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`Transcatheter Implantation of a Bovine Valve in Pulmonary
`Position
`A Lamb Study
`Philipp Bonhoeffer, Younes Boudjemline, Zakhia Saliba, Ana Olga Hausse, Yacine Aggoun, Damien Bonnet,
`Daniel Sidi, and Jean Kachaner
`
`Abstract
`Background—Pulmonary regurgitation can lead to severe right ventricular dysfunction, which is a
`delicate postoperative problem in the long-term follow-up of patients who had surgery for congenital
`heart diseases. Clinical conditions of patients suffering from pulmonary valve incompetence are
`improved by valve replacement with a prosthetic valve. To date, the surgical approach is the only
`option to replace a pulmonary valve. We report the first experience of percutaneous pulmonary valve
`implantation.
`
`Methods and Results—A fresh bovine jugular vein containing a native valve was sutured into a
`vascular stent and then cross-linked with a 0.6% glutaraldehyde solution for 36 hours. After being
`hand-crimped onto a balloon catheter, the device was inserted percutaneously according to
`standard stent-placing techniques. The valved stent was finally deployed in the position of the native
`pulmonary valve of the lamb. Hemodynamic evaluation was carried out before and 2 months after
`implantation. Anatomic evaluation was finally performed. Percutaneous pulmonary valve
`replacement was successful in 5 lambs. No complications were noted. Early and late angiographic
`and hemodynamic studies confirmed a good position of the stents with a competent valve at the
`end of the protocol. One stent was slightly stenotic, with macroscopically visible calcifications.
`
`Conclusions—Nonsurgical implantation of pulmonary valves is possible in the lamb. This new
`technique is similar to standard stent implantation. Thus, it should be feasible in humans, in whom it
`will lead to a significant reduction of reoperations in patients in need of pulmonary valve
`replacement.
`
`Originally published 15 Aug 2000 https://doi.org/10.1161/01.CIR.102.7.813 Circulation. 2000;102:813–816
`
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`The pulmonary valve is generally considered to be the least important cardiac valve. However, in
`patients with congenital cardiac malformations who had surgical pulmonary valvectomy or
`transannular pulmonary patches, pulmonary insufficiency can lead to severe right ventricular
`12
`failure.
`
`Surgical indications for pulmonary valve replacement in these patients are delicate.
`Cardiopulmonary bypass, in fact, aggravates right ventricular dysfunction, and clinical benefit for the
`patient solely through the reduction of the pulmonary regurgitant volume cannot be guaranteed.
`
`We set out to develop a nonsurgical technique for placement of a biological valve in the pulmonary
`position through a percutaneous approach. Here, we report our initial experience of percutaneous
`pulmonary valve implantation in lambs.
`
`Methods
`A vein segment containing a native biological valve was harvested from a bovine jugular vein,
`prepared, and sutured into a platinum stent. This unitary tubular structure was then reduced in
`profile and placed on a balloon catheter. The device was inserted percutaneously according to
`standard stent placement techniques. The valved stent was finally deployed and fixed in the position
`of the native pulmonary valve of the lamb. Hemodynamic evaluation was carried out before and
`after deployment. The measurements were repeated 2 months after implantation, and anatomic
`evaluation was performed.
`
`Expandable Vascular Platinum Stent
`The radially expandable vascular stent includes several cylindrical fine wire sections that are
`interconnected into a single tubular structure. The wires are made of a soft and highly malleable
`alloy consisting of ≈90% platinum and 10% iridium.
`
`Biological Valve
`A jugular vein was harvested from a fresh bovine cadaver, and a section of the vein containing a
`native valve was selected for preparation. The valves were bicuspid or tricuspid, with extremely thin
`leaflets. Thereafter, the venous wall of the harvested section was trimmed to remove extraneous
`material and to reduce profile. However, sufficient material had to remain to allow safe attachment
`of the valved venous segment to the stent.
`
`Valved Stent
`Before the biological valve was attached, the intravascular stent was preexpanded to a radial
`diameter of 18 mm. The biological valve was then sutured to the interior of the stent with a 7-0
`polypropylene thread. The tubular portion of the jugular vein spanned the entire axial length of the
`stent (Figure 1).
`
`In Vitro Testing
`Fluid passing into the valved stent in the appropriate direction filled the pouch-like valvar sinuses
`defined by each of the leaflets. In this way, the valve leaflets coapted inside the segment of the vein,
`thereby forming an effective valve closure. Fluid flow in the opposite direction was not restricted
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`(Figure 2). The valvar competence was tested before and after crimping and reexpansion by the
`balloon catheter.
`
`Sterilization of Valved Stent
`The valved stent was finally cross-linked with a buffered saline solution containing 0.6%
`glutaraldehyde for 36 hours at 4°C. After fixation, it was transferred to a 60% ethanol solution for
`storage. Before implantation, the valve assembly was immersed 3 times and carefully soaked in a
`physiological saline solution to remove the ethanol.
`
`Preparation of Animals
`Eleven lambs 2 months old and weighing 16 to 18 kg underwent catheterization for transcatheter
`pulmonary valve replacement. All lambs were treated according to the European regulations for
`3
`animal experimentation. Anesthesia was induced with 10 mg/kg of thiopental sodium and
`maintained with halothane in mechanically ventilated lambs. Cardiac and respiratory functions were
`monitored throughout the procedure. The right internal jugular vein was prepared for catheterization.
`Heparin (100 IU/kg) and penicillin were administered prophylactically. After the procedure, the
`jugular vein was preserved to allow for repeat catheterizations. Anticoagulant therapy was
`continued with low-molecular-weight heparin once a day and substituted 48 hours after stent
`implantation by low-dose aspirin.
`
`Implantation and Deployment Strategy
`Through the internal jugular approach, a guidewire was positioned in the pulmonary artery. The
`valved stent was then hand-crimped onto the inflatable portion of an 18-, 20-, or 22-mm balloon
`catheter. The size of the balloon was dependent on the size of the pulmonary artery measured by
`angiography. To limit the risk of dislodgment or slipping of the balloon, the assembly was front-
`loaded in a 16F Mullins long sheath (Arrow), as shown in Figure 1. After the loading onto the
`previously positioned guidewire, the whole system was advanced and percutaneously implanted.
`The position of the valved stent was easily tracked fluoroscopically because of the highly
`radiopaque material of the stent. The valved stent was then balloon-expanded and deployed in the
`native pulmonary valve of the lamb to impinge upon the function of this native valve and to fix the
`device on the pulmonary wall. The balloon was subsequently deflated, and the catheter was
`removed, leaving the replacement valve assembly in the desired position.
`
`Cardiac Catheterization, Angiographic Studies, and Hemodynamic Evaluation
`The right ventricular and pulmonary arterial pressures were measured before and after the
`implantation and before the animal was euthanized.
`
`Angiography was performed before the procedure to locate the precise position of the native
`pulmonary valve, after the procedure to confirm the appropriate position of the stent and to verify
`the function of the implanted valve, and at the end of the protocol.
`
`Graft Retrieval
`All grafts were explanted 2 months after implantation. Before harvesting, heparin (100 IU/kg IV) was
`administered. The valved stent was rinsed with a saline solution to remove excess intraluminal
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`blood. All grafts were inspected macroscopically, and in vitro testing of valvar competence was
`repeated.
`
`Results
`Seven of 11 lambs had implantation of a pulmonary valve. Technical failure occurred in the
`remaining 4 as a result of the narrow angle between the tricuspid valve and the right ventricular
`outlet.
`
`In the 7 lambs that received implants, 5 stents were in the desired position, impinging on the
`function of the native valve of the lamb. In the remaining 2, the stent was implanted proximal to the
`valve in one and distal in the other.
`
`No complications were noted during the procedure or the follow-up. There were no infectious
`processes. The mild fever that occurred in 2 animals disappeared within 48 hours without any
`antibiotic treatment other than the penicillin prophylaxis. No early or late migrations were observed.
`
`The pulmonary systolic, diastolic, and mean pressures before and after implantation and before
`retrieval are shown in Figure 3. Six of the 7 valved stents were angiographically competent just after
`the procedure. The early evaluation of the seventh revealed a small insufficiency, probably due to the
`catheter in the pulmonary valve during the angiographic evaluation. One valved stent was mildly
`stenotic, with a 15 mm Hg pressure gradient between the right ventricle and the pulmonary artery.
`
`In the 5 animals with a stent in the correct position, macroscopic findings at autopsy showed that
`the native pulmonary valve was nonfunctional because it was stuck between the pulmonary wall
`and the stent. The extremities of the stent were embedded into the pulmonary wall and the right
`ventricular outflow, respectively. Normal function of the native pulmonary valve was found in the
`animal with proximal placement of the stent. The valve inside the stent was completely covered by
`pannus ingrowth. The function of this valve could be restored in vitro after removal of the pannus.
`Similarly, the stent placed distal to the native valve interfered only partially with this valve. The valve
`in the stent showed one normally functioning leaflet, with the other being covered by pannus. The in
`vitro function of this valve could also be restored after removal of this fibrous tissue.
`
`Among the 5 well-placed stents, 4 revealed transparent, mobile, and competent valves (Figure 4).
`One stent was slightly stenotic and showed macroscopically visible calcifications.
`
`Discussion
`Pulmonary regurgitation can lead to severe right ventricular dysfunction, which is a delicate
`2
`postoperative problem in patients who have undergone surgery for congenital heart disease.
`Pulmonary insufficiency is usually well tolerated for a long time, but it overloads the right ventricle
`4
`chronically. Sometimes the conditions of patients with significant damage to the right ventricle can
`5
`be substantially improved by pulmonary valve replacement. Replacement is recommended in
`patients with deterioration of their clinical status or objective signs of right ventricular dysfunction.
`Furthermore, in women who wish to become pregnant, valve replacement is advised even in the
`6
`absence of symptoms. To date, the surgical approach is the only option to replace a pulmonary
`7
`valve to improve the clinical status and the actuarial survival rate of these patients. Unfortunately,
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`cardiopulmonary bypass may enhance right ventricular dysfunction, and clinical benefit from
`surgical pulmonary valvar replacement may therefore not be guaranteed.
`
`Surgical pulmonary valve replacement is usually done with either homograft material from the
`8
`human or the pulmonary valve from a pig. In addition, the bovine pericardium has been widely used
`to construct pulmonary valves, and more recently, the native bovine jugular valve has been used as a
`9
`valved conduit with very promising results.
`
`We had the idea of fixing a bovine jugular valve in an expandable stent designed for percutaneous
`placement. We sutured a valved venous segment into a stent. Thereafter, we verified the function of
`the resulting valved stent after reducing it in diameter and reexpanding it by a balloon catheter in our
`bench testing. The ability to reduce the external wall of the vein allowed us to reduce the diameter of
`the stent to a very low profile, without interfering with the function of the valve.
`
`Recent improvements in interventional catheterization and stent technology have made
`percutaneous stent placement a routine procedure in pediatric as well as adult cardiology and
`10
`radiology. More than 20 stent designs have been developed to fit the multiple indications.
` Stents
`are used extensively in many cardiovascular applications, including stent placement in prosthetic
`11
`12
`conduits.
` More recently, covered stents have enlarged the armamentarium of stent designs.
` The
`outside layer on the covered stents led to a considerable increase in the diameter of these devices
`and to the use of big introducer sheaths. Therefore, experience with 16F introducers, as required for
`the placement of a valve on an 18- to 22-mm balloon, has already been acquired in other
`applications.
`
`We succeeded in deploying 5 valved stents precisely in the native pulmonary valve of the lambs. In
`another 2 animals, stent delivery was possible, but the position of the stent was suboptimal,
`allowing for a residual function of the native pulmonary valve of the animal. In the remaining 4
`lambs, we failed to implant the stent because of the narrow angle between the tricuspid valve and
`the right ventricular outflow. Unfortunately, the femoral vein of the lambs is of small size because of
`their small hind limbs. This forced us to use the jugular venous approach. However, the large size of
`the femoral vein in the human should allow for a straighter catheter course, which should reduce
`this technical difficulty.
`
`The study was designed to continue for 2 months, considering the somatic growth of the lambs. In
`this period, all the lambs were completely asymptomatic and nearly doubled their body weight. At
`the end of the protocol, hemodynamic evaluation showed normal pulmonary pressure in all lambs in
`which stents were implanted. In the 5 lambs with correct position of the stent in particular, diastolic
`pressures in the pulmonary artery were as high as before implantation when the normal native
`valves were functioning. This confirmed the adequate diastolic valvar function throughout the time
`of the study. Moreover, only 1 animal had a mild systolic pressure gradient of 15 mm Hg through the
`stent between the right ventricle and the pulmonary artery.
`
`Pulmonary regurgitation occurred in 1 lamb, but angiographs were obtained with a catheter that
`passed through the valve. This made the interpretation of the pulmonary regurgitation difficult. After
`euthanasia, the in vitro testing confirmed a transparent, highly mobile, and well-functioning valve in 4
`of the 5 lambs in which the stent position was accurate. The valve that was mildly stenotic showed
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`macroscopic alterations with evidence of calcification. Interestingly, the 2 valved stents that were in
`suboptimal position had clear dysfunction of the valve. In 1, the function of the native valve of the
`lamb was entirely preserved, whereas the valve in the stent was embedded in fibrous tissue inside
`the stent. The stent, which only partially impeded the function of the native valve, showed 1 normally
`functioning leaflet, with the other being covered by the same fibrous reaction. After explantation, the
`valvar function of both stents could be restored for the bench testing by the simple removal of the
`fibrous tissue.
`
`13
` Various
`The degeneration of bioprosthetic valves has been widely studied in recent years.
`etiological factors are involved that influence the durability of the valve to different degrees. The
`actuarial functional life of small valves (<25 mm) is shorter than that of larger ones. The role of
`ventricular systolic pressure in accelerating the degenerative process of bioprosthetic valves is also
`14
`widely reported.
` After 2 months of growth, our lambs essentially doubled their body weight.
`Therefore, the implanted stent inflated to 18 mm could have become stenotic, leading to an
`increased ventricular systolic pressure. Furthermore, the chemical treatment of the valves for
`sterilization obviously plays a major role in the durability of the valves and their tendency to calcify.
`The presence of degenerative processes and early calcification in 1 of the valves is likely to be due
`1315
`to the suboptimal sterilization process we used in our protocol.
`
`As far as degeneration of the valve is concerned, the inconvenience is the same between the
`surgical and the interventional approaches. The specific risks of the valved stent placement
`(dislodgment, balloon rupture, etc) are similar to the ones described in the literature for normal stent
`16
`placement.
` Therefore, they are likely to be very acceptable and less important than the damage
`from cardiopulmonary bypass associated with the risks of reintervention. A not fully expanded stent
`implanted in a child can potentially be redilated to adapt its size to the somatic growth without
`interfering with valvar function. We verified this with in vitro testing. Indeed, we expanded our valved
`stents to different sizes from 10 to 28 mm; the valves were completely competent and functioning
`well at all sizes. The use of bigger jugular veins allowed bigger diameters if needed. Moreover, in the
`lamb with the 15 mm Hg systolic pressure gradient between the right ventricle and the pulmonary
`artery, we dilated the stenosis effectively without interfering with the closure of the valve, as
`confirmed by the hemodynamic profile of the diastolic pressure.
`
`Degenerated and stenotic valves in conduits, or better, in valved stents, potentially allow for a
`second valved stent implantation without the need for surgery. We explanted the valved stent at the
`end of the study and showed that surgical stent removal is possible and therefore, surgical options
`are not hampered by even multiple stent implantations. The morbidity of reoperation might also
`decrease after improvement of the right ventricular function by preliminary valved stent
`implantation.
`
`In conclusion, the future opportunity to implant pulmonary valves percutaneously in humans will
`lead to a significant reduction of reoperations in patients suffering from pulmonary valvar
`incompetence in need of a valve replacement. Although the implantation of such a valve is
`technically difficult in the lamb, application in humans should not fundamentally differ from routine
`stent implantation. The function of the implanted heterografts appears to be identical to
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`bioprosthetic valves implanted surgically. Therefore, we think that percutaneous pulmonary valve
`implantation in humans should be possible in the very near future.
`
`Download figure | Download PowerPoint
`Figure 1. View of valved venous segment in vascular platinum stent. Top, Stent reduced in
`profile and front-loaded into a 16F Mullins sheath.
`
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`Download figure | Download PowerPoint
`Figure 2. Bench test of valved stent explanted after 2 months. Left, Effective closure of valve is
`demonstrated when stent is held under a stream of water. When stent is held in opposite
`direction, fluid is freely flowing, as seen on right.
`
`Download figure | Download PowerPoint
`Figure 3. Pulmonary pressures (mean in mm Hg) before and after implantation and after 2
`months. Good function of valve is shown by unchanged diastolic pressures.
`
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`Download figure | Download PowerPoint
`Figure 4. Left, Valve before implantation; right, valve explanted after 2 months. Note thin and
`transparent leaflets.
`
`The authors thank Allen Tower, Mike Martin, and Dr Peter Osypka for their technical and financial
`support, without which this study would not have been possible.
`
`Footnotes
`Correspondence to Dr Philipp Bonhoeffer, Service de Cardiologie Pédiatrique, Hôpital Necker
`Enfants Malades, 149, rue de Sèvres, 75743 Paris Cedex 15, France. E-mail
`philipp.bonhoeffer@nck.ap-hop-paris.fr
`
`References
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`13 Rao KP, Shanthi C. Reduction of calcification by various treatments in cardiac valves. J Biomate
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