PEDIATRIC AND CONGENITAL HEART DISEASE

Original Studies

Minimally Invasive Insertion of an Equine StentedPulmonary Valve with a Built-in Sinus Portion in a

Sheep Model

Ali Dodge-Khatami,1* MD, PhD, Stefan Hallhagen,2 MD, Kuno Limacher,3 MSC,Bjorn Soderberg,2 MD, and Rolf Jenni,4 MD, MSEE

Objectives: This study evaluated the feasibility of inserting a new equine stented-valvewith a sinus portion in a lamb survival model, through a minimally invasive thoracot-omy with right ventricular access without cardiopulmonary bypass. Background:Extant surgical or percutaneous methods for inserting biological valves in the rightoutflow tract have drawbacks and limitations. Methods: A decellularized equine valvedjugular vein, sutured to a self-expanding stent with a sinus portion, was placedthrough a minimal right thoracotomy using a newly developed flexible hydraulic releasedevice in seven lambs. The approach through the right ventricle into the pulmonaryvalve position is achieved on a beating heart. Results: The stented valves were cor-rectly positioned in the right outflow tract, were competent up to 6 months as con-firmed by angiography and echocardiography, and were well-tolerated by the animals,with endothelialization of the valve demonstrated at 6 months. Conclusions: The newlydeveloped hydraulic release system allowed for safe and reliable insertion of an equinestented-valve with a sinus portion, through a right transventricular approach on abeating heart, in a sheep survival model. VC 2011 Wiley Periodicals, Inc.

Key words: animal model; biomaterials; heart valve (transapical, percutaneous); off-pump surgery; pulmonary valve

INTRODUCTION

The importance of a correctly functioning pulmonaryvalve is increasingly recognized. The extent to whichvarious degrees of pulmonary valve stenosis or insuffi-

ciency can or should be tolerated is still subject todebate, but increasing quantitative and qualitative diag-nostic measurements are being established better todetermine the timing for pulmonary valve replacement(PVR). Current established possibilities for PVR

1Divison of Pediatric Cardiac Surgery, University Heart Center,Hamburg, Germany2Divisons of Pediatric Cardiac Surgery and Pediatric Cardiol-ogy, Queen Silvia Children’s Hospital, Gothenburg, Sweden3Carag AG, Baar, Switzerland4Division of Cardiology, University Hospital, Zurich, Switzer-land

Conflict of interest: The coauthors (A.D.K., S.H., B.S., and R.J.) are

research consultants to Carag AG Company who manufactured the

valve. However, we have no further financial relationship with the

company, had full control and freedom of investigation with regards

to the design of the study, the methods used, as well as the outcome

measurements, data analysis, and the writing of the final manu-

script.

Grant sponsor: Carag AG (Baar, Switzerland)

*Correspondence to: Ali Dodge-Khatami, MD, PhD, Chief of Pediat-

ric Cardiac Surgery, Program Head for Congenital Heart Disease,

University Heart Center Hamburg-Eppendorf, Martinistrasse 52,

20246 Hamburg, Germany. E-mail: a.dodge-khatami@uke.de

Received 2 March 2011; Revision accepted 9 August 2011

DOI 10.1002/ccd.23354

Published online 8 December 2011 in Wiley Online Library

(wileyonlinelibrary.com)

VC 2011 Wiley Periodicals, Inc.

Catheterization and Cardiovascular Interventions 79:654–658 (2012)

include either surgical reoperation with cardiopulmo-nary bypass [1], or percutaneous PVR under fluoro-scopic guidance [2]. In animal experimental models,research is underway to investigate off-pump insertionof a functional pulmonary valve, using a combinationof minimal invasive surgical technique and percutane-ous release systems [3–6], which have also beenreported in scant case reports in humans [7,8]. Inde-pendently of the mode of insertion, the extant biologi-cal valvar implants all have a limited life span, so thatthe grail in the search of the ideal pulmonary valvereplacement remains to be found. Furthermore, percuta-neous valve insertion has inherent limitations due tothe size of the device, the vessels and the patients, ren-dering new solutions to approach mandatory to expandthe indications for an ever-growing patient populationin need of a competent pulmonary valve.

Attempting to overcome the drawbacks inherent tothe current systems, we describe the first time implan-tation of a decellularized biological valve made froman equine jugular vein, sutured into a self-expandingnitinol stent with a sinus portion using a hydraulicstent-delivery and release system, and describe our ex-perience with regards to minimally invasive surgicalinsertion of this prosthesis in a sheep survival model.

MATERIAL AND METHODS

A new equine stented pulmonary valve, with a built-in sinus portion, and a hydraulic mechanism release de-vice to allow transventricular valve release were newlydeveloped. The valve consisted of an equine jugularvein, freshly harvested from the slaughterhouse. Afterremoval of surrounding tissue, the valve areas wereidentified and the vein was cut in pieces containing

working valves. The grafts were decellularized andsutured with running sutures into a self-expanding niti-nol stent.

The self-expanding stent is laser-cut out of a nitinoltube, with a sinus portion fitting to the natural shape ofthe valve area. Two sizes of stents were used: the di-ameter of the stent at the tubular part was 22 and 25mm, respectively, and the sinus portion had a maxi-mum diameter of 25 and 27.5 mm, respectively. Thelength of the stent in its expanded shape was 29 mm.Thanks to the sinus portion of the stent, the valve isable to work in its natural manner to reduce or elimi-nate the so-called ‘‘hammock effect.’’ The stent haseyes at the proximal end to allow for a controlledrelease (Fig. 1).

The delivery instrument consists of a stent chamberwith an outer diameter of 25 F and a very flexibledelivery catheter with a diameter of 6 F. The stent con-taining the valve is crimped down to the necessary di-ameter and loaded into the stent chamber prior todelivery. A silicone tip is fixed to the distal end of thedelivery instrument to ease insertion of the instrumentthrough the myocardium, and reduce the risk of injuryto the vessels (Fig. 2). At the distal end of the instru-ment, a luer lock connection allows safe and leak-proofhydraulic connection of a standard 5 ml syringe. Thestent release is carried out by loading hydraulic pres-sure on the stent chamber using sterile saline. Duringrelease, the instrument can be locked into position,which eases positioning. The instrument can be deliv-ered over a 0.03500 guide wire.

Between November 2009 and August 2010, sevenGotlandsfar lambs weighing 34–56 kg underwent aright minithoracotomy for surgical insertion of thestented equine valves, through direct right ventricular

Fig. 1. Stented equine graft displaying the sinus configuration of the stent and the tricuspid leaflets.

Equine Stented Pulmonary Valve Insertion 655

Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).

access. Institutional Review Board approval wasgranted for the survival study in sheep. After shavingand prepping of the right thorax, the lambs were placedon their left side. Antibiotic prophylaxis was givenwith Cloxacillin 6 mg/kg prior to skin incision and onedose afterwards. Intravenous heparin was administeredwith a dose of 100 U/kg. A short right lateral thoracot-omy incision was made and the fourth intercostal spacewas entered. After pericardial opening, the lateral as-pect and apex of the right ventricle were accessed, andpurse strings were placed for insertion of the angio-catheter and delivery instrument, respectively. Aftervisualization of the right outflow tract and the pulmo-nary valve by dye contrast injection through the angio-catheter, a suitably sized prosthesis was selected, andmounted onto the introducer. Following the placementof a guidewire (Amplatz Super Stiff, Boston ScientificCorp., Natick, MA) through the purse string into thepulmonary artery, the introducer and prosthesis wereinserted into the right outflow tract, and the valve

released under angiographic visualization (Fig. 3). Theintroducer was removed and the purse string tied. Afterinsertion of a chest drain, the chest was closed inlayers, and the animals rapidly extubated. Post-opera-tive pain management was given with local administra-tion of Lidocaine by use of the Painbuster pain reliefsystem (IFlow Corp., Lake Forrest, CA) for three days.While the first animal was planned for an acute experi-ment, six sheep were scheduled for sacrifice at 6months.

RESULTS

The off-bypass procedure was well tolerated by allanimals, except for one, which suffered ventricular fi-brillation and expired after stent deployment, despiteangiographically apparent correct positioning of thevalve. Good access to the right ventricle was achievedthrough the right minithoracotomy, and positioning theintroducer device to the right outflow tract through thepurse-string was relatively straightforward. After angio-graphic measurements of the pulmonary annulus (range16.5–24 mm), the sinus of Valsalva portion (range 23–31 mm), and of the pulmonary artery at the sinotubularjunction (range 20–26 mm), the stented grafts (22–24mm) were successfully and smoothly released throughthe native pulmonary valve. Correct position and func-tioning of the valve was assessed by intraoperative an-giography and confirmed by transesophageal echocardi-ography. Procedure times ranged between 85 and 130min. One animal suffered from ventricular fibrillationafter stent release and expired, and another died fromrespiratory insufficiency from pneumothorax on post-operative day 1 due to injury by another animal. Atlast follow-up, transesophageal echocardiography dem-onstrated good position of the stented valve, minimal

Fig. 3. Implantation sequence in the right outflow tract with correct positioning of theequine stented valve through the native pulmonary valve.

Fig. 2. The hydraulic delivery device.

656 Dodge-Khatami et al.

Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).

to mild central pulmonary insufficiency, and peak gra-dients of 3–16 mm Hg over the right outflow tract.Histological analysis of the explanted grafts was per-formed in one sheep after 1 month (unplanned deathfrom pneumonia), in another after 3 months (unplanneddeath from bacteremia, heart failure with pericardialeffusion and tamponnade), and in two animals asplanned at 6 months. Macroscopically, pliable free-moving transparent non-calcified leaflets were observedin all four animals. At 3 months in one animal, noreendothelialization on the decellularized graft wasobserved. Bacterial colonies together with findingsfrom pathology confirmed a postoperative bacterialinfection leading to sepsis, with valve leaflets sur-rounded by fibrin. Histological examination at 6months showed a layer of endothelial cells on the sur-face of the valve (Fig. 4). Scant lymph follicles in onegraft wall indicated a mild unspecific immunogenicreaction. Light vascularization of the graft wall wasobserved.

DISCUSSION

Surgical pulmonary valve replacement throughrepeat sternotomy using cardiopulmonary bypass is astandardized procedure with excellent results [1], but isconsidered a relatively invasive procedure. Percutane-ous approaches for PVR may reduce the invasiveness,are also widely accepted, but currently still have lim-ited application due to prosthesis-vascular access mis-match. Common to both approaches is the biologicalfate and reduced longevity of the extant prosthesesavailable, be they of human or animal origin, renderingany measure at best palliative. More recently, research

and clinical attempts are striving for transventricularaccess to the right outflow, using a combination ofminimally invasive surgical techniques and percutane-ous technology [3–8].

Advantages of the newly designed stent with a sinusportion include the creation of vortex flow, which isvery important to promote active closure of the valve,also avoiding the so called ‘‘hammock effect’’ [9].Vortex flow reduces wear and shear stress, and there-fore increases the durability of the valve cusps [10,11].In contrast, in extant stents without a sinus portion, thevalve closes only passively because of backflow. Thedirect apical approach to the right ventricle allows forinsertion of stented valves with a larger diameter thanis otherwise possible with the current percutaneous sys-tems. Stent release with a hydraulic mechanism allowsfor a very flexible and narrow shaft of the instrument.The design permits easily following of the guide wireto the desired position. The release mechanism can becontrolled with one hand, keeping the other free tosecure the position of the device during release. Thestented valves have been echocardiographically docu-mented to function correctly up to 6 months, with his-tological evidence of vascularization of the graft wall,and endothelialization of the valve.

CONCLUSIONS

In an experimental sheep survival model, we havedemonstrated the feasibility and ease of insertion of anew stented equine valve with a sinus portion, using anew hydraulic device release system through a miniright thoracotomy, on a beating heart. This approachmay become a complement to the percutaneous trans-catheter one, either in much younger patients withsmall vascular access, or on the contrary in very largepatients with much wider outflow tracts than the extantpercutaneous valves. With direct access to the rightoutflow, problems pertaining to these two extremes inpatient vessel or outflow versus device mismatchpotentially allow a broader patient population to benefitfrom this type of therapy. Insertion through a smallincision avoiding repeat sternotomy, as well of the fea-sibility to insert the prosthesis without the use of car-diopulmonary bypass make this a more attractive andless invasive procedure. Mid to long-term functionaland histological results are required for further evalua-tion of this new valve.

ACKNOWLEDGEMENTS

The authors thank Monika Hilbe, MD, Institute ofVeterinary Pathology, Vetsuisse Faculty Zurich,

Fig. 4. Histology of an explanted competent valve at 6months, with pliable noncalcified leaflets (*), and an endothe-lial layer (arrows).

Equine Stented Pulmonary Valve Insertion 657

Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).

Zurich, Switzerland, for conducting the histologicalinvestigation.

Disclosures and Freedom of Investigation

This work was supported by Carag AG (Baar, Swit-zerland). The nitinol stent was designed by the authors,and the valves were fabricated by Carag prior to inser-tion. The authors are research consultants to Carag AGbut have no further financial relationship with the com-pany. They had full control and freedom of investiga-tion with regards to the design of the study, the meth-ods used, as well as the outcome measurements, dataanalysis, and writing of the final manuscript.

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