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DE GRUYTER Current Directions in Biomedical Engineering 2020;6(3): 20203117 Jan Oldenburg*, Sebastian Kaule, Stefan Siewert, Niels Grabow, Klaus-Peter Schmitz and Michael Stiehm Impact of aortic annulus geometry according to ISO 5840:2019 (draft) on hydrodynamic performance of transcatheter aortic valve prostheses Abstract: To assess the hydrodynamic performance of tendency with respect to radial protrusion of the step. The transcatheter aortic valve prostheses (TAVP), in vitro test EOA decreased as the radial protrusion increased. We also using pulse duplicators is required. Test conditions as well as present a suggestion to prevent migration without affecting minimum performance criteria are specified in ISO 5840- the general test results, by using a novel step design. We also 3:2013 and ISO 5840-3:2019-draft. In the 2019 published found that the novel annulus model with native leaflet draft, modifications regarding hydrodynamic testing are drastically reduced the regurgitation. proposed. Among others, the geometrical configuration of the Keywords: ISO 5840, aortic valve, TAVP, TAVI, annulus fixation has changed, with the intention to improve the aortic fixture, hydrodynamic anatomical representation as well as the comparability of https://doi.org/10.1515/cdbme-2020-3117 results from different test laboratories. We analyzed the consequences of altered annulus fixations regarding native leaflets as well as a step in the proximal area of the protheses to prevent their migration. The 1 Introduction analyses were conducted with regard to the degree of calcification of the annulus ring on hydrodynamic Transcatheter heart valve prostheses (TAVP) are used to treat parameters. By using 3D stereolithography printing valve stenosis and insufficiency. Due to good clinical technology, molds for casting of silicone elastomer of performance, extensions of therapy from high risk to annulus models with and without native leaflets were intermediate risk patients are discussed . In order to manufactured. A modular system enabled us to use the same predict the clinical performance of the TAVP, their annulus ring to model the degree of calcification as well as hydrodynamic characteristics are tested in vitro by using different step sizes. We performed in vitro hydrodynamic pulse duplicator systems. Pulse duplicator systems simulate testing according to ISO 5840-3:2019-draft of a self- the left heart circulatory system with clinically relevant expandable valve prototype with porcine pericardial leaflets pulsatile characteristics. These testing systems are well- by using a commercially available pulse duplicator system. established and are accepted as gold standard for in vitro As expected, regurgitation increases with increasing hydrodynamic performance characterization . degree of calcification, whereby the use of a step has no The ISO 5840-3 defines requirements, test conditions as influence on the backflow of fluid during diastole. The well as minimum criteria for aortic valves . A draft, effective orifice area (EOA) of the valve showed a clear introduced in 2019 to update this standard, includes changes of in vitro hydrodynamic testing . The draft also includes a more precise specification of the fixation of the valve in the ______ *Corresponding author: Jan Oldenburg: Institute for test system. The fixation, also called aortic fixture or annuls ImplantTechnology and Biomaterials e.V., Friedrich-Barnewitz-Str. model, is intended to mimic the anatomical features of the 4, 18119 Rostock-Warnemünde, Germany, e-mail: human annulus region. This includes the implantation firstname.lastname@example.org diameter, the annulus thickness and leaflet geometry. Sebastian Kaule, Stefan Siewert, Klaus-Peter Schmitz, Comparing to the former aortic fixture design, the novel Michael Stiehm: Institute for ImplantTechnology and Biomaterials e.V., Friedrich-Barnewitz-Str. 4, 18119 Rostock-Warnemünde, design differs in modelling a native leaflet configuration as Germany well as a nodule as pathological alteration caused by plaque Niels Grabow: Institute for Biomedical Engineering, Rostock or calcification. Since the annulus models are technical University Medical Center, Friedrich-Barnewitz-Str. 4, 18119 replicas of anatomical conditions, unexpected problems may Rostock-Warnemünde, Germany Open Access. © 2020 Jan Oldenburg et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 License. Jan Oldenburg et al., Impact of aortic annulus geometry according to ISO 5840:2019 (draft) on hydrodynamic performance of transcatheter aortic valve prostheses — 2 occur. For instance, there may be a proximal migration of the Specifications for the design of the aortic fixation are shown valve in the annulus model during testing. in Table 1. The ISO specifications are compared to the The consequences resulting from different interpretation annulus models manufactured and examined within the of the normative requirements in accordance to aortic fixture current study. on the one hand and major changes, e.g. regarding the We manufactured annulus models with and without specification of the fixation on the other hand, makes it leaflets. Furthermore, the step thickness was varied. The step difficult to objectively compare the results obtained from consists of a solid ring, which could be inserted into a groove hydrodynamic tests using different fixtures. in the annulus model. In this way, the radial protrusion of the The prevention of migration as well as the general shape step was changed stepwise by using the same modular aortic of the annulus model described in the draft, especially the fixture. Moreover, a customized anti-migration step was recently proposed geometry of the native leaflets, was designed and manufactured, see Figure 2. analyzed in this study. Implantation diameter 2 Materials and methods 2.1 Geometry and manufacturing of Radial protruding step aortic annulus models The geometry of the annulus models is in accordance with the specifications of the latest draft of the ISO 5840-3:2019. The aortic fixture composed of a ring, which represents the Figure 2: Schematic illustration of the 3-point step to prevent annulus environment, including the appropriate annular proximal migration during hydrodynamic testing (radial protrusion = 2 mm) plane. In distal direction from the annular plane, there are cylindrical structures supposed to mimic the native leaflets. Figure 1 schematically illustrates the geometric parameters of Furthermore, the degree of calcification was varied from such a fixation. The minimum shore hardness of the used 1.5 mm radial protrusion with 1.5 mm corner radius to 2 mm material should not be less than 10A . If it is intended to radial protrusion with 0.2 mm corner radius. treat aortic stenosis with the valve device, the calcification of the aortic annulus should also be considered. Additionally, Table 1: Specifications of geometric annulus model; parameters we established an “anti-migration step”, the step is supposed according to ISO 5840-3:2019 draft in comparison to to prevent proximal migration of the device during manufacturing parameters of the annulus model within the current hydrodynamic testing, see figure 1. The ISO standard does work. not prescribe any kind of step, but due to the absence of Specifications ISO Specification Parameter regulatory constraints for the inflow region, a manufacturer 5840-3:2019, draft annulus model min - max diameter only max diameter may argue that such a step could be used due to its necessity. Implantation diameter recommended per (26 mm) product specification thickness minimum 4 mm 10.5 mm Implantation diameter Annulus Leaflet height 5 - 7 mm 6.4 mm structure Leaflet thickness 1-2 mm 2 mm thickness Lealfet height 0.5 * implantation 13 mm Calcification Leaflet Annular diameter height nodule plane Nodule thickness minimum 4 mm 4 mm thickness Radial Annulus Nodule protrusion height equal annulus height 6.4 mm height height of nodule Calcification radial minimum 1.5 mm 1.5 mm and 2 mm Step Step Annulus nodule protrusion Anti migration height thickness thickness Anti migration step corner radius maximum 1.5 mm 1.5 mm and 0.2 step mm radial not intended without, 1 mm, Anti migration protrusion 2 mm, 3 mm step height not intended 2 mm Figure 1: Schematic representation of the aortic annulus fixture for hydrodynamic testing; in cross sectional view (left), and in All annulus models were manufactured using a silicone proximal top view (right). elastomer casting process (Sylgard 170 Silicone Elastomer, Dow Corning, Midland, MI, USA). The shore hardness of the Jan Oldenburg et al., Impact of aortic annulus geometry according to ISO 5840:2019 (draft) on hydrodynamic performance of transcatheter aortic valve prostheses — 3 material, as stated by the manufacturer, was 47A. The casting molds themselves as well as the anti-migration steps were Table 2: Regurgitation volume measured by means of pulse manufactured by means of stereolithographic additive duplicator system for hydrodynamic characterizing of an TAVP printing technology (3D-printer: Form 2, polymer: rigid with and without leaflet geometries on the aortic fixture. resin, Formlabs Inc. Somerville, MA, USA.). Annulus type Mean regurgitation [ml] Standard deviation [ml] Without native 23.83 0.14 2.2 In vitro hydrodynamic testing leaflets With native 6.86 0.20 In order to investigate the different annulus geometries, leaflets hydrodynamic tests were carried out by using a commercial pulse duplicator system (HDTi 6000, BDC Laboratories, With identical implantation height of the valves into the Wheat Ridge, CO, USA). A prototype of a self-expandable annulus models the regurgitation increased considerably in valve made of a nitinol frame with a sutured leaflet of case of no native leaflets. We assume that the native leaflet porcine pericardium was used as test valve. Initially, the serves as a sealing, resulting in a considerably reduced valve was crimped once before further testing. For testing the regurgitation. different annulus models the valve was manually implanted into the aortic fixture. For all hydrodynamic measurements the following 3.2 Impact of anti-migration step size testing parameter were used: heart rate: 70 BPM, mean aortic pressure: 100 mmHg ± 2 mmHg, diastolic to systolic and calcification on hydrodynamic pressure difference: 40 mmHg ± 2 mmHg, systolic duration: metrics 35 %, cardiac output: 5 l/min ± 0.2 ml, test solution: 0.9% Here the use of an anti-migration step was studied. Four saline, temperature: 37°C ± 2°C. different step designs (step radial protrusion: 1 mm, 2 mm, According to ISO standard n = 10 cycles were recorded 3 mm and 3-point step) were manufactured and analyzed for each measurement. Each annulus configuration was based on the hydrodynamic results. The corresponding examined three times. regurgitation volumes are shown below in Fig. 3. The Characteristic hydrodynamic metrics of the valve annulus ring without step (step radial protrusion: 0 mm) was depending on the aortic fixture were derived from the used as a reference. measured values of the pressure and volume flow curves. These included the effective valve opening area (EOA) and the regurgitation (backward flow over the valve). The calculations of the characteristic values were carried out in agreement with ISO 5840-3:2019 (Draft) . no calification mild calicifaction 3 Results and discussion 10 severe calcification 3.1 Effect of leaflet structure on hydrodynamic valve performance 0 mm 1 mm 2 mm 3 mm 3-point step Anti-migration step type Annulus models with and without leaflet were compared, to examine the effect of the leaflets that has recently been Figure 3: Regurgitation volume of transcatheter aortic valve updated in the standards. The average regurgitation, each prosthesis in annulus models with different anti-migration step from three measurements, is shown in Table 2. types (step radial protrusion: 1 mm, 2 mm, 3 mm and 3-point step) and varying degree of calcification (no calcification; mild calcification: radial protrusion 1.5 mm, corner radius: 1.5 mm; severe calcification: radial protrusion 2 mm, corner radius: Regurgitation volume [ml] Jan Oldenburg et al., Impact of aortic annulus geometry according to ISO 5840:2019 (draft) on hydrodynamic performance of transcatheter aortic valve prostheses — 4 0.2 mm), data shows means ± standard deviation of n = 30 cycles. 4 Conclusion In General, a clear correlation between regurgitation volume The new requirements for hydrodynamic testing of the and degree of calcification can be seen. As the degree of ISO 5840-3:2019-draft marks important aspects in order to calcification increases, the total regurgitation volume ensure consistency of inter-laboratory testing. In particular, increased from approximately 7.2 ml to over 20 ml. the precise description of the aortic fixture is strengthening Compared to the degree of stenosis, the influence of the step the gold standard of this test method as an in vitro size was negligible. Thus, no major difference can be performance test. In order to evaluate the changes of the detected when using a step. proposed aortic fixture, hydrodynamic tests were conducted. The effective valve opening area is shown in Fig. 4 As reference, results obtained by using the former fixture depending on the size of the step and the degree of design were compared. We have shown that the provided calcification. leaflet structure had a major influence on TAVR regurgitation. The leaflet probably acts as a sealing around 3.60 the valve. Secondly, we have demonstrated that a step, 3.40 designed for the prevention of proximal migration of the 3.20 valve during testing, can have an influence on the overall hydrodynamic characteristics. Based on the presented results, 3.00 no calification we recommend the use of a step of less than 1 mm height or 2.80 even the use of a valve design matching step geometry, such mild calicifaction 2.60 as the presented 3-point step design. The results presented severe 2.40 may not be simply transferable to other types of valves, thus calcification the exact effect, such as an anti-migration step for the valve 2.20 to be tested, should be evaluated on each individual test case. 2.00 0 mm 1 mm 2 mm 3 mm 3-point Author Statement step Financial support by the European Regional Development Anti-migration step type Fund (ERDF) and the European Social Fund (ESF) within the collaborative research between economy and science of the Figure 4: Effective Orifice Area of transcatheter aortic valve state Mecklenburg-Vorpommern, by the Federal Ministry of prosthesis in annulus models with different anti-migration step Education and Research (BMBF) within RESPONSE types (step radial protrusion: 1 mm, 2 mm, 3 mm and 3-point step) "Partnership for Innovation in Implant Technology" is and varying degree of calcification (no calcification; mild gratefully acknowledged. Conflict of interest: Authors state calcification: radial protrusion 1.5 mm, corner radius: 1.5 mm; no conflict of interest. Informed consent and ethical approval severe calcification: radial protrusion 2 mm, corner radius: are not applicable. 0.2 mm), data shows means ± standard deviation of n = 30 cycles. References A clear tendency of the reduction of EOA in connection with the increase of the radial protrusion of the step was seen. For  Leon M, Smith C, Mack MJ et al. Transcatheter or Surgical example, without stenosis, EOA is reduced from 3.3 cm Aortic-Valve Replacment in Intermediate-Risk Patients. N Engl J Med. 2016;347(17):1609-20. (without step) to 2.44 cm (with 3 mm step) meaning a  Wu C, Saikrishnan N., Chalekian A.J. et al. In-Vitro Pulsatile reduction of 26%. The reason for the reduction in EOA might Flow Testing of Prosthetic Heart Valves: A Round Robin be a decreased effective flow cross-section due to the radial Study by the ISO Cardiac Valves Working Group. step protrusion. Cardiovascular Engineering and Technology, 2019,10:397- On the basis of the presented valve characteristics, a step  Deutsches Institut für Normung ISO 5840-3: 2013, of up to 1 mm radial protrusion as well as a 3-point step can Cardiovascuar implants – Cardiac valve prostheses – Part 3: be applied which does not influence the test outcome. Heart valve substitutes implanted by transcatheter Furthermore, it was evident that a specific 3-point step design techniques.  Deutsches Institut für Normung ISO 5840-3: 2019, adapted to the valve could be considered feasible. There was Cardiovascuar implants – Cardiac valve prostheses – Part 3: no noticeable change in regurgitation volume or EOA Heart valve substitutes implanted by transcatheter compared with the reference measurement. techniques. Effective Orifice Area (EOA) [cm²]
Current Directions in Biomedical Engineering – de Gruyter
Published: Sep 1, 2020
Keywords: ISO 5840; aortic valve; TAVP; TAVI; annulus aortic fixture; hydrodynamic
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