Eur J Cardiothorac Surg 2008;34:960-963. doi:10.1016/j.ejcts.2008.05.060
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Hydrodynamic comparison of biological prostheses during progressive valve calcification in a simulated exercise situation. An in vitro study
Farhad Bakhtiarya,*,
Omer Dzemalia,
Ulrich Steinseifferb,
Christof Schmitzb,
Birgit Glasmacherc,
Anton Moritza,
Peter Kleinea
a Department of Thoracic & Cardiovascular Surgery, Johann Wolfgang Goethe University Hospital, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
b Cardiovascular Engineering Group, Helmholtz Institute Aachen, Germany
c Institute of Multiphase Processes, Leibniz University of Hannover, Germany
Received 10 December 2007;
received in revised form 1 May 2008;
accepted 7 May 2008.
* Corresponding author. Tel.: +49 69 6301 6527; fax: +49 69 6301 83279. (Email: farhad{at}bakhtiary.de).
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Abstract
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Objective: Despite continuous development of anticalcification treatment for biological valve prostheses, calcification remains one major cause of structural failure. The following study investigates hemodynamics and changes in opening and closing kinematics in progressively calcified porcine and pericardial valves in a simulated exercise situation. Materials and methods: Five pericardial (Edwards Perimount Magna) and five porcine (Medtronic Mosaic Ultra) aortic valve bioprostheses (23 mm) were investigated in an artificial circulation system (150 beats/min, cardiac output 8 l/min). Leaflet kinematics were visualized with a high-speed camera (3000 frames/s). Valves were exposed to a calcifying solution for 6 weeks. Repeated testing was performed every week. All prostheses underwent X-ray and photographic examination including measurement of calcium content for evaluation of progressive calcification. Results: In the exercise situation pericardial valves demonstrated lower pressure gradients initially compared to the porcine valves (8.5 ± 1.4 vs 11 ± 1.6 mmHg), but significantly higher closing volume (5.3 ± 1.2 ml vs 1.2 ± 0.2 ml of stroke volume) leading to an equal total energy. Neither valve type demonstrated a significant increase in gradient or closing volume compared to the normal output situation. Opening and closing times were longer for pericardial valves after 6 weeks (opening time 42 ± 10 ms vs 28 ± 10 ms, closing time 84 ± 12 vs 52 ± 10 ms after 6 weeks). Pericardial valves calcified faster and more severely leading to an increase in gradients and closure volume. Conclusions: In the exercise situation pericardial valves demonstrated superior systolic function compared to porcine valves. Therefore pericardial valves have some advantage in active patients due to the lower gradients. Total energy loss remained constant during progressive calcification for both valves. Leaflet opening and closing is faster in porcine valves; clinical impact of these findings is not known. Diastolic performance is also important and should always be tested also in vivo.
Key Words: Aortic valve bioprosthesis • Hemodynamics • Valve durability
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1. Introduction
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Despite new anticalcification treatment for pericardial and porcine biological valve prostheses, dystrophic calcification remains the most important cause of structural deterioration in biological valves [1,2]. In vivo the extent and progression of calcification depends on many factors such as patient age, renal function, pregnancy and other determinants and varies significantly between individual patients [3,4]. Therefore, in vitro methods excluding these individual factors are able to investigate the effectiveness of anticalcification treatment more objectively than animal studies and, especially, clinical trials.
The present study correlates valve calcification as the morphological substitute to hemodynamic performance and leaflet kinematics of aortic prostheses in a simulated exercise situation. The method has been used for in vitro calcification of biological aortic valves in our institution and demonstrated results reproducing modes of failure in human implantation [5,6].
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2. Materials and methods
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The study was performed in co-operation between the Department of Thoracic and Cardiovascular Surgery at the Johann Wolfgang Goethe University Frankfurt am Main, Institute of multiphase processes, Leibniz University of Hannover and the Cardiovascular Engineering Group at the Helmholtz Institute Aachen, Germany.
Five porcine (Mosaic Ultra, Medtronic Inc., Minneapolis, MN, USA) and five pericardial (Carpentier Edwards Perimount Magna, Edwards Lifesciences, Irvine, CA, USA) aortic valve prostheses Ø 23 mm were tested in a previously described artificial circulation system. The fluid used in the artificial circulation system was isotonic saline solution [6,21].
In an exercise hemodynamic situation (cardiac output of 8 l/min, heart rate 150 beats/min) standard in vitro testing was performed (mean and peak systolic pressure difference, EOA, closure volume, leakage flow) followed by calculation of systolic, diastolic and total energy loss. Energy loss was defined as the time integral of the product of the mean systolic gradient and aortic flow during a defined interval like systolic duration (systolic energy loss), closing interval (closing energy loss) or leakage duration (leakage energy loss). Energy loss values are expressed in % of ventricular workload. Additionally leaflet kinematics were recorded using a high-speed-camera (3000 frames/s). Three heart cycles were taped for further evaluation. The movies were evaluated for beginning and end of leaflet motion for valve opening (opening time) and beginning and end of leaflet motion for valve closure (closure time). During the first 4 weeks valves were taken out of the pulse duplicator weekly (after 3 million heart cycles) to undergo X-ray photography, measurement of calcium and phosphate concentration in the irrigation fluid, hydrodynamic testing and recording of leaflet kinematics with the high-speed-camera. From the X-ray pictures the area of leaflet calcification in relation to the total leaflet area was calculated using the program AdOculos (Adoculos software AG, Wettingen, Germany). Following this, the valves were subjected to an additional 2 weeks of calcification and then tested as noted above. The final examination included measurement of calcium content (dry weight) for the valves using an atom-absorption-spectrometer (Analytik Jena AG, Jena, Germany).
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3. Valve calcification
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After the initial test run all prosthesis were incorporated into a pulse duplicator running at 300 beats/min. The 10 valves were irrigated with an identical high concentration calcium phosphate-solution (3.3 mmol/ml) with renewal of the fluid every week. This in vitro method of calcification uses Ca–phosphate at a pH value of 7.4 and physiological temperature of 37 °C. This method has been used and investigated previously, demonstrating results comparable to in vivo valve degeneration [11,12,22]. The higher pulse rate accelerates the calcification process as additional mechanical stress is applied to the leaflets.
During the first 4 weeks, valves were taken out of the pulse duplicator weekly to undergo photography, hemodynamic testing, and leaflet kinematics recording with the high-speed camera. The valves were subjected to an additional 2 weeks of calcification and then tested as noted above. The valves were then investigated for calcium uptake within the leaflet tissue (Figs. 1 and 2
).
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Fig. 1. Area of leaflet calcification in relation to the total leaflet area (calculated from X-ray): The five pericardial prostheses calcified faster and more severely up to 22% of the leaflet area than the porcine valves, which calcified to a maximum of 7.5% of the leaflet area [1].
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Fig. 2. Leaflet calcification over the 6-week period was significantly earlier, faster and more severe degeneration for the pericardial prostheses.
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4. Statistical evaluation
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For the statistical analysis of baseline characteristics and outcomes of the two valves, Student's t test and Fisher's exact test were used. Results are reported as the mean ± standard deviation in text and tables. Statistical significance was defined as a p value less than 0.05.
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5. Results
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Fresh pericardial valves demonstrated significantly lower values for transvalvular gradients fresh Magna pericardial valves (mean 8.5 ± 1.4 mmHg) compared to the porcine valves (mean 11.0 ± 1.6 mmHg), (p
= 0.042) leading to significantly larger EOAs (1.88 ± 0.06 cm2 vs 1.46 ± 0.08 cm2, p
= 0.009), but closure volume was significantly higher for the fresh pericardial prostheses (1.65 ± 0.11 ml vs 0.39 ± 0.08 ml, p
= 0.00042) caused by longer closing times (42 ± 10 ms vs 28 ± 10 ms, p
= 0.00051). Pericardial valves calcified faster and more severely (calcified area after 6 weeks 16.5 ± 4.3% vs 5.6 ± 2%, p
= 0.0011) leading to increase in gradients and closure volume.
The difference in transvalvular gradients in favor of pericardial valves at the beginning persisted but narrowed during the test period (mean gradients after 6 weeks 8.5 ± 1.4 vs 11 ± 1.6 mmHg. Also the EOA difference in favor of Magna valves diminished, but remained statistically significant (mean EOA after 6 weeks 1.52 ± 0.05 vs 1.28 ± 0.11 cm2, p
= 0.044). This difference in closing volume and leakage flow in favor of porcine valves remained significant throughout the whole degeneration period with some increase for pericardial prostheses (5.3 ± 1.2 ml vs 1.2 ± 0.2 ml, 10% vs 2.3% of stroke volume) leading to an equal total energy loss.
Total energy loss demonstrated comparable results for the two valves throughout the test period. The higher systolic energy loss of the porcine valves and the higher closure and leakage energy loss of pericardial valves equalized each other leading to almost identical results for the total energy loss (energy loss for pericardial valves after 6 weeks 10.4 ± 1.01% vs 10.6 ± 1.20%, p
= 0.42).
There was a significant reduction of both the calcium and phosphate concentration in all compartments during each test period indicating calcium and phosphate-uptake in both valve types (mean initial calcium-concentration 3.19 ± 0.04 mmol/l and after valve irrigation 0.28 ± 0.11 mmol/l).
Standard X-ray was used to assess the grade of calcification. Figs. 1 and 2 summarize the leaflet calcification over the 6 weeks period with significantly earlier, faster and more severe degeneration of the pericardial prostheses. The area of leaflet calcification in relation to the total leaflet area was 16.5 ± 4.3% compared to 5.6 ± 2.0% for porcine valves after 6 weeks.
After completion of the test period (18 million cycles) pericardial valves showed significantly higher Ca (170 ± 71 µg/mg vs 103 ± 49 µg/mg, p
= 0.041) and phosphate concentration (60.7 ± 25.1 µg/mg vs 41.4 ± 14.0 µg/mg, p
= 0.045).
Valve opening was seen at the exact same time point for the two valves with the pericardial valves opening to a greater extent compared to the porcine prostheses. On the other hand Magna valves demonstrated delayed and slower closure. Porcine valves opened and closed significantly faster throughout the complete observation period of 6 weeks (p
= 0.089). Whereas the leaflet kinematics remained stable for the porcine valves, there was a tendency towards longer opening times and a significant rise in closure times for the pericardial valves (Fig. 3
).
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Fig. 3. Opening and closing times of porcine (black line) (Mosaic Ultra, Medtronic Inc, Minneapolis, MN) and pericardial (white line) (Perimount Magna, Edwards Lifesciences, Irvine, CA) valves at the beginning (fresh) of the test and after 6 weeks calcification.
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6. Discussion
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The present study correlates progressive calcification of two biological valve prostheses to their hemodynamic performance and leaflet kinematics in an exercise in vitro setup. Neither valve prostheses showed much higher gradients. In regards to systolic function, we observed good prosthesis performance in both valve types during progressive calcification in a simulated exercise situation. Pericardial valves have slightly lower gradients, but higher leakage. The leakage volume for pericardial valves in this situation is less than in low output simulation; therefore pericardial valves may have some advantages in active patients due to the lower gradients and based on stable and constant hemodynamic performance during exercise, both valves might be implanted in younger patients. Leaflet opening and closing is faster in porcine valves, clinical impact of these findings is not known.
The two compared bioprostheses had the same geometric measure (Ø 23 mm) but different effective orifice areas. Studies comparing CEP to Medtronic Mosaic valves demonstrated smaller metric diameters for the Mosaic valve leading to the ability to implant larger valve sizes in 28.4% for the porcine valve versus only in 8.3% in the pericardial valves [17]. Some of the results might have been influenced by the differences in inner valve diameter, because the leaflets were subjected to different mechanical stress.
Many investigations mainly focused on the forward flow dynamics and neglected the diastolic performance, which also contributes to the workload for the heart [7–10]. This might be considered a limited view on aortic valve hemodynamics [13–16].
The porcine valve behaved closer to the performance of native valves, but leaflet opening and therefore an effective orifice were limited by the mounting to the stent.
The described initial hemodynamic performance of tissue valves is relevant for the immediate postoperative course, but for the long-term outcome hemodynamic performance of fresh valves is less important than the following changes during progressive degeneration of tissue leaflets.
The clinical impact of this increased closing volume is speculative as aortic regurgitation is generally considered to be a rather benign disease, but gradual dilatation of the left ventricle followed by congestive heart failure seems a reasonable assumption, especially if the regurgitation is progressive as demonstrated in our in vitro simulation. Heart failure has been described to be a frequent clinical presentation after aortic valve replacement occurring in up to 25% of patients after 10 years [18,19]. Indication for valve replacement in aortic insufficiency patients is seen with decreased left ventricular function and end-systolic dilatation >50 mm [20]. Echocardiographic examinations following biological aortic valve replacement should search for these indirect signs of valve incompetence in all patients and consider valve reoperation, even if signs of structural valve deterioration are not severe and transvalvular gradients remain reasonable. Both forward and backward flow disturbance will contribute to the long-term outcome following aortic valve replacement.
Magna valves calcified faster and more severely in our experiments (22% vs 7.5% of leaflet area); this might be related to the different tissue structures of pericardial versus porcine valves. This hypothesis is supported by the fact that calcification mainly appeared on the rough ventricular side of pericardial leaflets. On the other hand, the different anticalcification treatments in the two prostheses might be responsible for the calcification results. Not much has been published on the ThermaFixTM treatment for the Magna valve, whereas the mechanism of AOATM used in the Mosaic Ultra valves has been studied in detail. In porcine valves, calcification was mainly seen close to stent mounting, the area of highest shear stresses during opening and closure.
In general, diastolic performance and its consequences such as coronary perfusion rates [21,22] should be included in all native and prosthetic aortic valve evaluation and total energy loss might be the key marker for the work load on the heart rather than the transvalvular pressure gradient, which is currently focussed on in the majority of scientific publications. We would suggest that echocardiographic evaluation should especially include diastolic performance and signs of ventricular dilatation following pericardial valve implantation, whereas in porcine prostheses systolic function might be considered as the critical factor. This conclusion is not directly proven by our data, but seems reasonable if the differences in systolic and diastolic performance are considered.
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7. Study limitations
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In vitro calcification of the aortic valves eliminates the individual factor of valve degeneration, which requires large patient numbers for in vivo studies. Also the method used in the present study has been previously verified. However, this is still an in vitro experiment with all the usual limitations including the fact that of course the process of valve calcification might be different in the individual patient. The valves were removed from the calcifying solution for hemodynamic testing each week, so the calcification process might have been interrupted and thus impacted the outcome.
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Footnotes
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Presented at the 21st Annual Meeting of the European Association for Cardio-thoracic Surgery, Geneva, Switzerland, September 16–19, 2007.
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Abstract
1. Introduction
