PERCUTANEOUS AORTIC VALVE REPLACEMENT
`
`This proposal for a project to advance the development of a technique and
`
`prosthetic value to be used in percutaneous aortic value replacement is divided into
`
`seven sections. The section on anatomy describes the native aortic valve and its
`
`function while the following section on the valve's dynamics and physics discusses the
`
`implications of the anatomy for the valves successful function. The sections on aortic
`
`stenosis and regurgitation describe the valve dysfunction and the section on surgical
`
`therapy discusses current surgical replacement therapy and its problems. The final two
`
`sections outline the study goals and stages. The purpose of the study is to advance the
`
`development of a potential percutaneous technique and prosthetic valve that would mimic
`
`the function of the native valve and avoid the problems associated with current methods
`
`for surgical replacement of the native aortic valve.
`
`I. Aortic Value Anatomy
`
`The aortic valve directs the flow of blood from the left ventricle into the
`
`systemic circulation through the aortic artery.
`
`It accomplishes this function by
`
`opening during the contraction of the left ventricle and closing when the left ventricle
`
`relaxes.
`
`In a normally functioning valve,
`
`three leaflet—shaped cusps open widely to allow
`
`the unimpeded transference of blood, and then close tightly, not allowing any blood back
`
`into the left ventricle. Significant restriction to blood flow is called stenosis, and
`
`blood leakage back into the left ventricle is called regurgitation.
`
`The aortic valve is a tricuspid structure. Each cusp folds up toward the aorta
`
`during the contraction phase and then folds back against the others in the relaxation
`
`phase.
`
`[Figure 1 show a picture] However, it is important
`
`to understand that the
`
`structure of the aortic valve is complex, with integral relationships beyond its three—
`
`leaflet valve structure.
`
`For instance, each leaflet sits directly opposite an out
`
`pouching of the proximal aorta. This dilated segment, called the sinus of valsalva,
`
`is
`
`part of an anatomic relationship that assists the repetitive opening and closing of the
`
`valve while minimizing the stress on any point within this valvular apparatus.
`
`Further,
`
`the proximal portion of the aortic valve is highly elastic, which allows it to dilate
`
`during the contraction phase of the left ventricle.
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`NORRED EXHIBIT 2043 - Page 1
`Medtronic, Inc., Medtronic Vascular, Inc.,
`& Medtronic Corevalve, LLC
`
`v. Troy R. Norred, MD.
`Case |PR2014-00110
`
`

`

`Moreover,
`
`these valvular structures are integrally related to the coronary
`
`arteries, which supply blood supply to the heart.
`
`These arteries, as represented in
`
`Figure 2, are located within 2 of the three sinuses Thus, each component plays a vital
`
`role in the function and durability of the valve.
`
`The first components of the aortic valve I would like to discuss are the leaflets.
`
`As stated,
`
`the number of leaflets within a normal aortic valve is three.
`
`-Any
`
`congenital variation in the number of leaflets causes significant problems with
`
`function. When there are less than three valves,
`
`the valve undergoes rapid stenosis and
`
`restriction. An individual with a unicusped valve rarely survives beyond the first year
`
`of life. Among individuals with congenital alterations in the valve number,
`
`the most
`
`frequently encountered is a bicuspid aortic valve.
`
`Individuals with this variations in
`
`valve number
`
`can survive into adulthood. However,
`
`this valve combination becomes more
`
`and more stenotic and regurgitant by the 4th and 5th decade, which usually results in
`
`the need for surgical replacement.
`
`(See figures 3 and 4). Rarely, an individual with a
`
`quadricusped valve will survive into adulthood. This alteration in design also results
`
`in marked stenosis.
`
`The anatomy of a normal aortic valve (three cusps, sinues, aortic arteries)
`
`permits the dispersion of pressure over a larger surface area in the structure.
`
`This
`
`dispersion resists the exhaustion of any one component of the valve. Moreover,
`
`the
`
`curvature of the cusp structure allows the leaflet to reverse curvature.
`
`An ability
`
`needed in order to fold and allow the maximum opening diameter during contraction.
`
`Finally,
`
`a curved design allows a redundancy in the coaptation area of the leaflets.
`
`The area of coaptation is the valve edge that must meet and close in order to prevent
`
`regurgitation.
`
`Hence, both the number of leaflets and their overall shape is important
`
`in the function and durability of the valve.
`
`As mentioned earlier,
`
`the valve leaflets have a direct relationship to the sinuses
`
`of valsalva.
`
`The sinus diameter is almost
`
`twice that of the aorta. This cavity plays
`
`an important role in the mechanism of valve closure.
`
`[referenced Mano Thubrikar]
`
`An
`
`oblique section through the leaflet—sinus assembly shows this remarkable relationship.
`
`(See Figure 4). This section reveals that the sinus and leaflet form a circle when the
`
`valve is in a closed position.
`
`Furthermore, it is angulated to a degree as to allow
`
`pressure
`
`transduction along the entire surface of this unit. All this suggests that
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`NORRED EXHIBIT 2043 - Page 2
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`the shape of the leaflet—sinus assembly is important
`
`in determining how stresses are
`
`developed within the valve. This relationship also allows the valve leaflets to close
`
`without straining the aortic valve, as has been suggested. Finally,
`
`this relationship
`
`of the sinuses and valve allow for the efficient flow of blood in the coronary ostia.
`
`Another structure,
`
`the aortic root, has been observed to expand during ventricular
`
`contraction.
`
`The dilatation of this structure
`
`(predicted by Poisselles'
`
`law, which
`
`describes the relationship of resistance to vessel diameter,
`
`length an fluid viscosity)
`
`reduces tension, which in turn reduces resistance to flow. This phenomenon also allows
`
`for complete opening of the aortic valve.
`
`Interestingly, when the cusps open,
`
`a
`
`circular dimension is maintained that is at least the same diameter as before
`
`contraction. Moreover, it is has been observed to be even larger than the original
`
`orifice.
`
`(Medical Engineering & Physics 19(8): 696—710,1997). This behavior reduces
`
`circumferential stress on the valve and generates a reduced Reynolds shear stress number
`
`(the number used to evaluate the amount of stress in a confined fluid system).
`
`In a
`
`similar manner,
`
`the inner lining of the cusp of the valve,
`
`the lamina ventricularis,
`
`extends into the ventricular myocardium when the valve is in an open position.
`
`A
`
`confluence of fibers at the base, called the fibrous coronet,
`
`is a distinct structure
`
`separating the elastic fibers above, and the myocardium below. However,
`
`this structure
`
`is not static.
`
`It is a very dynamic structure, which bends and molds to the forces
`
`exerted from the ventricular myocardium (Cardiovascular Research, 22,7,1988)(Journal of
`
`Biomechanics33 (6): 653—658, 2000 June).
`
`In a fashion similar to the aortic root,
`
`this
`
`structure allows the valvular apparatus to open with the least amount of strain.
`
`The coronary arteries arise within or above the sinus of valsalva.
`
`The blood flow
`
`to the heart occurs mostly when the ventricle relaxes. At this time,
`
`the cusps of the
`
`aortic valve are closed, and, as mentioned,
`
`the diastolic forces of the blood against
`
`the valve are dispersed along the valve and adjacent sinus.
`
`The opening, or ostia, of
`
`the coronary arteries, when located near the apex and middle of the sinuses, allows for
`
`least turbulent, most
`
`laminar flow characteristics.
`
`(This optimal
`
`location will be
`
`important
`
`to keep in mind when designing a replacement valve because this relationship
`
`promotes the greatest amount of flow with the least amount of resistance.)
`
`In disease
`
`states where these relationships are lost, it has been proposed that this loss could
`
`increase stress at the coronary ostia.
`
`(The Aortic Valve CRC press).
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`NORRED EXHIBIT 2043 - Page 3
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`These integral relationships are not only seen in the gross anatomy of the
`
`valvular apparatus. The microanatomy shows the integral nature of these structures as
`
`well.
`
`The amount of elastin shown by staining methods is in a higher concentration than
`
`anywhere else in the body.
`
`( American Journal of Pathology 445 (7): 1931). This
`
`concentration allows a greater amount of dilatation of the structures in this area.
`
`Further, scanning electron micrographs have shown the unique arrangement of collagen in
`
`the valves, which permits the unique reversal of curvature, which is vital in the
`
`function of the valve.
`
`(See Figure 6).
`
`(Anatomic Embryology 172(61): 1985).
`
`The fibers
`
`are unusually small and arranged in sheets with unique distances between each strand.
`
`In theory,
`
`this would give a greater amount of tensile strength while allowing continued
`
`flexibility.
`
`As always, nature has selected the most efficient machinery, and we have
`
`only to discover the reasons why.
`
`II. Aortic Valve Dynamics and Physics
`
`The aortic valve is not a static structure and is better understood in a dynamic
`
`state.
`
`Full understanding of this structure requires understanding the dynamics and
`
`physics of the opening and closing of the valve:
`
`the motion of the various parts,
`
`the
`
`design of the valve in vitro and the hydrodynamics of the valve.
`
`The valve's ultimate function is to allow fluid transfer from the ventricle to the
`
`systemic circulation.
`
`In order to do this efficiently, it minimizes shear stress,
`
`resistance to flow and tensile forces. The opening and closing of the aortic valve
`
`depends upon differential pressures,
`
`flow velocity characteristics and, as mentioned
`
`earlier,
`
`the unique anatomic relationship between the valves and the sinuses of
`
`valsalva.
`
`The most comprehensive model of this process has been developed by Bellhouse
`
`et al.
`
`In this model,
`
`the flow of fluid through the aortic valve was studied by
`
`injecting dye within the flow of fluid.
`
`Some of the pertinent observations incorporated
`
`in this model were as follows:
`
`1) The valve opens rapidly, and as the leaflets move into
`
`the sinuses, vortices form between the leaflet and the sinus walls; 2) The flow enters
`
`the sinus at the sinus ridge, curls back along the sinus wall and leaflet and flows then
`
`back into the main stream; 3) During the end of systole,
`
`the vorticeal motion created
`
`during contraction forces the valves back toward a closed position.
`
`These observations
`
`are important because they show that absolute pressure differences created between the
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`NORRED EXHIBIT 2043 - Page 4
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`aorta and ventricle are not the source of initial closure of the aortic valves.
`
`In
`
`fact, it would be detrimental to valve stress if these forces dictated closure of the
`
`aortic valve. For example,
`
`if two objects are separated and a set amount of force is
`
`applied to each,
`
`increasing the distance between them would produce greater velocity and
`
`the momentum at impact would be greater. Therefore,
`
`if the leaflets are closed or near
`
`closure as contraction is coming to an end,
`
`then the force used for coaptation would be
`
`less.
`
`Less force per cycle equates to greater longevity of the valve.
`
`This phenomenon would affect the design for prosthetic valves.
`
`The cusps and the
`
`relationship of closure for prosthetic valves must
`
`incorporate passive closure during
`
`systole in order to lengthen the life span of any such device.
`
`To understand how to do this, we must explore The theory of laminar flow as it
`
`relates to aortic valve function.
`
`Laminar flow is predicted by Reynolds number, which
`
`incorporates the laws as described by Outsell and Bernoulli.
`
`In general,
`
`the lower the
`
`Reynolds number,
`
`the more likely that flow will be laminar.
`
`The equation that
`
`describes the Reynolds number in the aorta is as follows:
`
`Ua/v = Reynolds number
`
`That is U, which equals the velocity of blood and a, which represents the radius of the
`
`aortic valve,
`
`is inversely related to the viscosity of blood.
`
`As
`
`the velocity increases
`
`or the viscosity decreases,
`
`the tendency towards turbulent
`
`flow also increases.
`
`Moreover,
`
`the behavior of the system is also predicted by the rate of acceleration
`
`or deceleration described by the Strouhal number, which predicts flow characteristics
`
`of
`
`a given fluid.
`
`In a system where viscosity, velocity and radius vary slightly,
`
`the
`
`rate of acceleration or deceleration predicts laminar versus non laminar flow. When
`
`looked at in this perspective, it is easy to see the relevance of this information to
`
`valve function. Only a small pressure difference is required to open the native aortic
`
`valve. Maintaining a small pressure difference minimizes acceleration to flow.
`
`Thus,
`
`laminar flow is more likely.
`
`The deceleration phase is naturally a gradual process;
`
`however, as stated above, it is the relationship between the sinuses and the cusps that
`
`allows this deceleration to occur without an abrupt pressure drop.
`
`When laminar flow
`
`is produced,
`
`the resistance to flow, wall stress, shear stress and circumferential
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`stress is reduced. This reduction decreases cardiac work and increases the longevity of
`
`the valvular apparatus. Ultimately,
`
`a design to replace a diseased aortic valve must
`
`incorporate many if not all of these relationships.
`
`III. Aortic Stenosis
`
`Aortic stenosis is the condition of restriction to the ejection of blood from the
`
`left ventricle to the systemic circulation at the aortic valve level.
`
`If the aortic
`
`valve cusps do not open, or there is failure of the valvular apparatus,
`
`then a pressure
`
`gradient develops.
`
`In order to overcome this pressure difference,
`
`the left ventricle
`
`begins to hypertrophy. Over a period of time,
`
`this process produces pressure overload
`
`on the left ventricle, which produces dramatic clinical symptoms.
`
`In the most severe
`
`form, it is fatal unless treated. The incidence of aortic stenosis varies considerably.
`
`In epidemiological studies,
`
`the incidence is between 2 to 4% of the general population.
`
`In the early 20th century,
`
`the most common etiology of aortic stenosis was
`
`rheumatic fever. This streptococcal infection produces inflammatory changes in the
`
`aortic valve.
`
`Interestingly,
`
`these
`
`changes affect the coaptation surface to a greater
`
`degree than the other structures of the aortic valve. Affecting the coaptation points
`
`results in fusion of cusps. This fusion results in a restriction to the opening of the
`
`cusps.
`
`A pressure difference develops as well as non—laminar flow. Once this cycle
`
`develops, valve deterioration and calcification increases. Unfortunately, post
`
`infectious aortic stenosis can result in rapid progression to severe aortic stenosis.
`
`Of the total cases of aortic stenosis in the 1940's,
`
`reportedly 52% were the result of
`
`rheumatic fever. Currently,
`
`less than 9% of the cases of aortic stenosis are post
`
`inflammatory.
`
`The second most common cause of aortic stenosis is a bicuspid aortic valve. This
`
`has remained relatively constant throughout
`
`the decades.
`
`It accounts for 33 to 40% of
`
`the total cases of aortic stenosis.
`
`This condition affects most parameters of aortic
`
`function because the optimal anatomic relationship between the sinuses, arteries and the
`
`valve cusp is lost.
`
`Further,
`
`the opening and closing characteristics of the valve are
`
`altered, which in turn alters the acceleration and deceleration of flow.
`
`As a result,
`
`non—laminar flow characteristics are developed.
`
`Because of the altered anatomy,
`
`a
`
`bicuspid aortic valve cannot easily reverse curvature.
`
`Due to this limitation,
`
`the
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`NORRED EXHIBIT 2043 - Page 6
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`bicuspid aortic valve has increased stress at the base.
`
`It is at this point where
`
`morphologic changes first appear. However,
`
`this valve is usually survived into
`
`adulthood. Currently,
`
`the most common cause of aortic stenosis is degenerative aortic
`
`stenosis.
`
`By the 7th decade,
`
`the normal aortic valve can undergo degenerative changes.
`
`The characteristic that defines these changes is increased calcium deposition along the
`
`body of the cusps.
`
`Predominantly the calcification is located at the bases of the cusp
`
`and on the aortic side. When enough calcium is deposited as to restrict flow,
`
`then
`
`there will be a variable amount of fusion along the coaptation surface.
`
`The incidence
`
`of aortic stenosis reaches as high as 12% in octogenarians. This population accounts
`
`for 51% of the current cases of aortic stenosis.
`
`The factors that promote aortic
`
`stenosis in a normal valve are the same as those, which contribute to athersclerosis in
`
`arteries (nejm 1996).
`
`Thus, degenerative aortic stenosis has become the most prevalent
`
`etiology. Clinically, symptomatic aortic stenosis not only has disabling symptoms, but
`
`also a high mortality. Currently aortic stenosis is graded according to the calculated
`
`aortic valve area.
`
`(See Figure7).
`
`As represented in the table severe aortic stenosis
`
`occurs when the valve area is less than 1.0cm2(AVA index of <0.6cm2/m2). The most
`
`frequent symptom is angina pectoris occurring in up to 70% of these cases. This is
`
`followed by syncope or presyncope. Once aortic stenosis becomes symptomatic,
`
`the 2—year
`
`mortality can be as high as 50% (Braunwal 1973).
`
`The 10—year survival is a dismal 10%.
`
`In conclusion, aortic stenosis can produce severe lifemlimiting symptoms and ultimately
`
`is fatal.
`
`IV. Aortic Regurgitation
`
`Aortic regurgitation is the condition of leaked backflow of blood from the aorta to the
`
`left ventricle.
`
`This regurgitation results in a decreased effective cardiac output.
`
`In turn,
`
`longstanding aortic regurgitation results in an increased volume of work on
`
`the left ventricle.
`
`In time,
`
`the left ventricle begins to dilate. Unlike aortic
`
`stenosis,
`
`this condition can be well tolerated for many years. However, once the left
`
`ventricle begins to dilate and lose its contractility, it becomes rapidly symptomatic.
`
`The most common symptoms result from heart failure. Etiologically, aortic regurgitation
`
`and stenosis are very similar. The most common etiology of aortic regurgitation has been
`
`NORRED EXHIBIT 2043 - Page 7
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`

`

`rheumatic fever. However,
`
`just as in stenosis,
`
`this incidence has decreased as the
`
`incidence of rheumatic fever has decreased. Logically whenever there is stenosis,
`
`there can be increase circumferential stress placed upon the proximal aortic root. It is
`
`this stress that promotes aortic root dilatation in certain patients. Moreover,
`
`a
`
`dilatation of the aortic root can separate the cusps of the aortic valve and create
`
`regurgitation.
`
`Thus, senile aortic stenosis, bicuspid aortic valves and distinctly
`
`rheumatic aortic valves have a propensity to leak.
`
`However,
`
`there are other unique entities, which promote aortic regurgitation.
`
`For
`
`example, Marfan's syndrome is defined by defective collagen deposition. This deficiency
`
`manifests as dilatation of the aortic root at a very young age, and tragically can
`
`result in the dissection of the aorta. More commonly,
`
`the aorta can become dilated in
`
`response to systemic hypertension.
`
`In a certain portion of patients, aortic dilatation
`
`with concomitant aortic regurgitation is the only manifestation of their hypertension.
`
`Thus,
`
`there are distinct different causes for aortic regurgitation in the presence of a
`
`structurally normal aortic valve.
`
`Severe aortic regurgitation has a poor prognosis.
`
`From the work by Goldschlager
`
`et al it was
`
`found that the survival of aortic regurgitation is about 50% at 8years (Am.
`
`J. Med.
`
`(54): 1973). With maximum medical therapy it still has a poor prognosis.
`
`Even
`
`among asymptomatic patients,
`
`there is a decrease in the max V02 as measured with a
`
`standard cardiopulmonary exercise test. Moreover, many patients who undergo surgical
`
`replacement
`
`of the native valve for aortic regurgitation report an increase level of
`
`functioning that they didn't realize they had lost.
`
`In fact, although more well
`
`tolerated, aortic valve regurgitation is a serious disease, which is limiting to a
`
`patient's lifestyle as well as life span.
`
`V. Surgical Therapy
`
`For patients suffering from aortic regurgitation or aortic stenosis,
`
`the best
`
`therapy to date is surgical. There is no questioning the benefit of surgical vs.
`
`medical management for these conditions.
`
`The 5—year survival for medical treatment only
`
`of symptomatic aortic stenosis is 20% vs.
`
`80% with a standard valve replacement.
`
`The
`
`natural history of the valve has been well characterized by the work of Braunwald et al
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`NORRED EXHIBIT 2043 - Page 8
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`

`in 1973. Unfortunately, aortic valve replacement carries certain surgical morbidity and
`
`mortality. Aortic valve replacement may be among the most invasive surgeries. It
`
`requires access to the native valve, which necessitates a sternotomy. Also,
`
`the heart
`
`must be stopped and placed on a bypass pump.
`
`Further,
`
`the ascending aorta is cross—
`
`clamped at a position proximal
`
`to the great vessels.
`
`The native valve is then excised,
`
`and depending upon the condition of the aortic root, it may be excised also.
`
`Then the
`
`mechanical or biomechanical valve is sutured into place.
`
`Although this is a life—
`
`saving procedure for those patients suffering from these disorders,
`
`the surgery is not
`
`without significant risk of mortality and morbidity.
`
`The risks of the surgery can be classified into immediate and long—term risks.
`
`The immediate risks of the surgery involve the mechanics of the valve replacement
`
`procedure.
`
`In accessing the heart,
`
`the sternum is split in two by a reciprocating saw.
`
`Given that this is a central point of attachment for the chest cavity, it must withstand
`
`considerable force.
`
`The sternum currently is wired back into place with a series or
`
`interrupted suture wire from the cranial end to the dorsal end.
`
`The difficulty is in
`
`wound dehiscence and infection.
`
`The patients who are at risk include diabetics,
`
`the
`
`immunosuppressed and the elderly. Wound dehiscence or infection can be mild and readily
`
`amendable to simple wound care techniques. Or,
`
`these can be so severe as to lead to
`
`death or significant morbidity.
`
`The incidence is reported to be as low as 1
`
`in 200 in
`
`low risk groups, and as high as 10 in 100 in high—risk groups.
`
`Among the immediate risks is a significant decreases in cerebral function.
`
`The
`
`bypass pump allows the surgeon to operate in a controlled fashion to achieve good
`
`results.
`
`It is becoming more and more apparent that this in and of itself promotes
`
`dysfunction.
`
`There is an immediate risk of major stroke reported to be 1
`
`to 3%.
`
`However,
`
`among those patients without recognizable strokes,
`
`there are still reported
`
`deficits in cognitive function. When this cognitive dysfunction is measure in terms of
`
`IQ points it can be dramatic.
`
`In one series, up to 60% of patient undergoing bypass
`
`surgery had an immediate drop in their IQ scores by 20 points. This can be dramatically
`
`recognized by family and friends who are likely to report a distinct drop in mental
`
`alertness.
`
`Thus even in a technically successful surgery,
`
`there can be a substantial
`
`drop in cognitive function.
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`The long—term risks are also serious and include infectious endocarditis,
`
`thromboembolism and valve dysfunction.
`
`VI. The Study Objectives and Stages
`
`The objective of this study is to demonstrate the feasibility of a percutaneously
`
`placed aortic valve as reflected in the testing of l4 hypotheses. We speculate that the
`
`following assertions can be demonstrated to be the case:
`
`1. A cross—linked nitinol expandable stent can be
`
`annealed to a biological
`
`valve (see
`
`appendix).
`
`2.The flow characteristics produced by this uniquely
`
`designed device will perform in a similar fashion to that of other bioprosthetic
`
`valves.
`
`3. The strain relationships will be proportionate to the native valve structure.
`
`4. The flexible base will allow more even dispersion of
`
`flexion strain.
`
`5. The interface of the stent aorta will be sufficient to maintain the valve in
`
`the
`
`proper position for function in—vivo.
`
`6. The stent/valve can be inserted percutaneously.
`
`7. The ascending aorta can accommodate a stented valve
`
`structure without rupture or significant dissection.
`
`8. The ascending aorta and coronary arteries can be
`
`visualized with existing techniques.
`
`9. With detailed visualization ,the stent/valve will be placed as to avoid
`
`obstructing
`
`the native valve function.
`
`10. The stent/valve combination will not significantly
`
`obstruct coronary flow.
`
`ll. A biotome can be directed across the interatrial
`
`septum into the left
`
`ventricle.
`
`12. Once a properly designed catheter is inserted into the left ventricle ,
`
`the
`
`native
`
`valve can be excised in a controlled manner.
`
`13. An animal would survive the placement of a
`
`percutaneous valve.
`
`NORRED EXHIBIT 2043 - Page 10
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`14. The stented aortic valve in vivo will have a gradient of less than lOmmhg.
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`Our belief is that a properly designed valve can be placed nonsurgically without
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`the assistance of a bypass pump and mimic the function of a native valve. The tasks of
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`the study will be divided into 4 related stages:
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`flow modeling, valve modification,
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`catheter design and in—vivo experiments. These stages are discussed in detail in the
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`following protocol
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`Protocol
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`Flow Modeling
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`The initial experiments will be performed to assess the valvular function in a
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`flow model.
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`As listed in equipment and supplies,
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`the systems used include a simulated
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`flow model and devices used to measure the pressure and resistance.
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`(See adjacent
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`picture). The models are static and therefore limit the assessment. However,
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`important
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`stress and strain relationships can be obtained.
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`The valve will be initially placed by
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`hand in the model system.
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`The basic measurements will be derived, and from these
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`measurements, we will publish our first data on the experimental valve.
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`The timeline for these experiments is expected to be 4
`
`to 6 weeks.
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`The
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`preparation for these experiments will take up the bulk of our project time. During
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`this time, several mock runs will be used to modify the devices in order to obtain the
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`most accurate hemodynamic information. Once we have accurate information concerning
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`laminar flow characteristics, Reynolds number and strain relationships, we will begin to
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`practice for in—vivo experiments.
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`Two types of flow systems have been developed, each with set points of
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`measurements embedded at certain distances from the valve.
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`One uses ultrasound sensors
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`and the other laser sensors.
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`In the pulsed laser system,
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`the lasers are set at
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`perpendicular angles to measure differential velocities.
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`Further,
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`these velocities can
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`measure shear stresses along the systolic flow and regurgitant flow.
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`The flow systems allow high—speed photographs
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`to be taken to demonstrate the
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`function of early closure in relationship with sinuses.
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`(Annals of Biomedical
`
`Engineering. Vol. 26).
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`Thus,
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`the flow model measurements coupled with functional data
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`will be reported.
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`

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`The final phase of these experiments will help prepare for a more successful
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`attempt at in-vivo placement of the experimental valve. With current software available
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`from Memry Corporation, we will have the data necessary to begin modification of the
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`valve system before our in—vivo attempts. This software can help deduce strain
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`relationships in a computer model. Differing values can be used to assess the effects
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`that variations in different geometric configurations alter the function.
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`These
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`detailed in—vitro experiments will save valuable time and resources in pre—experimental
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`troubleshooting.
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`Valve modification
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`The valve/stent combination has reached a point in design and development where
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`successful modification depends on experimentation.
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`The initial design has several
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`areas that may need modification.
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`The most obvious is the stent arrangement.
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`For maximum compression, it has been
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`proposed that an interlaced series of nitinol wire would be favorable. This may hold to
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`be true; however,
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`reinforcement at the base may be necessary for more stability.
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`Further, careful consideration of the sinuses may necessitate a more direct modeling
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`system.
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`It is possible that for each individual aortic root the normal variance may
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`preclude a one size fits all approach.
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`For example,
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`the placement of the coronary ostium varies significantly among
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`individuals.
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`It seems logical that a system that avoids directly obstructing the
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`coronaries would be preferable. Differing designs can be employed to exactly set the
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`relationship of an opening in the stented structure. Precise knowledge of the angle
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`between the coronaries,
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`the depth of the sinuses,
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`the size of the cusps directly
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`opposite the ostia and the degree in which the stented segments contour the ostia may be
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`needed for the most effective percutaneously replaced valve. With the placement of the
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`b tw en th nativ valv and the
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`valve, it is crucial to allow enough distanc
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`coronaries. Thus,
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`there are several considerations in the modification of this valvular
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`model.
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`I have made several prototypes and find considerable variability in the interface
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`of the stent and valve. Whether this variability will be important in the overall
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`function of the valve is unknown at this time.
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`Also, differing techniques of harvesting biological valves can have a dramatic
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`impact on their function. When a valve is harvested and placed in formalin, it
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`undergoes an amount of swelling from cellular death and necrosis, which can increase the
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`thickness of the valve.
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`Increasing the thickness of the valve can be detrimental to the
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`placement by inhibiting the flow of blood into the coronary ostia. Similarly, cellular
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`death affects valve longevity and function negatively .
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`These factors necessitate
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`experimentation with differing techniques of preservation in our initial valve
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`development.
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`We will try simple formalin preserved valves as well as cryopreserved
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`valves. Differing buffering solutions may also be evaluated if found necessary.
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`Furthermore, our initial experience reveals the meticulous nature of the annealing
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`process.
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`If a single suture is disrupted,
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`the entire valvular apparatus can tear.
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`Diligent work and documentation
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`of the most effective way to anneal
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`the two components
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`of the valve is necessary. Fortunately, much of this work has begun and many lessons
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`have been learned, but more time and resources will need to be devoted to this line of
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`modification.
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`An estimate of one 40—hour week dedicated to this endeavor is realistic.
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`Another potential problem with a nonsurgically placed valve is perivalvular
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`leak.
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`If the edges of the valve begin to lift and form a low resistance channel,
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`the
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`valve may begin to develop torque upon itself, which may ultimately lead to valvular
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`dysfunction and even failure.
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`In addressing this hypothetical problem, it has been
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`proposed to use a rim of perivalvular
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`tissue to act as a counter valve, which seals
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`itself hydrostatically and prevents or limits perivalvular leak.
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`The in~vitro flow
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`model will be invaluable in assessing this possibility. We will use the time at the end
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`of the flow modeling to adjust for this possibility.
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`Of
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`the many possibilities that have been entertained,
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`the two most direct
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`methods of limiting this leakage are root mimicry and pericardial sleeves.
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`In the first
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`method,
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`the aortic root with the sinus morphology preserved will be attached to the
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`proximal portion of the stented structure. Therefore, when the structure expands the
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`lateral force of blood will create a large surface from which the intima can adhere.
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`This same concept may be applied to the pericardium.
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`It may be more useful because it
`
`is more malleable and more easily sutured into the stent structure.
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`It is readily
`
`apparent that a detailed evaluation of the valve functions in each area will be needed
`
`before advancing to in—vivo experiments.
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`NORRED EXHIBIT 2043 - Page 13
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`The final area for consideration of valve modification involves the deployment of
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`the stented valve.
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`Several potential problems potentially limit the expansion of a
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`collapsed valve.
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`The most
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`immediate concern involves the ability of the stent/valve connections to
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`hold while expanding. Our initial experience has been favorable, but close evaluation
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`of the valves has revealed micro tears in the suture.
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`These micro tears obviously
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`promote the development of mechanical failure. Potential solutions to this problem
`
`involve differing suture techniques and bioglue to seal
`
`the valve before it is
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`collapsed. Histological examination will be required when the in—vi