UNIVERSITE DE LAUSANNE

FACULTE DE BIOLOGIE ET DE MEDECINE

SERVICE DE CHIRURGIE CARDIO-VASCULAIRE

Chef de service : Professeur Ludwig K. von Segesser

VALVED STENT FOR OFF-PUMP

MITRAL V AL VE REPLACEMENT

THESE

Présentée à la Faculté de biologie et de médecine de

L'Université de Lausanne pour l'obtention

du grade de

DOCTEUR EN MEDECINE /) J 1)

( \) '

~10 par

Liang Ma

Médecin diplômé de la République Populaire de Chine

Lausanne

2004

Résumé

Objectif: · . .,,

Evaluer un remplacement de valve mitrale hors-pompe avec des stents

valvés

M.éthode:

Des homografts préservés daps du glutaraldëhyde ont été sütur.és dans·

une-prothèse tubulq.ite avarit d'êtr:e soudés à deux stents Z en nitinol potir

creer d@ux couronnes auto- extensibles. A) Nous avons testé la valve in vitro

en utilisant un circüit pülsatile fermé (mock loop) avant de débuter le.9

expérienpes sur les porcs (n=8, 46.0± 4.3 kg: B). L'oreillette. gauche a été

exposée pat thoracotomie g~:uohe et un ëh.emin auric:ulo-ventricülaire a été ·

. tracé par· ultrason intravasculaire (IVUS) et intrac-ardiaque (Navigate). ainsi

que par fluôroscopie.· Les ste:tlts à double couroillle ont été comprimés

radialement; puis insérés hors-pompe dans un système de déploiement

développé dans notre laboratoire avant.d'être nüâchés en deux temps (stent

ventriculaire avant stent aüriculaire ).

Résultats:

A) Les stents ont résisté aux tests \n vitro démontrant une stabilité de

fonction et de fixation face à des pressions allant jusqu'à 120 mm Hg. B)

Une évaluation in vivo a permis de qéterminer le diamètre de l'anneau mitral

( 24;9±0.6mm) ainsi que la surface moyenne de la valve (421.4±17.Smm 2).

La hauteur moyenne dès stents était égale à 29.4±0.2mm avec un diamè~re

interne de 20.4±1.0mm et un diamètre externe de 25.5±0.8mm, Les stents

implantés ont bien fonctionné tout au long de l'expérience. Le temps moyen

de survie était de 97 .5±56.3 minutes (le temps de survie étant fixé entre 40 et

180 minutes, nous sacrifii_ons le porc si celui-ci survivait au delà de cette

limite). Une échocardiographîe . bidimensionnelle et un ultrason

intravasculaire ont conflrmé \lll processus cl' ouverture et de fermeture de

. valve intégral. Une évalu~tion. post-mortem a confirmé le positionnement

c_ortect des stents valvés dans l.a position mitrale·.

Conch1sioils:

L'implantàtion ]}.ors pompe d'üp stent valvé auto-extensfüle est possible

mais une performance à plus long terme doit encore être déterminée.

Contents

Contents .............................................................................. 1

Introduction ......................................................................... 3

1. History review ................................................................. 6

1.1 Mitral valve repair ................................... · ...................... 6

1.2 Mitral valve replacement ................................................ 10

1.3 Valved stent ................................................................ 13

2. Anatomy of mitral valve ................................................... 15

2.1 Components of mitral valve ............................................. 15

2.2 Special anamoty ........................................................... 20

3. In vitro evaluation of valved stents .......................................... 22 ·

3 .1 Device constn1ction ........................................................ 22

3.2 Valved stent delivery system construction .............................. 24

3.3 Device leakage test ........................................................ 26

3.3.l Objective .............................................................. 26

3.3.2 Materials .............................................................. 26

3.3.3 Methods ................................................. " .............. 26

3.3.4 Results ................................................................. 28

3 .3 .5 Conclusion ........................................................... 28

3 .4 Mock loop simulation test ................................................. 29

3.4.1 Objective ............................................................. 29

3.4.2 Materials .............................................................. 29

3.4.3 Methods ................................................................ 29

3.4.3.l Set up of the Mock loop ................................... 29

3.43.2 Deployment of the valved stent. .......................... 33

3.4.3.3 Measurement. ............................................... 33

3.4.4 Results ................................................................. 33

3 .4.5. Conclusion ............................................................. 35·

4. In vivo evaluation valved stepts ............................................... 36

Background ...... _ ....... ,. ..... _ ............. _ ..................... _ ................... 36

4.1 Materials· .. .- ... -............................................................. 37

4;2 Methods; ..... -.............................................................. 37

4.2 .1 Vg_lved stent and its' delivery system preparation ............ 3 7

4.2:2 Preparation of animals ........................................... 38

4.2.3 Implantation strategy ............................................ .40

4.2.4 Measun~ment ....................................................... 43

42.5 Sta:tisticcÙ analysis ............................................... .43

4.3 Rest1lts ..................................................................... 43

_4.4-Discussion ...... ,. ......................................................... 47

4.5 Conclt1sion; .............................................................. 51

References ............................................................................ 52

Ack:nowledgement ......... ; ....................................................... 60

. .

Appendië'es ......... ,;;_-.. ,, ............................................................. 61 ' "\ ;.' -: .

~· ·. . ~

··'.2

,.

Introduction

Since the heart-lung machine was successfully introduced in 1954[1]

and the first Starr-Edwards valve was successfully implanted in a patient in

1960[2], mitral valve replacement has generally been accomplished by using

a cardiac surgical procedure with extracorporeal bypass. However, off-pump

mitral valve replacement may provide an alternative for patients with mitral

valve diseases, especially for those with severe heart failure as well as

hepatic and renal function failure, where coagulation status is a big problem.

A number of minimally invasive techniques for mitral valve repair or

replacement have been developed recently. Video assisted and robotic mitral

valve surgery was reported by Chitwood WR Jr in 2000[3], while, in 2003,

endovascular edge-to-edge mitral valve repair was revealed by Frederick [ 4]

and Peter performed a percutaneous mitral valve repair[ 5].

Nevertheless, off-pump mitral valve replacement has not been

explored so far.

We thought that it was possible to perform off-pump mitral valve

replacement with a valved stent, although the idea of valved stent was not an

original one. In 1965, Davies H. deployed a catheter-mounted unicuspid

valve above the aortic valve for the relief of aortic insufficiency[ 6]. In 1971,

Moulpoulos S. et al designed a catheter-mounted aortic valve that consists of

an umbrella shaped membrane with a controlling unit that unfolds the

valve[7]. In 1990, Andersen H.R. performed a transluminal implantation of a

3

new expandable artificial cardiac valve( the stent-valve) in the aorta and in

the beating heart in a closed chest in pigs[8] and in 1992, he made a similar

report[9]. The same year, Dusan Pavcnik performed transcatheter placement

of a self-expanding caged-ball valve in the aortic valve position in

dogs[lO]. In 1996, Moazami N. et al constructed a trileaflet stent valve with

bovine pericardium sewn on the stent[ll] and in October of that same year,

Robert C. et al developed a mock circulatory loop system to test valves in

vitro[12]. In 2000, Sochman J. et al designed a catheter-based aortic valve

consisting of a stent cage and a prosthetic flexible tilting valve dise [ 15].

Later that year, Bonhoeffer P. and Boudjemline Y. sutured a biological valve

into a platinum stent and successfully performed a percutaneous pulmonary

valve implantation in sheep[13]. Two years later, they designed a special

valved stent to avoid blocking the coronary ostium and performed a

percutaneous aortic valve replacement[l4]. In 2002, Lutter G. et al

deployed a valved stent with barbs in a porcine aorta[16]. In 2003, Antonio F.

Corno et al implanted the self-explanding valved stent in the vena cava[l 7],

while that same year, Jun Qing Zhou et al achieved the successful

implantation of a valved stent in the pulmonary position[18]. Then, in 2004,

Christoph Buber explored whether valved stents compromised coronary

flow.[19]

All these experiments pioneered the use of valved stents but for the

mitral valve, however, their implantation is brand-new.

4

Therefore, we designed a type of valved stent specially for

atrio-ventricular valve and explored the feasibility of deployment in mitral

position by trans-atrium approach using left thoracotomy without

extracorporeal bypass.

5

1. History review

1.1 Mitral valve repair

Though the discussion about mitral valve surgery first arose at the

tum of the last century, no one was to broach the subject seriously until the

1920s, when a number of actual operations were undertaken. In 1923, Eliott

Cutler performed the first transventricular mitral valvulotomy at the Peter

Bent Brigham Hospital in Boston[20]. In 1925, Henry Souttar performed the

first finger dilation of a mitral valve stenosis by transatrial approach[21].

Nevertheless, the number of failed cases was high enough to

discourage the continuation of these operations, & another two decades

elapsed before surgery on the mitral valve became a reality. It was only in

1948 that Harken and Bailey performed their first transatrial

commissurotomies, Bailey on the 1 oth June and Harken on the 16th June

1948[22].

The advances of techniques in open-heart surgery were critical to the

advances of mitral valve surgery. On 6 May 1953, John Gibbon performed

the first successful open-heart operation on a human patient using a

heart-lung machine[l], which was to play a pivota} role in providing

surgeons the time and opportunity to look directly inside the heart. More

extensive surgeries were henceforth developed.

Lillehei completed the first surgical correction of mitral valve

insufficiency in 1956[23]. Soon thereafter, surgical repair of both regurgitant

6

and stenotic mitral valves became common[24] and man y innovative reports

conceming clinical experiences with annuloplasty appeared in the literature

of the late 1950s and the following years[25]. Barnard, Carpentier, Duran,

Kay, Lillehei, Kirklin among others narrowed the annulus in various ways,

mostly by plicating sutures positioned in one or more places & rings of a

number of designs and materials came into use. From the start, annuloplasty

was generally used alone, and later, was accompanied by other valvular

reparative manipulations. One of these methods consisted in placing a baffle

adjacent to the faulty leaflet. Lillehei, for example, used rolled tubes and

balls of Ivalon while in 1961, Barnard and his Cape Town colleagues

described their mobile silastic baffle and dumbbell-shaped Ivalon

subvalvular designs. On the other hand, Henry Nichols lengthened short

leaflets by inserting a piece of plastic in a defect created by a periannular

incision. Other methods involved using autogenous pericardium for leaflets'

advancement, or to attach pliable plastic or biologie materials to the free

edge.

Alain Carpentier devised tnlly evolutionary- reconstn1ctive procedures

for various heart valves. His techniques gradually gained a foothold in many

clinics, were used with increasing satisfaction, and avoided valve excision

and replacement in many instances[25].

But the development of successful prosthetic valves muted the

interest in valve repair in 1960s. Mitral valve repair was infrequently used

7

because it was technically challenging and was overshadowed by the use of

mechanical valves[24]. Sorne surgeons, however, continued to refine and

expand the surgical techniques for repair of stenosis and regurgitation.

Carpentier's group in France[26] and Duran's group in Spain[27] were the

first major contributors. Carpentier, who not only introduced several repair

techniques but also provided a functional classification of mitral valve

lesions and their indicated surgical repair methods, first demonstrated the

cnlCial fact that a quadrilateral resection of the diseased portions of the

minor leaflet of the mitral valve could be safely performed with a minor

leaflet excision as great as 2 to 4 cm. He also demonstrated that the thin

mitral leaflet tissue could be removed and successfully sutured without

dehiscence of the suture line in the reconstructed leaflets when cardiac

contractions began and generated systolic pressures ranged from 1 OO to 120

mmHg[28]. Carpentier primarily performed a careful annuloplasty,

supported by a prosthetic ring, which removed tension from the suture line

in the leaflets. Furthermore, the shortening of elongated chordae to the

anterior leaflet and the technique of chordal transposition were developed by

him in 1983[29].

Within the last two decades, mitral valve repair operations increased

dramatically in number[30]for the following reasons. First of all, mitral

valve replacement is associated with long-term complications, such as

bleeding, embolism etc., thus surgeons prefer to undertake mitral valve

8

repair instead. Second of all, surgeons have gradually improved techniques

for valve repair and have increased their understanding of functional defects

of the mitral valve and associated components. As a consequence, mitral

valve repair has become the preferred method for nearly all mitral valvular

diseases, which include degenerative valve disease, ruptured chordae, mitral

valve prolapse, myxomatous valves, and some cases of rheumatic valve

disease[3 l].

Nowadays, surgeons mainly use mitral repair procedures devised by

Carpentier, which include patching of leaflet perforations, shortening of

chordae to restore normal valve coaptation, transpositioning or replacing

chordae to improve leaflet coaptation, and prevention of further dilation and

maintainance of normal annular diameter with the insertion of annuloplasty

rings[32]. Recently, relatively straightforward mitral repairs have been

performed by video-assisted[33] or minimally invasive techniques[34][35],

percutaneous endovascular edge-to-edge repair[4][5], and robotic mitral

valve repair with the da Vinci Surgical Systemand[3]. All these methods

may have great promise in the field of cardiovascular surgery.

9

1.2 Mitral valve replacement

The first reported mitral valve replacement took place on 22 July

1955 in England, with Judson Chesterman performing the surgery. The

patient survived for 14 hours[36].

As the heart-lung machine was successfully introduced in 1954,

dreams of replacing diseased heart valves with prosthetic devices initiated

the great "valve rush" of the late 1950s and early l 960s. Numerous

investigators were involved in attempts to use tissues, plastics, Teflon,

silicone rubbers, polyurethane, Dacron and metals as substitutes for leaflets

or whole valves. However, there were many problems as the valves tended

to wear and tear and sometimes broke. Thrombosis was also a common

problem[25].

The first Starr-Edwards valve was implanted successfully in a patient

on August 25, 1960, marked a tuming point in cardiac valve surgery[2]. It

had a solid silastic ball and a cage of methyl methacrylate attached to the

Teflon-cloth-covered stainless steel sewing ring, which was easy to insert. It

soon gained widespread usage.

In order to reduce the protn1sion of the prosthesis into the left

ventricle when it was placed in the mitral position, valves with a lower

profile were developed. A number of tilting dise valves were produced in the

late 1960s and during the next decade. The Bjork-Shiley tilting dise

prostheses, m which the cage was Stellite and the final dise pyrolytic

1 0

carbon-coated graphite, became the most widely used prosthesis at the

time[37][38]. In the late 1970s, the St. Jude valve, with its light-weight,

very low profile, hinged, pyrolytic carbon, bi-leaflet, was one of the most

extensively used valves and remains popular still today[39]. Similar

effective dise prostheses in current use include the Medtronic-Hall,

Omniscience, Carbomedics amongst others[ 40]. However, the unsolved

problem of thromboembolism with metallic prostheses led to the

investigation of tissue prostheses [ 41].

In 1962, the use of homografts in the aortic position was described by

Ross[ 42]. But for the mitral position, it was troublesome to manage the

chordae tendineae. Because of the problems of inserting homografts in the

mitral area, Clarence Weldon at Hopkins published laboratory experiences

with the use of aortic homografts mounted on a frame, which greatly

facilitated their placement in animals[25]. In 2000, A.Sampath reported that

37 patients underwent mitral valve replacement with homografts, but the

au th ors didn 't achieve the desired results [ 4 3].

In 1967, Ross successfully perfornied replacement of aortic and mitral

valves with a pulmonary autograft [ 44]. Another promising type of autograft

was used in Zurich by Ake Senning in 1975[45]. He mounted the fascia lata

upon a frame with a sewing ring to replace the aortic valve, but their value

as mitral valve substitutes was considered controversial.

Heterografts were first used by Carpentier in 1965[46], and in 1968

1 1

Carpentier and Dubost reported experiences with heterograft replacement of

mitral and tricuspid valves[25]. In 1969, Kaiser and Hancock were the first

to report the implantation of a porcine aortic valve fixed with glutaraldehyde,

and this valve later evolved into the Hancock porcine xenograft[47]. In 1971,

Carpentier first used the term bioprosthesis for heterografts[ 48]. Five years

later, the Carpentier-Edwards bioprosthesis was introduced, which differed

from the Hancock bioprosthesis by being mounted on a flexible support

frame, instead of a rigid one[23]. Both the Carpentier-Edwards and Hancock

bioprostheses[ 49] have been used successfully in the mitral position and

continue to be used, even to this day.

However, both the mechanical and the bioprosthetic valves have their

shortcomings. It was recognized that the major clinical problems with

mechanical valves was thromboembolism and that bioprostheses had limited

durability because of valve degeneration[50]. People are trying to find a

"perfect" valve, and maybe, bioengineered prosthetic heart valves represent

a new and promising strategy that is just now beginning to unfold[ 41].

1 2

1.3 The valved stent

In 1965, Davies H. deployed a catheter-mounted unicuspid valve

above the aortic valve for the relief of aortic insufficiency[6]. In 1971,

Moulpoulos S. et al designed a catheter-mounted aortic valve that consists of

an umbrella shaped membrane with a controlling unit that unfolds the

valve[?]. In 1990, Andersen H.R. performed the transluminal implantation

of a new expandable artificial cardiac valve( the stent-valve) in the aorta and

the beating heart of closed chest in pigs[8]. Then, in 1992, he had a same

report[9]. The same year, Dusan Pavcnik performed the transcatheter

placement of a self-expanding caged-ball valve in the aortic valve position

in dogs[lO]. In 1996, Moazami N. et al constructed a trileaflet stent valve

with bovine pericardium sewn on the stent[ll] and in October of that year,

Robert C. et al developed a mock circulatory loop system to test valves in

vitro[l2]. In 2000, Bonhoeffer P. and Boudjemline Y. sutured a biological

valve into a platinum stent and successfully performed a percutaneous

pulmonary valve implantation in sheep[l3]. Two years later, they designed a

special valved stent to avoid blocking the coronary ostium and performed

percutaneous aortic valve replacement[14]. Back in 2000, Sochman J. et al

designed a catheter-based aortic valve consisting of a stent cage and a

prosthetic flexible tilting valve disc[15]. In 2002, Lutter G. et al deployed a

valved stent with barbs in a porcine aorta[16]. Then, in 2003, Antonio

F.Como et al implanted the self-explanding valved stent in the vena cava[l 7]

1 3

and the same year, Jun Qing Zhou et al managed to implante a valved stent

in the pulmonary position[l8]. Most recently, in 2004, Christoph Huber

undertook the experiment: Do valved stents compromise coronary flow?[19]

Valved stents for the mitral valve were not reported so far.

1 4

2. Anatomy of mitral valve

2.1 Components of mitral valve:

A thorough understanding of mitral valve anatomy and its

relationship to other cardiac stn1ctures is required for successful mitral valve

surgery. The mitral valve is a complex structure made up of several subunits

that work in conjunction to produce mitral valve competence. These

components include the annulus, anterior and posterior leaflets, chordae

tendineae & the anterolateral and posteromedial papillary muscles[ 51].

The annulus is asymmetrical, with a fixed portion ( corresponding to

the anterior leaflet) shared with the aortic annulus and a dynamic portion

( corresponding to the posterior leaflet) that represents most of the

circumference of the annulus. The fibrous mitral annulus is a dynamic

structure whose circumference changes from diastole to systole. The annulus

is D-shaped, with the straight portion representing the area of continuity

between the mitral and aortic valves. This continuity is limited by the right

and left fibrous trigones. It remains constant during the cardiac cycle and is

rarely distorted by valvular disease.

The two leaflets are asymmetrical as the anterior leaflet has the

greater length of tissue but occupies a smaller portion of the circumference

of the annulus than the posterior. The anterior leaflet is twice the height of

the posterior leaflet but has half its annular length (Fig 1). Both mitral

leaflets are normally similar in area. The larger (anterior) leaflet is roughly

1 5

triangular in shape, with the base of the triangle inserted at about one-third

of the annulus. It partially separates the ventricular inflow and outflow

tracts (Fig 2, video 1 in CD-rom). The anterier leaflet has a relatively smooth

free margin with few or no indentations. There is a distinct ridge separating

the region of closure (rough zone) from the remaining leaflet ( clear zone).

The clear zone is devoid of direct chordal insertions. The posterior mitral

leaflet is rectangular and is usually divided into three scallops with the

middle scallop being the largest of the three in the majority of normal hearts.

The smaller (posterior) leaflet inserts into about two-thirds of the annulus

and has rough and clear zones corresponding to those of the anterior leaflet,

as well as a basal zone close to the annulus, which receives chordae directly

from left ventricular trabeculae[52].

The chordae join each papillary muscle to the corresponding

commissure and the adjoining halves of both leaflets and maintain the two

leaflets in a position allowing coaptation. The tendinous cords are string-like

structures that attach the ventricular surface or the free edge of the leaflets to

the papillary muscles. The normal mitral leaflets have no chordal insertions

into the ventricular septum, unlike the tricuspid valve which has chordal

attachments to the ventricular septum allowing it to be distinguished from

the mitral valve on cross-sectional echocardiography. The tendinous cords of

the mitral valve are attached to two groups of papillary muscles or directly

to the postero-inferior ventricular wall to form the tensor apparatus of the

1 6

valve. Cords that arise from the apices of the papillary muscles attach to

both leaflets of the mitral valve. Since cords usually branch distal to their

muscular origins, there are five times as many cords attached to the leaflets

as there are to the papillary muscles.

The two papillary muscles and the adjacent wall attach the mitral

apparatus to the left ventricle. Viewed from the atrial aspect, the two groups

are located beneath the commissures, occupying anterolateral and

posteromedial positions(Fig 3). As a functional unit, the papillary muscle

includes a portion of the adjacent left ventricle wall. Papillary muscle

contraction pulls the two leaflets toward one another and thereby promotes

valve closure[53].

1 7

Fig 1. Mitral valve, viewed from left atrial aspect

Anterior leaflet

Fig 2. The anterier leaflet partially separates the ventricular inflow and

outflow tracts (Endoscopie View)

1 8

papillary muscle

(PMPM)

Fig 3. Gross anatomy of the mitral valve and papillary muscle-chordal

apparatus, as demonstrated in an excised and unfolded valve

1 9

2.2 Special anatomy:

The septal (anterior) leaflet is in fibrous continuity with the aortic

valve through the aortic-mitral annulus and forms one of the boundaries of

the left ventricular outflow tract. This region of continuity occupies about

one-quarter of the mitral annulus and corresponds to the region beneath half

of the left coronary cusp and half of the noncoronary cusp of the aortic

valve . The limits of this attachment are demarcated by the right and left

fibrous trigones. These points do not correspond to the commissures of the

mitral valve. The AV node and bundle are at risk of surgical damage adjacent

to the right trigone[54].

Anatomically important structures during mitral valve surgery also

include the left circumflex coronary artery, which courses within the left

atrioventricular groove near the anterolateral commissure, and the coronary

sinus, which courses within the left atrioventricular groove adjacent to the

annulus of the posterior mitral leaflet (Fig 4 ).

2 0

Right trigone

(conduction

fiber region)

Fig 4. Gross anatomy of the mitral valve and adjacent structures

2 l

3. In vitro evaluation of valved stents

3.1 Device construction

The following steps describe the procedure followed in constructing

valved stents.

(1) A glutaraldehyde preserved aortic or pulmonary valvular homograft

was trimmed to only keep the three leaflets and commissures (Fig 5 A).The

diameter of the homografts was 20.46±1.0lmm (Tab 1).

(2) A length of Dacron prosthesis was eut to fit the height of

commissure of homograft (Fig 5 B). The diameter of the Dacron prosthesis

was 23.80±1.09mm, and its height was 15.42±0.77mm (Tab 1).

(3) The aortic or pulmonary valvular homograft was mounted into the

Dacron segment with a running suture of 6-0 prolene. It was important to

keep the natural shape of the homograft (Fig 5 C).

( 4) Two self-expandable Z nitinol stents were dismantled from an

endovascular stent graft (Talent) (Fig 5 D). The diameter of the stents was

30mm, while their height was 15mm (Tab 1).

(5) Two self expandable Z stents were sutured at the center of the

mounted Dacron segment with 6-0 prolene, avoiding distortion of the

valvular homograft. It was the custom-made valved stent which looks like

double crowns (Fig 5 E). The dimension of 5 valved stents was measured

(Tab 2).

(6) All the valved stents were preserved in the glutaraldehyde solution.

2 2

Fig 5. The valved stent and each ofits parts.

2 3

3.2 Valved stent delivery system construction

The delivery system consists of one guide wire sheath, an interior

piston and an exterior Teflon sheath (30F), as shown in Fig 6. They were eut

clown to 25-30 cm in length, which was easier to manipulate. The introducer

tip couldn't be too long, because there was not enough space in left ventricle.

The valved stent was compressed to a small size and mounted inside the

Teflon sheath. Before being released by withdrawing the outside catheter

while holding the inside piston in place. After deployment, the introducing

system was withdrawn. The delivery process in vitro is shown in video 2.

Video 2. Valved stent delivery process in vitro

2 4

Fig 6. Valved stent delivery system

2 5

3.3 Device leakage test

3.3.1 Objective:

To test regurgitation of valved stents under static water pressure.

3.3.2 Materials:

• 5 Glutaraldehyde preserved valved stents

• One Dacron vessel prosthesis with an inner diameter of26mm

• A water reservoir

• A connecting tube

• A clamp

• A container and a measuring cylinder

• Aruler with 1500 mm

• An electronic timer

3.3.3 Methods:

The valved stented was tested for leakage by subjecting it to a pressure

of 80cm of water (or 60mmHg) . It was then sutured into a Dacron prosthesis

tube ( <P 26mm) at its center by a running suture and connected to the water

column (Fig 7) . Leakage from the valved stent was confirmed by measuring

the rate of water leakage below it. The rate of water filtered through the

Dacron prosthesis was subtracted from the rate of water leaked through the

Dacron prosthesis/stent in order to calculate the net leakage rate of valved

stent.

2 6

Fig 7. Static leakage test

2 7

3.3.4 Results:

In vitro static performance testing of the 5 valved stents showed a mean

leakage rate of 41.5±10.1 ml/min when subjected to a simulated afterload of

60mmHg, (See Tab 3).

3.3.5 Conclusion:

The new valved stent has little regurgitation under a static pressure of

60mmHg.

2 8

3.4 Mock loop simulation test

3.4.1 Objective:

To test the valved stents in an in vitro simulated dynamic circulation

system.

3.4.2 Materials

• A pig's heart

• 5 custom-made valved stents

• A self-made valved stent delivery system.

• A pulsatile pump (Datascope System 83).

• Several connecting tubes

• 2 reservoirs

• 3 5F Millar pressure transducer catheters (mpc-500, Houston, Texas,

USA.)

• A data recording system (Sampling rate 50 Hz)

• An intravascular ultrasound (Clearview, Boston Scientific

Corporation, Sunnyvale, Califomia)

• An intra-cardiac ultrasound, ICUS (Navigate, Accuson)

• An endoscope (Karl-Storz).

3.4.3 Methods

3.4.3.1 Setup of the Mock loop

To simulate the characteristics of the normal left heart system, a

mock circulatory loop system was set up according to Fig 8. The

2 9

picture of this experiment is shown in Fig 9. The testing process in vitro

is shown in video 3.

Before the test, the aorta , left atrium & apex of heart were sewn

with a Dacron tube prosthesis ( cP 25mm), which can facilitate a

connection with the silicone tube (Fig 10).

The system was powered by a ventricular-assist device (Datascope

System 83). The pneumatic pump was pulsatile and the pulse rate and

pressure in our system could be regulated easily.

3 0

8

T

- .... - -- - -

12 D 1

Fig 8. Schematic mock loop. 1, Pulsatile ventricular-assist device.

2, Left ventricle. 3, Left atrium. 4, Valved stent. 5, Aorta. 6, Right

atrium. 7, Connective silicone tube. 8, Water reservoir A (90cm in

height). 9, Water reservoir B (20cm m height). 10, Endoscope.

11, Intravascular ultrasound (IVUS). 12, Computer and pressure

recording system. 13 , Intra-cardiac ultrasound (ICUS). 14, Flow

recording system. 15, Machine pump (Datascope System 83)

3 1

Fig 9. Mock loop device and the dynamic test of the valve

Fig 10. The aorta,left atrium & apex of heart were sewn

with a Dacron prosthesis

3 2

3.4.3.2 Deployment of the valved stent

Using an endoscope, the valved stent was deployed into the mitral

annulus of heart via a Dacron tube sewn to left atrium. The valved stent

delivery process is explained in paragraph 3.2

3.4.3.3 Measurement

The Millar catheter was used to measure the pressure in the aorta, left

atrium and left ventricle.

The Intravascular ultrasound (IVUS) catheter was inserted through the

hemostatic valve to the valved stent to measure valvular function.

The endoscope was used to show intracardiac structures on video.

3.4.4 Results

( 1) During the experiment, pressures of LV and LA both before & after

implantation were measured(see Fig 11). The diastolic gradient across the

valved stent (mitral position) was almost zero space (0.48mmHg) at a mean

flow rate of 2.81±0.26 L/Min. There was no difference between before and

after implantation.

3 3

140 -120 -100

Ol I 80 -E 60 -E

40 -f---~~_.,~~~~---:il~"--~~~~~ --..-~~---~~-I

20 T'~ '"~ ,.. ·,.,;, --o 1111111111111111111111111111111111111111111111111111111111111!1111111111111111111 11111

1 ~ LV1 -o-- LV2 LA1 ~LA2 I

Fig 11. The pressure curves recorded by computer.

LV 1: left ventricle pressure before implantation;

LV2: left ventricle pressure after implantation;

LA 1: left atrium pressure before implantation;

LA2: left atrium pressure after implantation;

(2) Intra-vascular ultrasound showed complete valve closure and

opening. The open area of the valved stent was 254.8±10.5mm2 and the open

diameter was 19.6±1.4 mm (Fig 12, video 4 in CD-rom).

Fig 12. IVUS views of the valved stent in Mock loop test

3 4

(3) Endoscope imaging showed complete valve closure and opening

(Fig 13)(Video 5 in CD-rom). The valve was well fixed in the mitral annulus

without any migration.

Fig 13. Endoscope imaging showing complete

valve closure of valved stent

3.4.5 Conclusion:

The competence of the valved stent tested favorably under our mock

loop system according to the IVUS, endoscope and Millér catheter findings. ,...,

The valved stent was secured appropriately in the mitral valve position.

3 5

4. In vivo evaluation of valved stents

Background:

Valved stents have been studied for 40 years. The first attempt was

reported in 1965, when H. Davies deployed a catheter-mounted unicuspid

valve above the aortic valve for the relief of aortic insufficiency[6]. Years

later, some innovative reports conceming animal experiments or clinical

experiences with valved stent appeared in the literature, performed by

Moulpoulos S.[7], Andersen H.R.[8], Dusan Pavcnik[lO], Moazami N.[11],

Bonhoeffer P., Boudjemline Y.[13,14], Lutter G.[16] & von Segesser

L.K.[17-19]. Several expandable valved stents were designed and off-pump

or percutaneous transcatheter implantations of valved stent were performed,

including positioning in the aorta, aortic valve, pulmonary valve & verra

cava. Unfortunately, valved stents for mitral valve were not reported as of

yet.

The mitral valve is generally considered to be the one of most

important cardiac valves. Mitral valve repair and replacement is commonly

achieved using extracorporeal bypass. If, however, replacement could be

accomplished with an off-pump, it would be valuable endeavour.

This experiniental study has been designed to evaluate the feasibility of

an off-bypass implantation of a self-expandable valved stent in the mitral

position.

3 6

4.1 Materials:

Materials used were as follows:

• 5 custom-made valved stents.

• 2.5% Isoflurane for general anaesthesia.

• Heparin.

• A self-made valved stent delivery system.

• An X-ray machine (Telam C cornet)

• An intravascular ultrasound, IVUS (Clearview, Boston Scientific

Corporation, Sunnyvale, Califomia).

• An intra-cardiac ultrasound, ICUS (Navigate, Accuson)

• A machine for anaesthesia ( Drager sulla 909v).

• An oximeter (Ohmeda4700).

• An ECG and Pressure recording system (HEWLETT PACKARD

Madel 88s).

4.2 Methods:

4.2.1 Valved stent and its'delivery system preparation

The valved stents were constructed as described in Chapter 3 .1. After

the leakage and mock loop tests, these stents were sterilized and stored in

glutaraldehyde solution.

The valved stent was compressed to a small size and mounted inside a

Teflon sheath in order for open-end of the valve to face the introducer tip, as

described in Chapter 3.2.

3 7

4.2.2 Preparation of animais

8 pigs weighing 46.0±4.3kg ( 43-56kg), received care in compliance

with the "Principles of Laboratory Animals" formulated by the National

Society of Medical Research and «the Guide for the Care and Use of

Laboratory Animals» prepared by the Institute of Laboratory Animal

Resources and published by the National Institute of Health (NIH

publication 85-23, revised 1985). The protocol was approved by the

Institutional Committee on Animal Research. The pigs' data is seen m

Table 4.

After undergoing general anaesthesia with tracheal intubation and

mechanical ventilation (ketamine 22mg/kg and atropine 0.8mg/kg

intramuscularly, Thiopental 15mg/kg intravenously for induction, Isoflurane

2.5% for maintenance anesthesia), the pigs' left carotid artery was exposed

and a catheter was introduced to monitor the blood pressure. Likewise, both

the left and right internai jugular veins were exposed for infusion and

introduction of a Swan-Ganz catheter respectively. The left femoral vein was

also exposed for insertion of an intracardiac ultrasonic probe (Fig 14).

3 8

Fig 14. Preparation of the experiment

3 9

4.2.3 Implantation strategy

Under the continuous monitoring of an electrocardiogram measuring,

the arterial pressure, central venous pressure and oxygen saturation, we

made a left posterolateral thoracotomy in the fourth intercostal space and

opened the pericardium to reach the left atrium. The mitral valve diameter,

area and flow were measured by two-dimensional ultrasonography (the

probe was directly put on the surface of left atrium) .( Fig 15).

Fig 15. Left posterolateral thoracotomy

We marked the atrio-ventricular groove with 3-4 clips, showing the

position of mitral annulus, thus regarding it as the valved stent implantation

site .

Heparin (1 OOIU/kg) was administered intravenously. An intracardiac

ultrasonic probe was inse1ied into right atrium through the left femoral vein

in order to monitor our intracardiac manipulations.

Two purse strings were made with 6-0 prolene on the left atrium, a

4 0

needle then punctured it, a guide wire was inserted & a short 9-F sheath was

introduced.

The intravascular ultrasound (IVUS) Catheter (6F, 12.5MHZ

transducer) was inserted, the diameter and area of mitral valve were

measured and the position of annulus was confirmed under the guidance of

fluoroscopy.

An incision of 1 cm was made on left atrium, controlled by the purse

strings. The custom-made delivery introducer loaded with the valved stent

was pushed along the guide wire, until the stent was located at the desired

site ( the center of stent overlapped with clips under fluoroscopy). The

sheath was pulled back while the piston was held in place, and the first half

of the valved stent was deployed. We gently pulled the whole introducer to

ensure fixation of the valved stent before deploying the second half (Fig 16).

ECG, BP, HR, Sa02, CO, PAP, WPAP, CVP were monitored every 15

minutes.

4 1

Fig 16. Delivery of the valved stent under the guidance of fluoroscopy

4 2

4.2.4 Measurement

The intracardiac ultrasound (ICUS), intravascular ultrasound (IVUS)

and two-dimensional ultrasound were used to measure the diameter, area &

perivalvular leakage of the valved stent, as well as to assess the valve

function and fixation of valved stent.

Pressure of the left atrium and ventricle (proximal and distal to the

valved stent) was measured by puncturing them with a needle.

The animals were all sacrificed in order for as to check the adequate

position of the valved stents.

4.2.5 Statistical analysis

Data was analyzed with SPSS software (Statistical Package for the

Social Sciences). Paired t tests were used. Values were reported as mean±SD.

Data was used from all animals who survived the entire observation period

(n=8).

4.3 Results:

(1) During the experiment, the vital signs were stable & 8 pigs survived

the manipulation (Tab 5). The mean survival time was 97 .5±56.3 minutes

( 40-180 minutes, we killed the pig if it survived longer than 180

minutes)(Tab 6).

(2) Intra-vascular ultrasound showed complete opening and closure of

the valve (Fig 17, video 6 in CD-rom). The mean diameter of mitral valve

was 24.9±0.6 mm and the area was 421.4±17.5 mm2 before implantation.

4 3

Comparatively, they were 19.8±0.4mm and 238.5±15.2mm2 respectively

after implantation (Tab 7).

Fig 17 Intra-vascular ultrasound showed complete opening and closure of

the valve (left: before implantation; right: after implantation)

(3) The mean diastolic pressure gradient across the self-expanded

stent mounted valve was 2.6±3.l rnmHg (range 0-8 rnmHg) during invasive

measurement (Tab 8). The mean systolic pressure gradient across LVOT (left

ventricle outlet tract) was 6.6±5.2 mmHg (range 1-15 mmHg) using the

same procedure(Tab 9).

( 4) Two-dimensional echocardiography and intra-cardiac ultrasound

confirmed complete valve opening and closure of the valved stents and little

regurgitation (Fig 18)(video 7 in CD-rom).

4 4

Fig 18 Two-dimensional echocardiography and intra-cardiac ultrasound

showed a good fixation of the valved stent in the mitral position

(5) Postmortem evaluation also confirmed a good fixation of the

valved stents in mitral position. There was no significant obstn1ction in the

left ventricle outflow tract (Fig 19).

4 5

Valved stent in

mitral position

Fig 19 Postmortem evaluation confirmed a good fixation of the valved

stents in the mitral position and no left ventricle outflow tract

obstruction .

4 6

4.4 Discussion

Since Davies H. deployed a catheter-mounted unicuspid valve above the

aortic valve for the relief of aortic insufficiency in 1965[6], much effort has

been made to develop valved stent implantation. Off-bypass implantation of

a valved stent in the pulmonary position can now be achieved[18]. Aortic

valved stents can be successfully implanted without thoracotomy by using a

transluminal catheter technique [9-11,14-16,55]. Furthermore,

percutaneous insertion of pulmonary valve has also been achieved[13,56,57].

However, papers about valved stents focus on semilunar cardiac valves at all

times, while few studies can be found about valved stents in the mitral

position.

Although we were aware of the difficulties that we might encounter,

experiences from our previous off-pump pulmonary and aortic valved stent

implantation encouraged us to attempt implantation in the mitral valve

position[l 7-19], which has special anatomical significance. We designed a

type of self-expanding valved stent specially intended for an

atrio-ventricular valve. This valved stent is ") (" shape, lilœ double opposite

crowns, & secure fixation in mitral position was easily accomplished. We

thought of aortic or pulmonary homografts for mitral valves from the

Ross II procedure[ 44,58,59]. These special designs made it possible to

implant valved stents in the mitral position.

This article presents the first description and preliminary results of a

4 7

new self-expandable artificial heart valve designed for implantation in the

mitral position without extracorporeal bypass.

Valved stents design and deployment:

Because of the special anatomy of atrio-ventricular valve, the valved

stent was made up of two systems, a valve system and a fixation system. We

chose porcine aortic or pulmonary valves (homograft), as they were easily

obtainable and mounted them into a Dacron prosthetic tube graft, which was

used to support the homograft. Two self-expandable nitinol Z-stents were

constructed with ") (" shape, like double opposite crowns, and secure

fixation in the mitral position was easily accomplished. The two systems

were connected only in the center of the device to avoid mutual interference.

The valved stents had a profile of 1 Omm after hand compressing.

Fortunately, we deployed the valved stents via the left atrium, thus there

were few limitations for the size of the delivery introducer system. The

introducer was eut to 25 to 30 cm in length for easy manipulation, and its tip

was kept short ( <2cm ), because there was not enough space in left ventricle.

The valved stents were unloaded from the introducer system in a staged

procedure. The ventricular stent was deployed first, when we could still

adjust the position and direction of the valved stents, after which the atrial

stent was deployed. This approach increased the successful rate of

deployments.

4 8

Feasibility of implantation:

The most important goal of our study was to evaluate the feasibility of

the off-pump implantation of the self-made valved stent in the mitral

position. In our short-term experiment, the duration of deployment was

about 15-20 seconds, so hemodynamic stability could be expected. Via

pretest studies in 2 pigs, we successfully implanted the valved stents in the

mitral position in 8 pigs with the aforementioned method. The implanted

valved stents functioned well, and there were no significant changes in ECG,

HR, BP, CO, PAP readings before versus after implantation for the duration

of the experiments (survival time 40-180 minutes). Two-dimensional

echocardiography and intra-vascular ultrasound showed complete valve

opening & closure. Postmortem evaluation confirmed the good positioning

of the valved stents in the mitral position.

Possible clinicat implications:

This preliminary study showed the feasibility of an off-pump

implantation of the valved stent in the mitral position, which can be used as

part of the treatment of patients with mitral regurgitation who are not

candidates for open heart surgery, such as those with severe heart failure as

well as hepatic and renal function failure. Implantation of valved stents

may protect the left ventricular function from severe regurgitation, even

temporarily. The morbidity of reoperation might decrease after alleviation of

4 9

left heart dysfunction by implantation of valved stent.

Problems:

Because the native mitral leaflets were not removed in this study, le:ft

ventricle outflow tract (LYOT) obstnlCtion might have occurred due to a

compressed anterior leaflet. Maybe this was one of reasons that the pigs

couldn't survive longer. However, it must be underlined we used a healthy

heart in our experiment. Nevertheless, the large size of left ventricle in the

patients with severe mitral regurgitation should reduce LYOT obstn1ction.

Furthermore, we could incise the anterior leaflet by robotic surgery m

working heart before implantation if necessary[ 60].

Although we decided on the size of valved stent according to the size of

mitral annulus measured by ultrasonography, a mismatch between the valved

stent and annulus was observed in case 2, where paravalvular leakage and

dislodgement of the stent occurred inevitably. Maybe this was also one of

reasons that the pigs couldn't survive longer. Two pigs in our experiment

survived only forty minutes after implantation.

Because only an acute study was performed, the long-term durability

and stability of the valved stents are unknown.

However, up until now, all catheter-delivered valved stents had been

intended for temporary, not long-term placement and use. Our experiment

also focused on short-term testing at present .

5 0

4.5 Conclusion:

The in vivo acute experiments confirmed the feasibility of an off-pump

implantation of the self-expanding valved stent in mitral position, but

long-term performance must still be established.

5 1

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5 9

Acknowledgements

First of all, I would like to thank my supervisor & director, Professor

Ludwig K von Segesser for offering me the opportunity to work in his

department of cardiovascular surgery at the CHUV as well as his

well-equipped laboratory. Throughout the whole experiment and the writing

of the thesis, he offered me great guidance & excellent ideas for which I am

etemally grateful.

I wish to thank Monique Augstbuger, Marco Burki and Steeve Vermot

for their invaluable help and collaboration in the laboratory.

I am also grateful to Steevn Taub and Gabrielle Gerelle for reading this

thesis and assisting me dùring the experiment.

I also wish to thank Christoph Huber, Ilœr Mallabiabarrena, Antonio

Mucciolo, Giuseppe Mucciolo, for their assistance and technical support.

Finally, I wish to extend my appreciation to all those who taught me

during my time at the CHUV: Adam Fisher, Antonio F. Corno, Philippe

Gersbach, Michel Humi, Patrick Ruchat, Frank Stumpe, Bettina Marty,

Piergiorgio Tozzi, Dominique Delay, Ferrari, Christelle Lardi & Vincent

Dierieck.

6 0

Appendices I

Valved Homograft Dacron Z stent

stents Diameter Height Diameter Height Diameter Height (mm) (mm) (mm) (mm) (mm) (mm)

1 19.9 9.1 23 15.5 30.0 15.0

2 22.2 9.9 25 16.6 30.0 15.0

3 20.1 10.5 23 15.1 30.0 15.0

4 20.4. 9.9 25 15.4 30:0 15.0

5 19.7 9.5 23 14.5 3_0.0 15.0

Mean 20.46 9.78 23.80 15.42 30.0 15.0

SD 1.01 0.52 t09 0.77 0 0

Tab lThe dianiefer ahd height of each part ofthe valved stents.

Val ved stent Height

Inner diaineter (mm) Oùter diarileter (mm) (mm)

1 29.1. 19.9 24.5· 2 29.6 22.2 -26.3 3 29.4 20.1 24.8 4 29.4 ·. 20.4 25,9

5 22.2 19.7 24.5

Mean 29.34 20.46 25.20

SD 0.19' 1.00 0.84

Tab 2. The meà.sured sîzes of the coristructed valved stents

Leakage Valved stents

(ml/min) 1 2 3 4 5 mean±SD

1 68.2 29.6 46.5 31.5 40.4 43.2±15.5

2 53.4 33.4 55.2 41.l 28.8 42.4±11.8 ,..,

37.5 42.8 39.2 58.6 34.4 42.5±9.5 .)

4 30.8 54.7 36.8 42.1 35.6 40.0±9.1

5 45.4 47.6 30.9 34.3 39.8 39:6±7.1

mean±SD 47.1±14.5 41.2±10.2 41.7±9.4 41.6±10.6 35.-8±4.7 41.5±10. l

Tab 3 The leakage test un der a 80cmH20( 60mmHg)-water column pressure

61

•.•. œt<'

N Weight(kg) Age(weeks) sex . HR(bpm) BP(mmHg) CVP(mmBg) ECG

16 56 10 M 93 95/53 1 NSR

17 44 8 M 103 102/67 5 NSR

18 45 8 F 83 80/44 4 NSR

24 48 8 M 90 85/60 3 NSR

25 44 7 F 85 84/52 7 NS-R

26 44 6 F 83 95/60 5 ·NsR

27 44 6 F 95 110/60 3 NSR

28 43 6 M 103 88/52 4 NSR

Mean 46.0 7.3 91..9 92.4/56:0 4.0

SD 4.3 L4 8.2· 10.1/7.1 1.8:

Taq 4. Pigs' data(NSR: Normal sinus thythm)

Befote implantation After împlantation T value

HR 96.71:±:7.98 93:29±13.29 0.307 (no sig)

SBP 91.88±3.48 83.43±4.28 2.382 (no sig)

DBP 53.14±4.54 49.57±10.18 0.563 (no sig)

PAP 16.57±5.22 16.8.5±2,97 0.162 (no sig)

WPAP 3.86±0.89 4.14±0.69 0.603 (no sig)

CO 5.78±0.31 5.60±0.54 0.594 (no sig)

CVP 2.00±1.29 2.57±0.53 1.922 (no.sig)

Ta_b 5 Vital signs before and a:fter implantation (mean±SD) and ttest. (t<3.055,p>0.005,

no significance)

62

Number Survival time(minutes) Possible cause ofdeath

16 180 Killed by experimenter

17 80 Dislodgement ofvalved stent

18 60 Arrhythmia, [K+]7.2mmol/l

24 180 Killed by experimenter

25 50 LVOT obstruction

26 120 Dislôdgement of valved stent

27 40 ArrJiythmia, [K+]8. lmmol/l

28 70 Undefined

Meàn 97.5

SD 56.3

tab 6 The pigs' survival time and theirpo"ssibte Çauseof death

Before implantation . After implantation

N MV diameter(cm) MV area(èfu2) MV diameter(c!rl) MV area( cm2

)

16 25.6 440.53 20.2 256.40

17 24.8 427.46 19.8, 220.58

18 24.5 20.0

24 24.9 418.87 19.5 243.77

25 25.9 19.8

26 24.5 20.4

27 24.8 398.73 19.5 233.44

28 23.9 19.4

Mean 24.9 421.4 19.8 238.5

SD 0.6 17.5 0.4 15.2

Tab 7 Mitral valve diameter. and area before and after implantation.

63

N

24

25

26

27

28

Mean

SD

N

24

25

26

27

28

.Mean

.SD

LA pressure(mmHg) LV pressure(inmHg) Diastolic gradient(mmHg)

14 75/12 2

22 100/20 2

18 89/10 8

9 85/8 1

7 71/8 0

14.0 8_4.0/Ll .6 2.6

6.2 11.5/4.9 3.1

· Tab 8 The pressure gradiEmt aoross the mitral valved stent measured after the needle puncture.

LV press'Ure(rhmHg) AO preqs.ure(mmHg) Systolic gradient(mmHg)

75/12 70/40 5

100/20 85/48 15

89/10 82/50 7

85/8 80/45 5

71/8 70/40 1

84.0/11.6 77..4/44.6. 6.6

11.5/4.9 6.9/4.5 5.2

Tab 9 The pressure gradient across the LYOT measured:after the needle puncture.

64

Appendices Il

Videô 1. M~itral valve anatomy

Video 2_. Valved stent delivery process in vitro

Video 3.. Mock loop testing prooess

Vide ci 4. IVU~rshérvv valve& stept'ip_ m_ock loop test

Video 5. - Endoscfopic- view.6f va)v$d stent'in: rfiock.loop _tèst

Vicleo·6. ' rvus_\fÎ~cl~o dfV-alyecl'gtentinvivo·tySL

· Video 7. ICUS-video ofvalved stent in-vivo -tesl . . . . . ' . . . ' . -

65