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`waif-murmurM:
`
`Library of Congress Cataloging-in-Publication Data
`
`Printed in the United States
`
`Thubrikar. Mano.
`The aortic valve: author. Mano Thubrikar.
`p.
`cm.
`Includes bibliographies and- index.
`ISBN 0-8493—47Tt-8
`I. Title
`l. Aortic valve.
`[DNLMz t. Aortic Valve.
`QPl l4.A57'l‘48
`1990
`612’.12--dc20
`DNLM/DLC
`for Library of Congress
`
`WG 265 T532211
`
`89-9992
`CIP
`
`This. book represents information obtained from authentic and highly regarded sources. Reprinted material
`is quoted with permission. and sources are indicated; A wide variety of references. are listed. Every reasonable effort
`has been made to give reliable data and information; but-the .author and the publisher cannot assume responsibility for
`the validity of all materials or for the consequences of their use?
`
`All rights reserved. This book, or any parts thereof, may not be reproduced in any form without written
`consent from the publisher.
`'4
`
`Direct all- inquiries to CRC Press, lnc., 2000 Corporate Blvd. N.W., Boca Raton, Florida. 33431..
`
`©1990 by CRC Press. Inc.
`
`International Standard Book Number 0-8493—4771-8
`
`Library. of Congress Card Number 89—9992
`
`NORRED EXHIBIT 2226 - Page 2
`
`

`

`Chapter 3
`DYNAMICS OF THE AORTIC VALVE
`
`39
`
`I. INTRODUCTION
`The geometry ofthe static aortic valve was described in Chapter I. However, theaortic valve
`in its natural state is always in motion; it is nota static structure. In this chapter we will examine
`the dynamic behavior of the aortic valve in its natural functional state. The dynamic behavior
`will beconsideredin foursteps: (1) opening and closingofthe valve, (2)motionofvarious parts
`of the valve, (3) design of the valve in vivo;and (4) high—speed studies of leaflet motion.
`
`II. OPENING AND CLOSING OF THE VALVE
`
`The most prominent feature of the functioning aortic valve is the movement of the leaflets
`causing the valve to open and close. This movement occurs so rapidly that special techniques
`are necessary to view it. In humans, the technique of aortic root cineangiography is used to
`determine the opening and closing behavior of the valve. In this technique, radiopaque dye is
`injected into the aortic root and the movement ofthe contrast medium is visualized under X—ray
`and recorded on cine films or videotape. Although this technique is used commonly, it does not
`provide a precise definition of the valve orifice. Two-dhnensional echocardiography has been
`used to examine a cross—section of the valve orifice, but the orientation of the cross-section is
`difficult to ascertain (Chapter 6). The understanding of precise movements of the leaflets is
`gained from studies using a marker-fluoroscopy technique in dogs. In this technique, small
`radiopaque markers are placed at known positions on the valve and movement of the markers
`is studied. Other techniques used to study valve motion include injecting a clear liquid into the
`left atrium and then visualizing the valve. Valve motion has also been studied in vitro by use of
`a pulse duplicator system in which a clear liquid is pumped through the valve. Some of these
`studies are considered below.
`
`A. THE VALVE ORIFICE
`Stein et a1. studied the human aortic valve using aortic root angiography in which an eray
`tube was positioned at a predetermined angle in orderto obtain an almostdirect view ofthe valve
`orifice.‘ The angle of the X-ray tube was determined in patients with prosthetic aortic valves.
`In these studies the angle of the X—ray tube deviated from the valve axis by an average of 12",
`thereby resulting in an oblique projection. The normal open aortic valve was observed to have
`both a circular as well as a triangular orifice. As amatter offact, in angiograrns, depending upon
`the angle between the X-ray beam and the valve axis, different shapes ofthe orifice can be seen.
`Figure I shows a nearly circular and a nearly triangular orifice ofa human aortic valve. Figures
`2 and 3 Show other configurations of so-called valve orifice, where the central region of low
`contrast can be considered to represent the orifice. However, as we will see, this central region
`is not the true orifice of the open valve.
`'I'hubrikar et at. studied angiograms of human and canine aortic valves, and the projections
`of the aortic valve models to understand the angiograms? They made one model ofthe valve that
`showed a circular opening and another that showed a triangular opening. Using the appropriate
`orientation of the model with a circular opening, they established that almost all of the
`angiograms could be interpreted correctly. For example, Figures 2 and 3 show human
`angiograms and projections of the aortic valve model with a circular opening. The central
`openings in the angiograms are identical to those of the model (C, E, and G in Figures 2 and 3).
`it is important to note that the margins of the central openings do not consist ofjust the leaflet—
`
`NORRED EXHIBIT 2226 - Page 3
`
`.
`
`ctcfis'icssmim
`md Majno, G-s
`
`mutation tissue
`
`‘1 wwnd healmg
`re repair in aortic
`
`man heartvalves
`
`.
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`
`j.
`
`
`
`Page 3
`
`

`

`CK":”rs''.We’d—lung“
`
`40
`
`The Aortic Valve
`
`Page 4
`
`A detailed analysis of leaflet motion in a functioning valve in viva was carried out by
`
`NORRED EXHIBIT 2226 - Page 4
`
`FIGURE 1. Aortograms of patients with normal aortic valve (top) and with mild aortic regurgita-
`tion due to Mar-fan’s syndrome (bottom). Top — Orifice appears nearly circular as also outlined
`with dotted lines. Bottom — Orifice appears triangular and aortic sinuses appear aneurysmal. (From
`Stein1 P. D.I Am. Heart J.. 81(5). 622, 1971. With permission.)
`
`free margins, but rather of both the free margins and the lines of leaflet attachment. In Figures
`2G and 3G, for example, the margin of the central opening marked by the dotted line represents
`the line of leaflet attachment and that marked by the solid line represents the leaflet free edge.
`This means that in an oblique projection of the valve, the central opening does not represent the
`orifice of the valve. This is also true for angiograms obtained from dogs. Figures 4 and 5 show
`angiograms from dogs with appropriate projections of the aortic valve model with a circular
`opening. Once again the central opening in the angiograms is identical to that in the model (B,
`F, E, and H in Figure 4 and A and B in Figure 5). Thubrikar et al. found that the projections of
`the aortic valve model with a triangular Opening did not match with any of the angiograms.
`Therefore, they concluded that in humans and in dogs the aortic valve orifice is circular,
`particularly in early systole.
`In sun'unary, since angiographic projections most often show an oblique view. i.e., the X-ray
`beam is not exactly along the axis of the aorta, the margins of the valve orifice may appear
`straight or curved. This is because oblique projection of a curved line can be a straight line. In
`other words, a circular orifice can project itself as partly triangular. However, it is clear that the
`normal valve orifice is not triangular since a triangle will not project with curved borders. Also,
`the orifice decreases continuously during systole causing its shape to change. The shape of the
`aortic orifice, determined with two-dimensional echocardiography, is discussed in Chapter 6.
`
`III. THE LEAFLET MOTION
`
`

`

`41
`
`
`
`FIGURE 2. Biplane aortogram ofan infant (2 months) with a normal aortic valve. (A) Side View ofa closed valve.
`(B and C) Oblique views of the valve in diastole and in systole, msgecdvely. (D and E) Views of the cylindrical
`model matching those in A or F and C or G. (G) The valve orifice is composed of the line of attachment (dotted
`line) and the free edge (solid line) of the leaflets. (Fm Thubrikar, M. et al.. Cardiovasc. Res, 16. 16, 3982. With
`permission.)
`
`Thubrikar et a1. using the marker fluoroscopy technique.3 Small radiopaque markers were placed
`at various locations in the aortic valves of dogs and the movement of the markers was observed
`under X—ray. Figure 6 shows the position of the markers on the leaflets and in the commissures.
`The markers in the commissures were used forobtaining appropriate projections ofthe valve and
`for determining the outline of the valve orifice. The movement of the markers was recorded as
`described below. Figure 7 shows the orientation of the X-ray beam used for obtaining the
`projections. In the closed valve, when the X439! beam is along the valve axis, the commissure
`markers project at the apices of the triangle and the leaflet markers project at the center. When
`the X~ray beam is perpendicular to the valve axis, the commissure markers project in a straight
`line and the leaflet markers project below or above the straight line. Figure 8 shows the actual
`radiograms in which the markers can be seen in both the triangular and the straight line
`projections. The movement of the markers was recorded at a rate of 60 fields/s which provided
`60 data points/s.
`.
`Figure 9 shows a plot of distance between the two leaflet markers and the aortic pressure vs.
`time. The aortic valve opens rapidly at the beginning of systole and closes rapidly at the end of
`systole; During a cardiac cycle, one may picture the valve in action as follows: a sudden opening
`of the valve, then only a little movement while the valve remains open, a sudden closure of the
`valve, and then almost no movement while the valve remains closed. Little time is spent in the
`opening and closing process. During a cardiac cycle, most of the time is spent in filling the heart
`
`
`
`
`
`Page 5
`NORRED EXHIBIT 2226 - Page 5
`
`
`

`

`42
`
`The Aortic Valve.
`
`E g
`
`
`
`"1*‘xo‘tmnwtu-Vu,.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`when the valve is closed and ejecting the blood whenthe valve is open. This magnet—like to-and-
`fro motion of the leaflet is the most prominent feature ofthe aortic valve in action.
`It would be incorrect to say that no motion is taking place while the valve is open or closed.
`For example, while the valve is open, the leaflets are gradually moving towards the center of the
`valve. This is indicated in Figure 9 by a gradual decrease in the distance between the two leaflets.
`Hence, the valve is maximally open in early systole, gradually closes during systole, and rapidly
`closes at the end of systole. The time required for the rapid opening or the rapid closure of the
`valve is 17 to 20 ms. To analyze the leaflet motion in these two rapid phases, one needs a
`technique of high-speed recording, which is described later in this chapter.
`The orifice of the aortic valve appears circular or nearly circular (Figure 8). The orifice is
`gradually changing during systole as the leaflets are. moving towards the center of the valve.
`Therefore, the valve orifice may appear circular, bulged triangular, ortriangular depending upon
`whether it was observed in early, mid, or late systole. The shape of the orifice may also depend
`upon cardiac output, condition of the myocardium, and dynamics of the aortic root.
`The valve orifice has also been studied by direct visualization. Injection of a clear solution
`
`through the valve makes it visible in a beating heart. This technique makes it possible to see the
`
`
`entire free edge of the leaflet, unlike the marker technique which allows identification of only
`
`
`one point on the free edge. On the other hand, injection of a clear liquid creates artificial
`
`
`circumstances by changing the fluid environment (e.g., viscosity, density) and it might also
`change the cardiac function.
`
`
`FIGURE 3. Biplane aortogram of another infant (8 months) with a normal aortic valve. (A) Side view ofthe valve
`in diastole. (B and C) Oblique views of the valve in diastole and in systole, respectively. (D and E) Views of the
`cylindrical model matching those in A or F and C or G. (G) The valve orifice is composed of the line of attachment
`(dotted line) and the free edge (solid line) of the leaflets. (From 'I‘hubrikar. M. et al., Cardiovasc. Res. 16, 16. 1982.
`With permission.)
`'I
`
`
`
`
`
`
`
`
`
`
`
`
`Page 6
`
`NORRED EXHIBIT 2226 - Page 6
`
`

`

`
`
`43
`
`
`
`
`
`
`
`
`
`
`
`
`
`FIGURE 4. Cineangiograms of a canine aortic valve. A, B, and C moblique views of the valve. (A) Valve in diastole;
`(B and C) valve in systole; (D) a side View of the valve in diastole; and (E) the best obtainable top View of the valve
`in systole. Configurations of the valve orifice appear different (8, C, and B) when viewed from different angles. (F)
`An oblique view of the cylindrical model. (G and B) Side and top View, respectively. of the conical model ofthe aortic
`valve in systole. The views F. G. and H of the models match those in B, D. and E or l, I, and K. I and K show that the 7
`orifice is composed of the line ofattachment (dotted line) and the free edge (solid line) of the leaflets. (From Thubn'kar,
`M. et al., Cardiovasc. Res., 16, 16, 1982. With permission.)
`
`
`
`
`
`a"
`
`c
`
`FIGURE 5. (A) Cineangiogram of another canine aortic valve. (B) An oblique View of the cylindrical model that
`mmhes with the view in A or C. (C) The orifice in A is composed of the line of attachment (dotted line) and the free
`edge (solid line) of the leaflets. (From Thubrikar, M. et al., Cardiovasc. Res, 16, 16, 1982. With permission.)
`
`Steenhoven et al., using the technique of injection of a clear liquid in dogs, observed that
`while the valve orifice is nearly circular in early systole it changes to bulged triangular and‘then
`to triangular towards the end of systole.‘1 The configurations of the valve orifice during complete
`systole are shown in Figure 13, Chapter 4. Hider5 found, using a similar technique. that the valve
`
`
`
`
`
`
`
`
`
`Page 7
`NORRED EXHIBIT 2226 - Page 7
`
`

`

`
`
`
`44
`
`The Aortic Valve
`
`
`
`
`
`
`FIGURE 6. Schematic presentation ofan aortic valve opened by a vertical incision through the
`noncoronary sinus. L, R. and N are the left. right. and noncomnary leaflets, respectively. The
`dotted line is the line of leaflet coaptation. Three radiOpaque markers in the commissures (closed
`circles) and two markets at the center of the free edge of the leaflets (venical bars) are shown.
`(From Thubrikar, M. et al.. J. Thorac. Cardiovasc. Surg., 77, 863, 1979. With pennission.)
`
`
`
` Q9MAJ...~.‘_....N__._.M.....
`
`
`
`
`
`FIGURE 7. Aortic valve in the closed position. The portion of the leaflets shown is between
`the base and the level of coaptation; for clarity. the redundant portion has been omitted. One of
`the sinuses is shaded to give perspective to the sinus bulge. An X-_ray beam along the axis ofthe
`aorta (arrow pointing downward) projects the commissural markers in a triangle and the leaflet
`markers at the center as shown below the valve. An X-ray beam perpendicular to the axis of the
`. aorta (arrow pointing leftward) projects the conunissuralmarkers in a straight line and the leaflet
`markets below the straight line as shown to the left of the valve. (From Thubrikar, M. et al., Am.
`J. Cardial., 40, 563, 1977. With permission.)
`
`
`
`
`
`
`
`
`
`
` Page 8
`NORRED EXHIBIT 2226 - Page 8
`
`
`
`

`

` Elit
`liI
`z
`
`"t'J-v-‘c‘irxniwmrwr«
`:mt‘ovgi-w.mwmm-mww
`
`45
`
`
`
`FIGURE 8. Actual frames ofa cinemdiograph of the aortic valve. Panels A and B were obtained with the X~ray
`beam along the axis ofthe aorta. A -—in diastole, the three commissural markers fomi a triangle and the two leaflet
`market's sip-gearin the center. Arrows indicate the direction in which the leaflet markers move when the valve opens.
`l3 —- in systole, the two leaflet markers indicate that the orifice of the opened valve is circular. C and D were
`obtained with the X-ray beam perpendicularto the axisofthe aorta. C ~in diastole, the three commissural markers
`font-i a straight line and the two leaflet markers appear below the plane of the commissurcs. Arrows indicate the
`direction in which the leaflet markers move whenthe valve opens. One catheter in the left ventricle and another
`just above the valve are also visible. D -—— in systole, the three comissural markers are still in a straight line but
`the relative distance between the markets has changed because ofthe rotation of the heart (two markers on the left
`appear'to touch each other), The two leaflet markers above the plane of the commissures indicate once more that
`the orifice of the opened valve is circular. (From Thubiikan M. et al., Am. J. Cardiol., 40, 563,
`l977. With
`permission.)
`
`orifice is circular at normal viscosity and triangular at low viscosity. The fluid viscosities used
`were 3.4‘cSt and 0.7 081 where the former is similar to the blood viscosity. Padilla,6 using similar.
`techniques in dogs, observed that in a functioning heart, the valve orifice is circular in early
`systole and gradually changes to triangular in late systole. In the nonfunctioning heart, however,
`the orifice is triangular when a cloar fluid is pumped through the valve by a mechanical pump.
`These observations suggest that fluid viscosity and myocardial function are important in
`producing a circular orifice.
`
`IV. MOTION OF VARIOUS PARTS OF THE VALVE
`
`Although the leafletsare the most dynamic parts ofthe aortic valve, the motions ofotherparts
`of the Valve are also important because they play a role in the opening and closing ofthe valve.
`
`NORRED EXHIBIT 2226 - Page 9
`Page 9
`
`
`
`
`

`

`NORRED EXHIBIT 2226 - Page 10
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`

`

`«iv.amen«ruinous.»..
`
`
`
`
`
`
`
`46
`
`The Aortic Valve
`
`LEAFLH
`monon
`(mm)
`
`COMMlSSURE
`PERlMETER
`
`(mm)
`
`aonnc
`
`PRESSURE
`lmmHgl
`
`20
`
`to
`
`o
`
`I
`I
`
`t
`1
`
`50
`
`no
`
`so .y 0.]
`
`SEC
`
`FIGURE 9. Plot of leaflet motion (the distance between two leaflet markers), cornmissural perimeter (perimeter of
`a triangle formed by commissure markers) and pressure in the ascending aorta. The graph shows rapid opening of the
`leaflets, maximal opening in early systole, gradual decrease in the opening during systole and a rapid closure of the
`leaflets. The commissures expand during systole and the expansion begins 2010 40 ms before the valve opens. (From
`Thubrikar, M. et 31., Am. J. Cardiol.. 40, 563, 1977. With permission.)
`‘
`
`A. MOTION OF THE COMMISSURES
`. Thubrikar or al. studied the motion of the commissures ofthe aortic valve in dogs by placing
`radiopaque markers at the commissures and observing their movement under X’ray.3 The
`scheme ofthe marker placement is shown in Figure 6. Figures 7 and 8 show the triangular and
`the straight line projections of the markers in which the marker movement was determined.
`Commissure perimeter was measured as the perimeter of a triangle formed by the conunisSure
`markers, and commissure radius as the radius of a hypothetical circle that passes through the
`three commissure markers. The commissure radius was obtained from the straight line
`projection. The motion ofthe commissures was quantified in terms ofthe commissure perimeter
`or the commissure radius.
`Figure 9 shows a plot of commissure perimeter, leaflet motion, and aortic pressure during
`three cardiac cycles. The commissures move outward during systole and inward during diastole.
`Their motion follows the aortic pressure curve closely, suggesting that the motion is a function
`of the aortic pressure. The average increase in the perimeter of the commissures from diastole ~
`to systole is 12% fora control blood pressure in the range of 102/60 to 140/97 mmHg (Table l).
`The outward motion of the commissures begins 20 to 40 ms prior to the opening of the valve
`(Figure 9).
`The commissural motion was also studied as a function of systemic pressure. The pressure
`was increased by using angiotensin, which produces vasoconstriction, or decreased by using
`nitroprusside, which produces vasodilatation. Figure 10 shows a plot of leaflet motion,
`conunissure perimeter, and aortic pressure vs. time over a wide range of systemic pressures. In
`general, the commissure perimeter decreases as the systemic pressure decreases. When the
`commissurc perimeter is plotted versus aortic pressure, two separate curves, one for diastole and
`one for systole, are obtained (Figure l 1). The curve for diastole lies below the curve for systole,
`indicating that for a given aortic pressure commissure perimeter is greater in an open valve than
`
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`
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`
`was»...r
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`
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`
`in'a closed valve. This important observation suggests an interplay between the commissures
`
`
`
`
`
`NORRED EXHIBIT 2226 - Page 11
`
`
`

`

`.
`
`6
`
`E
`
`g
`
`:
`
`.
`
`‘
`
`5
`E
`a
`E
`
`.
`
`31%
`2‘:
`3%;
`F"
`§ 141%
`$7 ‘
`«2
`"
`49 ..
`3%
`é (
`1% _
`“
`
`TABLE 1
`
`47
`
`Change in the Commissure Perimeter
`(APC) During a Cardiac Cycle
`
`Dog
`
`no.
`
`Bloodpressure
`
`(mmHg)
`
`APc i SD (%)
`
`11.3 i 0.7
`11.8il.0
`11.7:11
`10.7 i 0.8.
`12.0 i 1.0
`11.4 i 1.9
`11.7 12.0
`12.9 :1: 1.5
`12.6 i 0.8
`12.3 i 0.5 .
`14.0 i 2.0
`12.0
`0.4
`
`Unanesthetized
`CA 110/65
`FA 120/78
`FA 126/85
`Asc Ao 102/60
`_ Unanesthetized
`FA 135/100 ‘
`FA 145/66
`Ase A0 102/70
`A50 A0 140/97
`FA 180/100
`
`1
`
`2
`3
`
`4
`5
`Mean
`SEM
`
`Note: CA — carotid artery, FA — femoral artery, Asc
`A0 — ascending aorta, SEM —— standard error of
`the mean.
`
`,
`From Thubrikar, M. et 111.. Am. J. Cardial., 40, 563, 1977.‘
`With permission.
`
`I!
`
`:33;
`1......
`
`I
`
`1a
`s
`5‘;
`
`mumswn so
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`
`‘°
`
`‘
`
`"°
`“m m .
`1:3:
`
`‘°
`o
`
`
`
`FIGURE 10. Plot of leaflet motion. commiSsural perimeter and aortic pressure showing the effect of a wide range
`of systemic pressure on commissural perimeter in one animal. Only one representative heart cycle is shown at each
`systemic pressure. The commissural perimeter-decreases when systemic pressure decreases. (From Thubrikar, M. et
`al., Am. J. Cardwl.. 40, 563, 1977. With pertmssron.)
`.
`and the leaflets. For example, when the aortic pressure remains unchanged, the commissural
`motion is a function of whether the leaflets are in the open position or closed position. This
`interplay will be studied in detail in the next section. During a single cardiac cycle, the
`commissural movement occurs as follows: When the pressure increases from 80 mmHg
`diastolic to 120 mmHg systolic, the commissures move by 12% from point A to point D in Figure
`
`
`
`NORRED EXHIBIT 2226 - Page 12
`
`

`

`
`
`
`
`48
`
`The Aortic Valve
`
`46
`COMMtSSURE
`
`
`PERIMETER
`
`
`{mm}
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`NORRED EXHIBIT 2226 - Page 13
`
`
`
`4O
`
` 20
`
`
`
`
`
`
`
`
`
`
`
`
`
`220 7140
`3‘.Msmtumtgrk»
`
`60
`BO
`300
`120
`I40
`160
`rl80_ 200
`PRESSURE IN YHE 'ASCENDlNG AORTA1(mmH9)
`
`FIGURE 1 1. Relation between aortic pressure and commissural.perimeter in one animal. The commissural perimeter
`
`at various systolic aortic pressures is indicated by closed triangles and at diastolic aortic pressures by closed circles.
`
`
`Diastolic and systolic curves indicate the relation with the valve in closed or open position,respectively. Fora pressure
`
`
`change from 80 to lZO mmHg the commissural perimeter increases 'fmm A to B if the valve remains closed or from
`
`C to D if the valve remains open (4 to 5% increase in either case). However, for the same pressure change the
`
`
`commissural perimeter increases from A to D lithe valve goes from‘ac‘lose’d to an openposition (12% increase). (From
`
`
`Thubrikar, M. et ‘31., Am. J. Cardiol” 40, 563, 1977. With permission.)
`
`
`
`
`ll. This total movement is composed of two parts, A toCVand C to D, where the former occurs
`
`in response to the opening ofthe valve at apressure of80 mmHg, and the latteroecurs inrosponsc
`
`
`to the increase in pressure from 80 to 120 mmHg. Asimilar phenomenon occurs during thevalve
`closure. About 5 to 6% motion of the commi‘ssures appears to occur in response to the aortic
`
`pressure and 6 to 7% in response to whether the valve is open or closed.
`
`
`The commissural movement suggests that the aortic root is elastic, a feature which is helpful
`
`
`in reducing the shock on the leaflet at the time ofvalve closure. The conunissural-expansion also
`
`
`plays a role in the mechanism of valve opening andis discussed in the next section. This outward
`
`
`movement of the commissures during systole has also been" observed by Brewer etal.7
`
`
` B. THE MECHANISM OF OPENING OF THE AORTIC VALVE
`, The aortic valve is generally regarded as a passive structure changing mainly in response to
`
`
`hemodynamic forces. For the most partthis is true; however, there areactive cornponents-to the
`
`
`valve behavior. For example; there is interaction between the commissures and the leaflets, as
`noted in the previous section. Classically, the aortic valve is thought to-‘open when blood ejected
`from the ventricle pushes the leaflets open. This would be true ifthe leaflets were attached to
`a nonexpansile structure. However, the leaflets are attached roan expansile strucmre and the
`expansion of that structure alone can open the valve. The leaflets are attadhedto‘the aortic wall
`at the commissures, which move outward during each cardiac cycle.
`Thubrikar et a1. studied the mechanism of opening of the aortic valve using the marker-
`fluoroscopy technique.“ Figure 6 shows the positions of the markers on the leaflets and in the
`connoissures. They studied the marker movcmoutin a triangular projection obtained with an X‘-
`
`

`

`'
`
`49
`
`2
`
`i ll ll ll1 l i
`
`t
`
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`
`'
`
`:1
`E
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`
`i
`
`E
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`f
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`a
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`.
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` l
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`3"
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`
`TRIANGULAR
`
`- CIRCULAR
`
`.
`-
`.
`.
`.
`.
`,
`.
`FIGURE 12. Single fields of a cmeradiograph of the aortlc valve, obtained With the X-ray beam parallel to the axts
`of the aorta. In a closed valve, the three commissure markers form a triangle and the two leaflet markers appear in the
`center. The separation of the leaflet markers indicates a stellate orifice. shown by the dotted line. The triangular and
`circular orifices are also shown by dotted lines. A catheter in the left ventricle, inserted through the aortic valve, is also
`visible. (From Thubrikar, M. et a]., J. Thorac. Ca'rdiovarc. Surg.. 77, 863. 1979. With permission.)
`
`ray beam along the valve axis (Figures 7 and 8). In this projection, the two leaflet markers touch
`each other in a closed valve, as shown in Figure 12, and appear almost at the center of the triangle
`formed by the three commissure markers. When the valve is open, the leaflet markers and the
`commissure markers together form the orifice ofthe open valve (Figure 12). To study the various
`stages of valve Opening, the valve was examined during premature cardiac cycles when the
`ventricular stroke volume was less than normal. Premature ventricular contractions are not
`_ uncommon and occur frequently if a catheter is present in the left ventricle. During their study,
`"aortic flow, aortic pressure, and ventricular pressure were recorded where the ventricular
`pressure was measured with a pressure catheter placed in the ventricle. The marker positions
`were recorded at a rate of60 video fields/s. During premature beats, the open valve could be seen
`for three ormore video fields. Depending upon the type ofventricular contraction, the open valve
`was observed-to show a stellate—shaped orifice, a triangularorifice, or a normal circularorifice
`(Figure 12). Leaflet displacement, conu'nissure perimeter, aortic blood flow, aortic pressure,
`ventricular pressure, and electrocardiogram are shown for both normal and premature heart
`
`beats in Figure 13. The normal and premature heart beats are identified from the electrocardio-
`gram. During the normal beats, A and C in Figure 13, the normal leaflet displacement,
`commissural expansion, and aortic flow are evident. During the premature beat, B, the peak
`ventricular pressure does not equal the aortic pressure and the valve does not open but the
`commissures expand. In the abnormal beat, D, the peak ventricular pressure barely exceeds the
`aortic pressure and the valve opens, the commissures-expand, and the blood flow occurs through
`
`
`
`NORRED EXHIBIT 2226 - Page 14
`
`

`

`
`
`50
`
`The Aortic Valve
`
`
`
`
`
`
`
`
`
`{ Leaflet
`Displacement
`(mm)
`
`0
`
`Commissure
`Perimete mmFl
`Aortic
`
`) so
`
`Blood Flow too
`Velocity
`(cm/sec)
`
`0
`
`'
`
`240
`
`120 ‘
`
`Pressure
`(mmHs)
`
`Jkadfiaxwm{rum-7..4“._;
`
`
`
`C
`
`
`
`
`
`EKG
`
` FIGURE 13. A continuous plot of leaflet displacement and commisSure perimeter, with corresponding
`
`
`recordings of aortic blood flow velocity, aortic pressure, ventricularpressure, and electrocardiogram (EKG).
`Each data point on the first and second curves was obtained from a single field of videotape. The normal beats
`
`
`A and C show normal leaflet displacement and a normal increase in the commissure perimeter. For the
`abnormal beat B the valve does not open but the commissure perimeter increases slightly. For the abnormal
`
`
`beat D (arrows) the valve opens to a normal orifice and the co‘mmissure perimeter increases 10%. The beat D
`is associated with a small volume of forward flow and a narrow aortic pulse pressure. (From 'I‘hubrikan M. at
`£11., J. Thorac. Cardiovasc. Surg., 77, 863, 1979. With permission.) "
`
`
` the valve. It is noteworthy that even for a small forward flow velocity, as in beat I), the valve
`
`
`
`Ventricular
`
`
`
`
`
`
`
`
`
`
`
`
`
`.
`‘
`opening reaches its maximum.
`Figure 14 shows the plot of leaflet displacement (i.e., size of the valve orifice), aortic blood
`flow velocity, and aortic pulse pressure. Leaflet displacement is expressed as a percentage of the
`maximum distance between the two leaflet markers in a normal cardiac cycle. Three types of
`orifice configurations were observed at different blood flow velocities. These configurations
`indicate intermediate stages in a continuing process of valve opening. As the leaflets begin to
`separate they first. produce a Etellate shape orifice, which then changes to a triangular shape, and
`then to a circular shape as the flow velocity increases. For a stellatc shape opening there is no
`forward flow and no aortic pulse pressure (Figure 141)). For a barely perceptible forward flow
`velocity and a barely perceptible aortic pulse pressure, the valve orifice is variable between a
`triangular and a circular shape (Figure 14B and C). For the normal forward flow velocity and
`the normal pulse pressure, the valve orifice is circular (Figure’l4A);
`Figure 15 relates the leaflet displacement (orifice shape) to forward flow velocity. At zero
`velocity the valve is either closed or open with a small leaflet separation and a stellate shape
`: orifice. Leaflet displacement increases rapidly as the velocity increases from O to 30 cm/s. In this
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`NORRED EXHIBIT 2226 - Page 15
`
`

`

`Leaflet
`Displacement
`(7..)
`
`10°
`
`o
`
`_
`
`.
`
`l
`l
`
`l
`I
`l
`
`l
`
`l
`I
`I
`
`51
`
`t.I
`
`Aortic
`
`20°
`
`Blood Flow
`
`100
`0
`
`Velocity
`(cm/sec)
`18° N
`Aortic
`Pressure W
`(mm H9) 6°
`
`I
`
`FIGURE 14. Four separate representative cardiac cycles showing leaflet displacement (percentage of full opening)
`with corresponding recordings of aortic blood flow velocity and aortic pressure. For the normal heat A the valve orifice
`is circular. For the abnormal beats B and C the valve orifices are circular and triangular, respectively, and are associated
`with a small blood flow velocity and a narrow pulse pressure. For the abnormal beat D the valve orifice is stellate and
`is associated with no detectable forward flow and no increase in the aortic pressure. (From Thubrikar, M. et al., J.
`Thorac. Cardiovaxc. Surg.. 77, 863. I979. With permission.)
`
`
`4,_@ fl
`
`
`
`
`_..
`
`A 100
`L\°
`
`80
`
`.1
`
`Ew
`
`60
`
`mmmb.‘~m..___,.._....-...._....._.._.__-.__.._._............
`
`‘
`
`E
`U
`2D.
`.2:
`Q 40
`L6
`*0
`
`'
`>
`'
`20 . ®
`
`
`
`5.-
`r,
`
`.2:
`
`
`
`
`-20 O\20 '
`60
`100
`140
`180
`220
`260
`300
`\
`Q Velocity (cm/sec)
`
`FIGURE 15. Relationship between the maximum aortic blood flow velocity and maximum leaflet displacement
`(percentage of full opening). The closed valve corresponds to 0% leaflet displacement. The initial valve orifice is
`stellate. and there is no detectable forward flow. As the blood flow velocity increases to 30 cm/s, the orifice becomes
`circular. The greatest change in the valve orifice (leaflet displacement) occurs over a narrow range of blood flow
`velocity. The negative velocity with the stellate orifice indicates regurgitant flow. (From Thubn'kar, M. et al., J. Thoma.
`Cardiovasc. Surg.. 77, 863, I979. With permission.)
`
`NORRED EXHIBIT 2226 - Page 16
`
`

`

`
`
`
`
`52
`
`[The Aortic Valve
`
`20
`
`Leaflet
`
`Displacement
`(nun)
`
`o
`
`Commissure 55
`Perimeter
`(mm)
`
`45
`
`120
`
`Pressure
`
`(mm Hg) ' 0
`
`Ventricular” 0.!
`
`sec
`
`FIGURE 16. A continuous plot of leaflet displacement and commissure perimeter with corresponding aortic and
`ventricular pressures. The normal beats A and C indicate a circular orifice, a normal increase in the commisure
`perimeter, and a normal aortic pulse pressure. The abnormal beat 8 indicates a stellate orifice, 10% increase in the
`commissure perimeter. and no increase in the aortic pressure. The stellate orifice occurs when the ventricular pressure
`equals the aortic pressure. (From Thubrilrar, M. ct al., J. Thorac. Cardiovasc. Surg, 77, 863. 1979. With permission.)
`
`range a triangular orifice can be seen. When the velocity exceeds 40 cm/s, a circular orifice is
`seen. The leaflet displacement and the orifice change very little for the velo