Transapical Aortic Valve Replacement under Real-time MagneticResonance Imaging Guidance: Experimental Results withBalloon-Expandable and Self-Expanding Stents

Keith A. Horvath, MD[Director of Cardiothoracic Surgery Research Program],Cardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, NationalInstitutes of Health

Dumitru Mazilu, PhD,Cardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, NationalInstitutes of Health

Ozgur Kocaturk, PhD, andTranslational Medicine Branch, National Heart, Lung and Blood Institute, National Institutes ofHealth

Ming Li, PhDCardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, NationalInstitutes of Health

AbstractObjective—Aortic valves have been implanted on self-expanding (SE) and balloon-expandable(BE) stents minimally invasively. We have demonstrated the advantages of transapical aorticvalve implantation (tAVI) under real-time magnetic resonance imaging (rtMRI) guidance.Whether there are different advantages to SE or BE stents is unknown. We report rtMRI guidedtAVI in a porcine model using both SE and BE stents, and compare the differences between thestents.

Methods—Twenty-two Yucatan pigs (45-57kgs.) underwent tAVI. Commercially availablestentless bioprostheses (21-25mm) were mounted on either BE platinum-iridium stents or SEnitinol stents. rtMRI guidance was employed as the intraoperative imaging. Markers on both typesof stents were used to enhance the visualization in rtMRI. Pigs were allowed to survive and hadfollow-up MRI scans and echocardiography at 1, 3 and 6 months postoperatively.

Results—rtMRI provided excellent visualization of the aortic valve implantation mounted onboth stent types. The implantation times were shorter with the SE stents (60±14 seconds) than BE(74±18s), (p=0.027). Total procedure time was 31 and 37 minutes respectively (p=0.12). It wasconsiderably easier to manipulate the SE stent during deployment without hemodynamiccompromise. This was not always the case with the BE stent and its placement occasionally

© 2010 Elsevier B.V. All rights reserved.Correspondence Author: Keith A. Horvath, MD, Cardiothoracic Surgery Research Program, National Heart, Lung and BloodInstitute, National Institutes of Health, Bldg 10, 2N246, 9000 Rockville Pike, Bethesda, MD 20892, horvathka@mail.nih.gov, Tel:1-301-451-7098.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to ourcustomers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review ofthe resulting proof before it is published in its final citable form. Please note that during the production process errors may bediscovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Published in final edited form as:Eur J Cardiothorac Surg. 2011 June ; 39(6): 822–828. doi:10.1016/j.ejcts.2010.09.030.

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resulted in coronary obstruction and death. Long-term results demonstrated stability of theimplants with preservation of myocardial perfusion and function over time for both stents.

Conclusions—SE stents were easier to position and deploy thus leading to fewer complicationsduring tAVI. Future optimization of SE stent design should improve clinical results.

Keywordstranscatheter aortic valve implantation; rtMRI guidance; self-expanding stent; balloon-expandablestent

1. IntroductionTo reduce trauma and speed recovery for the patient; minimally invasive aortic valvereplacement, both a percutaneous transfemoral approach [1-6] and a left ventriculartransapical approach [7-12], have been reported. Compared to the former, transapical aorticvalve implantation provides a direct and short access to the native valve. This approach maybe more applicable to a number of patients because of the lack of physical anatomiclimitations that can preclude a femoral approach.

MRI provides better anatomic detail than fluoroscopic or echocardiographic imagingwithout additional risk of radiation and contrast reaction. Calcification does not interferewith the MR imaging. Vascular as well as soft tissue visualization can easily be performedsimultaneously. The development of real-time magnetic resonance imaging (rtMRI) allowsthis imaging modality to provide intraoperative guidance for delivery of prosthetic aorticvalves [13]. MRI also provides the ability to assess results, such as ventricular and valvularfunction, and myocardial perfusion, immediately after intervention. Our group hassuccessfully performed transapical aortic valve replacements using rtMRI guidance [14,15].After acute feasibility studies confirmed the safety of the rtMRI guided procedure, initiallyusing a BE stent, we commenced a series of experiments with long term follow up [12].

In minimally invasive aortic valve replacement, a stent is employed to support the prosthesisand to anchor the prosthesis to the aorta. Two types of stents, balloon-expandable (BE) andself-expanding (SE), have been used. One of the first percutaneous prosthesis for thetreatment of aortic valve disease was the Cribier-Edwards Aortic PHV (EdwardsLifesciences Inc, Irvine, California). This balloon-expandable prosthesis is a tubular slottedstainless steel stent with an attached equine or bovine pericardial trileaflet valve [5,6,16-17].This prosthesis has also been used for both a transfemoral and a transapical approach [8-11].The other percutaneous prosthesis which has been used in a large clinical trial is the self-expanding CoreValve ReValving prosthesis, (CoreValve Inc, Irvine, California). Thisprosthesis uses a porcine bioprosthesis within a nitinol frame [18-20].

There are several other new stented prostheses in various stages of development forpercutaneous approaches [7,21-23]. While there are many advantages and perhaps severaldisadvantages with all of these devices, whether there are additional benefits or risksdepending on the mechanism whereby the stent expands and the valve is subsequentlydeployed are unknown.

In this paper, we report our rtMRI guided tAVI in a porcine model using both SE and BEstents, and compare the differences between the stents, in terms of the ease of performingthe tAVI, the valve function, the valve position and stability as well as stent integration withthe aorta in a preclinical survival experiment.

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2. Methods & Materials2.1 Self-expanding stent and stented prosthesis

As the name implies, the SE stent can expand without external force and can be crimpedbefore it is allowed to expand. For our study we designed a stent that could be used toaccommodate a conventional stentless aortic porcine bioprosthesis (Toronto SPV, St. JudeMedical, Inc, Minneapolis, MN or Freestyle, Medtronic Inc., Minneapolis, MN), whoseclinical durability and success rate are already been proven. As the aortic valve lies in closeproximity to both the anterior leaflet of the mitral valve and the coronary ostia, the correctposition and orientation of the implanted valve is critical. Misalignment of the prosthesiscould result in mitral valve damage or cardiac ischemia. The prosthesis must be adequatelyfixed in place such that migration or embolization does not occur despite high bloodpressures.

The design and development of the SE stent addressed the above requirements. The stent ismade from nitinol; it is safe and compatible in the high magnetic field of MRI. The materialis memory alloy. The stent can be crimped, and it will return to its original shape when thereis no external force. It was created with different diameters to accommodate theaforementioned 21-25mm stentless bioprosthetic valves that are used clinically to match thepatients’ aortic annulus. A special cylindrical geometric design with flare at both ends wasemployed to ensure better fixation and scaffolding. All the values of the geometricparameters guarantee even radial force and flexibility as well as rigidity of the stent.

The structure of the stent also makes it easily retractable into a delivery device. Adjustmentof the position during valve placement is therefore possible. Figure 1 left shows a St. JudeToronto SPV valve (St. Jude Medical Inc, Minneapolis, MN) mounted on the SE nitinolstent. Small austenitic stainless steel fragments (0.5mm) were welded on the side of the stentaligned with one of the prosthesis commissures. This paramagnetic passive marker is visibleas a dark signal in the MRI and is used to indicate the orientation of the stented prosthesis.

2.2 Balloon-expandable stented prosthesis and balloon-catheterA commercially available platinum-iridium stent (Cheatham Platinum, NuMed, Hopkinton,NY) was used for BE stented prosthesis. The BE stent was originally developed, approvedand commercially available for treatment of coarctation of the aorta. It is MR safe andcompatible. 21-25mm stentless bioprostheses (Toronto SPV, St. Jude Medical, Minneapolis,MN, or Freestyle, Medtronic Inc, Minneapolis, MN) with proper size based on pre-op MRIscan were mounted on the stent. Figure 1 shows a Freestyle (Medtronic Inc, Minneapolis,MN) mounted on the Numed platinum-iridium stent. The same passive markers were alsowelded to these stents. The stented prosthesis is then circumferentially compressed overtwo-stage balloon-tipped catheters (NuMed, 25-30mm OD, 50mm long). A central guidewire allowed passage and tracking of the balloon-tipped catheter antegrade across the nativeaortic valve.

2.3 Real-time Interactive MRI1.5-T Magnetom Espree (Siemens Medical Solutions, Munich, Germany) was used for theintervention and post intervention assessment. A real-time Interactive MRI systemconnected to the MRI scanner provides visualization of the progress of the procedure [13].This system is comprised of an interactive user interface, an operating room large-screendisplay, gated pulse sequences, and image reconstruction software. High-quality images canbe obtained at 5-10 frames per second with low latency. With the real-time interactive MRI,multiple oblique slices can be obtained in rapid succession and can be simultaneouslyrendered in their relative 3D positions to provide optimal 3D anatomic information. Image

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contrast, image plane orientations, acquisition speed, 3D rendering, and device tracking canbe readily adjusted as needed during scanning.

An active wire (ie, MR signal receiving loopless antennae) is used to indicate the orientationof the stented prosthesis. This wire was colorized and highlighted in the MR images. For theBE stent, the wire is temporarily affixed to the stent/catheter, and aligned with one of thevalve commissures [15]. For the SE stent, it is embedded in the delivery device, and isaligned with one of the valve commissures loaded in the delivery device.

2.4 Valve Implantation under MRI guidanceAll experiments were performed by a single operator under protocols approved by theNational Institutes of Health Animal Care and Use Committee. 1.5T MR imaging was usedto precisely identify the anatomic landmarks of the aortic annulus, coronary artery ostia, andthe mitral valve leaflets. Based on the pre-op image, an appropriate size prosthesis wasselected and mounted on either a BE or a SE stent of matching size. The animals thenunderwent rtMRI guided transapical aortic valve replacement without unloading by rapidventricular pacing or cardiopulmonary bypass. Details of the real time MR imaging duringtransapical aortic valve implantation have previously been reported [14,15].

To date we have operated on 42 Yucatan pigs, 20 for an acute feasibility study and theremaining 22 for a survival procedure comparing SE and BE stents. All the animals foracute feasibility study received BE prostheses. For the long term survival study, 11 animalsreceived a BE prosthesis and 11 animals had implantation with SE prosthesis. We recordedthe time of the procedures and observed the interference of the devices with the surroundingenvironment during the procedures. Post-placement images were acquired to evaluate theprostheses position, as well as, the valvular and heart function.

The procedures using the two types of the stents are slightly different. In a procedure usingthe BE prosthesis, the distal end of the sheath of the loaded delivery device is placed belowthe aorta annulus level; pushing the balloon tipped catheter will advance the crimpedprosthesis out of the sheath to the desired position, and then the balloon was inflated toexpand the stent and deploy the prosthesis. In a procedure using the SE prosthesis, theloaded delivery device was first advanced into the ascending aorta. The retraction of thesheath allowed crimped prosthesis to expand and affix to the desired position. Figure 2 andfigure 3 shows the progress of the BE prosthesis and SE prosthesis valve implantation underMRI guidance, respectively. We recorded the time for the procedures and compared the easeof performing the procedures with both stents.

During the procedure, the animals were heparinized and monitored with ECG, oxygensaturation, end-tidal CO2, systemic and left ventricular blood pressure, and arterial blood gasanalysis.

2.5 Post Implantation evaluationAt 1 and 3 months postoperatively, follow-up MRI scans and transthoracic echocardiogramswere acquired while at 6 months postoperatively MRI scans and confirmatory 2- and 3-dimensional transesophageal echocardiograms were acquired. After 6 months the animalswere sacrificed, and the histopathology analyses were performed. We compared the valvularfunction, the valve position and stability, stent integration with the aorta for both stentsduring the long-term follow up.

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3. ResultsrtMRI provided excellent visualization of the aortic prosthesis implantation mounted on bothstent types. The active wires were a superb indicator of the valve orientation in MRI. Thepassive markers on the SE stents were also help to identify the valve orientation. Thesemarkers were somewhat difficult to visualize via MRI when the stents were fully crimpedbut became more apparent as the stents were deployed.

We recorded the procedure time and deployment time for using BE stent and SE stent on 22survival animals. We also performed t-test to determine the significance of the differenceson the procedure time and deployment time between two groups. Total procedure time was37 and 31 minutes for using BE stent and SE stent respectively. The total procedure time forboth stents were not significantly different (p=0.12). The time from introduction of theprosthesis into the trocar to deployment the stent is fully expanded (deployment time) was74±18 seconds (mean ± std. dev.) and 60±14 seconds (mean ± std. dev.) respectively. Thisdeployment time was significantly shorter for the SE stent (p=0.027). Once the BEprosthesis was in place, the balloon is first partially inflated by using normal saline mixed100:1 with an MR contrast agent Gd-DTPA (Magnavist, Berlex Inc, Montville, NJ), theposition is re-confirmed to be ideal and the balloon is then fully expanded and the stentedprosthesis completely deployed. The procedures using BE prosthesis therefore took aslightly longer time because of this time for staging the balloon-inflation and the difficultyin orienting the valve knowing that once the balloon was completely inflated there was nomargin to allow for adjustment. When the balloon was inflated to deploy the BE stent therewas a significant change in the blood pressure and a concomitant decrease in the cardiacoutput. This hemodynamic compromise was seen even with partial inflation of the balloon.There was no significant blood pressure drop observed during the SE prosthesisimplantation. Even partially deployed the SE stent was not as obstructive as the combinationof balloon and stent for the BE device. Blood can flow through a partially deployed SE stentbut even a partially filled balloon for a BE stent is obstructive and had a negative impact onthe hemodynamic stability of the animal. Additionally the inability to easily controldeployment with the BE stent resulted in coronary obstruction and death. 4 out of 20 of theanimals in acute feasibility study with BE prosthesis implanted died of coronary obstruction.

Post-placement images were acquired to confirm the positions of the prostheses and assessthe valvular and heart function. Gated cine MRI revealed excellent myocardial function aftervalve implantation in both long- and short-axis views for animals in whom the valves wereappropriately positioned. The phase-contrast CINE MR images confirmed good systolicflow with excellent valve leaflet opening and no evidence of turbulence, diastolic regurgitantflow, or paravalvular leak. First-pass perfusion studies [24] demonstrated adequacy ofmyocardial blood flow after valve placement in all animals following successfuldeployment. The perfusion results confirmed adequacy of blood flow at the tissue level,indicating proper valve positioning with respect to the coronary ostia.

Among 11 animals implanted with a BE prosthesis, 3 died between 1 and 2 weekspostoperatively of respiratory complications. Among 11 animals implanted with SEprosthesis, 3 animals died within one month postoperatively due to late pneumothorax orpneumonia, 1 died of pneumonia at day 35. None of the survivors of the initial implantationdied of late coronary obstruction. Hemodynamic measurements of ventricular and valvularparameters of 15 animals based on 6 months follow-up echocardiograms (and confirmed byMRI scans) are presented in figure 4. There is no significant difference between the animalswith the BE prosthesis and those with the SE prosthesis. The degree of insufficiency of theaortic valve and the mitral valve at 6 months after the procedure were measured and are

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shown in figure 5. More aortic and mitral regurgitation was seen with the BE prosthesis butthis trend was not statistically significant.

Post-mortem pathologic analysis, after sacrifice at 6 months, verified that the implanted bothBE and SE prosthesis appeared in place in the aortic root. The prosthetic commissures wereincorporated with neointimal growth continuous with the native leaflet commissures. Theaverage strut fractures for the platinum iridium BE stent was 5.0±3.1 (mean ± std. dev.),while the average fractures for the nitinol SE stent was 1.6±2.5 (mean ± std. dev.)(p=0.046).There was no particular pattern of strut fractures observed. In eight animals with BE stent, 2animals had fractures at the level of the proximal crowns; 3 animals had fractures at thelevel of the distal crowns, and 3 animals had fractures scattered throughout the stent. Inseven animals with SE stent, 1 animal had fracture at the level of the proximal crowns, 1animal had fractures at the level of distal crowns, and 2 animals had fractures throughout thestent, 3 animals did not have fractures. The fractures are due to the stent material fatigue andthe expansion, contraction, torsion between the aorta and the stent. We performed a t-test todetermine the significance of the differences in the number of strut fractures between thetwo groups. The nitinol SE stent has elasticity and its geometry design permit to handle thetorsion better, while the BE stent has no elasticity and the material is relatively soft.

Some limitations were only observed in BE stent cases at the time of sacrifice. In oneanimal, the stent was collapsed/compressed on itself at its mid-section. Malapposed stentstruts at either ends were observed in five animals. In one animal, a prosthesis cusp appearedcollapsed. All of these were due to uneven deployment of the BE prosthesis. On the otherhand in the SE cases, transverse sections from the device (prosthetic aortic valve) showed awidely patent implant lumen with circular, symmetrical shape maintaining tight appositionof the stent frame to the aortic wall in all the animals with the SE prosthesis. Representativeradiographs of the BE stented prosthesis and the SE stented prosthesis are shown in figure 6.Autopsy confirmation of BE and SE prosthetic valve location after 6 months implantation isseen in figure 7.

4. DiscussionrtMRI provides excellent visualization for intraoperative guidance of aortic valvereplacement on the beating heart using both BE and SE stented prosthesis.

The uncertainty of the stented prosthesis’ orientation and position during the expanding of aballoon, may lead to the blockage of the coronary ostia. This was observed in our previousacute studies. Since the stented prosthesis is not rigidly mounted on the balloon, there is thepossibility that the prosthesis slides and rotates on the balloon during the balloon-expansion.Moreover, the balloon may not expand uniformly, causing the prosthesis to move from itsposition or be unevenly deployed. As a result, coronary cusp may collapse and focal gapsbetween stent and the native aortic wall may occur. The difficulty with uneven deploymentis due in part to the uneven expansion of the balloon when it is inflated. The force of theballoon is not equally distributed to the stent. This may be an even greater problem incalcified aortic valves where the calcium will impair balloon filling and stent expansion.When the radial force and position of the stent is primarily due to the balloon then unevenexpansion leads to uneven force and unbalanced strut expansion and would lead to long termunbalanced distribution of force on the stent with expansion and contraction and torsion ofthe aorta.

To deploy a BE stent, additional assistance may be required to inflate the balloon while thesurgeon controls the positioning. The balloon needs to be gradually inflated so that theorientation and position of the prosthesis can be adjusted before it is fully affixed. The more

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the balloon is inflated the more obstructive it is to the left ventricular outflow track. Toavoid significant hemodynamic compromise or embolization of a partially deployed device,unloading the heart by cardiopulmonary bypass or minimizing ejection by rapid ventricularpacing has been used clinically to assist in the placement of BE stented prostheses. The BEstent is not retrievable. Once it is outside of the protecting sheath, it cannot be easilyretracted. One advantage of the BE stent is its “universal” size. The final expanded size ofthe stent depends in part on the size of inflated balloon and can therefore be used to allowthe stent and prosthesis to conform to the native valve and annulus.

In our experience, SE stents were easier to position and deploy thus leading to fewercomplications during transapical aortic valve implantation. The intrinsic radial force allowsfor even expansion of the prosthesis. As a result, the orientation of the implanted valve ismore predictable. The elimination of the balloon inflation avoids the possibility of thehemodynamic compromise. Partially deployed the SE stent allows blood flow through thestent and there is no balloon to impede flow. The SE stent can be retrieved and repositionedbefore it is fully expanded; this helps with precise placement and diminishes the risk andembolization. All of these features favored the SE stent. This ease of implantation may be asubjective finding with any device but is nevertheless important to the practioner.

Additionally the long term impact of balloon expansion on the prosthetic valve leaflets isunknown. For both stents the valves are similarly crimped but only the BE stent putsadditional stress on the leaflets of the prosthesis as the balloon is inflated and stretches theleaflets as well as the stent. This could lead to short and long term damage and lessendurability.

Although we performed our experiments under intra-operative rtMRI guidance, thematerials and devices presented in the paper can be used in the transapical aortic valveimplantation under guidance with other imaging modalities. The conclusions areindependent to the image guidance method and the results apply to those centers withoutaccess to intra-operative rtMRI.

We continue to evaluate the long term results of using both stents. Further optimization ofthe SE stent design should facilitate the procedure and may improve clinical results. One ofthe earliest upgrades was the development of a stent retrieving device, which can be used toretrieve and reposition the stent as well as prevent unexpected motion of the stent duringdeployment.

AcknowledgmentsThe authors also would like to thank Dr. Renu Virmani and Russ Jones from CV Path Institute, Inc for thepathology analysis.

The authors are supported through the Intramural Research Program of the National Heart, Lung, and BloodInstitute, NIH, DHHS.

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Fig 1.St. Jude Toronto SPV valve sewn inside the nitinol self-expanding stent (left), MedtronicFreestyle valve sewn inside the Numed platinum-iridium stent balloon expandable stent(right).

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Fig. 2.Selected frames from the real-time MRI displayed within the scan room, showing thedeployment of the prosthetic valve mounted on a balloon-expandable stent. A: The positionof the aortic valve annulus is obvious. B. The prosthetic valve is advanced into position inthe left ventricular outflow track. C. interactive saturation used to enhance visualization ofextent of the balloon (filled with dilute Gd-DTPA) inflation. D. The balloon is deflated andthe delivery device is removed from the trocar.

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Fig 3.Selected frames from the real-time MRI displayed within the scan room, showing thedeployment of the self-expanding stented prosthetic valve. a: Stented prosthesis is insertedinside the trocar. b: The stented prosthesis is advanced to the end of the trocar. c: Theprosthesis is inserted across the native valve and aligned with coronary ostia and aorticannulus. d,e,f,g: Sequence of the prosthesis expansion. During this period, the prosthesis canbe retrieved. h:. The prosthesis is fully deployed. i: The delivery device is removed from thetrocar.

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Fig 4.Echocardiographic hemodynamic measurements 6 months after implantation. There were 8animals in Balloon-expandable prosthesis group, 7 animals in Self-expanding prosthesisgroup. The numbers above the bar are mean ± SD. We performed t-test to determine thesignificance of the differences between BE group and SE group on ejection fraction (EF),Aortic valve peak gradient (AV peak grad), Aortic valve mean gradient (AV peak grad). Thep-values are presented on the bottom of the graph.

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Fig 5.Aortic valve and mitral valve regurgitation of the animals 6 months after implantation asassessed by echocardiography.

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Fig 6.Radiographs of the hearts with balloon-expandable stent (top) and self-expanding stent(bottom) respectively. In the top row, both anterior and lateral views of the heart showseveral strut fractures at the level of proximal and distal crowns (arrows) of the balloon-expandable stent. In the bottom row, both views of the heart show an intact self-expandingstent frame without any fractures.

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Fig 7.Necropsy results of the hearts with the balloon-expandable prosthetic valve (top) and theself-expanding prosthetic valve (bottom) after 6 month implantation. The top row showsinferior and superior views of the balloon-expandable prosthetic valve leaflets, note severalof the stent frame crowns remain uncovered while the annulus of the prosthetic is coveredby opaque white tissue with focal brown areas in the region of the anterior mitral leaflet. Onthe right is the superior view of the prosthetic valve showing good coaptation of the freeedges of 3 valve leaflets. The bottom row shows inferior and superior views of the selfexpanding prosthetic aortic valve, note that the entire stent frame crowns are covered as wellas the annulus of the prosthetic valve is covered by opaque white tissue without pannusformation extending into the valve bases. The anterior mitral leaflet is unremarkable. On theright is the superior view of the aortic prosthetic valve showing good coaptation of the freeedges of the valve leaflets.

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