NORRED EXHIBIT 2146 - Page 1
`Medtronic, Inc., Medtronic Vascular, Inc.,
`& Medtronic Corevalve, LLC
`v. Troy R. Norred, M.D.
`Case IPR2014-00111
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`II.
`
`Aortic Valve Dynamics and Physics
`
`The aortic valve is better understood in a dynamic state given it is not a
`static structure. To fully understand this structure it is integral to understand 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 andgas mentioned earlierythe unique anatomic relationship ‘thrCi’
`between the valves and the @inuses of @alsalva. One of the most comprehensive study?
`encompassed a model 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 found within this model were as follows: l) 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
`
`.
`
`firm»
`wall and leaflet and then back into the main stream; 3) During the end of systole the r P“ :3 UN)
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`, M,
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`“A?"
`vorticeal motion created during contraction forces the valves back toward a closed
`.
`, X
`M MD,
`.
`.
`.
`.
`.
`posmon. These observations are important to show that absolute pressure differences
`flsu‘ifit”\i‘vf\€::)
`created between the aorta and ventricl are not the source of initial closure of the aortic
`valves.
`In fact,
`it would be detrimirral to valve stress if these forces dictated closure of
`the aortic valve.
`For example,
`if two objects are a greater distance apart and a set
`amount of force is applied to each, the greater distance 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.
`In conclusion,
`the cusps and the relationship of closure for prosthetic valves must incorporate passive
`closure during systole which would logically lengthen the lifespan of any such device.
`To expand these concepts, we must explore the theory of laminar flow as it relates
`to aortic valve function.
`(laminar flow is predicted by Reynold’s number,which
`incorporates the laws as described by Pouiselle and Bernoulli.
`In general, the lower the
`Reynold’s number the more likely that flow will be laminar. The equation that describes
`the Reynold’s 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 viscocity of bloongAs the velocity increases or the
`viscocity decreases, the tendency torwards turbulent flow also increases. Moreover, the
`behavior of the system is also predicted by the rate of acceleration or deceleration which
`is described by the Strouhal number.
`In explanation,
`in a system where viscocity,
`velocity and radius vary slightly,
`the rate of acceleration or deceleration predicts laminar
`versus norgaminar flow. When looked at in perspective,
`it is easy to see the relevance.
`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 which allows this deceleration to
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`occur without an abrupt pressure drop. When laminar flow is produced, the resistance to
`flow, wall stress, shear stress and circumferential 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.
`
`. g 313:5
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`m
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`III.
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`Adult Aortic Stenosis
`
`Aortic stenosis is a condition where there is a restriction to the ejection of
`blood from the left 4/ 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,
`m a pressure gradient develops.
`In order to overcome this pressure difference,
`the left ventricle begins to hypertrophy. Over a period of time this produces
`pressure overload on the left ventricle Clinically, this produces dramatic
`symptoms, and in the most severe form it is fatal unless treated.
`The incidence of aortic stenosis varies considerably.
`In epidemiologic 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 pointsfiresults in fusion of cusps. This filSlOI‘l
`results in a restriction to the opening of the cusps. A pressure difference develops as well
`as non—laminar flow. Once this cycle develops, then the valve has increased deterioration
`and calcification. 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 postinflammatory.
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`(A)
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`(B)
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`/has remained relatively constant throughout the decades It accounts for 33 to 40% of the
`/ total cases of aortic stenosis. This condition affects most paramete1s of aortic function
`lnherently, it loses the anatomic relationship between the sinuses and the valve cusp.
`Further, the opening and closing characteristics of the valve are alteredthich in turn
`alters the acceleration and deceleration to 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 bicuspid ao1tic valve has
`1nc1eased stress at the base It1s at this point where morphologic changes first appeai
`
`\ However this valve1s usually survived into adulthood
`Currently, the most common cause of aortic stenosis is degenerative aortic
`>
`stenosis By the 7t1 decade the normal aortic valve can undergo degenerative changes
`WI. W10 ~‘3
`The characteristics which define these changes are increased calcium deposition along
`the {limbody of the cusps aPredon‘iinantlyfiheealeifieatim located at the bases of the @1131.(m-“L1'/
`cusp and on the aortic side. When enough calcium1s deposited as to restrict flow, than
`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 which promote aortic stenosis in
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`a nomal valve are the same as those which affect atherosclerosis. (nejm 1996). Thus,
`degenerative aortic stenosis has become the mostprevalent etiology.
`Clinically, symptomatic a01tic stenosis has notNo‘nlyfidisabling symptoms, but also
`a high mortality. Currently aortic stenosis is graded upon the calculated aortic valve area
`(figure7). As represented in the table,,severe aortic stenosis occurs when the valve area
`is less than l.00m2(AVA index of <0.6cm2/m2). The most frequent symptom is angina
`pectoris occurring in up to 70%. 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 is a
`condition that can produce severe life‘limiting symptoms and ultimately is fatal.
`
`.lV.
`
`Aortic regurgitation
`
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`3O
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`3O
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`20
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`Aortic [liegurgitation is a condition where there is backflow of blood from
`the aorta to the left ventricle. This regurgitation results in a decreased effective 2,
`cardiac output.
`In turn, longstanding aortic regurgitation results in an increased
`amount of volume work on the left ventricle. In time, the left ventricle begins to
`dilate. Contrary to 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 7
`failure. Etiologically, aortic regurgitation and stenosis are very similar.
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`The most common etiology of aortic regurgitation has been rheumatic
`fever. However, just as in stenosisgthis incidence has decreased as the incidence
`of rheumatic fever has decreased. Logically whenever there is stenosis there can
`be increase‘Eircumferential stress placed upon the proximal aoltic root.
`It is this
`stress which promotes root dilatation in certain patients. Moreover, a dilatation
`of the aortic root can in essence separate the cusps of the aortic valve and create
`regurgitation. Thus, senile aortic stenosis, bicuspid aortic valves and distinctly?
`rheumatic a01tic valves have a propensity to leak.
`'
`However, there are unique entities which promote amtic regurgitation.
`For example, Marfan’s syndrome is a disease in which there is defective collagen
`deposition. This 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, aoitic dilatation with concominent aoltic regurgitation is the
`only manifestation of their hypertension. Thus, there are distinct differences
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`which can cause aortic regurgitation in the presence of a structurally normal aortic
`valve.
`
`Severe aortic regurgitation has a poor prognosis. From the work by
`Goldschlageriet 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 amongthose patients who undergo surgical replacement f01 aortic ....,
`regurgitation they report an increase level of functioningthat they didn’t realize \\
`they had lost.
`In fact, although more well tolerate, aortic valve regurgitation is a
`serious disease which is limiting to a patient’s lifestyle as well as life.
`,.
`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 symptomatic aortic stenosis is
`20% vs 80% with a standard valve replacement. The natural hist01y of the valve has
`been well characterized by the work of Braunwald et al in l 973. Unfortunately, aortic
`valve 1eplacement carries certain surgical morbidity and mortality1% *3
`Aortic valve 1eplacement may be amongthe most invasive surgeries. Logically,
`the surgery 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 sufferingfrom these disorders, the surgery is not
`without significant risk of mortality and morbidity
`,w r
`The risks of the surgeiy can be classified as immediate and long teim risks. The
`immediate risks of the surgery involve the mechanics of the valve 1eplacement procedure.
`In accessing the heait, 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.
`g
`.,
`The sternum currently1s wired back into place with a series(or)interrupted suture wire
`from the cranial end to the dorsal end The difficultyIS in wound dehiscence and , A] \7“
`infection The patients who are at risk include the diabetics, the immunosuppressed and
`the elderly. Wound dehiscence or infection can be mild and leadily 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 l in 200 in low risk groups, and as
`high as 10 in 100 in high risk groups.
`Among the immediate risk there are significant decreases in cerebral function.
`The bypass pump allows the surgeon to operate in a controlled fashion to achieve good
`results.
`It is being more and more realized that this in and of itself promotes dysfunction.
`There is an immediate risk of major stroke which is reported to be 1 to 3%. However,
`among those patients without recognizable strokes, there are still reported neurological
`deficits and 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
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`dramatically recognized by family and Friends who are likely to report a distinct drop in
`mental alertness. Thus even in a techniquely successfiJl surgery there can be a substantial
`drop in cognitive fitnction.
`
`The long term rifikiinclude infectious endocarditis, thromboembolism and valve
`
`J
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`dysfiinction.
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`Goals
`
`The objective of this study is to demonstrate the feasibility @ a percutaneously
`placed aortic valve.
`
`II.
`
`Hypotheses:
`
`1.
`
`DJ
`
`We speculate that a crosslinked nitinol expandable stent can be annealed
`to a biological valve (see appendix).
`We speculate that the flow characteristics produced by this uniquely
`designed device will perform in a similar fashion to Mothers-id”- this?“
`bioprosthetic valves.
`We speculate that the strain relationships will be proportionate to the
`native valve structure
`
`libl’
`/
`
`10.
`
`ll.
`
`We speculate that the flexible base will allow more even dispersion of
`flexion strain.
`We speculate that the interface of the stent aorta will be sufficient to
`maintain the valve in the proper position for fimction in-vivo.
`We speculate that the stem/valve can be inserted percutaneously.
`We speculate that the ascending aorta can accomidate a stented valve
`structure without rupture or significant dissection.
`We speculate that the ascending aorta and coronary arteries can be
`visualized Willi'éitistiné techniques.
`We speculate that with detailed visualization the stem/valve will be placed.1
`as to avoid obstructing the native valve Function.
`‘r"
`We speculate that the stentl'valve combination will not significantly
`obstruct coronary flow.
`We speCulate that a biotome can be directed across the interatrial septum
`into the left ventricle.
`We speculate that once inserted into the left ventricle that the native valve i all .9
`can be excised in a controlled manner.
`”2. Gram iii/UL) bl cat/valve .s t-Mr' 3
`~ -
`. We speculate that an animal would survive the placement of a
`percutaneous valve.
`We speculate that the stented aortic valve in vivo will have a gradient of
`less than lOmmhg.
`
`12.
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`14.
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`11].
`
`Equipment and supplies
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`Lab associated equipment for the modification if needed of the existing
`valve’ . ‘1_l'1I--'-
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`Nitinol wire
`
`Nitinol soldering device
`Template equipment II-
`
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`[aqueous solutions for the flow system
`
`PreservatiOn material (1-. 1
`Dissection tools
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`Pig Hearts
`Operating Room; Ht, .1
`Valve Flow Model with software
`
`.,\
`
`11..
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`Statistical Software
`
`10.
`
`ll.
`
`l2.
`
`Intracardiac echocardiography (Probes and Base)
`I
`Catheters!
`'|‘l"»l1n:,- "1
`('1I11»
`Biotomes and microengineering tools
`Associates
`
`l3
`
`14.
`
`IV.
`
`ll U "'l ""
`
`‘
`
`Flow Modeling
`i. Troy Norred MD
`ii. Steven Lombardo PhD
`
`iii. Frank Fu PhD
`
`Valve Development
`i. Troy Norred 1-1-11";
`ii. Fu Fung Hsieh H1} .1
`iii. Harold Huff ifs";
`In Vitro Modeling
`i. Troy Norred MD
`ii. Steve Lombardo PhD
`
`iii‘ Fu Fung Hsieh PhD
`Procedure
`
`i1 Troy Norred MD
`iii Timothy Catchings MD
`iii. Darla Hess MD
`
`iv. Wayne McDaniels PhD
`v. Michael Sturek PhD
`
`Editing and Data analysis
`i. Troy Norred MD
`ii. GregFlaker MD
`iii Fu Fung Hsieh PhD
`iv. Steven Lombardo Phd
`
`v. Timothy Catchings MD
`vi. Darla Hess MD
`vii. Frank Fu PhD
`
`viii. Wayne McDaniels PhD
`ix. Michael Sturek PhD
`DataAcquisition“N1 1 I
`Ly.”
`'J
`”1 .
`Hemodynamics
`
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`i. Pressure gradients
`ii. Cardiac Output
`iii. Peripheral resistance
`2. Dissection of the specimens
`i. Histologic Data
`ii. Morphologic data
`3. Visualization Data
`
`VI.
`
`In—Vitro Modeling system
`4.
`5. Histological sections
`Budget
`'1. Flow Model System
`i. Laser Doppler Anometer
`ii. Vivitec Flow Model
`iii. Software analysis System
`iv. Post~Doc Salary for 6 weeks
`V. Secretarial Time
`
`($1500.00)
`($13,500)
`($650.00)
`($3 750.00)
`($l 2.00/hr X25
`
`hr/wk)
`vi. Sodium Iodide glycerol 1%water by volume($75. 00)
`2. Valve Modification
`
`i. PigHeaits
`l. Slaughter House Material
`2. Technician Processing Time
`ii. Preservation Material
`
`1. Liquid Nitrogen
`2. Formalin
`3.
`clean up time
`4. Freezer Space Rental
`5. Lab Space Rental
`iii. Nitinol Wiring
`1. Soldering Kit
`2. Nitinol wiring
`3. Engineering Consultant Fee
`iv. Technician and Physical Plant time
`v. Secretarial Expense
`l.
`10 hours/week
`
`v1
`
`($10.00/heart)
`($150.00)
`($17.00/hr)
`
`($25.00/canister)
`($5.00/6oz)
`(1 7.00/hr)
`($10.00/day
`(1 3.00/h1')
`
`($1950.)
`($950.00/ft)
`($2500.00)
`($25.00/hr)
`
`3 Experiment with Pigs
`($75.00/pig)
`i. Pigs
`($110.00/day
`ii. FluOIOSCOpic Time
`($l7.00/hr)
`iii. Technician time
`($500.00)
`iv. Lab expense
`v. Catheters (variable if donated, but approx. $200.00)
`vi. Data Software (included in Flouroscopic room)
`vii. Statistician Expense
`($250.00)
`viii Secretaiial Time (20hrs)
`4. Total costfof for,6 week project
`
`$36,610.00
`
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`l
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`2 ll
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`VII.
`
`Protocol
`
`1. Flow Modeling
`The initial experiments will be performed to assess the valvular function in a
`flow model. As listed in equipment and supplies, the systems used include a
`simulated flow model and devices used to measure the pressure and resistance.
`(see adjacent picture). The models are static and therefore limit the assessment.
`However, important stress and strain relationships can be obtained. The valve
`will be initially placed by hand in the model system. The basic measurements
`will be derived, and fi’om these measurements we will publish our first data on the
`experimental valve. The timeline for these experiments are thought to be 4 to 6
`weeks. The initial bulk of our time will be in the preparation for these
`experiments. During this time several mock runs will be used to modify the
`devices as necessary to obtain the most accurate hemodynamic information.
`Once we have accurate information concerning laminar flow characteristics,
`Reynold’s number and strain relationships, we will procede to practice for in—
`vivo experiments.
`The flow system has been developed to have set points of measurements
`embedded at certains distances from the valve,
`In a pulsed laser system, the lasers
`are set at perpendicular angles to measure differential velocities. Further, these
`velocities can measure shear stresses along the systolic flow and regurgitant flow.
`In the flow models, there can be taken high speed photography to demonstrated
`the function of early closure in relationship with sinuses.(Annals of Biomedical
`Engineering Vol. 26). Thus, the flow model measurements coupled with
`functional data will be reported.
`The final phase of these experiments will help prepare for a more
`successful attempt at in—vivo placement of the experimental valve. With current
`software available from Memry Corporation, we will have the data necessary to
`begin modification of the valve system before our in—vivo attempts. This software
`can help deduce strain relationships in a computer model. Differing values can
`be used to assess the effects that variations in different geometric configurations
`alter the function. Thus, with detailed in~vitro experiments we will save valuable
`time and resources in pre—experimental
`trouble shooting.
`2. Valve modification
`
`The valve/stent combination has reached a point in design and
`development where modification must be backed by experimental direction. The
`initial design has several areas that may need modification. The most obvious is
`the stent arrangement. For maximum compression, it has been proposed that an
`interlaced series of nitinol wire would be favorable. This may hold to be true,
`however, reinforcement at the base may be necessary for more stability. Further,
`careful consideration of the sinuses may necessitate a more direct modeling
`system.
`.lt is possible that for each individual aortic root the normal variance may
`preclude a one size fits all approach. For example, the placement of the coronary
`ostium varies significantly among individuals.
`It seems logical that a system
`which avoids directly obstructing the coronaries would be preferable. Differing
`designs can be employed to exactly set the relationship of an opening in the
`stented structure. The angle between the coronaries, the depth of the sinuses, the
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`size of the cusps directly opposite the ostia and the degree in which the stented
`segments contour the ostia may be needed for the most effective percutaneously
`replaced valve.
`With the placement of the valve, it is crucial to allow enough distance
`between the native valve and the coronaries.
`It has been shown that differing
`techniques of harvesting biological valves can have a dramatic impact on the
`function. When a valve is harvested and placed in formalin, it undergoes an
`amount of swelling from cellular death and necrosis. This can increase the
`thickness of the valve. Increasing the thickness ofthe valve can be detrimental to
`the placement by inhibiting the flow of blood into the coronary ostia. Moreover,
`with more cellular death the longevity and function of the valve may be
`negatively implacted. Our initial valve development will necessitate differing
`techniques of preservation. We will try simple formalin preserved valves as well
`as cryopreserved valves. Differing buffering solutions may also be evaluated if
`found necessary. Thus there are several considerations in the modification of this
`valvular model.
`
`I have made several prototypes and find considerable variability in the
`interface of the stent and valve. Whether this variability will be important in the
`overall function of the valve is unknown at this time. Our initial experience
`reveals the meticulous nature of the annealing process. If a single suture is
`disrupted the the entire valvular apparatus can tear. Diligent work and
`documentation to the most effective way to anneal the two components of the
`valve is necessary. Fortunately, much of this work has begun and many lessons
`have been learned, but more time and resources will need to be devoted to this
`line of modification. An estimate of one 40 hour week dedicated to this
`endeavor is realistic.
`
`A potential problem with a nonsurgically placed valve is perivalvular leak.
`If the edges of the valve begin to lift and form a low resistance channel, the valve
`may begin to develop torque upon itself which may ultimately lead to valvular
`dysfuntion and even failure.
`In addressing this hypothetical problem, it has been
`proposed to use a rim of pervalvular material to act as a counter valve which seals
`itself hydrostatically and prevents or limits peri—valvular leak. The in-vitro flow
`model with be invaluable in assessing this possibility. We will use the time at the
`end of the flow modeling to adjust for this possibility. Of the many possibilities
`that have been entertained, the two most direct methods of limiting this possibility
`are root mimicry and pericardial sleeves.
`In explanation, the root with the sinus
`morphology preserved will be attached to the proximal portion of the stented
`structure. Therefore, when the structure expands the the lateral force of blood
`will create a large surface from which the intima can adhere. This same concept
`may be applied to the pericardium.
`It may be more useful because it is more
`maliable and more easily sutured into the stent structure. It is readily apparent
`that a detailed evaluation of the valve functions in each area will be needed before
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`advancing to in-vivo experiments.
`The final consideration of valve modification involves the deployment of
`the stented valve. Several issues are potentially limiting in the expansion of a
`collapsed valve. The most immediate concerns involve the ability of the
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`stent/valve connections to hold while expanding. Our initial experience has been
`favorable, but upon close evaluation of the valves we have discerned micro tears
`in the suture These micro tears are obviously concerning in the development of
`mechanical failure. Potential solutions to this problem involve differing suture
`techniques and bioglue to seal the valve before it is collapsed. Histological
`examination will be required when the in—vitro model is tested After all these
`points have been addressed we will proceed to in—vivo modeling.
`3. Catheter design
`The catheters required to place the experimental valve will be kept veiy
`simple initially. We will use the largest catheters available in the initial in—vitro
`attempts. The catheters from outdated stock are unfortunately too small.
`However, contact with cordis has produced some promising leads as to the
`availability of larger catheters. Further, in the Dept. of Engineering, there are
`facilities available for the development of new catheters. If needed, Dr.
`Lombardo and Dr Fu have the ability to liaison this portion of the experiment.
`The in—vivo experiments will necessitate an entire system of native valve
`modification or extraction.
`I have designed different catheters which promote the
`percutaneous removal of the aortic valve. However, it is premature to divert
`much time to its development in the initial stages. As a matter of discussion, the
`most direct way of removing tissue is by biotome extraction. Upon this theme
`several different catheter types have been proposed, but
`the most usefiil will
`employ an anchoring device in to the thickened aortic valve.
`Initially, a catheter
`will be guided into the left ventricle via a transeptal approach. The catheter will
`be attached by a deployable screw into the native valve. This will allow the
`catheter to move with the valve movement. By moving with the valve
`translational variation with movement will be minimized. For example, if a man
`is on a ladder which is swaying alongside a telephone pole which is also swaying
`then making repairs would be difficult. Especially if the two movements were
`independent of each other. However,
`if the man were wrapped to the pole then
`the pole and the man are moving with the same motion. To the man, it would
`appear as if the pole were stationary. The same concept applies with extraction of
`a moving valve. With the device anchored, controlled sections of the native valve
`will be snipped out, It is unknown at this time whether complete removal of the
`aortic valve will be necessary. At a minimum, there will always be a rim of
`valve remaining on which the percutaneous valve will sit. With further
`understanding of the technique it has become apparent that simple aggressive
`debulking may accomplish the same task. Thus, both possibilities should be
`explored.
`The second set of catheters are a more ambitious project. These catheters
`involve the system of rotablation.
`In this design, a catheter with two lumens is
`used to guide a rotablator device onto the native valve. The tip of the catheter has
`a roof of material to serve as a template guide. This allows the rotablator device
`to come into contact with the native valve and chip away the native structure. A
`continuous high flow saline solution is directed into the return lumen of the
`catheter. This creates a venturi effect upon the tip of the valve. The particulate
`matter is directed into the return lumen and back into a waste reservoir. However,
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`if any particles escape, the size of the particle should be exceedingly small. This
`would naturally limit the amount of injury from peripheral embolization.
`4.
`In Vivo Experiments
`The final stage of experiments will involve the placement of the stent
`valve into an animal. This experiment will start with the detailing of the aortic
`valve anatomy. A intracardiac echoprobe (ICE) will be advanced into the right
`atrium where a detailed view of the aorta is possible. The basic measurements of
`the root structures will include the valvular morphology and the description of the
`coronary ostia. Dr Darla Hess will be a collaborator in this area. From this
`description, the radius of the stent at final deployment will be known. This
`information will be used to individualize the stent to the experimental animals
`aorta. Also, the ICE will be used to measure the stent/aorta interface and the
`details of the experimental valve post deployment.
`The initial design will use sacrificed animals. The animals will be put
`under anesthesia and peructaneously a catheter will be advance into the ascending
`aorta through a sheath system. The valve is self expanding and will be deployed
`by backing the catheter off of the stented portion of the valve. With the valve
`properly seated, a detailed recording of its fiJnction will be made by the
`intracardiac echoprobe. Also, basic hemodynamic data will be gathered. A
`transeptal catheter will simultaneously record left ventricular pressure with
`ascending aorta pressure recorded from the stent catheter. The animal will be
`maintained through the day and sacrificed after approximately 8 hours. The aorta
`and root structures will be analyzed histologically for evidence of intimal
`dissection and rupture.
`Given the limited amount of time, a living animal model will not be
`attempted in the initial experiments. However, given that the basic
`hemodynamics can be acquired, this will be adequate to document the feasibility
`of the technique. The later experiments will include percutaneous removal and
`replacement of the native valve structure.
`
`VI Theory of Percutaneous Replacement
`]. Physics and equations
`2. Mathematics
`
`3. Dispersion of Force/area
`4. Maintenance of normal anatomic relationships
`Flexion
`
`(PG-”7.09.0.7?”
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`Reversal of curvature
`
`Barrow effect of the proximal aorta
`Dispersion ofForces along the sinuses
`Increasing flow characteristics of the coronaries
`Edy currents in the sinuses promotes early closure and reduces wear
`Favorable strain characteristics
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`h. Laminar flow preservation
`
`The understanding of the basic biological and physical properties of the aortic
`valve prompted my development of a novel approach to its replacement. As described
`above, with an expanded stent into the ascending aorta there exists a certain amount of
`interface between the aorta and the stent.
`In my model of a percutaneously placed aortic
`valve, the theory of its replacement hinges around dispersion of force along a large
`surface area. As you can see in the diagrammati