagenic potential and carcinogenicity, in addition to evidence that diepoxides are carcinogenic in mice and rats, prompted the evaluation of the mutagenic potential of the epoxy treated, clinically rinsed graft. Ames and sister chromatid exchange (SCE) test procedures were used to assess mutagenic potential. Normal saline and distilled water were selected as the most physiologically representative and procedurally acceptable extraction mediums for the Ames and SCE tests, respectively. The results of the Ames and SCE tests in both the activated and non activated systems indicated that there were no statistically significant differences detected between various test article concentrates and the spontaneous mutation controls for both the activated and non activated systems. The epoxy treated graft was determined to be non mutagenic and demonstrated no dose related responses by these methods.

A compliant biological vascular prosthesis.

One requirement of the mechanical parameters for an acceptable vascular prosthesis is compliance. The compliance of a vascular prosthesis is defined as the fractional change in luminal volume per unit change in applied pressure. A compliant prosthesis has been correlated to prosthesis patency and long-term efficacy in an animal study. However, there have been very few reports on how to manufacture a compliant prosthesis. It is the objective of this study to research the processing methods to manufacture a reasonably compliant vascular prosthesis. A new fixative, polyepoxy compound, was used to fix an artery. The arteries were fixed under different degrees of longitudinal retraction. By locking in the collagen micro-structure at an overly relaxed state and then crosslinking said collagen, the resulting biological prosthesis exhibited extreme compliance and pliability. A prosthesis matching its arterial origin in tensile modulus was achieved by crosslinking an artery at its 45% retraction longitudinally. This flexible prosthesis showed a volumetric compliance index of 18.4 +/- 0.9 % delta/100 mmHg and a longitudinal tensile modulus of 942 grams/cm2. Our current study indicated that a prosthesis fixed with polyepoxy compounds has shown more pliability than that with glutaraldehyde. Further animal study to correlate prostheses patency to different degrees of compliance is needed to confirm this proposed manufacturing approach.

In vitro pulsatile flow study on effective orifice area of prosthetic mechanical heart valves.

The effective orifice area (EOA) of a mechanical heart valve is an index of how well the valve design utilizes its primary orifice area (POA). In vitro measurements of EOA of aortic valves were maintained by means of pressure drop and root mean square flow rate measurements in a pulse duplicator during systole. Edwards-Duromedics, St. Jude Medical, and Carbomedics aortic valves of sizes 19 19 mm, 21 mm, 25 mm, and 27 mm were analyzed over a cardiac output range of 3 to 7 liters/min. The resultant ratios of EOA/POA were in the range of 0.6-0.8. A simplified equation suggested by the FDA was used in this study to calculate EOAs. To agree with original assumptions of the simplification, the entrance flow area (EFA) where upstream pressure is measured, must be large as compared to that of the test valves. If not, the formula can yield questionable results such as implying that the EOA can be larger than the POA (Walker P et al, 1992) [1]. This paper discusses the limitations in using such an equation. In conclusion, we suggest utilizing the parameter square root of 1-(POA/EFA)2 to evaluate the validity of the data processing, before using the equation. The parameter should be close to one, and in this study it was 0.997.