Adult Circulatory Support
Thrombogenic Potential of Innovia Polymer Valves versus Carpentier-Edwards Perimount Magna Aortic Bioprosthetic Valves
Claiborne, Thomas E.*; Girdhar, Gaurav*; Gallocher-Lowe, Siobhain†; Sheriff, Jawaad*; Kato, Yasushi P.‡; Pinchuk, Leonard‡; Schoephoerster, Richard T.§; Jesty, Jolyon¶; Bluestein, Danny*
From the *Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York; †Department of Biomedical Engineering, Florida International University; ‡Innovia LLC, Miami, Florida; §The University of Texas at El Paso, College of Engineering, El Paso, Texas; and ¶Division of Hematology, Department of Medicine, School of Medicine, Stony Brook University, Stony Brook, New York.
Submitted for consideration June 2010; accepted for publication in revised form September 2010.
Disclosure: Innovia LLC has research collaborations with Drs. Bluestein and Schoephoerster involving the development of polymer heart valves, but there is no shared commercial interest.
Reprint Requests: Danny Bluestein, PhD, Department of Biomedical Engineering, Stony Brook University, HSC T18-030, Stony Brook, NY 11794-8181. Email: email@example.com.
Trileaflet polymeric prosthetic aortic valves (AVs) produce hemodynamic characteristics akin to the natural AV and may be most suitable for applications such as transcatheter implantation and mechanical circulatory support (MCS) devices. Their success has not yet been realized due to problems of calcification, durability, and thrombosis. We address the latter by comparing the platelet activation rates (PARs) of an improved polymer valve design (Innovia LLC) made from poly(styrene-block-isobutylene-block-styrene) (SIBS) with the commercially available Carpentier-Edwards Perimount Magna Aortic Bioprosthetic Valve. We used our modified prothrombinase platelet activity state (PAS) assay and flow cytometry methods to measure platelet activation of a pair of 19 mm valves mounted inside a pulsatile Berlin left ventricular assist device (LVAD). The PAR of the polymer valve measured with the PAS assay was fivefold lower than that of the tissue valve (p = 0.005) and fourfold lower with flow cytometry measurements (p = 0.007). In vitro hydrodynamic tests showed clinically similar performance of the Innovia and Magna valves. These results demonstrate a significant improvement in thrombogenic performance of the polymer valve compared with our previous study of the former valve design and encourage further development of SIBS for use in heart valve prostheses.
An estimated 1%–2% of the American population is afflicted with valvular heart disease (VHD), and more than 100,000 heart valve replacement procedures are performed annually in the United States.1 The National Heart Lung and Blood Institute (NHLBI) Working Group on VHD reported the 10-year mortality rate for heart valve prosthesis implantation to be 30%–55%, and the incidence of bleeding and thromboembolic complications was 1.5%–3% per year.2 In 2005, the NHLBI posted an update stating that characterization of prosthetic heart valve (PHV) thrombogenicity was outdated and needed further study. These facts justify the continued research and development of VHD treatment, particularly the improvement of existing PHVs.
Currently, VHD is treated primarily at the end stages with open-heart surgical replacement of the diseased valve with either mechanical heart valve (MHV) prostheses or tissue heart valve (THV) prostheses. MHVs have proven to be not only highly durable, lasting up to the lifespan of the recipient, but also highly thrombogenic, mandating lifelong anticoagulant drug therapy,3 which involves significant risks, such as hemorrhage or stroke.4 In contrast, THVs are much less durable, with a lifespan highly dependent on the recipient's health, and are prone to calcification and structural damage.5 However, THV recipients typically require much less intensive anticoagulant drug therapy.3,6,7 An ideal PHV is one that combines the least thrombogenic and most durable features of each of these valves, while eliminating their deficiencies.8 To that end, polymer valves, which offer hemodynamic characteristics akin to the natural aortic valve (AV), were conceived and designed; however, all prototypes to date have proven to be vulnerable to early mechanical failure, tissue in growth, calcification, and thrombogenesis.9
Innovia LLC (Miami, FL), in conjunction with others, has been developing a polymer trileaflet heart valve prosthesis using poly(styrene-block-isobutylene-block-styrene) (SIBS).10,11 SIBS has been commercialized as a coating for the Taxus Paclitaxel-eluting coronary stent (Boston Scientific).12,13 Since our first evaluation of the Innovia valve,14 the valve design was changed from low to medium profile; the leaflet geometry was converted from a spherical to a cylindrical design; the leaflet reinforcement was changed from a low-density Dacron (LARS, Boston Scientific/Meadox Medical, Inc., Oakland, NJ) to a high-density Dacron (CR Bard, Covington, GA) with the same nominal thickness; and the leaflet fabrication process was improved from dip coating to casting. This contributed to significant improvements in valve durability, by minimizing the incidence of SIBS failure.15 Additionally, Innovia has developed a thermoset cross-linked version of SIBS, which offers increased durability, thus eliminating the need for Dacron reinforcement. Surface modification of SIBS by phospholipids has proven to be effective in the reduction of platelet adhesion.16 A novel biocompatibility testing animal model demonstrated the inertness of the SIBS polymer in a live rat aorta.17 Our group recently developed a novel transcatheter valve using SIBS.18 These advances in polymer technology have moved the SIBS polymer heart valve closer to becoming a viable clinical product.
The aim of this study was to assess the flow-induced thrombogenic potential of the new Innovia PHV design compared with a clinically relevant and Food and Drug Administration (FDA)-approved THV. Activation of platelets, the principal thrombogenic elements in blood, is required for both the initiation and propagation of clot formation19 and is responsible for thrombotic complications associated with mechanical circulatory support (MCS) devices.20
Materials and Methods
Human Blood Collection and Preparation
Whole blood donations (120 ml) were obtained with informed consent, in accordance with the Stony Brook University Institutional Review Board (IRB), from healthy volunteers as described previously.21 Whole blood was anticoagulated with 10% acid citrate dextrose solution A. Plasma and red blood cells were separated by centrifugation at 650g for 6 minutes. The platelet-rich plasma was then gel filtered in platelet buffer solution and counted as described previously.14,22 The gel-filtered platelets (GFPs) were used within 6 hours of the blood draw.
Test Flow Loop Set Up
A Berlin pulsatile left ventricular assist device (LVAD) was used to create near physiologic flow conditions for circulating the platelets through the valves as described previously (Figure 1).14,22 Two identical PHVs were mounted in the LVAD in opposite orientations by custom-designed ultra-high molecular weight polyethylene valve holders as the outflow and inflow valves to control unidirectional flow (Figure 1). The valve holders were connected by 1 inch diameter clinical grade surgical Penrose tubing (CR Bard, Inc., Covington, GA), referred to as the compliance reservoir. The volume of the compliance reservoir varied during the pumping cycle between 20 ml and 85 ml. At rest, the compliance reservoir had a 1 inch diameter and was 5 inches long.
LVAD experiments were conducted as described previously with a few exceptions.14,22 Briefly, the flow loop system was filled with 200 ml of a modified Tyrode's platelet buffer solution containing 3 mM CaCl2 and GFP at a count of 20,000/μl. The test was run for 30 minutes with 50 μl aliquots sampled from the system by syringe every 10 minutes. Negative controls consisted of running the LVAD without valves in situ. The stroke rate was set to 90 bpm, the stroke volume set to 65 ml, and the systole/diastole ratio was 0.375, which produced a flow rate of 5.85 L/min.
Platelet Activation State by Thrombin Generation
The near real-time platelet activation state was quantified using the previously described modified prothrombinase platelet activity state (PAS) assay23 and has been used by us in a number of studies in various PHVs.14,22,24 Each time point sample was analyzed in duplicate. All PAS values were then normalized against the activity of fully activated platelets from the same batch as described previously.23
Platelet Activation State by P Selectin
Flow cytometric measurements were performed using CD62P or P selectin as described previously.25 Platelet surface expression of P selectin was determined using phycoerythrin-labeled antibody against P selectin. Platelet activation was quantified as the ratio of gated positive platelets to total platelets, expressed as a percentage and normalized to maximum platelet activation for each platelet batch by 100 μM thrombin receptor activator peptide (TRAP; Sigma, St. Louis, MO). Gate settings remained unchanged for each pair of valves investigated. Fluorescence intensity was determined for 25,000 events.
The in vitro hydrodynamic performance of both previous and new designs of the Innovia polymer valve, and the Edwards tissue valve were assessed using a Vivitro Left Heart Simulator (LHS) (Vivitro Labs, Inc., Victoria, BC) at Florida International University, Miami, FL, in accordance with FDA Replacement Heart Valves Draft Guidance V.5.0 as described previously.10,15,18 Tests were run at 45, 70, 100, and 120 bpm over a range of 2.3–11.4 L/min. A custom Matlab program was used to calculate the output data as follows: the regurgitant volume fraction was measured as a function of cardiac output, and the pressure gradient during forward flow was measured as a function of forward flow rate.
PAS and Flow Cytometry Data.
Experiments were run in pairs using platelets from a single donor (n = 6 pairs). The average values of the six tests were plotted per time point. Linear trend lines were fitted using the least squares method; the slopes of which were the platelet activation rate (PAR) values. The
of each pair of valves was compared with zero using SigmaPlot software v.11.0 to calculate Student's t-test. The PAR for each valve was similarly compared with the PAR of the negative control. Significance level α = 0.05 was used. Data were shown with standard error bars.
Equation (Uncited)Image Tools
Data points correlating to 45, 70, 100, and 120 bpm were plotted and consisted of the average of three flow rate data entries per bpm category. Standard deviation is shown for each parameter, e.g., mean pressure gradient. The clinical American College of Cardiology (ACC) scale was used for comparison.26
Platelet Activation State by Modified Prothrombinase Assay
The Edwards tissue valve PAR was fivefold higher than the Innovia polymer valve (n = 6, p = 0.005) (Figure 2). Negative control tests (n = 6) conducted with the LVAD operated without the valves in situ had significantly lower PAR value (0.000027 min−1) than the PARs generated with the Innovia polymer and Edwards tissue valves mounted in the LVAD (p < 0.05, respectively).
Platelet Activation State by Flow Cytometry
The Edwards tissue valve PAR was fourfold higher than the Innovia polymer valve (Figure 3, n = 6, p = 0.007).
The valve in vitro hydrodynamic tests results are presented in Table 1. The most recent Innovia polymer valve design produced results clinically similar to the Edwards tissue valve, indicating normal physiologic regurgitation volume fraction as a function of the cardiac output (Figure 4A) and nonpathological pressure gradients, normally associated with mild stenosis (Figure 4B). In comparison, the older Innovia design produced moderate stenosis conditions and higher regurgitation. The effective orifice area (EOA) was calculated by the Gorlin equation
from ISO 5840:2005, which requires the minimum EOA for a PHV with a tissue annulus diameter (TAD) of 19 mm to be at least 0.70 cm2 (ρ is the blood analog density (1.057 g/cm3), QRMS is the root-mean-square of the forward flow rate, and Δp is the pressure gradient during forward flow). All valves exceed the International Organization for Standardization (ISO)-EOA requirements.
Equation (Uncited)Image Tools
Heart valve prostheses and MCS devices, e.g., LVADs and total artificial heart (TAH), have primarily been designed to prevent hemolysis. These devices have been lifesaving and clinically successful but only partially address hemodynamic safety and efficacy issues. Platelet activation is implicated in postimplant thromboembolic strokes and occurs at shear stresses 10-fold lower than those required for significant hemolysis.27–29 Device manufacturers mostly overlook this critical flow-induced thrombogenic evaluation during the research and development of these devices, thus mandating the use of risky anticoagulation drug therapy to mitigate the problem. Therefore, it is imperative to develop methods and tools for preclinical thrombogenic evaluation of these devices that feedback into the preclinical design process with the end goal being nonthrombogenic device design.20 Our group has previously established the currently reported methods to compare different PHV designs thrombogenic potential in vitro, and this study represents an evolution of that ongoing effort.14,22,24
In this study, we show that the latest Innovia polymer valve design is fivefold less thrombogenic (p = 0.005) in our test system than the Edwards tissue valve, whereas previously we found no significant difference between the earlier Innovia polymer valve design and a St. Jude tissue valve.14 Additionally, we found that both valves were significantly different from the pumping LVAD without valves in situ (p < 0.05). This illustrates the effect of the presence or absence of the valves in the test system. We have previously established that the platelet activation measured is predominantly a function of flow past the valves (MHV or PHV) in the LVAD test system.14,22,24 The purpose of the control experiments (without valves), therefore, is to partly distinguish the effect of flow induced platelet activation within the LVAD chamber itself. It has been reported that flow-induced stresses are much lower in the LVAD chamber than those measured due to flow past PHVs.30 The well-established flow cytometric P-selectin analysis correlated well with the PAS thrombin generation results demonstrating a fourfold difference in PAR (p = 0.007).31,32 The results suggest that hemodynamics influenced by the valve design is the primary platelet activator. Therefore, these results further validate our test methods by showing the detection of significantly different PARs influenced by valve design differences, and they demonstrate the relatively low thrombogenic potential of a SIBS PHV in our test system.
We have improved our methods by using freshly isolated platelets (<6 hours) at experimental counts of 20,000/μl to obtain a more realistic baseline activation level and linear response, respectively. We previously used expired (>120 hours) pheresis platelet bags from the Stony Brook University Medical Center Blood Bank and experimental platelet counts of 100,000/μl.14,22 The former method caused the baseline platelet activation to be roughly fivefold higher than normal, which may mask activation and induce platelet-platelet interactions.21 Furthermore, we have tested valves with identical nominal internal diameters (19 mm) in identical valve holders designed with psuedosinuses of Valsalva, whereas previously the Innovia polymer valve had an internal diameter of 25 mm and the St. Jude tissue valve had an internal diameter of 21 mm, although the valve holders had 25 mm diameters with adjustable internal sizing rings.14
It was reported that the in vivo mean pressure gradient of the 19 mm Edwards Perimount Magna tissue valve was 11.9 ± 4.1 mm Hg and the EOA = 1.58 ± 0.29 cm2, which was superior to the standard Perimount valve in both measures.33 Another study showed the Magna valve to be superior to the Medtronic Hancock II porcine valve in both measures.34 Therefore, the Magna valve was a good choice as a benchmark for comparison with the prototype Innovia polymer valve.
The in vitro hydrodynamics of the Innovia valve approach those of the Magna valve. The earlier Innovia valve prototype produced a mean pressure gradient during forward flow of 42.85 ± 9.52 mm Hg compared with the new design that produced 25.73 ± 8.12 mm Hg. This represents a clinically significant decrease in pressure gradient according to the ACC scale by a shift from moderate to mild stenosis.26 In comparison, the Magna valve produced a pressure gradient during forward flow of 17.91 ± 4.81 mm Hg, which was clinically similar to the new Innovia design.
We have extensively used and validated our experimental methodology in the past. However, it is important to note that the PAS assay methodology is designed with known limitations. Primarily, it uses GFP (as described previously)23 in lieu of whole blood, eliminating the activating potential of other serum components, e.g., effects of red blood cells on platelet activation by the action of adenosine diphosphate (ADP), and platelet-platelet cross-talk by the plasma von Willebrand factor (vWF) acting as a bridging factor. However, the PAS assay still retains the major contribution of activated platelets to clot formation by thrombin, namely the prothrombinase complex, and facilitates well-controlled and sensitive comparative measurements of flow-induced platelet activity in devices. The small volume LVAD produces near physiologic flow conditions but cannot produce the physiologic afterload back pressure as can be produced in large volume pulse duplicators systems, which may alter the valve opening and closing dynamics. However, this reiterates the efficacy of the method for comparative measurements, as it is sensitive enough to produce significant results even if the valves do not operate under more extreme conditions. The small volume used in our LVAD system means that any given platelet will pass through the valves more frequently over 30 minutes than would be the case in vivo, which translates into an accelerated platelet response measurement system (similar to accelerated fatigue testing typically performed to test valve durability). For these combined reasons, we used a slightly higher, albeit within range of normal physiology, flow rate than in our previous studies.14,22
In future studies, we plan to improve the Innovia valve design using a new cross-linked version of SIBS, called Quatroset, and compare it to the existing design. We will also perform fluid-structure interaction numerical modeling to confirm our hypothesis that the cause of elevated platelet activation is due to the localized and disturbed hemodynamics of the trileaflet valve. This will enable us to iteratively evaluate valve design changes to achieve the most durable and least thrombogenic valve design before clinical trials.35,36
We have found that the latest Innovia polymer valve design is an improvement over the former design and has a significantly lower thrombogenic potential in our test system than the commercially available and FDA-approved Edwards tissue valve. This strongly indicates that the new polymer valve design is approaching the performance level of the Edwards tissue valve. As this tissue valve does not require anticoagulation in most patients, it indicates that a PHV based on this new polymer valve design may not require anticoagulation as well. Further, this moves the SIBS-based polymer trileaflet valve closer to clinical applications such as traditional open-heart or transcatheter implantation and in MCS devices, of which the latter two may require a more durable material than animal tissue.
Supported by the National Institutes of Health Award No. 1R01EB008004-01 (to D.B.). Initial funding supporting this research at Innovia LLC was provided by SBIR Grants 1 R43 HL070401-01A1, SBIR phase I and 2 R44 HL070401-02 SBIR phase II. The authors thank Dr. Anthony McGoron, PhD, Interim Chair of the Department of Biomedical Engineering at Florida International University, Miami, FL, for use of their laboratory facilities for hydrodynamic testing of the valves.
1.Rosamond W, Flegal K, Friday G, et al
: Heart disease and stroke statistics—2007 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation
115: e69–e171, 2007.
2.Edmunds LH Jr, McKinlay S, Anderson JM, et al
: Directions for improvement of substitute heart valves: National Heart, Lung, and Blood Institute's Working Group report on heart valves. J Biomed Mater Res
38: 263–266, 1997.
3.Bonow RO, Carabello BA, Chatterjee K, et al
: 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients with Valvular Heart Disease): Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation
118: e523–e661, 2008.
4.Cannegieter SC, Rosendaal FR, Wintzen AR, et al
: Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med
333: 11–17, 1995.
5.Kulik A, Bédard P, Lam BK, et al
: Mechanical versus bioprosthetic valve replacement in middle-aged patients. Eur J Cardiothorac Surg
30: 485–491, 2006.
6.Senthilnathan V, Treasure T, Grunkemeier G, Starr A: Heart valves: Which is the best choice? Cardiovasc Surg
7: 393–397, 1999.
7.Gao G, Wu Y, Grunkemeier GL, et al
: Durability of pericardial versus porcine aortic valves. J Am Coll Cardiol
44: 384–388, 2004.
8.Ghanbari H, Viatge H, Kidane AG, et al
: Polymeric heart valves: New materials, emerging hopes. Trends Biotechnol
27: 359–367, 2009.
9.Hyde JA, Chinn JA, Phillips RE Jr: Polymer heart valves. J Heart Valve Dis
8: 331–339, 1999.
10.Gallocher SL, Aguirre AF, Kasyanov V, et al
: A novel polymer for potential use in a trileaflet heart valve. J Biomed Mater Res B Appl Biomater
79: 325–334, 2006.
11.Pinchuk L, Wilson GJ, Barry JJ, et al
: Medical applications of poly(styrene-block-isobutylene-block-styrene) (“SIBS”). Biomaterials
29: 448–460, 2008.
12.Strickler F, Richard R, McFadden S, et al
: In vivo and in vitro characterization of poly(styrene-b-isobutylene-b-styrene) copolymer stent coatings for biostability, vascular compatibility and mechanical integrity. J Biomed Mater Res A
92: 773–782, 2010.
13.Boden M, Richard R, Schwarz MC, et al
: In vitro and in vivo evaluation of the safety and stability of the TAXUS Paclitaxel-Eluting Coronary Stent. J Mater Sci Mater Med
20: 1553–1562, 2009.
14.Yin W, Gallocher S, Pinchuk L, et al
: Flow-induced platelet activation in a St. Jude mechanical heart valve, a trileaflet polymeric heart valve, and a St. Jude tissue valve. Artif Organs
29: 826–831, 2005.
15.Gallocher S: Durability Assessment of Polymer Trileaflet Heart Valves,
PhD Thesis. Miami, Biomedical Engineering, Florida International University; 2007.
16.Duraiswamy N, Choksi TD, Pinchuk L, Schoephoerster RT: A phospholipid-modified polystyrene-polyisobutylene-polystyrene (SIBS) triblock polymer for enhanced hemocompatibility and potential use in artificial heart valves. J Biomater Appl
23: 367–379, 2009.
17.Wang Q, McGoron AJ, Pinchuk L, Schoephoerster RT: A novel small animal model for biocompatibility assessment of polymeric materials for use in prosthetic heart valves. J Biomed Mater Res A
93: 442–453, 2010.
18.Claiborne TE, Bluestein D, Schoephoerster RT: Development and evaluation of a novel artificial catheter-deliverable prosthetic heart valve and method for in vitro testing. Int J Artif Organs
32: 262–271, 2009.
19.Kereiakes DJ, Michelson AD: Platelet activation and progression to complications. Rev Cardiovasc Med
7: 75–81, 2006.
20.Bluestein D, Chandran KB, Manning KB: Towards non-thrombogenic performance of blood recirculating devices. Ann Biomed Eng
38: 1236–1256, 2010.
21.Schulz-Heik K, Ramachandran J, Bluestein D, Jesty J: The extent of platelet activation under shear depends on platelet count: Differential expression of anionic phospholipid and factor Va. Pathophysiol Haemost Thromb
34: 255–262, 2005.
22.Yin W, Alemu Y, Affeld K, et al
: Flow-induced platelet activation in bileaflet and monoleaflet mechanical heart valves. Ann Biomed Eng
32: 1058–1066, 2004.
23.Jesty J, Bluestein D: Acetylated prothrombin as a substrate in the measurement of the procoagulant activity of platelets: Elimination of the feedback activation of platelets by thrombin. Anal Biochem
272: 64–70, 1999.
24.Bluestein D, Yin W, Affeld K, Jesty J: Flow-induced platelet activation in mechanical heart valves. J Heart Valve Dis
13: 501–508, 2004.
25.Girdhar G, Xu S, Bluestein D, Jesty J: Reduced-nicotine cigarettes increase platelet activation in smokers in vivo: A dilemma in harm reduction. Nicotine Tob Res
10: 1737–1744, 2008.
26.Bonow RO, Carabello BA, Kanu C, et al
: ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): Developed in collaboration with the Society of Cardiovascular Anesthesiologists: Endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation
114: e84–e231, 2006.
27.Leverett LB, Hellums JD, Alfrey CP, Lynch EC: Red blood cell damage by shear stress. Biophys J
12: 257–273, 1972.
28.Nobili M, Sheriff J, Morbiducci U, et al
: Platelet activation due to hemodynamic shear stresses: Damage accumulation model and comparison to in vitro measurements. ASAIO J
54: 64–72, 2008.
29.Brown CH 3rd, Lemuth RF, Hellums JD, et al
: Response of human platelets to sheer stress. Trans Am Soc Artif Intern Organs
21: 35–39, 1975.
30.Avrahami I, Rosenfeld M, Einav S: The hemodynamics of the Berlin pulsatile VAD and the role of its MHV configuration. Ann Biomed Eng
34: 1373–1388, 2006.
31.Hagberg IA, Lyberg T: Blood platelet activation evaluated by flow cytometry: Optimised methods for clinical studies. Platelets
11: 137–150, 2000.
32.Rubenstein DA, Yin W: Glycated albumin modulates platelet susceptibility to flow induced activation and aggregation. Platelets
20: 206–215, 2009.
33.Dalmau MJ, Maríagonzález-Santos J, López-Rodríguez J, et al
: The Carpentier-Edwards Perimount Magna aortic xenograft: A new design with an improved hemodynamic performance. Interact Cardiovasc Thorac Surg
5: 263–267, 2006.
34.Borger MA, Nette AF, Maganti M, Feindel CM: Carpentier- Edwards Perimount Magna valve versus Medtronic Hancock II: A matched hemodynamic comparison. Ann Thorac Surg
83: 2054–2058, 2007.
35.Xenos M, Girdhar G, Alemu Y, et al
: Device Thrombogenicity Emulator (DTE)—Design optimization methodology for cardiovascular devices: A study in two bileaflet MHV designs. J Biomech
43: 2400–2409, 2010.
36.Alemu Y, Girdhar G, Xenos M, et al
: Design optimization of a mechanical heart valve for reducing valve thrombogenicity—A case study with ATS valve. ASAIO J
56: 389–396, 2010.
Copyright © 2011 by the American Society for Artificial Internal Organs
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read